PMID- 24625102 TI - New criteria for supplementation of selected micronutrients in the era of nutrigenetics and nutrigenomics. AB - Advances in molecular biology, emergence of novel techniques and huge amount of information generated in the post-Human Genome Project era have fostered the emergence of new disciplines in the field of nutritional research: Nutrigenomics deals with the effect of diet on gene expression whereas nutrigenetics refers to the impact of inherited traits on the response to a specific dietary pattern, functional food or supplement. Understanding the role of micronutrient supplementation with specific genetic backgrounds may provide an important contribution to a new optimum health strategy based on individualized nutritional treatment and may provide the strategies for the development of safer and more effective dietary interventions. This overview of the various aspects of supplementation of micronutrients in the era of nutrigenetics and nutrigenomics may provide a better understanding of novel nutritional research approach and provide an additional insight that can be applied to the daily dietary practice. PMID- 24625103 TI - Allometric scaling for chemical restraint in greater rheas (Rhea americana) with tiletamine and zolazepam. AB - BACKGROUND: Chemical restraint is of great importance in the clinical practice of wildlife animals. In such, interspecific allometric scaling proposes pharmacological doses to a wide range of species, based on previously known doses for domestic animals and the target animal's body mass. The objective was to compare chemical restraint responses in the greater rhea (Rhea americana) with conventional doses of tiletamine/zolazepam, found in the literature for the species, and with doses calculated through interspecific allometric scaling extrapolation. From the Federal University of Piaui, six adult greater rheas (Rhea americana), three males and three females, were randomly selected to be subjects in this research. All six animals were submitted to two chemical restraint protocols with tiletamine and zolazepam, per intramuscular injection in the hind limb. The first protocol was composed of doses found on the literature for the species, while the second protocol used doses calculated by interspecific allometric scaling, with the domestic dog as model animal. Heart and respiratory rates, body temperature, eyelid reflex, digital pinch and metatarsal reflex were registered along with latency and ambulation times. RESULTS: The use of interspecific allometric scaling for chemical restraint with the combination tiletamine and zolazepam showed satisfying results, with great similarity to results obtained with conventional doses in Greater rheas. CONCLUSIONS: Literature on chemical restraint and use of tiletamine and zolazepam in rheas is scarce. Chemical restraint is of extreme importance on these animals, due to their aggressive nature and low level of domesticity. This research may further establish the interspecific allometric scaling method as a viable tool for the veterinary physician in formulating anesthetic and chemical restraint protocols for wildlife animals. PMID- 24625104 TI - Polymeric films with electric and magnetic anisotropy due to magnetically assembled functional nanofibers. AB - We demonstrate the fabrication of free-standing polymeric nanocomposite films, which present magnetic and electrically conductive anisotropic properties. Magnetically functionalized carbon nanofibers are dispersed in a polymeric solution and, upon casting under a weak external magnetic field, are easily oriented and permanently assembled in a head-to-tail orientation in the polymer film during solvent evaporation. Magnetic and conductive property studies reveal that the resulting films have a high degree of anisotropy in both cases, thus allowing their use in functional complex devices. As a proof of concept, we demonstrate the potential application of these films as flexible THz polarizers. The detailed study shows that very high attenuation values per unit film thickness and fiber mass concentration are achieved, paving thus the way for cost effective fabrication of substrate-free systems that have advantage over conventional devices realized so far. PMID- 24625105 TI - Biosynthesis of mycobacterial lipids by polyketide synthases and beyond. AB - Over a decade ago, the analysis of the complete sequence of the genome of the human pathogen Mycobacterium tuberculosis revealed an unexpectedly high number of open reading frames encoding proteins with homology to polyketide synthases (PKSs). PKSs form a large family of fascinating multifunctional enzymes best known for their involvement in the biosynthesis of hundreds of polyketide natural products with diverse biological activities. The surprising polyketide biosynthesis capacity of M. tuberculosis has been investigated since its initial inference from genome analysis. This investigation has been based on the genes found in M. tuberculosis or their orthologs found in other Mycobacterium species. Today, the majority of the PKS-encoding genes of M. tuberculosis have been linked to specific biosynthetic pathways required for the production of unique lipids or glycolipid conjugates that are critical for virulence and/or components of the extraordinarily complex mycobacterial cell envelope. This review provides a synopsis of the most relevant studies in the field and an overview of our current understanding of the involvement of PKSs and several other polyketide production pathway-associated proteins in critical biosynthetic pathways of M. tuberculosis and other mycobacteria. In addition, the most relevant studies on PKS-containing biosynthetic pathways leading to production of metabolites from mycobacteria other than M. tuberculosis are reviewed. PMID- 24625106 TI - Antibacterial activity of a series of N2,N4-disubstituted quinazoline-2,4 diamines. AB - A series of N(2),N(4)-disubstituted quinazoline-2,4-diamines has been synthesized and tested against multidrug resistant Staphylococcus aureus. A structure activity and structure-property relationship study was conducted to identify new hit compounds. This study led to the identification of N(2),N(4)-disubstituted quinazoline-2,4-diamines with minimum inhibitory concentrations (MICs) in the low micromolar range in addition to favorable physicochemical properties. Testing of biological activity revealed limited potential for resistance to these agents, low toxicity, and highly effective in vivo activity, even with low dosing regimens. Collectively, these characteristics make this compound series a suitable platform for future development of antibacterial agents. PMID- 24625107 TI - Measurement of three-dimensional morphological characteristics of the calcaneus using CT image post-processing. AB - BACKGROUND: Although computed tomography (CT) with three-dimensional (3D) rendering of the calcaneus is used for diagnostic evaluation of disorders, morphological measurements for the calcaneus are mostly based on a two dimensional plane. The purposes of this study were to design a method for 3D morphological measurements of the normal calcaneus based on CT post-processing techniques, to measure morphological parameters in the male and female groups and describe gender differences of the parameters, and to investigate the reliability of such measurements. METHODS: One hundred and seventy-nine patients (83 men and 96 women) with a mean age of 40.6 (range, 21 to 59) years who underwent CT scans for their feet were reviewed retrospectively. The 3D structure of a normal calcaneus after shaded surface display reconstruction was extracted by interactive and automatic segmentation. Morphological measurements were achieved by means of a 3D measurement method based on CT image post-processing. Lengths and heights of the main parts of the calcaneus, Gissane's angle, Bohler's angle and the area of articular facet were worked out in 3D space. Gender-related size differences of parameters were compared using analysis of covariance (ANCOVA), adjusting for body height. Intra-observer and inter-observer reliabilities were assessed using intraclass correlation coefficients (ICCs) and the root mean square standard deviation (RMS-SD) for precision study. RESULTS: A large range of measurement values was found. Only the length of the anterior process was without gender difference (p > 0.05). The other parameters in the male group were greater than those in the female group (p < 0.01 for each, ANCOVA). All parameters had excellent reliability and reproducibility (ICC > 0.8). Precision was acceptable for intra-observer RMS-SD (linear, angular and areal measurements no more than 0.6 mm, 1.2 degrees and 0.25 mm2, respectively). Inter-observer RMS-SD ranged from 0.4 to 1.6 mm for linear measurements, 1.2 to 2.5 degrees for angles and 0.24 to 0.40 mm2 for areas. CONCLUSIONS: Three-dimensional morphological measurement based on a CT post-processing technique was highly reliable and repeatable for calcaneal anatomic morphological measurement. The current data will be helpful for anatomic reduction of calcaneal fractures and calcaneal malunion. PMID- 24625108 TI - Time course-changes in phosphatidylcholine profile during oxidative modification of low-density lipoprotein. AB - BACKGROUND: Oxidized phosphatidylcholines (oxPC) and lysophosphatidylcholine (lysoPC) generated during the formation of oxidized low-density lipoprotein (oxLDL) are involved in atherosclerotic lesion development. We investigated the time course-changes in phosphatidylcholine (PC) molecular species during oxidation of LDL to determine how those atherogenic PCs are produced. METHODS: Human and rabbit LDLs were pretreated with or without a selective platelet activating factor acetylhydrolase (PAF-AH) inhibitor. LDL was oxidized by incubation with copper sulfate, and PC profiles were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: When human LDL was oxidized, the peak areas for polyunsaturated fatty acid (PUFA)-containing PC species dramatically decreased after a short lag period, concomitantly lysoPC species increased sharply. Although a variety of oxPC species containing oxidized fatty acyl groups or cleaved acyl chains are formed during LDL oxidation, only a few oxPC products accumulated in oxLDL: 1-palmitoyl-2-(9-oxo-nonanoyl) PC and long chain oxPC with two double bonds. Pretreatment of LDL with the PAF-AH inhibitor greatly reduced lysoPC production while it had no effect on lipid peroxidation reactions and oxPC profiles. Rabbit LDL, which has a different composition of PC molecular species and needs a longer time to reach achieve full oxidation than human LDL, also accumulated lysoPC during oxidation. The increase in lysoPC in rabbit oxLDL was suppressed by pretreatment with the PAF-AH inhibitor. The major oxPC species formed in rabbit oxLDL were almost the same as human oxLDL. CONCLUSIONS: These results suggest that lysoPC species are the major products and PAF-AH activity is crucial for lysoPC generation during oxidation of LDL. The oxPC species accumulated are limited when LDL is oxidized with copper ion in vitro. PMID- 24625111 TI - Association of sexual maturation with excess body weight and height in children and adolescents. AB - BACKGROUND: Studies addressing the influence of early sexual maturation on the excess of body weight and height of children and adolescents are scarce. The aim of the study was to analyze the association of sexual maturation with excess body weight and height in children and adolescents. METHODS: This was a cross sectional study performed in Florianopolis city, Brazil, in 2007, with 2339 school children, aged 8-14 years (1107 males). Selection was based on a probabilistic, cluster-stratified sampling technique. School children were classified according to the presence of excess body weight, using sex- and age specific body mass index (BMI) cutoff points. Z-scores were calculated from height and BMI data. Sexual maturation was self-assessed according to Tanner stages of development. Subjects were ranked based on tertiles of sexual maturation (early, normal and late) for each stage of development. Poisson and linear regression models were used. RESULTS: Compared to the reference group (normal sexual maturation), early maturing females had higher prevalence of excess weight (adjusted prevalence ratio: 1.70; 95% CI: 1.24 to 2.33) and increased height-for-age (adjusted beta: 0.37; 95% CI: 0.14 to 0.59), while late maturing females had lower prevalence of excess weight (adjusted prevalence ratio: 0.57; 95% CI: 0.37 to 0.87) and decreased height-for-age (adjusted beta: 0.38; 95% CI: -0.56 to -0.20). In males, early and late sexual maturation were associated with increased (adjusted beta: 0.37; 95% CI: 0.14 to 0.59) and decreased (adjusted beta: -0.38; 95% CI: -0.56 to -0.20) height-for-age, respectively. CONCLUSION: Early sexual maturation is associated with excess body weight in females and with greater height-for-age in both sexes. PMID- 24625110 TI - A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity. AB - INTRODUCTION: There is an unmet clinical need for biomarkers to identify breast cancer patients at an increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive (HER2+) brain metastasis. METHODS: We combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis (GSEA) using publicly available breast cancer gene expression data sets. RESULTS: In a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of BRCA1. Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of BRCA1, and therefore the aforementioned signature was designated BRCA1 Deficient-Like (BD L). Evaluation of an independent cohort of breast cancer metastases demonstrated that BD-L values are significantly higher in brain metastases as compared to other metastatic sites. Although the BD-L signature is present in all subtypes of breast cancer, it is significantly higher in BRCA1 mutant primary tumors as compared with sporadic breast tumors. Additionally, BD-L signature values are significantly higher in HER2-/ER- primary tumors as compared with HER2+/ER + and HER2-/ER + tumors. The BD-L signature correlates with breast cancer cell line pharmacologic response to a combination of poly (ADP-ribose) polymerase (PARP) inhibitor and temozolomide, and the signature outperformed four published gene signatures of BRCA1/2 deficiency. CONCLUSIONS: A BD-L signature is enriched in HER2+ breast cancer brain metastases without pathogenic BRCA1 mutations. Unexpectedly, elevated BD-L values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the BD-L signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional BRCA1-associated pathway. PMID- 24625112 TI - Recognition sequences and substrate evolution in cyanobactin biosynthesis. AB - Ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products are of broad interest because of their intrinsic bioactivities and potential for synthetic biology. The RiPP cyanobactin pathways pat and tru have been experimentally shown to be extremely tolerant of mutations. In nature, the pathways exhibit "substrate evolution", where enzymes remain constant while the substrates of those enzymes are hypervariable and readily evolvable. Here, we sought to determine the mechanism behind this promiscuity. Analysis of a series of different enzyme-substrate combinations from five different cyanobactin gene clusters, in addition to engineered substrates, led us to define short discrete recognition elements within substrates that are responsible for directing enzymes. We show that these recognition sequences (RSs) are portable and can be interchanged to control which functional groups are added to the final natural product. In addition to the previously assigned N- and C-terminal proteolysis RSs, here we assign the RS for heterocyclization modification. We show that substrate elements can be swapped in vivo leading to successful production of natural products in E. coli. The exchangeability of these elements holds promise in synthetic biology approaches to tailor peptide products in vivo and in vitro. PMID- 24625114 TI - Disclosing conflicts of interest in patient decision aids. AB - BACKGROUND: In 2005, the International Patient Decisions Aid Standards (IPDAS) Collaboration developed quality criteria for patient decisions aids; one of the quality dimensions dealt with disclosure of conflicts of interest (COIs). The purposes of this paper are to review newer evidence on dealing with COI in the development of patient decision aids and to readdress the theoretical justification and definition for this quality dimension. METHODS: The committee conducted a primary systematic literature review to seek published research addressing the question, "What is the evidence that disclosure of COIs in patient decision aids reduces biased decision making?" A secondary literature review included a systematic search for recent meta-analyses addressing COIs in other spheres of health care, including research and publication, medical education, and clinical care. RESULTS: No direct evidence was found addressing this quality dimension in the primary literature review. The secondary review yielded a comprehensive Institute of Medicine report, as well as four relevant meta analyses addressing disclosure of COIs in health care. They revealed a broad consensus that disclosure of COIs is desirable in such areas as research publication, guideline development, medical education, and clinical care. CONCLUSIONS: The committee recommends the criteria that are currently used to operationally define the quality dimension "disclosing conflicts of interest" be changed as follows (changes in italics): Does the patient decision aid: * report prominently and in plain language the source of funding to develop or exclusively distribute the patient decision aid? * report prominently and in plain language whether funders, authors, or their affiliations, stand to gain or lose by choices patients make after using the patient decision aid? Furthermore, based on a consensus that simple disclosure is insufficient to protect users from potentially biased information, the committee recommends that the IPDAS Collaboration consider adding the following criterion when the IPDAS consensus process is next conducted: "Does the patient decision aid: * report that no funding to develop or exclusively distribute the patient decision aid has been received from commercial, for-profit entities that sell tests or treatments included as options in the patient decision aid?" PMID- 24625113 TI - Born too soon: preterm birth matters. AB - Urgent action is needed to address preterm birth given that the fi rst country level estimates show that globally 15 million babies are born too soon and rates are increasing in most countries with reliable time trend data. As the fi rst in a supplement entitled "Born Too Soon", this paper focuses on the global policy context. Preterm birth is critical for progress on Millennium Development Goal 4 (MDG) for child survival by 2015 and beyond, and gives added value to maternal health (MDG 5) investments also linking to non-communicable diseases. For preterm babies who survive, the additional burden of prematurity-related disability may aff ect families and health systems. Prematurity is an explicit priority in many high-income settings; however, more attention is needed especially in low- and middle-income countries where the invisibility of preterm birth as well as its myths and misconceptions have slowed action on prevention and care. Recent global attention to preterm birth hit a tipping point in 2012, with the May 2 publication of Born Too Soon: The Global Action Report on Preterm Birth and with the 2nd annual World Prematurity Day on November 17 which mobilised the actions of partners in many countries to address preterm birth and newborn health. Interventions to strengthen preterm birth prevention and care span the continuum of care for reproductive, maternal, newborn and child health. Both prevention of preterm birth and implementation of care of premature babies require more research, as well as more policy attention and programmatic investment. PMID- 24625115 TI - Enantioselective synthesis of planar chiral ferrocenes via Pd(0)-catalyzed intramolecular direct C-H bond arylation. AB - A highly efficient synthesis of planar chiral ferrocenes by enantioselective Pd(0)-catalyzed direct C-H arylation from readily available starting materials under mild reaction conditions was developed (up to 99% yield, 99% ee). The products can be easily transformed to the highly efficient planar ferrocene ligands, which have demonstrated high efficiency in Pd-catalyzed asymmetric allylic alkylation and amination reactions. PMID- 24625116 TI - Urinary angiotensinogen, related factors and clinical implications in normotensive autosomal dominant polycystic kidney disease patients. AB - BACKGROUND: Although several lines of evidence suggest that renin angiotensin system (RAS) proteins are synthesized by cyst epithelium and dilated tubules, role of intrarenal RAS in the progression of otozomal dominant polycystic kidney disease (ADPKD) is not well known. We aimed to study the levels and clinical correlations of urinary angiotensinogen (UAGT) in normotensive ADPKD patients compared with age- and sex-matched healthy subjects. METHODS: The study included 20 normotensive ADPKD patients (F/M: 11/9) and 20 age and sex matched healthy controls (F/M: 9/11). Diagnosis of ADPKD was made based on Ravine criteria. Twenty-four hours ambulatory blood pressure monitoring (ABPM) was performed. Serum concentrations of creatinine, Na, K, uric acid, and urinary concentrations of Na, K, uric acid, creatinine, protein and albumin were measured. UAGT were measured via commercially available ELISA kit. RESULTS: ADPKD patients had higher urinary albumin:creatinine ratio (UAIb/UCrea) than healthy controls (p < 0.01). UAGT/UCrea levels significantly positively correlated with urinary protein: creatinine ratio (UPro/UCrea) (r = 0.785, p = 0.01), and UAIb/UCrea (r = 0.681, p = 0.01) in normotensive ADPKD patients. CONCLUSION: This pilot study demonstrates that UAGT levels tend to be elevated and are correlated with proteinuria and albuminuria in normotensive ADPKD patients during relatively early stages of the disease. PMID- 24625117 TI - Ureasil-poly(ethylene oxide) hybrid matrix for selective adsorption and separation of dyes from water. AB - Herein, we present a cross-linked ureasil-polyether-siloxane hybrid (labeled PEO500) that can function as a stimuli-sensitive material; it swells or shrinks in response to changes in the environmental conditions and it can also, effectively and selectively, remove dyes from water solution. We also developed a methodology to separate a mixture of cationic and anionic dyes present in water. Addition of PEO500 to an aqueous solution of the anionic orange II (OII) or the ponceau S (PS) dye rendered the solution colorless, but an aqueous solution of cationic methylene blue (MB) remained unchanged after 2 h of contact with the insoluble matrix. In situ small-angle X-ray scattering (SAXS) showed that the distance of siloxane nanodomains are strongly affected by the swelling or shriking. By in situ UV-vis adsorption experiments, we found that the kinetics of OII and PS removal followed a pseudo-first-order rate equation. We accomplished B3LYP calculations, to establish which sites on the matrix interacted with the dyes and to investigate the nature of the matrix-dye chemical bonds. On the basis of the experimental and theoretical investigations, we proposed some mechanisms to explain how PEO500 adsorbs anionic dyes efficiently. This "smart" matrix is potentially applicable as an efficient, fast, selective, and convenient device in water treatment and stimuli-sensitive response materials. PMID- 24625118 TI - A comparative study of genome organization and inferences for the systematics of two large bushcricket genera of the tribe Barbitistini (Orthoptera: Tettigoniidae: Phaneropterinae). AB - BACKGROUND: Poecilimon and Isophya are the largest genera of the tribe Barbitistini and among the most systematically complicated and evolutionarily intriguing groups of Palearctic tettigoniids. We examined the genomic organization of 79 taxa with a stable chromosome number using classical (C banding, silver and fluorochrome staining) and molecular (fluorescence in situ hybridization with 18S rDNA and (TTAGG)n telomeric probes) cytogenetic techniques. These tools were employed to establish genetic organization and differences or similarities between genera or species within the same genus and determine if cytogenetic markers can be used for identifying some taxonomic groups of species. RESULTS: Differences between the karyotypes of the studied genera include some general changes in the morphology of the X chromosome in Isophya (in contrast to Poecilimon). The number of major rDNA clusters per haploid genome divided Poecilimon into two main almost equal groups (with either one or two clusters), while two rDNA clusters predominated in Isophya. In both genera, rDNA loci were preferentially located in the paracentromeric region of the autosomes and rarely in the sex chromosomes. Our results demonstrate a coincidence between the location of rDNA loci and active NORs and GC-rich heterochromatin regions. The C/DAPI/CMA3 bands observed in most Poecilimon chromosomes suggest the presence of more families of repetitive DNA sequences as compared to the heterochromatin patterns in Isophya. CONCLUSIONS: The results show both differences and similarities in genome organization among species of the same genus and between genera. Previous views on the systematics and phylogenetic grouping of certain lineages are discussed in light of the present cytogenetic results. In some cases, variation of chromosome markers was observed to correspond with variation in other evolutionary traits, which is related to the processes of ongoing speciation and hybridization in zones of secondary contact. It was concluded that the physical mapping of rDNA sequences and heterochromatin may be used as an additional marker for understanding interspecific relationships in these groups and their routes of speciation. PMID- 24625119 TI - Assessing age and gender in studies of breakthrough pain medications. AB - OBJECTIVE: The present review was performed to identify possible differences observed between adults and elderly patients and between males and females in randomized clinical trials of breakthrough pain (BTP). METHODS: A systematic search of the existing literature from 1998 to September 2013 was performed. Randomized clinical trials reporting data on older patients were selected. RESULTS: Sixteen comparative studies were selected. The age range of inclusion criteria patients was mainly between 18-80 or >=18 years. In some cases this data was unreported. The mean age of patients was 48-64 years, but information regarding the number of elderly patients was present in three studies only. Gender distribution was more or less 50%:50%. No subgroup analysis of efficacy or adverse effects of BTP medications for age and gender was reported. CONCLUSION: There is a need for more information regarding the use of opioids for BTP according to age and gender. PMID- 24625120 TI - Comparison of plasma lipoprotein profiles and malondialdehyde between hyperlipidemia dogs with/without treatment. AB - BACKGROUND: The aim of this study is to compare metabolic parameters, malondialdehyde as a lipid oxidation marker, and lipid profiles between dogs with untreated hyperlipidemia and hyperlipidemia with treatment, in order to examine the usefulness of malondialdehyde and lipid profiles as diagnostic parameters at early stages of hyperlipidemia. RESULTS: Dog samples were collected from four different veterinary clinics across Japan from March to June 2013. They were separated into three groups: control, untreated hyperlipidemia based on temporally screening, and hyperlipidemia with current anti-hyperlipidemic (statins and fibrates) treatment. Triglyceride levels of untreated hyperlipidemia dogs were significantly higher than those of control dogs. ALT levels of hyperlipidemic dogs with treatment were the highest among three groups. VLDL and LDL of both cholesterol and triglyceride of untreated hyperlipidemia dogs were the highest among three groups. HDL1 levels in triglyceride of hyperlipidemia dogs with treatment were significantly higher than those of control and untreated hyperlipidemia dog. Malondialdehyde concentrations of untreated hyperlipidemia dogs were significantly higher than those of control and hyperlipidemic dogs with treatment. CONCLUSIONS: In this study, dogs with untreated hyperlipidemia clearly showed abnormal lipid status, whereas hyperlipidemic dogs under anti hyperlipidemia treatment showed more normal lipid status suggesting the effectiveness of the therapy. Anti-hyperlipidemics (statins and fibrates) for dogs are also effective in relieving elevated levels of lipids and lipid oxidation. Plasma lipid (triglyceride and cholesterol) profiles and malondialdehyde are useful diagnostic tools for identifying early stages of untreatment hyperlipidemia in dogs. PMID- 24625121 TI - 5,10-seco-neo-clerodanes and neo-clerodanes from Salvia microphylla. AB - Two new 5,10-seco-neo-clerodanes, salvimicrophyllins A and B (1 and 2), and two new neo-clerodanes, salvimicrophyllins C and D (3 and 4), were isolated from the leaves and flowers of Salvia microphylla. The structures of these compounds were elucidated mainly by analysis of their NMR spectroscopic and mass spectrometric data. The relative configurations of the salvimicrophyllins were determined by analysis of NOESY spectra and ECD curves, and the relative configuration of compound 2 was confirmed by single-crystal X-ray diffraction crystallography. PMID- 24625122 TI - Perceptions of health care services and HIV-related health-seeking behavior among Uganda adolescents. AB - Youth represent almost half of all new HIV infections globally. Although condom use is an effective method of HIV prevention among sexually active youth in sub Saharan Africa (SSA), they face substantial barriers in obtaining condoms in environments where adults hold attitudes condemning premarital sex. More research is needed to better understand the multitude of factors that affect SSA youths' behaviors regarding safe sex practices, including factors that may influence their ability to obtain condoms, and decisions to be tested for HIV. In this study of Uganda youth (n = 1503) from five secondary schools, logistic regression models highlight factors that influence perceptions regarding respect and confidentiality at health centers, condom acquisition, and HIV testing. Family support appears to be an especially important factor that affects youth perceptions about how they will be treated when seeking condoms and HIV testing. Condom acquisition and HIV-testing behaviors are also associated with peer influence, self-esteem, and demographic characteristics, such as age. PMID- 24625123 TI - Abstracts of the 5th Danish Emergency Medicine Conference, 18-19 April 2013, Aarhus, Denmark. PMID- 24625124 TI - Properties of patient-reported outcome measures in individuals following acute whiplash injury. AB - BACKGROUND: The aim of this study was to assess the acceptability, reliability, validity and responsiveness of the Short-Form Health Survey (SF-12) and its preference-based derivative (SF-6D), the EQ-5D and the Neck Disability Index (NDI) in patients recovering from acute whiplash injury. METHODS: Data from the Managing Injuries of the Neck Trial of 3,851 patients with acute whiplash injury formed the basis of this empirical investigation. The EQ-5D and SF-12 were collected at baseline, and all three outcome measures were then collected at 4 months, 8 months and 12 months post-randomisation. The measures were assessed for their acceptability (response rates), internal consistency, validity (known groups validity and discriminant validity) and their internal and external responsiveness. RESULTS: Response rates were broadly similar across the measures, with evidence of a floor effect for the NDI and a ceiling effect for the EQ-5D utility measure. All measures had Cronbach's alpha statistics of greater than 0.7, indicating acceptable internal consistency. The NDI and EQ-5D utility score correlated more strongly with the physical component scale of the SF-12 than the mental component scale, whilst this was reversed for the SF-6D utility score. The smaller standard deviations in SF-6D utility scores meant there were larger effect sizes for differences in utility score between patients with different injury severity at baseline than for the EQ-5D utility measure. However, the EQ 5D utility measure and NDI were both more responsive to longitudinal changes in health status than the SF-6D. CONCLUSIONS: There was no evidence of differences between the EQ-5D utility measure and NDI in terms of their construct validity, discriminant validity or responsiveness in patients with acute whiplash injury. However, both demonstrated superior responsiveness to longitudinal health changes than the SF-6D. PMID- 24625127 TI - Providing information about options in patient decision aids. AB - BACKGROUND: Legal, ethical, and psychological arguments indicate that patients need to receive information about their health situations before their care decisions are made. Patient decision aids (PtDAs) are designed to help patients make decisions; therefore, they should provide information that results in patients understanding their health situation. We reviewed studies that assessed the impact of PtDAs on patient knowledge and on their feeling of being uninformed. METHODS: Our data sources were a published Cochrane Collaboration review that included randomized controlled trials (RCTs) published before 2010 and a systematic review we conducted of RCTs published in 2010. We included trials that compared 1) PtDAs to usual care, and 2) PtDAs with simple information to PtDAs with more detailed information. Outcomes included patients' knowledge and their feeling of being uninformed. Data were analyzed quantitatively and qualitatively. Meta-analyses of similar studies estimated the size of differences. RESULTS: Thirty-nine RCTs compared a PtDA to usual care and all showed higher knowledge scores for patients in the PtDA groups; a meta-analysis estimated the advantage at 14 (of 100) points. Sixteen (of 39) studies used the Feeling Uninformed subscale; a meta-analysis estimated a reduction of 7 (of 100) points in the PtDA group over usual care. Twenty-one studies compared simple- to more-detailed information in PtDAs. There was a small overall advantage for more detailed information on knowledge scores; a meta-analysis estimated the advantage at 5 (of 100) points. Only one study found higher mean knowledge scores for simpler information. Nine (of 21) studies reported using the Feeling Uninformed subscale and a meta-analysis suggested a reduction of 3 (of 100) points for the more-detailed PtDAs over those with simpler information. Only one study found that simpler information resulted in patients feeling more informed. CONCLUSIONS: It appears that PtDAs result in patients having higher knowledge scores and in reduced feelings of being uninformed over patients who receive usual care. It also appears that PtDAs with more detailed information generally result in slightly higher knowledge and lower "Feeling Uninformed" scores than those with simpler information, but the differences are small and can be reversed under some circumstances. PMID- 24625128 TI - Deciphering the role of the ADAM17-dependent secretome in cell signaling. AB - ADAM17 has been initially identified as the main sheddase responsible for releasing the soluble form of a variety of cell-surface proteins, including growth factors, cytokines, cell adhesion molecules, and receptors, most of which are associated with pathological processes, including cancer and inflammation. However, the function and composition of the ADAM17-dependent secretome on a proteome-wide scale is poorly understood. In this study, we observed that the ADAM17-dependent secretome plays an important role in promoting cell proliferation and migration. To further demonstrate the repertoire of proteins involved in this cross-talk, we employed mass-spectrometry-based proteomics using nonmetabolic and metabolic labeling approaches to explore the secretome composition of wild-type and ADAM17(-/-) knockout mouse embryonic fibroblast (mEF) cells. Bioinformatic analyses indicated the differential regulation of 277 soluble proteins in the ADAM17-dependent secretome as well as novel direct ADAM17 cleavage substrates, such as mimecan and perlecan. Furthermore, we found that the ADAM17-dependent secretome promoted an opposite regulation of ERK and FAK pathways as well as PPARgamma downstream activation. These findings demonstrated fine-tuning of cell signaling rendered by the soluble molecules mediated by ADAM17. PMID- 24625130 TI - The effects of X-ray irradiation on the proliferation and apoptosis of MCF-7 breast cancer cells. AB - To investigate the effects of X-ray irradiation on the proliferation and apoptosis of MCF-7 breast cancer cells; MCF-7 breast cancer cells were irradiated with X-ray. After irradiation, morphological changes and growth inhibition rate of the irradiated cells were observed under an inverted microscope. 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess the proliferation of the irradiated MCF-7 cells. Transmission electron microscope was used to observe the morphology and ultrastructure of the irradiated MCF-7 cells. Western blotting was used to analyze the expression level of apoptosis related protein caspase-3. Our results showed, at 48 h after the irradiation (0 Gy and 8 Gy), cells oval in shape, cell shrinkage or swelling and partial formation of debris under inverted microscope; as well as cytoplasmic vacuolization or inspissation, increased electron density of cytoplasm, structural damage of organelles, blurred mitochondrial cristae and chromatin margination under transmission electron microscopy; the survival rate of MCF-7 cells in X-ray group was 17.3% lower than that in control group (0 Gy) (p < 0.001); while caspase-3 expression increased evidently in X-ray group compared with control group (0 Gy) (p < 0.05). In conclusion, X-ray irradiation can inhibit the proliferation of MCF-7 cells and induce apoptosis through increasing caspase-3 expression. PMID- 24625131 TI - S-P coupling induced unusual open-shell metal clusters. AB - Metal clusters featuring closed supershells or aromatic character usually exhibit remarkably enhanced stability in their cluster series. However, not all stable clusters are subject to these fundamental constraints. Here, by employing photoelectron imaging spectroscopy and ab initio calculations, we present experimental and theoretical evidence on the existence of unexpectedly stable open-shell clusters, which are more stable than their closed-shell and aromatic counterparts. The stabilization of these open-shell Al-Mg clusters is proposed to originate from the S-P molecular orbital coupling, leading to highly stable species with increased HOMO-LUMO gaps, akin to s-p hybridization in an organic carbon atom that is beneficial to form stable species. Introduction of the coupling effect highlighted here not only shows the limitations of the conventional closed-shell model and aromaticity but also provides the possibility to design valuable building blocks. PMID- 24625129 TI - Born too soon: the global epidemiology of 15 million preterm births. AB - This second paper in the Born Too Soon supplement presents a review of the epidemiology of preterm birth, and its burden globally, including priorities for action to improve the data. Worldwide an estimated 11.1% of all livebirths in 2010 were born preterm (14.9 million babies born before 37 weeks of gestation), with preterm birth rates increasing in most countries with reliable trend data. Direct complications of preterm birth account for one million deaths each year, and preterm birth is a risk factor in over 50% of all neonatal deaths. In addition, preterm birth can result in a range of long-term complications in survivors, with the frequency and severity of adverse outcomes rising with decreasing gestational age and decreasing quality of care. The economic costs of preterm birth are large in terms of immediate neonatal intensive care, ongoing long-term complex health needs, as well as lost economic productivity. Preterm birth is a syndrome with a variety of causes and underlying factors usually divided into spontaneous and provider-initiated preterm births. Consistent recording of all pregnancy outcomes, including stillbirths, and standard application of preterm definitions is important in all settings to advance both the understanding and the monitoring of trends. Context specific innovative solutions to prevent preterm birth and hence reduce preterm birth rates all around the world are urgently needed. Strengthened data systems are required to adequately track trends in preterm birth rates and program effectiveness. These efforts must be coupled with action now to implement improved antenatal, obstetric and newborn care to increase survival and reduce disability amongst those born too soon. PMID- 24625132 TI - Two-dimensional materials as emulsion stabilizers: interfacial thermodynamics and molecular barrier properties. AB - A new application for two-dimensional (2D) materials is emulsification, where they can serve as ultrathin platelike interfacial stabilizers in two-liquid systems. We present a first detailed thermodynamic analysis of atomically thin 2D materials at organic-aqueous liquid-liquid interfaces and derive expressions for the transfer free energies of emulsion stabilization that account for material geometry, van der Waals transparency or opacity, and variable hydrophobicity. High mass potency is shown to be an intrinsic property of the 2D geometry, which at the atomically thin limit places every atom in contact with both liquid phases, resulting in unit atom efficiency. The thermodynamic model successfully predicts that graphene oxide but not pristine graphene has a favorable hydrophobic-hydrophilic balance for oil-water emulsion stabilization. Multilayer tiling is predicted to occur by the passivation of droplet surface patches left uncovered by packing inefficiencies in the first monolayer, and complete multilayer coverage is confirmed by cryogenic scanning electron microscopy. The molecular barrier function of graphene interfacial films causes a significant suppression of dispersed-phase evaporation rates with potential applications in controlled release. Finally, these emulsions can be used as templates for creating solid graphene foams or graphene microsacks filled with lipophilic cargos. Emerging 2D materials are promising as dispersants or emulsifiers where high mass potency and multifunctional properties are desired. PMID- 24625134 TI - Studies related to energy based devices. PMID- 24625133 TI - Relocation of genes generates non-conserved chromosomal segments in Fusarium graminearum that show distinct and co-regulated gene expression patterns. AB - BACKGROUND: Genome comparisons between closely related species often show non conserved regions across chromosomes. Some of them are located in specific regions of chromosomes and some are even confined to one or more entire chromosomes. The origin and biological relevance of these non-conserved regions are still largely unknown. Here we used the genome of Fusarium graminearum to elucidate the significance of non-conserved regions. RESULTS: The genome of F. graminearum harbours thirteen non-conserved regions dispersed over all of the four chromosomes. Using RNA-Seq data from the mycelium of F. graminearum, we found weakly expressed regions on all of the four chromosomes that exactly matched with non-conserved regions. Comparison of gene expression between two different developmental stages (conidia and mycelium) showed that the expression of genes in conserved regions is stable, while gene expression in non-conserved regions is much more influenced by developmental stage. In addition, genes involved in the production of secondary metabolites and secreted proteins are enriched in non-conserved regions, suggesting that these regions could also be important for adaptations to new environments, including adaptation to new hosts. Finally, we found evidence that non-conserved regions are generated by sequestration of genes from multiple locations. Gene relocations may lead to clustering of genes with similar expression patterns or similar biological functions, which was clearly exemplified by the PKS2 gene cluster. CONCLUSIONS: Our results showed that chromosomes can be functionally divided into conserved and non-conserved regions, and both could have specific and distinct roles in genome evolution and regulation of gene expression. PMID- 24625135 TI - Over-diagnosed and over-treated: a survey of Australian public attitudes towards the acceptability of drug treatment for depression and ADHD. AB - BACKGROUND: Over the last decade the use of psychotropic medications to treat common mental health problems has increased in Australia. This paper explores: 1) public attitudes towards the acceptability of using prescription drugs to treat depression and attention deficit hyperactivity disorder (ADHD), and 2) beliefs about over-diagnosis of depression and ADHD. METHOD: 1293 members of the general public were surveyed about their attitudes towards drug treatment for depression and ADHD through the Queensland Social Survey (QSS), an omnibus state-wide survey of households in the state of Queensland. The survey was administered through a CATI (computer-assisted telephone interviewing) system. Logistic regression analyses were used to predict belief that drug treatment is acceptable, and that depression and ADHD are over-diagnosed. RESULTS: Most participants (60.9%) said that it was acceptable to use prescription drugs to treat depression. In contrast, attitudes towards the use of prescription drugs to treat ADHD were much less positive with around the same proportion saying it was acceptable (42.1%) as unacceptable (38.2%). More than half of the sample agreed that too many people are diagnosed with depression when they don't really have it (57.7%), and 78.3% of participants agreed that too many children are diagnosed with ADHD when they don't really have it. Participants who said depression or ADHD were over diagnosed were less likely to say that it is acceptable to treat these conditions with prescription drugs. CONCLUSIONS: Despite increases in prescribing rates there is still considerable scope for increasing the public's acceptance of treating common mental illnesses with psychotropic drugs. Furthermore, the public's views on over-diagnosis of depression and ADHD appear to reflect ongoing controversy about the proper identification of these conditions, and these views negatively impact attitudes towards drug treatment. This may be a barrier to effective treatment of these conditions given that drug treatment is often recommended as a first line response. PMID- 24625136 TI - HIV disclosure and its effect on treatment outcomes in perinatal HIV-infected Thai children. AB - The World Health Organization guideline recommends informing children of their HIV status between the ages of 6-12 years. Primary caregivers of perinatal HIV infected Thai children >=6 years were interviewed in order to assess the HIV status disclosure rate. In addition, pill counts of antiretroviral therapy (ART) were performed every three months. CD4 and HIV-RNA were performed every six months. Of the 260 children/adolescents included, the median age of disclosure was 14.8 years. The disclosure rate among those from 6 to 12 years was 21% and for those greater than 12 years of age was 84%. When comparing children aged 6-12 years whose HIV status had been disclosed to them, to children whose HIV had yet to be disclosed, no difference was noted in median ART adherence by pill count, CD4 count, or proportion of HIV-RNA <50 copies/ml (p > 0.05). Factors associated with HIV disclosure were an age of >=12 years (OR 17.8, 95% CI 8.86-35.79) and a current CD4 <= 30% (OR 2.09, 95% CI 1.20-3.62). In conclusion, although the majority of adolescents >=12 years were aware of their HIV status only one-fifth of children aged 6-12 years were aware. Moreover, the child's/adolescent's disclosure status had no bearing on ART adherence by pill count or immunological and virological outcomes. PMID- 24625137 TI - Clinical review is essential to evaluate 30-day mortality after trauma. AB - BACKGROUND: Securing high-quality mortality statistics requires systematic evaluation of all trauma deaths. We examined the proportion of trauma patients dying within 30 days from causes not related to the injury and the impact of exclusion of patients dead on arrival on 30-day trauma mortality. We also defined the demographics, injury characteristics, cause of death and time to death in patients admitted to our trauma center who died within 30 days, between 2007 2011. METHODS: Demographics, injury characteristics, status alive/dead on arrival, cause of death and time to death of all patients were reviewed. Deaths were analyzed based on injury mechanism (penetrating, blunt trauma and low energy blunt trauma) and cause of death (traumatic brain injury (TBI), hemorrhage, organ dysfunction and other/unknown). RESULTS: Of the 7422 admissions, 343 deaths were identified of which 36 (10.5%) involved causes not related to the injury. The overall age was 71 years, Injury Severity Score (ISS) 29 and time to death 24 hours (all medians). Fifty-four patients (17.6%) were dead on arrival. Exclusion of patients dead on arrival reduced the overall mortality rate (P < 0.05) and median ISS (P < 0.05) and increased median age (P < 0.01) and time to death (P < 0.001). Injury mechanism was penetrating trauma in 7.5%, blunt trauma in 56.0%, and low energy blunt trauma in 36.5%. TBI accounted for 58.6%; hemorrhage 16.3%, organ dysfunction 15.0%, and other/unknown for 10.1% of the deaths. Patients who died after low energy blunt trauma were older, had lower ISS and longer time to death compared to those who died after penetrating and blunt trauma (all P < 0.01). CONCLUSIONS: Clinical review of all trauma deaths was essential to interpret mortality. Thirty-day trauma mortality included 10.5% deaths not directly related to the injury and the exclusion of patients dead on arrival significantly affected the unadjusted mortality rate, ISS, median age and time to death. PMID- 24625138 TI - Reconstruction of large-size abdominal wall defect using biodegradable poly-p dioxanone mesh: an experimental canine study. AB - BACKGROUND: Reconstruction of large-size abdominal wall defect (AWDs) is a huge challenge faced in current surgical practice. In this study, we aimed to evaluate the effectiveness and safety of biodegradable poly-p-dioxanone (PDO) mesh for reconstructing large-size AWDs in an experimental canine model. METHODS: Eighteen experimental canines were randomly and equally divided into three groups, namely, a PDO group, a Marlex group and a control group (n = 6 each). Following the creation of a 6 cm * 5.5 cm AWD, PDO mesh and Marlex mesh were used to reconstruct the defect in the PDO and Marlex groups, respectively. The defect was closed using relaxation sutures alone in the control group. Animals were killed 24 weeks after surgery, and reconstruction outcomes were evaluated using radiography, histology and biomechanical testing. RESULTS: All animals except those in the control group survived the experiment. The PDO group showed no wound dehiscence, herniation or infection, whereas the animals in the Marlex group exhibited marked foreign body reactions. The PDO group had less intraabdominal adhesion than the Marlex group. As shown by radiography, histology and biomechanical testing, PDO mesh exhibited complete degradation and favorable biochemical strength at 24 weeks postsurgery. CONCLUSIONS: PDO mesh implantation is an effective, safe treatment modality for reconstructing large-size AWDs. PMID- 24625139 TI - Comparative analysis of mouse-induced pluripotent stem cells and mesenchymal stem cells during osteogenic differentiation in vitro. AB - Induced pluripotent stem cells (iPSCs) can differentiate into mineralizing cells and are, therefore, expected to be useful for bone regenerative medicine; however, the characteristics of iPSC-derived osteogenic cells remain unclear. Here, we provide a direct in vitro comparison of the osteogenic differentiation process in mesenchymal stem cells (MSCs) and iPSCs from adult C57BL/6J mice. After 30 days of culture in osteogenic medium, both MSCs and iPSCs produced robustly mineralized bone nodules that contained abundant calcium phosphate with hydroxyapatite crystal formation. Mineral deposition was significantly higher in iPSC cultures than in MSC cultures. Scanning electron microscopy revealed budding matrix vesicles in early osteogenic iPSCs; subsequently, the vesicles propagated to exhibit robust mineralization without rich fibrous structures. Early osteogenic MSCs showed deposition of many matrix vesicles in abundant collagen fibrils that became solid mineralized structures. Both cell types demonstrated increased expression of osteogenic marker genes, such as runx2, osterix, dlx5, bone sialoprotein (BSP), and osteocalcin, during osteogenesis; however, real-time reverse transcription-polymerase chain reaction array analysis revealed that osteogenesis-related genes encoding mineralization-associated molecules, bone morphogenetic proteins, and extracellular matrix collagens were differentially expressed between iPSCs and MSCs. These data suggest that iPSCs are capable of differentiation into mature osteoblasts whose associated hydroxyapatite has a crystal structure similar to that of MSC-associated hydroxyapatite; however, the transcriptional differences between iPSCs and MSCs could result in differences in the mineral and matrix environments of the bone nodules. Determining the biological mechanisms underlying cell-specific differences in mineralization during in vitro iPSC osteogenesis may facilitate the development of clinically effective engineered bone. PMID- 24625140 TI - Early life conditions, adverse life events, and chewing ability at middle and later adulthood. AB - OBJECTIVES: We sought to determine the extent to which early life conditions and adverse life events impact chewing ability in middle and later adulthood. METHODS: Secondary analyses were conducted based on data from waves 2 and 3 of the Survey of Health, Ageing, and Retirement in Europe (SHARE), collected in the years 2006 to 2009 and encompassing information on current chewing ability and the life history of persons aged 50 years or older from 13 European countries. Logistic regression models were estimated with sequential inclusion of explanatory variables representing living conditions in childhood and adverse life events. RESULTS: After controlling for current determinants of chewing ability at age 50 years or older, certain childhood and later life course socioeconomic, behavioral, and cognitive factors became evident as correlates of chewing ability at age 50 years or older. Specifically, childhood financial hardship was identified as an early life predictor of chewing ability at age 50 years or older (odds ratio = 1.58; 95% confidence interval = 1.22, 2.06). CONCLUSIONS: Findings suggest a potential enduring impact of early life conditions and adverse life events on oral health in middle and later adulthood and are relevant for public health decision-makers who design strategies for optimal oral health. PMID- 24625141 TI - Socioeconomic status, food security, and dental caries in US children: mediation analyses of data from the National Health and Nutrition Examination Survey, 2007 2008. AB - OBJECTIVES: We examined associations of household socioeconomic status (SES) and food security with children's oral health outcomes. METHODS: We analyzed 2007 and 2008 US National Health and Nutrition Examination Survey data for children aged 5 to 17 years (n = 2206) to examine the relationship between food security and untreated dental caries and to assess whether food security mediates the SES caries relationship. RESULTS: About 20.1% of children had untreated caries. Most households had full food security (62%); 13% had marginal, 17% had low, and 8% had very low food security. Higher SES was associated with significantly lower caries prevalence (prevalence ratio [PR] = 0.77; 95% confidence interval = 0.63, 0.94; P = .01). Children from households with low or very low food security had significantly higher caries prevalence (PR = 2.00 and PR = 1.70, respectively) than did children living in fully food-secure households. Caries prevalence did not differ among children from fully and marginally food-secure households (P = .17). Food insecurity did not appear to mediate the SES-caries relationship. CONCLUSIONS: Interventions and policies to ensure food security may help address the US pediatric caries epidemic. PMID- 24625142 TI - Relation between higher physical activity and public transit use. AB - OBJECTIVES: We isolated physical activity attributable to transit use to examine issues of substitution between types of physical activity and potential confounding of transit-related walking with other walking. METHODS: Physical activity and transit use data were collected in 2008 to 2009 from 693 Travel Assessment and Community study participants from King County, Washington, equipped with an accelerometer, a portable Global Positioning System, and a 7-day travel log. Physical activity was classified into transit- and non-transit related walking and nonwalking time. Analyses compared physical activity by type between transit users and nonusers, between less and more frequent transit users, and between transit and nontransit days for transit users. RESULTS: Transit users had more daily overall physical activity and more total walking than did nontransit users but did not differ on either non-transit-related walking or nonwalking physical activity. Most frequent transit users had more walking time than least frequent transit users. Higher physical activity levels for transit users were observed only on transit days, with 14.6 minutes (12.4 minutes when adjusted for demographics) of daily physical activity directly linked with transit use. CONCLUSIONS: Because transit use was directly related to higher physical activity, future research should examine whether substantive increases in transit access and use lead to more physical activity and related health improvements. PMID- 24625143 TI - From the sidelines to the frontline: how the Substance Abuse and Mental Health Services Administration embraced smoking cessation. AB - Smoking is a major contributor to premature mortality among people with mental illness and substance abuse. Historically, the Substance Abuse and Mental Health Services Administration (SAMHSA) did not include smoking cessation in its mission. We describe the development of a unique partnership between SAMHSA and the University of California, San Francisco's Smoking Cessation Leadership Center. Starting with an educational summit in Virginia in 2007, it progressed to a jointly sponsored "100 Pioneers for Smoking Cessation" campaign that provided grants and technical assistance to organizations promoting cessation. By 2013, the partnership established 7 "Leadership Academies," state-level multidisciplinary collaboratives of organizations focused on cessation. This academic-public partnership increased tobacco quit attempts, improved collaboration across multiple agencies, and raised awareness about tobacco use in vulnerable populations. PMID- 24625144 TI - Impact of a Rewards-Based Incentive Program on Promoting Fruit and Vegetable Purchases. AB - Objectives. We assessed the impact of a rewards-based incentive program on fruit and vegetable purchases by low-income families. Methods. We conducted a 4-phase prospective cohort study with randomized intervention and wait-listed control groups in Philadelphia, Pennsylvania, in December 2010 through October 2011. The intervention provided a rebate of 50% of the dollar amount spent on fresh or frozen fruit and vegetables, reduced to 25% during a tapering phase, then eliminated. Primary outcome measures were number of servings of fruit and of vegetables purchased per week. Results. Households assigned to the intervention purchased an average of 8 (95% confidence interval [CI] = 1.5, 16.9) more servings of vegetables and 2.5 (95% CI = 0.3, 9.5) more servings of fruit per week than did control households. In longitudinal price-adjusted analyses, when the incentive was reduced and then discontinued, the amounts purchased were similar to baseline. Conclusions. Investigation of the financial costs and potential benefits of incentive programs to supermarkets, government agencies, and other stakeholders is needed to identify sustainable interventions. PMID- 24625145 TI - Resistant to the recession: low-income adults' maintenance of cooking and away from-home eating behaviors during times of economic turbulence. AB - OBJECTIVES: We examined the effects of state-level unemployment rates during the recession of 2008 on patterns of home food preparation and away-from-home (AFH) eating among low-income and minority populations. METHODS: We analyzed pooled cross-sectional data on 118 635 adults aged 18 years or older who took part in the American Time Use Study. Multinomial logistic regression models stratified by gender were used to evaluate the associations between state-level unemployment, poverty, race/ethnicity, and time spent cooking, and log binomial regression was used to assess respondents' AFH consumption patterns. RESULTS: High state-level unemployment was associated with only trivial increases in respondents' cooking patterns and virtually no change in their AFH eating patterns. Low-income and racial/ethnic minority groups were not disproportionately affected by the recession. CONCLUSIONS: Even during a major economic downturn, US adults are resistant to food-related behavior change. More work is needed to understand whether this reluctance to change is attributable to time limits, lack of knowledge or skill related to food preparation, or lack of access to fresh produce and raw ingredients. PMID- 24625146 TI - Centering perspectives on Black women, hair politics, and physical activity. AB - As researchers categorize issues facing Black women's health, obesity and physical exercise continue to be significant topics of debate. General interventions targeted toward Black women to address obesity and increase physical exercise have been largely ineffective. In this article, I situate the current public health discourse on obesity and related interventions within a sociocultural context of body appearance, with a specific focus on hair. Why do some African American women feel such strong ties to their hair that they will avoid exercise? What can be done to understand this phenomenon and address alternatives that may make both hair maintenance and regular exercise feasible? I map a theoretical argument for why hair matters for some women, and discuss how physical activity intervention strategies might be improved by considering such complexities. PMID- 24625147 TI - Cigarette Smoking, Desire to Quit, and Tobacco-Related Counseling Among Patients at Adult Health Centers. AB - Objectives. We determined cigarette smoking prevalence, desire to quit, and tobacco-related counseling among a national sample of patients at health centers. Methods. Data came from the 2009 Health Center Patient Survey and the 2009 National Health Interview Survey. The analytic sample included 3949 adult patients at health centers and 27 731 US adults. Results. Thirty-one percent of health center patients were current smokers, compared with 21% of US adults in general. Among currently smoking health center patients, 83% desired to quit and 68% received tobacco counseling. In multivariable models, patients had higher adjusted odds of wanting to quit if they had indications of severe mental illness (adjusted odds ratio [AOR] = 3.26; 95% confidence interval [CI] = 1.19, 8.97) and lower odds if they had health insurance (AOR = 0.43; 95% CI = 0.22, 0.86). Patients had higher odds of receiving counseling if they had 2 or more chronic conditions (AOR = 2.05; 95% CI = 1.11, 3.78) and lower odds if they were Hispanic (AOR = 0.57; 95% CI = 0.34, 0.96). Conclusions. Cigarette smoking prevalence is substantially higher among patients at health centers than US adults in general. However, most smokers at health centers desire to quit. Continued efforts are warranted to reduce tobacco use in this vulnerable group. PMID- 24625148 TI - Neighborhood food environment and obesity in community-dwelling older adults: individual and neighborhood effects. AB - OBJECTIVES: We tested hypotheses about the relationship between neighborhood level food sources and obesity, controlling for individual-level characteristics. METHODS: Data (collected November 2006-April 2008) derived from a random-digit dial sample of 5688 community-dwelling adults aged 50 to 74 years residing in 1644 census tracts in New Jersey. Using multilevel structural equation models, we created latent constructs representing density of fast-food establishments and storefronts (convenience stores, bars and pubs, grocery stores) and an observed indicator for supermarkets at the neighborhood level, simultaneously modeling obesity and demographic characteristics (age, gender, race, education, household income) at the individual level. RESULTS: When we controlled for individual-level age, gender, race, education, and household income, densities of fast-food establishments and storefronts were positively associated with obesity. Supermarkets were not associated with obesity. CONCLUSIONS: Because people living in neighborhoods with a higher density of fast food and storefronts are more likely to be obese, these neighborhoods may be optimal sites for interventions. PMID- 24625149 TI - Influence of point-of-sale tobacco displays and graphic health warning signs on adults: evidence from a virtual store experimental study. AB - OBJECTIVES: We tested the impact of banning tobacco displays and posting graphic health warning signs at the point of sale (POS). METHODS: We designed 3 variations of the tobacco product display (open, enclosed [not visible], enclosed with pro-tobacco ads) and 2 variations of the warning sign (present vs absent) with virtual store software. In December 2011 and January 2012, we randomized a national convenience sample of 1216 adult smokers and recent quitters to 1 of 6 store conditions and gave them a shopping task. We tested for the main effects of the enclosed display, the sign, and their interaction on urge to smoke and tobacco purchase attempts. RESULTS: The enclosed display significantly lowered current smokers' (B = -7.05; 95% confidence interval [CI] = -13.20, -0.91; P < .05) and recent quitters' (Beta = -6.00, 95% CI = -11.00, -1.00; P < .01) urge to smoke and current smokers' purchase attempts (adjusted odds ratio = 0.06; 95% CI = 0.03, 0.11; P < .01). The warning sign had no significant main effect on study outcomes or interaction with enclosed display. CONCLUSIONS: These data show that POS tobacco displays influence purchase behavior. Banning them may reduce cues to smoke and unplanned tobacco purchases. PMID- 24625150 TI - Insurer views on reimbursement of preventive services in the dental setting: results from a qualitative study. AB - OBJECTIVES: We explored insurers' perceptions regarding barriers to reimbursement for oral rapid HIV testing and other preventive screenings during dental care. METHODS: We conducted semistructured interviews between April and October 2010 with a targeted sample of 13 dental insurance company executives and consultants, whose firms' cumulative market share exceeded 50% of US employer-based dental insurance markets. Participants represented viewpoints from a significant share of the dental insurance industry. RESULTS: Some preventive screenings, such as for oral cancer, received widespread insurer support and reimbursement. Others, such as population-based HIV screening, appeared to face many barriers to insurance reimbursement. The principal barriers were minimal employer demand, limited evidence of effectiveness and return on investment specific to dental settings, implementation and organizational constraints, lack of provider training, and perceived lack of patient acceptance. CONCLUSIONS: The dental setting is a promising venue for preventive screenings, and addressing barriers to insurance reimbursement for such services is a key challenge for public health policy. PMID- 24625151 TI - Miller et al. respond. PMID- 24625152 TI - Vaccination interest and trends in human papillomavirus vaccine uptake in young adult women aged 18 to 26 years in the United States: an analysis using the 2008 2012 National Health Interview Survey. AB - OBJECTIVES: Human papillomavirus (HPV) vaccines have been approved since 2006, yet vaccination rates remain low. We investigated HPV vaccination trends, interest, and reasons for nonvaccination in young adult women. METHODS: We used data from the 2008-2012 National Health Interview Survey to analyze HPV vaccine uptake trends (>= 1 dose) in women aged 18 to 26 years. We used data from the 2008 and 2010 National Health Interview Survey to examine HPV vaccination interest and reasons for nonvaccination among unvaccinated women. RESULTS: We saw significant increases in HPV vaccination for all young women from 2008 to 2012 (11.6% to 34.1%); however, Hispanics and women with limited access to care continued to have lower vaccination rates. Logistic regression demonstrated lower vaccination interest among unvaccinated women in 2010 than 2008. Respondents in 2010 were significantly less likely to give lack of knowledge as a primary reason for nonvaccination. CONCLUSIONS: Uptake of HPV vaccine has increased from 2008 to 2012 in young women. Yet vaccination rates remain low, especially among women with limited access to care. However, unvaccinated women with limited health care access were more likely to be interested in receiving the vaccine. PMID- 24625153 TI - "I did it for us and I would do it again": perspectives of rural latinos on providing biospecimens for research. AB - OBJECTIVES: We elicited perspectives of rural Latino farmworkers and non farmworkers about their participation in a community-based participatory pesticides exposure study in which they provided multiple biospecimens. METHODS: Between March and April 2012, we conducted semistructured, one-on-one interviews with 39 rural Latino farmworkers and non-farmworkers in Washington State (n = 39). Nineteen open-ended interview questions aimed to elicit participants' attitudes toward, expectations and experiences of biospecimen collection for research, and willingness to participate in future biomedical research studies. We reviewed and coded transcriptions using qualitative principles of grounded theory in which concepts were identified and themes derived from interview data. RESULTS: We grouped themes into 3 major categories: (1) motivation to participate, (2) challenges of participation, and (3) perceived rewards of participation. Many participants were motivated by the perceived importance of the study topic and a desire to acquire and contribute to new knowledge. Respondents said that the benefits of participation outweighed the challenges, and many expressed satisfaction to be able to contribute to research that would benefit future generations. CONCLUSIONS: Our findings supported the use of community-based participatory research to engage minorities as participants and invested parties in such studies. PMID- 24625154 TI - Ethics and obesity prevention: ethical considerations in 3 approaches to reducing consumption of sugar-sweetened beverages. AB - Obesity and overweight prevalence soared to unprecedented levels in the United States, with 1 in 3 adults and 1 in 6 children currently categorized as obese. Although many approaches have been taken to encourage individual behavior change, policies increasingly attempt to modify environments to have a more positive influence on individuals' food and drink choices. Several policy proposals target sugar-sweetened beverages (SSBs), consumption of which has become the largest contributor to Americans' caloric intake. Yet proposals have been criticized for unduly inhibiting choice, being overly paternalistic, and stigmatizing low-income populations. We explored the ethical acceptability of 3 approaches to reduce SSB consumption: restricting sale of SSBs in public schools, levying significant taxes on SSBs, and prohibiting the use of Supplemental Nutrition and Assistance Program (formerly food stamps) benefits for SSB purchases. PMID- 24625155 TI - Long-term consequences of adolescent gang membership for adult functioning. AB - OBJECTIVES: We examined the possible public health consequences of adolescent gang membership for adult functioning. METHODS: Data were drawn from the Seattle Social Development Project, a longitudinal study focusing on the development of positive and problem outcomes. Using propensity score matching and logistic regression analyses, we assessed the effects of adolescent gang membership on illegal behavior, educational and occupational attainment, and physical and mental health at the ages of 27, 30, and 33 years. RESULTS: In comparison with their nongang peers, who had been matched on 23 confounding risk variables known to be related to selection into gang membership, those who had joined a gang in adolescence had poorer outcomes in multiple areas of adult functioning, including higher rates of self-reported crime, receipt of illegal income, incarceration, drug abuse or dependence, poor general health, and welfare receipt and lower rates of high school graduation. CONCLUSIONS: The finding that adolescent gang membership has significant consequences in adulthood beyond criminal behavior indicates the public health importance of the development of effective gang prevention programs. PMID- 24625156 TI - Longitudinal associations between poverty and obesity from birth through adolescence. AB - OBJECTIVES: We examined the relationship between timing of poverty and risk of first-incidence obesity from ages 3 to 15.5 years. METHODS: We used the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (1991-2007) to study 1150 children with repeated measures of income, weight, and height from birth to 15.5 years in 10 US cities. Our dependent variable was the first incidence of obesity (body mass index >= 95th percentile). We measured poverty (income-to-needs ratio < 2) prior to age 2 years and a lagged, time-varying measure of poverty between ages 2 and 12 years. We estimated discrete-time hazard models of the relative risk of first transition to obesity. RESULTS: Poverty prior to age 2 years was associated with risk of obesity by age 15.5 years in fully adjusted models. These associations did not vary by gender. CONCLUSIONS: Our findings suggest that there are enduring associations between early life poverty and adolescent obesity. This stage in the life course may serve as a critical period for both poverty and obesity prevention. PMID- 24625157 TI - Secular trends in fast-food restaurant use among adolescents and maternal caregivers from 1999 to 2010. AB - OBJECTIVES: We examined trends from 1999 to 2010 in adolescents' self-reported fast-food restaurant use alongside maternal reports of fast-food consumption and purchasing from restaurants for family meals. METHODS: Middle- and high-school student participants from Minneapolis-St Paul, Minnesota, represented diverse ethnic/racial and socioeconomic backgrounds. Adolescents completed classroom administered surveys and maternal caregivers responded by phone or mail. RESULTS: The overall prevalence of frequent fast-food consumption, defined as 3 or more times per week, decreased from 1999 to 2010 among adolescents (1999: 25%; 2010: 19%; P < .001) and maternal caregivers (1999: 17%; 2010: 11%; P < .001), but sociodemographic disparities were apparent. For example, the prevalence of frequent fast-food consumption remained highest and did not significantly decrease among Black or Native American youths. The overall prevalence of frequent fast-food purchases for family meals did not significantly decrease; large decreases were observed only among Hispanic families (1999: 18%; 2010: 6%; P < .001). CONCLUSIONS: In light of previous findings linking frequent fast-food consumption to greater weight gain and poor nutrition, the observed decreases in consumption are encouraging and interventions are needed to address observed disparities. PMID- 24625158 TI - Losing the forest for the trees. PMID- 24625159 TI - National trends in smoking behaviors among Mexican, Puerto Rican, and Cuban men and women in the United States. AB - OBJECTIVES: We examined trends in smoking behaviors across 2 periods among Mexicans, Puerto Ricans, and Cubans in the United States. METHODS: We analyzed data from the 1992-2007 Tobacco Use Supplements to the Current Population Survey. We constructed 2 data sets (1990s vs 2000s) to compare smoking behaviors between the 2 periods. RESULTS: Significant decreases in ever, current, and heavy smoking were accompanied by increases in light and intermittent smoking across periods for all Latino groups, although current smoking rates among Puerto Rican women did not decline. Adjusted logistic regression models revealed that in the 2000s, younger Mexicans and those interviewed in English were more likely to be light and intermittent smokers. Mexican and Cuban light and intermittent smokers were less likely to be advised by healthcare professionals to quit smoking. Mexicans and Puerto Ricans who were unemployed and Mexicans who worked outdoors were more likely to be heavy smokers. CONCLUSIONS: Increases in light and intermittent smoking among Mexican, Puerto Rican, and Cuban Americans suggest that targeted efforts to further reduce smoking among Latinos may benefit by focusing on such smokers. PMID- 24625160 TI - Health information privacy and health information technology in the US correctional setting. AB - Electronic health records and electronic health information exchange are essential to improving quality of care, reducing medical errors and health disparities, and advancing the delivery of patient-centered medical care. In the US correctional setting, these goals are critical because of the high numbers of Americans affected, yet the use of health information technology is quite limited. In this article, I describe the legal environment surrounding health information sharing in corrections by focusing on 2 key federal privacy laws: the Health Insurance Portability and Accountability Act of 1996 and the federal Confidentiality of Alcohol and Drug Abuse Patient Records laws. In addition, I review stakeholder concerns and describe possible ways forward that enable electronic exchange while ensuring protection of inmate information and legal compliance. PMID- 24625161 TI - Life-course accumulation of neighborhood disadvantage and allostatic load: empirical integration of three social determinants of health frameworks. AB - OBJECTIVES: We examined if the accumulation of neighborhood disadvantages from adolescence to mid-adulthood were related to allostatic load, a measure of cumulative biological risk, in mid-adulthood, and explored whether this association was similar in women and men. METHODS: Data were from the participants in the Northern Swedish Cohort (analytical n = 818) at ages 16, 21, 30, and 43 years in 1981, 1986, 1995, and 2008. Personal living conditions were self-reported at each wave. At age 43 years, 12 biological markers were measured to operationalize allostatic load. Registered data for all residents in the cohort participants' neighborhoods at each wave were used to construct a cumulative measure of neighborhood disadvantage. Associations were examined in ordinary least-squares regression models. RESULTS: We found that cumulative neighborhood disadvantage between ages 16 and 43 years was related to higher allostatic load at age 43 years after adjusting for personal living conditions in the total sample (B = 0.11; P = .004) and in men (B = 0.16; P = .004), but not in women (B = 0.07; P = .248). CONCLUSIONS: Our findings suggested that neighborhood disadvantage acted cumulatively over the life course on biological wear and tear, and exemplified the gains of integrating social determinants of health frameworks. PMID- 24625162 TI - Disparities among younger and older persons alike. PMID- 24625163 TI - Dentists' willingness to provide expanded HIV screening in oral health care settings: results from a nationally representative survey. AB - OBJECTIVES: Using a nationally representative survey, we determined dentists' willingness to provide oral rapid HIV screening in the oral health care setting. METHODS: From November 2010 through November 2011, a nationally representative survey of general dentists (sampling frame obtained from American Dental Association Survey Center) examined barriers and facilitators to offering oral HIV rapid testing (n = 1802; 70.7% response). Multiple logistic regression analysis examined dentists' willingness to conduct this screening and perceived compatibility with their professional role. RESULTS: Agreement with the importance of annual testing for high-risk persons and familiarity with the Centers for Disease Control and Prevention's recommendations regarding routine HIV testing were positively associated with willingness to conduct such screening. Respondents' agreement with patients' acceptance of HIV testing and colleagues' improved perception of them were also positively associated with willingness. CONCLUSIONS: Oral HIV rapid testing is potentially well suited to the dental setting. Although our analysis identified many predictors of dentists' willingness to offer screening, there are many barriers, including dentists' perceptions of patients' acceptance, that must be addressed before such screening is likely to be widely implemented. PMID- 24625164 TI - Primary prevention of falls: effectiveness of a statewide program. AB - OBJECTIVES: We examined a population-wide program, Pennsylvania's Healthy Steps for Older Adults (HSOA), designed to reduce the incidence of falls among older adults. Older adults completing HSOA are screened and educated regarding fall risk, and those identified as being at high risk are referred to primary care providers and home safety resources. METHODS: From 2010 to 2011, older adults who completed HSOA at various senior center sites (n = 814) and a comparison group of older adults from the same sites who did not complete the program (n = 1019) were recruited and followed monthly. Although participants were not randomly allocated to study conditions, the 2 groups did not differ in fall risk at baseline or attrition. We used a telephone interactive voice response system to ascertain the number of falls that occurred each month. RESULTS: In multivariate models, adjusted fall incidence rate ratios (IRRs) were lower in the HSOA group than in the comparison group for both total (IRR = 0.83; 95% confidence interval [CI] = 0.72, 0.96) and activity-adjusted (IRR = 0.81; 95% CI = 0.70, 0.93) months of follow-up. CONCLUSIONS: Use of existing aging services in primary prevention of falls is feasible, resulting in a 17% reduction in our sample in the rate of falls over the follow-up period. PMID- 24625165 TI - Noncommunicable diseases and human rights: a promising synergy. AB - Noncommunicable diseases (NCDs) have finally emerged onto the global health and development agenda. Despite the increasingly important role human rights play in other areas of global health, their contribution to NCD prevention and control remains nascent. The recently adopted Global Action Plan for the Prevention and Control of NCDs 2013-2020 is an important step forward, but the lack of concrete attention to human rights is a missed opportunity. With practical implications for policy development, priority setting, and strategic design, human rights offer a logical, robust set of norms and standards; define the legal obligations of governments; and provide accountability mechanisms that can be used to enhance current approaches to NCD prevention and control. Harnessing the power of human rights can strengthen action for NCDs at the local, national, and global levels. PMID- 24625166 TI - Developing built environment programs in local health departments: lessons learned from a nationwide mentoring program. AB - Local health departments (LHDs) have a key role to play in developing built environment policies and programs to encourage physical activity and combat obesity and related chronic diseases. However, information to guide LHDs' effective engagement in this arena is lacking. During 2011-2012, the New York City Department of Health and Mental Hygiene (DOHMH) facilitated a built environment peer mentoring program for 14 LHDs nationwide. Program objectives included supporting LHDs in their efforts to achieve built environment goals, offering examples from DOHMH's built environment work to guide LHDs, and building a healthy built environment learning network. We share lessons learned that can guide LHDs in developing successful healthy built environment agendas. PMID- 24625167 TI - Listening to community health workers: how ethnographic research can inform positive relationships among community health workers, health institutions, and communities. AB - Many actors in global health are concerned with improving community health worker (CHW) policy and practice to achieve universal health care. Ethnographic research can play an important role in providing information critical to the formation of effective CHW programs, by elucidating the life histories that shape CHWs' desires for alleviation of their own and others' economic and health challenges, and by addressing the working relationships that exist among CHWs, intended beneficiaries, and health officials. We briefly discuss ethnographic research with 3 groups of CHWs: volunteers involved in HIV/AIDS care and treatment support in Ethiopia and Mozambique and Lady Health Workers in Pakistan. We call for a broader application of ethnographic research to inform working relationships among CHWs, communities, and health institutions. PMID- 24625168 TI - Are Latino immigrants a burden to safety net services in nontraditional immigrant states? Lessons from Oregon. AB - The significant growth of the Latino population in the midst of an economic recession has invigorated anti-Latino, anti-immigrant sentiments in many US states. One common misconception is that Latino immigrants are a burden to safety net services. This may be particularly true in nontraditional immigrant states that have not historically served Latino immigrants. Oregon data suggest that despite a higher prevalence of poverty, use of safety net services among Latino immigrants in Oregon is lower than that among non-Latino Whites. Immigration status, costs, lack of insurance coverage, and discrimination are among the reasons for this group's limited use of services. Nevertheless, policies designed to strengthen community and institutional support for Latino immigrant families should be considered in the context of current health care and immigration reform efforts. PMID- 24625169 TI - A systematic review of the correlates of violence against sex workers. AB - We conducted a systematic review in June 2012 (updated September 2013) to examine the prevalence and factors shaping sexual or physical violence against sex workers globally. We identified 1536 (update = 340) unique articles. We included 28 studies, with 14 more contributing to violence prevalence estimates. Lifetime prevalence of any or combined workplace violence ranged from 45% to 75% and over the past year, 32% to 55%. Growing research links contextual factors with violence against sex workers, alongside known interpersonal and individual risks. This high burden of violence against sex workers globally and large gaps in epidemiological data support the need for research and structural interventions to better document and respond to the contextual factors shaping this violence. Measurement and methodological innovation, in partnership with sex work communities, are critical. PMID- 24625170 TI - Examination of a theoretical model for oral health-related quality of life among youths with cleft. AB - OBJECTIVES: We evaluated relationships among physical and psychological indicators and oral health-related quality of life (OHRQOL) in youths with cleft. METHODS: We recruited youths aged 7 to 18 years with cleft palate (n = 282) or cleft lip and palate (n = 918) and their caregivers into a 5-year observational investigation at 6 US treatment centers from 2009 to 2011. At baseline, youths completed surveys to assess psychological status. After clinical evaluation, 433 youths received a recommendation for surgery. We developed structural models from the baseline data incorporating age, gender, race, and cleft diagnosis to examine direct relationships between depressive symptoms and, in separate models, self concept and sense of mastery and OHRQOL. Subsequent models examined the possible mediating effect of surgical recommendation. RESULTS: Depressive symptoms were negatively and self-concept and self-efficacy were positively associated with OHRQOL. Surgical recommendation appeared to mediate the effect of psychological well-being, but not depression, on OHRQOL, even after adjustment for cleft diagnosis. In some models, individual-level characteristics were significant. CONCLUSIONS: Path analyses support the theoretical model and underscore the importance of examining positive psychosocial characteristics such as resiliency and self-concept in this patient population. PMID- 24625171 TI - The first concussion crisis: head injury and evidence in early American football. AB - In the early 21st century, sports concussion has become a prominent public health problem, popularly labeled "The Concussion Crisis." Football-related concussion contributes much of the epidemiological burden and inspires much of the public awareness. Though often cast as a recent phenomenon, the crisis in fact began more than a century ago, as concussions were identified among footballers in the game's first decades. This early concussion crisis subsided-allowing the problem to proliferate-because work was done by football's supporters to reshape public acceptance of risk. They appealed to an American culture that permitted violence, shifted attention to reforms addressing more visible injuries, and legitimized football within morally reputable institutions. Meanwhile, changing demands on the medical profession made practitioners reluctant to take a definitive stance. Drawing on scientific journals, public newspapers, and personal letters of players and coaches, this history of the early crisis raises critical questions about solutions being negotiated at present. PMID- 24625173 TI - Access to supermarkets and fruit and vegetable consumption. AB - OBJECTIVES: We examined whether supermarket choice, conceptualized as a proxy for underlying personal factors, would better predict access to supermarkets and fruit and vegetable consumption than mere physical proximity. METHODS: The Seattle Obesity Study geocoded respondents' home addresses and locations of their primary supermarkets. Primary supermarkets were stratified into low, medium, and high cost according to the market basket cost of 100 foods. Data on fruit and vegetable consumption were obtained during telephone surveys. Linear regressions examined associations between physical proximity to primary supermarkets, supermarket choice, and fruit and vegetable consumption. Descriptive analyses examined whether supermarket choice outweighed physical proximity among lower income and vulnerable groups. RESULTS: Only one third of the respondents shopped at their nearest supermarket for their primary food supply. Those who shopped at low-cost supermarkets were more likely to travel beyond their nearest supermarket. Fruit and vegetable consumption was not associated with physical distance but, with supermarket choice, after adjusting for covariates. CONCLUSIONS: Mere physical distance may not be the most salient variable to reflect access to supermarkets, particularly among those who shop by car. Studies on food environments need to focus beyond neighborhood geographic boundaries to capture actual food shopping behaviors. PMID- 24625172 TI - A systematic review of effective interventions for reducing multiple health risk behaviors in adolescence. AB - We systematically searched 9 biomedical and social science databases (1980-2012) for primary and secondary interventions that prevented or reduced 2 or more adolescent health risk behaviors (tobacco use, alcohol use, illicit drug use, risky sexual behavior, aggressive acts). We identified 44 randomized controlled trials of universal or selective interventions and were effective for multiple health risk behaviors. Most were school based, conducted in the United States, and effective for multiple forms of substance use. Effects were small, in line with findings for other universal prevention programs. In some studies, effects for more than 1 health risk behavior only emerged at long-term follow-up. Integrated prevention programs are feasible and effective and may be more efficient than discrete prevention strategies. PMID- 24625174 TI - Confronting the emerging epidemic of HCV infection among young injection drug users. AB - Hepatitis C virus infection is a significant public health problem in the United States and an important cause of morbidity and mortality. Recent reports document HCV infection increases among young injection drug users in several US regions, associated with America's prescription opioid abuse epidemic. Incident HCV infection increases among young injectors who have recently transitioned from oral opioid abuse present an important public health challenge requiring a comprehensive, community-based response. We summarize recommendations from a 2013 Office of HIV/AIDS and Infectious Disease Policy convening of experts in epidemiology, behavioral science, drug prevention and treatment, and other research; community service providers; and federal, state, and local government representatives. Their observations highlight gaps in our surveillance, program, and research portfolios and advocate a syndemic approach to this emerging public health problem. PMID- 24625175 TI - Association between social network communities and health behavior: an observational sociocentric network study of latrine ownership in rural India. AB - OBJECTIVES: We identified communities of interconnected people that might serve as normative reference groups for individual-level behavior related to latrine adoption. METHODS: We applied an algorithmic social network method to determine the network community from respondent-reported social ties of 16 403 individuals in 75 villages in rural Karnataka, India; data were collected from 2006 to 2008. We used multilevel modeling to test the association between latrine ownership and community-level and village-level latrine ownership. We also investigated the degree to which network cohesion affected individual latrine ownership. RESULTS: Three levels of social contacts (direct friends, social network community, and village) significantly predicted individual latrine ownership, but the strongest effect was found at the level of social network communities. In communities with high levels of network cohesion, the likelihood was decreased that any individual would own a latrine; this effect was significant only at lower levels of latrine ownership, suggesting a role for network cohesion in facilitating the nonownership norm. CONCLUSIONS: Although many international health and development interventions target village units, these results raise the possibility that the optimal target for public health interventions may not be determined through geography but through social network interactions. PMID- 24625176 TI - Neighborhood Contributions to Racial and Ethnic Disparities in Obesity Among New York City Adults. AB - Objectives. We assessed neighborhood confounding on racial/ethnic obesity disparities among adults in New York City after accounting for complex sampling, and how much neighborhood factors (walkability, percentage Black or Hispanic, poverty) contributed to this effect. Methods. We combined New York City Community Health Survey 2002-2004 data with Census 2000 zip code-level data. We estimated odds ratios (ORs) for obesity with 2 sets of regression analyses. First, we used the method incorporating the conditional pseudolikelihood into complex sample adjustment. Second, we compared ORs for race/ethnicity from a conventional multilevel model for each neighborhood factor with those from a hybrid fixed effect model. Results. The weighted estimate for obesity for Blacks versus Whites (OR = 1.8; 95% confidence interval = 1.6, 2.0) was attenuated when we controlled neighborhood confounding (OR = 1.4; 95% confidence interval = 1.2, 1.6; first analysis). Percentage of Blacks in the neighborhood made a large contribution whereas the walkability contribution was minimal (second analysis). Conclusions. Percentage of Blacks in New York City neighborhoods explained a large portion of the disparity in obesity between Blacks and Whites. The study highlights the importance of estimating valid neighborhood effects for public health surveillance and intervention. PMID- 24625177 TI - Strategic messaging to promote taxation of sugar-sweetened beverages: lessons from recent political campaigns. AB - OBJECTIVES: This study explored the use of strategic messaging by proponents of sugar-sweetened beverage (SSB) taxation to influence public opinion and shape the policy process, emphasizing the experiences in El Monte and Richmond, California, with SSB tax proposals in 2012. METHODS: We conducted 18 semistructured interviews with key stakeholders about the use and perceived effectiveness of messages supporting and opposing SSB taxation, knowledge sharing among advocates, message dissemination, and lessons learned from their messaging experiences. RESULTS: The protax messages most frequently mentioned by respondents were reinvesting tax revenue into health-related programs and linking SSB consumption to health outcomes such as obesity and diabetes. The most frequently mentioned antitax messages addressed negative economic effects on businesses and government restriction of personal choice. Factors contributing to perceived messaging success included clearly defining "sugar-sweetened beverage" and earmarking funds for obesity prevention, incorporating cultural sensitivity into messaging, and providing education about the health effects of SSB consumption. CONCLUSIONS: Sugar-sweetened beverage taxation has faced significant challenges in gaining political and public support. Future campaigns can benefit from insights gained through the experiences of stakeholders involved in previous policy debates. PMID- 24625179 TI - Huguet et al. respond. PMID- 24625178 TI - A social network-informed latent class analysis of patterns of substance use, sexual behavior, and mental health: Social Network Study III, Winnipeg, Manitoba, Canada. AB - OBJECTIVES: We assessed whether a meaningful set of latent risk profiles could be identified in an inner-city population through individual and network characteristics of substance use, sexual behaviors, and mental health status. METHODS: Data came from 600 participants in Social Network Study III, conducted in 2009 in Winnipeg, Manitoba, Canada. We used latent class analysis (LCA) to identify risk profiles and, with covariates, to identify predictors of class. RESULTS: A 4-class model of risk profiles fit the data best: (1) solitary users reported polydrug use at the individual level, but low probabilities of substance use or concurrent sexual partners with network members; (2) social-all-substance users reported polydrug use at the individual and network levels; (3) social noninjection drug users reported less likelihood of injection drug and solvent use; (4) low-risk users reported low probabilities across substances. Unstable housing, preadolescent substance use, age, and hepatitis C status predicted risk profiles. CONCLUSIONS: Incorporation of social network variables into LCA can distinguish important subgroups with varying patterns of risk behaviors that can lead to sexually transmitted and bloodborne infections. PMID- 24625180 TI - Bringing public health back into public health policy debates. PMID- 24625181 TI - Improving ethical knowledge and sensemaking from cases through elaborative interrogation and outcome valence. AB - The case-based approach to learning is popular among many applied fields. However, results of case-based education vary widely on case content and case presentation. This study examined two aspects of case-based education-outcome valence and case elaboration methods-in a two-day case-based Responsible Conduct of Research (RCR) ethics education program. Results suggest that outcome information is an integral part of a quality case. Furthermore, valence consistent outcomes may have certain advantages over mixed valence outcome information. Finally, students enjoy and excel working with case material, and the use of elaborative interrogation techniques can significantly improve internally-focused ethical sensemaking strategies associated with personal biases, constraints, and emotions. PMID- 24625182 TI - Perceptions of academic health science research center personnel regarding informed consent processes and therapeutic misconception. AB - INTRODUCTION: Instrumentation exists to measure voluntariness and misunderstanding in informed consent processes. However, research personnel's perspectives about using instrumentation to measure therapeutic misconceptions in research participants has not been reported. We designed a workshop to promote research personnel knowledge of emerging instrumentation and to study the perceptions of research personnel regarding such instruments. METHODS AND FINDINGS: Two nationally recognized experts who have developed psychometric instruments to measure aspects of informed consent presented their recent findings to research personnel of the Medical University of South Carolina at a one-day workshop. Following the presentations, workshop attendees divided into two focus groups and shared their perceptions regarding the presentation content. Inductive thematic analysis detected themes related to informed consent processes including: investigator/provider role clarity; investigator transparency; therapeutic misconception; and screening subjects for understanding. CONCLUSION: Our findings suggest future directions in applied, proactive empirical research to better understand investigator perceptions and practices related to transparency in research, and to develop instrumentation to detect risks to the integrity of informed consent in order to promote voluntariness and autonomy and minimize therapeutic misconception in research practices. PMID- 24625183 TI - Overcoming language barriers in the informed consent process: regulatory and compliance issues with the use of the "short form". AB - Language barriers in the informed consent process can be a significant impediment when recruiting non-English speaking subjects into clinical research studies. Regulatory guidelines indicate that the short form procedure be utilized in such circumstances. In this paper, we examine some of the ambiguities in the regulatory framework, the resulting need for institutional policy guidelines, and compliance issues with the short form process. PMID- 24625184 TI - Expanding the scope of responsible conduct of research instruction. AB - We argue that responsible conduct research (RCR) instruction should be extended beyond students and trainees funded by the National Institutes of Health (NIH) or National Science Foundation (NSF) to include all students, trainees, faculty, and research staff involved in research. Extending the scope of RCR instruction can help institutions develop and maintain an environment that promotes ethical research conduct. Universities and scientific organizations have objected to expanding the scope of RCR instruction on the grounds that it would be a major undertaking that would require the expenditure of additional institutional resources. We argue, however, that expanding the scope of RCR instruction can be done efficiently without placing undue burdens on institutions. PMID- 24625186 TI - 10th International Conference on Conservative Management of Spinal Deformities - SOSORT 2013 Annual Meeting. PMID- 24625185 TI - Letter to the editor: a commentary on "referees often miss obvious errors in computer and electronic publications" (de Gloucester, 2013). PMID- 24625187 TI - IMS study of climate, altitude, temperature and vasomotor symptoms in the United Arab Emirates. AB - OBJECTIVE: To examine the relationships between temperature, season (summer versus winter), lifestyle, health, mood, beliefs, and experience of hot flushes and night sweats (HFNS), amongst mid-aged women living in the United Arab Emirates (UAE). METHODS: The UAE climate is hyper-arid, being a hot desert climate, with warm winters and hot summers. A total of 372 peri- and postmenopausal women, aged from 45 to 55 years, from urban UAE regions were included. Data were collected during both summer and winter months. Participants completed questionnaires eliciting information about sociodemographics, HFNS (prevalence, frequency and problem-rating), health and lifestyle (body mass index (BMI), diet, exercise), mood (Women's Health Questionnaire) and menopause attributions and beliefs (Menopause Representations Questionnaire). RESULTS: HFNS were currently being experienced by 46.5% of women, with an average weekly frequency of five and problem-rating of 5.7/10. Seasonal variation in temperature was not associated with prevalence, frequency or problem-rating. Hot flush prevalence was associated with poor health, life satisfaction, mood, employment, lower BMI and diet. Higher frequency was associated with higher BMI and more years since the last period. HFNS were more problematic mainly for women who reported lower life satisfaction and held more negative beliefs about the menopause. CONCLUSIONS: In this UAE study, temperature and seasonal temperature variation did not appear to influence HFNS-reporting, but health, life satisfaction, BMI, beliefs and lifestyle factors partially explained women's experiences of menopausal symptoms. A qualitative study might provide further information about the meanings of HFNS and menopause amongst UAE women. PMID- 24625188 TI - Alcohol and associated characteristics among older persons living with human immunodeficiency virus on antiretroviral therapy. AB - BACKGROUND: Alcohol use, and particularly unhealthy alcohol use, is associated with poor human immunodeficiency virus (HIV)-related outcomes among persons living with HIV (PLWH). Despite a rapidly growing proportion of PLWH >=50 years, alcohol use and its associated characteristics are underdescribed in this population. The authors describe alcohol use, severity, and associated characteristics using data from a sample of PLWH >=50 years who participated in a trial of a telephone-based intervention to improve adherence to antiretroviral therapy (ART). METHODS: Participants were recruited from acquired immunodeficiency syndrome (AIDS) service organizations in 9 states and included PLWH >=50 years who were prescribed ART, reported suboptimal adherence at screening (missing >1.5 days of medication or taking medications 2 hours early or late on >3 days in the 30 days prior to screening), and consented to participate. The AUDIT-C (Alcohol Use Disorders Identification Test-Consumption) alcohol screen, sociodemographic characteristics, substance use, and mental health comorbidity were assessed at baseline. AUDIT-C scores were categorized into nondrinking, low-level drinking, and mild-moderate unhealthy, and severe unhealthy drinking (0, 1-3, 4-6, and 7-12, respectively). Analyses described and compared characteristics across drinking status (any/none) and across AUDIT-C categories among drinkers. RESULTS: Among 447 participants, 57% reported drinking in the past year (35%, 15%, and 7% reported low-level drinking, mild-moderate unhealthy drinking, and severe unhealthy drinking, respectively). Any drinking was most common among men and those who were lesbian, gay, bisexual, or transgender (LGBT), married/partnered, had received past-year alcohol treatment, and never used injection drugs (P values all <.05). Differences in race, employment status, past-year alcohol treatment, and positive depression screening (P values all <.05) were observed across AUDIT-C categories, with African American race, less than full-time employment, past-year alcohol treatment, and positive depression screening being most common among those with the most severe unhealthy drinking. CONCLUSIONS: In this sample of older PLWH with suboptimal ART adherence, a majority reported past-year alcohol use and 22% screened positive for unhealthy alcohol use. Any and unhealthy alcohol use were associated with demographics, depression, and substance use history. Further research is needed regarding alcohol use among older PLWH. PMID- 24625190 TI - Biosynthesis of mupirocin by Pseudomonas fluorescens NCIMB 10586 involves parallel pathways. AB - Mupirocin, a clinically important antibiotic produced via a trans-AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens, consists of a mixture of mainly pseudomonic acids A, B, and C. Detailed metabolic profiling of mutant strains produced by systematic inactivation of PKS and tailoring genes, along with re-feeding of isolated metabolites to mutant stains, has allowed the isolation of a large number of novel metabolites, identification of the 10,11 epoxidase, and full characterization of the mupirocin biosynthetic pathway, which proceeds via major (10,11-epoxide) and minor (10,11-alkene) parallel pathways. PMID- 24625189 TI - Born too soon: care before and between pregnancy to prevent preterm births: from evidence to action. AB - Providing care to adolescent girls and women before and between pregnancies improves their own health and wellbeing, as well as pregnancy and newborn outcomes, and can also reduce the rates of preterm birth. This paper has reviewed the evidence-based interventions and services for preventing preterm births, reported the findings from research priority exercise, and prescribed actions for taking this call further. Certain factors in the preconception period have been shown to increase the risk for prematurity and, therefore, preconception care services for all women of reproductive age should address these risk factors through preventing adolescent pregnancy, preventing unintended pregnancies, promoting optimal birth spacing, optimizing pre-pregnancy weight and nutritional status (including a folic acid-containing multivitamin supplement) and ensuring that all adolescent girls have received complete vaccination. Preconception care must also address risk factors that may be applicable to only some women. These include screening for and management of chronic diseases, especially diabetes; sexually-transmitted infections; tobacco and smoke exposure; mental health disorders, notably depression; and intimate partner violence. The approach to research in preconception care to prevent preterm births should include a cycle of development and delivery research that evaluates how best to scale up coverage of existing evidence-based interventions, epidemiologic research that assesses the impact of implementing these interventions and discovery science that better elucidates the complex causal pathway of preterm birth and helps to develop new screening and intervention tools. In addition to research, policy and financial investment is crucial to increasing opportunities to implement preconception care, and rates of prematurity should be included as a tracking indicator in global and national maternal child health assessments. PMID- 24625191 TI - Basing information on comprehensive, critically appraised, and up-to-date syntheses of the scientific evidence: a quality dimension of the International Patient Decision Aid Standards. AB - BACKGROUND: Patients and clinicians expect patient decision aids to be based on the best available research evidence. Since 2005, this expectation has translated into a quality dimension of the International Patient Decision Aid Standards. METHODS: We reviewed the 2005 standards and the available literature on the evidence base of decision aids as well as searched for parallel activities in which evidence is brought to bear to inform clinical decisions. In conducting this work, we noted emerging and research issues that require attention and may inform this quality dimension in the future. RESULTS: This dimension requires patient decision aids to be based on research evidence about the relevant options and the nature and likelihood of their effect on outcomes that matter to patients. The synthesis of evidence should be comprehensive and up-to-date, and the evidence itself subject to critical appraisal. Ethical (informed patient choice), quality-of-care (patient-centered care), and scientific (evidence-based medicine) arguments justify this requirement. Empirical evidence suggests that over two thirds of available decision aids are based on high-quality evidence syntheses. Emerging issues identified include the duties of developers regarding the conduct of systematic reviews, the impact of comparative effectiveness research, their link with guidelines based on the same evidence, and how to present the developers' confidence in the estimates to the end-users. Systematic application of the GRADE system, common in contemporary practice guideline development, could enhance satisfaction of this dimension. CONCLUSIONS: While theoretical and practical issues remained to be addressed, high-quality patient decision aids should adhere to this dimension requiring they be based on comprehensive and up-to-date summaries of critically appraised evidence. PMID- 24625194 TI - Co-transport of polycyclic aromatic hydrocarbons by motile microorganisms leads to enhanced mass transfer under diffusive conditions. AB - The environmental chemodynamics of hydrophobic organic chemicals (HOCs) are often rate-limited by diffusion in stagnant boundary layers. This study investigated whether motile microorganisms can act as microbial carriers that enhance mass transfer of HOCs through diffusive boundary layers. A new experimental system was developed that allows (1) generation of concentration gradients of HOCs under the microscope, (2) exposure and direct observation of microorganisms in such gradients, and (3) quantification of HOC mass transfer. Silicone O-rings were integrated into a Dunn chemotaxis chamber to serve as sink and source for polycyclic aromatic hydrocarbons (PAHs). This resulted in stable concentration gradients in water (>24 h). Adding the model organism Tetrahymena pyriformis to the experimental system enhanced PAH mass transfer up to hundred-fold (benzo[a]pyrene). Increasing mass transfer enhancement with hydrophobicity indicated PAH co-transport with the motile organisms. Fluorescence microscopy confirmed such transport. The effective diffusivity of T. pyriformis, determined by video imaging microscopy, was found to exceed molecular diffusivities of the PAHs up to four-fold. Cell-bound PAH fractions were determined to range from 28% (naphthalene) to 92% (pyrene). Motile microorganisms can therefore function as effective carriers for HOCs under diffusive conditions and might significantly enhance mobility and availability of HOCs. PMID- 24625193 TI - Safety in numbers: multiple occurrences of highly similar homologs among Azotobacter vinelandii carbohydrate metabolism proteins probably confer adaptive benefits. AB - BACKGROUND: Gene duplication and horizontal gene transfer are common processes in bacterial and archaeal genomes, and are generally assumed to result in either diversification or loss of the redundant gene copies. However, a recent analysis of the genome of the soil bacterium Azotobacter vinelandii DJ revealed an abundance of highly similar homologs among carbohydrate metabolism genes. In many cases these multiple genes did not appear to be the result of recent duplications, or to function only as a means of stimulating expression by increasing gene dosage, as the homologs were located in varying functional genetic contexts. Based on these initial findings we here report in-depth bioinformatic analyses focusing specifically on highly similar intra-genome homologs, or synologs, among carbohydrate metabolism genes, as well as an analysis of the general occurrence of very similar synologs in prokaryotes. RESULTS: Approximately 900 bacterial and archaeal genomes were analysed for the occurrence of synologs, both in general and among carbohydrate metabolism genes specifically. This showed that large numbers of highly similar synologs among carbohydrate metabolism genes are very rare in bacterial and archaeal genomes, and that the A. vinelandii DJ genome contains an unusually large amount of such synologs. The majority of these synologs were found to be non-tandemly organized and localized in varying but metabolically relevant genomic contexts. The same observation was made for other genomes harbouring high levels of such synologs. It was also shown that highly similar synologs generally constitute a very small fraction of the protein-coding genes in prokaryotic genomes. The overall synolog fraction of the A. vinelandii DJ genome was well above the data set average, but not nearly as remarkable as the levels observed when only carbohydrate metabolism synologs were considered. CONCLUSIONS: Large numbers of highly similar synologs are rare in bacterial and archaeal genomes, both in general and among carbohydrate metabolism genes. However, A. vinelandii and several other soil bacteria harbour large numbers of highly similar carbohydrate metabolism synologs which seem not to result from recent duplication or transfer events. These genes may confer adaptive benefits with respect to certain lifestyles and environmental factors, most likely due to increased regulatory flexibility and/or increased gene dosage. PMID- 24625195 TI - Variant-beta luteinizing hormone is not associated with poor ovarian response to controlled ovarian hyperstimulation. AB - BACKGROUND: The most common genetic variant of luteinizing hormone (LH), variant betaLH, has a different bioactivity than the wildtype. Carrying the variant allele was associated with an increased consumption of exogenous gonadotropin to achieve optimal ovarian response for in vitro fertilization procedures (IVF). The aim of this study was to examine if variant-betaLH was also more common in patients with a poor ovarian response to exogenous gonadotropin which negatively influenced treatment outcome. FINDINGS: 36 patients with poor ovarian response to ovarian stimulation for IVF and 98 controls with a normal response were genotyped for variant-betaLH using DNA sequencing. The carrier frequency in the control group was 17%. No association was found between poor ovarian response and variant betaLH. CONCLUSIONS: Testing patients for variant-betaLH prior to IVF is unlikely to predict poor ovarian response. PMID- 24625196 TI - Perceptions of collaboration between general practitioners and community pharmacists: findings from a qualitative study based in Spain. AB - According to the theory of reasoned action (TRA), collaboration is only possible when it is perceived as useful by the participants involved. This paper describes a qualitative study using semi-structured interviews to explore the preceived usefulness of general practitioner (GPs)-community pharmacists (CPs)' collaboration from these professionals' perspectives based in two Spanish regions. Thirty-seven interviews were conducted with GPs and CPs with and without previous experience of collaborating with the other groups of professionals. Analysis of the data indicated that the GPs and CPs considered that collaboration between practitioners and pharmacists to have different forms of usefulness, ranging from positive to negative perceptions of usefulness. Negative and neutral opinions (collaboration generates conflict and/or is not benefitial) could prevent practitioners from initiating collaboration with the other group of professionals, which is explained by the TRA. These perceptions were only found among those participants without experience in collaboration. When collaboration was perceived as advantageous, it could be beneficial on three levels: health system (i.e. provision of integrated care, increased efficiency of the system), GPs and CPs (i.e. increased job satisfaction and patient loyalty) and patients (i.e. improved patient safety). Although GPs and CPs with experience identified benefits using a range of examples, GPs and CPs who had never collaborated also believed that if collaboration was undertaken there would be benefits for the health system, patients and health professionals. These results should be considered when developing strategies to encourage and improve the implementation of collaborative working relationships between GPs and pharmacists in primary care. PMID- 24625197 TI - The development and validation of an interprofessional scale to assess teamwork in mental health settings. AB - Currently, no evaluative scale exists to assess the quality of interprofessional teamwork in mental health settings across the globe. As a result, little is known about the detailed process of team development within this setting. The purpose of this study is to develop and validate a global interprofessional scale that assesses teamwork in mental health settings using an international comparative study based in Japan and the United States. This report provides a description of this study and reports progress made to date. Specifically, it outlines work on literature reviews to identify evaluative teamwork tools as well as identify relevant teamwork models and theories. It also outlines plans for empirical work that will be undertaken in both Japan and the United States. PMID- 24625198 TI - Barriers and enablers that influence sustainable interprofessional education: a literature review. AB - The effective incorporation of interprofessional education (IPE) within health professional curricula requires the synchronised and systematic collaboration between and within the various stakeholders. Higher education institutions, as primary health education providers, have the capacity to advocate and facilitate this collaboration. However, due to the diversity of stakeholders, facilitating the pedagogical change can be challenging and complex, and brings a degree of uncertainty and resistance. This review, through an analysis of the barriers and enablers investigates the involvement of stakeholders in higher education IPE through three primary stakeholder levels: Government and Professional, Institutional and Individual. A review of eight primary databases using 21 search terms resulted in 40 papers for review. While the barriers to IPE are widely reported within the higher education IPE literature, little is documented about the enablers of IPE. Similarly, the specific identification and importance of enablers for IPE sustainability and the dual nature of some barriers and enablers have not been previously reported. An analysis of the barriers and enablers of IPE across the different stakeholder levels reveals five key "fundamental elements" critical to achieving sustainable IPE in higher education curricula. PMID- 24625199 TI - Sex differences in benzodiazepine use in the HIV-infected population. AB - In the HIV-infected population there is a high prevalence of psychiatric disorders, conditions that often coexist with drug and alcohol dependence. Symptoms associated with psychiatric disorders are frequently managed with benzodiazepines, a class of medication often abused. We examined whether HIV infected patients were more likely to fill a benzodiazepine prescription than their uninfected counterparts using a privately insured, nationally representative sample receiving clinical care between January 2007 and December 2009. Odds ratios (OR) and 95% confidence intervals (CI) to quantify the likelihood of receiving a benzodiazepine were calculated using multivariate logistic regression models. We examined the presence of interaction between HIV infection and sex using backwards elimination and by comparing stratum-specific OR to identify clinically meaningful differences. Overall, 323,796 beneficiaries were included in the sample, of which 723 were HIV infected. Bivariate analyses showed that compared to the uninfected sample, HIV-infected patients were more likely to have filled a benzodiazepine prescription (24% vs. 19%) during the study period. HIV-infected patients were also more likely to be male (80% vs. 44%), black (21% vs. 7%) and have a diagnosis of depression (12% vs. 8%) or insomnia (6% vs. 3%) than were uninfected patients. Adjusted for other covariates, HIV infection was associated with an increase (OR): 1.68, 95% CI: 1.39, 2.02) in the likelihood of filling a benzodiazepine prescription. When stratified by sex, HIV-infected males were more likely (OR: 1.68, 95% CI: 1.05, 2.67) than uninfected males to fill a benzodiazepine prescription while there was no observed difference in the likelihood of filling a benzodiazepine prescription between HIV-infected and uninfected females (OR: 1.12, 95% CI: 0.73, 1.70). Our findings suggest that HIV-infected patients, particularly HIV-infected males, are more likely to fill benzodiazepine prescriptions than their uninfected counterparts, highlighting the need for further research to investigate reasons for these observed differences. PMID- 24625200 TI - Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. AB - RATIONALE: Chronic infection with Pseudomonas aeruginosa is associated with an increased exacerbation frequency, a more rapid decline in lung function, and increased mortality in patients with bronchiectasis. OBJECTIVES: To perform a randomized placebo-controlled study assessing the efficacy and safety of inhaled colistin in patients with bronchiectasis and chronic P. aeruginosa infection. METHODS: Patients with bronchiectasis and chronic P. aeruginosa infection were enrolled within 21 days of completing a course of antipseudomonal antibiotics for an exacerbation. Participants were randomized to receive colistin (1 million IU; n = 73) or placebo (0.45% saline; n = 71) via the I-neb twice a day, for up to 6 months. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time to exacerbation. Secondary endpoints included time to exacerbation based on adherence recorded by the I-neb, P. aeruginosa bacterial density, quality of life, and safety parameters. All analyses were on the intention-to-treat population. Median time (25% quartile) to exacerbation was 165 (42) versus 111 (52) days in the colistin and placebo groups, respectively (P = 0.11). In adherent patients (adherence quartiles 2-4), the median time to exacerbation was 168 (65) versus 103 (37) days in the colistin and placebo groups, respectively (P = 0.038). P. aeruginosa density was reduced after 4 (P = 0.001) and 12 weeks (P = 0.008) and the St. George's Respiratory Questionnaire total score was improved after 26 weeks (P = 0.006) in the colistin versus placebo patients, respectively. There were no safety concerns. CONCLUSIONS: Although the primary endpoint was not reached, this study shows that inhaled colistin is a safe and effective treatment in adherent patients with bronchiectasis and chronic P. aeruginosa infection. Clinical trial registered with http://www.isrctn.org/ (ISRCTN49790596). PMID- 24625201 TI - The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. AB - BACKGROUND: Epilepsy has long been considered to be a risk factor for psychosis. However there is a lack of consistency in findings across studies on the effect size of this risk which reflects methodological differences in studies and changing diagnostic classifications within neurology and psychiatry. The aim of this study was to assess the prevalence of psychosis in epilepsy and to estimate the risk of psychosis among individuals with epilepsy compared with controls. METHODS: A systematic review and meta-analysis was conducted of all published literature pertaining to prevalence rates of psychosis in epilepsy using electronic databases PUBMED, OVIDMEDLINE, PsychINFO and Embase from their inception until September 2010 with the following search terms: prevalence, incidence, rate, rates, psychosis, schizophrenia, schizophreniform illness, epilepsy, seizures, temporal lobe epilepsy. RESULTS: The literature search and search of reference lists yielded 215 papers. Of these, 58 (27%) had data relevant to the review and 157 were excluded following a more detailed assessment. 10% of the included studies were population based studies. The pooled odds ratio for risk of psychosis among people with epilepsy compared with controls was 7.8. The pooled estimate of prevalence of psychosis in epilepsy was found to be 5.6% (95% CI: 4.8-6.4). There was a high level of heterogeneity. The prevalence of psychosis in temporal lobe epilepsy was 7% (95% CI: 4.9-9.1). The prevalence of interictal psychosis in epilepsy was 5.2% (95% CI: 3.3-7.2). The prevalence of postictal psychosis in epilepsy was 2% (95% CI: 1.2-2.8). CONCLUSIONS: Our systematic review found that up to 6% of individuals with epilepsy have a co-morbid psychotic illness and that patients have an almost eight fold increased risk of psychosis. The prevalence rate of psychosis is higher in temporal lobe epilepsy (7%). We suggest that further investigation of this association could give clues to the aetiology of psychosis. PMID- 24625202 TI - Structural characterization and antioxidant activity of a heteropolysaccharide isolated from Hedysarum polybotrys. AB - A water-soluble polysaccharide (HPS3aS) with a molecular mass of 1.22 * 10(4) Da was isolated from Hedysarum polybotrys using anion-exchange and gel-permeation chromatography. HPS3aS exhibits a globular-shaped conformation in 0.1 M NaNO3 by size exclusion chromatography with multi-angle laser light scattering (SEC MALLS). The investigation of the structural features of this heteropolysaccharide through a combination of chemical and instrumental analyses revealed that the backbone of HPS3aS is composed of alpha-D-(1 -> 4)-linked glucopyranose residues, which occasionally branched at O-6. The branches are composed of (1 -> 4)-linked galactopyranose residues and terminated with glucopyranose residues. HPS3aS possesses good in vitro antioxidant activity, as evaluated by scavenging assays with 1,1-diphenyl-2-picrylhydrazyl, hydroxyl, and superoxide radicals, which suggests that HPS3aS could be a potential antioxidant. PMID- 24625203 TI - Predicting menopausal age with anti-Mullerian hormone: a cross-validation study of two existing models. AB - OBJECTIVE: This study aimed to cross-validate two comparable Weibull models of prediction of age at natural menopause from two cohorts, the Scheffer, van Rooij, de Vet (SRV) cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. It summarizes advantages and disadvantages of the models and underlines the need for achieving correct time dependency in dynamic variables like anti-Mullerian hormone. METHODS: Models were fitted in the original datasets and then applied to the cross-validation datasets. The discriminatory capacity of each model was assessed by calculating C-statistics for the models in their own data and in the cross-validation data. Calibration of the models on the cross-validation data was assessed by measuring the slope, intercept and Weibull shape parameter. RESULTS: The C-statistic for the SRV model on the SRV data was 0.7 (95% confidence interval (CI) 0.7-0.8) and on the TLGS data it was 0.8 (95% CI 0.8-0.9). For the TLGS model on the TLGS data, it was 0.9 (95% CI 0.8-0.9) and on the SRV data it was 0.7 (95% CI 0.6-0.8). After calibration of the SRV model on the TLGS data, the slope was 1, the intercept -0.3 and the shape parameter 1.1. The TLGS model on the SRV data had a slope of 0.3, an intercept of 12.7 and a shape parameter of 0.6. CONCLUSIONS: Both models discriminate well between women that enter menopause early or late during follow-up. While the SRV model showed good agreement between the predicted risk of entering menopause and the observed proportion of women who entered menopause during follow-up (calibration) in the cross-validation dataset, the TLGS model showed poor calibration. PMID- 24625204 TI - Glycan-functionalized fluorescent chitin nanocrystals for biorecognition applications. AB - A new platform based on chitin nanocrystals has been developed for biorecognition applications. TEMPO-oxidized chitin nanocrystals (TCNs) were labeled with a fluorescent imidazoisoquinolinone dye, and simultaneously conjugated with carbohydrate ligands, resulting in dually functionalized TCNs. The biorecognition properties of the nanocrystals were probed with lectins and bacteria, resulting in selective interactions with their corresponding cognate carbohydrate-binding proteins, as visualized by optical, fluorescence, STEM, and TEM imaging. This represents a new approach to multifunctional nanomaterials based on naturally occurring polymers, holding high potential for biomedical applications. PMID- 24625205 TI - Lysine methylation mapping of crenarchaeal DNA-directed RNA polymerases by collision-induced and electron-transfer dissociation mass spectrometry. AB - Enzymatic machineries fundamental for information processing (e.g., transcription, replication, translation) in Archaea are simplified versions of their eukaryotic counterparts. This is clearly noticeable in the conservation of sequence and structure of corresponding enzymes (see for example the archaeal DNA directed RNA polymerase (RNAP)). In Eukarya, post-translational modifications (PTMs) often serve as functional regulatory factors for various enzymes and complexes. Among the various PTMs, methylation and acetylation have been recently attracting most attention. Nevertheless, little is known about such PTMs in Archaea, and cross-methodological studies are scarce. We examined methylation and N-terminal acetylation of endogenously purified crenarchaeal RNA polymerase from Sulfolobus shibatae (Ssh) and Sulfolobus acidocaldarius (Sac). In-gel and in solution protein digestion methods were combined with collision-induced dissociation (CID) and electron-transfer dissociation (ETD) mass spectrometry analysis. Overall, 20 and 26 methyl-lysines for S. shibatae and S. acidocaldarius were identified, respectively. Furthermore, two N-terminal acetylation sites for each of these organisms were assessed. As a result, we generated a high confidence data set for the mapping of methylation and acetylation sites in both Sulfolobus species, allowing comparisons with the data previously obtained for RNAP from Sulfolobus solfataricus (Sso). We confirmed that all observed methyl lysines are on the surface of the RNAP. PMID- 24625206 TI - Functional comparison of human-induced pluripotent stem cell-derived mesenchymal cells and bone marrow-derived mesenchymal stromal cells from the same donor. AB - Mesenchymal stem cells (MSCs) have a high potential for therapeutic efficacy in treating diverse musculoskeletal injuries and cardiovascular diseases, and for ameliorating the severity of graft-versus-host and autoimmune diseases. While most of these clinical applications require substantial cell quantities, the number of MSCs that can be obtained initially from a single donor is limited. Reports on the derivation of MSC-like cells from pluripotent stem cells (PSCs) are, thus, of interest, as the infinite proliferative capacity of PSCs opens the possibility to generate large amounts of uniform batches of MSCs. However, characterization of such MSC-like cells is currently inadequate, especially with regard to the question of whether these cells are equivalent or identical to MSCs. In this study, we have derived MSC-like cells [induced PSC-derived MSC-like progenitor cells (iMPCs)] using four different methodologies from a newly established induced PSC line reprogrammed from human bone marrow stromal cells (BMSCs), and compared the iMPCs directly with the originating parental BMSCs. The iMPCs exhibited typical MSC/fibroblastic morphology and MSC-typical surface marker profile, and they were capable of differentiation in vitro along the osteogenic, chondrogenic, and adipogenic lineages. However, compared with the parental BMSCs, iMPCs displayed a unique expression pattern of mesenchymal and pluripotency genes and were less responsive to traditional BMSC differentiation protocols. We, therefore, conclude that iMPCs generated from PSCs via spontaneous differentiation represent a distinct population of cells which exhibit MSC-like characteristics. PMID- 24625208 TI - The impact of incorporating Bayesian network meta-analysis in cost-effectiveness analysis - a case study of pharmacotherapies for moderate to severe COPD. AB - OBJECTIVE: To evaluate the impact of using network meta-analysis (NMA) versus pair wise meta-analyses (PMA) for evidence synthesis on key outputs of cost effectiveness analysis (CEA). METHODS: We conducted Bayesian NMA of randomized clinical trials providing head-to-head and placebo comparisons of the effect of pharmacotherapies on the exacerbation rate in chronic obstructive pulmonary disease (COPD). Separately, the subset of placebo-comparison trials was used in a Bayesian PMA. The pooled rate ratios (RR) were used to populate a decision analytic model of COPD treatment to predict 10-year outcomes. RESULTS: Efficacy estimates from the NMA and PMA were similar, but the NMA provided estimates with higher precision. This resulted in similar incremental cost-effectiveness ratios (ICER). Probabilities of being cost-effective at willingness-to-pay thresholds (WTPs) between $25,000 and $100,000 per quality adjusted life year (QALY) varied considerably between the PMA- and NMA-based approaches. The largest difference in the probabilities of being cost-effective was observed at a WTP of approximately $40,000/QALY. At this threshold, with the PMA-based analysis, ICS, LAMA and placebo had a 43%, 30, and 18% probability of being the most cost-effective. By contrast, with the NMA based approach, ICS, LAMA, and placebo had a 56%, 19%, and 21% probability of being cost-effective. For larger WTP thresholds the probability of LAMA being the most cost-effective became higher than that of ICS. Under the PMA-based analyses the cross-over occurred at a WTP threshold between $60,000/QALY-$65,000/QALY, whereas under the NMA-based approach, the cross-over occurred between $85,000/QALY-$90,000/QALY. CONCLUSION: Use of NMAs in CEAs is feasible and, as our case study showed, can decrease uncertainty around key cost effectiveness measures compared with the use of PMAs. The approval process of health technologies in many jurisdictions requires estimates of comparative efficacy and cost-effectiveness. NMAs play an increasingly important role in providing estimates of comparative efficacy. Their use in the CEAs therefore results in methodological consistency and reduced uncertainty. PMID- 24625207 TI - Pre-radiotherapy FDG PET predicts radiation pneumonitis in lung cancer. AB - BACKGROUND: A retrospective analysis is performed to determine if pre-treatment [18 F]-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) image derived parameters can predict radiation pneumonitis (RP) clinical symptoms in lung cancer patients. METHODS AND MATERIALS: We retrospectively studied 100 non-small cell lung cancer (NSCLC) patients who underwent FDG PET/CT imaging before initiation of radiotherapy (RT). Pneumonitis symptoms were evaluated using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) from the consensus of 5 clinicians. Using the cumulative distribution of pre-treatment standard uptake values (SUV) within the lungs, the 80th to 95th percentile SUV values (SUV(80) to SUV(95) were determined. The effect of pre-RT FDG uptake, dose, patient and treatment characteristics on pulmonary toxicity was studied using multiple logistic regression. RESULTS: The study subjects were treated with 3D conformal RT (n=23), intensity modulated RT (n=64), and proton therapy (n=13). Multiple logistic regression analysis demonstrated that elevated pre-RT lung FDG uptake on staging FDG PET was related to development of RP symptoms after RT. A patient of average age and V(30) with SUV(95)=1.5 was an estimated 6.9 times more likely to develop grade >= 2 radiation pneumonitis when compared to a patient with SUV(95)=0.5 of the same age and identical V(30). Receiver operating characteristic curve analysis showed the area under the curve was 0.78 (95% CI=0.69 - 0.87). The CT imaging and dosimetry parameters were found to be poor predictors of RP symptoms. CONCLUSIONS: The pretreatment pulmonary FDG uptake, as quantified by the SUV(95), predicted symptoms of RP in this study. Elevation in this pre-treatment biomarker identifies a patient group at high risk for post-treatment symptomatic RP. PMID- 24625209 TI - Evidence of translocation and physiological impacts of foliar applied CeO2 nanoparticles on cucumber (Cucumis sativus) plants. AB - Currently, most of the nanotoxicity studies in plants involve exposure to the nanoparticles (NPs) through the roots. However, plants interact with atmospheric NPs through the leaves, and our knowledge on their response to this contact is limited. In this study, hydroponically grown cucumber (Cucumis sativus) plants were aerially treated either with nano ceria powder (nCeO2) at 0.98 and 2.94 g/m(3) or suspensions at 20, 40, 80, 160, and 320 mg/L. Fifteen days after treatment, plants were analyzed for Ce uptake by using ICP-OES and TEM. In addition, the activity of three stress enzymes was measured. The ICP-OES results showed Ce in all tissues of the CeO2 NP treated plants, suggesting uptake through the leaves and translocation to the other plant parts. The TEM results showed the presence of Ce in roots, which corroborates the ICP-OES results. The biochemical assays showed that catalase activity increased in roots and ascorbate peroxidase activity decreased in leaves. Our findings show that atmospheric NPs can be taken up and distributed within plant tissues, which could represent a threat for environmental and human health. PMID- 24625210 TI - Absorption and metabolism of piceatannol in rats. AB - Piceatannol (trans-3,3',4,5'-tetrahydroxystilbene), a natural analogue of resveratrol, has multiple biological functions. Nevertheless, piceatannol's biological fate is yet to be determined. In this study, we evaluated the absorption and metabolism of piceatannol in rats. Furthermore, the area under the plasma concentration curves (AUC) and metabolic pathway of piceatannol were compared with those of resveratrol. We determined the plasma concentrations of piceatannol, resveratrol, and their respective metabolites following their intragastric administration. Resveratrol metabolites were only conjugates, whereas piceatannol metabolites were piceatannol conjugates, O-methyl piceatannol, and its conjugates. The AUC for piceatannol, resveratrol, and their metabolites increased in a dose-dependent manner (90-360 MUmol/kg). The AUC for total piceatannol was less than that for total resveratrol, whereas the AUC for piceatannol (8.6 MUmol.h/L) after piceatannol and resveratrol coadministration was 2.1 times greater than that for resveratrol (4.1 MUmol.h/L). The greater AUC for piceatannol was a result of its higher metabolic stability. PMID- 24625211 TI - Retro-orbital blood acquisition facilitates circulating microRNA measurement in zebrafish with paracetamol hepatotoxicity. AB - Paracetamol is the commonest cause of acute liver failure in the Western world and biomarkers are needed that report early hepatotoxicity. The liver-enriched microRNA (miRNA), miR-122, is a promising biomarker currently being qualified in humans. For biomarker development and drug toxicity screening, the zebrafish has advantages over rodents; however, blood acquisition in this model remains technically challenging. We developed a method for collecting blood from the adult zebrafish by retro-orbital (RO) bleeding and compared it to the commonly used lateral incision method. The RO technique was more reliable in terms of the blood yield and minimum amount per fish. This new RO technique was used in a zebrafish model of paracetamol toxicity. Paracetamol induced dose-dependent increases in liver cell necrosis, serum alanine transaminase activity, and mortality. In situ hybridization localized expression of miR-122 to the cytoplasm of zebrafish hepatocytes. After collection by RO bleeding, serum miR-122 could be measured and this miRNA was substantially increased by paracetamol 24 h after exposure, an increase that was prevented by delayed (3 h poststart of paracetamol exposure) treatment with acetylcysteine. In summary, collection of blood by RO bleeding facilitated measurement of miR-122 in a zebrafish model of paracetamol hepatotoxicity. The zebrafish represents a new species for measurement of circulating miRNA biomarkers that are translational and can bridge between fish and humans. PMID- 24625212 TI - Screening, detection and management of delirium in the emergency department - a pilot study on the feasibility of a new algorithm for use in older emergency department patients: the modified Confusion Assessment Method for the Emergency Department (mCAM-ED). AB - BACKGROUND: Delirium in emergency department (ED) patients occurs frequently and often remains unrecognized. Most instruments for delirium detection are complex and therefore unfeasible for the ED. The aims of this pilot study were first, to confirm our hypothesis that there is an unmet need for formal delirium assessment by comparing informal delirium ratings of ED staff with formal delirium assessments performed by trained research assistants. Second, to test the feasibility of an algorithm for delirium screening, detection and management, which includes the newly developed modified Confusion Assessment Method for the Emergency Department (mCAM-ED) at the ED bedside. Third, to test interrater reliability of the mCAM-ED. METHODS: This was a pilot study with a pre-post-test design with two data collection periods before and after the implementation of the algorithm. Consecutive ED patients aged 65 years and older were screened and assessed in the ED of a tertiary care center by trained research assistants. The delirium detection rate of informal ratings by nurses and physicians was compared with the standardized mCAM-ED assessment performed by the research assistants. To show the feasibility at the ED bedside, defined as adherence of ED staff to the algorithm, only post-test data were used. Additionally, the ED nurses' assessments were analyzed qualitatively. To investigate the agreement between research assistants and the reference standard, the two data sets were combined. RESULTS: In total, 207 patients were included in this study. We found that informal delirium assessment was inappropriate, even after a teaching intervention: Sensitivity of nurses to detect delirium without formal assessment was 0.27 pretest and 0.40 post-test, whilst sensitivity of physicians' informal rating was 0.45 pre-test and 0.6 post-test. ED staff demonstrated high adherence to the algorithm (76.5%). Research assistants assessing delirium with the mCAM-ED demonstrated a high agreement compared to the reference standard (kappa = 0.729). CONCLUSIONS: Informal assessment of delirium is inadequate. The mCAM-ED proved to be useful at the ED bedside. Performance criteria need to be tested in further studies. The mCAM-ED may contribute to early identification of delirious ED patients. PMID- 24625213 TI - Normative Data for the Neurobehavioral Symptom Inventory (NSI) and post concussion symptom profiles among TBI, PTSD, and nonclinical samples. AB - The Neurobehavioral Symptom Inventory (NSI) is a self-report measure of symptoms commonly associated with Post-Concussion Syndrome (PCS) that may emerge after mild traumatic brain injury (mTBI). Despite frequent clinical use, no NSI norms have been developed. Thus, the main objective of this study was to establish NSI normative data using the four NSI factors (i.e., vestibular, somatic, cognitive, and affective) identified by Vanderploeg, Silva, et al. ( 2014 ) among nonclinical epidemiological samples of deployed and non-deployed Florida National Guard members as well as a reference sample of Guard members with combat-related mTBI. In addition, NSI subscale profile patterns were compared across four distinct subgroups (i.e., non-deployed-nonclinical, deployed-nonclinical, deployed-mTBI, and deployed-PTSD). The deployed-nonclinical group endorsed greater PCS symptom severity than the non-deployed group, and the mTBI group uniformly endorsed more symptoms than both nonclinical groups. However, the PTSD group endorsed higher symptom severity relative to the other three subgroups. As such, this highlights the non-specificity of PCS symptoms and suggests that PTSD is associated with higher symptom endorsement than mTBI. PMID- 24625214 TI - Balancing the presentation of information and options in patient decision aids: an updated review. AB - BACKGROUND: Standards for patient decision aids require that information and options be presented in a balanced manner; this requirement is based on the argument that balanced presentation is essential to foster informed decision making. If information is presented in an incomplete/non-neutral manner, it can stimulate cognitive biases that can unduly affect individuals' knowledge, perceptions of risks and benefits, and, ultimately, preferences. However, there is little clarity about what constitutes balance, and how it can be determined and enhanced. We conducted a literature review to examine the theoretical and empirical evidence related to balancing the presentation of information and options. METHODS: A literature search related to patient decision aids and balance was conducted on Medline, using MeSH terms and PubMed; this search supplemented the 2011 Cochrane Collaboration's review of patient decision aids trials. Only English language articles relevant to patient decision making and addressing the balance of information and options were included. All members of the team independently screened clusters of articles; uncertainties were resolved by seeking review by another member. The team then worked in sub-groups to extract and synthesise data on theory, definitions, and evidence reported in these studies. RESULTS: A total of 40 articles met the inclusion criteria. Of these, six explained the rationale for balancing the presentation of information and options. Twelve defined "balance"; the definition of "balance" that emerged is as follows: "The complete and unbiased presentation of the relevant options and the information about those options-in content and in format-in a way that enables individuals to process this information without bias". Ten of the 40 articles reported assessing the balance of the relevant decision aid. All 10 did so exclusively from the users' or patients' perspective, using a five-point Likert-type scale. Presenting information in a side-by-side display form was associated with more respondents (ranging from 70% to 96%) judging the information as "balanced". CONCLUSION: There is a need for comparative studies investigating different ways to improve and measure balance in the presentation of information and options in patient decision aids. PMID- 24625215 TI - Born too soon: care during pregnancy and childbirth to reduce preterm deliveries and improve health outcomes of the preterm baby. AB - Pregnancy and childbirth represent a critical time period when a woman can be reached through a variety of mechanisms with interventions aimed at reducing her risk of a preterm birth and improving her health and the health of her unborn baby. These mechanisms include the range of services delivered during antenatal care for all pregnant women and women at high risk of preterm birth, services provided to manage preterm labour, and workplace, professional and other supportive policies that promote safe motherhood and universal access to care before, during and after pregnancy. The aim of this paper is to present the latest information about available interventions that can be delivered during pregnancy to reduce preterm birth rates and improve the health outcomes of the premature baby, and to identify data gaps. The paper also focuses on promising avenues of research on the pregnancy period that will contribute to a better understanding of the causes of preterm birth and ability to design interventions at the policy, health care system and community levels. At minimum, countries need to ensure equitable access to comprehensive antenatal care, quality childbirth services and emergency obstetric care. Antenatal care services should include screening for and management of women at high risk of preterm birth, screening for and treatment of infections, and nutritional support and counselling. Health workers need to be trained and equipped to provide effective and timely clinical management of women in preterm labour to improve the survival chances of the preterm baby. Implementation strategies must be developed to increase the uptake by providers of proven interventions such as antenatal corticosteroids and to reduce harmful practices such as non-medically indicated inductions of labour and caesarean births before 39 weeks of gestation. Behavioural and community-based interventions that can lead to reductions in smoking and violence against women need to be implemented in conjunction with antenatal care models that promote women's empowerment as a strategy for reducing preterm delivery. The global community needs to support more discovery research on normal and abnormal pregnancies to facilitate the development of preventive interventions for universal application. As new evidence is generated, resources need to be allocated to its translation into new and better screening and diagnostic tools, and other interventions aimed at saving maternal and newborn lives that can be brought to scale in all countries. PMID- 24625217 TI - Development, implementation and outcome of standards to restrict fatty meat in the food supply and prevent NCDs: learning from an innovative trade/food policy in Ghana. AB - BACKGROUND: Diet-related noncommunicable diseases represent a major global public health challenge, and require a multisectoral policy response. However, the use of trade policy in this context has met with varied success in the face of strong global trade liberalization agendas. The Government of Ghana has implemented an innovative food standards policy to limit the amount of fat in meat and meat cuts, in response to rising imports of low quality fatty meat cuts. This paper presents an analysis of the policy process and outcomes, as well as contextual factors in policy development, to enable policy learning in other jurisdictions. METHODS: We conducted 28 semi-structured policy analysis interviews with 37 stakeholders at the national and regional level in Ghana, and collated relevant documents. We analysed the data using the health policy analysis triangle and policy theories related to lesson drawing. RESULTS: The standards were developed in response to health concerns related to fatty meat (particularly turkey tails), in a context of rising meat imports and a generalised concern about the low quality and high fat content of imported meats. The standards were the result of collaboration between the trade and health sectors. The standards apply to both imported and domestic meat, and were designed to be compliant with Ghana's multilateral trade commitments. The overall effect of the ban has been to reduce availability of specific 'low quality' high-fat meats in the Ghanaian food supply, namely turkey tails and chicken feet. CONCLUSIONS: This study indicates that the use of standards can reduce availability of high-fat meat in a national food supply. The main strength of a standards approach to reducing fatty meat (mainly imported) in the food supply is compliance with global trade law, while the main challenge is effective enforcement. However, the Government of Ghana appears to have developed a functional and flexible application of the policy. Features of this policy approach useful for policy learning include: collaboration at every stage between ministries of trade and health; considerations relating to compliance with international trade law; strategic enforcement of the policy; and the importance of public awareness efforts. PMID- 24625218 TI - HIV-related neurocognitive impairment screening: the patient's perspective on its utility and psychological impact. AB - Despite ever improving advances in antiretroviral therapy, neurocognitive impairments such as asymptomatic and mild neurocognitive impairment remain a significant problem for the HIV-positive population. We distributed a post neurocognitive impairment screening service evaluation questionnaire to assess satisfaction and anxiety. Subjects were HIV positive and aged 18-50. They were screened using the Brief Neurocognitive Score and International HIV Dementia Score as well as undergoing screening for anxiety (Generalised Anxiety Disorder Assessment [GAD-7]), depression (Participant Health Questionnaire Mood Scale [PHQ 9]) and memory (Everyday Memory Questionnaire [EMQ-R]). On completion, they were either reassured that the tests were normal or were referred for further investigation. Following assessment, subjects were asked to complete an anonymous satisfaction survey; 101 surveys were analysed. Forty-nine per cent of participants stated that they "felt better" following screening, 43% said it "made no difference", 6% stated it "worried me" and 1% "did not understand". On a scale of 0-10 of helpfulness, the mean score was 7.53. Forty-seven subjects indicated that they were referred for further investigation and 46 subjects that nothing else was needed; 8 reported they did not know. Those referred on rated satisfaction at a mean of 7.54/10 and those with normal screen as 7.09/10 (p = 0.46). Of the groups that were referred for further investigation, 6% said the test "worried them" compared to 4% in the non-referred group. Forty-nine per cent said they "felt better" despite an abnormal result compared to 50% in a normal screening result (p = 0.76). The results of this survey show that screening for neurocognitive impairment by this method is acceptable and helpful to participants. It did not lead to an increase in anxiety and there was no correlation between referred for further investigations and anxiety suggesting concerns about creating undue anxiety by screening and referral are unfounded. PMID- 24625219 TI - Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells. AB - Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD. PMID- 24625220 TI - Vectorology and factor delivery in induced pluripotent stem cell reprogramming. AB - Induced pluripotent stem cell (iPSC) reprogramming requires sustained expression of multiple reprogramming factors for a limited period of time (10-30 days). Conventional iPSC reprogramming was achieved using lentiviral or simple retroviral vectors. Retroviral reprogramming has flaws of insertional mutagenesis, uncontrolled silencing, residual expression and re-activation of transgenes, and immunogenicity. To overcome these issues, various technologies were explored, including adenoviral vectors, protein transduction, RNA transfection, minicircle DNA, excisable PiggyBac (PB) transposon, Cre-lox excision system, negative-sense RNA replicon, positive-sense RNA replicon, Epstein-Barr virus-based episomal plasmids, and repeated transfections of plasmids. This review provides summaries of the main vectorologies and factor delivery systems used in current reprogramming protocols. PMID- 24625221 TI - Independent absorbed-dose calculation using the Monte Carlo algorithm in volumetric modulated arc therapy. AB - PURPOSE: To report the result of independent absorbed-dose calculations based on a Monte Carlo (MC) algorithm in volumetric modulated arc therapy (VMAT) for various treatment sites. METHODS AND MATERIALS: All treatment plans were created by the superposition/convolution (SC) algorithm of SmartArc (Pinnacle V9.2, Philips). The beam information was converted into the format of the Monaco V3.3 (Elekta), which uses the X-ray voxel-based MC (XVMC) algorithm. The dose distribution was independently recalculated in the Monaco. The dose for the planning target volume (PTV) and the organ at risk (OAR) were analyzed via comparisons with those of the treatment plan.Before performing an independent absorbed-dose calculation, the validation was conducted via irradiation from 3 different gantry angles with a 10- * 10-cm2 field. For the independent absorbed dose calculation, 15 patients with cancer (prostate, 5; lung, 5; head and neck, 3; rectal, 1; and esophageal, 1) who were treated with single-arc VMAT were selected. To classify the cause of the dose difference between the Pinnacle and Monaco TPSs, their calculations were also compared with the measurement data. RESULT: In validation, the dose in Pinnacle agreed with that in Monaco within 1.5%. The agreement in VMAT calculations between Pinnacle and Monaco using phantoms was exceptional; at the isocenter, the difference was less than 1.5% for all the patients. For independent absorbed-dose calculations, the agreement was also extremely good. For the mean dose for the PTV in particular, the agreement was within 2.0% in all the patients; specifically, no large difference was observed for high-dose regions. Conversely, a significant difference was observed in the mean dose for the OAR. For patients with prostate cancer, the mean rectal dose calculated in Monaco was significantly smaller than that calculated in Pinnacle. CONCLUSIONS: There was no remarkable difference between the SC and XVMC calculations in the high-dose regions. The difference observed in the low-dose regions may have arisen from various causes such as the intrinsic dose deviation in the MC calculation, modeling accuracy, and CT-to-density table used in each planning system It is useful to perform independent absorbed-dose calculations with the MC algorithm in intensity-modulated radiation therapy commissioning. PMID- 24625222 TI - 17p13.3 microduplication, a potential novel genetic locus for nonsyndromic bilateral cleft lip and palate. AB - Cleft lip and palate (CLP) is a relatively common congenital malformation. The etiology is complex and postulated to be a combination of genetic and environmental factors. The genetic loci for nonsyndromic CLP remain poorly characterized. Two families have recently been reported with a chromosome 17p13.3 microduplication and CLP. We report a third family with four individuals affected by nonsyndromic bilateral CLP and a 350-kb chromosome 17p13.3 microduplication (17:1,113,102-1,461,838). Our family possesses the smallest overlapping chromosome 17p13.3 microduplication associated with CLP, narrowing down the critical region for this potential new genetic locus for CLP. PMID- 24625223 TI - Chondromyxoid fibroma of the mandible in an adolescent: case report and microsurgical reconstructive option. AB - Chondromyxoid fibroma is a rare bony tumor that usually presents in the lower extremities of middle-aged adults. Involvement of the craniofacial skeleton is extremely rare. We present the unique case of an adolescent boy with a chondromyxoid fibroma of the mandible. The chondromyxoid fibroma in this patient recurred after initial treatment with curettage. We treated the recurrence with resection of the involved mandible and immediate reconstruction using a vascularized musculo-osseus seventh rib flap ("Eve procedure"). Despite complex reconstruction in adolescents due to skeletal immaturity, the rib flap has successfully grown with the patient up to 3 years postoperatively. Therefore, we believe the musculo-osseus rib flap is a feasible solution for complex ramus and condyle reconstruction of the growing mandible in the adolescent patient. PMID- 24625225 TI - Antitumor metastasis pregnane alkaloids from Pachysandra terminalis. AB - Three new pregnane alkaloids, named terminamines H-J (1-3), together with two known alkaloids (4 and 5), were isolated from the ethanol extract of Pachysandra terminalis. The structures of isolated compounds were elucidated by spectroscopic methods, including (1)H and (13)C NMR, 2D NMR, and HR-ESI-MS. Compounds 1, 4, and 5 revealed significant anti-metastasis activities. In addition, compound 1 inhibited the expression of p-PKCzeta in MDA-MB-231 cells, and compound 4 inhibited the expressions of p-PKCzeta in MDA-MB-231 and A549 cells. PMID- 24625224 TI - Regulation gene expression of miR200c and ZEB1 positively enhances effect of tumor vaccine B16F10/GPI-IL-21 on inhibition of melanoma growth and metastasis. AB - BACKGROUND: Genetically modified cells have been shown to be one of the most effective tumor vaccine strategies. However, in many cases, such as in melanoma, induction of a potent immune responses against the disease still remains a major challenge. Thus, novel strategies to reinforce tumor vaccine efficacy are needed. Using microRNA (miR) and Zinc-finger E-box binding homeobox (ZEB) have received much attention for potentially regulating tumor progression. To elicit a potent antitumor efficacy against melanoma, we used tumor vaccine in combination with miR200c overexpression or ZEB1 knockdown to assess the efficacy of treatment of murine melanoma. METHODS: B16F10 cell vaccine expressing interleukin 21 (IL-21) in the glycosylpho- sphatidylinositol (GPI)-anchored form (B16F10/GPI-IL-21) were developed. The vaccine was immunized into mice challenged by B16F10 cells or B16F10 cells stably transduced with lentiviral-miR200c (B16F10/miR200c) or transfected with the ZEB1-shRNA recombinant (B16F10/shZEB1) or the B16F10/GPI-IL 21 vaccine. The immune responses, tumorigenicity and lung metastasis in mice were evaluated, respectively. RESULTS: The vaccination with B16F10/GPI-IL-21 markedly increased the serum cytokine levels of IFN-gamma, TNF-alpha, IL-4 and decreased TGF-beta level as well as augmented the cytotoxicity of splenocytes in immunized mice compared with control mice. In addition, the tumor vaccine B16F10/GPI-IL-21 significantly inhibited the tumor growth and reduced counts of lung metastases in mice challenged by B16F10/GPI-IL-21, B16F10/shZEB1 and B16F10/miR200c respectively compared with the control mice challenged by B16F10 cells. The efficacy mechanisms may involve in reinforcing immune responses, increasing expression of miR200c, E-cadherin and SMAD-7 and decreasing expression of TGF beta, ZEB1, Vimentin and N-cadherin in tumor tissues from the immunized mice. CONCLUSIONS: These results indicate that the tumor vaccine B16F10/GPI-IL-21 in combination with miR200c overexpression or ZEB1 knockdown effectively inhibited melanoma growth and metastasis a murine model. Such a strategy may, therefore, be used for the clinical trials. PMID- 24625227 TI - Proceedings of the EPMA World Congress. PMID- 24625226 TI - Kinetics and threshold level of 2,3,4,5-tetrachlorobiphenyl dechlorination by an organohalide respiring bacterium. AB - The time required for a PCB-contaminated site to recover cannot yet be predicted due in part to lack of quantitative information on rates of PCB dechlorination in the porewater phase. We developed a method to measure rate of dechlorination in the aqueous phase at very low PCB concentrations. This approach utilizes a polymer functioning concurrently as a passive dosing system for maintaining a steady-state PCB substrate concentration in the water phase and as a passive equilibrium sampler to monitor the dechlorination product. Rates of dechlorination of 2,3,4,5-tetrachlorobiphenyl (PCB 61) to 2,3,5-trichlorobiphenyl (PCB 23) by an organohalide respiring bacterium, Dehalobium chlorocoercia DF-1, were measured over an environmentally relevant range of 1 to 500 ng L(-1) in sediment-free medium using a high concentration of cells (>10(6) cells mL(-1)). The results indicate that rate of dechlorination is a linear function of PCB substrate concentration below the maximum aqueous solubility of PCB 61 and occurs at concentrations as low as 1 ng L(-1). Demonstration of PCB 61 dechlorination at environmentally relevant concentrations suggests that low numbers of organohalide respiring bacteria rather than bioavailability accounts for low rates of dechlorination typically observed in sediments. Using passive samplers to measure the concentration of dissolved PCBs in the porewater combined with knowledge of congener-specific rates for organohalide respirer(s), it will be possible to project the in situ rate and final concentration of PCBs for a specific site after treatment by bioaugmentation. PMID- 24625228 TI - The expression of CYP2W1 in colorectal primary tumors, corresponding lymph node metastases and liver metastases. AB - INTRODUCTION: Metastatic disease is a major cause of death in patients with colorectal cancer (CRC). We have previously investigated expression of an orphan cytochrome P450 (CYP) enzyme, CYP2W1, and found high expression in about one third of colorectal tumors. CYP2W1 has proven to metabolize duocarmycin analogs into cytotoxic substances, compounds that in xenografts of CRC cells expressing CYP2W1 completely inhibit tumor growth. This study was designed to evaluate whether the enzyme is expressed in primary CRC and corresponding metastases. MATERIAL AND METHODS: Samples from primary tumors, corresponding lymph node metastases and liver metastases from 96 patients were collected and analyzed by immunohistochemistry. Data regarding patient's demographics, tumor characteristics and survival were also collected. RESULTS: Out of 96 patients, 25 (26%) had high CYP2W1 expression in the primary tumor and 46 (48%) showed high levels in the liver metastasis. In total 59 patients had lymph node metastases, and 31% of them had high CYP2W1 expression. When comparing the expression in primary tumor with that of the first liver metastasis, the increase in expression was statistically significant (p = 0.005). CONCLUSION: High CYP2W1 expression is seen in 26% of primary CRC and in 48% of corresponding liver metastases. This opens possibilities for new targeted therapies to metastatic CRC in the future. PMID- 24625229 TI - Cost-effectiveness analysis of intra-articular injections of a high molecular weight bioengineered hyaluronic acid for the treatment of osteoarthritis knee pain. AB - OBJECTIVE: To determine the cost-effectiveness of bioengineered hyaluronic acid (BioHA, 1% sodium hyaluronate) intra-articular injections in treating osteoarthritis knee pain in poor responders to conventional care (CC) including non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics. METHODS: Two decision analytic models compared BioHA treatment with either continuation of patient's baseline CC with no assumption of disease progression (Model 1), or CC including escalating care costs due to disease progression (NSAIDs and analgesics, corticosteroid injections, and surgery; Model 2). Analyses were based on patients who received two courses of 3-weekly intra-articular BioHA (26-week FLEXX Trial + 26-week Extension Study). BioHA group costs included fees for physician assessment and injection regimen, plus half of CC costs. Cost effectiveness ratios were expressed as averages and incremental costs per QALY. One-way sensitivity analyses used the 95% confidence interval (CI) of QALYs gained in BioHA-treated patients, and +/-20% of BioHA treatment and CC costs. Probabilistic sensitivity analyses were performed for Model 2. RESULTS: For 214 BioHA patients, the average utility gain was 0.163 QALYs (95% CI = -0.162 to 0.488) over 52 weeks. Model 1 treatment costs were $3469 and $4562 for the BioHA and CC groups, respectively; sensitivity analyses showed BioHA to be the dominant treatment strategy, except when at the lower end of the 95% CI. Model 2 annual treatment costs per QALY gained were $1446 and $516 for the BioHA and CC groups, respectively. Using CC as baseline strategy, the incremental cost-effectiveness ratio (ICER) of BioHA was $38,741/QALY gained, and was sensitive to response rates in either the BioHA or CC groups. CONCLUSION: BioHA is less costly and more effective than CC with NSAIDs and analgesics, and is the dominant treatment strategy. Compared with escalating CC, the $38,741/QALY ICER of BioHA remains within the $50,000 per QALY willingness-to-pay threshold to adopt a new technology. PMID- 24625230 TI - Inhibition of HSP70 reduces porcine reproductive and respiratory syndrome virus replication in vitro. AB - BACKGROUND: Successful viral infection requires the involvement of host cellular factors in their life cycle. Heat shock protein 70 (HSP70) can be recruited by numerous viruses to promote the folding, maturation, or assembly of viral proteins. We have previously shown that HSP70 is significantly elevated in porcine reproductive and respiratory syndrome virus (PRRSV)-infected lungs, suggesting HSP70 may play a potential role during PRRSV infection. In this study, we tried to investigate the role of HSP70 during PRRSV infection. RESULTS: In this study, we observed that PRRSV infection induced the expression of HSP70. The down-regulation of HSP70 using quercetin, a HSPs synthesis inhibitor, or small interfering RNAs (siRNA) reduced the viral protein level and viral production. Notably, these inhibitory effects on PRRSV infection could be attenuated by heat shock treatment. In addition, HSP70 was found to colocalize with the viral double stranded RNA (dsRNA) and knockdown of HSP70 decreased the dsRNA levels, suggesting HSP70 is involved in the formation of viral replication and transcription complex (RTC) and thus affects the viral replication. CONCLUSIONS: Our study revealed that HSP70 is an essential host factor required for the replication of PRRSV. The inhibition of HSP70 significantly reduced PRRSV replication, which may be applied as an effective antiviral strategy. PMID- 24625231 TI - Investigation of novel chemical inhibitors of human lysosomal acid lipase: virtual screening and molecular docking studies. AB - In the current study, identification of new potent small inhibitors of human lysosomal acid lipase using structure-based methods has been reported. Virtual Screening (VS), compounds from literature and molecular docking studies were employed to find the suitable inhibitors against lysosomal acid lipase (LAL). Specifically for this study a homology model of LipA enzyme was generated based on the structure of dog gastric lipase. As a result of structurebased virtual screening 28 inhibitors were identified from ZINC database. Rest of the inhibitors were selected from literature. Among the studied 65 inhibitors, compound having zinc ID ZINC15707335 exhibiting minimum binding affinity and hydrogen bond and hydrophobic interactions with specific amino acid residues was selected as lead compound. PMID- 24625232 TI - Synthesis and biological evaluation of novel N' (4-aryloxybenzylidene)- 1H benzimidazole-2 carbohydrazide derivatives as anti-tubercular agents. AB - A series of structurally novel, (E)-N'-(4-aryloxybenzylidene)-1H-benzimidazole-2 carbohydrazide derivatives were synthesized by molecular hybridization technique. All these compounds were evaluated against Mycobacterium tuberculosis H37Rv strains using Resazurin Microtiter assay (REMA) method. These compounds showed good antituberculosis activity with minimum inhibitory concentration (MIC) value of the range of 1.5-25 ug/mL. PMID- 24625234 TI - Improving cervical cancer screening rates in an urban HIV clinic. AB - Human immunodeficiency virus (HIV)-infected women are at increased risk of invasive cervical cancer; however, screening rates remain low. The objectives of this study were to analyze a quality improvement intervention to increase cervical cancer screening rates in an urban academic HIV clinic and to identify factors associated with inadequate screening. Barriers to screening were identified by a multidisciplinary quality improvement committee at the Washington University Infectious Diseases clinic. Several strategies were developed to address these barriers. The years pre- and post-implementation were analyzed to examine the clinical impact of the intervention. A total of 422 women were seen in both the pre-implementation and post-implementation periods. In the pre implementation period, 222 women (53%) underwent cervical cancer screening in the form of Papanicolaou (Pap) testing. In the post-implementation period, 318 women (75.3%) underwent cervical cancer screening (p < 0.01). Factors associated with lack of screening included fewer visits attended (pre: 4.2 +/- 1.5; post: 3.4 +/- 1.4; p < 0.01). A multidisciplinary quality improvement intervention was successful in overcoming barriers and increasing cervical cancer screening rates in an urban academic HIV clinic. PMID- 24625233 TI - Born too soon: care for the preterm baby. AB - As part of a supplement entitled "Born Too Soon", this paper focuses on care of the preterm newborn. An estimated 15 million babies are born preterm, and the survival gap between those born in high and low income countries is widening, with one million deaths a year due to direct complications of preterm birth, and around one million more where preterm birth is a risk factor, especially amongst those who are also growth restricted. Most premature babies (>80%) are between 32 and 37 weeks of gestation, and many die needlessly for lack of simple care. We outline a series of packages of care that build on essential care for every newborn comprising support for immediate and exclusive breastfeeding, thermal care, and hygienic cord and skin care. For babies who do not breathe at birth, rapid neonatal resuscitation is crucial. Extra care for small babies, including Kangaroo Mother Care, and feeding support, can halve mortality in babies weighing <2000 g. Case management of newborns with signs of infection, safe oxygen management and supportive care for those with respiratory complications, and care for those with significant jaundice are all critical, and are especially dependent on competent nursing care. Neonatal intensive care units in high income settings are de-intensifying care, for example increasing use of continuous positive airway pressure (CPAP) and this makes comprehensive preterm care more transferable. For health systems in low and middle income settings with increasing facility births, district hospitals are the key frontier for improving obstetric and neonatal care, and some large scale programmes now include specific newborn care strategies. However there are still around 50 million births outside facilities, hence home visits for mothers and newborns, as well as women's groups are crucial for reaching these families, often the poorest. A fundamental challenge is improving programmatic tracking data for coverage and quality, and measuring disability-free survival. The power of parent's voices has been important in high-income countries in bringing attention to preterm newborns, but is still missing from the most affected countries. PMID- 24625235 TI - Developing anti-tobacco messages for Australian Aboriginal and Torres Strait Islander peoples: evidence from a national cross-sectional survey. AB - BACKGROUND: Smoking rates in Australian Aboriginal and Torres Strait Islander peoples remain high, with limited impact of government measures for many subgroups. The aim of this cross-sectional study was to investigate differences in organisational practice for developing anti-tobacco messages for these target populations. METHODS: Telephone interviews were conducted with 47 organisation representatives using a structured questionnaire based on health communication and health promotion frameworks. Responses were coded into phases of message development, message types (educational, threat, positive or advocacy), target groups, message recommendations, and evaluations undertaken. Cultural sensitivity for message development was divided into surface structure (use of images, language, demographics) and deep structure (use of socio-cultural values). A categorical principal component analysis explored the key dimensions of the findings and their component relationships. RESULTS: Among organisations interviewed, a community-orientated, bottom-up approach for developing anti tobacco messages was reported by 47% (n=24); 55% based message development on a theoretical framework; 87% used a positive benefit appeal; 38% used threat messages. More Aboriginal Medical Services (AMSs) targeted youth (p<0.005) and advised smokers to quit (p<0.05) than other types of organisations. AMSs were significantly more likely to report using deep structure in tailoring messages compared with non-government (p<0.05) and government organisations (p<0.05). Organisations that were oriented to the general population were more likely to evaluate their programs (p<0.05). A two-dimensional non-linear principal component analysis extracted components interpreted as "cultural understanding" (bottom-up, community-based approaches, deep structures) and "rigour" (theoretical frameworks, and planned/completed evaluations), and accounted for 53% of the variability in the data. CONCLUSION: Message features, associated with successful campaigns in other populations, are starting to be used for Aboriginal and Torres Strait Islander peoples. A model is proposed to facilitate the development of targeted anti-tobacco messages for Aboriginal and Torres Strait Islander peoples. Organisations could consider incorporating both components of cultural understanding-rigour to enable the growth of evidence-based practice. PMID- 24625236 TI - Abstracts of the 23rd World Congress of the World Society of Cardio-thoracic Surgeons, 12-15 September 2013, Split, Croatia. PMID- 24625238 TI - Transitory beneficial effects of professional continuous glucose monitoring on the metabolic control of patients with type 1 diabetes. AB - BACKGROUND: The benefit of professional continuous glucose monitoring (PCGM) in the metabolic control of patients with type 1 diabetes mellitus (T1DM) is uncertain. SUBJECTS AND METHODS: This was a retrospective study of all consecutive T1DM patients who underwent a 6-day PCGM in our Diabetes Unit over the course of 17 months. According to the indication, two groups were arbitrarily defined: "hyperglycemic" and "hypoglycemic." Data from medical files and sensor reports were reviewed. Glycated hemoglobin (HbA1c) was evaluated 2-4 weeks prior to PCGM, as well as 3-5 and 12 months after PCGM. In the hypoglycemic group, the number of self-reported mild hypoglycemic episodes (as defined by the American Diabetes Association) was collected. RESULTS: Of the 67 patients reviewed, 43 were in the hyperglycemic group, and 24 were in the hypoglycemic group. In the hyperglycemic group, the HbA1c level dropped at 3-5 months post-intervention from 8.45 +/- 0.72% to 8.04 +/- 0.9%, with the decline being statistically significant (-0.4%; P = 0.001) and positively correlated with the initial HbA1c value (0.366; P=0.016). One year after the PCGM study, the HbA1c level tended to return to the initial values: 8.20 +/- 1.05% (-0.24%; P = 0.081). In the hypoglycemic group, HbA1c did not change either 3-5 or 12 months after PCGM, although the percentage of patients in whom the number of mild hypoglycemic episodes was significantly reduced was 86% (P=0.001). CONCLUSIONS: Although a transient phenomenon, PCGM can be useful in the short term in improving metabolic and clinical profile of suboptimally controlled T1DM subjects, including those with repeated hypoglycemia. PMID- 24625237 TI - Presenting quantitative information about decision outcomes: a risk communication primer for patient decision aid developers. AB - BACKGROUND: Making evidence-based decisions often requires comparison of two or more options. Research-based evidence may exist which quantifies how likely the outcomes are for each option. Understanding these numeric estimates improves patients' risk perception and leads to better informed decision making. This paper summarises current "best practices" in communication of evidence-based numeric outcomes for developers of patient decision aids (PtDAs) and other health communication tools. METHOD: An expert consensus group of fourteen researchers from North America, Europe, and Australasia identified eleven main issues in risk communication. Two experts for each issue wrote a "state of the art" summary of best evidence, drawing on the PtDA, health, psychological, and broader scientific literature. In addition, commonly used terms were defined and a set of guiding principles and key messages derived from the results. RESULTS: The eleven key components of risk communication were: 1) Presenting the chance an event will occur; 2) Presenting changes in numeric outcomes; 3) Outcome estimates for test and screening decisions; 4) Numeric estimates in context and with evaluative labels; 5) Conveying uncertainty; 6) Visual formats; 7) Tailoring estimates; 8) Formats for understanding outcomes over time; 9) Narrative methods for conveying the chance of an event; 10) Important skills for understanding numerical estimates; and 11) Interactive web-based formats. Guiding principles from the evidence summaries advise that risk communication formats should reflect the task required of the user, should always define a relevant reference class (i.e., denominator) over time, should aim to use a consistent format throughout documents, should avoid "1 in x" formats and variable denominators, consider the magnitude of numbers used and the possibility of format bias, and should take into account the numeracy and graph literacy of the audience. CONCLUSION: A substantial and rapidly expanding evidence base exists for risk communication. Developers of tools to facilitate evidence-based decision making should apply these principles to improve the quality of risk communication in practice. PMID- 24625239 TI - Effect of a 6-month intervention with cooking oils containing a high concentration of monounsaturated fatty acids (olive and canola oils) compared with control oil in male Asian Indians with nonalcoholic fatty liver disease. AB - OBJECTIVE: We investigated the effects of dietary intervention with canola or olive oil in comparison with commonly used refined oil in Asian Indians with nonalcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS: This was a 6 month intervention study including 93 males with NAFLD, matched for age and body mass index (BMI). Subjects were randomized into three groups to receive olive oil (n=30), canola oil (n=33), and commonly used soyabean/safflower oil (control; n=30) as cooking medium (not exceeding 20 g/day) along with counseling for therapeutic lifestyle changes. The BMI, fasting blood glucose (FBG) and insulin levels, lipids, homeostasis model of assessment for insulin resistance (HOMA-IR), HOMA denoting beta-cell function (HOMA-betaCF), and disposition index (DI) were measured at pre- and post-intervention. Data were analyzed with one-way analysis of variance (ANOVA) and Tukey's Honestly Significant Difference multiple comparison test procedures. RESULTS: Olive oil intervention led to a significant decrease in weight and BMI (ANOVA, P=0.01) compared with the control oil group. In a comparison of olive and canola oil, a significant decrease in fasting insulin level, HOMA-IR, HOMA-betaCF, and DI (P<0.001) was observed in the olive oil group. Pre- and post-intervention analysis revealed a significant increase in high-density lipoprotein level (P=0.004) in the olive oil group and a significant decrease in FBG (P=0.03) and triglyceride (P=0.02) levels in the canola oil group. The pre- and post-intervention difference in liver span was significant only in the olive (1.14 +/- 2 cm; P<0.05) and canola (0.66 +/- 0.33 cm; P<0.05) oil groups. In the olive and canola oil groups, post-intervention grading of fatty liver was reduced significantly (grade I, from 73.3% to 23.3% and from 60.5% to 20%, respectively [P<0.01]; grade II, from 20% to 10% and from 33.4% to 3.3%, respectively [P<0.01]; and grade III, from 6.7% to none and from 6.1% to none, respectively). In contrast, in the control oil group no significant change was observed. CONCLUSIONS: Results suggest significant improvements in grading of fatty liver, liver span, measures of insulin resistance, and lipids with use of canola and olive oil compared with control oils in Asian Indians with NAFLD. PMID- 24625240 TI - Surgical resection for local recurrence after radiofrequency ablation for colorectal liver metastasis is more extensive than primary resection. AB - OBJECTIVE: As a minimally invasive modality, radiofrequency ablation (RFA) has been increasingly applied not only for the treatment of hepatocellular carcinoma, but also for that of colorectal liver metastasis (CLM). However, RFA for CLM has been shown to be associated with a high local recurrence rate, and no optimal treatment for RFA failure has been established yet. The aim of this study was to evaluate the feasibility and outcome of surgical resection for local recurrence after RFA. MATERIAL AND METHODS: A retrospective study of 17 patients, who underwent surgery for local recurrence after RFA for resectable CLM, was carried out. The surgical procedures involved in the actual surgery were compared with those envisioned for the primary resection if RFA had not been selected. RESULTS: Surgical resection for RFA recurrence was more invasive than the envisioned surgical procedure in 10 cases (58%). In addition, the proportions of cases that required technically demanding procedures among the patients receiving surgery for RFA recurrence were higher than those in envisioned operations; major hepatectomy, eight cases [47%] versus two cases [12%] (p<0.0205); excision and/or reconstruction of the major hepatic veins, three cases [18%] versus zero case [0%] (p=0.035); excision of diaphragm: three cases [18%] versus zero case [0%] (p=0.035). The 1-, 3- and 5-year overall survival rates were 92%, 45% and 45%, respectively. CONCLUSIONS: Surgical resection for RFA recurrence for CLM required more invasive and technically demanding procedures. Thus, RFA for CLM should be limited to unresectable cases, and patients with resectable CLM should be thoroughly advised not to undergo RFA, but rather surgical resection. PMID- 24625241 TI - Geographic, technologic, and economic analysis of using reclaimed water for thermoelectric power plant cooling. AB - Use of reclaimed water-municipal wastewater treatment plant effluent-in nonpotable applications can be a sustainable and efficient water management strategy. One such nonpotable application is at thermoelectric power plants since these facilities require cooling, often using large volumes of freshwater. To evaluate the geographic, technologic, and economic feasibility of using reclaimed water to cool thermoelectric power plants, we developed a spatially resolved model of existing power plants. Our model integrates data on power plant and municipal wastewater treatment plant operations into a combined geographic information systems and optimization approach to evaluate the feasibility of cooling system retrofits. We applied this broadly applicable methodology to 125 power plants in Texas as a test case. Results show that sufficient reclaimed water resources exist within 25 miles of 92 power plants (representing 61% of capacity and 50% of generation in our sample), with most of these facilities meeting both short-term and long-term water conservation cost goals. This retrofit analysis indicates that reclaimed water could be a suitable cooling water source for thermoelectric power plants, thereby mitigating some of the freshwater impacts of electricity generation. PMID- 24625242 TI - Non-invasive assessment of cardiac function and pulmonary vascular resistance in an canine model of acute thromboembolic pulmonary hypertension using 4D flow cardiovascular magnetic resonance. AB - BACKGROUND: The purpose of this study was to quantify right (RV) and left (LV) ventricular function, pulmonary artery flow (QP), tricuspid valve regurgitation velocity (TRV), and aorta flow (QS) from a single 4D flow cardiovascular magnetic resonance (CMR) (time-resolved three-directionally motion encoded CMR) sequence in a canine model of acute thromboembolic pulmonary hypertension (PH). METHODS: Acute PH was induced in six female beagles by microbead injection into the right atrium. Pulmonary arterial (PAP) and pulmonary capillary wedge (PCWP) pressures and cardiac output (CO) were measured by right heart catheterization (RHC) at baseline and following induction of acute PH. Pulmonary vascular resistance (PVRRHC) was calculated from RHC values of PAP, PCWP and CO (PVRRHC = (PAP PCWP)/CO). Cardiac magnetic resonance (CMR) was performed on a 3 T scanner at baseline and following induction of acute PH. RV and LV end-diastolic (EDV) and end-systolic (ESV) volumes were determined from both CINE balanced steady-state free precession (bSSFP) and 4D flow CMR magnitude images. QP, TRV, and QS were determined from manually placed cutplanes in the 4D flow CMR flow-sensitive images in the main (MPA), right (RPA), and left (LPA) pulmonary arteries, the tricuspid valve (TRV), and aorta respectively. MPA, RPA, and LPA flow was also measured using two-dimensional flow-sensitive (2D flow) CMR. RESULTS: Biases between 4D flow CMR and bSSFP were 0.8 mL and 1.6 mL for RV EDV and RV ESV, respectively, and 0.8 mL and 4 mL for LV EDV and LV ESV, respectively. Flow in the MPA, RPA, and LPA did not change after induction of acute PAH (p = 0.42 0.81). MPA, RPA, and LPA flow determined with 4D flow CMR was significantly lower than with 2D flow (p < 0.05). The correlation between QP/TRV and PVRRHC was 0.95. The average QP/QS was 0.96 +/- 0.11. CONCLUSIONS: Using both magnitude and flow sensitive data from a single 4D flow CMR acquisition permits simultaneous quantification of cardiac function and cardiopulmonary hemodynamic parameters important in the assessment of PH. PMID- 24625243 TI - When obesity and chronic obstructive pulmonary disease collide. Physiological and clinical consequences. AB - In many parts of the world, the prevalence of both chronic obstructive pulmonary disease (COPD) and obesity is increasing at an alarming rate. Such patients tend to have greater respiratory symptoms, more severe restriction of daily activities, poorer health-related quality of life, and greater health care use than their nonobese counterparts. Physiologically, increasing weight gain is associated with lung volume reduction effects in both health and disease, and this should be considered when interpreting common pulmonary function tests where lung volume is the denominator, such as FEV1/FVC and the ratio of diffusing capacity of carbon monoxide to alveolar volume, or indeed when evaluating the physiological consequences of emphysema in obese individuals. Contrary to expectation, the presence of mild to moderate obesity in COPD appears to have little deleterious effect on respiratory mechanics and muscle function, exertional dyspnea, and peak symptom-limited oxygen uptake during cardiopulmonary exercise testing. Thus, in evaluating obese patients with COPD reporting activity restriction, additional nonpulmonary factors, such as increased metabolic loading, cardiocirculatory impairment, and musculoskeletal abnormalities, should be considered. Care should be taken to recognize the presence of obstructive sleep apnea in obese patients with COPD, as effective treatment of the former condition likely conveys an important survival advantage. Finally, morbid obesity in COPD presents significant challenges to effective management, given the combined effects of erosion of the ventilatory reserve and serious metabolic and cardiovascular comorbidities that collectively predispose to an increased risk of death from respiratory failure. PMID- 24625244 TI - Burden of venous leg ulcers in the United States. AB - OBJECTIVE: To estimate the annual incremental per-patient and overall payer burden (2012USD) of venous leg ulcers (VLU) in the US. METHODS: Beneficiaries with and without VLU were identified using two de-identified insurance claims databases: aged 65+ from a 5% random sample of Medicare beneficiaries (2007-2010: n ~ 2.3 million); and aged 18-64 from a privately-insured population (2007-2011: n ~ 8.4 million). The index date was selected as the date of a VLU claim with no other VLU diagnoses in the preceding 12 months for the VLU cohort and as the date of a random medical claim for the non-VLU patients. These groups were matched using propensity scores to account for differences in demographics, comorbidities, resource utilization, and costs in the 12 month pre-index period. Medical resource use and costs incurred during the 12 month follow-up period were calculated for both payers. Drug costs and indirect work-loss due to disability and medically-related absenteeism were estimated for the privately-insured sample only. Annual VLU incidence rates were also estimated for both payers. RESULTS: Data for 58,672 matched VLU/non-VLU pairs of Medicare and 22,476 matched pairs of privately-insured patients were analyzed. Relative to matched non-VLU patients, VLU patients used more medical resources and incurred annual incremental medical costs of $6391 in Medicare ($18,986 vs $12,595), and $7030 ($13,653 vs $6623) in private insurance ($7086 including drug costs). Compared with non-VLU patients, privately-insured VLU patients had more days missed from work (14.0 vs 10.0), resulting in 29% higher work-loss costs (comparisons significant at p < 0.0001). The average annual incidence rate of VLU was 2.2% in Medicare and 0.5% in private insurance. LIMITATIONS: Findings did not account for out-of-pocket payments or other indirect costs (e.g., lost productivity), and relied on accuracy of diagnosis and procedure codes contained in claims data. CONCLUSION: These findings suggest an annual US payer burden of $14.9 billion. PMID- 24625245 TI - TP53 p.R337H prevalence in a series of Brazilian hereditary breast cancer families. AB - BACKGROUND: Approximately 5-10% of breast cancers are hereditary. Among hereditary syndromes, Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Li Fraumeni Syndrome (LFS) have received the most attention. HBOC is due to mutations in the BRCA1 and BRCA2 genes and is characterized by breast adenocarcinoma and/or epithelial ovarian carcinoma. LFS is associated with germline mutations in TP53; the most frequent cancer types associated with this syndrome are sarcoma, breast cancer, leukemia, brain tumors and adrenocortical carcinomas. Other cancers related to LFS are found at lower frequencies. In Brazil, especially in the southern part of the country, a specific mutation in the TP53 gene, TP53 p.R337H, occurs at a high frequency in childhood adrenocortical tumors. It has been proposed that this mutation increases breast cancer risk in southern Brazilian women. METHODS: We carried out a case-control study to determine the prevalence of the TP53 p.R337H mutation in 28 female cancer patients attended at the Cancer Genetic Counseling Service of the General Hospital of the University of Sao Paulo Medical School of Ribeirao Preto who fulfilled Hereditary Breast and Ovary Cancer Syndrome genetic test criteria compared to healthy woman (controls). TP53 p.R337H mutation status was determined using the High Resolution Melting (HRM) method, followed by DNA sequencing. Fisher's test was used to compare the prevalence of TP53 p.R337H in the patient and control groups. RESULTS: Two of the breast cancer cases (7.1%) and none of the controls carried the TP53 p.R337H mutation. At the time of the investigation, both cases fulfilled testing criteria for Hereditary Breast and Ovary Cancer Syndrome but not Li-Fraumeni or Li-Fraumeni-like Syndrome, based on genetic testing criteria of NCCN Clinical Practice Guidelines in Oncology (v.1.2010). CONCLUSIONS: We suggest that genetic screening of Brazilian breast cancer patients who fulfill Hereditary Breast and Ovary Cancer Syndrome criteria and have a family history that includes other tumors of the LFS/LFL spectrum be tested for the TP53 p.R337H mutation. PMID- 24625246 TI - Direct characterization of fluid lipid assemblies on mercury in electric fields. AB - Phospholipid monolayers on mercury (Hg) surfaces have received substantial and extensive scientific interest not only because of their use as a biomembrane model but also for their application as a successful toxicity-sensing element. The monolayers show characteristic and very reproducible phase transitions manifest as consecutive voltammetric peaks in response to applied transverse electric fields. Unfortunately, apart from the results of simulation studies, there is a lack of data on the lipid phase structures to help interpret these voltammetric peaks. In this paper we report on the direct measurement of the structural changes underlying the phase transitions of phospholipid layers of dioleoyl phosphatidylcholine (DOPC) at electrified Hg surfaces using atomic force microscopy force-distance techniques. These direct measurements enable a description of the following structural changes in fluid lipid assemblies on a liquid electrode within an increasing transverse electric field. At about -1.0 V (vs Ag/AgCl) a field-facilitated ingress of ions and water into the monolayer results in a phase transition to a structured 2D emulsion. This is followed by a further phase transition at more negative potentials involving the readsorption of bilayer patches. At stronger values of field the bilayer patches form semivesicles, which subsequently collapse to form a monolayer of uncertain composition at very negative potentials. The observation that a monolayer on Hg converts to a bilayer by increasing the applied potential has allowed techniques to be developed for preparing and characterizing a near-continuous DOPC bilayer on Hg in an applied potential window within -1.0 and -1.4 V (vs Ag/AgCl). PMID- 24625247 TI - Fabrication of a visible-light-driven plasmonic photocatalyst of AgVO3@AgBr@Ag nanobelt heterostructures. AB - In this article, AgVO3@AgBr@Ag nanobelt heterostructures were fabricated as an efficient visible-light photocatalyst through a hydrothermal process, an anion exchange reaction, and a light-induced reduction. SEM and TEM characterization revealed that anion exchange followed by light-induced reduction is an efficient method to synthesize well-dispersed AgBr@Ag nanoparticles on the surface of AgVO3 nanobelts. The composite photocatalyst efficiently combines visible-light active AgBr and AgVO3 with the surface plasmon resonance (SPR) effect of Ag nanoparticles. The obtained catalyst displayed a high performance for removing organic dye in the range of visible light. This improved visible-light response likely originates from a synergistic effect of the different components. This work provides a versatile approach for accessing efficient, stable, and recyclable visible-light-driven plasmonic photocatalysts. PMID- 24625248 TI - Analysis of dihedral angle preferences for alanine and glycine residues in alpha and beta transmembrane regions. AB - For the past 50 years, the Ramachandran map has been used effectively to study the protein structure and folding. However, though extensive analysis has been done on dihedral angle preferences of residues in globular proteins, related studies and reports of membrane proteins are limited. It is of interest to explore the conformational preferences of residues in transmembrane regions of membrane proteins which are involved in several important and diverse biological processes. Hence, in the present work, a systematic comparative computational analysis has been made on dihedral angle preferences of alanine and glycine in alpha and beta transmembrane regions (the two major classes of transmembrane proteins) with the aid of the Ramachandran map. Further, the conformational preferences of residues in transmembrane regions were compared with the non transmembrane regions. We have extracted cation-pi interacting residues present in transmembrane regions and explored the dihedral angle preferences. From our observations, we reveal the higher percentage of occurrences of glycine in alpha and beta transmembrane regions than other hydrophobic residues. Further, we noted a clear shift in psi-angle preferences of glycine residues from negative bins in alpha transmembrane regions to positive bins in beta transmembrane regions. Also, cation-pi interacting residues in beta transmembrane regions avoid preferring psi angles in the range of -59 degrees to -30 degrees . In this article, we insist that the studies on preferences of dihedral angles in transmembrane regions, thorough understanding of structure and folding of transmembrane proteins, can lead to modeling of novel transmembrane regions towards designing membrane proteins. PMID- 24625249 TI - Quantification of pediatric and adult cervical vertebra-anatomical characteristics by age and gender for automotive application. AB - OBJECTIVE: The cervical anatomy has been shown to affect injury patterns in vehicle crashes. Characterizing the spine anatomy and changes associated with growth and gender is important when assessing occupant protection. In this study, selected cervical characteristics were quantified. METHODS: Computed tomography (CT) scans of 750 patients were selected from the University of Michigan trauma database; 314 were children and 436 were adults. Four variables were obtained: the maximum spinal canal radius, vertebral body depth, facet angles, and retroversion angles. RESULTS: The cervical spine measurements varied with age and gender. The body depth increased nonlinearly with age. The average vertebral body depth at C4 was 9.2 +/- 0.38 mm in the 0-3 age group, 15.7 +/- 0.29 mm in the 18 29 age group, and 17.2 +/- 0.46 mm in the 60+ age group. Pediatric and adult males had larger vertebral body depth than females overall, irrespective of vertebral level (P <.001). Compared to females, the vertebral body depth was 8-9 percent greater in male children and 13-16 percent greater in adult males. The average radius varied with gender, with male children generally having a larger radius than females irrespective of vertebral level (P <.001). Overall, spinal canal radius was smallest in the 0-3 and 60+ age groups and largest in the 18-29 age group. The C4 radius was 5.91 +/- 0.17, 6.28 +/- 0.14, and 6.73 +/- 0.17 mm respectively. The radius was larger in the 4-7 age group than in the 0-3 age group, irrespective of vertebral level (P <.0001). There were nonsignificant radius changes between the 4-7 and 8-11 age groups and the 8-11 and age 12-17 groups, suggesting that the size of the spinal cord reaches near maturation by the age of 7. Facet angles decreased with age in children and increased with age in adults. The average facet angles were largest in the 0-3 age group (P <.1, C2 C6). Adult facet angles were greater in the 60+ age group than in the 18-29 age group (P <.0001, C2-C6). Males had larger facet angles than females overall (P <.01 at C2, C5-C7). The retroversion angles were largest at C6 and C7. They increased with age in children and decreased in the adult population; they were larger (5-22%) in the 18-29 age group than in the 60+ age group (P <.0001, C2 C6). CONCLUSIONS: The results obtained in this study help explain variations in cervical anatomical changes associated with age and gender. The information is useful when assessing differences in injury patterns between different segments of the population. Anatomical measurements of the cervical spine should be considered for the development of models used to assess injury mechanisms for various occupant age groups. PMID- 24625250 TI - Abstracts from the 7th Postgraduate Forum on Health Systems and Policies, 24-25 June 2013, Phitsanulok, Thailand. PMID- 24625251 TI - Conference report: 6th Clinical Trials on Alzheimer's Disease (CTAD) Conference, Nov 14-16, 2013, The Westin San Diego Gaslamp Quarter Hotel, San Diego, CA, USA. PMID- 24625252 TI - Born too soon: accelerating actions for prevention and care of 15 million newborns born too soon. AB - Preterm birth complication is the leading cause of neonatal death resulting in over one million deaths each year of the 15 million babies born preterm. To accelerate change, we provide an overview of the comprehensive strategy required, the tools available for context-specifi c health system implementation now, and the priorities for research and innovation. There is an urgent need for action on a dual track: (1) through strategic research to advance the prevention of preterm birth and (2) improved implementation and innovation for care of the premature neonate. We highlight evidence-based interventions along the continuum of care, noting gaps in coverage, quality, equity and implications for integration and scale up. Improved metrics are critical for both burden and tracking programmatic change. Linked to the United Nation's Every Women Every Child strategy, a target was set for 50% reduction in preterm deaths by 2025. Three analyses informed this target: historical change in high income countries, recent progress in best performing countries, and modelling of mortality reduction with high coverage of existing interventions. If universal coverage of selected interventions were to be achieved, then 84% or more than 921,000 preterm neonatal deaths could be prevented annually, with antenatal corticosteroids and Kangaroo Mother Care having the highest impact. Everyone has a role to play in reaching this target including government leaders, professionals, private sector, and of course families who are aff ected the most and whose voices have been critical for change in many of the countries with the most progress. PMID- 24625253 TI - Abstracts of the 17th Annual SCMR Scientific Sessions, 16-19 January 2014 New Orleans, LA, USA. PMID- 24625254 TI - Late abstracts of the 23rd World Congress of the World Society of Cardio-Thoracic Surgeons, 12-15 September 2013, Split, Croatia. PMID- 24625255 TI - Degradation mechanism of cyanobacterial toxin cylindrospermopsin by hydroxyl radicals in homogeneous UV/H2O2 process. AB - The degradation of cylindrospermopsin (CYN), a widely distributed and highly toxic cyanobacterial toxin (cyanotoxin), remains poorly elucidated. In this study, the mechanism of CYN destruction by UV-254 nm/H2O2 advanced oxidation process (AOP) was investigated by mass spectrometry. Various byproducts identified indicated three common reaction pathways: hydroxyl addition (+16 Da), alcoholic oxidation or dehydrogenation (-2 Da), and elimination of sulfate (-80 Da). The initiation of the degradation was observed at the hydroxymethyl uracil and tricyclic guanidine groups; uracil moiety cleavage/fragmentation and further ring-opening of the alkaloid were also noted at an extended reaction time or higher UV fluence. The degradation rates of CYN decreased and less byproducts (species) were detected using natural water matrices; however, CYN was effectively eliminated under extended UV irradiation. This study demonstrates the efficiency of CYN degradation and provides a better understanding of the mechanism of CYN degradation by hydroxyl radical, a reactive oxygen species that can be generated by most AOPs and is present in natural water environment. PMID- 24625256 TI - Prevention of thrombogenesis from whole human blood on plastic polymer by ultrathin monoethylene glycol silane adlayer. AB - In contemporary society, a large percentage of medical equipment coming in contact with blood is manufactured from plastic polymers. Unfortunately, exposure may result in undesirable protein-material interactions that can potentially trigger deleterious biological processes such as thrombosis. To address this problem, we have developed an ultrathin antithrombogenic coating based on monoethylene glycol silane surface chemistry. The strategy is exemplified with polycarbonate--a plastic polymer increasingly employed in the biomedical industry. The various straightforward steps of surface modification were characterized with X-ray photoelectron spectroscopy supplemented by contact angle goniometry. Antithrombogenicity was assessed after 5 min exposure to whole human blood dispensed at a shear rate of 1000 s(-1). Remarkably, platelet adhesion, aggregation, and thrombus formation on the coated surface was greatly inhibited (>97% decrease in surface coverage) compared to the bare substrate and, most importantly, nearly nonexistent. PMID- 24625257 TI - Selecting decision strategies: the differential role of affect. AB - Many theories on cognition assume that people adapt their decision strategies depending on the situation they face. To test if and how affect guides the selection of decision strategies, we conducted an online study (N = 166), where different mood states were induced through video clips. Results indicate that mood influenced the use of decision strategies. Negative mood, in particular anger, facilitated the use of non-compensatory strategies, whereas positive mood promoted compensatory decision rules. These results are in line with the idea that positive mood broadens the focus of attention and thus increases the use of compensatory decision strategies that take many pieces of information into account, whereas negative mood narrows the focus of attention and thus fosters non-compensatory strategies that rely on a selective use of information. The results further indicate that gaining a deeper theoretical understanding of the cognitive mechanisms that govern decision processes requires taking emotions into account. PMID- 24625258 TI - Direct C-H arylation of thiophenes at low catalyst loading of a phosphine-free bis(alkoxo)palladium complex. AB - An efficient phosphine-free direct C-H arylation of thiophenes at the alpha position has been developed at low catalyst loading of bis(alkoxo)palladium complex (Cat.I, 0.1-0.2 mol %). The developed synthetic method can be applied to the synthesis of alpha-aryl/heteroaryl thiophenes from aryl or heteroaryl bromides in good to excellent yields and is compatible with the substrates bearing electron-donating or electron-withdrawing groups. The reactivities of the 2- and 5-positions of thiophenes are equivalent and not dependent on steric hindrance under optimal conditions. This condition can also be applied to other heterocyclic moieties such as benzothiophene, benzofuran, and pyrrole with high conversion yields. PMID- 24625259 TI - Risk factors for suicide attempts in a clinic-based sample of people living with HIV in Puerto Rico. AB - Puerto Rico (PR) has a large and rapidly growing population of people living with HIV. However, relatively little behavioral or clinical research has been done in this population. As treatment for HIV increasingly moves into a chronic condition model, it is becoming increasingly important to understand the needs of this population so critical social and behavioral interventions can be developed, thus enabling the individual and community-level benefits of antiretroviral (ARV) treatment to be fully realized. To date, however, there has been very little research on the mental health needs of people living with HIV in PR, a fact that constrains intervention development and implementation. This paper describes data from a public sexually transmitted infection (STI) and HIV clinic study in the San Juan metropolitan area between April 2010 and December 2012 (n = 1185), roughly a third (36%) of whom are living with HIV. Descriptive statistics, chi square, t-tests, and binary logistic regressions were used to assess associations between HIV status and a history of suicide attempt. The overall prevalence of a history of suicide attempt was 20.4%. No statistically significant relationship was found between a history of suicide attempt and being HIV positive, although people with HIV infection did evidence a higher prevalence of attempts than HIV negative subjects (23.4% vs. 19.0%). Factors associated with having a history of suicide attempt within the overall sample included gender, current employment status, a lifetime history of drug use, and a lifetime history of sex work. Similar patterns were seen in the HIV-positive subsample. There was a nonsignificant trend toward increased risk for a post-diagnosis suicide attempt. These findings suggest that additional research on mental health risks among populations at risk for HIV in PR is needed. PMID- 24625260 TI - Mushroom dietary fiber from the fruiting body of Pleurotus tuber-regium: fractionation and structural elucidation of nondigestible cell wall components. AB - The cell wall of mushroom fruiting body is constituted of nondigestible macromolecules that are a rich source of dietary fiber with biological functions that are beneficial to human health. The cell wall components of an edible mushroom fruiting body from Pleurotus tuber-regium (PTR) were fractionated, and their chemical structures were investigated by chemical, physicochemical, and microscopic analyses. The present results suggest that the cell wall of the PTR mushroom fruiting body contains four main fractions: an outer fraction of polysaccharide and protein complex, which can be extracted using boiling water; a cold alkali-soluble fraction of heteropolysaccharides associated with a small amount of proteins; a hot alkali-soluble fraction of hyper-branched glucans; and an alkali-insoluble fraction of glucan-chitin complex with a normalized relative percentage of 3.6:21.9:55.7:18.8. The anomeric linkage of all the glucans was revealed by infrared spectroscopy to be beta type. The structure of the major mushroom fruiting body cell wall polysaccharide (the hot alkali-soluble one, FHA I) was elucidated by the methylation analysis to be composed of ->1)-Glcp-(4-> linkages as the backbone with a 52% degree of branching consisting of ->1)-Glcp (6-> linkages in the side chains, whereas some ->1)-Glcp-(3-> linkages might exist in the backbone or side chains. Size exclusion chromatography coupled with multiangle laser light scattering analysis revealed that FHA-I had a molecular weight of 4.224 * 10(6) g/mol and a root-mean-square radius of 30.4 nm. Both scanning electron and atomic force microscopy further showed the highly branched microstructure of FHA-I when dispersed in an aqueous sodium dodecyl sulfate solution. PMID- 24625261 TI - Clarifying values: an updated review. AB - BACKGROUND: Consensus guidelines have recommended that decision aids include a process for helping patients clarify their values. We sought to examine the theoretical and empirical evidence related to the use of values clarification methods in patient decision aids. METHODS: Building on the International Patient Decision Aid Standards (IPDAS) Collaboration's 2005 review of values clarification methods in decision aids, we convened a multi-disciplinary expert group to examine key definitions, decision-making process theories, and empirical evidence about the effects of values clarification methods in decision aids. To summarize the current state of theory and evidence about the role of values clarification methods in decision aids, we undertook a process of evidence review and summary. RESULTS: Values clarification methods (VCMs) are best defined as methods to help patients think about the desirability of options or attributes of options within a specific decision context, in order to identify which option he/she prefers. Several decision making process theories were identified that can inform the design of values clarification methods, but no single "best" practice for how such methods should be constructed was determined. Our evidence review found that existing VCMs were used for a variety of different decisions, rarely referenced underlying theory for their design, but generally were well described in regard to their development process. Listing the pros and cons of a decision was the most common method used. The 13 trials that compared decision support with or without VCMs reached mixed results: some found that VCMs improved some decision-making processes, while others found no effect. CONCLUSIONS: Values clarification methods may improve decision-making processes and potentially more distal outcomes. However, the small number of evaluations of VCMs and, where evaluations exist, the heterogeneity in outcome measures makes it difficult to determine their overall effectiveness or the specific characteristics that increase effectiveness. PMID- 24625262 TI - Lipid nanoparticles loaded with 7-ethyl-10-hydroxycamptothecin-phospholipid complex: in vitro and in vivo studies. AB - 7-Ethyl-10-hydroxy-camptothecin (SN38), the active metabolite of irinotecan (CPT 11), is an effective antineoplastic agent against many malignancies. Although it is 100-fold to 1000-fold more potent than CPT-11, the clinical utility of SN38 has been extremely restricted because of its poor solubility in any pharmaceutically acceptable solvents. The aim of this study was to develop SN38 nanoparticles (SN38-PC-LNs) using pharmaceutically acceptable excipients, and investigate the therapeutic efficacies in vitro and in vivo. SN38-phospholipid complex (SN38-PC) was prepared and loaded into lipid nanoparticles. The particle size was approximately 200 nm with a narrow size distribution. A high encapsulation efficiency of 88.11% +/- 1.41% and drug loading of 9.55% +/- 0.84% were achieved under the optimal condition. SN38-PC-LNs exhibited potent cytotoxic effects against a panel of human tumor cell lines (HT-29, HepG2, A549 and MCF-7). In vivo evaluation proved the enhanced antitumor efficacy of SN38-PC-LNs in mice bearing S180 tumor as well. The results from this study demonstrated an effective formulation of SN38 has been developed, which is promising for the delivery of SN38 for tumor chemotherapy. PMID- 24625263 TI - The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier. AB - To further develop cholesterol-modified pullulan self-aggregated nanoparticles (CHSPNs) as a drug nanocarrier, CHSP was synthesized and characterized. Its cholesterol degree determined by 1H NMR was 5.2 cholesterol groups per hundred glucose units. CHSPNs were prepared in aqueous media and characterized by dynamic laser light-scattering (DLS), zeta potential and transmission electron microscopy (TEM). These nanoparticles were almost spherical in shape, and the zeta potentials of CHSPNs were near zero in aqueous media. CHSPNs can be stable at least 2 months with no significant size and zeta potential changes. Single dose toxicity test in mice was investigated for the safety evaluation of CHSPNs as a drug nanocarrier, and the result showed CHSPNs were well tolerated at the dose of 200 mg/kg in mice. Epirubicin (EPI)-loaded CHSPNs (EPI-CHSPNs) were prepared and the in vivo pharmacokinetics and biodistribution were studied. Compared with the EPI solution, EPI-CHSPNs have exhibited higher plasma drug concentration, longer half-life time (t(1/2)) and the larger area under-the-curve (AUC). Moreover, the drug level of EPI-CHSPNs increased in liver and decreased in heart. The results indicated that CHSPNs were stable, safe and may be a promising drug delivery carrier. PMID- 24625264 TI - Effect of high-pressure homogenization on formulation of TPGS loaded nanoemulsion of rutin - pharmacodynamic and antioxidant studies. AB - Polyphenolic bioflavonoid, Rutin possesses wide range of pharmacological activities. However, it shows poor bioavailability when administered orally. The aim of this study was to formulate and compare the potential of nanoemulsions for the solubility enhancement of rutin (RU) by using different techniques. RU-loaded nanoemulsions were prepared by spontaneous emulsification method and high pressure homogenization (HPH) technique using sefsol 218 and tocopheryl polyethylene glycol 1000 succinate (TPGS) (1:1), solutol HS15 andtranscutol P as oil phase, surfactant and co-surfactant, respectively. The prepared formulations were compared for various parameters like droplet size, percentage transmittance, zeta potential, viscosity, refractive index and in vitro release. The HPH nanoemulsions showed smaller droplet size and increased in vitro release when compared to nanoemulsions prepared by spontaneous emulsification method. The optimized formulation showed spherical globules with average globule diameter of 18 nm and zeta potential of -41 mV. Cumulative percentage drug released obtained for RU, PF6 (spontaneous emulsification formulation F6) and HF6 (HPH formulation F6) were 41.5 +/- 0.04%, 49.5 +/- 0.06% and 94.8 +/- 0.03%, respectively, after 6 h. The permeability of RU from HF6 was found to be ~4.6 times higher than RU suspension during ex vivo everted gut sac studies. Antioxidant activity was determined by using DPPH assay and reducing power assay method. Results showed a high scavenging efficiency toward DPPH radicals by HF6. Anti-inflammatory effect of RU as determined by carrageenan-induced rat paw edema method was found to be higher (75.2 +/- 4.8%) when compared to RU suspension (46.56 +/- 3.5%). It can be inferred that TPGS-loaded nanoemulsion of RU serve as an effective tool in increasing solubility and permeability of RU. PMID- 24625266 TI - Designing breathalyser technology for the developing world: how a single breath can fight the double disease burden. AB - The meteoric rise in the prevalence of non-communicable diseases, alongside already high rates of infectious diseases, is exacerbating the 'double disease burden' in the developing world. There is a desperate need for affordable, accessible and ruggedized diagnostic tools that detect diseases early and direct patients to the correct channels. Breath analysis, the science of utilizing biomarkers in the breath for diagnostic measures, is growing rapidly, especially for use in clinical diagnostic settings. Breathalyser technologies are improving scientifically, but are not yet ready for productization and dissemination to address healthcare challenges. How does one ensure that these new biomedical devices will be suitable for use in developing communities? This article presents a comprehensive review of breath analysis technologies followed by a discussion on how such devices can be designed to conform with WHO's ASSURED criteria so as to reach and sustain in developing countries where they are needed the most. PMID- 24625267 TI - Abstracts of the International Network on Brief Interventions for Alcohol and Other Drugs (INEBRIA) Meeting 2013, 18-20 September 2013, Rome, Italy. PMID- 24625268 TI - Negative differential resistance behavior and memory effect in laterally bridged ZnO nanorods grown by hydrothermal method. AB - A novel memory device based on laterally bridged ZnO nanorods (NRs) in the opposite direction was fabricated by the hydrothermal growth method and characterized. The electrodes were defined by a simple photolithography method. This method has lower cost, simpler process, and higher reliability than the traditional focused ion beam lithography method. For the first time, the negative differential resistance and bistable unipolar resistive switching (RS) behavior in the current-voltage curve was observed at room temperature. The memory device is stable and rewritable; it has an ultra-low current level of about 1 * 10(-13) A in the high resistance state; and it is nonvolatile with an on-off current ratio of up to 1.56 * 10(6). Moreover, its peak-to-valley current ratio of negative differential resistance behavior is greater than 1.76 * 10(2). The negative differential resistance and RS behavior of this device may be related to the boundaries between the opposite bridged ZnO NRs. Specifically, the RS behavior found in ZnO NR devices with a remarkable isolated boundary at the NR/NR interface was discussed for the first time. The memory mechanism of laterally bridged ZnO NR-based devices has not been discussed in the literature yet. In this work, results show that laterally bridged ZnO NR-based devices may have next generation resistive memories and nanoelectronic applications. PMID- 24625269 TI - Head morphology of Tricholepidion gertschi indicates monophyletic Zygentoma. AB - The relic silverfish Tricholepidion gertschi is the sole extant representative of the family Lepidotrichidae. Its phylogenetic position is of special interest, since it may provide crucial insights into the early phenotypic evolution of the dicondylian insects. However, the phylogenetic position of T. gertschi is unclear. Originally, it was classified among silverfish (Zygentoma), but various alternative relationships within Zygentoma as well as a sistergroup relationship to all remaining Zygentoma + Pterygota are discussed, the latter implying a paraphyly of Zygentoma with respect to Pterygota. Since characters of the head anatomy play a major role in this discussion, we here present the so far most detailed description of the head of T. gertschi based on anatomical studies by synchrotron micro-computer tomography and scanning electron microscopy. A strong focus is put on the documentation of mouthparts and the anatomy of the endoskeleton as well as the muscle equipment. In contrast to former studies we could confirm the presence of a Musculus hypopharyngomandibularis (0md4). The ligamentous connection between the mandibles composed of Musculus tentoriomandibularis inferior (0md6) is also in contact with the anterior tentorium. Phylogenetic analysis of cephalic data results in monophyletic Zygentoma including T. gertschi. Zygentoma are supported by the presence of a set of labial muscles originating at the postocciput, presence of an additional intralabral muscle, and four labial palpomeres. Character systems like the genitalic system, the mating behaviour, the segmentation of the tarsi, the overall body form, and the presence of ocelli which were proposed in other studies as potentially useful for phylogenetic reconstruction are evaluated. PMID- 24625270 TI - Self-organization of highly symmetric nanoassemblies: a matter of competition. AB - The properties and applications of metallic nanoparticles are inseparably connected not only to their detailed morphology and composition but also to their structural configuration and mutual interactions. As a result, the assemblies often have superior properties as compared to individual nanoparticles. Although it has been reported that nanoparticles can form highly symmetric clusters, if the configuration can be predicted as a function of the synthesis parameters, more targeted and accurate synthesis will be possible. We present here a theoretical model that accurately predicts the structure and configuration of self-assembled gold nanoclusters. The validity of the model is verified using quantitative experimental data extracted from electron tomography 3D reconstructions of different assemblies. The present theoretical model is generic and can in principle be used for different types of nanoparticles, providing a very wide window of potential applications. PMID- 24625271 TI - The role of emotion on the recall of central and peripheral information from script-based text. AB - In three experiments, script-based stories were used to provide thematic emotion. Consistent with past research expressing emotion thematically, emotion aided recall of both central and peripheral information. However, emotion had to be directly associated with the central or peripheral information, and emotion only facilitated memory for peripheral information when peripheral information alone was associated with the emotion. Emotion did not aid overall recall of stories. Positive and negative emotions were generally better recalled when they were incongruent with the information they were associated with, such as a positive emotion associated with an interruptive action. These results provide evidence that thematically expressed, low arousal emotion can have facilitative effects on memory. Implications for the role of emotion on memory are discussed. PMID- 24625272 TI - Molecular docking of different inhibitors and activators to butyrylcholinesterase. AB - There are three major active sites of butyrylcholinesterase: catalytic site, peripheral site, and activator site. In this study, pseudosubstrate inhibitors, 1,3,5-alkylcarbamyloxybenzenes (1-11), were designed as the catalytic site directed inhibitors of the enzyme. Automated docking of 1,3,5-tri-n octylcarbamyloxybenzene 1 into the X-ray crystal structure of butyrylcholinesterase suggested that the configuration of the inhibitor in the enzyme complex is in the (1,3,5)-(cis,trans,trans)-form. Thus, the cis n octylcarbamyl group of 1 extended itself to the peripheral site; furthermore, two trans n-octylcarbamyl moieties of 1 shielded W82 of the anionic site. 5-N-n Butylcarbamyloxyresorcinol (12) was further used to characterize the butyryl group binding site of the catalytic site. Automated docking of 12 into the enzyme showed that the best bound rotamer of the inhibitor in the enzyme complex was the trans form. Moreover, the butylcarbamyl moiety of 12 was bound well into the butyryl group binding site of the enzyme. Docking of cage amines into the enzyme indicated that these compounds were bound into the peripheral site of the enzyme. We also found that a small cave, located outside the enzyme around A277-Y282, might play an important role in the activation of the enzyme. Two activators of butyrylcholinesterase, n-butyl-N-carbamyloxy-3,3-dimethylbutane and 2,4,6 trinitrotoluene, were docked well into the above-mentioned cave. PMID- 24625273 TI - Subacromial impingement syndrome and pain: protocol for a randomised controlled trial of exercise and corticosteroid injection (the SUPPORT trial). AB - BACKGROUND: Subacromial impingement syndrome is the most frequent cause of shoulder problems which themselves affect 1 in 3 adults. Management commonly includes exercise and corticosteroid injection. However, the few existing trials of exercise or corticosteroid injection for subacromial impingement syndrome are mostly small, of poor quality, and focus only on short-term results. Exercise packages tend to be standardised rather than individualised and progressed. There has been much recent interest in improving outcome from corticosteroid injections by using musculoskeletal ultrasound to guide injections. However, there are no high-quality trials comparing ultrasound-guided and blind corticosteroid injection in subacromial impingement syndrome. This trial will investigate how to optimise the outcome of subacromial impingement syndrome from exercise (standardised advice and information leaflet versus physiotherapist-led exercise) and from subacromial corticosteroid injection (blind versus ultrasound-guided), and provide long-term follow-up data on clinical and cost-effectiveness. METHODS/DESIGN: The study design is a 2x2 factorial randomised controlled trial. 252 adults with subacromial impingement syndrome will be recruited from two musculoskeletal Clinical Assessment and Treatment Services at the primary secondary care interface in Staffordshire, UK. Participants will be randomised on a 1:1:1:1 basis to one of four treatment groups: (1) ultrasound-guided subacromial corticosteroid injection and a physiotherapist-led exercise programme, (2) ultrasound-guided subacromial corticosteroid injection and an advice and exercise leaflet, (3) blind subacromial corticosteroid injection and a physiotherapist-led exercise programme, or (4) blind subacromial corticosteroid injection and an advice and exercise leaflet. The primary intention-to-treat analysis will be the mean differences in Shoulder Pain and Disability Index (SPADI) scores at 6 weeks for the comparison between injection interventions and at 6 months for the comparison between exercise interventions. Although independence of treatment effects is assumed, the magnitude of any interaction effect will be examined (but is not intended for the main analyses). Secondary outcomes will include comparison of long-term outcomes (12 months) and cost effectiveness. A secondary per protocol analysis will also be performed. DISCUSSION: This protocol paper presents detail of the rationale, design, methods and operational aspects of the SUPPORT trial. TRIAL REGISTRATION: Current controlled trials ISRCTN42399123. PMID- 24625274 TI - Replacing the axial ligand tyrosine 75 or its hydrogen bond partner histidine 83 minimally affects hemin acquisition by the hemophore HasAp from Pseudomonas aeruginosa. AB - Hemophores from Pseudomonas aeruginosa (HasAp), Serratia marcescens (HasAsm), and Yersinia pestis (HasAyp) bind hemin between two loops. One of the loops harbors conserved axial ligand Tyr75 (Y75 loop) in all three structures, whereas the second loop (H32 loop) contains axial ligand His32 in HasAp and HasAsm, but a noncoordinating Gln32 in HasAyp. Binding of hemin to the Y75 loop of HasAp or HasAsm causes a large rearrangement of the H32 loop that allows His32 coordination. The Q32 loop in apo-HasAyp is already in the closed conformation, such that binding of hemin to the conserved Y75 loop occurs with minimal structural rearrangement and without coordinative interaction with the Q32 loop. In this study, structural and spectroscopic investigations of the hemophore HasAp were conducted to probe (i) the role of the conserved Tyr75 loop in hemin binding and (ii) the proposed requirement of the His83-Tyr75 hydrogen bond to allow the coordination of hemin by Tyr75. High-resolution crystal structures of H83A holo HasAp obtained at pH 6.5 (0.89 A) and pH 5.4 (1.25 A) show that Tyr75 remains coordinated to the heme iron, and that a water molecule can substitute for Ndelta of His83 to interact with the Oeta atom of Tyr75, likely stabilizing the Tyr75-Fe interaction. Nuclear magnetic resonance spectroscopy revealed that in apo-Y75A and apo-H83A HasAp, the Y75 loop is disordered, and that disorder propagates to nearby elements of secondary structure, suggesting that His83 Ndelta-Tyr75 Oeta interaction is important to the organization of the Y75 loop in apo-HasA. Kinetic analysis of hemin loading conducted via stopped-flow UV-vis and rapid-freeze quench resonance Raman shows that both mutants load hemin with biphasic kinetic parameters that are not significantly dissimilar from those previously observed for wild-type HasAp. When the structural and kinetic data are taken together, a tentative model emerges, which suggests that HasA hemophores utilize hydrophobic, pi-pi stacking, and van der Waals interactions to load hemin efficiently, while axial ligation likely functions to slow hemin release, thus allowing the hemophore to meet the challenge of capturing hemin under inhospitable conditions and delivering it selectively to its cognate receptor. PMID- 24625275 TI - Respiratory health equality in the United States. The American thoracic society perspective. AB - Because the frequency of major risk factors for respiratory diseases (e.g., tobacco use) differs across demographic groups (defined by socioeconomic status, race/ethnicity, sexual orientation, health care access, occupation, or other characteristics), health disparities are commonly encountered in pediatric and adult pulmonary, critical care, and sleep medicine. As part of its policy on respiratory health disparities, the American Thoracic Society (ATS) Executive Committee created a Health Equality Subcommittee of the Health Policy Committee, with an initial mandate of defining respiratory health equality and, as a subsequent task, providing recommendations to the ATS leadership as to how our society may help attain such equality in the United States. After receiving input from the ATS assemblies and committees, the subcommittee developed this document on respiratory health equality. This document defines respiratory health disparities and respiratory health equality, and expands on a recent ATS and European Respiratory Society policy statement on disparities in respiratory health. Attainment of respiratory health equality requires the ending of respiratory health disparities, which can be achieved only through multidisciplinary efforts to eliminate detrimental environmental exposures while promoting a healthy lifestyle, implementing all components of high-quality health care (prevention, screening, diagnosis, and treatment), and conducting research that will lead to better prevention and management of respiratory diseases for everyone. The ATS recognizes that such efforts must include all stakeholders: members of society at large, governmental and nongovernmental organizations, and other professional societies. The ATS urges all of its members and those of sister societies to work to achieve this laudable goal. PMID- 24625276 TI - Isothermal microcalorimetry provides new insight into terrestrial carbon cycling. AB - Energy is continuously transformed in environmental systems through the metabolic activities of living organisms, but little is known about the relationship between the two. In this study, we tested the hypothesis that microbial energetics are controlled by microbial community composition in terrestrial ecosystems. We determined the functional diversity profiles of the soil biota (i.e., multiple substrate-induced respiration and microbial energetics) in soils from an arable ecosystem with contrasting long-term management regimes (54 years). These two functional profiling methods were then related to the soils' microbial community composition. Using isothermal microcalorimetry, we show that direct measures of energetics provide a functional link between energy flows and the composition of below-ground microbial communities at a high taxonomic level (Mantel R = 0.4602, P = 0.006). In contrast, this link was not apparent when carbon dioxide (CO2) was used as an aggregate measure of microbial metabolism (Mantel R = 0.2291, P = 0.11). Our work advocates that the microbial energetics approach provides complementary information to soil respiration for investigating the involvement of microbial communities in below-ground carbon dynamics. Empirical data of our proposed microbial energetics approach can feed into carbon climate based ecosystem feedback modeling with the suggested conceptual ecological model as a base. PMID- 24625277 TI - Neuropeptides as therapeutic targets to combat stress-associated behavioral and neuroendocrinological effects. AB - Stress has become an integral part of human life and organisms are being constantly subjected to stress and the ability to cope with such stress is a crucial determinant of health and disease. Neuropeptides (bioactive peptides) play a crucial role in mediating different effects of acute and chronic stress. Some of these neuropeptides including oxytocin, urocortins, neuropeptide Y (NPY), neuropeptide S, cocaine and amphetamine regulated transcript, endorphins, enkephalins, ghrelin and thyrotropin-releasing hormone primarily attenuate stress and act as anxiolytic. On the other hand, neuropeptides including corticotropin releasing hormone, vasopressin, dynorphin, angiotensin, nesfatin-1, orexin and cholecystokinin primarily tend to promote stress related anxiety behavior. However, these neuropeptide tend to produce different actions depending on the type of receptors, the nature and intensity of the stressor. For example, NPY may exhibit anxiolytic effects by activating NPY1 and Y5 receptors, while pro depressive effects are produced through NPY2 and Y4 receptors. Galanin may produce 'prodepressive' effects by activating its Gal 1 receptors and exert 'antidepressant' effects through Gal 2 receptors. The present review describes different neuropeptides as therapeutic targets to attenuate stress-induced behavioral and neuroendocrinological effects. PMID- 24625278 TI - Molecular cloning of a Poria cocos protein that activates Th1 immune response and allays Th2 cytokine and IgE production in a murine atopic dermatitis model. AB - Edible fungus Poria cocos (Schw.) Wolf is a cooking material that has myriad health benefits. However, its active constituents have not been well-defined. We previously purified an immunomodulatory protein, PCP, from P. cocos and described its biochemical features and its ability to activate primary macrophage via TLR4. In this study, we cloned the gene of PCP and demonstrated its ability to activate Th1 response in cell cultures and in mice. The complete cDNA sequence of PCP consisted of 807 bp, which included a 579 bp coding sequence that encoded 194 amino acids. With the addition of co-stimulatory CD3/CD28 signals, PCP significantly increased the surface expression of CD44 and CD69 on effector T cells. PCP could also up-regulate T-bet and STAT4 expressions and IFN-gamma and IL-2 secretions. Oral administration of PCP suppressed the production of both total and OVA-specific IgG1 in serum and enhanced the amounts of serum and OVA specific IgG2a and Th1-related cytokine production in BALB/c splenocytes. In addition, oral administration of PCP significantly reduced IL-4 and IgE expressions in a murine model of atopic dermatitis. In conclusion, these results provide evidence that PCP could regulate mammalian immune cells and reveal their pharmaceutical potential in developing therapeutic strategies against Th2 mediated immune disorders. PMID- 24625280 TI - Abstracts of the Molecular Neurodegeneration: Basic biology and disease pathways meeting, 10-12 September 2013, Cannes, France. PMID- 24625279 TI - An assessment of health-care students' attitudes toward patients with or at high risk for HIV: implications for education and cultural competency. AB - Stigma perpetuated by health-care providers has been found to be a barrier to care for vulnerable populations, including HIV-infected, people who inject drugs (PWIDs), and men who have sex with men (MSM) in multiple clinical contexts and remains unexamined among professional health-care students in Malaysia. This cross-sectional, anonymous, and Internet-based survey assessed the attitudes of medical and dental students toward HIV-infected, PWID, and MSM patients. Survey invitation was emailed to 3191 students at 8 professional schools; 1296 (40.6%) responded and scored their attitudes toward these patient groups using a feeling thermometer, indicating their attitudes on a sliding scale from 0 (most negative) to 100 (most positive). Compared to general patients (mean = 76.50), the mean scores for HIV-infected (mean = 54.04; p < 0.001), PWID (mean = 37.50; p < 0.001), and MSM (mean = 32.13; p < 0.001) patients were significantly lower and significantly different between each group comparison. Within group differences, most notably religion, ethnicity, and personally knowing someone from these populations were associated with significant differences in attitudes. No differences were noted between pre-clinical and clinical year of training. Health care students represent the next generation of clinicians who will be responsible for future HIV prevention and treatment efforts. Our findings suggest alarmingly negative attitudes toward these patients, especially MSM, necessitating prompt and effective interventions designed to ameliorate the negative attitudes of health-care students toward vulnerable populations, specifically HIV-infected, PWID, and MSM patients in Malaysia. PMID- 24625281 TI - Clinical predictors of a positive genetic test in hypertrophic cardiomyopathy in the Brazilian population. AB - BACKGROUND: Hypertrophic cardiomyopathy is a genetic autosomal dominant disease characterized by left ventricular hypertrophy. The molecular diagnosis is important but still expensive. This work aimed to find clinical predictors of a positive genetic test in a Brazilian tertiary centre cohort of index cases with HCM. METHODS: In the study were included patients with HCM clinical diagnosis. For genotype x phenotype comparison we have evaluated echocardiographic, electrocardiographic, and nuclear magnetic resonance measures. All patients answered a questionnaire about familial history of HCM and/or sudden death. beta myosin heavy chain, myosin binding protein C, and troponin T genes were sequenced for genetic diagnosis. RESULTS: The variables related to a higher probability of a positive genetic test were familial history of HCM, higher mean heart frequency, presence of NSVT and lower age. Probabilities of having a positive molecular genetic test were calculated from the final multivariate logistic regression model and were used to identify those with a higher probability of a positive molecular diagnosis. CONCLUSIONS: We developed an easy and fast screening method that takes into account only clinical data that can help to select the patients with a high probability of positive genetic results from molecular sequencing of Brazilian HCM patients. PMID- 24625282 TI - Fumigatosides A-D, four new glucosidated pyrazinoquinazoline indole alkaloids from a jellyfish-derived fungus Aspergillus fumigatus. PMID- 24625284 TI - 9th WINFOCUS World Congress on Ultrasound in Emergency and Critical Care. PMID- 24625283 TI - Do personal stories make patient decision aids more effective? A critical review of theory and evidence. AB - BACKGROUND: Patient decision aids support people to make informed decisions between healthcare options. Personal stories provide illustrative examples of others' experiences and are seen as a useful way to communicate information about health and illness. Evidence indicates that providing information within personal stories affects the judgments and values people have, and the choices they make, differentially from facts presented in non-narrative prose. It is unclear if including narrative communications within patient decision aids enhances their effectiveness to support people to make informed decisions. METHODS: A survey of primary empirical research employing a systematic review method investigated the effect of patient decision aids with or without a personal story on people's healthcare judgements and decisions. Searches were carried out between 2005-2012 of electronic databases (Medline, PsycINFO), and reference lists of identified articles, review articles, and key authors. A narrative analysis described and synthesised findings. RESULTS: Of 734 citations identified, 11 were included describing 13 studies. All studies found participants' judgments and/or decisions differed depending on whether or not their decision aid included a patient story. Knowledge was equally facilitated when the decision aids with and without stories had similar information content. Story-enhanced aids may help people recall information over time and/or their motivation to engage with health information. Personal stories affected both "system 1" (e.g., less counterfactual reasoning, more emotional reactions and perceptions) and "system 2" (e.g., more perceived deliberative decision making, more stable evaluations over time) decision-making strategies. Findings exploring associations with narrative communications, decision quality measures, and different levels of literacy and numeracy were mixed. The pattern of findings was similar for both experimental and real-world studies. CONCLUSIONS: There is insufficient evidence that adding personal stories to decision aids increases their effectiveness to support people's informed decision making. More rigorous research is required to elicit evidence about the type of personal story that a) encourages people to make more reasoned decisions, b) discourages people from making choices based on another's values, and c) motivates people equally to engage with healthcare resources. PMID- 24625285 TI - Histologic differences in placentas of preeclamptic/eclamptic gestations by birthweight, placental weight, and time of onset. AB - With preeclampsia/eclampsia (PE/E), infants more often are either large or small for gestational age. We explored whether the differences in infant birthweight (BW), placental weights (PW), or time of onset are associated with histologic features of maternal vascular underperfusion. A retrospective chart identified 243 PE/E gestations between 2007 and 2010. Gestational age only was known at slide review. Investigated features included increased syncytial knots, villous agglutination, increased intervillous fibrin, distal villous hypoplasia, acute atherosis, mural hypertrophy of membrane arterioles, muscularized basal plate arteries, increased placental site giant cells, increased immature intermediate trophoblasts, infarcts, and villitis. The results were correlated with BW, PW, and onset time PE/E. One hundred thirty-eight PE/E gestations were identified with adequate slides and history. Increased BW placentas had decreased syncytial knots and increased mural hypertrophy of membrane arterioles. Decreased BW had increased placenta site giant cells. Increased PW had decreased distal villous hypoplasia. Decreased PW had increased syncytial knots, increased intervillous fibrin, and increased acute atherosis. Early-onset disease had increased syncytial knots, distal villous hypoplasia, villous agglutination, and infarcts. This suggests PE/E is not a single process resulting in a uniform distribution of lesions but, rather, is composed of several different processes manifesting a single clinical presentation. PMID- 24625286 TI - Epidemiology and antibiotic resistance in a large Italian teaching hospital. AB - We focused our attention on susceptibility profile of Acinetobacter spp., Pseudomonas spp., and Klebsiella spp. isolated from biological specimens at the University Hospital of Salerno between June 2011 and October 2012. Acinetobacter, with a prevalence of Acinetobacter baumannii (97%) presented a high range of resistance to the antimicrobials considered, excluding colistin (COL). Klebsiella spp. isolates, with a prevalence of Klebsiella pneumoniae (90%), presented a variable pattern of resistance [from 9.8% for COL to 50% for levofloxacin (LEV)]. Extended-spectrum beta-lactamases production was detected in 15% of isolates. Most Pseudomonas isolates were P. aeruginosa with a high rate of resistance (95% to amoxicillin/clavulanate and trimethoprim/sulfamethoxazole, and <50% to the other antibiotics). Colistin remained the most effective drug tested. This study provided useful information of the local bacterial epidemiology hopefully permitting to establish a more effective empirical therapy, preventing the inappropriate use of antibacterial agents and possibly limiting the diffusion of antibacterial resistance. PMID- 24625287 TI - Preparation of vincristine sulfate-loaded poly (butylcyanoacrylate) nanoparticles modified with pluronic F127 and evaluation of their lymphatic tissue targeting. AB - In order to improve the lymphatic targeting efficiency of anti-cancer agent vincristine sulfate (VCR), the poly (butylcyanoacrylate) nanoparticles (VCR-PBCA NPs) were prepared by emulsion polymerization and modified superficially with Pluronic F127. These prepared nanoparticles with (F127-VCR-PBCA-NPs) and without surface modification (VCR-PBCA-NPs) were characterized and their lymphatic targeting efficiencies were evaluated in vitro and in vivo. The results showed that VCR was released more sustained from both kinds of VCR-loaded nanoparticles, compared with the VCR solution. The up-taking efficiency of VCR into raji cells was enhanced by F127-VCR-PBCA-NPs, compared with the VCR-PBCA-NPs or VCR solution. Lower clearance (CL) of VCR from the systemic circulation and higher lymphatic targeting efficiency of VCR were observed for F127-VCR-PBCA-NPs than the VCR-PBCA-NPs or VCR solution, and F127-VCR-PBCA-NPs showed greater antitumor efficacy than the VCR-PBCA-NPs or VCR solution in the human Burkitt's lymphoma (raji)-bearing nude mice. These findings suggest that superficially modified nanoscale carriers might be promising vehicles for chemotherapeutic agents in the treatments of metastatic tumors and malignant lymphoma. PMID- 24625288 TI - Differential resistance of drinking water bacterial populations to monochloramine disinfection. AB - The impact of monochloramine disinfection on the complex bacterial community structure in drinking water systems was investigated using culture-dependent and culture-independent methods. Changes in viable bacterial diversity were monitored using culture-independent methods that distinguish between live and dead cells based on membrane integrity, providing a highly conservative measure of viability. Samples were collected from lab-scale and full-scale drinking water filters exposed to monochloramine for a range of contact times. Culture independent detection of live cells was based on propidium monoazide (PMA) treatment to selectively remove DNA from membrane-compromised cells. Quantitative PCR (qPCR) and pyrosequencing of 16S rRNA genes was used to quantify the DNA of live bacteria and characterize the bacterial communities, respectively. The inactivation rate determined by the culture-independent PMA-qPCR method (1.5-log removal at 664 mg.min/L) was lower than the inactivation rate measured by the culture-based methods (4-log removal at 66 mg.min/L). Moreover, drastic changes in the live bacterial community structure were detected during monochloramine disinfection using PMA-pyrosequencing, while the community structure appeared to remain stable when pyrosequencing was performed on samples that were not subject to PMA treatment. Genera that increased in relative abundance during monochloramine treatment include Legionella, Escherichia, and Geobacter in the lab-scale system and Mycobacterium, Sphingomonas, and Coxiella in the full-scale system. These results demonstrate that bacterial populations in drinking water exhibit differential resistance to monochloramine, and that the disinfection process selects for resistant bacterial populations. PMID- 24625289 TI - Computer game-based upper extremity training in the home environment in stroke persons: a single subject design. AB - BACKGROUND: The objective of the present study was to assess whether computer game-based training in the home setting in the late phase after stroke could improve upper extremity motor function. METHODS: Twelve subjects with prior stroke were recruited; 11 completed the study. DESIGN: The study had a single subject design; there was a baseline test (A1), a during intervention test (B) once a week, a post-test (A2) measured directly after the treatment phase, plus a follow-up (C) 16-18 weeks after the treatment phase. Information on motor function (Fugl-Meyer), grip force (GrippitR) and arm function in activity (ARAT, ABILHAND) was gathered at A1, A2 and C. During B, only Fugl-Meyer and ARAT were measured. The intervention comprised five weeks of game-based computer training in the home environment. All games were designed to be controlled by either the affected arm alone or by both arms. Conventional formulae were used to calculate the mean, median and standard deviations. Wilcoxon's signed rank test was used for tests of dependent samples. Continuous data were analyzed by methods for repeated measures and ordinal data were analyzed by methods for ordered multinomial data using cumulative logistic models. A p-value of < 0.05 was considered statistically significant. RESULTS: Six females and five males, participated in the study with an average age of 58 years (range 26-66). FMA-UE A D (motor function), ARAT, the maximal grip force and the mean grip force on the affected side show significant improvements at post-test and follow-up compared to baseline. No significant correlation was found between the amount of game time and changes in the outcomes investigated in this study. CONCLUSION: The results indicate that computer game-based training could be a promising approach to improve upper extremity function in the late phase after stroke, since in this study, changes were achieved in motor function and activity capacity. PMID- 24625290 TI - The role of primary sequence in helical control compared across short alpha- and beta(3)-peptides. AB - alpha-helices are the most common form of secondary structure found in proteins. In order to study controlled protein folding, as well as manipulate the interface of helical peptides with targets in protein-protein interactions, many techniques have been developed to induce and stabilize alpha-helical structure in short synthetic peptides. Furthermore, short, non-natural beta-peptides have been established that fold into predictable 14-helices that mimic alpha-helical structure. We created a panel of short 6-8 residue alpha- and beta-peptides that used confirmed primary sequence design features which influence helical control and directly compared the helicity across peptides with the most minimal epitopes. Using CD spectroscopy, we found that both alpha- and beta-peptides abided by their respective design principles, with no significant "cross helicity" inducing an alpha- or a beta-peptide to fold into the oppositely controlled helix. Generally, the beta-peptide of the most optimal sequence displayed the largest percent of 14-helicity, whereas the two alpha-peptides of most favorable design showed some alpha-helicity and a marked 310-helical contribution. Overall, the results can inform future peptidomimetic designs, especially in the development of short, structured peptides with biological function. PMID- 24625291 TI - ImproWin(r) in the treatment of gastric ulceration of the squamous mucosa in trotting racehorses. AB - BACKGROUND: Gastric ulceration is highly prevalent in horses, and there is a large commercial market for feed-additives and non-licenced products that claim effect for prevention and treatment of gastric ulceration. ImproWin(r) has been used as a feed additive in horses with anecdotal evidence that it may have some positive effects on gastric ulceration.The aim of this study was to investigate the effect of ImproWin(r) treatment on spontaneously occurring gastric ulcers of the squamous mucosa in Standardbred and Coldblooded trotting racehorses. The study was performed as a randomised, double-blinded, single centre study with stratified semi cross-over design with breed as stratification factors. The horses were clinically and endoscopically examined prior to start and after three weeks of treatment. The ulcerations were scored in accordance with Equine Gastric Ulcer Council (EGUC) recommendations on a 5 point scale and on a 10 cm Visual Analogue Scale (VAS). The patients were responder-classified after 3 weeks. Responders in need of ulcer treatment were randomly allocated to 2 or 4 weeks of additional treatment. Non-responders to placebo were crossed to ImproWin(r). RESULTS: The 5-point EGUC score and VAS recorded score was significantly reduced (P <= 0.01) in both groups after 3 weeks of treatment. From 3 weeks to the end of treatment the score was further significantly reduced in the ImproWin(r) group (P <= 0.05). At the end of treatment, 78% in the ImproWin(r) group and 54.8% in the placebo group were classified as responders. The difference was significant (P = 0.04). CONCLUSIONS: ImproWin(r) may aid the healing process of ulcers of the gastric squamous mucosa of trotters. PMID- 24625293 TI - The impact of HIV on children's education in eastern Zimbabwe. AB - Little is known about how HIV impacts directly and indirectly on receiving, or particularly succeeding in, education in sub-Saharan Africa. To address this gap, we used multivariable logistic regression to determine the correlation between education outcomes in youth (aged 15-24) (being in the correct grade-for-age, primary school completion and having at least five "O" level passes) and being HIV-positive; having an HIV-positive parent; being a young carer; or being a maternal, paternal or double orphan, in five rounds (1998-2011) of a general population survey from eastern Zimbabwe. The fifth survey round (2009-2011) included data on children aged 6-17, which were analysed for the impacts of the above risk factors on regular attendance in primary and secondary schools and being in the correct grade-for-age. For data pooled over all rounds, being HIV positive had no association with primary school completion, "O" level passes, or being in the correct grade-for-age in adolescents aged 16-17 years. Additionally, HIV status had no significant association with any education outcomes in children aged 6-17 surveyed in 2009-2011. In 2009-2011, being a young carer was associated with lower attendance in secondary school (69% vs. 85%, AOR: 0.44; p=0.02), whilst being a maternal (75% vs. 83%, AOR: 0.67; p<0.01), paternal (76% vs. 83%, AOR: 0.67; p=0.02) or double (75% vs. 83%, AOR: 0.68; p=0.02) orphan was associated with decreased odds of being in the correct grade-for-age. All forms of orphanhood also significantly decreased the odds of primary school completion in youths surveyed from 1998 to 2011 (all p<0.01). We found no evidence that HIV status affects education but further evidence that orphans do experience worse education outcomes than other children. Combination approaches that provide incentives for children to attend school and equip schools with tools to support vulnerable children may be most effective in improving education outcomes and should be developed and evaluated. PMID- 24625294 TI - Proceedings of 20th Pediatric Rheumatology European Society (PReS) Congress. PMID- 24625296 TI - Comparative degradation and regeneration of polymer solar cells with different cathodes. AB - A comparative degradation study of solar cells based on a bulk-heterojunction (BHJ) blend of poly(3-hexylethiophene) (P3HT) and phenyl [6,6] C61 butyric acid methyl ester (PCBM) with two different cathodes is reported. Poly(ethylene dioxythiphene):poly(styrene sulfonate) (PEDOT:PSS) coated ITO electrodes were used as the anode, whereas Ca/Al and Ca/Ag electrodes were used as cathodes. Fully degraded devices were subjected to thermal annealing under inert atmosphere. The performance of degraded solar cells with a Ca/Al cathode exhibited no improvement after treatment. However the solar cells with a Ca/Ag cathode exhibited a considerable recovery in their performance following annealing under a nitrogen atmosphere. Indeed, these solar cells could be subjected to many degradation and regeneration cycles. Current density-voltage (J V) characteristics and X-ray photoelectron spectroscopy (XPS) studies show that this behavior arises from the complex chemical thermodynamics of the reactions that can occur at the cathode/active layer interface. In particular, the recovery of device performance for solar cells with a Ca/Ag cathode is due to the reversible oxidation of Ag upon thermal annealing. PMID- 24625295 TI - The arabidopsis histone methyltransferase SUVR4 binds ubiquitin via a domain with a four-helix bundle structure. AB - In eukaryotes, different chromatin states facilitate or repress gene expression and restrict the activity of transposable elements. Post-translational modifications (PTMs) of amino acid residues on the N-terminal tails of histones are suggested to define such states. The histone lysine methyltransferase (HKMTase) SU(VAR)3-9 RELATED4 (SUVR4) of Arabidopsis thaliana functions as a repressor of transposon activity. Binding of ubiquitin by the WIYLD domain facilitates the addition of two methyl groups to monomethylated lysine 9 of histone H3. By using nuclear magnetic resonance (NMR) spectroscopy, we identified SUVR4 WIYLD (S4WIYLD) as a domain with a four-helix bundle structure, in contrast to three-helix bundles of other ubiquitin binding domains. NMR titration analyses showed that residues of helix alpha1 (Q38, L39, and D40) and helix alpha4 (N68, T70, A71, V73, D74, I76, S78, and E82) of S4WIYLD and residues between the first and second beta-strands (T9 and G10) and on beta-strands 3 (R42, G47, K48, and Q49) and 4 (H68, R72, and L73) undergo significant chemical shift changes when the two proteins interact. A model of the complex, generated using HADDOCK, suggests that the N-terminal and C-terminal parts of S4WIYLD constitute a surface that interacts with charged residues close to the hydrophobic patch of ubiquitin. The WIYLD domains of the closely related SUVR1 and SUVR2 Arabidopsis proteins also bind ubiquitin, indicating that this is a general feature of this domain. The question of whether SUVR proteins act as both readers of monoubiquitinated H2B and writers of histone PTMs is discussed. PMID- 24625297 TI - Taiwanese Green Propolis and Propolin G Protect the Liver from the Pathogenesis of Fibrosis via Eliminating TGF-beta-Induced Smad2/3 Phosphorylation. AB - Pathogenesis of fibrosis is a common process leading to chronic liver diseases and liver cirrhosis. New compounds for disease treatment and adjuvant therapy have been important issues in recent years. In this study, we isolated propolin G from Taiwanese green propolis (TGP) and investigated its antifibrotic effects by utilizing active hepatic stellate cells (HSCs) fibrosis model. Our results showed that TGP and propolin G inhibited alpha-SMA, collagen expression, and proliferation of HSC-T6 cells after TGF-beta treatment. They also reduced the accumulation of extracellular matrix (ECM) components such as collagen Ialpha1 (Col Ialpha1) through down-regulating JNK signaling. Subsequently, mRNA and protein expression of Smad2/3 but no other Smad members was specifically down regulated in the presence of propolin G. This effect also significantly induced apoptosis-associated expression of cleaved caspase-3 and caspase-7 proteins for fibrotic cell clearance. In in vivo experiments, we found that propolin G and TGP can reduce plasma alanine aminotransferase (ALT) activation and perhaps lead to the prevention of alcohol-induced liver cirrhosis. Furthermore, TGP can significantly decrease the malondialdehyde (MDA) level but has no influence on plasma or hepatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels, suggesting TGP protects the liver from alcohol-induced injury through antioxidant-independent pathways. In conclusion, this study provides a new perspective of propolin G and TGP on liver protection, and its application has potential for health management by daily supplement or adjuvant therapy in related diseases. PMID- 24625298 TI - Covalent bonding: the role of exchange effects. AB - It is stressed that the two-center exchange energy components lead to a significant lowering of the total molecular energy because of exclusion of self repulsion, and this is inevitable for covalent bond formation. The success of the two-center bond order index relies on the fact that it gives a qualitative estimate of this important phenomenon. PMID- 24625299 TI - Abstracts from the 26th National Congress of the Italian Society of Geriatric Surgery, 19-22 June 2013, Naples, Italy. PMID- 24625300 TI - A photoinduced, benzyne click reaction. AB - The [3 + 2] cycloaddition of azides and alkynes has proven invaluable across numerous scientific disciplines for imaging, cross-linking, and site-specific labeling among many other applications. We have developed a photoinitiated, benzyne-based [3 + 2] cycloaddition that is tolerant of a variety of functional groups as well as polar, protic solvents. The reaction is complete on the minute time scale using a single equivalent of partner azide, and the benzyne photoprecursor is stable for months under ambient light at room tempurature. Herein we report the optimization and scope of the photoinitiated reaction as well as characterization of the cycloaddition products. PMID- 24625301 TI - No high level evidence to support the use of oral H1 antihistamines as monotherapy for eczema: a summary of a Cochrane systematic review. AB - BACKGROUND: The most important symptom as well as one of the major diagnostic criteria for eczema is itch. Although oral antihistamines continue to be prescribed for people with eczema, it is unclear if they are effective and safe in relieving itch and skin lesions. We sought to evaluate the available evidence on effectiveness of oral antihistamines (H1 antagonists) as monotherapy in children and adults with eczema. METHODS: Searches included 10 databases and trial registers as well as conference proceedings (January 2014). Randomised controlled trials that assessed the effects of oral H1 antihistamines as monotherapy in children and adults with eczema were included. RESULTS: Our searches retrieved 757 references, but no randomised controlled trial met our inclusion criteria. Most studies allowed concomitant treatments, making the assessment of the individual effects of oral H1 antihistamines impossible. CONCLUSIONS: There is currently no high-level evidence to support or refute the efficacy or safety of oral H1 antihistamines used as monotherapy for eczema. A further review of studies that assesses the effects of oral H1 antihistamines as 'add-on' therapy together with concomitant treatments is warranted to determine the beneficial effects of this group of medications in the treatment of eczema. PMID- 24625302 TI - Supporting informed decision making when clinical evidence and conventional wisdom collide: papers developed from the Eisenberg Center Conference Series 2012. PMID- 24625303 TI - Competency in menopause management: whither goest the internist? AB - BACKGROUND: After publication of the Women's Health Initiative study in 2002, use of menopausal hormone therapy (HT) has declined by nearly 80% worldwide and internists now play only a limited role in menopause management. Over the past decade, new data have increased our knowledge of the multiple effects and mechanisms of HT. METHODS: Existing literature was reviewed. RESULTS: A consensus has emerged that the benefits of HT outweigh the risks for the relief of symptoms in women who have recently undergone menopause and are not at excess risk of breast cancer and cardiovascular disease. Non-hormonal agents, selective estrogen receptor modulators (SERMs), and tibolone are also useful in management. Factors entering into the decision-making process regarding menopause management are increasingly complex and involve consideration of effects on multiple systems and potential disease-related events. These considerations suggest that internists trained to evaluate and integrate factors influencing multiple organ systems should re-engage in menopause management. Most internists currently lack the core competencies and experience necessary to address menopausal issues and meet the needs of women who have completed their reproductive years. We believe that this situation is detrimental to women's health, leads to fragmented care, and should change. CONCLUSIONS: We propose that the multidimensional expertise that characterizes the internist may provide the most comprehensive approach to menopause management. For the internist to meet this need, a set of core competencies must be attained, which will require new didactic programs to be developed for medical students, residents and practicing physicians. PMID- 24625305 TI - Orthotopic liver transplantation in situs inversus adult from an ABO-incompatible donor with situs inversus. AB - BACKGROUND: Situs inversus is a rare congenital anomaly characterized by the complete inversion of thoracic and abdominal organs. Liver transplantation in such patients or from donors in situs inversus is technically challenging because of the reversed anatomic structures. A small number of successful liver transplantation cases concerning situs inverus in either recipients or donors have been recently reported with different graft position and orientation. Here we reported an extremely rare case of liver retransplantation from an ABO incompatible situs inversus donor to an adult situs inversus recipient. CASE PRESENTATION: A 53-year-old complete situs inversus man developed graft failure due to severe biliary complication after his first liver transplantation from a situs solitus donor. Re-transplantation was performed using a graft liver from a likewise situs inversus donor. Although the blood type between donor and recipient was incompatible, the post-operative outcome was excellent under proper prophylaxis to the antibody-mediated rejection. CONCLUSION: To the best of our knowledge, this is the first report of liver transplantation from situs inversus to situs inversus in adult recipient. Liver transplantation using situs matching donor makes the procedure much easier at the surgical point of view, which has a benefit of less potential surgical complications. Furthermore, ABO incompatibility is acceptable for donor allocation in cases that both donor and recipient are situs inversus. PMID- 24625306 TI - Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma. AB - INTRODUCTION: Melanoma is an aggressive disease characterized by a complex etiology. The discovery of key driving mutations (primarily BRAF mutations) led to the development of specific molecular inhibitors providing clinical benefit. AREAS COVERED: Although BRAF-specific drugs have perhaps yielded the best results in melanoma-targeted therapy, there still remain several limitations, mostly due to the emergence of resistance and the lack of efficacy in patients without BRAF mutation. Novel drugs are currently being tested in clinical trials and showed encouraging results. Such drugs can specifically target molecular pathways aberrantly activated or repressed during melanoma development (targeted therapy) or act in a way to enhance the host immune system to fight cancer (immunotherapy). Here we provide a detailed overview of the current clinical strategies, which lay beyond BRAF-targeted therapy, spanning from molecular targeted therapy to immunotherapy and to combination therapy. EXPERT OPINION: Major advances in our understanding of the mechanisms behind melanoma development have led to the implementation of novel therapeutic drugs. Unfortunately, tools allowing prediction of responsiveness to a given treatment are not available yet. The increasing availability of high-throughput technologies will allow the elucidation of molecular mechanisms underlying responsiveness to cancer therapy and unveil an increased number of potential therapeutic targets. PMID- 24625308 TI - Wearable accelerometry-based technology capable of assessing functional activities in neurological populations in community settings: a systematic review. AB - BACKGROUND: Integrating rehabilitation services through wearable systems has the potential to accurately assess the type, intensity, duration, and quality of movement necessary for procuring key outcome measures. OBJECTIVES: This review aims to explore wearable accelerometry-based technology (ABT) capable of assessing mobility-related functional activities intended for rehabilitation purposes in community settings for neurological populations. In this review, we focus on the accuracy of ABT-based methods, types of outcome measures, and the implementation of ABT in non-clinical settings for rehabilitation purposes. DATA SOURCES: Cochrane, PubMed, Web of Knowledge, EMBASE, and IEEE Xplore. The search strategy covered three main areas, namely wearable technology, rehabilitation, and setting. STUDY SELECTION: Potentially relevant studies were categorized as systems either evaluating methods or outcome parameters. METHODS: Methodological qualities of studies were assessed by two customized checklists, depending on their categorization and rated independently by three blinded reviewers. RESULTS: Twelve studies involving ABT met the eligibility criteria, of which three studies were identified as having implemented ABT for rehabilitation purposes in non clinical settings. From the twelve studies, seven studies achieved high methodological quality scores. These studies were not only capable of assessing the type, quantity, and quality measures of functional activities, but could also distinguish healthy from non-healthy subjects and/or address disease severity levels. CONCLUSION: While many studies support ABT's potential for telerehabilitation, few actually utilized it to assess mobility-related functional activities outside laboratory settings. To generate more appropriate outcome measures, there is a clear need to translate research findings and novel methods into practice. PMID- 24625309 TI - High correlation between salivary cortisol awakening response and the psychometric profiles of healthy children. AB - BACKGROUND: Cortisol awakening response (CAR) as an indicator of psychological stress and related physical and psychiatric diseases has attracted growing attention from researchers. Although CAR changes have been investigated extensively in children with behavioral and psychiatric disorders, the association between CAR and conventional psychometric scales for healthy children has not been reported. The aim of this study was to investigate the association between salivary CAR and subscales of Profiles of Mood States (POMS), a self assessment questionnaire widely used to evaluate the temporal emotional states of healthy children. FINDINGS: This study included 18 healthy girls aged 13-16 years. Saliva was collected immediately on awakening, 30 min and 60 min after waking, and then at 2-hour intervals from 9 am to 5 pm. The current mood state, including depression, anxiety, fatigue, and other psychometric profiles were assessed using POMS. The magnitude of salivary CAR and the area under the concentration-time curve (AUC) for diurnal salivary cortisol were compared with the profiles. There were significant positive correlations between the magnitude of CAR and the POMS subscales for "Depression-Dejection", "Tension-Anxiety", "Fatigue", and "Confusion". No correlation was found between the AUC salivary cortisol level and the psychometric profiles. CONCLUSIONS: Salivary CAR was associated with various mood states of healthy female children but diurnal salivary cortisol AUC was not. Salivary CAR may be a biomarker of the physical and mental condition of healthy female children. PMID- 24625310 TI - Atomically precise doping of monomanganese ion into coreless supertetrahedral chalcogenide nanocluster inducing unusual red shift in Mn(2+) emission. AB - We report a simple and yet effective method to introduce Mn(2+) ions into semiconducting nanoclusters with atomically precise control. Our method utilizes one type of micrometer-sized crystals, composed of well-defined isolated supertetrahedral chalcogenide nanoclusters (~2 nm, [Cd6In28S52(SH)4]) whose core metal site is unoccupied in as-synthesized pristine form. This unique model structure with vacant core site makes it possible to achieve ordered distribution of Mn(2+) dopants, and at the same time effectively preclude the formation of Mn(2+) clusters in the host matrix. A two-step synthesis strategy is applied to realize an atomically precise doping of Mn(2+) ion into the core site of the nanoclusters, and to achieve uniform distribution of Mn(2+) dopants in the crystal lattice. The PL, X-ray photoelectron (XPS), as well as the electron paramagnetic resonance (EPR) spectra reveal the successful incorporation of Mn(2+) ion into the core site of the nanocluster. Different from the pristine host material with weak green emission (~490 nm), the Mn(2+)-doped material shows a strong red emission (630 nm at room temperature and 654 nm at 30 K), which is significantly red-shifted relative to the orange emission (~585 nm) observed in traditional Mn(2+)-doped II-VI semiconductors. Various experiments including extensive synthetic variations and PL dynamics have been performed to probe the mechanistic aspects of synthesis process and resultant unusual structural and PL properties. The quaternary semiconductor material reported here extends the emission window of Mn(2+)-doped II-VI semiconductor from yellow-orange to red, opening up new opportunities in applications involving photonic devices and bioimaging. PMID- 24625311 TI - Genetic polymorphisms of DAT1 and COMT differentially associate with actigraphy derived sleep-wake cycles in young adults. AB - Accumulating evidence suggests that dopamine plays a key role in sleep-wake regulation. Cerebral dopamine levels are regulated primarily by the dopamine transporter (DAT) in the striatum and by catechol-O-methyl-transferase (COMT) in the prefrontal cortex. We hypothesized that the variable-number-tandem-repeat (VNTR) polymorphism in the 3'-untranslated region of the gene encoding DAT (DAT1, SLC6A3; rs28363170) and the Val158Met polymorphism of COMT (rs4680) differently affect actigraphy-derived rest-activity cycles and sleep estimates in healthy adults (65 men; 45 women; age range: 19-35 years). Daytime sleepiness, continuous rest-actigraphy and sleep diary data during roughly 4-weeks were analyzed. Nine repeat (9R) allele carriers of DAT1 (n = 48) more often reported elevated sleepiness (Epworth sleepiness score >=10) than 10-repeat (10R) allele homozygotes (n = 62, p < 0.02). Moreover, male 9R allele carriers showed higher wrist activity, whereas this difference was not present in women ("DAT1 genotype" * "gender" interaction: p < 0.005). Rest-activity patterns did not differ among COMT genotypes. Nevertheless, a significant "COMT genotype" * "type of day" (workdays vs. rest days) interaction for sleep duration was observed (p = 0.04). The Val/Val (n = 36) and Met/Met (n = 24) homozygotes habitually prolonged sleep on rest days compared to workdays by more than 30 min, while Val/Met heterozygotes (n = 50) did not significantly extend their sleep (mean difference: 7 min). Moreover, whereas the proportion of women among the genotype groups did not differ, COMT genotype affected body-mass-index (BMI), such that Val/Met individuals had lower BMI than the homozygous genotypes (p < 0.04). While awaiting independent replication and confirmation, our data support an association of genetically-determined differences in cerebral dopaminergic neurotransmission with daytime sleepiness and individual rest-activity profiles, as well as other sleep-associated health characteristics such as the regulation of BMI. The differential associations of DAT1 and COMT polymorphisms may reflect the distinct local expression of the encoded proteins in the brain. PMID- 24625314 TI - Proceedings of the Tenth International Society of Sports Nutrition (ISSN) Conference and Expo. PMID- 24625313 TI - Correlations between objective and subjective sleep and circadian markers in remitted patients with bipolar disorder. AB - Bipolar disorder (BD) is a chronic psychiatric condition characterized by recurrences of depressive and (hypo)manic episodes. Patients in remission report a wide range of sleep and circadian disturbances that correlate with several outcomes measures such as functioning or physical health. The most appropriate way to measure these abnormalities in clinical practice requires further investigation since the external validity of self-reports, as compared to more physiological measures (such as polysomnography or actigraphy), has been questioned. Despite the fact that questionnaires are inexpensive, fast and easy to use, they need to be validated against objective measures. This study aims to validate three sleep and circadian questionnaires, namely the Pittsburgh Sleep Quality Index (PSQI), the Composite Scale of Morningness (CSM) and the Circadian Type Inventory (CTI) - against actigraphy in BD patients in remission. Twenty-six carefully assessed BD patients in remission completed the PSQI, the CTI and the CSM, and wore an actigraph (AW7, Camntech) for 21 consecutive days. Phase preference assessed by the CSM strongly correlated with actigraphic phase markers (M10 onset rho = -0.69 and L5 onset rho = -0.63). Sleep duration and sleep latency assessed by the PSQI and by actigraphy were also highly correlated (rho = -0.76; rho = 0.50). Moderate correlation coefficients were observed between questionnaires and actigraphy for markers that explored the stability of rhythms, sleep quality, sleep latency and sleep disturbances (|rho| > 0.40) although these were not significant after correcting for multiple testing. No correlation was observed between markers for the amplitude of rhythms. While the external validity of the CTI clearly requires further investigation, this study supported the external validity of the CSM and the PSQI for phase preference, sleep duration and latency. We conclude that the CSM and the PSQI could be useful in routine practice and research when actigraphy is not easily available. PMID- 24625315 TI - Wire, mesh, and fiber electrodes for paper-based electroanalytical devices. AB - Here, we report the use of microwire and mesh working electrodes in paper analytical devices fabricated by origami paper folding (oPADs). The important new result is that Au wires and carbon fibers having diameters ranging from micrometers to tens of micrometers can be incorporated into oPADs and that their electrochemical characteristics are consistent with the results of finite element simulations. These electrodes are fully compatible with both hollow channels and paper channels filled with cellulose fibers, and they are easier to incorporate than typical screen-printed carbon electrodes. The results also demonstrate that the Au electrodes can be cleaned prior to device fabrication using aggressive treatments and that they can be easily surface modified using standard thiol based chemistry. PMID- 24625316 TI - Modelling and predicting the biological effects of nanomaterials. AB - The commercial applications of nanoparticles are growing rapidly, but we know relatively little about how nanoparticles interact with biological systems. Their value--but also their risk--is related to their nanophase properties being markedly different to those of the same material in bulk. Experiments to determine how nanoparticles are taken up, distributed, modified, and elicit any adverse effects are essential. However, cost and time considerations mean that predictive models would also be extremely valuable, particularly assisting regulators to minimize health and environmental risks. We used novel sparse machine learning methods that employ Bayesian neural networks to model three nanoparticle data sets using both linear and nonlinear machine learning methods. The first data comprised iron oxide nanoparticles decorated with 108 different molecules tested against five cell lines, HUVEC, pancreatic cancer, and three macrophage or macrophage-like lines. The second data set comprised 52 nanoparticles with various core compositions, coatings, and surface attachments. The nanoparticles were characterized using four descriptors (size, relaxivities, and zeta potential), and their biological effects on four cells lines assessed using four biological assays per cell line and four concentrations per assay. The third data set involved the biological responses to gold nanoparticles functionalized by 80 different small molecules. Nonspecific binding and binding to AChE were the biological endpoints modelled. The biological effects of nanoparticles were modelled using molecular descriptors for the molecules that decorated the nanoparticle surface. Models with good statistical quality were constructed for most biological endpoints. These proof-of-concept models show that modelling biological effects of nanomaterials is possible using modern modelling methods. PMID- 24625317 TI - LiNi1/3Co1/3Mn1/3O2 nanoplates with {010} active planes exposing prepared in polyol medium as a high-performance cathode for Li-ion battery. AB - As we know, Li(+)-ion transport in layered LiNi1/3Co1/3Mn1/3O2 (NCM) is through two-dimensional channels parallel to the Li(+)-ion layers that are indexed as {010} active planes. In this paper, NCM nanoplates with exposed {010} active facets are synthesized in a polyol medium (ethylene glycol) and characterized by XRD, XPS, SEM, and HR-TEM. In addition, the effects of reaction conditions on the morphologies, structures and electrochemical performances are also evaluated. The results show that more {010} facets can be exposed with the thickness of NCM nanoplates increasing which can lead to more channels for Li(+)-ion migration. However, when the annealing temperatures exceed 900 degrees C, many new crystal planes grow along the thickness direction covering the {010} facets. In all of the NCM nanoplates obtained at different conditions, the NCM nanoplates calcined at 850 degrees C for 12 h (NCM-850-12H) display a high initial discharge capacity of 207.6 mAh g(-1) at 0.1 C (1 C = 200 mA g(-1)) between 2.5 and 4.5 V higher than most of NCM materials as cathodes for lithium ion batteries. The discharge capacities of NCM-850-12H are 169.8, 160.5, and 149.3 mAh g(-1) at 2, 5, and 7 C, respectively, illustrating the excellent rate capability. The superior electrochemical performance of NCM-850-12H cathode can be attributed to more {010} active planes exposure. PMID- 24625318 TI - Development and psychometric testing of a scale assessing the sharing of medical information and interprofessional communication: the CSI scale. AB - BACKGROUND: Interprofessional collaboration is essential in creating a safer patient environment. It includes the need to develop communication and coordination between professionals, implying a better sharing of medical information. Several questionnaires exist in the literature, but none of them have been developed in the French context. The objective was to develop and test the psychometric properties of the communication and sharing information (CSI) scale which assesses specifically interprofessional communication, especially the sharing of medical information and the effectiveness of communication between members of the team. METHODS: The questionnaire construction process used a literature review and involved a panel of voluntary professionals. A list of 32 items explored the quality of shared information delivered to patients and the effectiveness of interprofessional communication. The study was conducted in 16 voluntary units in a University Hospital (France), which included medical, surgical, obstetrics, intensive care, pediatrics, oncology and rehabilitation care. The scale-development process comprised an exploratory principal component analysis, Cronbach's alpha-coefficients and structural equation modeling (SEM). RESULTS: From these 16 units, a total of 503 health professionals took part in the study. Among them, 23.9% were physicians (n = 120), 43.9% nurses (n = 221) and 32.2% nurse assistants (n = 162).The validated questionnaire comprised 13 items and 3 dimensions relative to "the sharing of medical information" (5 items), "communication between physicians" (4 items) and "communication between nurses and nurse assistants" (4 items). The 3 dimensions accounted for 63.7% of the variance of the final questionnaire. Their respective Cronbach's alpha coefficients were 0.80, 0.87 and 0.81. SEM confirmed the existence of the 3 latent dimensions but the best characteristics were obtained with a hierarchical model including the three latent factors and a global "communication between healthcare professionals" latent factor, bringing the 8 items linked to communication together. All the structural coefficients were highly significant (P < 0.001). CONCLUSIONS: This self-perception CSI scale assessing several facets of interprofessional communication is the first one developed in the French context. The development study exhibited excellent psychometric properties. Further psychometric analysis is needed to establish test-retest reliability, sensibility to change and concurrent validity. PMID- 24625319 TI - Mixed epithelial and mesenchymal metaplastic carcinoma (carcinosarcoma) of the breast: a case report. AB - Metaplastic breast carcinoma (MBC) is an uncommon malignancy characterized by the co-existence of two or more cellular types, commonly a mixture of epithelial and mesenchymal components. A case of a female patient aged 46 years with MBC (carcinosarcoma) is presented, including mammographic, ultrasonic, gross examination, and pathological findings. After undergoing modified radical mastectomy of the left breast and subsequent six courses of adjuvant chemotherapy and endocrine therapy, the patient is now doing well with no recurrence and metastasis. Conventional treatments for invasive ductal carcinoma (IDC) may appear to be less effective. Patients with MBC would be appropriate candidates for innovative or targeted therapy regimens. PMID- 24625320 TI - Mitochondrial thiol oxidase Erv1: both shuttle cysteine residues are required for its function with distinct roles. AB - Erv1 (essential for respiration and viability 1), is an essential component of the MIA (mitochondrial import and assembly) pathway, playing an important role in the oxidative folding of mitochondrial intermembrane space proteins. In the MIA pathway, Mia40, a thiol oxidoreductase with a CPC motif at its active site, oxidizes newly imported substrate proteins. Erv1 a FAD-dependent thiol oxidase, in turn reoxidizes Mia40 via its N-terminal Cys30-Cys33 shuttle disulfide. However, it is unclear how the two shuttle cysteine residues of Erv1 relay electrons from the Mia40 CPC motif to the Erv1 active-site Cys130-Cys133 disulfide. In the present study, using yeast genetic approaches we showed that both shuttle cysteine residues of Erv1 are required for cell growth. In organelle and in vitro studies confirmed that both shuttle cysteine residues were indeed required for import of MIA pathway substrates and Erv1 enzyme function to oxidize Mia40. Furthermore, our results revealed that the two shuttle cysteine residues of Erv1 are functionally distinct. Although Cys33 is essential for forming the intermediate disulfide Cys33-Cys130' and transferring electrons to the redox active-site directly, Cys30 plays two important roles: (i) dominantly interacts and receives electrons from the Mia40 CPC motif; and (ii) resolves the Erv1 Cys33 Cys130 intermediate disulfide. Taken together, we conclude that both shuttle cysteine residues are required for Erv1 function, and play complementary, but distinct, roles to ensure rapid turnover of active Erv1. PMID- 24625321 TI - Black cobra (Naja naja karachiensis) lysates exhibit broad-spectrum antimicrobial activities. AB - It is hypothesized that animals living in polluted environments possess antimicrobials to counter pathogenic microbes. The fact that snakes feed on germ infested rodents suggests that they encounter pathogenic microbes and likely possess antimicrobials. The venom is used only to paralyze the rodent, but the ability of snakes to counter potential infections in the gut due to disease ridden rodents requires robust action of the immune system against a broad range of pathogens. To test this hypothesis, crude lysates of different organs of Naja naja karachiensis (black cobra) were tested for antimicrobial properties. The antimicrobial activities of extracts were tested against selected bacterial pathogens (neuropathogenic Escherichia coli K1, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Streptococcus pneumonia), protist (Acanthamoeba castellanii), and filamentous fungus (Fusarium solani). The findings revealed that plasma and various organ extracts of N. n. karachiensis exhibited antimicrobial activity against E. coli K1, MRSA, P. aeruginosa, S. pneumoniae, A. castellanii, and F. solani in a concentration dependent manner. The results of this study are promising for the development of new antimicrobials. PMID- 24625322 TI - Hepatitis C virus core antigen, an earlier and stronger predictor on sustained virological response in patients with genotype 1 HCV infection. AB - BACKGROUND: Earlier kinetics of serum HCV core antigen (HCVcAg) and its predictive value on sustained virological response (SVR) were investigated in patients with genotype 1 HCV infection during antiviral treatment. METHODS: In a multi-centered, randomized and positive drug-controlled phase IIb clinical trial on type Y peginterferon alpha-2b ( NCT01140997), forty-eight CHC patients who participated in pharmacokinetics were randomly divided into 4 cohorts and treated with PegIFNalpha (type Y peginterferon alpha-2b 90 MUg, 135 MUg, 180 MUg and PegIFNalpha-2a 180 MUg, respectively, once a week) and ribavirin (< 75 kg, 1000 mg daily and >= 75 kg, 1200 mg daily) for 48 weeks, and then followed up for 24 weeks. 32 patients infected with genotype 1 HCV and completed the whole process were included in this study. HCV RNAs were detected at baseline, and weeks 4, 12, 24, 48 and 72 using Cobas TaqMan. ARCHITECT HCVcAg was performed at 24, 48, 72, 96, 120 and 144 h in addition to the above time points. The receiver operating curves (ROCs) were performed to study the predictive values of HCVcAg decline on SVR. RESULTS: Following antiviral treatment, serum HCVcAg levels rapidly declined within the first week and correlated well with corresponding HCV RNA at baseline, weeks 4, 12, 24, 48 and 72 (rs = 0.969, 0.928, 0.999, 0.983, 0.985 and 0.946, respectively, P < 0.001). All of the areas under the receiver operating curves (AUROCs) were more than 0.80 and showed good predictive power on SVR at 24, 48, 72, 96, 120 and 144 h. The144 h was the best predictive time point of HCVcAg decline on SVR because of its largest AUROC (more than 0.90). CONCLUSIONS: Early kinetics of serum HCVcAg predicts SVR very well in genotype 1 CHC patients during antiviral treatment, and its reduction value at 144 h is an earlier and stronger predictor on SVR than rapid virological response and early virological response. (TRN: NCT01140997). PMID- 24625323 TI - Simultaneous detection of RNA and DNA targets based on multiplex isothermal amplification. AB - The detection of pathogenic microorganisms present in food, feed, plant, and other samples is important for providing safe food as well as for preventing the spread of microbes. The genome of pathogens is made of DNA or RNA, therefore a multiplex diagnostics tool would ideally be able to amplify and detect both RNA and DNA targets in parallel. With this goal we have developed an isothermal nucleic acid sequence based amplification [NASBA] implemented microarray analysis (NAIMA) procedure, suitable for the simultaneous multiplex amplification of RNA and DNA targets, coupled with the detection on ArrayTubes. The method is demonstrated to be very sensitive and specific for the detection of two economically important quarantine plant pathogens of potato, the potato spindle tuber viroid (RNA target) and Ralstonia solanacearum (DNA target). Because of its isothermal amplification and simple detection equipment, the method is also applicable for on-site analyses. NAIMA can be used in any domain where there is the need to detect RNA and DNA targets simultaneously. PMID- 24625324 TI - In vivo magnetic resonance imaging of type I collagen scaffold in rat: improving visualization of bladder and subcutaneous implants. AB - Noninvasive monitoring of implanted scaffolds is important to understand their behavior and role in tissue engineering, in particular to follow their degradation and interaction with host tissue. Magnetic resonance imaging (MRI) is well suited for this goal, but its application is often hampered by the low contrast of scaffolds that are prepared from biomaterials such as type I collagen. The aim of this study was to test iron oxide particles incorporation in improving their MRI contrasts, and to follow their degradation and tissue interactions. Scaffolds with and without iron oxide particles were implanted either subcutaneously or on the bladder of rats. At predetermined time points, in vivo MRI were obtained and tissues were then harvested for histology analysis and transmission electron microscopy. The result showed that the incorporation of iron oxide particles improved MRI contrast of the implants, providing information on their location, shapes, and degradation. Second, the host tissue reaction to the type I collagen implants could be observed in both MRI and histology. Finally, MRI also revealed that the degradation and host tissue reaction of iron particles-loaded scaffolds differed between subcutaneous and bladder implantation, which was substantiated by histology. PMID- 24625325 TI - Methylenetetrahydrofolate reductase polymorphisms in myelodysplastic syndromes and therapy-related myeloid neoplasms. PMID- 24625326 TI - Treatment of diffuse large B-cell lymphoma in the elderly: regimens without anthracyclines are common and not futile. AB - Anthracycline-containing regimens (ACRs) are recommended for patients with diffuse large B-cell lymphoma (DLBCL). However, over 40% of elderly patients do not receive ACRs, possibly due to expected toxicities. We characterized treatment choices and compared the 3-year overall survival (OS) rates of 8262 Medicare beneficiaries diagnosed with DLBCL in 2000-2006 identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Of the cohort, 45% had ACR with rituximab (ACR-R), 13% had ACR without R, 6% had non-ACR with R (non ACR-R), 4% had R monotherapy, 3% had non-ACR and 29% had no systemic therapy. Patients not receiving ACR were older and/or had more comorbidities. The unadjusted OS was highest in ACR-R (65%), followed by ACR without R (55%) and non ACR-R (44%). After adjusting patient covariates, ACR-R showed the best survival (63%). However, OS was comparable between non-ACR-R (52%) and ACR without R (52%). Non-ACR-R could be considered for patients who are poor candidates for ACR. PMID- 24625327 TI - Pediatric acute lymphoblastic leukemia: the missing pieces in risk and survival. PMID- 24625328 TI - Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma. AB - Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells that have been implicated as inhibitors of lymphopoiesis in patients with malignancies. They have a consensus phenotype of CD33+/CD11b+/HLA-DRlo/- and can be further divided into CD15 + granulocytic (G-MDSC) and CD14 + monocytic (M MDSC) subsets. We characterized MDSCs in patients with multiple myeloma (MM) and found a significant increase in G-MDSCs in the blood of patients with progressive MM. Flow-sorted MDSCs from patients with MM induced the generation of regulatory T cells (Treg). MDSCs from both patients with MM and aged-matched controls demonstrated a dose-dependent inhibition of lymphocyte proliferation in carboxyfluorescein succinimidyl ester (CFSE)-tracking experiments. Granulocyte colony stimulating factor (G-CSF) administered to induce stem cell mobilization caused an increase in the number of MDSCs in the peripheral blood of patients with MM and a concentration of these immune-suppressive cells in peripheral blood stem cell collections. MDSCs are likely to cause immune dysfunction in patients with MM. PMID- 24625329 TI - Association between neutropenia and brain abscess due to Bacillus cereus bacteremia in patients with hematological malignancies. PMID- 24625330 TI - Fibrin sealants: surgical hemostat, sealant and adhesive. AB - INTRODUCTION: Fibrin sealants (FS) have been approved for use in the United States since 1998. Since approval, they have been used in a wide variety of clinical settings and new products continue to be introduced. AREAS COVERED: This review covers the literature supporting the USA FDA-approved indications for FS products produced by Baxter Corp. Literature review of PubMed, the Cochrane Library, FDA approval documents and product websites yielded information contained in this article. Mechanism of action, efficacy and safety of these products are covered. EXPERT OPINION: FS are generally safe, popular and are used for a wide variety of off-label indications. Their use appears to be expanding rapidly. For many uses, including approved ones, large well-controlled trials are still needed. Additionally, cost-effectiveness data for these products would be a great benefit in guiding their future use. PMID- 24625331 TI - Biological applications of LbL multilayer capsules: from drug delivery to sensing. AB - Polyelectrolyte multilayer (PEM) capsules engineered with active elements for targeting, labeling, sensing and delivery hold great promise for the controlled delivery of drugs and the development of new sensing platforms. PEM capsules composed of biodegradable polyelectrolytes are fabricated for intracellular delivery of encapsulated cargo (for example peptides, enzymes, DNA, and drugs) through gradual biodegradation of the shell components. PEM capsules with shells responsive to environmental or physical stimuli are exploited to control drug release. In the presence of appropriate triggers (e.g., pH variation or light irradiation) the pores of the multilayer shell are unlocked, leading to the controlled release of encapsulated cargos. By loading sensing elements in the capsules interior, PEM capsules sensitive to biological analytes, such as ions and metabolites, are assembled and used to detect analyte concentration changes in the surrounding environment. This Review aims to evaluate the current state of PEM capsules for drug delivery and sensing applications. PMID- 24625333 TI - Calcium channel blockers suppress daily variations of blood pressure in hypertensive patients with end-stage renal diseases. AB - Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension. Furthermore, daily variations of blood pressure are relatively large in patients treated with hemodialysis, partly due to ultrafiltration. Twenty hypertensive patients with end-stage renal diseases whose blood pressure was controlled by a single antihypertensive agent, either angiotensin receptor antagonist (ARB) or calcium channel blocker (CCB), were enrolled into the study. Home blood pressure measurements were also performed. Average systolic and diastolic blood pressures were similar between two agents. However, variations of systolic blood pressure during ARB treatment were greater than those of CCB, and maximal differences in daily systolic blood pressure during treatment with ARB (19+/-7 mmHg) were greater than those with CCB (14+/-6 mmHg, p<0.01). Systolic blood pressure measured after hemodialysis under ARB therapy (110+/-6 mmHg) was lower than that of CCB (118+/-6 mmHg, p<0.05). Daily variations of diastolic blood pressure were similar between ARB and CCB periods. Our results indicate that variations of systolic blood pressure during ARB treatment are larger than CCB, and suggest that CCB is useful to obtain the better quality of blood pressure control, improving blood pressure stability by preventing substantial drops in blood pressure in hypertensive patients with end stage renal diseases. PMID- 24625334 TI - The velocity of home blood pressure reduction in response to low-dose eplerenone combined with other antihypertensive drugs determined by exponential decay function analysis. AB - BACKGROUND/OBJECTIVE: Eplerenone is a highly selective aldosterone blocker, which has the potential to lower blood pressure (BP) in patients with hypertension. The objective of this study was to assess the hypotensive effects of low-dose eplerenone (25 mg) using home BP measurements. We also assessed the time required to reach 95% of the maximum antihypertensive effect (stabilization time) by analyzing exponential decay functions using home BP measurements. METHODS: We reviewed the medical records of 83 hypertensive patients who were taking eplerenone 25 mg (age, 68.6+/-11.8 years; men, 36.1%) in addition to other antihypertensive agents. Home BPs were averaged in each patient for the last 5 days of each observation period. The morning versus evening effect (M/E ratio) and the evening versus morning effect (E/M ratio) were calculated to assess the duration of action of eplerenone. RESULTS: The mean home systolic/diastolic BPs at baseline were 136.8+/-8.8/77.2+/-9.3 mmHg, respectively. After 8 weeks of treatment with eplerenone, home systolic/diastolic BP significantly decreased by 7.1+/-10.1/-2.6+/-5.0 mmHg (p<0.0001). The time for stabilization of home systolic and diastolic BPs was 13.7 days (p=0.006) and 16.5 days (p=0.001), respectively. When eplerenone was administered in the morning, the M/E ratio was 1.1+/-0.3. The corresponding E/M ratio for evening administration was 0.9+/-0.6. Although no nocturia was observed, there was a slight but significant increase in serum potassium levels (p=0.03). CONCLUSIONS: Our data suggest that the combination of eplerenone with other antihypertensive drugs may be a promising therapeutic strategy for the treatment of essential hypertension. PMID- 24625335 TI - Characteristics of the hypertensive patients with good and poor compliance to long-term salt restriction. AB - Although salt restriction is very important for the management of blood pressure (BP), it is difficult to maintain low salt intake in hypertensive patients. The purpose of the present study is to investigate comparatively the characteristics of hypertensive patients with good or poor compliance to long-term salt restriction. Subjects included 248 hypertensive patients who underwent successful 24-h home urine collection for >5 times with the observation period of 9.4 years in average. When the subjects were categorized based on the mean 24-h urinary salt excretion during the observation period to the groups with good (<8 g/day) or poor (10 g/day or more) compliance to long-term salt restriction, subjects with poor compliance were more frequently to be male, younger and had higher BMI than those with good compliance. Although there were no significant differences in BP and the number of antihypertensive drugs between the subjects with good and poor compliance, the subjects with poor compliance were given more diuretics, more frequently complicated with diabetes mellitus and hyperuricemia and had higher urinary protein excretion than those with good compliance. Thus, strict nutritional intervention and the management of BP as well as the complicated cardiovascular risk are important for the patients with poor compliance to salt restriction. PMID- 24625336 TI - Lifestyle monitoring with the use of an earphone-type thermometer, an ambulatory blood pressure monitoring and a new wristwatch-type pulsimeter with accelerometer. AB - We investigated the relationship among 24-h blood pressure (BP), pulse rate (PR) and core temperature by using an ambulatory BP monitoring, a new wristwatch-type pulsimeter with accelerometer (WPA) and an ear thermometer simultaneously. Our results suggest that the ear temperature which reflects the core body temperature was lowest at base PR during sleep and 75% of normotensives and 54% of subjects without hypertensive medication had a significant correlation between BP and PR. Diabetic subjects showed a significantly higher PR during sleep than non-diabetic subjects. Three types of equipments, especially a new WPA, are expected to be useful for daily lifestyle monitoring to evaluate risk of complications of hypertension and diabetes. PMID- 24625337 TI - Trend of office and home blood pressure control in treated hypertensive patients: changes in antihypertensive medication and salt intake. AB - Blood pressure (BP) control in hypertensives has improved in recent years; however, it remains insufficient. We investigated the trend of BP control status in hypertensive patients with antihypertensive medication and salt intake. Two hundred and eight treated hypertensive patients were prospectively followed between 2007 and 2012. During this period, average clinic BP significantly decreased from 137+/-12/80+/-9 to 133+/-11/76+/-8 mmHg, and the achievement rate of BP control defined as <140/90 mmHg increased from 58% to 71% (p<0.01). Morning home BP also significantly decreased from 132+/-8/80+/-8 to 130+/-8/76+/-7 mmHg, and the percentage of patients with sustained hypertension (CBP>=140/90 mmHg and HBP>=135/85 mmHg) decreased from 27% to 16% (p<0.05). The number of antihypertensive drugs increased significantly from 2.1+/-1.2 to 2.3+/-1.1 (p<0.01), while no differences were observed in urinary salt excretion (9.0+/-2.4 g/day in 2007, 9.0+/-2.6 g/day in 2012). Office and home BP decreased and the rate of BP control increased in treated hypertensive patients in the past 5 years. Intensive pharmacological therapy, but not a reduction in salt intake appears to have contributed to improved BP control. PMID- 24625338 TI - Aldosterone-to-renin ratio and nocturnal blood pressure decline assessed by self measurement of blood pressure at home: the Ohasama Study. AB - Based on ambulatory blood pressure (BP) monitoring, the aldosterone-to-renin ratio (ARR) has been reported to be associated with a diminished nocturnal decline in BP, generally referred to as a "non-dipping" pattern. The objective of this cross-sectional study was to investigate the association between ARR and the non-dipping pattern based on home BP measurements. This study included 177 participants>=55 years from the general population of Ohasama (mean age: 67.2 years; 74.6% women); no patient was receiving antihypertensive treatment. The median plasma renin activity (PRA), plasma aldosterone concentration (PAC) and ARR were 0.8 ng/mL/h, 8.1 ng/dL and 9.7 ng/dL per ng/mL/h, respectively. Each 1 SD increase in log-transformed (ln) ARR was significantly associated with the prevalence of the non-dipping pattern after adjustments for possible confounding factors including home morning systolic BP (odds ratio, 1.45; p=0.049). However, no significant associations of PRA or PAC with the non-dipping pattern were observed (p>=0.2). When participants were divided into four groups according to median levels of home morning and night-time systolic BPs, the group with a higher home morning systolic BP (>=128.4 mmHg) with a higher home night-time systolic BP (>=114.4 mmHg) had the greatest ARR levels (ANCOVA p=0.01). These results support the hypothesis that relative aldosterone excess may be related to a non-dipping pattern in a general population and suggest that a non-dipping pattern can be accurately observed by home BP measurements. PMID- 24625339 TI - Liposomes containing recombinant gp85 protein vaccine against ALV-J in chickens. AB - To study the potential of liposome vaccines in the clinical prevention of ALV-J, the effect of recombinant gp85 protein of subgroup J avian leukosis virus (ALV-J) entrapped by liposomes in chickens against ALV-J infection was investigated in this paper. A recombinant plasmid (PET28a-gp85) containing the PET28a vector and gp85 gene was constructed and then expressed in Rosetta (DE3) cells with 0.5mM IPTG to produce recombinant gp85 proteins that could be entrapped by liposomes through reverse-phase evaporation. The chickens were inoculated intramuscularly either once or twice with the liposomes or with Freund's adjuvant emulsion containing recombinant gp85 protein. Sixty chickens were raised to one week old for the first inoculation and to three weeks old for the second inoculation. Chickens raised to five weeks old were challenged with a 10(2.4) 50% tissue culture infective dose (TCID50) of ALV-J. Blood samples were collected from each chicken at weekly intervals for serum antibody and viremia analyses. Changes in serum antibodies showed that positive serum antibodies (S/P value >0.6) could be induced in all groups regardless of the frequency of inoculation but improved significantly in the twice-inoculated groups. As well, high levels of antibodies emerged earlier in the Freund's adjuvant groups but persisted longer in the liposome groups. Detection of viremia indicated that the liposomes provide better protection against ALV-J than Freund's adjuvant emulsion and that this protection is directly influenced by serum antibody levels. Overall, this study reveals the potential of liposome vaccines containing recombinant gp85 protein in the clinical prevention of ALV-J. PMID- 24625340 TI - Heat shock protein complex vaccination induces protection against Helicobacter pylori without exogenous adjuvant. AB - BACKGROUND: The development of a vaccine against the human gastric pathogen Helicobacter pylori, the main causative agent of gastric adenocarcinoma, has been hampered by a number of issues, including the lack of a mucosal adjuvant for use in humans. Heat shock proteins (Hsp), highly conserved molecules expressed by both bacteria and mammalian species, possess a range of functions, including acting as chaperones for cellular proteins and the ability to activate innate immune receptors. Hsp complex (HspC) vaccines, containing Hsp derived from pathogenic bacteria, are immunostimulatory without addition of an exogenous adjuvant and can induce immunity against their chaperoned proteins. In this study we explored in mice the potential utility of a H. pylori HspC vaccine. RESULTS: Vaccination with H. pylori HspC, by either the subcutaneous or respiratory mucosal route, induced a strong antibody response, elevated gastric cytokine levels and significant protection against subsequent live challenge with this pathogen. The level of protection induced by non-adjuvanted HspC vaccine was equivalent to that which resulted from vaccination with adjuvanted vaccines. While protection induced by immunisation with adjuvanted vaccines was associated with the development of a moderate to severe atrophic gastritis, that induced by H. pylori HspC only resulted in a mild inflammatory response, despite an increase in pro-inflammatory gastric cytokines. This reduced gastritis correlated with an increase in IL-10 and IL-13 levels in the gastric tissues of HspC vaccinated, H. pylori challenged mice. CONCLUSIONS: H. pylori HspC vaccines have the potential to overcome some of the issues preventing the development of a human vaccine against this pathogen: HspC induced protective immunity against H. pylori without addition of an adjuvant and without the induction of a severe inflammatory response. However, complete protection was not obtained so further optimisation of this technology is needed if a human vaccine is to become a reality. PMID- 24625341 TI - Immunogenicity and safety of a trivalent inactivated 2010-2011 influenza vaccine in Taiwan infants aged 6-12 months. AB - This prospective study aimed to investigate the immune responses and safety of an influenza vaccine in vaccine-naive infants aged 6-12 months, and was conducted from November 2010 to May 2011. Fifty-nine infants aged 6-12 months received two doses of trivalent inactivated influenza vaccine 4 weeks apart. Hemagglutination inhibition titers were measured 4 weeks after the two doses of study vaccine. Based on the assumption that a hemagglutination inhibition titer of 1:40 or greater against the antigen would be protective in adults, two doses of the study vaccine generated a protective immune response of 63.2% against influenza A(H1N1), 82.5% against influenza A(H3N2) and 38.6% against influenza B viruses in infants aged 6-12 months. The geometric mean fold rises against influenza type A and B viruses also met the European Medicines Agency criteria for flu vaccines. The solicited events within 7 days after vaccination were mild in intensity. No deaths or adverse events such as optic neuritis, cranial neuropathy, and brachial neuropathy or Guillain-Barre syndrome were reported. Two doses of inactivated influenza vaccine were well tolerated and induced a protective immune response against influenza in infants aged 6-12 months. PMID- 24625342 TI - Vaccine preventable diseases: time to re-examine global surveillance data? AB - While data driven estimates of the global burden of disease for some vaccine preventable diseases (VPDs) are limited, aggregate case numbers of VPDs are reported annually by country in the Joint Reporting Form (JRF). We examined pertussis surveillance data in the JRF, and vaccine coverage estimates, in comparison to measles, which is a priority disease for elimination and eradication efforts and is supported by the WHO Global Measles and Rubella Laboratory Network. In 2012, highest pertussis case numbers and incidence were reported from high income countries with high vaccine coverage, discordant with countries that had low vaccine coverage. Use of laboratory diagnostics for pertussis cases varied among countries. In contrast, highest reported numbers of measles cases and incidences tended to occur in low income countries. These observations imply poor quality global surveillance data for some VPDs, limiting capacity for monitoring global epidemiology or making vaccination policy decisions. Efforts are needed to improve the availability of quality surveillance data for all VPDs. PMID- 24625343 TI - Emergence of antigenic variants of Foot-and-Mouth Disease Virus serotype O in Ecuador and preliminary evaluation of a field strain as a vaccine candidate. AB - Foot-and-Mouth Disease Virus serotype O has been circulating regularly throughout most provinces of Ecuador, one of the two South American countries that still remain endemic, although satisfactory vaccination coverage was reported. This study concentrates in the characterization of isolates collected during 2008 2011, focusing particularly on the antigenic and immunogenic relationships of the field viruses with the O1/Campos vaccine strain in use in the region and with an experimental vaccine formulated with a representative strain of the 2010 epidemic. The results established that antigenically divergent variants poorly protected by the vaccine in use emerged and co-circulated in a limited period of time. A monovalent vaccine formulated with the representative 2010 strain elicited high antibody titers and protected against challenge with homologous virus. In addition, cross-reactive antibodies to predominant viruses in the region were established. In overall this study indicates the ability of the virus to diversify under field conditions in which a vaccine strain with poor match is applied, and the potential of the selected 2010 field virus as a vaccine candidate for incorporation into strategic antigen banks and/or for addition to current formulations for systematic vaccination, in order to prevent the emergence of even more divergent isolates in the future. PMID- 24625344 TI - Antimicrobial resistance in urinary pathogens among Swedish nursing home residents remains low: a cross-sectional study comparing antimicrobial resistance from 2003 to 2012. AB - BACKGROUND: There are several risk factors for the colonisation, infection and spreading of antibiotic resistant bacteria among elderly residents of nursing homes. An updated estimate of the native prevalence of antimicrobial resistance in uropathogens among Swedish nursing home residents is needed. METHODS: Urine specimens were collected for culture and antimicrobial susceptibility testing against mecillinam, ampicillin, cefadroxil, trimethoprim, nitrofurantoin and quinolones from the residents of 32 and 22 nursing homes, respectively. The residents were capable of providing a voided urine sample in 2003 and 2012. In 2012 urine specimens were also collected from residents with urinary catheters. Any antibiotic treatment during the previous month was registered in 2003 as well as hospitalisation and any antibiotic treatment during the previous six months in 2012. RESULTS: The proportion of positive urine cultures was 32% (207/651) in voided urine specimens in 2003, 35% (147/421) in 2012, and 46% (27/59) in urine samples from catheters in 2012. Escherichia coli (E. coli) was the most commonly occurring bacteria.Resistance rates in E. coli (voided urine specimens) in 2012 were; ampicillin 21%, trimethoprim 12%, mecillinam 7.7%, ciprofloxacin 3.4%, cefadroxil 2.6% and nitrofurantoin 0.85%. There were no significant changes in the average resistance rates in E. coli for antibiotics tested 2003-2012.In 2012, two isolates of E. coli produced extended spectrum beta-lactamase enzymes (ESBL) and one with plasmid mediated AmpC production.Any antibiotic treatment during the previous month increased the risk for resistance in E. coli, adjusted for age and gender; for mecillinam with an odds ratio (OR) of 7.1 (2.4-21; p = 0.00049), ampicillin OR 5.2 (2.4-11; p = 0.000036), nalidixic acid OR 4.6 (1.4-16; p = 0.014) and trimethoprim OR 3.9 (1.6-9.2; p = 0.0023). Hospitalisation during the previous six months increased the risk for antibiotic resistance in E. coli to ampicillin, ciprofloxacin and any antimicrobial tested, adjusted for age, gender and antibiotic treatments during the previous six months. CONCLUSIONS: The average rates of antimicrobial resistance were low and did not increase between 2003 and 2012 in E. coli urinary isolates among Swedish nursing home residents. Antibiotic treatment during the previous month and hospitalisation during the previous six months predicted higher resistance rates. PMID- 24625345 TI - Regoaling: a conceptual model of how parents of children with serious illness change medical care goals. AB - BACKGROUND: Parents of seriously ill children participate in making difficult medical decisions for their child. In some cases, parents face situations where their initial goals, such as curing the condition, may have become exceedingly unlikely. While some parents continue to pursue these goals, others relinquish their initial goals and generate new goals such as maintaining the child's quality of life. We call this process of transitioning from one set of goals to another regoaling. DISCUSSION: Regoaling involves factors that either promote or inhibit the regoaling process, including disengagement from goals, reengagement in new goals, positive and negative affect, and hopeful thinking. We examine these factors in the context of parental decision making for a seriously ill child, presenting a dynamic conceptual model of regoaling. This model highlights four research questions that will be empirically tested in an ongoing longitudinal study of medical decision making among parents of children with serious illness. Additionally, we consider potential clinical implications of regoaling for the practice of pediatric palliative care. SUMMARY: The psychosocial model of regoaling by parents of children with a serious illness predicts that parents who experience both positive and negative affect and hopeful patterns of thought will be more likely to relinquish one set of goals and pursue a new set of goals. A greater understanding of how parents undergo this transition may enable clinicians to better support them through this difficult process. PMID- 24625346 TI - Laparoscopic surgery for gastric gastrointestinal stromal tumor is feasible irrespective of tumor size. AB - PURPOSE: To compare the outcomes of laparoscopic surgery and open surgery for gastric gastrointestinal stromal tumors (GISTs) by size-matched analysis and evaluate whether laparoscopic surgery for lesions of >5 cm is feasible. PATIENTS AND METHODS: Data of 44 consecutive patients with gastric GIST who underwent surgery from 1988 to 2011 were reviewed. Twenty-three patients who underwent successful laparoscopic surgery were compared with 10 patients with similar tumor sizes who underwent open surgery. Among the 23 patients in the laparoscopic group, we compared postoperative results between GISTs of <=5 cm and >5 cm. RESULTS: There were no differences in clinicopathological characteristics between the laparoscopic surgery group (LG) and the open surgery group (OG). The operation time was not different, but the blood loss (5.5 mL [range, 0-425 mL] in LG and 125 mL [range, 0-676 mL] in OG) (P=.008) and postoperative hospital stay (21 days in OG and 8 days in LG) (P<.001) were significantly less in the LG. Postoperative complications and recurrence were not different. Comparison between patients with lesions of >5 cm and patients with smaller lesions in the LG found that smaller lesions were associated with a shorter postoperative hospital stay (7.5 days versus 11 days) (P=.037). CONCLUSIONS: Laparoscopic resection of primary gastric GISTs is feasible even for tumors of >5 cm. PMID- 24625347 TI - Laparoscopic-assisted versus open distal gastrectomy with D2 lymph node resection for advanced gastric cancer: effect of learning curve on short-term outcomes. a meta-analysis. AB - Laparoscopic-assisted distal gastrectomy (LADG) with D2 resection is gradually being performed for treating advanced gastric cancer. This meta-analysis aims to compare the clinical outcomes between LADG and open distal gastrectomy (ODG) when considering the impact of the learning curve. The PubMed, Embase, and ISI databases and the Cochrane Library were electronically searched. Randomized controlled trails and retrospective comparative studies published between 1994 and 2013 were collected. We divided the included studies into two subgroups according to whether the authors had experience of at least or fewer than 40 cases of LADG with D2 resection and then compared the operative time, intraoperative bleeding, the amount of resected lymph nodes, short-term recovery parameters, and complications between LADG and ODG groups. Ten comparative studies including 1100 patients were selected. Meta-analysis showed that when LADG was compared with ODG, surgeons with experience of at least 40 cases could achieve more resected lymph nodes (P=.002), reduced time to flatus (P<.0001), shortened time to liquid diet (P<.00001), and lower complication rates (P=.02). However, the above advantages of LADG faded in the subgroup of surgeons with experience of fewer than 40 cases. Our meta-analysis suggested that the learning curve has significant effects on most of the important surgical and short-term recovery outcome parameters. Accomplishment of 40 cases of LADG with D2 lymphadenectomy is required to achieve optimum proficiency. PMID- 24625348 TI - Safety and effect on quality of life of laparoscopic Douglasectomy with radical excision for deeply infiltrating endometriosis in the cul-de-sac. AB - OBJECTIVE: To evaluate the safety and effects on health-related quality of life (HRQOL) of radical excision of deeply infiltrating endometriosis (DIE) in the cul de-sac. PATIENTS AND METHODS: This study included 390 patients with pathologically proven DIE in the cul-de-sac who underwent laparoscopic surgery between January 2000 and December 2011. The preoperative and postoperative visual analog scale (VAS) pain scores and HRQOL data from the 36-item Short Form (SF-36) questionnaire were recorded in 343 patients. Surgical outcomes, complications, and HRQOL were compared between patients who underwent hysterectomy and those who did not. Data were analyzed using the paired t test, Student's t test, and Pearson's correlation analysis. RESULTS: In the group overall, the VAS pain score and all SF-36 scales improved after surgery. In patients who underwent hysterectomy, all SF-36 scales improved except physical functioning, role physical, general health, and vitality. In patients who did not undergo hysterectomy, all SF-36 scales improved except general health. There were significant associations between gonadotropin-releasing hormone agonist therapy and SF-36 mental health, SF-36 mental component summary, and oral medication use. The VAS pain score and SF-36 body pain score showed the greatest improvement, and the SF-36 general health score showed the least improvement. Patients who underwent hysterectomy had more severe disease and poorer surgical outcomes than those who did not undergo hysterectomy. CONCLUSIONS: Laparoscopic radical excision of DIE in the cul-de-sac is safe and significantly improves HRQOL, especially in terms of pain. The severity of endometriosis may affect the degree of improvement in HRQOL scores. PMID- 24625349 TI - Pediatric laparoscopic inguinal hernia repair: a review of the current evidence. PMID- 24625350 TI - Technical options of the laparoscopic pediatric inguinal hernia repair. AB - The approach to inguinal hernia in the pediatric population has historically been via an open technique. Over the last decade there have been numerous reports and descriptions of laparoscopic techniques to repair inguinal hernias in this population. This article highlights different techniques and clearly outlines the currently utilized approach in our institutions. PMID- 24625351 TI - International Conference on Genome Informatics (GIW 2013) in Singapore: Introduction to the systems biology contributions. PMID- 24625352 TI - Calcein-modified multinanochannels on PET films for calcium-responsive nanogating. AB - Calcein-modified multiporous films with conical channels are introduced in a nanofluid device to enhance the calcium-responsive intensity and stability of ionic currents. Calcein with more carboxyls enhances the response of channels to calcium ions, and the capability of immobilized calcein for Ca(2+)-binding could be regulated by the deprotonation of these carboxyls. PMID- 24625353 TI - Human equilibrative nucleoside transporter 1 predicts survival in patients with pancreatic cancer treated with gemcitabine: a meta-analysis. AB - CONTEXT: Increasing scientific evidence suggests that human equilibrative nucleoside transporter 1 (hENT1) may be a powerful predictor of survival in patients with pancreatic cancer treated with adjuvant gemcitabine-based chemotherapy after operative resection, but many existing studies have yielded inconclusive results. OBJECTIVE: This meta-analysis aims to assess the prognostic role of hENT1 in predicting survival in patients with pancreatic cancer treated with gemcitabine. METHODS: An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude hazard ratio (HR) with 95% confidence interval (CI) was calculated. RESULTS: Eleven clinical studies were included in this meta-analysis with a total of 851 pancreatic cancer patients, including 478 patients in the high hENT1 expression group and 373 patients in the low hENT1 expression group. Our meta-analysis revealed that high hENT1 expression was associated with improved overall survival (OS) of pancreatic cancer patients (HR=2.61, 95% CI=2.02-3.34). Pancreatic cancer patients with high hENT1 expression also had a longer disease-free survival (DFS) than those with low hENT1 expression (HR=2.62, 95% CI=1.94-3.54). Further, high hENT1 mRNA showed significant association with improved OS and DFS of pancreatic cancer patients (HR=2.65, 95% CI=1.75-4.00; HR=3.29, 95% CI=1.85-5.84; respectively). CONCLUSION: In conclusion, our meta-analysis suggests that high hENT1 expression may be associated with improved OS and DFS of pancreatic cancer patients treated with gemcitabine. Detection of hENT1 expression may be a promising biomarker for gemcitabine response and prognosis in pancreatic cancer patients. PMID- 24625354 TI - Comparative analyses of the complete mitochondrial genomes of the two ruminant hookworms Bunostomum trigonocephalum and Bunostomum phlebotomum. AB - Bunostomum trigonocephalum and Bunostomum phlebotomum are blood-feeding hookworms of sheep and cattle, causing considerable economic losses to the live stock industries. Studying genetic variability within and among hookworm populations is critical to addressing epidemiological and ecological questions. Mitochondrial (mt) DNA is known to provide useful markers for investigations of population genetics of hookworms, but mt genome sequence data are scant. In the present study, the complete mitochondrial DNA (mtDNA) sequences of the sheep and goat hookworm B. trigonocephalum were determined for the first time, and the mt genome of B. phlebotomum from yak in China was also sequenced for comparative analyses of their gene contents and genome organizations. The lengths of mt DNA sequences of B. trigonocephalum sheep isolate, B. trigonocephalum goat isolate and B. phlebotomum China yak isolate were 13,764bp, 13,771bp and 13,803bp in size, respectively. The identity of the mt genomes was 99.7% between B. trigonocephalum sheep isolate and B. trigonocephalum goat isolate. The identity of B. phlebotomum China yak isolate mt genomes was 85.3% with B. trigonocephalum sheep isolate, and 85.2% with B. trigonocephalum goat isolate. All the mt genes of the two hookworms were transcribed in the same direction and gene arrangements were consistent with those of the GA3 type, including 12 protein-coding genes, 2 rRNA genes and 22 tRNA genes, but lacking ATP synthetase subunit 8 gene. The mt genomes of B. trigonocephalum and B. phlebotomum were similar to prefer bases A and T, the contents of A+T are 76.5% (sheep isolate), 76.4% (goat isolate) and 76.9% (China yak isolate), respectively. Phylogenetic relationships reconstructed using concatenated amino acid sequences of 12 protein-coding genes with three methods (maximum likelihood, Bayesian inference and neighbor joining) revealed that the B. trigonocephalum and B. phlebotomum represent distinct but closely-related species. These data provide novel and useful genetic markers for studying the systematics, and population genetics of the two ruminant hookworms. PMID- 24625355 TI - Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent. AB - OBJECTIVE: Gynecomastia is a benign breast enlargement in males that affects approximately one-third of adolescents. The exact mechanism is not fully understood; however, it has been proposed that estrogen receptors and aromatase enzyme activity may play important roles in the pathogenesis of gynecomastia. While many studies have reported that aromatase enzyme (CYP19) gene polymorphism is associated with gynecomastia, only one study has shown a relationship between estrogen receptor (ER) alpha and beta gene polymorphism and gynecomastia. Thus, the aim of this study was to evaluate the relationships between CYP19 (rs2414096), ER alpha (rs2234693), ER beta (rs4986938), leptin (rs7799039), and leptin receptor (rs1137101) gene polymorphisms and gynecomastia. METHODS: This study included 107 male adolescents with gynecomastia and 97 controls. Total serum testosterone (T) and estradiol (E2) levels were measured, and DNA was extracted from whole blood using the PCR-RFLP technique. The polymorphic distributions of CYP19, ER alpha, ER beta, leptin and leptin receptor genes were compared. RESULTS: The median E2 level was 12.41 (5.00-65.40) pg/ml in the control group and 16.86 (2.58-78.47) pg/ml in the study group (p<0.001). The median T level was 2.19 (0.04-7.04) ng/ml in the control group and 1.46 (0.13 12.02) ng/ml in the study group (p=0.714). There was a significant relationship between gynecomastia and leptin receptor rs1137101 (p=0.002) and ER beta receptor rs4986938 gene polymorphisms (p=0.002). CONCLUSIONS: According to our results, increased E2 level and ER beta gene rs4986938 polymorphism might explain why some adolescents have gynecomastia. Leptin receptor gene rs1137101 polymorphism might affect susceptibility to gynecomastia. PMID- 24625356 TI - Investigational inhibitors of PTP4A3 phosphatase as antineoplastic agents. AB - INTRODUCTION: Protein tyrosine (Tyr) phosphatases have been implicated in many diseases, most notably in cancer. While there are a significant number of clinically approved inhibitors of protein Tyr kinases, there are no drugs specifically targeting protein Tyr phosphatases in clinical use despite the attractiveness of the molecular target. AREAS COVERED: This review examines the investigational challenges in identifying Tyr phosphatase inhibitors using the oncogenic phosphatase PTP4A3 as a prototype. The article includes a review of the structure, functionality and validation of PTP4A3 as a cancer target. It also provides an evaluation of existing small molecule and antibody inhibitors and provides new computational guidance for potentially more potent small molecule inhibitors. EXPERT OPINION: Tyr phosphatases, like PTP4A3, represent high value but ignored molecular targets for the treatment of cancer and other diseases. Although phosphatases are challenging targets, it seems likely that drug-like inhibitors of this important enzyme family would complement the growing number of protein Tyr kinase inhibitors. Animal models are beginning to provide validation for PTP4A3 as a molecular target for cancer progression and metastasis. The authors posit that greater efforts should be directed towards identifying Tyr phosphatase inhibitors for lead optimization and tool compounds to assist in interrogating and validating phosphatase involvement in physiological and pathological processes. PMID- 24625357 TI - Simultaneous determination of caffeine and some selected polyphenols in Wuyi Rock tea by high-performance liquid chromatography. AB - The primary taste and healthy benefits of tea are mainly attributed to tea polyphenols and caffeine. Due to very many kinds of flavonoid glycosides in tea and the lack of commercial standards of flavonoid glycosides, it is critical to develop a rapid and cheap method for determining flavonoid glycosides of tea. Contents of myricetin glycosides and quercetin glycosides in Wuyi Rock tea were determined by detecting contents of corresponding myricetin and quercetin. Optimizing hydrolysis conditions for hydrolyzing flavonoid glycosides to their corresponding flavonols including quercetin and myricetin in Wuyi Rock tea was a key technology for detecting contents of corresponding myricetin and quercetin. The results showed that hydrolysis at 2 mol/L HCl solution and at 90 degrees C for 1 h was an optimizing condition for hydrolyzing flavonoid glycosides to myricetin and quercetin in Wuyi Rock tea. Caffeine and seven kinds of polyphenols (GA, EGC, C, EGCG, EC, ECG, and CGA) in 20 samples of Wuyi Rock tea were simultaneously determined using a simple and fast reverse-phase high-performance liquid chromatography procedure coupled with photodiode array detector (RP-HPLC PDAD). The results indicated that there were significant (P < 0.05) differences of ECG, CGA, ECG, and myricetin glycosides in 'Wuyi Rougui' and 'Wuyi Shuixian', which were credited with causing the difference in taste between these two cultivar of Wuyi Rock tea. The study may be useful for clarifying the cause of "cultivated varieties flavor" of Wuyi Rock tea. PMID- 24625358 TI - Rise in children on adult mental health wards is condemned by UK doctors and campaigners. PMID- 24625359 TI - Mice depleted of the coxsackievirus and adenovirus receptor display normal spermatogenesis and an intact blood-testis barrier. AB - The coxsackievirus and adenovirus receptor (CXADR (CAR)) is a cell adhesion molecule expressed mainly in epithelial cells. Numerous evidence indicate that CXADR has an important role in testis development and function of the blood testis barrier (BTB) in vitro. The role of CXADR in testis physiology in vivo has, however, not been addressed. We therefore constructed a conditional CXADR knockout (cKO) mouse model in which CXADR can be depleted at any chosen timepoint by the administration of tamoxifen. We report for the first time that testicular depletion of CXADR in adult and pubertal mice does not alter BTB permeability or germ cell migration across the BTB during spermatogenesis. Adult cKO mice display normal junctional ultra-structure and localization of the junctional proteins claudin-3, occludin, junction-associated molecule-A (JAM-A), and ZO1. The BTB was intact with no leakage of biotin and lanthanum tracers into the tubular lumen. Adult CXADR cKO mice were fertile with normal sperm parameters and litter size. Breeding experiments and genotyping of the pups demonstrated that CXADR-negative sperm could fertilize WT eggs. In addition, knocking down CXADR from postnatal day 9 (P9) does not affect testicular development and BTB formation. These cKO mice were analyzed at P49 and P90 and display an intact barrier and uncompromised fertility. We conclude that CXADR possesses no direct role in testicular physiology in vivo. PMID- 24625360 TI - Demand for long acting and permanent contraceptive methods and associated factors among married women of reproductive age group in Debre Markos Town, North West Ethiopia. AB - BACKGROUND: Ethiopia is the second most populous country in sub Saharan Africa with high total fertility rate, and high maternal and child mortality rates. In sub Saharan African countries, including Ethiopia, even though studies show that demand for contraception is high, the practice is low. Particularly, in Ethiopia, despite the fact that practices on long acting and permanent methods are believed to be low, there are limited evidences on the real magnitude of demand for the methods. METHODS: To assess demand for long acting and permanent contraceptive methods and associated factors among married women of reproductive age group in Debre Markos town, Amhara Regional State, North West Ethiopia, A community based cross sectional study was conducted, from April 08-19, 2012. Systematic sampling technique was used to select 523 study participants. Pre tested structured Amharic version questionnaire was used to collect the data through interview. Both bivariate and multiple logistic regressions were used to identify associated factors. RESULTS: Among 519 respondents, 323 (62.2%) were using modern family planning (FP) methods in which 101 (19.5%) were using long acting and permanent contraceptive methods (LAPMs). Among all respondents, 171 (32.9%) had unmet need for LAPMs. The total demand for LAPMs was 272 (52.4%) of which 37.1% were satisfied and 62.9% unsatisfied demand. Being in the older age group (40-44 years) [AOR = 2.8; 95% CI:1.12, 9.55], having no desire for more child [AOR = 20.37; 95% CI:9.28, 44.72], desire to have a child after 2 years [AOR = 6.4; 95%CI:3.04,13.47], not ever heard of modern FP [AOR = 5.73; 95% CI:1.26, 25.91], not ever using of modern FP [AOR = 1.89; 95% CI:1.01, 3.55] and having no spousal discussion in the last six month [AOR = 1.642, 95% CI: 1.049, 2.57) were some of the factors significantly associated with demand for LAPMs. CONCLUSIONS: Demand and unmet need for LAPMs were high in the study area. Therefore raising awareness of the community, counseling/discussion about the methods with all clients, encouraging spousal involvement are fundamental areas of intervention. Moreover, increasing the availability and accessibility of LAPMs is required to meet the unmet needs. PMID- 24625361 TI - Relationships between housing and food insecurity, frequent mental distress, and insufficient sleep among adults in 12 US States, 2009. AB - INTRODUCTION: Housing insecurity and food insecurity may be psychological stressors associated with insufficient sleep. Frequent mental distress may mediate the relationships between these variables. The objective of this study was to examine the relationships between housing insecurity and food insecurity, frequent mental distress, and insufficient sleep. METHODS: We analyzed data from the 2009 Behavioral Risk Factor Surveillance System in 12 states. Housing insecurity and food insecurity were defined as being worried or stressed "sometimes," "usually," or "always" during the previous 12 months about having enough money to pay rent or mortgage or to buy nutritious meals. RESULTS: Of 68,111 respondents, 26.4% reported frequent insufficient sleep, 28.5% reported housing insecurity, 19.3% reported food insecurity, and 10.8% reported frequent mental distress. The prevalence of frequent insufficient sleep was significantly greater among those who reported housing insecurity (37.7% vs 21.6%) or food insecurity (41.1% vs 22.9%) than among those who did not. The prevalence of frequent mental distress was also significantly greater among those reporting housing insecurity (20.1% vs 6.8%) and food insecurity (23.5% vs 7.7%) than those who did not. The association between housing insecurity or food insecurity and frequent insufficient sleep remained significant after adjustment for other sociodemographic variables and frequent mental distress. CONCLUSION: Sleep health and mental health are embedded in the social context. Research is needed to assess whether interventions that reduce housing insecurity and food insecurity will also improve sleep health and mental health. PMID- 24625362 TI - Engaging the community to improve nutrition and physical activity among houses of worship. AB - BACKGROUND: Obesity, physical inactivity, and poor nutrition have been linked to many chronic diseases. Research indicates that interventions in community-based settings such as houses of worship can build on attendees' trust to address health issues and help them make behavioral changes. COMMUNITY CONTEXT: New Brunswick, New Jersey, has low rates of physical activity and a high prevalence of obesity. An adapted community-based intervention was implemented there to improve nutrition and physical activity among people who attend houses of worship and expand and enhance the network of partners working with Rutgers Cancer Institute of New Jersey. METHODS: An adapted version of Body & Soul: A Celebration of Healthy Living and Eating was created using a 3-phase model to 1) educate lay members on nutrition and physical activity, 2) provide sustainable change through the development of physical activity programming, and 3) increase access to local produce through collaborations with community partners. OUTCOME: Nineteen houses of worship were selected for participation in this program. Houses of worship provided a questionnaire to a convenience sample of its congregation to assess congregants' physical activity levels and produce consumption behaviors at baseline using questions from the Health Information National Trends Survey instrument. This information was also used to inform future program activities. INTERPRETATION: Community-based health education can be a promising approach when appropriate partnerships are identified, funding is adequate, ongoing information is extracted to inform future action, and there is an expectation from all parties of long-term engagement and capacity building. PMID- 24625363 TI - State practitioner insights into local public health challenges and opportunities in obesity prevention: a qualitative study. AB - INTRODUCTION: The extent of obesity prevention activities conducted by local health departments (LHDs) varies widely. The purpose of this qualitative study was to characterize how state obesity prevention program directors perceived the role of LHDs in obesity prevention and factors that impact LHDs' success in obesity prevention. METHODS: From June 2011 through August 2011, we conducted 28 semistructured interviews with directors of federally funded obesity prevention programs at 22 state and regional health departments. Interviews were transcribed verbatim, coded, and analyzed to identify recurring themes and key quotations. RESULTS: Main themes focused on the roles of LHDs in local policy and environmental change and on the barriers and facilitators to LHD success. The role LHDs play in obesity prevention varied across states but generally reflected governance structure (decentralized vs centralized). Barriers to local prevention efforts included competing priorities, lack of local capacity, siloed public health structures, and a lack of local engagement in policy and environmental change. Structures and processes that facilitated prevention were having state support (eg, resources, technical assistance), dedicated staff, strong communication networks, and a robust community health assessment and planning process. CONCLUSIONS: These findings provide insight into successful strategies state and local practitioners are using to implement innovative (and evidence informed) community-based interventions. The change in the nature of obesity prevention requires a rethinking of the state-local relationship, especially in centralized states. PMID- 24625364 TI - Designing audience-centered interactive voice response messages to promote cancer screenings among low-income Latinas. AB - INTRODUCTION: Cancer screening rates among Latinas are suboptimal. The objective of this study was to explore how Latinas perceive cancer screening and the use and design of interactive voice response (IVR) messages to prompt scheduling of 1 or more needed screenings. METHODS: Seven focus groups were conducted with Latina community health center patients (n = 40) in need of 1 or more cancer screenings: 5 groups were of women in need of 1 cancer screening (breast, cervical, or colorectal), and 2 groups were of women in need of multiple screenings. A bilingual researcher conducted all focus groups in Spanish using a semistructured guide. Focus groups were recorded, transcribed, and translated into English for analysis. Emergent themes were identified by using thematic content analysis. RESULTS: Participants were familiar with cancer screening and viewed it positively, although barriers to screening were identified (unaware overdue for screening, lack of physician referral, lack of insurance or insufficient insurance coverage, embarrassment or fear of screening procedures, fear of screening outcomes). Women needing multiple screenings voiced more concern about screening procedures, whereas women in need of a single screening expressed greater worry about the screening outcome. Participants were receptive to receiving IVR messages and believed that culturally appropriate messages that specified needed screenings while emphasizing the benefit of preventive screening would motivate them to schedule needed screenings. CONCLUSION: Participants' receptiveness to IVR messages suggests that these messages may be an acceptable strategy to promote cancer screening among underserved Latina patients. Additional research is needed to determine the effectiveness of IVR messages in promoting completion of cancer screening. PMID- 24625365 TI - Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. AB - BACKGROUND: Probiotics are extensively used to promote gastrointestinal health, and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of postinfarction heart failure. METHODS AND RESULTS: Rats were subjected to 6 weeks of sustained coronary artery occlusion and administered the probiotic Lactobacillus rhamnosus GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment and gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the 6-week follow up period including a marked preservation of left ventricular ejection fraction and fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at 4 weeks, suggesting persistence of the GR 1 effects after cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin:adiponectin plasma concentration ratio in rats subjected to coronary ligation, which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels. CONCLUSIONS: The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure. PMID- 24625368 TI - Is the agenda for global mental health a form of cultural imperialism? PMID- 24625369 TI - Hydrophobic mutations in buried polar residues enhance HIV-1 gp41 N-terminal heptad repeat-C-terminal heptad repeat interactions and C-peptides' anti-HIV activity. AB - OBJECTIVE: To investigate the effect of mutations in a highly conserved buried polar area on the function of HIV-1 gp41. DESIGN: During HIV-1 entry, a six helical bundle (6-HB) formation between the C-terminal and N-terminal heptad repeat (CHR and NHR) of gp41 provides energy for virus cell membrane fusion. In 6 HB, residues at a and d (a-d) positions of CHR directly interact with NHR and are buried. They are considered critical residues for 6-HB stability and for anti-HIV 1 activity of CHR-derived peptides (C-peptides). Most of a-d residues in CHR are hydrophobic, as buried hydrophobic residues facilitate protein stability. However, HIV-1 gp41 CHR contains a highly conserved polar area with four successive buried a-d polar residues: S649/Q652/N656/E659. We mutated these buried polar residues to hydrophobic residues, either Leu or Ile, and studied its effect on the gp41 NHR-CHR interactions and anti-HIV activities of the C peptides. METHODS: We measured the C-peptide mutants' ability to form 6-HB with NHR, thermal stability of the 6-HBs and C-peptides' inhibitory activity against both T20-sensitive and resistant HIV-1 strains. RESULTS: All the mutated C peptides retained their ability to form stable 6-HB with NHR and strongly inhibited HIV-1 replication. Strikingly, S649L and E659I mutations endow C peptide with a significantly enhanced activity against T20-resistant HIV-1 strains. CONCLUSION: The highly conserved buried a-d polar residues in HIV-1 gp41 CHR can be mutated as a means of developing new fusion inhibitors against drug resistant HIV-1 strains. The concept can also be utilized to design fusion inhibitors against other viruses with similar mechanisms. PMID- 24625370 TI - Fluorescent nanomicelles for selective detection of Sudan dye in Pluronic F127 aqueous media. AB - Novel self-assembled water-soluble nanomicelles that contain fluorescent conjugated polymers (poly(9,9-dioctylfluorene) (PFO) or poly[2,7-(9,9 dihexylfluorene)-alt-4,4'-phenylether] (PF-PE)) have been obtained and used as the highly sensitive/selective platform for Sudan dye detection. The Fluorescent nanomicelles exhibited a highly selective fluorescence quenching by the prohibited food additive Sudan I, while not for the natural pigments: Capsanthin and Beta-carotene, due to the more suitable matching of the LUMOs (lowest unoccupied molecular orbital) of the conjugated polymers with that of Sudan I molecules. The Stern-Volmer constants (K(SV)) of PF-PE/F127 and PFO/F127 for Sudan I were 1,040,480 and 665,000 M(-1), respectively, which were more than 100 times higher than those of the same conjugated polymers in the orgainc solvents. The significantly enhanced sensitivity was due to the collective effect of the F127 micelles to both chromophore and analyte, through which the fluorophone analyte binding interaction is significantly strengthened and efficient photoinduced charge transfer occurs. The as-proposed materials and approach may be potentially applied in the real-time food safety screening. PMID- 24625371 TI - Clinical studies on bone-related outcome and the effect of TNF-alpha blocking therapy in ankylosing spondylitis. AB - PURPOSE OF REVIEW: To provide an overview of clinical trials and observational studies investigating the effect of tumor necrosis factor-alpha (TNF-alpha) blocking therapy on bone formation and bone loss in patients with ankylosing spondylitis (AS). RECENT FINDINGS: The effect of TNF-alpha blocking therapy on excessive bone formation or osteoproliferation remains inconclusive. Radiographic assessment of spinal osteoproliferation is complicated by the overall slow rate of progression and the high variability between individual AS patients. Multiple studies demonstrated that TNF-alpha blocking therapy results in a significant increase in bone mineral density (BMD) at the lumbar spine and hip. Based on bone turnover marker (BTM) analysis, this can mainly be explained by an increase in mineralization and decrease in bone resorption. SUMMARY: Both osteoproliferation (e.g. syndesmophytes and ankylosis of vertebrae) and excessive bone loss resulting in osteoporosis and vertebral fractures are frequently present in AS. Previous studies showed that BMD increases during TNF-alpha blocking therapy. Long-term follow-up in a large cohort of patients is needed to investigate whether TNF-alpha blockers can consolidate or stop spinal osteoproliferation and prevent vertebral fractures. Future studies should focus on the effect of these agents on bone-related outcome in AS patients with early vs. advanced disease. PMID- 24625372 TI - Established and forthcoming drugs for the treatment of osteoporosis. AB - PURPOSE OF REVIEW: The aim of treatment in patients at high risk for fractures is to reduce the risk of a first or a subsequent fracture. New data are available on the antifracture effects and side-effects of antiresorptive and osteoanabolic drugs, and new emerging therapies with new modes of action are on the horizon. RECENT FINDINGS: Calcium and vitamin D intake should be sufficient, but not too high. Vertebral, nonvertebral (including hip fracture) prevention with antiresorptive drugs such as bisphosphonates (alendronate, risedronate and zoledronic acid) and denosumab exceeds the risk of rare side-effects such as atypical femur fracture and osteonecrosis of the jaw. Teriparatide is an osteoanabolic drug that improves quality of life in severe osteoporosis. Strontium ranelate decreases dynamic parameters of bone formation during the first year of treatment, and could increase the risk of cardiovascular events in high-risk patients. Initiation of and adherence to fracture prevention drugs are still low. New potential developments in antiresorptive drugs include odanacatib, a selective inhibitor of cathepsin K, and, in osteoanabolic drugs, monoclonal antibodies against sclerostin. SUMMARY: These recent data indicate that fracture prevention with antiresorptives and teriparatide is effective with a reasonable safety profile. Odanacatib and antisclerostin are promising new drugs with new mechanisms of action, as they are able to disconnect the normal coupling between bone resorption and bone formation. PMID- 24625373 TI - The use of biologic therapy in pregnancy: a gastroenterologist's perspective. AB - PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) often affects women in their peak reproductive years, and therapy is often continued during pregnancy to maintain stable disease activity. Therapeutic options have expanded over the last 2 decades with the advent of new biologic options. It is, therefore, important for the gastroenterologists and other clinicians caring for patients with IBD to understand safety data regarding the treatment options, both biologic and nonbiologic, in pregnant IBD patients. RECENT FINDINGS: In general, quality of evidence in this area remains low. However, larger prospective studies are beginning to provide evidence regarding the potential safety of biologics both alone and in conjunction with nonbiologic therapy. SUMMARY: The majority of treatment options for IBD appears to be of low risk and may often be continued through pregnancy and lactation. Not treating IBD, for example, by discontinuing therapy prior to or with pregnancy, may pose a greater risk to mother and fetus in many cases. PMID- 24625374 TI - Facile and quantitative electrochemical detection of yeast cell apoptosis. AB - An electrochemical method based on square wave anodic stripping voltammetry (SWASV) was developed to detect the apoptosis of yeast cells conveniently and quantitatively through the high affinity between Cu(2+) and phosphatidylserine (PS) translocated from the inner to the outer plasma membrane of the apoptotic cells. The combination of negatively charged PS and Cu(2+) could decrease the electrochemical response of Cu(2+) on the electrode. The results showed that the apoptotic rates of cells could be detected quantitatively through the variations of peak currents of Cu(2+) by SWASV, and agreed well with those obtained through traditional flow cytometry detection. This work thus may provide a novel, simple, immediate and accurate detection method for cell apoptosis. PMID- 24625375 TI - Efficacy and safety of a new surgical method to treat malignant glaucoma in pseudophakia. AB - PURPOSE: To assess the efficacy and safety of a relatively new surgical method in pseudophakic malignant glaucoma patients. METHODS: This study is a retrospective, non-comparative, interventional case series. Ten eyes of nine pseudophakic malignant glaucoma patients with mean age of 63.3 years were analysed. All 10 eyes underwent a novel surgical technique, an anterior chamber capsulo hyaloidectomy and anterior vitrectomy through the peripheral iridectomy. Main outcome measures were: reformation of the anterior chamber, intraocular pressure (IOP), best-corrected visual acuity (BCVA), and complications. RESULTS: All 10 eyes with pseudophakic malignant glaucoma were treated successfully by using a new surgical technique. All cases had a relief of aqueous misdirection with anterior chamber deepening during and after the surgery and post-operative intraocular pressure (IOP) normalization. No relapses have been observed so far. There were no complications during surgery and in the post-operative period. CONCLUSION: The presented surgical technique seems to be safe and effective in all cases of malignant glaucoma in pseudophakia. PMID- 24625376 TI - Effects and adverse events after CXL for keratoconus are independent of age: a 1 year follow-up study. AB - PURPOSE: To compare the effect, failure rate and the risks of corneal cross linking (CXL) in keratoconus patients aged >=35 years to patients <35 years. METHODS: In 141 eyes of 116 keratoconus patients we compared the changes in best phoropter-corrected visual acuity (BCVA) and maximum keratometry values (Kmax) before and 12 months after CLX in patients aged >=35 years (n=34, 38 eyes) to the cohort of patients below 35 years of age. RESULTS: Overall, CXL significantly improved BCVA from 0.487 logMAR (95% confidence interval (CI) 0.426-0.548) by 0.197 logMAR (95% CI -0.243 to -0.150; P<0.001) and reduced Kmax from 48.96 diopter (Dpt) by -1.33 Dpt (95% CI -1.85 to -0.81: P<0.001). Age >=35 years had no effect on the changes of BCVA (-0.02 (95% CI -0.13 to 0.09); P=0.757) or Kmax (0.58 (95%CI -0.51 to 1.68); P=0.294) as compared with younger patients. In 54 patients (55 eyes, 38.5%) aged <35 years and in 18 patients (18 eyes, 47.4%) aged >=35 years, BCVA increased by >=2 Snellen lines. Failure (increase in Kmax >=1 Dpt) was observed in 17 eyes (16.5%) of patients aged <35 years and in 3 eyes (7.9%) of patients aged >=35 years during the 12-month follow-up period. Adverse outcomes (loss of >=2 Snellen lines) occurred in 4 (3.9%) eyes of patients aged <35 years and 1 (2.6%) eye of a patient aged >=35 years. CONCLUSION: Effects and adverse events of CXL treatment do not seem to differ between subjects younger or older than 35 years. PMID- 24625377 TI - Reliability and validity of Cirrus and Spectralis optical coherence tomography for detecting retinal atrophy in Alzheimer's disease. AB - BACKGROUND: To evaluate and compare the ability of two Fourier-domain optical coherence tomography (OCT) devices to detect retinal and retinal nerve fibre layer (RNFL) atrophy in patients with Alzheimer's disease (AD) compared with healthy subjects; to test the intra-session reliability of two OCT devices in AD patients and healthy subjects. METHODS: AD patients (n=75) and age-matched healthy subjects (n=75) underwent three Macular Cube 200 * 200 protocols using the Cirrus and Spectralis OCT devices and three 360 degrees circular scans centred on the optic disc using the Cirrus OCT device, the classic glaucoma application, and the new Nsite Axonal Analytics application of the Spectralis OCT instrument. Differences between healthy and AD eyes were compared, and measurements provided by each OCT protocol were compared. Reliability was measured using intraclass correlation coefficients and coefficients of variation. Correlations between OCT measurements and disease duration and severity were also analysed. RESULTS: Retinal thinning was observed in AD eyes in all areas except the fovea using both OCT devices. RNFL atrophy was detected in AD eyes with all three protocols, but the Nsite Axonal application was the most sensitive. Measurements by the two OCT devices were correlated, but differed significantly. Reliability was good using all protocols, but better with the glaucoma application of Spectralis. Mean RNFL thickness provided by the Nsite Axonal application correlated with disease duration. CONCLUSIONS: Fourier-domain OCT is a valid and reliable technique for detecting subclinical RNFL and retinal atrophy in AD, especially using the Nsite Axonal application. RNFL thickness decreased with disease duration. PMID- 24625378 TI - Prevalence and risk factors for age-related macular degeneration in the elderly Chinese population in south-western Taiwan: the Puzih eye study. AB - AIM: This study aimed to ascertain the prevalence of and the risk factors associated with early and late age-related macular degeneration (AMD) among Chinese individuals aged >=65 years residing in Puzih, Taiwan. METHODS: This population-based cross-sectional study graded digital colour photographs of the ocular fundus of 673 individuals using the Wisconsin Age-Related Maculopathy Grading System. We compared the characteristics of individuals with early and late AMD using chi(2)-analyses and described risk factors for early and late AMD using odds ratios and 95% confidence intervals. RESULTS: Individuals with late AMD were significantly older and more likely to have hypertension. Further, their sunlight exposure time was longer than that of those with early AMD, only drusen, or no AMD lesions (P<0.01). A history of hyperlipidaemia for >10 years was a significant risk factor for early AMD, while old age, hypertension for >10 years, and exposure to sunlight for >8 h per day were associated with late AMD. CONCLUSIONS: The prevalence rate of early AMD in the present study was 15.0%, which is similar to that reported for Caucasians and Japanese included in the European Eye Study and the Hisayama Study, respectively. The late AMD prevalence rate of 7.3% found among our study participants was comparable to that reported by the Greenland Inuit Eye Study and Reykjavik Study, but considerably lower than that reported for Caucasians, indicating that late AMD might be less prevalent among Asians than Caucasians. PMID- 24625379 TI - An introduction to patient-reported outcome measures in ophthalmic research. AB - Clinical outcomes, such as quantifying the extent of visual field loss by automated perimetry, are valued highly by health professionals, but such measures do not capture the impact of the condition on a patient's life. Patient-reported outcomes describe any report or measure of health reported by the patient, without external interpretation by a clinician or researcher. In this review, we discuss the value of the measures that capture this information (patient-reported outcome measures; PROMs), and why they are important to both the clinician and the researcher. We also consider issues around developing or selecting a PROM for ophthalmic research, the emerging challenges around conducting and reporting PROMs in clinical trials and highlight best practice for their use. Search terms for this review comprised: (1) (patient-reported outcomes OR patient-reported outcome measures) AND (2) randomised controlled trials AND (3) limited to ophthalmic conditions. These terms were expanded as follows: ((('patients'(MeSH Terms) OR 'patients'(All Fields) OR 'patient'(All Fields)) AND ('research report'(MeSH Terms) OR ('research'(All Fields) AND 'report'(All Fields)) OR 'research report'(All Fields) OR 'reported'(All Fields)) AND outcomes(All Fields)) OR (('patients'(MeSH Terms) OR 'patients'(All Fields) OR 'patient'(All Fields)) AND ('research report'(MeSH Terms) OR ('research'(All Fields) AND 'report'(All Fields)) OR 'research report'(All Fields) OR 'reported'(All Fields) AND ('outcome assessment (health care)'(MeSH Terms) OR ('outcome'(All Fields) AND 'assessment'(All Fields) AND '(health'(All Fields) AND 'care)'(All Fields)) OR 'outcome assessment (health care)'(All Fields) OR ('outcome'(All Fields) AND 'measures'(All Fields)) OR 'outcome measures'(All Fields)))) AND ('randomized controlled trial'(Publication Type) OR 'randomized controlled trials as topic'(MeSH Terms) OR 'randomised controlled trials'(All Fields) OR 'randomized controlled trials'(All Fields)) AND (ophth*(All Fields)). The authors also utilised the extensive non-ophthalmic literature and online resources relating to PROs and PROMs to inform this review. PMID- 24625380 TI - Is it safe to discharge treated proliferative diabetic retinopathy patients from the hospital eye service to a community screening programme? AB - PURPOSE: To investigate the distribution of new vessels (NV) in patients treated with pan-retinal photocoagulation for proliferative diabetic retinopathy (PDR). To assess whether it is safe to discharge treated PDR patients to the NHS Diabetic Eye Screening Programme (DESP) which uses two mydriatic 45 degrees fields of each eye. METHODS: Consecutive treated PDR patients undergoing fundus fluorescein angiography between July 2010 and October 2011 for the purpose of looking for NV were included. The distribution of NV was mapped. In particular it was noted whether NV occurred in the area covered by the DESP standard screening images. RESULTS: A total of 76 patients (108 eyes) met the inclusion criteria for the study. Leaking NV were found inside the DESP fields in 89% of study patients. In 108 eyes with leaking NV, there were a total of 35 NVD and 336 NVE. NV were found within DESP fields in 83% of eyes. Of the 336 NVE, 54% occurred within and 46% outside DESP standard fields. There was no statistically significant difference in the retinal quadrant distribution of NVE. CONCLUSIONS: If these findings apply to the whole treated PDR population, NVE would be identified in 89% of patients undergoing DESP screening. This would support stable treated PDR patients being monitored within the DESP. We found no preferential clustering of NV within quadrants or between posterior and less posterior retina suggesting that there would be no benefit to the DESP of taking an additional field or graders concentrating on one particular quadrant more than another. PMID- 24625381 TI - Response to 'Preventable eye injuries while fly fishing'. PMID- 24625382 TI - Preventable eye injuries while fly fishing. PMID- 24625383 TI - Presoaking with BSS used for thin manually dissected DSEK (TMDSEK): a viable option for thin DSEK. AB - AIM: To describe a novel technique for the safe manual dissection of thin donor lenticules in 10 consecutive patients undergoing DSEK surgery. METHODS: A key element of our new technique was to presoak the donor cornea in balanced salt solution (BSS) for 30 min before manual dissection. The cornea was placed on an artificial anterior chamber and pressure in the chamber was maintained at 80 mm Hg. The limbus of the donor cornea was incised to the same depth as the central corneal thickness. Lamellar dissection was started with the short side of the Morlet dissector (Duckworth & Kent Ltd) and completed using the lamellar (less sharp) end of the Morlet dissector. Outcomes of 10 consecutive cases of thin manually dissected DSEK (TMDSEK) were prospectively analysed for thickness and visual outcome. RESULTS: Mean graft thicknesses measured less than 100 MUm at 1 month post surgery (mean thickness 90.7 MUm, range 48-137 MUm, SD 29.96 MUm). Presoaked donor corneal pachymetry was strongly negatively correlated with graft thickness (correlation r=-0.75, P<0.05). DISCUSSION: Our dissection technique achieves consistently thin endothelial donor corneal grafts that can be safely produced with minimal financial investment and no limitations on surgical time. This technique is likely to be of significant importance for a large proportion of the eye centres where microkeratomes may not be routinely available. PMID- 24625384 TI - Dynamics of intraretinal fluid accumulation evidenced by SD-OCT in a case of cat scratch neuroretinitis. PMID- 24625385 TI - Current practices, attitudes, and perceived barriers for treating smokers by Hong Kong dentists. AB - OBJECTIVES: To assess the attitudes of dentists towards smoking cessation advice, as well as to investigate their current practice and perceived barriers to giving such advice and the relationships among their peers regarding such activity. DESIGN: Cross-sectional survey. SETTING: Hong Kong. PARTICIPANTS: Self-reporting questionnaires were mailed to 330 dentists in Hong Kong by systematic sampling. Information on their attitudes, practices, and perceived barriers towards smoking cessation advice and relevant background information was collected. RESULTS: A total of 218 questionnaires were returned (response rate, 66%). The majority (97%) reported that they would enquire into every patient's smoking status, yet only around half of them did so routinely. Most (95%) of the dentists who always enquired about smoking status would actually offer smoking cessation advice to their patients. Multiple logistic regression of the results revealed that government dentists (odds ratio=2.7; 95% confidence interval, 1.4-5.1), those who received training in smoking cessation advice (2.5; 1.2-5.1), and those aged over 40 years (1.9; 1.0-3.4) were significantly more likely to enquire about smoking status. In most practices (93%), smoking cessation advice was offered by the dentists themselves rather than by other team members. "Lack of training", "unlikely to be successful", and "possibility of losing patients" were the three barriers regarded as "very important" by dentists. CONCLUSIONS: Dentists in Hong Kong generally had positive attitudes towards smoking cessation advice. The dental team is in a very good position to help smokers quit. However, training and guidelines designed specifically for dental teams are paramount to overcome barriers in delivering smoking cessation advice by dental professionals. PMID- 24625386 TI - Severe acute pyelonephritis: a review of clinical outcome and risk factors for mortality. AB - OBJECTIVE. To review demographics of patients with acute pyelonephritis, their outcomes of severe upper urinary tract infection, and to identify risk factors for long hospital stay and mortality. DESIGN. Case series. SETTING. A regional hospital in Hong Kong. PATIENTS. Patients admitted between June 2007 and June 2012 for acute pyelonephritis were identified. Those with the most severe outcomes were analysed of their mortality, need for care in the intensive care unit, or necessitation of urological intervention. RESULTS. Overall, 68 patients fulfilled our criteria for severe acute pyelonephritis. The female-to-male ratio was 7:3. Their mean age was 58 years. Overall, 57% of the patients had impaired renal function and 37% were diabetic; 47% developed shock after admission and 56% required further intensive care unit care; 75% of the patients demonstrated radiological evidence of urinary tract obstruction and required subsequent drainage procedures. Five patients died due to severe acute pyelonephritis. The prevalence of bacteraemia and bacteriuria was 57% and 74%, respectively. Escherichia coli accounted for the majority of causative organisms. Four risk factors-bacteraemia, shock, need for intensive care, and suppurative pyelonephritis-were associated with hospital stay of longer than 14 days. Old age (>=65 years), male sex, deranged renal function, and presence of disseminated intravascular coagulation were associated with mortality. CONCLUSION. There was high prevalence of bacteraemia and septic shock in patients with severe acute pyelonephritis. The factors of old age (>=65 years), male sex, deranged renal function, and presence of disseminated intravascular coagulation were associated with mortality. With the support of intensive care, early recognition of urinary tract obstruction and timely drainage, patients with severe acute pyelonephritis generally carry a good prognosis. PMID- 24625387 TI - Public knowledge and attitudes towards cardiopulmonary resuscitation in Hong Kong: telephone survey. AB - OBJECTIVES: To investigate the public's knowledge and attitudes about cardiopulmonary resuscitation in Hong Kong. DESIGN: Cross-sectional telephone survey. SETTING: Hong Kong. PARTICIPANTS: Hong Kong residents aged 15 to 64 years. MAIN OUTCOME MEASURES: The knowledge and attitudes towards cardiopulmonary resuscitation. RESULTS: Among the 1013 respondents, only 214 (21%) reported that they had received cardiopulmonary resuscitation training. The majority (72%) of these trained respondents had had their latest training more than 2 years earlier. The main reasons for not being involved in cardiopulmonary resuscitation training included lack of time or interest, and "not necessary". People with full time jobs and higher levels of education were more likely to have such training. Respondents stating they had received cardiopulmonary resuscitation training were more willing to try it if needed at home (odds ratio=3.3; 95% confidence interval, 2.4-4.6; P<0.001) and on strangers in the street (4.3; 3.1-6.1; P<0.001) in case of emergencies. Overall cardiopulmonary resuscitation knowledge of the respondents was low (median=1, out of 8). Among all the respondents, only four of them (0.4%) answered all the questions correctly. CONCLUSIONS: Knowledge of cardiopulmonary resuscitation was still poor among the public in Hong Kong and the percentage of population trained to perform it was also relatively low. Efforts are needed to promote educational activities and explore other approaches to skill reinforcement and refreshment. Besides, we suggest enacting laws to protect bystanders who offer cardiopulmonary resuscitation, and incorporation of relevant training course into secondary school and college curricula. PMID- 24625388 TI - Public lacks knowledge on chronic kidney disease: telephone survey. AB - OBJECTIVES: To examine knowledge of chronic kidney disease in the general public. DESIGN: Cross-sectional telephone survey. SETTING: Hong Kong. PARTICIPANTS: Community-dwelling adults who spoke Chinese in Hong Kong. RESULTS: The response rate was 47.3% (516/1091) out of all subjects who were eligible to participate. The final survey population included 516 adults (55.6% female), of whom over 80% had received a secondary level of education or higher. Close to 20% of the participants self-reported a diagnosis of hypertension. Few (17.8%) realised the asymptomatic nature of chronic kidney disease. Less than half of these individuals identified hypertension (43.8%) or diabetes (44.0%) as risk factors of kidney disease. Awareness of high dietary sodium as a risk factor for chronic kidney disease was high (79.5%). CONCLUSIONS: The public in Hong Kong is poorly informed about chronic kidney disease, with major knowledge gaps regarding the influence of hypertension on kidney disease. We are concerned about the public's unawareness of hypertension being a risk factor for kidney disease. Future health education should target areas of knowledge deficits. PMID- 24625389 TI - Auer rod-like inclusions in plasma cells in multiple myeloma. PMID- 24625390 TI - MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma. AB - The p53 pathway regulates stress response, and variations in p53, MDM2, and MDM4 may predispose an individual to tumor development. The aim of this study was to study the impact of genetic variation on sporadic and hereditary melanoma. We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls. Genotyping was performed by PCR restriction fragment length polymorphism, pyrosequencing, and allelic discrimination. We found an increased risk for hereditary melanoma in MDM2 GG homozygotes, which was more pronounced among women (P=0.035). In the event of pairwise combinations of the single nucleotide polymorphisms, a risk elevation was shown for MDM2 GG homozygotes/p53 wild-type Arg in hereditary melanoma (P=0.01). Individuals with sporadic melanomas of the superficial spreading type, including melanoma in situ, showed a slightly higher frequency of the MDM2 GG genotype compared with those with nodular melanomas (P=0.04). The dysplastic nevus phenotype, present in the majority of our hereditary melanoma cases and also in some sporadic cases, further enhanced the effect of the MDM2 GG genotype on melanoma risk (P=0.005). In conclusion, the results show an association between MDM2 SNP309 and an increased risk for hereditary melanoma, especially among women. Analysis of sporadic melanoma also shows an association between MDM2 and the superficial spreading melanoma subtype, as well as an association with the presence of dysplastic nevi in sporadic melanoma. PMID- 24625391 TI - Protective effects of Croton campestris A. St-Hill in different ulcer models in rodents: evidence for the involvement of nitric oxide and prostaglandins. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Croton campestris A. St.-Hill., popularly known as "velame do campo", is a species native from savannah area of Northeast Brazil, which is used by traditional communities in folk medicine for a variety of health problems, especially detoxification, inflammation and gastritis. The present study investigates the possible gastric antiulcer activity of Croton campestris root extract (CCRE) and mechanisms of action underlying this effect. MATERIALS AND METHODS: Gastric lesions were induced in mice by ethanol, acidified ethanol and indomethacin. CCRE was previously administered orally in doses ranging from 50 to 750 mg/kg. Stomach lesions were measured. The involvement of Nitric Oxide (NO), prostaglandins (PGEs), ATP-dependent K+ channel and adrenergic receptor was investigated through specific inhibitors. RESULTS: CCRE produced significant antiulcer activity against absolute ethanol, acidified ethanol and indomethacin induced gastric lesions. The pretreatment with L-NAME (10 mg/kg, p.o.), an inhibitor of nitric oxide synthesis and indomethacin (10 mg/kg, s.c.), an inhibitor of prostaglandin production, reversed the antiulcer action of CCRE. CONCLUSION: Taking together, these results suggest that the antiulcer activity of CCRE is dependent of NO and prostaglandin pathways possibly due to its ability to stimulate the synthesis of NO, and activation of endogenous prostaglandin production. Therefore, the use of CCRE in traditional Brazilian medicine against gastric disorders has a scientific basis. PMID- 24625392 TI - Cerebrospinal fluid alpha-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort. AB - Most patients with Parkinson disease (PD) develop both cognitive and motor impairment, and biomarkers for progression are urgently needed. Although alpha synuclein is altered in cerebrospinal fluid of patients with PD, it is not known whether it predicts motor or cognitive deterioration. We examined clinical data and alpha-synuclein in >300 unmedicated patients with PD who participated in the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, with up to 8 years of follow-up. Longitudinal measures of motor and cognitive function were studied before (phase 1) and during (phase 2) levodopa therapy; cerebrospinal fluid was collected at the beginning of each phase. Correlations and linear mixed models were used to assess alpha-synuclein association with disease severity and prediction of progression in the subsequent follow-up period. Despite decreasing alpha-synuclein (phase 1 to phase 2 change of -0.05 +/ 0.21 log-transformed values, P < 0.001), no correlations were observed between alpha-synuclein and motor symptoms. Longitudinally, lower alpha-synuclein predicted better preservation of cognitive function by several measures [Selective Reminding Test total recall alpha-synuclein * time interaction effect coefficient, -0.12 (P = 0.037); delayed recall, -0.05 (P = 0.002); New Dot Test, 0.03 (P = 0.002)]. Thus, alpha-synuclein, although not clinically useful for motor progression, might predict cognitive decline, and future longitudinal studies should include this outcome for further validation. PMID- 24625393 TI - Spatio-temporal simulation of first pass drug perfusion in the liver. AB - The liver is the central organ for detoxification of xenobiotics in the body. In pharmacokinetic modeling, hepatic metabolization capacity is typically quantified as hepatic clearance computed as degradation in well-stirred compartments. This is an accurate mechanistic description once a quasi-equilibrium between blood and surrounding tissue is established. However, this model structure cannot be used to simulate spatio-temporal distribution during the first instants after drug injection. In this paper, we introduce a new spatially resolved model to simulate first pass perfusion of compounds within the naive liver. The model is based on vascular structures obtained from computed tomography as well as physiologically based mass transfer descriptions obtained from pharmacokinetic modeling. The physiological architecture of hepatic tissue in our model is governed by both vascular geometry and the composition of the connecting hepatic tissue. In particular, we here consider locally distributed mass flow in liver tissue instead of considering well-stirred compartments. Experimentally, the model structure corresponds to an isolated perfused liver and provides an ideal platform to address first pass effects and questions of hepatic heterogeneity. The model was evaluated for three exemplary compounds covering key aspects of perfusion, distribution and metabolization within the liver. As pathophysiological states we considered the influence of steatosis and carbon tetrachloride-induced liver necrosis on total hepatic distribution and metabolic capacity. Notably, we found that our computational predictions are in qualitative agreement with previously published experimental data. The simulation results provide an unprecedented level of detail in compound concentration profiles during first pass perfusion, both spatio-temporally in liver tissue itself and temporally in the outflowing blood. We expect our model to be the foundation of further spatially resolved models of the liver in the future. PMID- 24625394 TI - The mortality associated with erythema nodosum leprosum in Ethiopia: a retrospective hospital-based study. AB - BACKGROUND: Erythema nodosum leprosum (ENL) is a debilitating multisystem disorder which complicates leprosy. It is characterised by fever, malaise and painful erythematous cutaneous nodules. ENL is often recurrent or chronic in nature and frequently severe. Patients often require prolonged treatment with high doses of oral corticosteroids. There are no data on the mortality associated with treated ENL. METHODOLOGY: The notes of patients who were admitted, discharged, transferred to another facility or died with a diagnosis of leprosy or a leprosy-related complication for a five year period were reviewed. RESULT/DISCUSSION: 414 individuals were identified from the ward database. 312 (75.4%) patient records were located and reviewed. Ninety-nine individuals had ENL and 145 had a Type 1 reaction. The median age of individuals with ENLwas 25 years. Eight patients with erythema nodosum leprosum died compared with two diagnosed with Type 1 reaction. This difference is statistically significant (p = 0.0168, Fisher's Exact Test). There is a significant mortality and morbidity associated with ENL in this Ethiopian cohort. The adverse outcomes seen are largely attributable to the chronic administration of oral corticosteroids used to control the inflammatory and debilitating symptoms of the condition. PMID- 24625395 TI - Impact of domestic care environment on trauma and posttraumatic stress disorder among orphans in western Kenya. AB - OBJECTIVE: The aim of this study was to determine the impact of the domestic care environment on the prevalence of potentially traumatic events (PTEs) and posttraumatic stress disorder (PTSD) among orphaned and separated children in Uasin Gishu County, western Kenya. METHODS: A total of 1565 (55.5% male) orphaned and separated adolescents aged 10-18 years (mean 13.8 years, sd 2.2), were assessed for PTSD and PTEs including bullying, physical abuse and sexual abuse. In this sample, 746 lived in extended family households, 746 in Charitable Children's Institutions (CCIs), and 73 on the street. Posttraumatic stress symptom (PTSS) scores and PTSD were assessed using the Child PTSD Checklist. RESULTS: Bullying was the commonest PTE in all domestic care environments, followed by physical and sexual abuse. All PTEs were commonest among the street youth followed by CCIs. However, sexual abuse was more prevalent in households than in CCIs. Prevalence of PTSD was highest among street youth (28.8%), then households (15.0%) and CCIs (11.5%). PTSS scores were also highest among street youth, followed by CCIs and households. Bullying was associated with higher PTSS scores and PTSD odds than either sexual or physical abuse. CONCLUSION: This study demonstrated differences in distribution of trauma and PTSD among orphaned and separated children in different domestic care environments, with street youth suffering more than those in CCIs or households. Interventions are needed to address bullying and sexual abuse, especially in extended family households. Street youth, a heretofore neglected population, are urgently in need of dedicated mental health services and support. PMID- 24625397 TI - Effects of exposure to aluminum on long-term potentiation and AMPA receptor subunits in rats in vivo. AB - OBJECTIVE: To explore the effects of exposure to aluminum (Al) on long-term potentiation (LTP) and AMPA receptor subunits in rats in vivo. METHODS: Different dosages of aluminum-maltolate complex [Al(mal)3] were given to rats via acute intracerebroventricular (i.c.v.) injection and subchronic intraperitoneal (i.p.) injection. Following Al exposure, the hippocampal LTP were recorded by field potentiation technique in vivo and the expression of AMPAR subunit proteins (GluR1 and GluR2) in both total and membrane-enriched extracts from the CA1 area of rat hippocampus were detected by Western blot assay. RESULTS: Acute Al treatment produced dose-dependent suppression of LTP in the rat hippocampus and dose-dependent decreases of GluR1 and GluR2 in membrane extracts; however, no similar changes were found in the total cell extracts, which suggests decreased trafficking of AMPA receptor subunits from intracellular pools to synaptic sites in the hippocampus. The dose-dependent suppressive effects on LTP and the expression of AMPA receptor subunits both in the membrane and in total extracts were found after subchronic Al treatment, indicating a decrease in AMPA receptor subunit trafficking from intracellular pools to synaptic sites and an additional reduction in the expression of the subunits. CONCLUSION: Al(mal)3 obviously and dose-dependently suppressed LTP in the rat hippocampal CA1 region in vivo, and this suppression may be related to both trafficking and decreases in the expression of AMPA receptor subunit proteins. However, the mechanisms underlying these observations need further investigation. PMID- 24625398 TI - Influence of Genista tinctoria L. or methylparaben on subchronic toxicity of bisphenol A in rats. AB - OBJECTIVE: To evaluate the influence of an extract of Genista tinctoria L. herba (GT) or methylparaben (MP) on histopathological changes and 2 biomarkers of oxidative stress in rats subchronicly exposed to bisphenol A (BPA). METHODS: Adult female Wistar rats were orally exposed for 90 d to BPA (50 mg/kg), BPA+GT (35 mg isoflavones/kg) or BPA+MP (250 mg/kg). Plasma and tissue samples were taken from liver, kidney, thyroid, uterus, ovary, and mammary gland after 30, 60, and 90 d of exposure respectively. Lipid peroxidation and in vivo hydroxyl radical production were evaluated by histological analysis along with malondialdehyde and 2,3-dihydroxybenzoic acid detection. RESULTS: The severity of histopathological changes in liver and kidneys was lower after GT treatment than after BPA or BPA+MP treatment. A minimal thyroid receptor antagonist effect was only observed after BPA+MP treatment. The abnormal folliculogenesis increased in a time-dependent manner, and the number of corpus luteum decreased. No significant histological alterations were found in the uterus. The mammary gland displayed specific estrogen stimulation changes at all periods. Both MP and GT revealed antioxidant properties reducing lipid peroxidation and BPA-induced hydroxyl radical generation. CONCLUSION: GT L. extract ameliorates the toxic effects of BPA and is proved to have antioxidant potential and antitoxic effect. MP has antioxidant properties, but has either no effect or exacerbates the BPA induced histopathological changes. PMID- 24625399 TI - Combined effects of 50 Hz magnetic field and magnetic nanoparticles on the proliferation and apoptosis of PC12 cells. AB - OBJECTIVE: To investigate the bioeffects of extremely low frequency (ELF) magnetic field (MF) (50 Hz, 400 MUT) and magnetic nanoparticles (MNPs) via cytotoxicity and apoptosis assays on PC12 cells. METHODS: MNPs modified by SiO2 (MNP-SiO2) were characterized by transmission electron microscopy (TEM), dynamic light scattering and hysteresis loop measurement. PC12 cells were administrated with MNP-SiO2 with or without MF exposure for 48 h. Cytotoxicity and apoptosis were evaluated with MTT assay and annexin V-FITC/PI staining, respectively. The morphology and uptake of MNP-SiO2 were determined by TEM. MF simulation was performed by Ansoft Maxwell based on the finite element method. RESULTS: MNP-SiO2 were identified as ~20 nm (diameter) ferromagnetic particles. MNP-SiO2 reduced cell viability in a dose-dependent manner. MF also reduced cell viability with increasing concentrations of MNP-SiO2. MNP-SiO2 alone did not cause apoptosis in PC12 cells; instead, the proportion of apoptotic cells increased significantly under MF exposure and increasing doses of MNP-SiO2. MNP-SiO2 could be ingested and then cause a slight change in cell morphology. CONCLUSION: Combined exposure of MF and MNP-SiO2 resulted in remarkable cytotoxicity and increased apoptosis in PC12 cells. The results suggested that MF exposure could strengthen the MF of MNPs, which may enhance the bioeffects of ELF MF. PMID- 24625400 TI - Dyslipidemia and outcome in patients with acute ischemic stroke. AB - OBJECTIVE: To study the relationship between dyslipidemia and outcome in patients with acute ischemic stroke. METHODS: Data about 1 568 patients with acute ischemic stroke were collected from 4 hospitals in Shandong Province from January 2006 to December 2008. National Institute of Health Stroke Scale (NIHSS) >10 at discharge or death was defined as the outcome. Effect of dyslipidemia on outcome in patients with acute ischemic stroke was analyzed by multivariate logistic regression analysis and propensity score-adjusted analysis, respectively. RESULTS: The serum levels of TC, LDL-C, and HDL-C were significantly associated with the outcome in patients with acute ischemic stroke. Multivariate logistic regression analysis and propensity score-adjusted analysis showed that the ORs and 95% CIs were 3.013 (1.259, 7.214)/2.655 (1.298, 5.43), 3.157 (1.306, 7.631)/3.405 (1.621, 7.154), and 0.482 (0.245, 0.946)/0.51 (0.282, 0.921), respectively, for patients with acute ischemic stroke. Hosmer-Lemeshow goodness of-fit test showed no significant difference in observed and predicted risk in patients with acute ischemic stroke (chi-square=8.235, P=0.411). CONCLUSION: Serum levels of TC, LDL-C, and HDL-C are positively related with the outcome in patients with acute ischemic stroke. PMID- 24625401 TI - Effects of HIV-1 tat on secretion of TNF-alpha and IL-1beta by U87 cells in AIDS patients with or without AIDS dementia complex. AB - OBJECTIVE: To explore the role of HIV-1 tat gene variations in AIDS dementia complex (ADC) pathogenesis. METHODS: HIV-1 tat genes derived from peripheral spleen and central basal ganglia of an AIDS patient with ADC and an AIDS patient without ADC were cloned for sequence analysis. HIV-1 tat gene sequence alignment was performed by using CLUSTAL W and the phylogentic analysis was conducted by using Neighbor-joining with MEGA4 software. All tat genes were used to construct recombinant retroviral expressing vector MSCV-IRES-GFP/tat. The MSCV-IRES-GFP/tat was cotransfected into 293T cells with pCMV-VSV-G and pUMVC vectors to assemble the recombinant retrovirus. After infection of gliomas U87 cells with equal amount of the recombinant retrovirus, TNF-alpha, and IL-1beta concentrations in the supernatant of U87 cells were determined with ELISA. RESULTS: HIV-1 tat genes derived from peripheral spleen and central basal ganglia of the AIDS patient with ADC and the other one without ADC exhibited genetic variations. Tat variations and amino acid mutation sites existed mainly at Tat protein core functional area (38-47aa). All Tat proteins could induce U87 cells to produce TNF-alpha and IL 1beta, but the level of IL-1beta production was different among Tat proteins derived from the ADC patient's spleen, basal ganglia, and the non-ADC patient's spleen. The level of Tat proteins derived from the ADC patient's spleen, basal ganglia, and the non-ADC patient's spleen were obviously higher than that from the non-ADC patient's basal ganglia. CONCLUSION: Tat protein core functional area (38-47aa) may serve as the key area of enhancing the secretion of IL-1beta. This may be related with the neurotoxicity of HIV-1 Tat. PMID- 24625402 TI - Isolation and characterization of recombinant variable domain of heavy chain anti idiotypic antibodies specific to aflatoxin B1. AB - Some unique subclasses of Camelidae antibodies are devoid of the light chain, and the antigen binding site is comprised exclusively of the variable domain of the heavy chain (VHH). The recombinant VHHs have a high potential as alternative reagents for the next generation of immunoassay. In particular, they might be very useful for molecular mimicry. The present study demonstrated an alpaca immunized with the F(ab')2 fragment of anti-aflatoxin B1 mAb and developed an important anti-idiotypic (anti-Id) responses. Antigen-specific elution method was used for panning private anti-Id VHHs from the constructed alpaca VHH library. The selected VHHs were expressed, renatured, purified, and then identified by a competitive enzyme-linked immunosorbent assay (ELISA). Our findings indicated that the VHH would be an alternative tool for haptens mimicry studies. PMID- 24625403 TI - Subacute effect of decabromodiphenyl ethane on hepatotoxicity and hepatic enzyme activity in rats. AB - Information regarding decabromodiphenyl ethane (DBDPE) effects on hepatotoxicity and metabolism is limited. In the present study, Wistar rats were given oral DBDPE at different doses. DBDPE induced oxidative stress, elevated blood glucose levels, increased CYP2B2 mRNA, CYP2B1/2 protein, 7-pentoxyresorufin O-depentylase (PROD) activity, and induced CYP3A2 mRNA, CYP3A2 protein, and luciferin benzylether debenzylase (LBD) activity. UDPGT activity increased with its increasing exposure levels, suggesting that oral DBDPE exposure induces drug metabolizing enzymes in rats via the CAR/PXR signaling pathway. The induction of CYPs and co-regulated enzymes of phase II biotransformation may affect the homeostasis of endogenous substrates, including thyroid hormones, which may, in turn, alter glucose metabolism. PMID- 24625404 TI - The development of a fluorescence polarization immunoassay for aflatoxin detection. AB - A fluorescence polarization immunoassay (FPIA) was developed for the analysis ofaflatoxins (AFs) using an anti-aflatoxin B1 (AFB1) monoclonal antibody and a novel fluorescein-labeled AFB1 tracer. The FPIA showed an IC50 value of 23.33 ng/mL with a limit of detection of 13.12 ng/mL for AFB1. The cross-reactivities of AFB1, AFB2, AFG1, AFG2, AFM1, and AFM2 with the antibody were 100%, 65.7%, 143%, 23.5%, 111.4%, and 2%, respectively. The group-specificity of anti-AFB1mAb indicated that the FPIA could potentially be used in a screening method for the detection of total AFs, albeit not AFG2 and AFM2. The total time required for analyzing 96 samples in one microplate was less than 5 min. This study demonstrates the potential usefulness of the FPIA as a rapid and simple technique for monitoring AFs. PMID- 24625405 TI - Carbon ion irradiation induces reduction of beta-tubulin in sperm of pubertal mice. PMID- 24625406 TI - Lateral flow immunoassay for quantitative detection of ractopamine in swine urine. AB - A strip reader based lateral flow immunoassay (LFIA) was established for the rapid and quantitative detection of ractopamine (RAC) in swine urine. The ratio of the optical densities (ODs) of the test line (AT) to that of the control line (AC) was used to effectively minimize interference among strips and sample variations. The linear range for the quantitative detection of RAC was 0.2 ng/mL to 3.5 ng/mL with a median inhibitory concentration (IC50) of 0.59 +/- 0.06 ng/mL. The limit of detection (LOD) of the LFIA was 0.13 ng/mL. The intra-assay recovery rates were 92.97%, 97.25%, and 107.41%, whereas the inter-assay rates were 80.07%, 108.17%, and 93.7%, respectively. PMID- 24625407 TI - Relaxin inhibit cardiac fibrosis induced by phorbol 12-myristate 13-acetate. AB - Relaxin is known to inhibit cardiac fibrosis. However, it is unclear whether relaxin could regulate the effects of Phorbol 12-myristate 13-acetate (PMA, PKC activator) on cardiac fibrosis. So the influence of relaxin on the cell proliferation and collagen expression induced by PMA in cultured cardiac fibroblasts was studied. It showed that PMA significantly increased cardiac fibroblasts proliferation, Type I pro-collagen protein expression, Type I pro collagen mRNA expression, and rhRLX absolutely significantly decreased PMA induced effects on cardiac fibroblasts proliferation and Type I pro-collagen expressions, indicating that relaxin could inhibit cardiac fibrosis induced by PMA. PMID- 24625408 TI - Immune control strategies for vaccinia virus-related laboratory-acquired infections. AB - While presenting biological characteristics of vaccinia virus and laboratory acquired infections during related research processes, this paper focuses on benefits and risks of vaccinia virus immunization in relation to laboratory acquired infections, describes characteristics and the adaptation of vaccinia virus vaccine, analyses the role vaccinia virus immunization plays in the prevention and control of laboratory-acquired infections, and finally proposes solutions and countermeasures to further promote and implement immune control strategies. The problem related to immune strategy and laboratory- acquired infections which is being raised, analyzed and explored plays an active and instructive role in vaccinia virus related researches and laboratory- acquired infections, and also helps to recommend and develop relevant immune strategy for future vaccine control of such infections. PMID- 24625409 TI - Risk analysis of sulfites used as food additives in China. AB - This study was to analyze the risk of sulfites in food consumed by the Chinese people and assess the health protection capability of maximum-permitted level (MPL) of sulfites in GB 2760-2011. Sulfites as food additives are overused or abused in many food categories. When the MPL in GB 2760-2011 was used as sulfites content in food, the intake of sulfites in most surveyed populations was lower than the acceptable daily intake (ADI). Excess intake of sulfites was found in all the surveyed groups when a high percentile of sulfites in food was in taken. Moreover, children aged 1-6 years are at a high risk to intake excess sulfites. The primary cause for the excess intake of sulfites in Chinese people is the overuse and abuse of sulfites by the food industry. The current MPL of sulfites in GB 2760-2011 protects the health of most populations. PMID- 24625410 TI - STEME: a robust, accurate motif finder for large data sets. AB - Motif finding is a difficult problem that has been studied for over 20 years. Some older popular motif finders are not suitable for analysis of the large data sets generated by next-generation sequencing. We recently published an efficient approximation (STEME) to the EM algorithm that is at the core of many motif finders such as MEME. This approximation allows the EM algorithm to be applied to large data sets. In this work we describe several efficient extensions to STEME that are based on the MEME algorithm. Together with the original STEME EM approximation, these extensions make STEME a fully-fledged motif finder with similar properties to MEME. We discuss the difficulty of objectively comparing motif finders. We show that STEME performs comparably to existing prominent discriminative motif finders, DREME and Trawler, on 13 sets of transcription factor binding data in mouse ES cells. We demonstrate the ability of STEME to find long degenerate motifs which these discriminative motif finders do not find. As part of our method, we extend an earlier method due to Nagarajan et al. for the efficient calculation of motif E-values. STEME's source code is available under an open source license and STEME is available via a web interface. PMID- 24625411 TI - Accelerated barrier optimization compressed sensing (ABOCS) for CT reconstruction with improved convergence. AB - Recently, we proposed a new algorithm of accelerated barrier optimization compressed sensing (ABOCS) for iterative CT reconstruction. The previous implementation of ABOCS uses gradient projection (GP) with a Barzilai-Borwein (BB) step-size selection scheme (GP-BB) to search for the optimal solution. The algorithm does not converge stably due to its non-monotonic behavior. In this paper, we further improve the convergence of ABOCS using the unknown-parameter Nesterov (UPN) method and investigate the ABOCS reconstruction performance on clinical patient data. Comparison studies are carried out on reconstructions of computer simulation, a physical phantom and a head-and-neck patient. In all of these studies, the ABOCS results using UPN show more stable and faster convergence than those of the GP-BB method and a state-of-the-art Bregman-type method. As shown in the simulation study of the Shepp-Logan phantom, UPN achieves the same image quality as those of GP-BB and the Bregman-type methods, but reduces the iteration numbers by up to 50% and 90%, respectively. In the Catphan(c)600 phantom study, a high-quality image with relative reconstruction error (RRE) less than 3% compared to the full-view result is obtained using UPN with 17% projections (60 views). In the conventional filtered-backprojection reconstruction, the corresponding RRE is more than 15% on the same projection data. The superior performance of ABOCS with the UPN implementation is further demonstrated on the head-and-neck patient. Using 25% projections (91 views), the proposed method reduces the RRE from 21% as in the filtered backprojection (FBP) results to 7.3%. In conclusion, we propose UPN for ABOCS implementation. As compared to GP-BB and the Bregman-type methods, the new method significantly improves the convergence with higher stability and fewer iterations. PMID- 24625412 TI - Synthesis of hierarchical micro/mesoporous structures via solid-aqueous interface growth: zeolitic imidazolate framework-8 on siliceous mesocellular foams for enhanced pervaporation of water/ethanol mixtures. AB - A new hierarchical micro/mesoporous composite is synthesized via direct growth of microporous zeolitic imidazolate framework-8 (ZIF-8) on siliceous mesocellular foams (MCF). Depending on different synthetic conditions, ZIF-8 with two different particle sizes, i.e., ZIF-8 microparticles and ZIF-8 nanoparticles, were successfully formed on the external surface of amine-functionalized MCF (denoted as microZIF-8@MCF and nanoZIF-8@MCF, respectively). The synthesized hierarchical micro/mesoporous ZIF-8@MCF structures were characterized with several spectroscopic techniques including X-ray diffraction (XRD), solid-state NMR, and FT-IR and electron microscopic techniques (scanning electron microscope, SEM, and transmission electron microscopy, TEM). In addition, the pervaporation measurements of the liquid water/ethanol mixture show that nanoZIF-8@MCF/PVA (poly(vinyl alcohol) mixed-matrix membrane exhibits enhanced performance both on the permeability and separation factor. Compared to conventional routes for chemical etching, this study demonstrates a promising and simple strategy for synthesizing novel hierarchical porous composites exhibiting both advantages of mesoporous materials and microporous materials, which is expected to be useful for gas adsorption, separation, and catalysis. PMID- 24625413 TI - Post-transcriptional regulation of MRE11 expression in muscle-invasive bladder tumours. AB - Predictive assays are needed to help optimise treatment in muscle-invasive bladder cancer, where patients can be treated by either cystectomy or radical radiotherapy. Our finding that low tumour MRE11 expression is predictive of poor response to radiotherapy but not cystectomy was recently independently validated. Here we investigated further the mechanism underlying low MRE11 expression seen in poorly-responding patients. MRE11 RNA and protein levels were measured in 88 bladder tumour patient samples, by real-time PCR and immunohistochemistry respectively, and a panel of eight bladder cancer cell lines was screened for MRE11, RAD50 and NBS1 mRNA and protein expression. There was no correlation between bladder tumour MRE11 protein and RNA scores (Spearman's rho 0.064, p=0.65), suggesting MRE11 is controlled post-transcriptionally, a pattern confirmed in eight bladder cancer cell lines. In contrast, NBS1 and RAD50 mRNA and protein levels were correlated (p=0.01 and p=0.03, respectively), suggesting primary regulation at the level of transcription. MRE11 protein levels were correlated with NBS1 and RAD50 mRNA and protein levels, implicating MRN complex formation as an important determinant of MRE11 expression, driven by RAD50 and NBS1 expression. Our findings of the post-transcriptional nature of the control of MRE11 imply that any predictive assays used in patients need to be performed at the protein level rather than the mRNA level. PMID- 24625414 TI - Intimal sarcoma is the most frequent primary cardiac sarcoma: clinicopathologic and molecular retrospective analysis of 100 primary cardiac sarcomas. AB - We report novel molecular and pathologic features of sarcomas involving the heart. Intimal sarcoma appears as the most frequent primary cardiac sarcoma within the largest described series of 100 primary cardiac sarcomas. Immunohistochemical analysis, fluorescence in situ hybridization, real-time polymerase chain reaction, and array-comparative genomic hybridization were performed on materials from 65 women and 35 men, aged 18 to 82 years (mean 50 y), retrieved from the French Departments of Pathology, between 1977 and early 2013. Right and left heart was involved in 44 and 56 cases, respectively. There were 42 intimal sarcomas, 26 angiosarcomas, 22 undifferentiated sarcomas, 7 synovial sarcomas, 2 leiomyosarcomas, and 1 peripheral neuroectodermal tumor. All but 1 angiosarcomas originated from the right heart, whereas 83% of the intimal sarcomas and 72% of the undifferentiated sarcomas were from the left heart. MDM2 overexpression was immunohistochemically observed in all intimal sarcomas, as well as in 10 of the 22 undifferentiated sarcomas and in 5 of the 26 angiosarcomas. MDM2 amplification was only demonstrated in intimal sarcomas. Genomic analysis showed a complex profile, with recurrent 12q13-14 amplicon involving MDM2, 4q12 amplicon involving KIT and PDGFRA, 7p12 gain involving EGFR, and 9p21 deletion targeting CDKN2A. Immunohistochemical detection of MDM2 overexpression can easily detect intimal sarcoma, provided that molecular aberration is proved. As resections are limited to the left atrium, this histologic subtype could benefit from therapies targeting PDGFRA or MDM2. PMID- 24625415 TI - Clinical significance of MYC expression and/or "high-grade" morphology in non Burkitt, diffuse aggressive B-cell lymphomas: a SWOG S9704 correlative study. AB - The clinicopathologic findings in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) may show significant overlap, and MYC abnormalities, found in all BLs, also occur in a subset of DLBCL. The 2008 World Health Organization classification introduced the category of "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (BCLU) in recognition of this overlap, but the clinical significance of BCLU (ie, "high-grade") morphology and the relationship between BCLU morphology and MYC abnormalities remains unclear. In this study, we identified 260 cases of non-Burkitt, diffuse aggressive B-cell lymphomas from SWOG S9704, a phase 3 randomized study of standard immunochemotherapy versus autologous stem cell transplantation. Of these, 31 cases (12%) showed BCLU morphology, and 229 (88%) showed typical DLBCL morphology. Of 198, 27 (14%) were positive for MYC by immunohistochemistry. BCLU morphology was associated with an increased incidence of MYC expression but otherwise was not associated with distinct clinicopathologic features or significantly decreased survival. MYC-positive cases were morphologically and phenotypically heterogenous and were associated with poor progression-free and overall survival in multivariate analysis. These findings confirm that BCLU does not represent a distinct clinicopathologic entity and demonstrate that BCLU morphology alone does not significantly impact survival compared with typical DLBCL. In contrast, MYC protein expression is a poor prognostic factor that may be associated with either BCLU or DLBCL morphology, and MYC immunohistochemistry is suggested for routine prognostic evaluation (Clinicaltrials.gov identifier: NCT00004031). PMID- 24625416 TI - Immunohistochemistry for annexin A10 can distinguish sporadic from Lynch syndrome associated microsatellite-unstable colorectal carcinoma. AB - Differentiating sporadic microsatellite-unstable colorectal carcinoma due to MLH1 promoter hypermethylation from Lynch syndrome (LS)-associated tumors due to mutations in mismatch-repair proteins is time consuming, cost intensive, and requires advanced laboratory testing. A mutation in BRAF has been shown to be highly specific for sporadic tumors; however, a significant proportion of sporadic microsatellite-unstable tumors lack BRAF mutations. MLH1 promoter methylation analysis is subsequently used to differentiate LS and sporadic tumors, but both tests require specialized laboratories and are costly. Through previous gene expression profiling of serrated polyps, we identified annexin A10 as a protein highly expressed in sessile serrated adenomas/polyps. As these polyps give rise to the majority of sporadic microsatellite-unstable tumors, we evaluated the ability of annexin A10 expression to discriminate between LS and sporadic tumors. A marked increase in annexin A10 mRNA was observed in sporadic microsatellite-unstable tumors compared with LS tumors (378-fold increase, P<0.001). Using immunohistochemistry, annexin A10 was expressed in 23/53 (43%) BRAF-mutated and 9/22 (41%) BRAF wild-type sporadic tumors. In contrast, only 3/56 (5%) LS tumors were positive for annexin A10 (P<0.0001). One patient had a deleterious MSH2 mutation, and another had a variant of uncertain significance in MSH6. These 2 tumors could be easily distinguished from sporadic tumors using mismatch-repair protein immunohistochemistry. Only 1/28 (4%) LS tumors with loss of MLH1 was positive for annexin A10. This patient did not have a deleterious MLH1 mutation but rather germline promoter hypermethylation of MLH1. On the basis of these results, immunohistochemistry for annexin A10 may be a useful marker to distinguish sporadic from LS-associated microsatellite-unstable colon cancer. PMID- 24625417 TI - Adenocarcinoma of the minor duodenal papilla and its precursor lesions: a clinical and pathologic study. AB - The minor duodenal papilla drains the accessory pancreatic duct of Santorini and lies proximal to the ampulla of Vater. Adenocarcinoma and its precursor lesions arising in the minor papilla are rare. Literature data thus far are limited to a few individual case reports, and the condition is consequently poorly defined. Our study cases were composed of carcinomas fulfilling all of the following criteria: location at 1.5 to 2.5 cm proximal to the major papilla; presence of associated submucosal pancreatobiliary-type ducts with periductal glands or acinar tissue; a predominant submucosal location of the tumor; and lack of an intestinal-type adenoma in the adjacent duodenal mucosa. Tumors were studied morphologically, immunohistochemically, and clinically. Nine cases fulfilling the inclusion criteria were identified. There were 5 men and 4 women with an age range of 50 to 76 years (median, 72 y). The tumor size ranged from 1.2 to 4.4 cm (median, 3 cm). The carcinomas were of colloid type (3 tumors), pancreatobiliary type (4), or nonmucinous intestinal type (2). Five cases were associated with an intraductal papillary mucinous neoplasm (IPMN)-like precursor lesion within the residual structures of the minor papilla in the duodenal submucosa. Immunohistochemically, the intestinal-type and mucinous-type tumors tended to be positive for CK20, CDX2, MUC2, and B72.3, and pancreatobiliary-type tumors tended to be positive for CK7, MUC1, B72.3, and CA125. Loss of DPC4 (Smad4) expression was found in the pancreatobiliary-type carcinomas only. Two tumors showed loss of DNA mismatch-repair protein expression, one losing MLH1 and PMS2 and the other losing MSH6. Both patients were older than 60 years, and neither had germline mutation testing. Follow-up information was available for 6 patients (median follow-up time, 67.5 mo): 3 of the 6 patients died of disease at 60, 75, and 85 months after surgery, respectively, and all 3 patients had an intestinal-type carcinoma (1 colloid and 2 nonmucinous). The patient whose tumor was MSH6 deficient was alive without evidence of disease 51 months after surgery. In conclusion, adenocarcinomas of the minor papilla are rare tumors occurring predominantly in the sixth to seventh decade. Some of them arise from IPMN-like precursors in the residual submucosal minor papilla tissue. Morphologically, immunohistochemically, and clinically they are similar to ampullary or IPMN associated pancreatic carcinomas and can exhibit either an intestinal, colloid, or pancreaticobiliary phenotype. DNA mismatch-repair deficiency may occur. A careful gross and histologic examination is essential to accurately recognize the site of origin of minor papilla carcinomas. PMID- 24625418 TI - Basal cell carcinomas of the vulva: high-risk human papillomavirus DNA detection, p16 and BerEP4 expression. AB - Basal cell carcinoma (BCC) of the vulva is rare and may be confused with the much more commonly encountered high-risk human papillomavirus (HPV)-related basaloid squamous cell carcinoma (SCC). The HPV status of BCCs is not well established. This study assesses the utility of p16 and BerEP4 expression patterns and high risk HPV detection for distinction of these tumors. Thirteen cases of vulvar BCC were analyzed by immunohistochemistry for p16 and BerEP4 expression. HPV status was assessed by in situ hybridization (ISH) with a high-risk HPV wide-spectrum probe and HPV 16 and 18 type-specific probes. All tumors (13/13) demonstrated patchy p16 positivity, with <50% of tumor cells expressing p16 in all cases. None demonstrated the diffuse p16 expression characteristic of high-risk HPV associated lesions. No high-risk HPV was detected by ISH (0/13). Eleven of 13 (85%) vulvar BCCs showed diffuse, intense expression of BerEP4. The 2 BerEP4 negative cases were notably squamatized. The lack of diffuse p16 expression and failure to detect high-risk HPV by ISH in vulvar BCCs indicate that these tumors are unrelated to high-risk HPV. Thus, these ancillary techniques, particularly p16 immunohistochemistry, are useful for distinguishing vulvar BCCs from basaloid forms of high-risk HPV-related vulvar SCC. BerEP4 expression can help in distinction of these tumors except in cases of BCC with extensive squamatization. Distinction of vulvar BCC from basaloid SCC is important because of differences in extent of surgical treatment for these entities. PMID- 24625419 TI - BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. AB - Pulmonary Langerhans cell histiocytosis (PLCH) has been postulated to be a smoking-related non-neoplastic condition, distinct from extrapulmonary LCH, which is generally regarded as a clonal, neoplastic process. Recent genomic studies demonstrated BRAF V600E mutation in 38% to 57% of extrapulmonary LCH cases by polymerase chain reaction. We evaluated the BRAF V600E expression by immunohistochemistry (IHC) in PLCH and extrapulmonary LCH cases. We compared BRAF V600E expression in PLCH and extrapulmonary LCH with BRAF V600E mutation status. Our study included 25 PLCH (age 42.0+/-11.4, 10 men) and 54 extrapulmonary LCH (age 27.6+/-21.8, 37 men) cases. Seven of 25 (28%) PLCH cases were positive for BRAF V600E expression (age 45.3+/-8.1, 2 men); 6 of 7 cases with BRAF V600E expression were also positive by mutation analysis. Nineteen of 54 (35%) extrapulmonary LCH cases were positive for BRAF V600E expression (age 27.6+/ 22.1, 13 men) as well as mutation. Two IHC-negative cases, however, were positive by mutation analysis. All PLCH cases were current or former smokers, whereas 28 of 54 extrapulmonary LCH patients were never-smokers. The cumulative tobacco exposure at the time of diagnosis was significantly higher in BRAF V600E-positive than in BRAF V600E-negative PLCH patients (mean pack-years 48.3 vs. 23.7, 2 tailed t test P=0.01). BRAF V600E expression by IHC correlated with BRAF V600E mutational status in most of the cases in our study except in 3 patients (4.4%). In conclusion, a subset of PLCH with BRAF V600E expression may be a clonal proliferative process, in which cigarette smoking might play a role. PMID- 24625420 TI - STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. AB - Solitary fibrous tumor (SFT) is an uncommon fibroblastic neoplasm. Although histologic characteristics and frequent CD34 expression allow for an accurate diagnosis in the majority of SFT cases, a wide histologic spectrum and an occasional unexpected immunophenotype may pose diagnostic challenges. Molecular analyses have discovered that almost all SFTs harbor an NAB2-STAT6 fusion gene, which is considered specific to this tumor type. Recent studies have suggested that STAT6 immunohistochemistry is a reliable surrogate for detection of the fusion gene. Our aim was to validate these findings by examining a large number of SFT cases and a broad array of 30 different types of non-SFT tumors. A total of 49 SFTs with a range of histologic characteristics and 159 benign or malignant tumors that can mimic SFTs were retrieved and stained for STAT6. All 49 SFTs (100%) showed STAT6 expression that was restricted in the nucleus, mostly in a diffuse and strong manner, irrespective of the tumor sites and histologic patterns. The staining was uniform in most cases but was heterogenous in about 20% of the cases in which zonal staining attenuation was observed, likely reflecting variability in fixation or tissue ischemia. In contrast, only 4 non SFT tumors (2.5%) exhibited weak nuclear STAT6 expression, whereas the remaining 155 cases showed no staining or often weak reactivity in both the cytoplasm and the nucleus. Therefore, nuclear STAT6 immunoreactivity is a highly sensitive and specific marker of SFTs and can be helpful when diagnosis is inconclusive by conventional methods. PMID- 24625421 TI - Succinate dehydrogenase deficiency is rare in pituitary adenomas. AB - Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy. PMID- 24625422 TI - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid autopsy report of metastatic renal cell carcinoma. AB - Rapid ("warm") autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)-the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, "pseudohypoxic" upregulation of hypoxia-inducible factor 1alpha (HIF-1alpha) dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient's RCC demonstrated extensive sarcomatoid and rhabdoid features-morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules. PMID- 24625423 TI - Further evidence of the existence of benign teratomas of the postpubertal testis. PMID- 24625424 TI - The minipterional craniotomy for anterior circulation aneurysms: initial experience with 72 patients. AB - BACKGROUND: The pterional craniotomy is well established for microsurgical clipping of most anterior circulation aneurysms. The incision and temporalis muscle dissection impacts postoperative recovery and cosmetic outcomes. The minipterional (MPT) craniotomy offers similar microsurgical corridors, with a substantially shorter incision, less muscle dissection, and a smaller craniotomy flap. OBJECTIVE: To report our experience with the MPT craniotomy in select unruptured anterior circulation aneurysms. METHODS: From January 2009 to July 2013, 82 unruptured aneurysms were treated in 72 patients, with 74 MPT craniotomies. Seven patients had multiple aneurysms treated with a single MPT craniotomy. The average patient age was 56 years (range: 24-87). Aneurysms were located along the middle cerebral artery (n = 36), posterior communicating (n = 22), paraophthalmic (n = 22), choroidal (n = 1), and dorsal ICA segments (n = 1). The MPT craniotomy utilized an incision just posterior to the hairline and a single myocutaneous flap. RESULTS: The average aneurysm size was 5.45 mm (range: 1-14). There were no instances of compromised operative corridors requiring craniotomy extension. Three significant early postoperative complications included epidural and subdural hematomas requiring evacuation, and a middle cerebral artery infarction. Average length of hospitalization was 3.96 days (range: 2-20). Two patients required reoperation for wound infections. Average follow-up was 421 days (range: 5-1618). Minimal to no temporalis muscle wasting was noted in 96% of patients. CONCLUSION: The MPT craniotomy is a worthwhile alternative to the standard pterional craniotomy. There were no instances of suboptimal operative corridors and clip applications when the MPT craniotomy was utilized in the treatment of unruptured middle cerebral artery and supraclinoid internal carotid artery aneurysms proximal to the terminal internal carotid artery bifurcation. PMID- 24625425 TI - Greater extent of resection improves ganglioglioma recurrence-free survival in children: a volumetric analysis. AB - BACKGROUND: Gangliogliomas are rare, low-grade, glial-neural tumors that are most often found in children. They can recur with varying frequency; yet few data are available that adequately predict such events. OBJECTIVE: To review our institution's large series of gangliogliomas in children and identify clinical features that predict recurrence-free survival. METHODS: Clinical records were retrospectively reviewed from 1990 to 2011. Fifty-three children were identified, and pertinent clinical features were analyzed against survival data to categorize lesions at high risk of recurrence. RESULTS: Fifteen children (28%) experienced a recurrence during the study period with a median time to recurrence of 8.8 months and a mean follow-up of 4.2 years. The 5-year recurrence-free survival rate was 70.5%, whereas the overall survival rate was 98.1%. Older age at diagnosis (P = .02), seizure history (P < .001), supratentorial tumor location (P < .001), and greater extent of surgical resection (P < .001) were all associated with improved recurrence-free survival on univariate analysis. Extent of surgical resection was the only clinical variable that retained its significance in multivariate models (P = .01). Patients who received 94% or greater volumetric extent of resection had prolonged recurrence-free survival compared with those individuals who received a less than 94% resection (P = .02). CONCLUSION: Attention to specific clinical variables, most notably the extent of surgical resection, can further stratify grade I gangliogliomas into low- and high-risk groups among children. Although 100% resection should remain an operative goal for surgically accessible gangliogliomas, a thorough yet subtotal resection may improve recurrence-free survival. PMID- 24625426 TI - How accurately can MRI detect indolent disease? AB - PURPOSE OF REVIEW: The current challenge in prostate cancer diagnosis is how to accurately measure the risk of disease progression and guide the treatment decision process between effective intervention for potentially harmful tumors and active surveillance for indolent disease. The issue is how to better identify patients harboring insignificant disease using the current diagnosis pathway based on 12-core systematic biopsy, which misclassifies tumor volume and/or grade in up to 30% of cases. Integrating MRI into the diagnosis process may help to better determine if the cancer is at very low risk of disease progression, i.e. clinically indolent or insignificant. RECENT FINDINGS: Recent advances in prostate imaging techniques suggest that multiparametric MRI has a high negative predictive value (up to 95%) in ruling out clinically significant prostate cancer and may potentially have clinical use in diagnostic pathways in men at risk for prostate cancer. Prospective studies should be performed to examine the rate of reclassification using MRI-targeted biopsy in patients potentially eligible for active surveillance based on current tests (12-cores systematics biopsies). SUMMARY: Patients with nonsuspicious multiparametric MRI represent a special very low-risk group of men with either no disease or clinically insignificant disease, allowing them to be managed conservatively. PMID- 24625427 TI - Laser ablation as focal therapy for prostate cancer. AB - PURPOSE OF REVIEW: Focal laser ablation (FLA) is an emerging treatment paradigm for prostate cancer that aims to successfully eradicate disease while also reducing the risk of side-effects compared with whole-gland therapies. RECENT FINDINGS: Preclinical and phase I clinical trials for low-risk prostate cancer have shown that FLA produces accurate, predictable, and reproducible ablation zones with negligible injury to the surrounding tissues. Because FLA is magnetic resonance compatible, the procedure can be monitored with real-time feedback to optimize targeted treatment of cancerous foci and minimize quality-of-life side effects. The oncologic efficacy of MRI-guided FLA is currently being evaluated in ongoing phase II clinical trials. SUMMARY: FLA is a well tolerated and feasible therapy for low-risk prostate cancer, and the oncologic efficacy of this treatment modality is currently under investigation in phase II clinical trials at several institutions. PMID- 24625428 TI - How to select the right patients for focal therapy of prostate cancer? AB - PURPOSE OF REVIEW: Just as lumpectomy for breast cancer aims at achieving oncological control with maximal tissue preservation, the concept of focal therapy for prostate cancer has evolved with the aim of controlling disease while preserving urinary and erectile function. Our review aims at describing the evolution of focal therapy in time and the resulting advances in patient selection. RECENT FINDINGS: Originally, focal therapy was developed as an alternative to active surveillance for men with low-risk disease and a minimal burden of cancer. However, with improvement of the diagnostic technologies, the entry criteria for this therapeutic approach are broadening. Since its introduction, focal therapy has evolved from ablation of half or three-quarters of the prostate in men with low-risk disease to only selected cancer foci even if they present with Gleason pattern 4. This development has become possible because of a better understanding of the biology of the index lesion(s) and the improvement of biopsy techniques. Candidates were selected at first with conventional transrectal random prostate biopsies. To overcome the sampling bias of standard techniques, a more thorough multicore sampling utilizing transperineal three-dimensional template mapping biopsies was developed. Today, advances in multiparametric MRI allow for detection and targeted biopsies of high grade and high-volume lesions. SUMMARY: In light of the less stringent selection criteria, enrollment for focal therapy protocols should encourage patient education on the need of possible subsequent cycles of ablation as well as the need for surveillance of the untreated prostatic tissue, as prostate cancer is transformed into a chronic, manageable condition. PMID- 24625429 TI - What should we tell prostate cancer patients about (secondary) prevention? AB - PURPOSE OF REVIEW: To briefly summarize the epidemiologic findings of selected lifestyle factors for prostate cancer progression, metastasis, or death, with a focus on behaviors after diagnosis where possible. We conclude by providing guidance on the lifestyle practices that physicians may wish to prioritize for discussion with their patients. RECENT FINDINGS: Growing, but still limited, evidence suggests that lifestyle factors after prostate cancer diagnosis may impact prostate-cancer-specific and overall morality. In particular, smoking and obesity may increase the risk of disease progression and mortality, whereas engaging in vigorous physical activity or brisk walking and consuming a diet rich in vegetables (particularly tomato sauce and cruciferous) and vegetable fats may lower the risk. SUMMARY: Patients should be counseled not to use tobacco products; to engage in daily physical activity; to minimize sedentary behavior; to consume plenty of healthy fats (i.e. fish, nuts, vegetable oils, soybeans, avocados, and flaxseed) and vegetables; to focus on getting nutrients from foods rather than supplements; and to limit refined grains, sugars, processed meat, and high-fat dairy. PMID- 24625430 TI - How to diagnose and treat focal therapy failure and recurrence? AB - PURPOSE OF REVIEW: Focal therapy presents an alternative option for disease targeted therapy while preserving erectile and urinary function without compromising oncological outcome. Such treatment, which preserves normal prostate parenchyma, presents a clinical challenge to the urologist, as typical disease surveillance parameters are not as reliable in post-ablation follow-up. We propose an integrated approach to post-ablation surveillance to identify treatment failure as well as recurrence. RECENT FINDINGS: Post-ablation prostate specific antigen kinetics, imaging based on multiparametric MRI and control biopsies are the tools currently used to follow patients after focal therapy. Good treatment response is indicated by a negative control biopsy, absence of persistent lesion on post-treatment imaging and a reduction in prostate-specific antigen of at least 50%. SUMMARY: When histological evidence of therapeutic failure or recurrence is present, different options of management may be proposed to the patient including active surveillance, focal salvage therapy or radical salvage treatment, depending on the characteristics of the lesion found. A recommended post-ablation surveillance protocol is presented as well as a discussion of management strategies based on the data currently available. PMID- 24625431 TI - Genomic analysis in active surveillance: predicting high-risk disease using tissue biomarkers. AB - PURPOSE OF REVIEW: For patients newly diagnosed with prostate cancer, the most significant question is whether the 'truly malignant' disease has been identified. This review will provide an overview of current prostate cancer genomic and biomarker discovery - validation strategies geared towards identifying aggressive, clinically significant disease at the time of diagnosis. RECENT FINDINGS: Based on recent findings the prostate cancer aggressive disease phenotype develops as a result of mutations (TP53, PTEN), structural events (TMPRSS2-ETS), epigenetic changes (EZH2, DAB2IP, histone alteration), and transcriptional modifications (SChLAP, PCAT-1). Copy number variability and dysregulation of specific pathways including androgen receptor signaling, PTEN/PAKT and TGF-beta continue to play an important role in invasion and metastasis. SUMMARY: Given the current challenges for applying prostate cancer genomics to clinical management, this review will incorporate some of the current novel genomic approaches and techniques including systems-based precise pathology platforms, and the role of fluid-based assays, notably, exosomes and circulating tumor cells (liquid biopsy), as tools for future diagnostic-treatment algorithms. PMID- 24625432 TI - Phenylephrine eye drops: a rare complication in preterm neonate. PMID- 24625433 TI - Are high flow nasal cannulae noisier than bubble CPAP for preterm infants? AB - BACKGROUND: Noise exposure in the neonatal intensive care unit is believed to be a risk factor for hearing loss in preterm neonates. Continuous positive airway pressure (CPAP) devices exceed recommended noise levels. High flow nasal cannulae (HFNC) are an increasingly popular alternative to CPAP for treating preterm infants, but there are no in vivo studies assessing noise production by HFNC. OBJECTIVE: To study whether HFNC are noisier than bubble CPAP (BCPAP) for preterm infants. METHODS: An observational study of preterm infants receiving HFNC or BCPAP. Noise levels within the external auditory meatus (EAM) were measured using a microphone probe tube connected to a calibrated digital dosimeter. Noise was measured across a range of frequencies and reported as decibels A-weighted (dBA). RESULTS: A total of 21 HFNC and 13 BCPAP noise measurements were performed in 21 infants. HFNC gas flows were 2-5 L/min, and BCPAP gas flows were 6-10 L/min with set pressures of 5-7 cm of water. There was no evidence of a difference in average noise levels measured at the EAM: mean difference (95% CI) of -1.6 (-4.0 to 0.9) dBA for HFNC compared to BCPAP. At low frequency (500 Hz), HFNC was mean (95% CI) 3.0 (0.3 to 5.7) dBA quieter than BCPAP. Noise increased with increasing BCPAP gas flow (p=0.007), but not with increasing set pressure. There was a trend to noise increasing with increasing HFNC gas flows. CONCLUSIONS: At the gas flows studied, HFNC are not noisier than BCPAP for preterm infants. PMID- 24625434 TI - Additional post-natal diagnoses following antenatal diagnosis of isolated cleft lip +/- palate. AB - INTRODUCTION: Cleft lip with or without palate (CLP) can be diagnosed antenatally through ultrasound, and may be categorised as apparently isolated versus associated with other malformations. Limited data exist on the long-term outcomes following antenatal diagnosis of apparently isolated CLP. AIM: This study examined the long-term post-natal outcomes of CLP when found in isolation antenatally, in order to determine the rates of unexpected additional anomalies, developmental delay or genetic syndromes. PATIENTS AND METHODS: A retrospective chart review of antenatal and post-natal medical charts was completed for a ten year period between January 2000 and December 2009. At least 2 years of available post-natal clinical information was required for inclusion in the study. RESULTS: A total of 97 cases of antenatally isolated CLP were ascertained. Fifteen pregnancies were terminated. Follow-up data were available for 81 liveborns, though 4 were lost to follow-up prior to 2 years of age. Twelve of the 77 children meeting study criteria were identified to have other major malformations and/or developmental disability either later in the pregnancy or post-natally. Findings included familial clefting syndromes, trisomy 21, autism spectrum disorders, brain malformations, fetal alcohol syndrome and Kabuki syndrome, among other findings. Another 11 children had additional anomalies of minor impact. Examples of findings include a perimembranous ventricular septal defect, mild unilateral optic nerve hypoplasia, mild pulmonary artery stenosis with a small atrial septal defect, and transient delays in fine and gross motor skills. No children with clefting of the lip only had major additional diagnoses. PMID- 24625435 TI - Congenital ulcer: what do you think? PMID- 24625436 TI - Left atrial resection for T4 lung cancer without cardiopulmonary bypass: technical aspects and outcomes. AB - BACKGROUND: Extended resection for lung cancer may improve survival of selected patients. Left-atrial resection is infrequently performed and surgical techniques are rarely reported; thus, oncologic results and survival rates remain uncertain. Our study describes surgical techniques, postoperative outcomes, and oncologic results of patients who received a combined multimodality treatment. METHODS: Between October 2004 and March 2012 in our institution, 19 patients underwent extended lung resection involving the left atrium without cardiopulmonary bypass. We reviewed perioperative treatments, surgical procedures, and postoperative morbidity, mortality, and long-term survival rates. RESULTS: Sixteen patients (68.4%) underwent neoadjuvant treatment including chemotherapy or radiotherapy. Eighteen pneumonectomies (94.7%) were performed, of which 12 (63.1%) were right sided. Dissection of the interatrial septum was complete in 4 patients (33.3%). Complete resection was achieved in 17 patients (89.4%) and 2 other patients (10.5%) were considered R1. The T-status was pT4 in all patients. Overall postoperative morbidity was 52.6%. The 30-day mortality rate was 10.5% and the 90 day mortality rate was 15.7%. Fifteen patients (93.7%) underwent adjuvant treatment. The mean follow-up time was 32.5 months. The 5-year probability of survival was 43.7%. Three patients (15.7%) were alive at greater than 6 years postsurgery. CONCLUSIONS: Extended lung surgery with partial resection of the left atrium is a feasible procedure with acceptable morbidity. An interatrial septum dissection, by increasing the length of the atrial cuff, allows complete resection. Long-term survival can be achieved in highly selected patients who have undergone multimodal therapy. PMID- 24625438 TI - Metal free half metallicity in 2D system: structural and magnetic properties of g C4N3 on BN. AB - Synthesis of a half metallic material on a substrate is highly desirable for diverse applications. Herein, we have investigated structural, adsorptive, and magnetic properties of metal free graphitic carbon nitride (g-C4N3) layer on hexagonal BN layer (h-BN) using the optB88-vdW van der Waals density functional theory. It is found that g-C4N3 layer can be adsorbed on BN layer due to the change of lattice constant of the hybridized system. The newly found lattice constant of g-C4N3 was 9.89 A, which is approximately 2% lower and larger than to those of free standing BN and g-C4N3, respectively. Also, 2 * 2 surface reconstruction geometry predicted in free standing g-C4N3 layer disappears on the BN layer. Interestingly, we have found that metal free half metallic behavior in g-C4N3 can be preserved even on BN layer and the characters of spin polarized planar orbitals suggest that our theoretical prediction can be verified using normal incidence of K-edge X-ray magnetic circular dichroism (XMCD) measurement. PMID- 24625437 TI - KeraSkin-VM: a novel reconstructed human epidermis model for skin irritation tests. AB - Several alternative in vitro methods to evaluate skin irritants have been developed recently. In July 2010, OECD officially endorsed the validated reference method (VRM) that uses reconstituted human epidermis (RhE) models as replacements for the in vivo skin irritation test. This study evaluated the KeraSkin-VM model, a novel human epidermis model that was reconstructed with Asian skin tissue using 20 reference chemicals according to the OECD TG 439 performance standard. The test chemicals were applied to the epidermal surface side for 45 min and then rinsed, and then incubated for 42 h post-treatment. An overall accuracy of 80%, sensitivity of 90% and specificity of 70% were obtained when the results from KeraSkin-VM were compared with UN GHS categories, which was comparable to the EpiDerm Skin irritation test (SIT) rates. Furthermore, KeraSkin VM demonstrated good performance in terms of within-laboratory reproducibility and predictive capacity to screen skin irritants. PMID- 24625439 TI - Blockade of CXCR2 signalling: a potential therapeutic target for preventing neutrophil-mediated inflammatory diseases. AB - Polymorphonuclear neutrophils (PMN) play a key role in host innate immune responses by migrating to the sites of inflammation. Furthermore, PMN recruitment also plays a significant role in the pathophysiology of a plethora of inflammatory disorders such as chronic obstructive pulmonary disease (COPD), gram negative sepsis, inflammatory bowel disease (IBD), lung injury, and arthritis. Of note, chemokine-dependent signalling is implicated in the amplification of immune responses by virtue of its role in PMN chemotaxis in most of the inflammatory diseases. It has been clinically established that impediment of PMN recruitment ameliorates disease severity and provides relief in majority of other immune associated disorders. This review focuses on different novel approaches clinically proven to be effective in blocking chemokine signalling associated with PMN recruitment that includes CXCR2 antagonists, chemokine analogs, anti CXCR2 monoclonal antibodies, and CXCR2 knock-out models. It also highlights the significance of the utility of nanoparticles in drugs used for blocking migration of PMN to the sites of inflammation. PMID- 24625440 TI - Understanding Lunasin's biology and potential as a cancer therapeutic by utilizing Drosophila genetics. AB - Soy contains many bioactive molecules known to elicit anticancer effects. One such peptide, Lunasin, has been shown to selectively act on newly transformed cells while having no cytotoxic effect on non-tumorigenic or established cancer cell lines. While this effect on in vitro systems is promising, Lunasin's efficacy in an in vivo system is yet to be assessed. In this review, we discuss the state of knowledge with respect to Lunasin and then review some of the powerful genetic tools available in Drosophila. The availability of a sophisticated genetic tool box makes Drosophila an excellent genetic model well suited to studying the biology of Lunasin and its effect on tumor progression in an in vivo model organism. PMID- 24625441 TI - Temporary mineralocorticoid receptor antagonism during the development of hypertension improves cerebral artery dilation. AB - Hypertension causes cerebral artery remodeling and increases the risk of stroke. Renin angiotensin system blockade during the development of hypertension has therapeutic effects even after treatment withdrawal. Mineralocorticoid receptor (MR) activation has been implicated in artery remodeling and impaired endothelial function. The possibility that there is a critical therapeutic window for MR antagonism has not been investigated. We hypothesized that temporary MR antagonism while hypertension develops would improve middle cerebral artery (MCA) structure and function in stroke-prone spontaneously hypertensive rats (SHRSP), even after treatment withdrawal. Six-week-old SHRSP were treated with spironolactone (25 mg/kg/day) from 6 to 12 weeks and when aged to 18 weeks, these rats were compared to age-matched untreated SHRSP. Surprisingly, temporary spironolactone treatment reduced the MCA outer and lumen diameter but had no effect on the wall thickness. Temporary spironolactone treatment improved nitric oxide and endothelium-derived hyperpolarizing factor mediated dilation but had no effect on blood pressure. Spironolactone treatment caused a very small reduction in the damage caused by permanent focal cerebral ischemia. These results suggest that temporary MR antagonism during the development of hypertension has divergent effects on the MCA, in that it causes a potentially detrimental reduction in the lumen diameter while improving vasodilation. PMID- 24625442 TI - Featured article: autophagic activation with nimotuzumab enhanced chemosensitivity and radiosensitivity of esophageal squamous cell carcinoma. AB - Chemotherapy and radiotherapy are two indispensible methods for esophageal squamous cell carcinoma (ESCC), especially for those recurring and metastatic ones, but therapeutic toxicity remains a major problem to overcome. In the present study, the potential therapeutic value of nimotuzumab (an antiepidermal growth factor receptor [EGFR] monoclonal antibody) in combination with chemotherapy and radiotherapy was evaluated on Eca109 and TE-1 ESCC cells, with high and low expression of EGFR, respectively. It was shown that nimotuzumab enhanced the sensitivity of Eca109 cells to other cytotoxic agents (paclitaxel and cis-platinum) and X-ray radiation, and the cytotoxicity was associated with increased autophagy. Conversely, the chemo- and radio-sensitivity of TE-1 cells showed no improvement with addition of nimotuzumab, but could be increased by combining with rapamycin, an autophagy inducer. Therefore, it was concluded that autophagic activation mediated by nimotuzumab could promote autophagic cell death and produce additive antitumor effects. PMID- 24625443 TI - Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy. AB - PURPOSE: Autosomal recessive retinal dystrophies are clinically and genetically heterogeneous, which hampers molecular diagnosis. We evaluated identity-by descent-guided Sanger sequencing or whole-exome sequencing in 26 families with nonsyndromic (19) or syndromic (7) autosomal recessive retinal dystrophies to identify disease-causing mutations. METHODS: Patients underwent genome-wide identity-by-descent mapping followed by Sanger sequencing (16) or whole-exome sequencing (10). Whole-exome sequencing data were filtered against identity-by descent regions and known retinal dystrophy genes. The medical history was reviewed in mutation-positive families. RESULTS: We identified mutations in 14 known retinal dystrophy genes in 20/26 (77%) families: ABCA4, CERKL, CLN3, CNNM4, C2orf71, IQCB1, LRAT, MERTK, NMNAT1, PCDH15, PDE6B, RDH12, RPGRIP1, and USH2A. Whole-exome sequencing in single individuals revealed mutations in either the largest or smaller identity-by-descent regions, and a compound heterozygous genotype in NMNAT1. Moreover, a novel deletion was found in PCDH15. In addition, we identified mutations in CLN3, CNNM4, and IQCB1 in patients initially diagnosed with nonsyndromic retinal dystrophies. CONCLUSION: Our study emphasized that identity-by-descent-guided mutation analysis and/or whole-exome sequencing are powerful tools for the molecular diagnosis of retinal dystrophy. Our approach uncovered unusual molecular findings and unmasked syndromic retinal dystrophies, guiding future medical management. Finally, elucidating ABCA4, LRAT, and MERTK mutations offers potential gene-specific therapeutic perspectives. PMID- 24625444 TI - The impact of chromosomal microarray on clinical management: a retrospective analysis. AB - PURPOSE: Chromosomal microarray has been widely adopted as the first-tier clinical test for individuals with multiple congenital anomalies, developmental delay, intellectual disability, and autism spectrum disorders. Although chromosomal microarray has been extensively shown to provide a higher diagnostic yield than conventional cytogenetic methods, some health insurers refuse to provide coverage for this test, claiming that it is experimental and does not affect patients' clinical management. METHODS: We retrospectively reviewed the electronic medical records of all patients who had abnormal chromosomal microarray findings reported by our laboratory over a 3-year period and quantified the management recommendations made in response to these results. RESULTS: Abnormal chromosomal microarray findings were reported for 12.7% of patients (227/1,780). For patients with clinical follow-up notes available, these results had management implications for 54.5% of patients in the entire abnormal cohort (102/187) and for 42.1% of patients referred for isolated neurodevelopmental disorders (16/38). Recommendations included pharmacological treatment, cancer-related screening or exclusion of screening, contraindications, and referrals for further evaluation. CONCLUSION: These results empirically demonstrate the clinical utility of chromosomal microarray by providing evidence that management was directly affected for the majority of patients in our cohort with abnormal chromosomal microarray findings. PMID- 24625445 TI - Genetics and the veterans health administration. PMID- 24625447 TI - Acute care utilization for inherited metabolic diseases among children identified through newborn screening in New York state. AB - BACKGROUND: Currently, very few studies on long-term follow up of health outcomes and health-care utilization of children with inherited metabolic disorders identified through newborn screening are available. In this project, we analyzed acute care utilization for children with inherited metabolic disorders. METHODS: A cohort of children up to 3 years of age who were born to New York State residents in 2006-2007 with confirmed inherited metabolic disorders identified through newborn screening, was linked to hospital discharge records. For children with multiple acute care encounters (emergency department visits and/or hospital inpatient stays), rehospitalization intervals were quantified as days between a discharge date and the next encounter. RESULTS: Inherited metabolic disorder related hospital care encounters were more frequent for non-Hispanic black children, Medicaid recipients, and children of younger mothers. A majority (~73%) of the children without health insurance had inherited metabolic disorder-related emergency department visits. Children with private insurance were more likely to have hospital stays. Hospital acute care utilization patterns differed with respect to inherited metabolic disorder category. Children with fatty acid oxidation disorder or organic acid disorders required the most care. CONCLUSIONS: The information collected by the unique population-based surveillance program about hospital care utilization for the affected children can be helpful in assessing health outcomes of the children, identifying at-risk populations, and improving access to essential medical services for children in need. PMID- 24625448 TI - Dynamic alignment models for neural coding. AB - Recently, there have been remarkable advances in modeling the relationships between the sensory environment, neuronal responses, and behavior. However, most models cannot encompass variable stimulus-response relationships such as varying response latencies and state or context dependence of the neural code. Here, we consider response modeling as a dynamic alignment problem and model stimulus and response jointly by a mixed pair hidden Markov model (MPH). In MPHs, multiple stimulus-response relationships (e.g., receptive fields) are represented by different states or groups of states in a Markov chain. Each stimulus-response relationship features temporal flexibility, allowing modeling of variable response latencies, including noisy ones. We derive algorithms for learning of MPH parameters and for inference of spike response probabilities. We show that some linear-nonlinear Poisson cascade (LNP) models are a special case of MPHs. We demonstrate the efficiency and usefulness of MPHs in simulations of both jittered and switching spike responses to white noise and natural stimuli. Furthermore, we apply MPHs to extracellular single and multi-unit data recorded in cortical brain areas of singing birds to showcase a novel method for estimating response lag distributions. MPHs allow simultaneous estimation of receptive fields, latency statistics, and hidden state dynamics and so can help to uncover complex stimulus response relationships that are subject to variable timing and involve diverse neural codes. PMID- 24625446 TI - Social and behavioral research in genomic sequencing: approaches from the Clinical Sequencing Exploratory Research Consortium Outcomes and Measures Working Group. AB - The routine use of genomic sequencing in clinical medicine has the potential to dramatically alter patient care and medical outcomes. To fully understand the psychosocial and behavioral impact of sequencing integration into clinical practice, it is imperative that we identify the factors that influence sequencing related decision making and patient outcomes. In an effort to develop a collaborative and conceptually grounded approach to studying sequencing adoption, members of the National Human Genome Research Institute's Clinical Sequencing Exploratory Research Consortium formed the Outcomes and Measures Working Group. Here we highlight the priority areas of investigation and psychosocial and behavioral outcomes identified by the Working Group. We also review some of the anticipated challenges to measurement in social and behavioral research related to genomic sequencing; opportunities for instrument development; and the importance of qualitative, quantitative, and mixed-method approaches. This work represents the early, shared efforts of multiple research teams as we strive to understand individuals' experiences with genomic sequencing. The resulting body of knowledge will guide recommendations for the optimal use of sequencing in clinical practice. PMID- 24625449 TI - Significance of DNMT3b in oral cancer. AB - The aim of this study was to explore specific molecular markers that could lead to new insights into the identification of innovative treatments. The role of DNMT3b and its predictive power in the prognosis of oral cancer were identified. Human oral cancer cell lines including SCC4 and SCC25 were selected for cellular experiments. Changes in tumor growth, aggressiveness and the responsible signaling pathway were investigated in vitro and in vivo. Furthermore, 125 oral cancer tissue specimens were analyzed using immunohistochemical staining on tissue microarray slides, and correlations calculated between the level of DNMT3b and the clinical outcome of patients. Our data revealed that inhibition of DNMT3b resulted in slower tumor growth, attenuated tumor invasion ability and epithelial mesenchymal transition, as determined by in vitro and in vivo experiments. Activated IL-6 signaling might be responsible to the induction of DNMT3b overexpression on oral cancer. Regarding clinical data, the incidence of DNMT3b immunoreactivity in oral cancer specimens was significantly higher than in non malignant epithelium, and positively linked to expression of IL-6. Furthermore, expression of DNMT3b was significantly linked with the risk of lymph node involvement, disease recurrence and shorter survival in patients with pathological stage III-IV oral cancer. In conclusion, IL-6 -DNMT3b axis could be used to predict the prognosis of oral cancer in clinics, and targeting DNMT3b could represent a promising treatment strategy. PMID- 24625451 TI - Insights into Clostridium phytofermentans biofilm formation: aggregation, microcolony development and the role of extracellular DNA. AB - Biofilm formation is a critical component to the lifestyle of many naturally occurring cellulose-degrading microbes. In this work, cellular aggregation and biofilm formation of Clostridium phytofermentans, a cellulolytic anaerobic bacterium, was investigated using a combination of microscopy and analytical techniques. Aggregates included thread-like linkages and a DNA/protein-rich extracellular matrix when grown on soluble cellobiose. Similar dense biofilms formed on the surface of the model cellulosic substrate Whatman no. 1 filter paper. Following initially dispersed attachment, microcolonies of ~500 um diameter formed on the filter paper after 6 days. Enzymic treatment of both the biofilm and cellular aggregates with DNase and proteinase resulted in significant loss of rigidity, pointing to the key role of extracellular DNA and proteins in the biofilm structure. A high-throughput biofilm assay was adapted for studying potential regulators of biofilm formation. Various media manipulations were shown to greatly impact biofilm formation, including repression in the presence of glucose but not the beta(1->4)-linked disaccharide cellobiose, implicating a balance of hydrolytic activity and assimilation to maintain biofilm integrity. Using the microtitre plate biofilm assay, DNase and proteinase dispersed ~60 and 30 % of mature biofilms, respectively, whilst RNase had no impact. This work suggests that Clostridium phytofermentans has evolved a DNA/protein-rich biofilm matrix complementing its cellulolytic nature. These insights add to our current understanding of natural ecosystems as well as strategies for efficient bioprocess design. PMID- 24625452 TI - Anthracyclines and taxanes in the neo/adjuvant treatment of breast cancer: does the sequence matter? AB - BACKGROUND: In early breast cancer, adjuvant chemotherapy decreases the risks of recurrence and breast cancer mortality, and neoadjuvant treatment leads to equivalent long-term outcomes. A large number of clinical trials have attempted to refine systemic therapeutic strategies in early breast cancer, but little attention has been paid to the sequence of anthracyclines and taxanes. Based on preclinical observations, there is limited rationale to administer the taxane before the anthracycline. METHODS: We searched PubMed, the American Society of Clinical Oncology website, and clinicaltrials.gov with the goal of identifying published or ongoing studies that aimed at comparing reverse sequences of anthracyclines and taxanes. Given the nature and the small number of studies identified, we did not attempt to quantitatively pool the study results. RESULTS: We retrieved seven studies in the adjuvant setting and eight in the neoadjuvant setting: 10 randomized trials (only 2 were phase IIII), 3 retrospective studies, and 2 ongoing phase II trials. A total of nearly 5000 patients were included in such studies. None of the clinical trials has shown disadvantages in terms of efficacy or toxicity for sequences in which the taxane was administered first. In the neoadjuvant setting, studies have collectively shown similar or increased pathological complete response rates for sequences in which the taxane was administered first. CONCLUSION: Given the available information, there seems to be sufficient evidence to suggest that a taxane followed by an anthracycline is a sequence option that can be incorporated into daily clinical practice. PMID- 24625450 TI - RAN nucleo-cytoplasmic transport and mitotic spindle assembly partners XPO7 and TPX2 are new prognostic biomarkers in serous epithelial ovarian cancer. AB - PURPOSE: Epithelial ovarian cancer has the highest mortality rate of all gynecological malignancies. We have shown that high RAN expression strongly correlates with high-grade and poor patient survival in epithelial ovarian cancer. However, as RAN is a small GTPase involved in two main biological functions, nucleo-cytoplasmic transport and mitosis, it is still unknown which of these functions associate with poor prognosis. METHODS: To examine the biomarker value of RAN network components in serous epithelial ovarian cancer, protein expression of six specific RAN partners was analyzed by immunohistochemistry using a tissue microarray representing 143 patients associated with clinical parameters. The RAN GDP/GTP cycle was evaluated by the expression of RANBP1 and RCC1, the mitotic function by TPX2 and IMPbeta, and the nucleo-cytoplasmic trafficking function by XPO7, XPOT and IMPbeta. RESULTS: Based on Kaplan-Meier analyses, RAN, cytoplasmic XPO7 and TPX2 were significantly associated with poor overall patient survival, and RAN and TPX2 were associated with lower disease free survival in patients with high-grade serous carcinoma. Cox regression analysis revealed that RAN and TPX2 expression were independent prognostic factors for both overall and disease free survival, and that cytoplasmic XPO7 expression was a prognostic factor for overall patient survival. CONCLUSIONS: In this systematic study, we show that RAN and two protein partners involved in its nucleo-cytoplasmic and mitotic functions (XPO7 and TPX2, respectively) can be used as biomarkers to stratify patients based on prognosis. In particular, we reported for the first time the clinical relevance of the exportin XPO7 and showed that TPX2 expression had the strongest prognostic value. These findings suggest that protein partners in each of RAN's functions can discriminate between different outcomes in high-grade serous epithelial ovarian cancer patients. Furthermore, these proteins point to cellular processes that may ultimately be targeted to improve the survival in serous epithelial ovarian cancer. PMID- 24625453 TI - Pain related to cancer treatments and diagnostic procedures: a no man's land? AB - BACKGROUND: While guidelines are available for the management of cancer-related pain, little attention is given to the assessment and treatment of pain caused by treatments and diagnostic procedures in cancer patients. METHODS: We evaluated the literature on pain related to cancer treatment and diagnostic procedures within a critical analysis. RESULTS: The data available are sparse, suggesting that little attention has been directed at this important aspect of oncology. This points to potentially suboptimal patient management. CONCLUSIONS: Appropriate studies are necessary in order to understand the incidence and appropriate management of pain, both during and/or after oncological treatments and diagnostic procedures. At the same time, Health Care Professionals should have heightened awareness of the causes and treatment of pain with the aim of anticipating and managing pain most appropriately for each individual patient. This is clearly an important component of holistic patient care before, during, and after oncological treatment. PMID- 24625455 TI - Review of current best practice and priorities for research in radiation oncology for elderly patients with cancer: the International Society of Geriatric Oncology (SIOG) task force. AB - Radiotherapy (RT) is a key component of the management of older cancer patients. Level I evidence in older patients is limited. The International Society of Geriatric Oncology (SIOG) established a task force to make recommendations for curative RT in older patients and to identify future research priorities. Evidence-based guidelines are provided for breast, lung, endometrial, prostate, rectal, pancreatic, oesophageal, head and neck, central nervous system malignancies and lymphomas. Patient selection should include comorbidity and geriatric evaluation. Advances in radiation planning and delivery improve target coverage, reduce toxicity and widen eligibility for treatment. Shorter courses of hypofractionated whole breast RT are safe and effective. Conformal RT and involved-field techniques without elective nodal irradiation have improved outcomes in non-small-cell lung cancer (NSCLC) without increasing toxicity. Where comorbidities preclude surgery, stereotactic body radiotherapy (SBRT) is an option for early-stage NSCLC and pancreatic cancer. Modern involved-field RT for lymphoma based on pre-treatment positron emission tomography data has reduced toxicity. Significant comorbidity is a relative contraindication to aggressive treatment in low-risk prostate cancer (PC). For intermediate-risk disease, 4-6 months of hormones are combined with external beam radiotherapy (EBRT). For high risk PC, combined modality therapy (CMT) is advised. For high-intermediate risk, endometrial cancer vaginal brachytherapy is recommended. Short-course EBRT is an alternative to CMT in older patients with rectal cancer without significant comorbidities. Endorectal RT may be an option for early disease. For primary brain tumours, shorter courses of postoperative RT following maximal debulking provide equivalent survival to longer schedules. MGMT methylation status may help select older patients for temozolomide alone. Stereotactic RT provides an alternative to whole-brain RT in patients with limited brain metastases. Intensity-modulated radiation therapy provides an excellent technique to reduce dose to the carotids in head and neck cancer and improves locoregional control in oesophageal cancer. Best practice and research priorities are summarised. PMID- 24625454 TI - Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era. AB - BACKGROUND: The introduction of rituximab (R) to conventional CHOP chemotherapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) led to an unequivocal improvement in survival, establishing RCHOP as the standard of care. Still, nearly 40% of DLBCL patients will eventually die of relapsed disease. Efforts to improve outcomes by addition of new biologic agents (X) to the RCHOP backbone are underway. In this era of R(X)CHOP, it is imperative to develop prognostic and predictive markers, not only to identify patients who will suffer a particularly aggressive course, but also to accurately select patients for clinical trials from which they will most benefit. DESIGN: The following review was undertaken to describe prognostic factors in DLBCL, with emphasis on markers that are accurate, relatively available, and clinically applicable in 2014. RESULTS: The International Prognostic Index retains its validity in the era of RCHOP, although with limited ability to predict those with <50% chance of long-term survival. Gene expression profiling has provided novel insights into the biology of DLBCL and led to the development of immunohistochemistry (IHC) algorithms that are in routine practice. Identification of a 'double-hit' (DH) lymphoma by fluorescent in situ hybridization with aberrations involving MYC and/or BCL2 and BCL6 genes has important implications due to its extremely dismal prognosis with RCHOP. Other markers such as the absolute lymphocyte count (ALC), serum immunoglobulin free light chains, vitamin D levels, serum cytokines/chemokines, and imaging with positron emission tomography (PET) have all shown promise as future predictive/prognostic tests. CONCLUSIONS: The future for new treatment options in DLBCL is promising with current clinical trials testing novel targeted agents such as bortezomib, lenalidomide, and ibrutinib as the 'X' in R(X)CHOP. Predictive factors are required to select and randomize patients appropriately for these trials. We envision the day when 'X' will be chosen based on the biological characteristics of the tumor. PMID- 24625456 TI - Dengue virus type 2 (DENV2)-induced oxidative responses in monocytes from glucose 6-phosphate dehydrogenase (G6PD)-deficient and G6PD normal subjects. AB - BACKGROUND: Dengue virus is endemic in peninsular Malaysia. The clinical manifestations vary depending on the incubation period of the virus as well as the immunity of the patients. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is prevalent in Malaysia where the incidence is 3.2%. It has been noted that some G6PD-deficient individuals suffer from more severe clinical presentation of dengue infection. In this study, we aim to investigate the oxidative responses of DENV2-infected monocytes from G6PD-deficient individuals. METHODOLOGY: Monocytes from G6PD-deficient individuals were infected with DENV2 and infection rate, levels of oxidative species, nitric oxide (NO), superoxide anions (O2-), and oxidative stress were determined and compared with normal controls. PRINCIPAL FINDINGS: Monocytes from G6PD-deficient individuals exhibited significantly higher infection rates compared to normal controls. In an effort to explain the reason for this enhanced susceptibility, we investigated the production of NO and O2- in the monocytes of individuals with G6PD deficiency compared with normal controls. We found that levels of NO and O2- were significantly lower in the DENV infected monocytes from G6PD-deficient individuals compared with normal controls. Furthermore, the overall oxidative stress in DENV-infected monocytes from G6PD deficient individuals was significantly higher when compared to normal controls. Correlation studies between DENV-infected cells and oxidative state of monocytes further confirmed these findings. CONCLUSIONS/SIGNIFICANCE: Altered redox state of DENV-infected monocytes from G6PD-deficient individuals appears to augment viral replication in these cells. DENV-infected G6PD-deficient individuals may contain higher viral titers, which may be significant in enhanced virus transmission. Furthermore, granulocyte dysfunction and higher viral loads in G6PD deificient individuals may result in severe form of dengue infection. PMID- 24625457 TI - Plerixafor added to G-CSF-supported paclitaxel-ifosfamide-cisplatin salvage chemotherapy enhances mobilization of adequate numbers of hematopoietic stem cells for subsequent autografting in hard-to-mobilize patients with relapsed/refractory germ-cell tumors: a single-center experience. AB - An appreciable percentage of patients with relapsed/refractory germ-cell tumors (GCTs), candidates for high-dose chemotherapy (HDC) and autologous hematopoietic cell transplantation (HCT), fail to mobilize adequate hematopoietic stem cells (HSCs) numbers with granulocyte colony-stimulating factor (G-CSF)+/-salvage chemotherapy. Plerixafor has shown a potential to mobilize adequate CD34+HSCs numbers in this context. Here, we applied plerixafor in combination with G-CSF after salvage chemotherapy in 'poor' mobilizers with relapsed/refractory GCTs for HDC+HCT. Patients with relapsed/refractory GCTs (n=10) received salvage paclitaxel-ifosfamide-cisplatin (TIP) chemotherapy+G-CSF to mobilize adequate HSCs to support HDC, mainly with two courses of high-dose thiotepa-etoposide carboplatin (TEC). Patients failing to achieve the minimum collection threshold of 2.0*10/kg CD34+ cells, to support at least one cycle of HDC, were administered plerixafor before the anticipated HSC collection during subsequent cycle(s). Overall, seven patients mobilized adequate CD34+ cells (>5.0*10/kg) aiming to support two cycles of HDC. Three patients did not mobilize adequate numbers of CD34+ cells after previous G-CSF plus salvage TIP, and plerixafor was added in subsequent cycle(s). This led to a collection of adequate CD34+ cells, able to support HDC with TEC (1-2 cycles). Hematopoietic engraftment for neutrophils (absolute neutrophil count>500/MUl) and platelets (platelet count>20 000/MUl) with plerixafor-mobilized HSCs occurred after a median of 9 and 14 days, respectively. Salvage TIP+G-CSF leads to successful HSC mobilization in patients with less heavily pretreated GCTs, whereas the addition of plerixafor to G CSF+TIP led to mobilization of adequate HSCs that supported autografting after one to two TEC cycles. PMID- 24625458 TI - Engineering of the chemical reactivity of the Ti/HfO2 interface for RRAM: experiment and theory. AB - The Ti/HfO2 interface plays a major role for resistance switching performances. However, clear interface engineering strategies to achieve reliable and reproducible switching have been poorly investigated. For this purpose, we present a comprehensive study of the Ti/HfO2 interface by a combined experimental theoretical approach. Based on the use of oxygen-isotope marked Hf*O2, the oxygen scavenging capability of the Ti layer is clearly proven. More importantly, in line with ab initio theory, the combined HAXPES-Tof-SIMS study of the thin films deposited by MBE clearly establishes a strong impact of the HfO2 thin film morphology on the Ti/HfO2 interface reactivity. Low-temperature deposition is thus seen as a RRAM processing compatible way to establish the critical amount of oxygen vacancies to achieve reproducible and reliable resistance switching performances. PMID- 24625459 TI - Metabolism and antiretroviral activity of tenofovir alafenamide in CD4+ T-cells and macrophages from demographically diverse donors. AB - BACKGROUND: Tenofovir alafenamide (TAF) is a novel investigational prodrug of tenofovir (TFV) that permits enhanced delivery of TFV into peripheral blood mononuclear cells (PBMCs) and lymphatic tissues. A critical step in the intracellular metabolic activation of TAF is mediated by the lysosomal protease cathepsin A (CatA). Here, we investigated CatA levels together with intracellular metabolism and antiretroviral activity of TAF in primary CD4+ T-lymphocytes (CD4s) and monocyte-derived macrophages (MDMs) isolated from a demographically diverse group of blood donors. METHODS: CD4s and MDMs were prepared from fresh PBMCs. CatA levels were quantified in cell extracts by monitoring TAF hydrolysis using HPLC. Intracellular TAF metabolites were quantified by HPLC combined with mass spectrometry. Antiviral activities in activated CD4s and MDMs were determined using HIV-1 single-cycle reporter and p24 antigen production assays, respectively. RESULTS: The levels of CatA and intracellular TAF metabolites differed minimally in CD4s and MDMs among 13 tested donors. TAF was >600-fold and 80-fold more potent than parent TFV in CD4s and MDMs, respectively, and its relative range of antiviral activity across all tested donors was comparable to that of other HIV-1 reverse transcriptase inhibitors, with mean +/-sd (range) EC50 values of 11.0 +/-3.4 (6.6-19.9) nM and 9.7 +/-4.6 (2.5-15.7) nM in CD4s and MDMs, respectively. CONCLUSIONS: These results indicate consistent intracellular metabolism and antiretroviral potency of TAF in relevant target cells of HIV-1 infection across multiple donors of variable gender, age and ethnicity, supporting further clinical investigation of TAF. PMID- 24625461 TI - Takeaway food and health. PMID- 24625460 TI - Associations between exposure to takeaway food outlets, takeaway food consumption, and body weight in Cambridgeshire, UK: population based, cross sectional study. AB - OBJECTIVES: To examine the association between environmental exposure to takeaway food outlets, takeaway food consumption, and body weight, while accounting for home, work place, and commuting route environments. DESIGN: Population based, cross sectional study, using data on individual participants' diet and weight, and objective metrics of food environment exposure. PARTICIPANTS: Working adults participating in the Fenland Study, Cambridgeshire, UK (n = 5442, aged 29-62 years), who provided home and work addresses and commuting preferences. Takeaway food outlet exposure was derived using data from local authorities for individual environmental domains (at home, at work, and along commuting routes (the shortest route between home and work)), and for exposure in all three domains combined. Exposure was divided into quarters (Q); Q1 being the least exposed and Q4 being the most exposed. MAIN OUTCOME MEASURES: Self reported consumption of takeaway type food (g/day; pizza, burgers, fried foods, and chips) using food frequency questionnaires, measured body mass index, and cut-offs for body mass index as defined by the World Health Organization. RESULTS: In multiple linear regression models, exposure to takeaway food outlets was positively associated with consumption of takeaway food. Among domains at home, at work, and along commuting routes, associations were strongest in work environments (Q4 v Q1; beta coefficient = 5.3 g/day, 95% confidence interval 1.6 to 8.7; P<0.05), with evidence of a dose-response effect. Associations between exposure in all three domains combined and consumption were greater in magnitude across quarters of exposure (Q4 v Q1; 5.7 g/day, 2.6 to 8.8; P<0.001), with evidence of a dose response effect. Combined exposure was especially strongly associated with increased body mass index (Q4 v Q1; body mass index 1.21, 0.68 to 1.74; P<0.001) and odds of obesity (Q4 v Q1; odds ratio 1.80, 1.28 to 2.53; P<0.05). There was no evidence of effect modification by sex. CONCLUSIONS: Exposure to takeaway food outlets in home, work, and commuting environments combined was associated with marginally higher consumption of takeaway food, greater body mass index, and greater odds of obesity. Government strategies to promote healthier diets through planning restrictions for takeaway food could be most effective if focused around the workplace. PMID- 24625462 TI - PharmGKB summary: abacavir pathway. PMID- 24625463 TI - Waiting for Godot: an analysis of 2622 operating room turnover times. PMID- 24625464 TI - Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock: a prospective observational study. AB - BACKGROUND: Central venous-to-arterial carbon dioxide partial pressure difference (DeltaPCO2) can be used as a marker for the efficacy of venous blood in removing the total CO2 produced by the tissues. To date, this role of DeltaPCO2 has been assessed only in patients after resuscitation from septic shock with already normalised central venous oxygen saturation (ScvO2 >=70%). There are no reports on the behaviour of DeltaPCO2 and its relationship to cardiac index (CI) and clinical outcome before normal ScvO2 has been achieved. OBJECTIVES: To investigate the behaviour of DeltaPCO2 and its relationship to CI, blood lactate concentration and 28-day mortality during resuscitation in the very early phase of septic shock. To examine whether patients who normalise both DeltaPCO2 and ScvO2 during the first 6 h of resuscitation will have a greater percentage decrease in blood lactate concentration than those who only achieve normal ScvO2. DESIGN: Prospective observational study. SETTING: Intensive Care Unit (ICU) in a university hospital. PATIENTS: Eighty patients with septic shock were consecutively recruited. INTERVENTIONS: Patients were resuscitated in accordance with the recommendations of the Surviving Sepsis Campaign. MAIN OUTCOME MEASURES: Blood lactate concentrations, and haemodynamic and oxygen-derived variables were obtained at ICU admission (T0) and 6 h after admission (T6). Lactate decrease was defined as the percentage decrease in lactate concentration from T0 to T6. All cause 28-day mortality was also recorded. RESULTS: Data are presented as median (interquartile range). At T0, there were significant differences (P < 0.0001) between normal (DeltaPCO2 <=0.8 kPa) and high DeltaPCO2 groups for CI (3.9 [3.3 to 4.7] vs. 2.9 [2.3 to 3.1] l min m) and ScvO2 (73 [65 to 80] vs. 61 [53 to 63]%). The correlation between changes in CI and DeltaPCO2 was r = 0.62, P < 0.0001. Patients who reached a normal DeltaPCO2 at T6 had larger decreases in blood lactate concentration and Sequential Organ Failure Assessment scores on day 1. The lactate decrease was greatest in the subgroup achieving both normal ScvO2 and DeltaPCO2 at T6. Lactate decrease, unlike DeltaPCO2 and ScvO2, was an independent predictor of 28-day mortality. CONCLUSION: Monitoring DeltaPCO2 may be a useful tool to assess the adequacy of tissue perfusion during resuscitation. The normalisation of both DeltaPCO2 and ScvO2 is associated with a greater decrease in blood lactate concentration than ScvO2 alone. The lactate decrease is an independent predictor of 28-day mortality. Further research is needed to confirm this hypothesis. PMID- 24625465 TI - A scoping review of interventions to supplement spoken communication for children with limited speech or language skills. AB - BACKGROUND: Augmentative and Alternative Communication (AAC) is used for treating children with severe disorders of speech-language production and/or comprehension. Various strategies are used, but research and debate on their efficacy have remained limited to a specific area and have rarely reached the general medical community. OBJECTIVE: To systematically evaluate outcomes of AAC interventions in children with limited speech or language skills. METHODS: Searches were conducted (up to December 2012) in the MEDLINE, EMBASE, PsycINFO, CINAHL, DARE, and Cochrane Library databases. Furthermore, relevant journals were searched by hand. References from identified studies were examined. Only RCTs were considered. Trial quality was assessed according to a standardized and validated set of criteria. RESULTS: Fourteen of 1661 retrieved papers met inclusion criteria. A total of 666 children were included in the review and 7 papers involved only children <5 years old. Papers were of average quality and all but one had been published during the previous 10 years by one of 8 research groups, 5 of which from the United States. Seven studies directly addressed AAC use by children with different disabilities. Seven studies enrolled typically developing children: 5 evaluated the use of AAC technologies by children without disabilities in order to obtain results that could be used to improve interventions in peers with disabilities, and 2 evaluated peers' attitudes towards children who used AAC. Both interventions and outcome measures varied widely between studies. Overall findings demonstrate the effectiveness of the AAC interventions considered, but the focus on RCTs alone appears too restrictive. CONCLUSIONS: Solid evidence of the positive effects of AAC interventions in children with severe communication disorders must be generated, and different methods are needed besides RCTs. Moreover, it is important that knowledge, research, and debate extend to the medical community in order to ensure clinically effective AAC provision for these children (and their parents). PMID- 24625466 TI - Red bone marrow dose calculations in radiotherapy of prostate cancer based on the updated VCH adult male phantom. AB - Red bone marrow (RBM) is an important dose-limiting tissue that has high radiosensitivity but is difficult to identify on clinical medical images. In this study, we investigated dose distribution in RBM for prostate cancer radiotherapy. Four suborgans were identified in the skeleton of the visible Chinese human phantom: cortical bone (CB), trabecular bone (TB), RBM, and yellow bone marrow (YBM). Dose distributions in the phantom were evaluated by the Monte Carlo method. When the left os coxae was taken as the organ-at-risk (OAR), the difference in absorbed dose between RBM and each CB and TB was up to 20%, but was much less (<=3.1%) between RBM and YBM. When the left os coxae and entire bone were both taken as OARs, RBM dose also increased with increasing planning target volume size. The results indicate the validity of using dose to homogeneous bone marrow mixture for estimating dose to RBM when RBM is not available in computational phantoms. In addition, the human skeletal system developed in this study provides a model for considering RBM dose in radiotherapy planning. PMID- 24625467 TI - A guide to study Drosophila muscle biology. AB - The development and molecular composition of muscle tissue is evolutionarily conserved. Drosophila is a powerful in vivo model system to investigate muscle morphogenesis and function. Here, we provide a short and comprehensive overview of the important developmental steps to build Drosophila body muscle in embryos, larvae and pupae. We describe key methods, including muscle histology, live imaging and genetics, to study these steps at various developmental stages and include simple behavioural assays to assess muscle function in larvae and adults. We list valuable antibodies and fly strains that can be used for these different methods. This overview should guide the reader to choose the best marker or the appropriate method to obtain high quality muscle morphogenesis data in Drosophila. PMID- 24625469 TI - Comparison between visual clinical examination and the replica method for assessments of sealant retention over a 2-year period. AB - To compare the levels of agreement and the survival rates of sealant retention for different sealing materials over a 2-year period assessed using the visual clinical examination and replica methods, sealant retention data were obtained by visual clinical examination and from replicas of the same sealed tooth at baseline and at 0.5-, 1- and 2-year evaluation points in 407 children and were compared for agreement using kappa coefficients. Survival curves of retained sealants on occlusal surfaces were created using modified categorisation (fully retained sealants and those having all pits and fissures partly covered with the sealant material versus completely lost sealants that included pit and fissure systems that had >=1 pit re-exposed) according to the Kaplan-Meier method. The kappa coefficient for the agreement between both assessment methods over the three evaluation time points combined was 0.38 (95% confidence interval (CI): 0.35-0.41). More sealant retention was observed from replicas than through visual clinical examination. Cumulative survival curves at the three evaluation times were not statistically significantly higher when assessed from replicas (P=0.47). Using the replica method, more retained sealant material was observed than through visual clinical examination during the 2-year period. This finding did not result in a difference in the survival rates of sealants assessed by the two assessment methods. When replicas cast in die stone are used for assessing sealant retention, the level of reliability of the data is higher than that of data obtained through the commonly used visual clinical examination, particularly if such assessments are conducted over time. PMID- 24625468 TI - An in-silico model of lipoprotein metabolism and kinetics for the evaluation of targets and biomarkers in the reverse cholesterol transport pathway. AB - High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic plaques. The recent failures of HDL-cholesterol (HDL-C) raising therapies have initiated a re-examination of the link between CVD risk and the rate of RCT, and have brought into question whether all target modulations that raise HDL-C would be atheroprotective. To help address these issues, a novel in-silico model has been built to incorporate modern concepts of HDL biology, including: the geometric structure of HDL linking the core radius with the number of ApoA-I molecules on it, and the regeneration of lipid-poor ApoA-I from spherical HDL due to remodeling processes. The ODE model has been calibrated using data from the literature and validated by simulating additional experiments not used in the calibration. Using a virtual population, we show that the model provides possible explanations for a number of well-known relationships in cholesterol metabolism, including the epidemiological relationship between HDL-C and CVD risk and the correlations between some HDL-related lipoprotein markers. In particular, the model has been used to explore two HDL-C raising target modulations, Cholesteryl Ester Transfer Protein (CETP) inhibition and ATP-binding cassette transporter member 1 (ABCA1) up-regulation. It predicts that while CETP inhibition would not result in an increased RCT rate, ABCA1 up-regulation should increase both HDL-C and RCT rate. Furthermore, the model predicts the two target modulations result in distinct changes in the lipoprotein measures. Finally, the model also allows for an evaluation of two candidate biomarkers for in-vivo whole-body ABCA1 activity: the absolute concentration and the % lipid-poor ApoA-I. These findings illustrate the potential utility of the model in drug development. PMID- 24625470 TI - Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension. PMID- 24625471 TI - Timing is everything in protecting the heart and lungs in a "sympathetic storm": alpha before beta? PMID- 24625472 TI - Sweetened carbonated beverage consumption and cancer risk: meta-analysis and review. AB - There is speculation on an association between sweetened, carbonated beverage consumption and cancer risk. This study aimed to examine this issue. Over 50 independent estimates of risk were available, 11 for colas specifically. A random effects meta-analysis was carried out with tests for publication bias performed as well as Higgins and Thompson's I measure of the percentage of heterogeneity between studies that could not be explained by chance. Over all the different sites of cancer, the summary relative risk (SRR), when all 55 independent estimates were considered together, was SRR=1.03 [95% confidence interval (0.96; 1.11)]. When individual cancer sites were considered, there was no significant increase or decrease in the meta-analysis estimate of risk of cancer of the pancreas, bladder, kidney, squamous cell or adenocarcinoma of the oesophagus, colon, gastric cardia, gastric noncardia, prostate, breast, larynx and ovary or of the oral cavity, pharynx or glioma. There was no evidence in a sensitivity analysis from those studies that reported results separately for colas of an associated risk of pancreas cancer [SRR=1.00, 95% confidence interval (0.61; 1.65)]. The results for all other forms of cancers were considerably hampered by poor methodology and small numbers of studies (mainly one report on each cancer site studied). Overall, the findings are reassuring in terms of the association between soft drinks, including colas, and cancer risk, although the quality of many of the studies is quite poor by acceptable, modern standards and no study has been carried out with use of carbonated beverages as a primary hypothesis. PMID- 24625473 TI - [The knowledge diffusion as an educational tool]. AB - To disseminate knowledge, several instruments have been used, among them periodicals. Since the 1960s, the impact factor has been used to rate the importance of journals, and simultaneously, the work of researchers. In this paper we propose to evaluate journals, in addition to the impact factor, through their circulation, readership size, print runs, and internet access. PMID- 24625474 TI - [What do parametric tests compare?]. PMID- 24625475 TI - [Answer to the letter "Whay do parametric tests compare?"]. PMID- 24625476 TI - [Comment on the article "Current scenario of obesity..."]. PMID- 24625477 TI - [Meet the family medicine specialist]. PMID- 24625478 TI - [ApoE polymorphisms and dopaminergic replacement therapy in Parkinson's disease]. AB - BACKGROUND: The expression of apolipoprotein E (apoE) polymorphisms has been proposed as a risk factor for early development of psychotic symptoms in patients with Parkinson's disease. The association between apoE polymorphisms and motor complications is controversial. The aim was to determine the association between apoE polymorphisms and its allele frequency with the development of complications secondary to dopaminergic replacement therapy. METHODS: We evaluated 231 patients with the diagnosis of Parkinson's disease. The presence of motor complications secondary to treatment was determined by a neurologist, and the genotypification of apoE polymorphisms was performed. Descriptive statistics and chi-squared test were used. RESULTS: Genotype ?3/?3 was expressed in 80.5 % of the sample; there was no association between genotype or allele frequency of apoE polymorphisms and the development of psychosis or dyskinesia. Patients who expressed the ?2 allele showed a tendency to develop motor fluctuations, but without reaching statistical significance (p = 0.08). CONCLUSIONS: ApoE polymorphisms are not associated with the development of complications from dopaminergic replacement therapy. PMID- 24625479 TI - [Blood and urine lead levels in children with attention deficit hyperactivity disorder]. AB - BACKGROUND: Attention deficit hyperactivity disorder is the most common neuropsychiatric disorder in children; symptoms can persist into adult life by 60 %. Our objective was to quantify the levels of lead in blood and urine in pediatric patients with attention deficit hyperactivity disorder. METHODS: We did an observational study which included a captive population of children diagnosed with attention deficit hyperactivity disorder in the mental health service of Hospital General, from Centro Medico Nacional La Raza. Lead levels were determined in blood and urine by atomic absorption technique. RESULTS: We included 39 patients, 932 % male, with a mean age of 9.2 +/- 2.16 years. The deficit and hyperactivity disorder combined type was the most frequent (69.2 %); 49 % of patients were found with toxic lead levels in blood (above 10 mg/dL); 17.9 % with stage III and 5.12 % with stage IV, according to the Mexican Official Standard (NOM-199-SSA-2000). Significant association was found between blood lead levels and the clinical expression of attention deficit hyperactivity disorder. CONCLUSIONS: Levels of lead exposure during early childhood have been shown to be inversely proportional to neurological development in the first seven years of life. Data results are insufficient to relate them with causality. PMID- 24625480 TI - [Concordance in blood lead quantification between laboratories]. AB - OBJECTIVE: To establish a blood lead quantification correlation from two occupational health laboratories (OHL1V and OHL2DF), and the ABC Hospital (LABC) metals laboratory. METHODS: A cross-sectional study was performed in 84 workers from a voltage regulators company, where lead is welded; in 54 % (46 of them) a blood sample was taken and analyzed by OHL1V, and in 28.6 % (24) by OHL2DF. All samples were analyzed by atomic absorption spectrophotometry. Pearson correlation (r), coefficient of determination (r2), Lin (rho) concordance test, and Bland Altman plots were calculated. RESULTS: The blood lead mean: LABC was 5.8 +/- 2.4 MUg/dL vs. OHL2DF of 4.4 +/- 3.6 MUg/dL (r = 0.25 [p = 0.24], r2 = 0.06 [p = 0.24], and rho = 0.21 [p = 0.21]). And with LABC, 6.75 +/- 3.3 MUg/dL vs. OHL1V 5.6 +/- 2.9 MUg/dL (r = 0.91 [p < 0.001], r2 = 0.83 [p < 0001], and rho = 0.85 [p< 0.001]). CONCLUSIONS: Agreement between LABC and OHL1V was poor (< 0.90), and with OHL2DF was null. An occupational health laboratory certification is needed in order to have reliable biological exposure index measurements in lead occupational exposure. PMID- 24625482 TI - [The impact of family characteristics in sexual risk behaviour of teens]. AB - OBJECTIVE: To assess risk sexual behaviour in adolescents and its relationship with family characteristics. METHODS: In a representative and random sample of 909 teenagers, their sex life, structure, satisfaction and family dynamics were evaluated. It was used chi-squared test, in order to compare the frequency of family negative characteristics between the groups of adolescents with and without risky sexual behaviors. RESULTS: The early onset of sexual life was more frequent in adolescents with dysfunctional expression of affection in their families, and single-parent or nuclear family structure. The lack of condom use was associated with a lack of affection, and a poor comunication within the family. Having more than three partners was related to the expression of affection and the degree of satisfaction of the teenager with his family. Unplanned pregnancies and sex transmission diseases were most frequent in adolescents belonging to extended families with a poor expression of affection. CONCLUSIONS: The level of communication, the monitoring of conduct, the warmth and proximity play a very important role as protectors of sexual risk behaviour in teens. PMID- 24625481 TI - [Risk factors for recurrent retinal detachment]. AB - OBJECTIVE: To determine the risk factors associated with recurrent retinal detachment in patients vitrectomized. METHODS: Case-control study nested in a cohort. We included patients with a diagnosis of rhegmatogenous retinal detachment treated with vitrectomy for one year, with a six months follow-up. We monitored the presence of incident event in the emergency department, and the examination room. Statistical analysis was performed by descriptive statistics (median, minimum and maximum) and inferential statistics (chi-squared test, Cox regression, Kaplan-Meier). RESULTS: A population of 94 patients with a median age of 55 years (21-83) was analyzed. The silicone was the most widely used type of tamponade in 62 patients (66 %) and recurrent retinal detachment occurred in 19 cases (20 %). In the relation between the non-relapse group and the relapse group, the statistically significant variable was the use of silicone (p = 0.05, OR = 0.03, 0.013-0.98), wich had a lower probability of recurrent detachment compared with the use of sulfur hexafluoride (SF6 gas) (p = 0.012). CONCLUSIONS: The use of silicone compared with the use of SF6 gas has shown to be a protective factor for recurrent retinal detachment; however, the choice of method of tamponade should be individualized for each patient. PMID- 24625483 TI - [Otoneurologic and cardiovascular abnormalities associated to carbon monoxide poisoning in occupational exposed workers]. AB - BACKGROUND: Even though Federal Labor Law includes carbon monoxide poisoning in the list of occupational diseases, the registration of this intoxication rarely occurs in a work environment. The objective was to determine the association of this poisoning with cardiovascular and otoneurologic disorders, in order to establish adequately this diagnosis as a work-related illness. METHODS: Cross sectional survey performed in a group of broiler production workers, compared with a control group (n = 54). The sample consisted of people aged between 18 and 74 years, males and females, smokers and non-smokers. We excluded those participants with clinical history of cardiac attack. We determined carboxyhemoglobin (COHb) rates in exhaled air, and performed an audiometric test, and a 12-lead electrocardiogram. RESULTS: We studied 54 workers (57 % males and 43 % females). We obtained a statistically significant difference (p < 0.05) to develop hearing loss between the two groups, an odds ratio > 1 also in regards to hearing loss, and cardiovascular manifestations (anterior fascicle hemiblock). CONCLUSIONS: Otoneurologic and cardiovascular abnormalities in occupationally exposed workers to carbon monoxide are not casual, and suggest a cause-effect relationship. PMID- 24625484 TI - [Prevalence of rhinitis and asthma respiratory symptoms in Spanish working population]. AB - OBJECTIVE: The aims were to examine the prevalence of respiratory symptoms associated with rhinitis and asthma in Spanish workers and its variations by age, sex, work sector, location in the workplace, smoking habits and the relationship between symptoms in the upper and lower respiratory tract. METHODS: The sample was of 2603 workers in different sectors and regions throughout the country. They agreed and answered the questions regarding respiratory symptoms, with the supervision of the company's physician. RESULTS: Chronic nasal symptoms were present in 438 workers (16.9 %); 193 (7.5 %) had pulmonary symptoms. With nasal and pulmonary symptoms were 124 patients (28.3 %). Likewise, of the 190 workers with pulmonary symptoms, 124 (64.2 %) had also nasal manifestations. We observed variations in nasal symptoms by sex, professional sector, work area and smoking habits, and variations in pulmonary symptoms by work sector. A higher prevalence was noted in the healthcare, postal, and transport sector as opposed to the construction, furniture or metal sector. CONCLUSIONS: The prevalence of nasal symptoms was higher than that of pulmonary symptoms in the working population. The workers affected by these pathologies were not treated adequately, despite they were presenting symptoms. We observed a relationship between pulmonary and nasal symptoms. PMID- 24625485 TI - [Difficult for intubation in a simulator with laryngoscope with and without mirror]. AB - BACKGROUND: The mirror laryngoscope blade (Siker blade) is used often in patients with anatomical variations, because it improves the visibility of epiglottis, shortening the intubation time. The objective was to compare the degree of difficulty in intubation with Macintosh blade versus Siker blade in a simulator, among anesthesiologists and residents in training. METHODS: A comparative study in 29 medical residents in training and 21 anesthesiologists was conducted. They had three attempts of 30 seconds to perform intubation with each laryngoscope in two different stages. The time and the intubation attempt, in which a successful intubation was performed, were registered. The data were processed using Statistica software, version 6. RESULTS: there was no difference for intubation between anesthesiologists and residents. Siker blade required more number of attempts (normal airway p < 0.001, difficult airway p = 0.02) and longer time for intubation (normal airway p < 0.0001, difficult airway p = 0.003). With a greater proportion of anesthesiologists, 20 % of the sample failed the intubation with Siker blade. CONCLUSIONS: It was more difficult for anesthesiologists and residents in training the use of the Siker blade in both stages, with normal or difficult airway on a simulator. PMID- 24625486 TI - [Current position about the use of estrogen therapy in women during the climacteric period]. AB - The hormonal therapy should begin only in order to control the symptoms of the climacteric in women; its use is not recommended to prevent other types of affections associated to the posmenopause, because, despite some other recognizable benefits have been described, many of them have not been demonstrated. Before beginning the treatment of hormonal therapy, it is recommended to analyze the risk factors for heart attack or other cardiovascular diseases, and also estimate risk for osteoporosis and breast cancer. Diverse presentations and ways of administration of the hormonal therapy have been used, with which outcome have been obtained that vary in connection with predominant symptoms. Recently, the introduction of the concept based on the combined use of an estrogen associated to selective estrogen receptor modulator (SERM), the tissue selective estrogen complex (TSEC), allows a better clinical profile for the patient. With this combination it is obtained endometrial protection and positive action about the changes that the menopause produces. The decision to continue the hormonal therapy should be individualized, based on the severity of the symptoms and recurrence, considering the risk-benefit foreseen with the woman in the clinic. PMID- 24625487 TI - [Clinical research XIX. From clinical judgment to analysis of covariance]. AB - The analysis of covariance (ANCOVA) is based on the general linear models. This technique involves a regression model, often multiple, in which the outcome is presented as a continuous variable, the independent variables are qualitative or are introduced into the model as dummy or dichotomous variables, and factors for which adjustment is required (covariates) can be in any measurement level (i.e. nominal, ordinal or continuous). The maneuvers can be entered into the model as 1) fixed effects, or 2) random effects. The difference between fixed effects and random effects depends on the type of information we want from the analysis of the effects. ANCOVA effect separates the independent variables from the effect of co-variables, i.e., corrects the dependent variable eliminating the influence of covariates, given that these variables change in conjunction with maneuvers or treatments, affecting the outcome variable. ANCOVA should be done only if it meets three assumptions: 1) the relationship between the covariate and the outcome is linear, 2) there is homogeneity of slopes, and 3) the covariate and the independent variable are independent from each other. PMID- 24625488 TI - [Associated costs with dental studies in a public Mexican university]. AB - OBJECTIVE: To calculate associated costs with dental studies (ACDS) in a public university. METHODS: We performed a cross-sectional study using a costing system on a random sample of 376 dental students enrolled at any semester in a public university. To calculate ACDS (Mexican pesos of 2009-1), we used a questionnaire divided into eight sections. Sociodemographic and socioeconomic variables, housing costs, food, transportation, instruments and equipment, as well as remunerations associated with patient care along 16 weeks of classes in each semester were included. We used linear regression. RESULTS: The average of ACDS was of 18,357.54 +/- 12,746.81 Mexican pesos. The largest percentage of ACDS (30.2 %) was for clinical instruments (5,537.66 +/- 6,260.50). Students also spent funds in paying to patients for their time during care delivered (2,402.11 +/- 4,796.50). Associated variables (p < 0.001) with the ACDS were having completed at least one clinical course or one theoretical-practical course, living within the state or out of state (compared to students who live in the city where dental studies take place), and being enrolled in the more advanced dental studies. CONCLUSIONS: The results indicate that a significant percentage of the cost to students (13.1 %) is related with clinical care delivery. PMID- 24625489 TI - [Clinical aspects and microbiology of peritoneal dyalisis-related peritonitis]. AB - OBJECTIVE: The aim of this study was to describe the clinical and bacteriological characteristics of patients with peritoneal dyalisis-related peritonitis. METHODS: A cross-sectional, descriptive study conducted at an Instituto Mexicano del Seguro Social hospital, in Zacapetec, Morelos, Mexico. The sample included was non-probabilistic and consecutive. All the patients with current registration, and diagnosed with peritoneal dyalisis-related peritonitis were included in the sample. RESULTS: During the study period there were 30 cases of peritoneal dyalisis-related peritonitis, most commonly associated with continuous ambulatory peritoneal dialysis patients, with a high incidence in intermittent dialysis. The main characteristics of patients with peritonitis were turbid liquid (100 %), abdominal pain (73 %) and fever (43 %). Gram staining revealed that 53 % was gram-positive, and 10 % was gram-negative. Bacterial cultures showed that 53.3 % of the obtained peritoneal cultures were positive. The most frequent bacterial specimen was Staphylococcus aureus. CONCLUSIONS: Rates of infection and percentage of negative cultures were higher than reported previously. The symptoms are in accord with the international literature. Preventive measures must be employed to reduce the incidence of infections related to peritoneal dialysis. PMID- 24625490 TI - [Chromosomal abnormalities in patients from Obstetrics and Gynaecology hospital]. AB - BACKGROUND: Chromosomal abnormalities are present in 2-4 % of all newborns, and they cause 20 % of deaths in the first year of life. The estimated prevalence of chromosomal abnormalities is one for each 500-1000 newborns. These abnormalities can be numerical or structural, and they can affect autosomal or sexual chromosomes. They affect from 1 to 3 % of general population, and from 6 to 7 % of individuals with congenital anomalies. METHODS: Descriptive study, which included all the registries of cytogenetic analysis (of adults and newborns) made in a genetic laboratory in a period of 14 years. The prevalence of polymorphisms and chromosomal abnormalities in the patients from the Hospital de Ginecoobstetricia 23, Instituto Mexicano del Seguro Social (Monterrey, Nuevo Leon) was assessed. RESULTS: Of 4006 cytogenetic studies, 253 (6.3 %) did not show in vitro growth, 2667 (66.5 %) were normal, and 1175 (29.3 %) were abnormal. Of these, 614 (52.2 %) had polymorphisms, and 561 (47.7 %) structural or numerical chromosomal abnormalities. In regards to these chromosomopathies (561), trisomy 21 was observed in 429 (36.5 %); Turner's syndrome, in 84 (7.1 %); trisomy 18, in 57 (4.8 %); and trisomy 13, in 32 (2.7 %). With G-band technique, we found 93 % of in vitro cell growth. CONCLUSIONS: Of these studies, 55 % was performed due to non-numerical abnormalities; 14.4 %, due to structural abnormalities; and the rest, due to polymorphisms. PMID- 24625491 TI - [Chronic myeloid leukemia in an adult with common variable immunodeficiency]. AB - BACKGROUND: Common variable immunodeficiency is a primary immunodeficiency, in which from 70 to 80 % of patients have tumors and 25 % of cases are associated with autoimmune diseases. Common variable immunodeficiency patients have a higher incidence of neoplasms, with a risk 12-18 times higher than the general population. There are few cases of common variable immunodeficiency patients with leukemia. CLINICAL CASE: Female of 36 years old, with left upper quadrant pain, early satiety, weight loss of 8 kg in three months and splenomegaly. The complete blood count showed: leukocytosis 206 000/mL, with 8 % blasts, platelets 530 000/mL and hemoglobin 8 mg/dL. Abdominal ultrasound: 19??12 cm splenomegaly. Karyotype BCR/ABL IS 64.20 %, 100 % Philadelphia chromosome. The diagnosis was of chronic myeloid leukemia. Given the presence of recurrent respiratory tract infection, frequent diarrheas and reduced concentrations of IgG, IgM and IgA, common variable immunodeficiency was diagnosed and human immunoglobulin was used successfully. CONCLUSIONS: The association between chronic myeloid leukemia and common variable immunodefficiency is unusual. Given the high frequency of hematological neoplasm in common variable immunodeficiency patients, we suggest that hematological patients with repeated infections and decreased concentrations of immunoglobulin be referred to an immunological evaluation. PMID- 24625492 TI - [Systemic loxoscelism presented in a pregnant patient]. AB - BACKGROUND: Loxoscelism is a condition caused by the inoculation of a series of proteolytic enzymes through the loxosceles spider bite (violinist). Morbidity and mortality is unknown in our country. The loxoscelism toxi-syndrome of local expression may have a good prognosis; however, viscera-cutaneus or systemic form has a serious and often fatal evolution. We report a case of a systemic variant developed in a pregnant patient. CLINICAL CASE: We present the first reported case of systemic loxoscelism in a pregnant patient, highlighting the survival of the mother-son, in the presence of viscera-cutaneus behavior. We describe the natural history of clinical expression, highlighting the benefit of current therapeutic antivenom fourth generation and immunoregulation role in supporting the therapeutic approach and the guideline of the surgical approach. CONCLUSIONS: The appropriate multidisciplinary management coupled with an early use of antivenom limits the severity and the potential development of complications. Clinical suspicion is the cornerstone of therapeutic management of these patients. PMID- 24625493 TI - [Wernicke's encephalopathy and Caine criteria. Report of six cases]. AB - BACKGROUND: Wernicke's encephalopathy is an acute and reversible neurologic disorder due to deficiency of thiamin. Chronic alcoholism was the main cause in the past; currently, there are many other situations which favour this condition: prolonged intravenous feeding, hyperemesis gravidarum, anorexia nervosa, regional enteritis, malabsorption syndrome, hemodialysis, peritoneal dialysis, and abdominal surgery. CLINICAL CASE: We report six patients, three male and three female, who had in common total parenteral nutrition over two months, secondary to abdominal surgery complications and restriction to enteral nutrition. Clinical manifestations were drowsiness, psychomotor hyperactivity, ophthalmoplegia with bilateral abduction impairment, horizontal nystagmus; three patients with ataxia and appendicular dysmetria. Magnetic resonance imaging showed abnormal T2 hyperintensity of the superior colliculus, periaqueductal gray matter, mammillary bodies and dorsomedial nucleus of the thalamus, as well as abnormal T1 hyperintensity in both lenticular nucleus from manganese deposits due to total parenteral nutrition. CONCLUSIONS: The classical triad is global confusional state, ocular abnormalities and ataxia. However, using the Caine criteria, the diagnosis could be faster in susceptible patients without previous alcoholism. PMID- 24625494 TI - [Clinical practice guideline. Diagnosis and treatment of insomnia in the elderly]. AB - Insomnia is the difficulty to initiate or to maintain sleep. It also has to do with waking up too early at least for a month. A patient with insomnia has daytime consequences such as fatigue, sleepiness, changes in mood, lose of concentration, as well as changes in his social performance and his family relationships, among others. The relationship between this disorder and physical and mental health is important due to the impact that it has on the quality of life and life expectancy of those who suffer from it. Unfortunately, insomnia usually goes unnoticed or untreated, which contributes to the onset or worsening of psychiatric and medical conditions. This exacerbates the problem of insomnia in the elderly people. In relation to the treatment it is recommended: 1) the search and management of secondary causes of insomnia, 2) a non-drug therapy that includes sleep hygiene measures, 3) pharmacotherapy. It is not recommended to start a treatment with a hypnotic drug without rule out medications or diseases that cause or exacerbate insomnia. It is not recommended the use of narcoleptics, melatonin, antihistamines or long half-life benzodiazepines. The consequences include limitations on activities of daily living, loss of functionality, impaired quality of life, increased morbidity and mortality, as well as the worsening of preexisting chronic conditions. PMID- 24625495 TI - The effects of Ti carbonization on the nucleation and oriented growth of diamond films on cemented carbide. AB - To better understand the influence of carbonization of the Ti interlayer on diamond nucleation and growth, a series of Ti/diamond composite films were deposited on cemented carbide (WC:Co) substrates using a two-step deposition technique. The microstructural properties of the composite films were then characterized by scanning electron microscopy, X-ray diffractometry, and Raman spectroscopy, and their tribological properties were evaluated using a ball-on disc tester and a metalloscope. The results showed that differences in carbonization for five Ti interlayers of different thicknesses led to variations in the preferred orientations of the TiC layers and in the subsequent nucleation and oriented growth of diamond. This suggests that Ti carbonization significantly influences the nucleation and growth of diamond and subsequently causes variations in the tribological properties of the produced diamond films. PMID- 24625496 TI - A methodology for adaptable and robust ecosystem services assessment. AB - Ecosystem Services (ES) are an established conceptual framework for attributing value to the benefits that nature provides to humans. As the promise of robust ES driven management is put to the test, shortcomings in our ability to accurately measure, map, and value ES have surfaced. On the research side, mainstream methods for ES assessment still fall short of addressing the complex, multi-scale biophysical and socioeconomic dynamics inherent in ES provision, flow, and use. On the practitioner side, application of methods remains onerous due to data and model parameterization requirements. Further, it is increasingly clear that the dominant "one model fits all" paradigm is often ill-suited to address the diversity of real-world management situations that exist across the broad spectrum of coupled human-natural systems. This article introduces an integrated ES modeling methodology, named ARIES (ARtificial Intelligence for Ecosystem Services), which aims to introduce improvements on these fronts. To improve conceptual detail and representation of ES dynamics, it adopts a uniform conceptualization of ES that gives equal emphasis to their production, flow and use by society, while keeping model complexity low enough to enable rapid and inexpensive assessment in many contexts and for multiple services. To improve fit to diverse application contexts, the methodology is assisted by model integration technologies that allow assembly of customized models from a growing model base. By using computer learning and reasoning, model structure may be specialized for each application context without requiring costly expertise. In this article we discuss the founding principles of ARIES--both its innovative aspects for ES science and as an example of a new strategy to support more accurate decision making in diverse application contexts. PMID- 24625497 TI - Mechanical property and structure of covalent functionalised graphene/epoxy nanocomposites. AB - Thermally reduced graphene nanoplatelets were covalently functionalised via Bingel reaction to improve their dispersion and interfacial bonding with an epoxy resin. Functionalised graphene were characterized by microscopic, thermal and spectroscopic techniques. Thermal analysis of functionalised graphene revealed a significantly higher thermal stability compared to graphene oxide. Inclusion of only 0.1 wt% of functionalised graphene in an epoxy resin showed 22% increase in flexural strength and 18% improvement in storage modulus. The improved mechanical properties of nanocomposites is due to the uniform dispersion of functionalised graphene and strong interfacial bonding between modified graphene and epoxy resin as confirmed by microscopy observations. PMID- 24625498 TI - Identification of factors influencing the restoration of cyanobacteria-dominated biological soil crusts. AB - Biological soil crusts (BSCs) cover >35% of the Earth's land area and contribute to important ecological functions in arid and semiarid ecosystems, including erosion reduction, hydrological cycling, and nutrient cycling. Artificial rapid cultivation of BSCs can provide a novel alternative to traditional biological methods for controlling soil and water loss such as the planting of trees, shrubs, and grasses. At present, little is known regarding the cultivation of BSCs in the field due to lack of knowledge regarding the influencing factors that control BSCs growth. Thus, we determined the effects of various environmental factors (shade; watering; N, P, K, and Ca concentrations) on the growth of cyanobacteria-dominated BSCs from the Sonoran Desert in the southwestern United States. The soil surface changes and chlorophyll a concentrations were used as proxies of BSC growth and development. After 4 months, five factors were found to impact BSC growth with the following order of importance: NH4NO3 ~ watering frequency>shading>CaCO3 ~ KH2PO4. The soil water content was the primary positive factor affecting BSC growth, and BSCs that were watered every 5 days harbored greater biomass than those watered every 10 days. Groups that received NH4NO3 consistently exhibited poor growth, suggesting that fixed N amendment may suppress BSC growth. The effect of shading on the BSC biomass was inconsistent and depended on many factors including the soil water content and availability of nutrients. KH2PO4 and CaCO3 had nonsignificant effects on BSC growth. Collectively, our results indicate that the rapid restoration of BSCs can be controlled and realized by artificial "broadcasting" cultivation through the optimization of environmental factors. PMID- 24625499 TI - Re: Is there really evidence for detection of submaximal capacity in patients with chronic low back pain? van der Meer S, Trippolini MA, van der Palen J, et al. Which instruments can detect submaximal physical and functional capacity in patients with chronic nonspecifi c back pain? A systematic review Spine (Phila Pa 1976)2013;38(25):E1608-15. PMID- 24625500 TI - In response. PMID- 24625502 TI - A comparison of intense pulsed light and laser treatment of telangiectases in patients with systemic sclerosis: a within-subject randomized trial. AB - OBJECTIVE: Cutaneous telangiectases are a characteristic and psychologically distressing feature of SSc. Our aim was to assess the efficacy of two light-based treatments: pulsed dye laser (PDL) and intense pulsed light (IPL). METHODS: Nineteen patients with facial or upper limb telangiectases underwent three treatments with PDL and IPL (randomly assigned to left- and right-sided lesions). Outcome measures were clinical photography (assessed by two clinicians), dermoscopy (assessed by two observers), laser Doppler imaging (LDI) and observer and patient opinion, including patient self-assessment psychological questionnaires [Hospital Anxiety and Depression Scale (HADS), Adapted Satisfaction with Appearance Scale (ASWAP)]. RESULTS: Comparison between 16-week follow-up and baseline photography scores (from -2 to +2 on a Likert scale, with >0 being improvement) were a mean score for PDL of 1.7 (95% CI 1.4, 2.0) and for IPL 1.4 (0.9, 1.8), with a mean difference between PDL and IPL of -0.3 (-0.5, 0.1) (P = 0.01). Dermoscopy scores also improved with both therapies: PDL 1.3 (1.1, 1.5) and IPL 0.8 (0.5, 1.1), again greater with PDL (P = 0.01). LDI showed decreases in blood flow at 16 weeks, indicating a response to both therapies. All patients reported benefit from treatment (more preferred PDL at 16 weeks). Psychological questionnaires also indicated improvement after therapy with mean change in ASWAP of -13.9 (95% CI -20.5, -7.4). No side effects were reported for IPL; PDL caused transient bruising in most cases. CONCLUSION: Both PDL and IPL are effective treatments for SSc-related telangiectases. Outcome measures indicate that PDL has better outcomes in terms of appearance, although IPL had fewer side effects. PMID- 24625503 TI - Multiple upper gastrointestinal perforations in a 15-year-old patient treated with tocilizumab. PMID- 24625504 TI - Limited effectiveness for the therapeutic blockade of interferon alpha in systemic lupus erythematosus: a possible role for type III interferons. PMID- 24625505 TI - Renal involvement in hypocomplementaemic urticarial vasculitis syndrome: a report of three paediatric cases. AB - OBJECTIVE: To describe the diagnosis and management of renal disease in three paediatric cases of hypocomplementaemic urticarial vasculitis syndrome (HUVS). METHODS: Three children who were diagnosed with HUVS and developed abnormalities of renal function during the disease course are described. RESULTS: Urinary findings were heterogeneous: all the patients developed persistent microhaematuria, which was isolated in patient 1, associated with mild proteinuria in patient 2 and with nephrotic syndrome in patient 3. Renal biopsies were performed in all the patients: patients 1 and 2, who had normal levels of serum autoantibodies, shared a full-house IF (C3, C1q and Ig deposits), compatible with an SLE-like disease; patient 3 showed negative staining for IgG and IgM, but developed positive anti-dsDNA without fulfilling criteria for the diagnosis of SLE. CONCLUSION: Renal involvement in HUVS is probably more frequent and more severe than in adults and may appear later. Isolated microhaematuria can be the only sign of subclinical renal involvement: its role should not be underestimated and a renal biopsy should be considered. Previous observations of rapidly progressive nephritis and consequent end-stage renal disease in children suggest the need for prompt diagnosis and treatment of renal involvement. PMID- 24625506 TI - Long-term efficacy of infliximab in autoimmune sensorineural hearing loss associated with rheumatoid arthritis. PMID- 24625507 TI - The informational needs of patients with ANCA-associated vasculitis-development of an informational needs questionnaire. AB - OBJECTIVE: The aim of the study was to compare the informational needs of patients with ANCA-associated vasculitis (AAV). METHODS: We developed a Vasculitis Informational Needs Questionnaire that was distributed to members of Vasculitis UK (VUK) by mail and registrants of the Vasculitis Clinical Research Consortium (VCRC) online registry with self-reported AAV. Patients were asked to use a 5-point scale (1 = not important, 5 = extremely important) to rank aspects of information in the following domains: disease, investigations, medication, disease management and psychosocial care. The source and preferred method of educational delivery were recorded. RESULTS: There were 314 VUK and 273 VCRC respondents. Respondents rated information on diagnosis, prognosis, investigations, treatment and side effects as extremely important. Information on patient support groups and psychosocial care was less important. There was no difference in the ratings of needs based on group, sex, age, disease duration, disease or method of questionnaire delivery. The most-preferred methods of providing information for both groups were by a doctor (with or without written material) or web based; educational courses and compact disc/digital video disc (CD/DVD) were the least-preferred methods. CONCLUSION: This study demonstrates that people with AAV seek specific information concerning their disease, treatment regimes and side effects and the results of investigations. Individuals preferred to receive this information from a doctor. Patients with AAV should be treated in a similar manner to patients with other chronic illnesses in which patient education is a fundamental part of care. PMID- 24625509 TI - Biomechanical comparison of different suturing techniques in rabbit medial gastrocnemius muscle laceration repair. AB - INTRODUCTION: Skeletal muscle laceration is a common injury. Repair of disrupted delicate tissue is still a clinical challenge for surgeons. A few different muscle repair techniques have been reported. However, the best muscle repair technique has not been identified. The aim of the present study is to compare the biomechanical features of different repair techniques in muscles to identify the most effective one. MATERIAL AND METHODS: New Zealand white rabbits (2.5-3 kg) were euthanized and medial gastrocnemius muscles were isolated. The muscles were completely transected with scalpels and then repaired by 3 different techniques, namely, (1) 2-strand mattress, (2) 4-strand Kessler (with epitendinous suture), and (3) Mason-Allen. To measure suture performance, the repaired specimens were mounted onto a mechanical testing machine Instron 5543. The muscles were loaded to failure at a constant speed of 60 mm/min. Data collected from Merlin v5.31 software were used to compute the biomechanical properties of each specimen. RESULTS: There was no significant difference in the mean maximum load of Kessler group (15.5 N) and Mason-Allen group (13.2 N), whereas the mean maximum load of the control (Mattress) group (4.4 N) was significantly smaller than the other 2 groups. Moreover, Kessler stitches were the stiffest among the 3. It is noteworthy that the mechanisms of failure were different: Kessler stitches were all pulled out longitudinally, whereas Mason-Allen stitches transmitted load across the laceration and ruptures occur at areas adjacent to the stitches, indicating that muscle is the weakest element in the biomechanical testing. CONCLUSIONS: Both Kessler and Mason-Allen stitches have shown better biomechanical features compared with the control group. Further study has to be done to compare the effect of these 2 techniques on muscle regeneration and scar formation in an in vivo model. PMID- 24625510 TI - The guide wire method: a new technique for easier side-to-end lymphaticovenular anastomosis. AB - Lymphaticovenular anastomosis has become one of the treatment options for lymphedema. Among several types of anastomosis, side-to-end anastomosis in which a window is made on the wall of a lymphatic vessel is considered to be the most effective, because it creates bidirectional bypasses through 1 anastomosis. However, making a side-to-end anastomosis with a small lymphatic vessel and a venule can be technically challenging. We developed a new technique using an intravascular stenting that significantly facilitates the procedure. PMID- 24625511 TI - Breast reconstruction with a turbocharged transverse rectus abdominis myocutaneous flap on the contralateral perforator. AB - Seventeen patients were submitted to delayed unilateral breast reconstruction using pedicled, muscle-sparing turbocharged transverse rectus abdominis myocutaneous flap based on the contralateral perforator vessels. The lateral portion of the rectus abdominis muscle on the pedicled side was preserved in 12 patients. Zones II and IV were included in the flap in all cases. Mean duration of surgery was 7 hours and 15 minutes. Four complications developed in the abdominal donor site: contralateral abdominal bulging (n=1), minor suture dehiscence (n=2), and epidermolysis at the border of the abdominal flap and umbilical scar (n=1). Three partial losses (10%-30%) occurred in the reconstructed breast (17.64% of cases), whereas 2 cases of fat necrosis were associated with partial losses. One patient developed deep vein thrombosis with pulmonary embolism; however, outcome was favorable. This proved a viable alternative for breast reconstruction, with satisfactory results in most patients and acceptable morbidity and surgical time. PMID- 24625512 TI - Determination of a perfusion threshold in experimental perforator flap surgery using indocyanine green angiography. AB - Indocyanine green (ICG) angiography has been used in the evaluation of flap perfusion but the viability threshold has not been elucidated. In this study, we determined the threshold by comparing perfusion, using ICG imaging (SPY imaging system, LifeCell Corporation), to clinical evidence of nonviability in rat abdominal perforator flaps. Abdominal flaps, based on a single perforator, were elevated and re-inset in Sprague-Dawley rats. ICG imaging and clinical assessments were conducted preoperatively, as well as 0, 24, and 48 hours postoperatively. SPY-Q software allowed standardization of the perforator's perfusion for comparison purposes. A total of 278 random percentage measurements were made from postoperative day 0 giving a mean (SE) percentage perfusion of 26.8% (1.6%) and 59.1% (1.3%), respectively, for necrosis and survival (P<0.05). We demonstrate that ICG angiography can be readily analyzed in a perforator flap environment allowing a determination of the perfusion threshold. PMID- 24625513 TI - Intralesional laser therapy for vascular malformations. AB - Intralesional laser therapy for the treatment of vascular malformations (VMs) has been previously reported for select patient populations. Larger studies, over a wider variety of indications, are needed to better define the potential role of this technology. In the current study, a 12-year, retrospective review of 44 patients who underwent 73 intralesional Nd:YAG or diode laser treatments of VMs was performed. The most commonly encountered lesions were venous malformations (66%) and the most commonly involved anatomic locations were the head and neck regions (41%) and lower extremity (39%). Primary indications for treatment were enlargement (73%) and pain (52%). Lesion size was reduced in 94% of cases after treatment and pain was improved in 91% of cases. Minor postoperative complications occurred in 16 (36%) patients. There was no difference in treatment response among various VM subtypes or anatomic locations (P=0.497, P=0.866) or in the incidence of complications (P=0.531, P=0.348). Age was the only factor associated with an increased risk of complications (odds ratio, 1.034; P=0.038). When used in accordance with the suggested guidelines, intralesional laser therapy is a safe and effective treatment modality for VMs of varying compositions and locations. PMID- 24625514 TI - Therapeutic outcomes in the treatment of unilateral glenoid fossa fractures using intermaxillary elastic traction. AB - INTRODUCTION: This study aimed to evaluate the therapeutic outcomes of intermaxillary elastic traction in the treatment of unilateral glenoid fossa fractures. METHODS: Five patients with traumatic unilateral glenoid fossa fractures were treated with intermaxillary elastic traction at the Sun Yat-Sen University Hospital of Stomatology during a 5-year period from 2006 to 2011. Pantomography and Schuller position radiographs were obtained at days 7, 28, and 90 to monitor glenoid fossa fracture healing. Removal of the intermaxillary elastic traction and the arch bar splint occurred at day 90, and the patients were advised to initiate mouth-opening exercises. RESULTS: Schuller position radiographs revealed a 100% reduction rate of the glenoid fossa fracture for all patients; morphologies of the glenoid fossa and mandibular condyle were normal. Follow-up ranged from 6 months to 2 years. The occlusal relationship (degree of mouth opening) was excellent in all cases. Patient recoveries were uneventful; no complications occurred such as pain, snapping, or limitations of mouth opening. Average mouth opening was measured at 3.6 cm at the last follow-up. CONCLUSIONS: Intermaxillary elastic traction is an effective, simple, and feasible method in the treatment of a glenoid fossa fracture. Accurate reduction and stable fixation may be achieved without significant complications. PMID- 24625515 TI - Augmentation mammoplasty with silicone implant using transumbilical approach at a subpectoral level. AB - Endoscopic placement of breast implants has been described through an umbilical incision. Limitations include the fact that only inflatable implant can be used through umbilical approach. The purpose of this study is to describe the authors' evolutionary transumbilical technique with cohesive silicone gel implant insertion and to retrospectively analyze preliminary results. The authors' technique is the placement of a cohesive silicone gel implant using a transumbilical approach in a subpectoral plane. Patients who were selected had mammary hypoplasia without ptosis and who requests breast augmentation with a scarless and natural feel breast were considered candidates. The technique and indications are presented thoroughly. From June of 2011 to January of 2012, 42 women aged 23 to 46 years (average, 31.6 years) underwent the endoscopic transumbilical breast augmentation. All patients had round silicone implants placed in the retropectoral pocket location. The results of this study indicate that transumbilical technique is highly successful. Complication included transient periumbilical bulging (5 patients, 11.9%), hypertrophic scar needing revision (1 patient, 2.3%), and conversion to other breast incision due to capsular contracture (3 of 84 breasts, 3.5%). Transumbilical breast augmentation with prefilled implant is a safe and attractive technique for breast implant placement in selected patients. With this inventory modification, the result can permit surgeons expanded spectrum of implant selection for transumbilical approach. PMID- 24625508 TI - High level of viral suppression and low switch rate to second-line antiretroviral therapy among HIV-infected adult patients followed over five years: retrospective analysis of the DART trial. AB - In contrast to resource-rich countries, most HIV-infected patients in resource limited countries receive treatment without virological monitoring. There are few long-term data, in this setting, on rates of viral suppression or switch to second-line antiretroviral therapy. The DART trial compared clinically driven monitoring (CDM) versus routine laboratory (CD4/haematology/biochemistry) and clinical monitoring (LCM) in HIV-infected adults initiating therapy. There was no virological monitoring in either study group during follow-up, but viral load was measured in Ugandan participants at trial closure. Two thousand three hundred and seventeen (2317) participants from this country initiated antiretroviral therapy with zidovudine/lamivudine plus tenofovir (n = 1717), abacavir (n = 300), or nevirapine (n = 300). Of 1896 (81.8%) participants who were alive and in follow up at trial closure (median 5.1 years after therapy initiation), 1507 (79.5%) were on first-line and 389 (20.5%) on second-line antiretroviral therapy. The overall switch rate after the first year was 5.6 per 100 person-years; the rate was substantially higher in participants with low baseline CD4 counts (<50 cells/mm3). Among 1207 (80.1%) first-line participants with viral load measured, HIV RNA was <400 copies/ml in 963 (79.8%), 400-999 copies/ml in 37 (3.1%), 1,000 9,999 copies/ml in 110 (9.1%), and >=10,000 copies/ml in 97 (8.0%). The proportion with HIV RNA <400 copies/ml was slightly lower (difference 7.1%, 95% CI 2.5 to 11.5%) in CDM (76.3%) than in LCM (83.4%). Among 252 (64.8%) second line participants with viral load measured (median 2.3 years after switch), HIV RNA was <400 copies/ml in 226 (89.7%), with no difference between monitoring strategies. Low switch rates and high, sustained levels of viral suppression are achievable without viral load or CD4 count monitoring in the context of high quality clinical care. TRIAL REGISTRATION: ISRCTN13968779. PMID- 24625517 TI - The contribution from transit dose for (192)Ir HDR brachytherapy treatments. AB - Brachytherapy treatment planning systems that use model-based dose calculation algorithms employ a more accurate approach that replaces the TG43-U1 water dose formalism and adopt the TG-186 recommendations regarding composition and geometry of patients and other relevant effects. However, no recommendations were provided on the transit dose due to the source traveling inside the patient. This study describes a methodology to calculate the transit dose using information from the treatment planning system (TPS) and considering the source's instantaneous and average speed for two prostate and two gynecological cases. The trajectory of the (192)Ir HDR source was defined by importing applicator contour points and dwell positions from the TPS. The transit dose distribution was calculated using the maximum speed, the average speed and uniform accelerations obtained from the literature to obtain an approximate continuous source distribution simulated with a Monte Carlo code. The transit component can be negligible or significant depending on the speed profile adopted, which is not clearly reported in the literature. The significance of the transit dose can also be due to the treatment modality; in our study interstitial treatments exhibited the largest effects. Considering the worst case scenario the transit dose can reach 3% of the prescribed dose in a gynecological case with four catheters and up to 11.1% when comparing the average prostate dose for a case with 16 catheters. The transit dose component increases by increasing the number of catheters used for HDR brachytherapy, reducing the total dwell time per catheter or increasing the number of dwell positions with low dwell times. This contribution may become significant (>5%) if it is not corrected appropriately. The transit dose cannot be completely compensated using simple dwell time corrections since it may have a non-uniform distribution. An accurate measurement of the source acceleration and maximum speed should be incorporated in clinical practice or provided by the manufacturer to determine the transit dose component with high accuracy. PMID- 24625516 TI - Use of a recombinant cysteine proteinase from Leishmania (Leishmania) infantum chagasi for the Immunotherapy of canine visceral Leishmaniasis. AB - BACKGROUND: A recombinant cysteine proteinase from Leishmania (Leishmania) infantum chagasi (rLdccys1) was previously shown to induce protective immune responses against murine and canine visceral leishmaniasis. These findings encouraged us to use rLdccys1 in the immunotherapy of naturally infected dogs from Teresina, Piaui, a region of high incidence of visceral leishmaniasis in Brazil. METHODOLOGY/PRINCIPAL FINDINGS: Thirty naturally infected mongrel dogs displaying clinical signs of visceral leishmaniasis were randomly divided in three groups: one group received three doses of rLdccys1 in combination with the adjuvant Propionibacterium acnes at one month interval between each dose; a second group received three doses of P. acnes alone; a third group received saline. The main findings were: 1) dogs that received rLdccys1 with P. acnes did not display increase of the following clinical signs: weight loss, alopecia, onychogryphosis, cachexia, anorexia, apathy, skin lesions, hyperkeratosis, ocular secretion, and enlarged lymph nodes; they also exhibited a significant reduction in the spleen parasite load in comparison to the control dogs; 2) rLdccys1 treated dogs exhibited a significant delayed type cutaneous hypersensitivity elicited by the recombinant antigen, as well as high IgG2 serum titers and low IgG1 serum titers; sera from rLdccys1-treated dogs also contained high IFN-gamma and low IL-10 concentrations; 3) control dogs exhibited all of the clinical signs of visceral leishmaniasis and had low serum IgG2 and IFN-gamma levels and high concentrations of IgG1 and IL-10; 4) all of the dogs treated with rLdccys1 were alive 12 months after treatment, whereas dogs which received either saline or P. acnes alone died within 3 to 7 months. CONCLUSIONS/SIGNIFICANCE: These findings illustrate the potential use of rLdccys1 as an additional tool for the immunotherapy of canine visceral leishmaniasis and support further studies designed to improve the efficacy of this recombinant antigen for the treatment of this neglected disease. PMID- 24625518 TI - Bringing back the old: time to reevaluate the high-frequency ventilation strategy. AB - OBJECTIVE: To examine the role of frequency in high-frequency ventilation (HFV) on carbon-dioxide (CO2) elimination and lung injury, independent of its effect on tidal volume. STUDY DESIGN: An anatomically representative lung model was attached to a mechanical ventilator capable of providing HFV with a constant volume. CO2 was infused directly into the lung, and a commercially available end tidal CO2 detector was used to determine CO2 elimination. CO2 elimination and amplitude of pressure transmissions were evaluated using frequencies ranging from 5 to 15 Hz. The pressure-volume index (PVI) was described as the product of the volume and pressures delivered to the lung, a surrogate for lung injury. RESULT: The use of increasing frequencies directly correlated with improved CO2 clearance when keeping the tidal volume fixed, expressed as percent CO2 remaining in the lung at 25 s (66.5 (+/-1.1)%, 50.5 (+/-0.1)% and 37.8 (+/-0.3)% at 5, 10 and 15 Hz, respectively, P<0.05). With a fixed tidal volume, there was a decrease in pressure amplitudes transmitted to the lung with a decline in the PVI (53.9 (+/ 2.7) mmHg ml(-1), 41.1 (+/-0.9) mmHg ml(-1) and 23.4 (+/-3.6) mmHg ml(-1), at 5, 10 and 15 Hz, respectively, P<0.05). CONCLUSION: Frequency has a direct relationship with CO2 elimination when tidal volume is fixed. Using low delivered tidal volumes and high frequencies may allow for improved ventilation efficacy, while minimizing lung injury. PMID- 24625519 TI - Peripherally inserted central venous catheters: frequency of complications in premature newborn depends on the insertion site. AB - OBJECTIVE: The use of peripherally inserted central venous catheters (PICC lines) has reduced the mortality and morbidity of premature newborns. The usual sites of insertion are the veins in the upper arms but other locations are being used as well. STUDY DESIGN: To examine whether using the axillary vein as a site of insertion of a PICC line affects the frequency of complications. Our study has a clinical trial design. A total of 62 neonates that had a PICC line inserted were recruited and randomly divided equally in two groups: in Group A (mean birth weight, standard deviation (s.d.)=1353 (142) g), the PICC line was inserted through the axillary vein, and in Group B (birth weight=1308 (112) g), the PICC line was inserted in other sites further from the axillary vein. The outcomes measured were the total PICC line-related complications, the reason for removing the catheter, the number of total attempts until successful insertion and the mean duration of stay of the catheter. The likelihood of having an adverse outcome was assessed with Mantel-Haenszel odds ratio (OR). RESULTS: Premature neonates with axillary PICC lines were 12 times less likely to have line-related complications (inflammation, blockage, edema, infection) as compared with any other site of insertion (OR= 95%, confidence interval (CI)=0.10 (0.01 to 0.8)) and they were seven times more likely to have the PICC line removed because they achieved full enteral nutrition as compared with the other causes (OR 95%, confidence interval (CI)=10.35 (4.88 to 21.96)). There was no statistical difference between the two groups in the number of attempts until successful PICC line insertion (P=0.667) and the mean duration of stay of the PICC line (P=0.97). CONCLUSION: The use of the axillary vein as a site of insertion of a PICC line was correlated with significantly less complications in premature newborns as opposed to the other sites of insertion. PMID- 24625520 TI - The effect of incisura angularis biopsy sampling on the assessment of gastritis stage. AB - OBJECTIVES: It is important to stratify patients according to the magnitude of risk for gastric cancer development; the OLGA (Operative Link for Gastritis Assessment) and OLGIM (Operative Link on Gastric Intestinal Metaplasia) staging systems of lesions in the stomach mucosa have been proposed for this purpose. There are some discrepancies in the current guidelines regarding the value of incisura angularis biopsies. The aim of our study was to assess the value of incisura angularis biopsy in staging gastritis according to the OLGA and OLGIM systems by examining the atrophic, metaplastic and inflammatory changes in the antrum, incisura angularis and corpus. PATIENTS AND METHODS: We enrolled 835 patients undergoing upper endoscopy. Three expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification and the stage of gastritis was assessed by the OLGA and OLGIM systems. RESULTS: The results demonstrated that severe atrophic, metaplastic and chronic inflammatory changes were more frequently observed in the incisura angularis mucosa than in the antrum or corpus mucosae (P<0.05). There was a general downgrading of stage by 18.0% for OLGA and by 4.0% for OLGIM when the incisura angularis was excluded from the staging. Furthermore, there was a 30-35% downgrading for high-risk OLGA/OLGIM stages. CONCLUSION: The incisura angularis undergoes more severe atrophic, metaplastic and chronic inflammatory changes than the antrum and corpus. Incisura angularis biopsies should be routinely included in the biopsy sampling protocol. PMID- 24625521 TI - Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability. AB - Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6*10(-5)). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6*10(-5)), and 43% ID rate increase (CI: [23%, 67%], p<6*10(-5)). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26*10(-16)). PMID- 24625522 TI - Primary cutaneous T cell lymphoma with bone marrow infiltration and erythroblastopenia--a rare association. PMID- 24625523 TI - Robust membrane detection based on tensor voting for electron tomography. AB - Electron tomography enables three-dimensional (3D) visualization and analysis of the subcellular architecture at a resolution of a few nanometers. Segmentation of structural components present in 3D images (tomograms) is often necessary for their interpretation. However, it is severely hampered by a number of factors that are inherent to electron tomography (e.g. noise, low contrast, distortion). Thus, there is a need for new and improved computational methods to facilitate this challenging task. In this work, we present a new method for membrane segmentation that is based on anisotropic propagation of the local structural information using the tensor voting algorithm. The local structure at each voxel is then refined according to the information received from other voxels. Because voxels belonging to the same membrane have coherent structural information, the underlying global structure is strengthened. In this way, local information is easily integrated at a global scale to yield segmented structures. This method performs well under low signal-to-noise ratio typically found in tomograms of vitrified samples under cryo-tomography conditions and can bridge gaps present on membranes. The performance of the method is demonstrated by applications to tomograms of different biological samples and by quantitative comparison with standard template matching procedure. PMID- 24625524 TI - Vulnerable people are being oppressed because of failures of Mental Capacity Act, say peers. PMID- 24625525 TI - Automated coronary artery calcification scoring in non-gated chest CT: agreement and reliability. AB - OBJECTIVE: To determine the agreement and reliability of fully automated coronary artery calcium (CAC) scoring in a lung cancer screening population. MATERIALS AND METHODS: 1793 low-dose chest CT scans were analyzed (non-contrast-enhanced, non gated). To establish the reference standard for CAC, first automated calcium scoring was performed using a preliminary version of a method employing coronary calcium atlas and machine learning approach. Thereafter, each scan was inspected by one of four trained raters. When needed, the raters corrected initially automaticity-identified results. In addition, an independent observer subsequently inspected manually corrected results and discarded scans with gross segmentation errors. Subsequently, fully automatic coronary calcium scoring was performed. Agatston score, CAC volume and number of calcifications were computed. Agreement was determined by calculating proportion of agreement and examining Bland-Altman plots. Reliability was determined by calculating linearly weighted kappa (kappa) for Agatston strata and intraclass correlation coefficient (ICC) for continuous values. RESULTS: 44 (2.5%) scans were excluded due to metal artifacts or gross segmentation errors. In the remaining 1749 scans, median Agatston score was 39.6 (P25-P75?0-345.9), median volume score was 60.4 mm3 (P25 P75?0-361.4) and median number of calcifications was 2 (P25-P75?0-4) for the automated scores. The kappa demonstrated very good reliability (0.85) for Agatston risk categories between the automated and reference scores. The Bland Altman plots showed underestimation of calcium score values by automated quantification. Median difference was 2.5 (p25-p75?0.0-53.2) for Agatston score, 7.6 (p25-p75?0.0-94.4) for CAC volume and 1 (p25-p75?0-5) for number of calcifications. The ICC was very good for Agatston score (0.90), very good for calcium volume (0.88) and good for number of calcifications (0.64). DISCUSSION: Fully automated coronary calcium scoring in a lung cancer screening setting is feasible with acceptable reliability and agreement despite an underestimation of the amount of calcium when compared to reference scores. PMID- 24625526 TI - Protecting children from taking up smoking: parents' views on what would help. AB - ISSUE ADDRESSED: The present study investigated what factors the parents of children in low-income areas of Auckland, New Zealand, thought could help protect their children from smoking initiation. METHODS: Participants in a large quasi experimental trial that tested a community-, school- and family-based smoking initiation intervention were asked in a questionnaire 'What could we do to help you protect your children from smoke and taking up smoking?' Free-text responses were divided into distinct meaning units and categorised independently by two of the researchers. RESULTS: 1806 participants (70% of parents who returned the questionnaire) completed the question. The majority of respondents (80%) were either Pacific Island or Maori mothers and 25% were current smokers. Five main categories of suggested strategies for preventing smoking initiation were identified: building children's knowledge of the ill-effects of smoking; denormalising smoking; reducing access to tobacco; building children's resilience; and health promotion activities. The most common suggestion was to educate children about smoking. CONCLUSION: Building children's knowledge of smoking risks was the main strategy parents proposed. There was some support for banning smoking in most public areas and for tougher moves to stop tobacco sales to minors. Few parents suggested innovative or radical strategies, such as banning the sale of tobacco, fining children for smoking or use of competitions. So what? To ensure reductions in smoking initiation for lower socioeconomic and Maori and Pacific Island people, further research should engage Maori, Pacific Island and lower socioeconomic parents in a process that elicits innovative thinking about culturally acceptable strategies. PMID- 24625528 TI - Interactome analysis of AMP-activated protein kinase (AMPK)-alpha1 and -beta1 in INS-1 pancreatic beta-cells by affinity purification-mass spectrometry. AB - The heterotrimeric enzyme AMP-activated protein kinase (AMPK) is a major metabolic factor that regulates the homeostasis of cellular energy. In particular, AMPK mediates the insulin resistance that is associated with type 2 diabetes. Generally, cellular processes require tight regulation of protein kinases, which is effected through their formation of complex with other proteins and substrates. Despite their critical function in regulation and pathogenesis, there are limited data on the interaction of protein kinases. To identify proteins that interact with AMPK, we performed large-scale affinity purification (AP)-mass spectrometry (MS) of the AMPK-alpha1 and -beta1 subunits. Through a comprehensive analysis, using a combination of immunoprecipitaion and ion trap mass spectrometry, we identified 381 unique proteins in the AMPKalpha/beta interactomes: 325 partners of AMPK-alpha1 and 243 for AMPK-beta1. Further, we identified 196 novel protein-protein interactions with AMPK-alpha1 and AMPK beta1. Notably, in our bioinformatics analysis, the novel interaction partners mediated functions that are related to the regulation of actin organization. Specifically, several such proteins were linked to pancreatic beta-cell functions, including glucose-stimulated insulin secretion, beta-cell development, beta-cell differentiation, and cell-cell communication. PMID- 24625529 TI - Fruit self-thinning: a trait to consider for genetic improvement of apple tree. AB - In apple (Malus*domestica Borkh), as in many fruiting crops, fruit maintenance vs abscission is a major criteria for production profitability. Growers routinely make use of chemical thinning agents to control total fruit load. However, serious threats for the environment lead to the demand for new apple cultivars with self-thinning properties. In this project, we studied the genetic determinism of this trait using a F1 progeny derived from the cross between the hybrid INRA X3263, assumed to possess the self-thinning trait, and the cultivar 'Belrene'. Both counting and percentage variables were considered to capture the fruiting behaviour on different shoot types and over three consecutive years. Besides low to moderate but significant genetic effects, mixed models showed considerable effects of the year and the shoot type, as well as an interaction effect. Year effect resulted mainly from biennial fruiting. Eight Quantitative Trait Locus (QTL) were detected on several linkage groups (LG), either independent or specific of the year of observation or the shoot type. The QTL with highest LOD value was located on the top third of LG10. The screening of three QTL zones for candidate genes revealed a list of transcription factors and genes involved in fruit nutrition, xylem differentiation, plant responses to starvation and organ abscission that open new avenues for further molecular investigations. The detailed phenotyping performed revealed the dependency between the self-thinning trait and the fruiting status of the trees. Despite a moderate genetic control of the self-thinning trait, QTL and candidate genes were identified which will need further analyses involving other progenies and molecular investigations. PMID- 24625530 TI - Bone mineral density changes among HIV-uninfected young adults in a randomised trial of pre-exposure prophylaxis with tenofovir-emtricitabine or placebo in Botswana. AB - BACKGROUND: Tenofovir-emtricitabine (TDF-FTC) pre-exposure prophylaxis (PrEP) has been found to be effective for prevention of HIV infection in several clinical trials. Two studies of TDF PrEP among men who have sex with men showed slight bone mineral density (BMD) loss. We investigated the effect of TDF and the interaction of TDF and hormonal contraception on BMD among HIV-uninfected African men and women. METHOD: We evaluated the effects on BMD of using daily oral TDF FTC compared to placebo among heterosexual men and women aged 18-29 years enrolled in the Botswana TDF2 PrEP study. Participants had BMD measurements at baseline and thereafter at 6-month intervals with dual-energy X-ray absorptiometry (DXA) scans at the hip, spine, and forearm. RESULTS: A total of 220 participants (108 TDF-FTC, 112 placebo) had baseline DXA BMD measurements at three anatomic sites. Fifteen (6.8%) participants had low baseline BMD (z-score of <-2.0 at any anatomic site), including 3/114 women (2.6%) and 12/106 men (11.3%) (p = 0.02). Low baseline BMD was associated with being underweight (p = 0.02), having high blood urea nitrogen (p = 0.02) or high alkaline phosphatase (p = 0.03), and low creatinine clearance (p = 0.04). BMD losses of >3.0% at any anatomic site at any time after baseline were significantly greater for the TDF FTC treatment group [34/68 (50.0%) TDF-FTC vs. 26/79 (32.9%) placebo; p = 0.04]. There was a small but significant difference in the mean percent change in BMD from baseline for TDF-FTC versus placebo at all three sites at month 30 [forearm 0.84% (p = 0.01), spine -1.62% (p = 0.0002), hip -1.51% (p = 0.003)]. CONCLUSION: Use of TDF-FTC was associated with a small but statistically significant decrease in BMD at the forearm, hip and lumbar spine. A high percentage (6.8%) of healthy Batswana young adults had abnormal baseline BMD Further evaluation is needed of the longer-term use of TDF in HIV-uninfected persons. TRIAL REGISTRATION: ClinicalTrials.gov NCT00448669. PMID- 24625532 TI - Stroke while on long-term left ventricular assist device support: incidence, outcome, and predictors. AB - Development of stroke while on left ventricular assist device (LVAD) support can be a source of significant morbidity and mortality. From March 2006 through November 2011, one hundred patients with chronic heart failure underwent implantation of a HeartMate II (HM II) LVAD (Thoratec Corp.) as a bridge to transplant (BTT; n = 65) or destination therapy (DT; n = 35). Records were reviewed to determine the prevalence and type of postimplant stroke, anatomic cerebral location of strokes, and associated morbidity and mortality. Cox multivariate logistic regression analysis was conducted to identify independent predictors of postoperative stroke. Strokes occurred in 12 patients (12.0%): four embolic and eight hemorrhagic. Median duration of support at the time of stroke was 281.0 days for embolic strokes and 380.5 days for hemorrhagic strokes (p = 0.028). Stroke patients had a significantly higher incidence of diabetes (66.7% vs. 40.9%; p = 0.024), history of preimplant stroke (16.7% vs. 4.5%; p = 0.046), and aortic cross-clamping with cardioplegic arrest during their LVAD implant (50.0% vs. 20.2%; p = 0.034) compared with patients without postoperative strokes. Mean international normalized ratio (INR) at the time of stroke was subtherapeutic in all four patients with embolic strokes (mean: 1.5 +/- 0.1 IU; range 1.3-1.6 IU) and supratherapeutic in four of eight patients with hemorrhagic strokes (mean: 3.2 +/- 2.2 IU, range: 1.4-7.0 IU; p = 0.024). There was a 25.0% 30 day mortality after stroke. Diabetes (odds ratio [OR] 6.36; p = 0.029), aortic cross-clamping with cardioplegic arrest (OR 4.75; p = 0.025), duration of LVAD support (OR 1.00; p = 0.008), and INR (OR 4.42; p = 0.020) were independent predictors of stroke in multivariate analysis with a trend toward significance for history of stroke (OR 6.25; p = 0.075). Stroke represented an important source of morbidity and mortality for patients on HM II LVAD support. As long term device therapy continues to gain popularity for both BTT and DT, a better understanding of the predictors of stroke, more strict control of postoperative anticoagulation, and the establishment of a risk stratification model may aid in minimizing its occurrence. PMID- 24625531 TI - EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation, migration and adhesion. AB - Still 20% of pediatric acute lymphoblastic leukemia (ALL) patients relapse on or after current treatment strategies. Treatment failure is associated with resistance to prednisolone. We aimed to find new druggable targets that modulate prednisolone resistance. We generated microarray gene expression profiles of 256 pediatric ALL patient samples and identified a 3.4-fold increase in epithelial membrane protein 1 (EMP1) expression in in vitro prednisolone-resistant compared with -sensitive patients (P=0.003). EMP1 silencing in six precursor-B ALL (BCP ALL) and T-ALL cell lines induced apoptosis and cell-cycle arrest leading to 84.1+/-4.5% reduction in survival compared with non-silencing control transduced cells (non-silencing control short hairpin, shNSC) (P=0.014). Moreover, EMP1 silencing sensitized to prednisolone up to 18.8-fold (P<0.001). EMP1 silencing also abrogated migration and adhesion to mesenchymal stromal cells (MSCs) by 78.3+/-9.0 and 29.3+/-4.1% compared with shNSC (P<0.05). We discovered that EMP1 contributes to MSC-mediated prednisolone resistance. Pathway analysis indicated that EMP1 signals through the Src kinase family. EMP1-high BCP-ALL patients showed a poorer 5-year event-free survival compared with EMP1-low patients (77+/ 2 vs. 89+/-2%, P=0.003). Multivariate analysis taking along white blood cell count, age, prednisolone resistance and subtype identified EMP1 as an independent predictor for poor outcome in BCP-ALL (P=0.004, hazard ratio: 2.36 (1.31-4.25). This study provides preclinical evidence that EMP1 is an interesting candidate for drug development to optimize treatment of BCP-ALL. PMID- 24625533 TI - Extracorporeal membrane oxygenation support in acardia. AB - In extreme situations, such as hyperacute rejection of heart transplant or major heart trauma, heart preservation may not be possible. Our experimental team works on a project of peripheral extracorporeal membrane oxygenation (ECMO) support in acardia as a bridge to heart transplantation or artificial heart implantation. An ECMO support was established in five calves (58.6 +/- 6.9 kg) by the transjugular insertion to the caval axis of a self-expanded cannula, with carotid artery return. After baseline measurements, ventricular fibrillation was induced, great arteries were clamped, heart was excised, and right and left atria remnants, containing pulmonary veins, were sutured together leaving an atrial septal defect over the caval axis cannula. Measurements of pump flow and arterial pressure were taken with the pulmonary artery clamped and anastomosed with the caval axis for a total of 6 hours. Pulmonary artery anastomosis to the caval axis provided an acceptable 6 hour hemodynamic stability, permitting a peripheral access ECMO support in extreme scenarios indicating a heart explantation. PMID- 24625534 TI - ECMO for adult respiratory failure: current use and evolving applications. AB - Extracorporeal membrane oxygenation (ECMO) is increasingly being used to support adults with severe forms of respiratory failure. Fueling the explosive growth is a combination of technological improvements and accumulating, although controversial, evidence. Current use of ECMO extends beyond its most familiar role in the support of patients with severe acute respiratory distress syndrome (ARDS) to treat patients with various forms of severe hypoxemic or hypercapnic respiratory failure, ranging from bridging patients to lung transplantation to managing pulmonary hypertensive crises. The role of ECMO used primarily for extracorporeal carbon dioxide removal (ECCO2R) in the support of patients with hypercapnic respiratory failure and less severe forms of ARDS is also evolving. Select patients with respiratory failure may be liberated from invasive mechanical ventilation altogether and some may undergo extensive physical therapy while receiving extracorporeal support. Current research may yield a true artificial lung with the potential to change the paradigm of treatment for adults with chronic respiratory failure. PMID- 24625535 TI - Management of cardiac arrest caused by acute massive pulmonary thromboembolism: importance of percutaneous cardiopulmonary support. AB - Cardiac arrest caused by acute pulmonary embolism is associated with high patient mortality. We reviewed patients who had cardiac arrest caused by acute pulmonary embolism. Between January 2001 and September 2013, we identified 20 patients at our institution with a confirmative diagnosis of acute pulmonary thromboembolism and cardiac arrest. Percutaneous cardiopulmonary support (PCPS) and surgical embolectomy are the standard course of care for patients with shock or cardiac arrest caused by pulmonary thromboembolism at our institution. Patients were divided into two groups (PCPS group and non-PCPS group). Percutaneous cardiopulmonary support was used in 60% of patients. Surgical embolectomy was performed for 85% of patients. Overall in-hospital and surgical mortalities were 35% and 29%, respectively. On the basis of the multivariate analysis, both cardiopulmonary resuscitation more than 15 minutes and absence of PCPS were significant risk factors affecting survival (p = 0.001 and 0.049, respectively). When the duration of cardiac arrest is short, surgical embolectomy is a viable option after cardiac arrest caused by pulmonary thromboembolism. Percutaneous cardiopulmonary support may be a useful tool for both stabilizing the patient and providing a bridge when deciding on further management options. PMID- 24625536 TI - A novel rotary pulsatile flow pump for cardiopulmonary bypass. AB - It has been suggested that pulsatile blood flow is superior to continuous flow (CF) in cardiopulmonary bypass (CPB). However, adoption of pulsatile flow (PF) technology has been limited because of practicality and complexity of creating a consistent physiologic pulse. A pediatric pulsatile rotary ventricular pump (PRVP) was designed to address this problem. We evaluated the PRVP in an animal model and determined its ability to generate PF during CPB. The PRVP (modified peristaltic pump, with tapering of the outlet of the pump chamber) was tested in four piglets (10-12 kg). Cannulation was performed with right atrial and aortic cannulae, and pressure sensors were inserted into the femoral arteries. Pressure curves were obtained at different levels of flow and compared with both the animal's baseline physiologic function and a CF roller pump. Pressure and flow waveforms demonstrated significant pulsatility in the PRVP setup compared with CF at all tested conditions. Measurement of hemodynamic energy data, including the percentage pulsatile energy and the surplus hydraulic energy, also revealed a significant increase in pulsatility with the PRVP (p < 0.001). The PRVP creates physiologically significant PF, similar to the pulsatility of a native heart, and has the potential to be easily implemented in pediatric CPB. PMID- 24625537 TI - Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants. AB - BACKGROUND: Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers. METHODS: A three-stage gene environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden. RESULTS: Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17-1.93]; in Sweden, OR = 1.35 [1.04-1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (P(corrected) < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19-2.56]; Sweden, OR = 1.62 [1.05-2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17 12.33]). CONCLUSIONS: We conducted a three-stage analysis using two population based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility. PMID- 24625538 TI - Education and cause-specific mortality: the mediating role of differential exposure and vulnerability to behavioral risk factors. AB - BACKGROUND: Differential exposures to behavioral risk factors have been shown to play an important mediating role on the education-mortality relation. However, little is known about the extent to which educational attainment interacts with health behavior, possibly through differential vulnerability. METHODS: In a cohort study of 76,294 participants 30 to 70 years of age, we estimated educational differences in cause-specific mortality from 1980 through 2009 and the mediating role of behavioral risk factors (smoking, alcohol intake, physical activity, and body mass index). With the use of marginal structural models and three-way effect decomposition, we simultaneously regarded the behavioral risk factors as intermediates and clarified the role of their interaction with educational exposure. RESULTS: Rate differences in mortality comparing participants with low to high education were 1,277 (95% confidence interval = 1,062 to 1,492) per 100,000 person-years for men and 746 (598 to 894) per 100,000 person-years for women. Smoking was the strongest mediator for cardiovascular disease, cancer, and respiratory disease mortality when conditioning on sex, age, and cohort. The proportion mediated through smoking was most pronounced in cancer mortality as a combination of the pure indirect effect, owing to differential exposure (men, 42% [25% to 75%]; women, 36% [17% to 74%]) and the mediated interactive effect, owing to differential vulnerability (men, 18% [2% to 35%], women, 26% [8% to 50%]). The mediating effects through body mass index, alcohol intake, or physical activity were partial and varied for the causes of deaths. CONCLUSION: Differential exposure and vulnerability should be addressed simultaneously, as these mechanisms are not mutually exclusive and may operate at the same time. PMID- 24625540 TI - Performance of a multi-axis ionization chamber array in a 1.5 T magnetic field. AB - At the UMC Utrecht a prototype MR-linac has been installed. The system consists of an 8 MV Elekta linear accelerator and a 1.5 T Philips MRI system. This paper investigates the performance of the IC PROFILERTM, a multi-axis ionization chamber array, in a 1.5 T magnetic field. The influence of the magnetic field on the IC PROFILERTM reproducibility, dose response linearity, pulse rate frequency dependence, power to electronics, panel orientation and ionization chamber shape were investigated. The linearity, reproducibility, pulse rate frequency dependence, panel orientation and ionization chamber shape are unaffected by the magnetic field. When the measurements results are normalized to the centre reference chamber, the measurements can commence unaltered. Orientation of the ionization chambers in the magnetic field is of importance, therefore caution must be taken when comparing or normalizing results from several different axes. IC PROFILERTM dose profiles were compared with film dose profiles obtained simultaneously in the MR-linac. Deviation between the film and the IC PROFILERTM data was caused by the noise in the film, indicating correct performance of the IC PROFILERTM in the transverse 1.5 T magnetic field. PMID- 24625539 TI - Prevalence of trachoma at sub-district level in ethiopia: determining when to stop mass azithromycin distribution. AB - BACKGROUND: To eliminate blinding trachoma, the World Health Organization emphasizes implementing the SAFE strategy, which includes annual mass drug administration (MDA) with azithromycin to the whole population of endemic districts. Prevalence surveys to assess impact at the district level are recommended after at least 3 years of intervention. The decision to stop MDA is based on a prevalence of trachomatous inflammation follicular (TF) among children aged 1-9 years below 5% at the sub-district level, as determined by an additional round of surveys limited within districts where TF prevalence is below 10%. We conducted impact surveys powered to estimate prevalence simultaneously at the sub district and district in two zones of Amhara, Ethiopia to determine whether MDA could be stopped. METHODOLOGY: Seventy-two separate population-based, sub district surveys were conducted in 25 districts. In each survey all residents from 10 randomly selected clusters were screened for clinical signs of trachoma. Data were weighted according to selection probabilities and adjusted for correlation due to clustering. PRINCIPAL FINDINGS: Overall, 89,735 residents were registered from 21,327 households of whom 72,452 people (80.7%) were examined. The prevalence of TF in children aged 1-9 years was below 5% in six sub-districts and two districts. Sub-district level prevalence of TF in children aged 1-9 years ranged from 0.9-76.9% and district-level from 0.9-67.0%. In only one district was the prevalence of trichiasis below 0.1%. CONCLUSIONS/SIGNIFICANCE: The experience from these zones in Ethiopia demonstrates that impact assessments designed to give a prevalence estimate of TF at sub-district level are possible, although the scale of the work was challenging. Given the assessed district-level prevalence of TF, sub-district-level surveys would have been warranted in only five districts. Interpretation was not as simple as stopping MDA in sub-districts below 5% given programmatic challenges of exempting sub-districts from a highly regarded program and the proximity of hyper-endemic sub-districts. PMID- 24625541 TI - Development and validation of a liquid chromatography-tandem mass spectrometry assay to quantify plasma busulfan. AB - BACKGROUND: Busulfan is an anti-leukemic, DNA alkylating agent that is used in conditioning regimens for patients undergoing hematopoietic stem cell transplantation. Because of the large intraindividual and interindividual variations seen in busulfan pharmacokinetics, therapeutic drug monitoring is necessary. Currently at the authors' institution, plasma busulfan in adults is measured by gas chromatography-mass spectrometry (GC-MS) at a reference laboratory, whereas pediatric specimens are sent to a different reference laboratory also for GC-MS analysis. As the result turnaround time is not optimal and this practice is of significant cost, a liquid chromatography-tandem mass spectrometry assay to quantify plasma busulfan was developed. METHODS: Protein precipitation with D8-busulfan (deuterated internal standard) in acetonitrile was carried out on 50 uL of heparinized plasma. Gradient elution with ammonium acetate, formic acid, water, and methanol at 0.6 mL/min had a 4-minute run time. Multiple reaction monitoring was employed using Q1/Q3 transitions of 264/151 and 264/55 for busulfan and 272/159 and 272/62 for D8-busulfan. RESULTS: Sample preparation took ~30 minutes for 6 patient samples. Six calibrators were used (0 2000 ng/mL) with 3 quality controls (means of 12, 356, and 1535 ng/mL). The limits of detection and quantitation were 1 and 6 ng/mL, respectively. Extraction recovery was ~77% and ion suppression ~5%. Within-run and between-run precision studies yielded <15% coefficient of variation at the limit of quantitation and <6% coefficient of variation through the rest of the linear range. Method comparisons between this assay and 2 GC-MS assays revealed mean biases of 7% and 1%. CONCLUSIONS: An accurate, rapid, and sensitive liquid chromatography-tandem mass spectrometry assay for quantification of plasma busulfan was developed. This assay reduces current specimen volume requirements, reduces result turnaround time for patients and clinicians, and additionally saves institutional funds. PMID- 24625542 TI - Investigating the use of hair to assess polybrominated diphenyl ether exposure retrospectively. AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are chemicals that are added to a variety of consumer products as flame-retardants and have been classified as emerging endocrine disruptors. They are persistent and have been detected in humans. Previous studies have suggested that hair is a suitable matrix for examining human exposure to organic pollutants such as PBDEs. It is believed that the majority of exposure is from our indoor environment. The aim of this study was to investigate the changes in PBDE patterns and levels along the hair shaft, by using segmental analysis to retrospectively assess long-term exposure over a 1 year period. METHODS: Questionnaires and hair samples from 65 women were collected at the Hospital for Sick Children, in Toronto, as part of a larger study. To assess long-term stability, hair samples were separated into 4- and 3 cm segments representing a 1-year period. Hair segments were analyzed for levels of 8 PBDE congeners, BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, BDE-183, and BDE-209 on gas chromatography-mass spectrometry (MS). A Friedman test was used to detect the differences in exposure among segments, and factors such as dietary habits, hair care routine, and site of residence were investigated to determine if they might affect hair levels. RESULTS: A significant increase (P < 0.0001) in total PBDEs was seen among segments moving from proximal (root end) to distal along the hair shaft (median in pg/mg): first (33.3), second (43.0), third (61.6), and fourth (75.5) segments. Significantly lower levels of PBDEs were observed in artificially colored hair samples (P = 0.032), and a significant increase in PBDE levels was observed in women who consumed meat on a daily basis as opposed to weekly consumption (P = 0.040). CONCLUSIONS: The increase in PBDEs along the hair shaft suggests that hair PBDEs may be influenced by diet and artificial coloring. More work is needed to validate the use of PBDEs in hair as a biomarker of long-term exposure. PMID- 24625543 TI - Suicidal autointegration of sleeping beauty and piggyBac transposons in eukaryotic cells. AB - Transposons are discrete segments of DNA that have the distinctive ability to move and replicate within genomes across the tree of life. 'Cut and paste' DNA transposition involves excision from a donor locus and reintegration into a new locus in the genome. We studied molecular events following the excision steps of two eukaryotic DNA transposons, Sleeping Beauty (SB) and piggyBac (PB) that are widely used for genome manipulation in vertebrate species. SB originates from fish and PB from insects; thus, by introducing these transposons to human cells we aimed to monitor the process of establishing a transposon-host relationship in a naive cellular environment. Similarly to retroviruses, neither SB nor PB is capable of self-avoidance because a significant portion of the excised transposons integrated back into its own genome in a suicidal process called autointegration. Barrier-to-autointegration factor (BANF1), a cellular co-factor of certain retroviruses, inhibited transposon autointegration, and was detected in higher-order protein complexes containing the SB transposase. Increasing size sensitized transposition for autointegration, consistent with elevated vulnerability of larger transposons. Both SB and PB were affected similarly by the size of the transposon in three different assays: excision, autointegration and productive transposition. Prior to reintegration, SB is completely separated from the donor molecule and followed an unbiased autointegration pattern, not associated with local hopping. Self-disruptive autointegration occurred at similar frequency for both transposons, while aberrant, pseudo-transposition events were more frequently observed for PB. PMID- 24625545 TI - Thermal neutron calibration channel at LNMRI/IRD. AB - The Brazilian Metrology Laboratory of Ionizing Radiations (LNMRI) standard thermal neutron flux facility was designed to provide uniform neutron fluence for calibration of small neutron detectors and individual dosemeters. This fluence is obtained by neutron moderation from four (241)Am-Be sources, each with 596 GBq, in a facility built with blocks of graphite/paraffin compound and high-purity carbon graphite. This study was carried out in two steps. In the first step, simulations using the MCNPX code on different geometric arrangements of moderator materials and neutron sources were performed. The quality of the resulting neutron fluence in terms of spectrum, cadmium ratio and gamma-neutron ratio was evaluated. In the second step, the system was assembled based on the results obtained on the simulations, and new measurements are being made. These measurements will validate the system, and other intercomparisons will ensure traceability to the International System of Units. PMID- 24625544 TI - Gene sequence variability of the three surface proteins of human respiratory syncytial virus (HRSV) in Texas. AB - Human respiratory syncytial virus (HRSV) has three surface glycoproteins: small hydrophobic (SH), attachment (G) and fusion (F), encoded by three consecutive genes (SH-G-F). A 270-nt fragment of the G gene is used to genotype HRSV isolates. This study genotyped and investigated the variability of the gene and amino acid sequences of the three surface proteins of HRSV strains collected from 1987 to 2005 from one center. Sixty original clinical isolates and 5 prototype strains were analyzed. Sequences containing SH, F and G genes were generated, and multiple alignments and phylogenetic trees were analyzed. Genetic variability by protein domains comparing virus genotypes was assessed. Complete sequences of the SH-G-F genes were obtained for all 65 samples: HRSV-A = 35; HRSV-B = 30. In group A strains, genotypes GA5 and GA2 were predominant. For HRSV-B strains, the genotype GB4 was predominant from 1992 to 1994 and only genotype BA viruses were detected in 2004-2005. Different genetic variability at nucleotide level was detected between the genes, with G gene being the most variable and the highest variability detected in the 270-nt G fragment that is frequently used to genotype the virus. High variability (>10%) was also detected in the signal peptide and transmembrane domains of the F gene of HRSV A strains. Variability among the HRSV strains resulting in non-synonymous changes was detected in hypervariable domains of G protein, the signal peptide of the F protein, a not previously defined domain in the F protein, and the antigenic site O in the pre-fusion F. Divergent trends were observed between HRSV -A and -B groups for some functional domains. A diverse population of HRSV -A and -B genotypes circulated in Houston during an 18 year period. We hypothesize that diverse sequence variation of the surface protein genes provide HRSV strains a survival advantage in a partially immune protected community. PMID- 24625547 TI - Fungi in the cystic fibrosis lung: bystanders or pathogens? AB - Improvement to the life expectancy of people with cystic fibrosis (PWCF) brings about novel challenges including the need for evaluation of the role of fungi in the cystic fibrosis (CF) lung. To determine if such organisms represent bystanders or pathogens affecting clinical outcomes we review the existing knowledge from a clinical, biochemical, inflammatory and immunological perspective. The prevalence and importance of fungi in the CF airway has likely been underestimated with the most frequently isolated filamentous fungi being Aspergillus fumigatus and Scedosporium apiospermum and the major yeast Candida albicans. Developing non-culture based microbiological methods for fungal detection has improved both our classification and understanding of their clinical consequences including localized, allergic and systemic infections. Cross-kingdom interaction between bacteria and fungi are discussed as is the role of biofilms further affecting clinical outcome. A combination of host and pathogen-derived factors determines if a particular fungus represents a commensal, colonizer or pathogen in the setting of CF. The underlying immune state, disease severity and treatment burden represent key host variables whilst fungal type, form, chronicity and virulence including the ability to evade immune recognition determines the pathogenic potential of a specific fungus at a particular point in time. Further research in this emerging field is warranted to fully elucidate the spectrum of disease conferred by the presence of fungi in the CF airway and the indications for therapeutic interventions. PMID- 24625546 TI - Deep repetitive transcranial magnetic stimulation with H-coil on lower limb motor function in chronic stroke: a pilot study. AB - OBJECTIVES: To assess the efficacy of high-frequency (20 Hz) brain stimulation on lower limb motor function in subjects with chronic (> 6 mo) subcortical stroke. DESIGN: Double-blind, placebo-controlled crossover study. SETTING: University hospital. PARTICIPANTS: Right-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study. INTERVENTIONS: Repetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period. MAIN OUTCOME MEASURES: Lower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up. RESULTS: Real rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation. CONCLUSIONS: These data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment. PMID- 24625548 TI - Sterol regulatory element-binding proteins are regulators of the rat thyroid peroxidase gene in thyroid cells. AB - Sterol regulatory element-binding proteins (SREBPs)-1c and -2, which were initially discovered as master transcriptional regulators of lipid biosynthesis and uptake, were recently identified as novel transcriptional regulators of the sodium-iodide symporter gene in the thyroid, which is essential for thyroid hormone synthesis. Based on this observation that SREBPs play a role for thyroid hormone synthesis, we hypothesized that another gene involved in thyroid hormone synthesis, the thyroid peroxidase (TPO) gene, is also a target of SREBP-1c and 2. Thyroid epithelial cells treated with 25-hydroxycholesterol, which is known to inhibit SREBP activation, had about 50% decreased mRNA levels of TPO. Similarly, the mRNA level of TPO was reduced by about 50% in response to siRNA mediated knockdown of both, SREBP-1 and SREBP-2. Reporter gene assays revealed that overexpression of active SREBP-1c and -2 causes a strong transcriptional activation of the rat TPO gene, which was localized to an approximately 80 bp region in the intron 1 of the rat TPO gene. In vitro- and in vivo-binding of both, SREBP-1c and SREBP-2, to this region in the rat TPO gene could be demonstrated using gel-shift assays and chromatin immunoprecipitation. Mutation analysis of the 80 bp region of rat TPO intron 1 revealed two isolated and two overlapping SREBP-binding elements from which one, the overlapping SRE+609/InvSRE+614, was shown to be functional in reporter gene assays. In connection with recent findings that the rat NIS gene is also a SREBP target gene in the thyroid, the present findings suggest that SREBPs may be possible novel targets for pharmacological modulation of thyroid hormone synthesis. PMID- 24625549 TI - The association of trauma center closures with increased inpatient mortality for injured patients. AB - BACKGROUND: Trauma centers are an effective but costly element of the US health care infrastructure. Some Level I and II trauma centers regularly incur financial losses when these high fixed costs are coupled with high burdens of uncompensated care for disproportionately young and uninsured trauma patients. As a result, they are at risk of reducing their services or closing. The impact of these closures on patient outcomes, however, has not been previously assessed. METHODS: We performed a retrospective study of all adult patient visits for injuries at Level I and II, nonfederal trauma centers in California between 1999 and 2009. Within this population, we compared the in-hospital mortality of patients whose drive time to their nearest trauma center increased as the result of a nearby closure with those whose drive time did not increase using a multivariate logit linked generalized linear model. Our sensitivity analysis tested whether this effect was limited to a 2-year period following a closure. RESULTS: The odds of inpatient mortality increased by 21% (odds ratio, 1.21; 95% confidence interval, 1.04-1.40) among trauma patients who experienced an increased drive time to their nearest trauma center as a result of a closure. The sensitivity analyses showed an even larger effect in the 2 years immediately following a closure, during which patients with increased drive time had 29% higher odds of inpatient death (odds ratio, 1.29; 95% confidence interval, 1.11-1.51). CONCLUSION: Our results show a strong association between closure of trauma centers in California and increased mortality for patients with injuries who have to travel further for definitive trauma care. These adverse impacts were intensified within 2 years of a closure. LEVEL OF EVIDENCE: Prognostic and epidemiologic, level III. PMID- 24625550 TI - Disseminated tuberculosis associated with ruxolitinib. PMID- 24625551 TI - p53 haploinsufficiency and functional abnormalities in multiple myeloma. AB - Hemizygous deletion of 17p13, which harbors the TP53 gene, has been identified in >10% of newly diagnosed multiple myeloma (MM) patients and is associated with poor prognosis. To date, there is no conclusive evidence that TP53 is the critical gene. Furthermore, the functional effect of TP53 haploinsufficiency is not well characterized. By utilizing human myeloma cell lines, we showed that TP53 hemizygous loss was associated with decreased basal expression level with a partially or severely inactivated p53 response upon genotoxic and non-genotoxic stress. The pathway deficiency was manifested as defective p53 transcriptional activities, together with significant resistance to apoptosis. In some cases with p53 WT/- and no p53 protein expression, the remaining allele was silenced by promoter hypermethylation. We also developed a p53 target gene signature to summarize the complexity of the p53 pathway abnormalities in MM and showed that it is strongly associated with genomic complexity and patient survival. In conclusion, this study identified TP53 as the critical gene located in 17p13, and revealed its haploinsufficiency properties in MM. Furthermore, we have elucidated that multiple mechanisms can deregulate the p53 functions and that this has important prognostic impact in MM. PMID- 24625552 TI - Immunophenotypic alterations of bone marrow myeloid cell compartments in multiple myeloma patients predict for myelodysplasia-associated cytogenetic alterations. PMID- 24625553 TI - Hydrophobic hydration of poly-N-isopropyl acrylamide: a matter of the mean energetic state of water. AB - The enthalpically favoured hydration of hydrophobic entities, termed hydrophobic hydration, impacts the phase behaviour of numerous amphiphiles in water. Here, we show experimental evidence that hydrophobic hydration is strongly determined by the mean energetics of the aqueous medium. We investigate the aggregation and collapse of an amphiphilic polymer, poly-N-isopropyl acrylamide (PNiPAM), in aqueous solutions containing small amounts of alcohol and find that the thermodynamic characteristics defining the phase transitions of PNiPAM evolve relative to the solvent composition at which the excess mixing enthalpy of the water/alcohol mixtures becomes minimal. Such correlation between solvent energetics and solution thermodynamics extends to other mixtures containing neutral organic solutes that are considered as kosmotropes to induce a strengthening of the hydrogen bonded water network. This denotes the energetics of water as a key parameter controlling the phase behaviour of PNiPAM and identifies the excess mixing enthalpy of water/kosmotrope mixtures as a gauge of the kosmotropic effect on hydrophobic assemblies. PMID- 24625554 TI - Efficacy of 5-nitroimidazoles for the treatment of giardiasis: a systematic review of randomized controlled trials. AB - BACKGROUND: Giardiasis is one of the most common causes of diarrheal disease worldwide and 5-nitroimidazoles (5-NI) are the most commonly prescribed drugs for the treatment of giardiasis. We evaluated the efficacy of 5-nitroimidazoles (5 NI) in the treatment of giardiasis in a systematic review of randomized controlled trials (RCTs). METHODOLOGY/PRINCIPAL FINDINGS: We conducted a comprehensive literature search in PubMed-Medline, Scopus, Web of Science and Cochrane Library for RCTs evaluating the efficacy of 5-NI vs. control (placebo or active treatment) on parasitological cure in patients with parasitologically demonstrated giardiasis. The search was performed in May 2013 with no language restriction by two authors independently. The efficacy outcome was parasitological cure, and harmful outcomes were abdominal pain, bitter or metallic taste, and headache. We included 30 RCTs (n = 3,930). There was a significant and slightly higher response rate with 5-NI in giardiasis treatment (RR 1.06, 95%CI 1.02-1.11, p = 0.005). There was high heterogeneity among studies (I2 = 72%). The response rates for metronidazole, tinidazole and secnidazole were similar (RR 1.05, 95%CI 1.01-1.09, p = 0.01; RR 1.32 95%CI 1.10-1.59, p = 0.003; and RR 1.18 95%CI 0.93-1.449, p = 0.18, respectively). On subgroup analyses, the response rates did not vary substantially and high heterogeneity persisted (I2 = 57%-80%). Harmful outcomes were uncommon, and 5-NIs were associated with lower risk of abdominal pain, and higher risk of both bitter or metallic taste and headache. CONCLUSIONS: Studies investigating the efficacy of 5-NI in giardiasis treatment are highly heterogeneous. 5-NIs have a slightly better efficacy and worse profile for mild harmful outcomes in the treatment of giardiasis in comparison to controls. Larger high quality RCTs are needed to further assess efficacy and safety profiles of 5-NI. PMID- 24625555 TI - The association between contrast dose and renal complications post PCI across the continuum of procedural estimated risk. AB - BACKGROUND: Prior studies have proposed to restrict the contrast volume (CV) to <3x calculated creatinine clearance (CCC), to prevent contrast induced nephropathy (CIN) post percutaneous coronary interventions (PCI). The predictive value of this algorithm for CIN and therefore the benefit of this approach in high risk patients has been questioned. The aim of our study was to assess the association between contrast dose and the occurrence of CIN in patients at varying predicted risks of CIN and baseline CCC following contemporary PCI. METHODS: Consecutive patients undergoing PCI between 2010-2012 were included. Baseline risk of CIN was calculated using a previously validated risk tool. High contrast dose was defined as CV/CCC >3. Likelihood ratio tests were used to evaluate whether the effect of a high contrast dose on the risk of CIN and nephropathy requiring dialysis (NRD) varied across the spectrum of baseline predicted risk. RESULTS: Of the 82,120 PCI included in our analysis, 25% were performed using a high contrast dose. Patients treated with a high compared with a low contrast dose were at increased risks of CIN and NRD, throughout the entire range of baseline predicted risk and CCC in our population. The effect size of a high contrast dose on risks of both outcomes varied significantly with baseline predicted CIN risk and CCC (CIN p = 0.004, NRD p<0.001 for adding interactions), and was largest for patients with predicted CIN risk <10% and pre-existing chronic kidney disease. CONCLUSIONS: The use of a high contrast dose is associated with increased risks of CIN and NRD across the continuum of baseline predicted risk and CCC. Efforts to reduce contrast dose may therefore be effective in preventing renal complications in all patients undergoing PCI. PMID- 24625557 TI - Delta9-THC exposure attenuates aversive effects and reveals appetitive effects of K2/'Spice' constituent JWH-018 in mice. AB - The emergence of high-efficacy synthetic cannabinoids as drugs of abuse in readily available K2/'Spice' smoking blends has exposed users to much more potent and effective substances than the phytocannabinoids present in cannabis. Increasing reports of adverse reactions, including dependence and withdrawal, are appearing in the clinical literature. Here we investigated whether the effects of one such synthetic cannabinoid, 1-pentyl-3-(1-naphthoyl)indole (JWH-018), would be altered by a prior history of Delta9-tetrahydrocannabinol (Delta9-THC) exposure, in assays of conditioned taste aversion and conditioned place preference. In the conditioned taste aversion procedure, JWH-018 induced marked and persistent aversive effects in mice with no previous cannabinoid history, but the magnitude and duration of these aversive effects were significantly blunted in mice previously treated with an ascending dose regimen of Delta9-THC. Similarly, in the conditioned place preference procedure, JWH-018 induced dose dependent aversive effects in mice with no previous drug history, but mice exposed to Delta9-THC before place conditioning showed reduced aversions at a high JWH-018 dose and apparent rewarding effects at a low dose of JWH-018. These findings suggest that a history of Delta9-THC exposure 'protects' against aversive effects and 'unmasks' appetitive effects of the high-efficacy synthetic cannabinoid JWH-018 in mice. This pattern of results implies that cannabinoid naive individuals administering K2/'Spice' products for the first-time may be at an increased risk for adverse reactions, whereas those with a history of marijuana use may be particularly sensitive to the reinforcing effects of high efficacy cannabinoids present in these commercial smoking blends. PMID- 24625556 TI - Deregulation of COMMD1 is associated with poor prognosis in diffuse large B-cell lymphoma. AB - BACKGROUND: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. METHODS: We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. RESULTS: We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. CONCLUSION: COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01502982. PMID- 24625558 TI - Candida albicans uses the surface protein Gpm1 to attach to human endothelial cells and to keratinocytes via the adhesive protein vitronectin. AB - Candida albicans is a major cause of invasive fungal infections worldwide. Upon infection and when in contact with human plasma as well as body fluids the fungus is challenged by the activated complement system a central part of the human innate immune response. C. albicans controls and evades host complement attack by binding several human complement regulators like Factor H, Factor H-like protein 1 and C4BP to the surface. Gpm1 (Phosphoglycerate mutase 1) is one fungal Factor H/FHL1 -binding protein. As Gpm1 is surface exposed, we asked whether Gpm1 also contributes to host cell attachment. Here, we show by flow cytometry and by laser scanning microscopy that candida Gpm1 binds to human umbilical vein endothelial cells (HUVEC) to keratinocytes (HaCaT), and also to monocytic U937 cells. Wild type candida did bind, but the candida gpm1Delta/Delta knock-out mutant did not bind to these human cells. In addition Gpm1 when attached to latex beads also conferred attachment to human endothelial cells. When analyzing Gpm1-binding to a panel of extracellular matrix proteins, the human glycoprotein vitronectin was identified as a new Gpm1 ligand. Vitronectin is a component of the extracellular matrix and also a regulator of the terminal complement pathway. Vitronectin is present on the surface of HUVEC and keratinocytes and acts as a surface ligand for fungal Gpm1. Gpm1 and vitronectin colocalize on the surface of HUVEC and HaCaT as revealed by laser scanning microscopy. The Gpm1 vitronectin interaction is inhibited by heparin and the interaction is also ionic strength dependent. Taken together, Gpm1 the candida surface protein binds to vitronectin and mediates fungal adhesion to human endothelial cells. Thus fungal Gpm1 and human vitronectin represent a new set of proteins that are relevant for fungal attachment to human cells interaction. Blockade of the Gpm1 vitronectin interaction might provide a new target for therapy. PMID- 24625560 TI - Measurement of charged particle yields from PMMA irradiated by a 220 MeV/u (12)C beam. AB - The radiation used in hadrontherapy treatments interacts with the patient body producing secondary particles, either neutral or charged, that can be used for dose and Bragg peak monitoring and to provide a fast feedback on the treatment plans. Recent results obtained from the authors on simplified setups (mono energetic primary beams interacting with homogeneous tissue-like target) have already indicated the correlation that exists between the flux of these secondaries coming from the target (e.g. protons and photons) and the position of the primary beam Bragg peak. In this paper, the measurements of charged particle fluxes produced by the interaction of a 220 MeV/u carbon ion beam at GSI, Darmstadt, with a polymethyl methacrylate target are reported. The emission region of protons (p), deuterons (d) and tritons (t) has been characterized using a drift chamber while the particle time-of-flight, used to compute the kinetic energy spectra, was measured with a LYSO scintillator. The energy released in the LYSO crystal was used for particle identification purposes. The measurements were repeated with the setup at 60 degrees and 90 degrees with respect to the primary beam direction. The accuracy on the fragments emission profile reconstruction and its relationship with the Bragg peak position have been studied. Based on the acquired experimental evidence, a method to monitor the dose profile and the position of the Bragg peak inside the target is proposed. PMID- 24625559 TI - Dwarf Tiller1, a Wuschel-related homeobox transcription factor, is required for tiller growth in rice. AB - Unlike many wild grasses, domesticated rice cultivars have uniform culm height and panicle size among tillers and the main shoot, which is an important trait for grain yield. However, the genetic basis of this trait remains unknown. Here, we report that Dwarf Tiller1 (DWT1) controls the developmental uniformity of the main shoot and tillers in rice (Oryza sativa). Most dwt1 mutant plants develop main shoots with normal height and larger panicles, but dwarf tillers bearing smaller panicles compared with those of the wild type. In addition, dwt1 tillers have shorter internodes with fewer and un-elongated cells compared with the wild type, indicating that DWT1 affects cell division and cell elongation. Map-based cloning revealed that DWT1 encodes a Wuschel-related homeobox (WOX) transcription factor homologous to the Arabidopsis WOX8 and WOX9. The DWT1 gene is highly expressed in young panicles, but undetectable in the internodes, suggesting that DWT1 expression is spatially or temporally separated from its effect on the internode growth. Transcriptomic analysis revealed altered expression of genes involved in cell division and cell elongation, cytokinin/gibberellin homeostasis and signaling in dwt1 shorter internodes. Moreover, the non-elongating internodes of dwt1 are insensitive to exogenous gibberellin (GA) treatment, and some of the slender rice1 (slr1) dwt1 double mutant exhibits defective internodes similar to the dwt1 single mutant, suggesting that the DWT1 activity in the internode elongation is directly or indirectly associated with GA signaling. This study reveals a genetic pathway synchronizing the development of tillers and the main shoot, and a new function of WOX genes in balancing branch growth in rice. PMID- 24625561 TI - Calprotectin and cardiovascular events. A narrative review. AB - OBJECTIVES: Calprotectin, also known as S100A8/A9 complex, is currently considered as a valid biomarker for diagnosis, follow-up and therapeutic monitoring of inflammatory bowel diseases. The attractive evidence that this protein may be actively produced and released by leukocytes (especially neutrophils) and by nonmyeloid cardiovascular cell types has paved the way to a series of studies that have assessed its biology in the setting of cardiovascular disease. The aim of this review was thus to investigate the diagnostic and prognostic utility of this biomarker in cardiovascular disease and in particular in myocardial infarction. DESIGN AND METHODS: We performed a systematic, electronic search on Medline, Scosus and Web of Science, using the keywords "calprotectin" or "S100A8/A9" or "MRP-8/14" and "myocardial infarction" or "acute coronary syndrome" or "cardiovascular disease", from inception to June 2013. The bibliographic references of articles published in English, French and Italian were reviewed for additional relevant studies. RESULTS: The data of the current scientific literature seems to confirm that calprotectin is actively secreted in the setting of cardiac ischemia and its concentration is significantly associated with the prognosis. Nevertheless, the evidence provided by recent articles that have assessed its performance for diagnosing acute myocardial infarction, either alone or in combination with troponin, supports the hypothesis that this biomarker may be of limited value for enabling a better or faster diagnosis of cardiac ischemia. Even its putative role as an independent prognostic biomarker of cardiovascular morbidity and death is still largely uncertain. CONCLUSIONS: It can hence be concluded that calprotectin does not currently meet the requirements for efficient diagnosis and prognostication of patients with cardiovascular disease. PMID- 24625562 TI - Prognostic role of isolated left ventricular diverticuli detected by cardiovascular magnetic resonance. AB - BACKGROUND: Isolated left ventricular diverticulum, a rare cardiac malformation, can be asymptomatic or associated with systemic embolization, ventricular arrhythmias, or sudden death. MRI allows for the detection of diverticuli and the distinction between fibrous and muscular types using the delayed enhancement technique. AIM: To evaluate the prevalence of left ventricular diverticuli in nonselected consecutive patients who had undergone MRI. METHODS: In a total of 3273 consecutive patients who had undergone cardiac magnetic resonance from January 2001 to December 2005, isolated ventricular diverticuli were found in 25 patients (0.76%), with no apparent cardiac disease. A delayed enhancement technique was used to distinguish fibrous and muscular types. The prevalence of complications was evaluated with a follow-up of 52 +/- 8 months. RESULTS: The site of the left ventricular diverticuli was the septum in 10 (37%) cases, inferior wall in 6 (22%) cases, lateral wall in 4 (15%) cases, and apical in 7 (26%) cases. In two cases, multiple diverticuli were found. In delayed enhancement images, a partial or total fibrous diverticulum was found in 6 (24%) patients. At follow-up, clinical complications were recorded in 6 (24%) patients; 2 (8%) patients had arrhythmic complications and 4 (12%) patients had embolic complications of presumed cardiac origin. In addition, two patients (8%) had nonsustained ventricular tachycardia diagnosed using 24-h ECG Holter monitoring. Fibrous type diverticuli were associated with a higher incidence of arrhythmic complications than the muscular type. CONCLUSION: The prevalence of isolated ventricular diverticuli detected by MRI is higher than that previously reported with other imaging techniques. Fibrous diverticuli are associated with a higher incidence of arrhythmic complications. PMID- 24625563 TI - Constrictive pericarditis: an underdiagnosed cause of chest pain. AB - Constrictive pericarditis is an underdiagnosed condition characterized by a rigid pericardium leading to restriction in cardiac filling with consequent fluid overload and decreased cardiac output. The authors provide classic echocardiographic and cardiac catheterization images which, in addition to good clinical acumen, assist in making the correct diagnosis. PMID- 24625564 TI - Prevalence of stroke and the need for thromboprophylaxis in young patients with atrial fibrillation: a cohort study. AB - Atrial fibrillation is the most common cardiac arrhythmia, and age is a well established independent risk factor for stroke in these patients. Whereas high risk patients clearly benefit from anticoagulation to prevent stroke, less is known about how to treat low-risk patients. Despite the recent guidelines and studies demonstrating no benefit and excess bleeding risk with aspirin, many low risk patients still receive this medication. Our objective was to determine the stroke rate in young patients with atrial fibrillation, a group of previously unstudied and predominantly low-risk patients. We hypothesized that the event rate would be so low as to preclude benefit from antithrombotic medications. A retrospective chart review identified patients with atrial fibrillation between the age of 18 and 35. Exclusion criteria included no ECG documentation of atrial fibrillation, anticoagulation, except around the time of cardioversion, and surgical valve disease. The primary outcome was stroke during the period of observation. The final cohort included 99 patients, mean age 27.6 years, followed for a mean of 4.3 years. Mean CHADS2 and CHA2DS2-VASc scores were 0.26 and 0.4, respectively. A total of 42.4% were taking aspirin for over 50% of the time. There was one event identified, a transient ischemic attack in a man not on aspirin with CHADS2 and CHADS2-VASc scores of 1, resulting in event rates of 0.234 per 100 patient-years overall or 0.392 among those not on aspirin. Patients with nonvalvular atrial fibrillation under age 35 have an exceedingly low stroke risk. We assert that aspirin may be unnecessary for most patients in this population, especially those with a CHA2DS2-VASc score of 0. PMID- 24625565 TI - Aortic valve replacement in systemic sclerosis. AB - Systemic sclerosis (scleroderma) is a chronic systemic autoimmune disease of the connective tissue, which can involve the cardiac valves, the mitral valve being more frequently affected, although involvement of the aortic valve has been rarely described. We report a patient with aortic stenosis and systemic sclerosis who required aortic valve replacement. Awareness of this rare association may help to provide adequate management of such patients and prevent complications related to the underlying disease. PMID- 24625566 TI - Homocysteine and risk of periprocedural myocardial infarction in patients undergoing coronary stenting. AB - BACKGROUND: Despite improvements in pharmacological and mechanical devices, the risk of periprocedural myocardial infarction (PMI) is still high, particularly in prothrombotic conditions. Hyperhomocysteinemia has been associated with enhanced platelet function, impaired endothelial function and prothrombotic status, thus increasing the risk of cardiovascular events. No study has, so far, investigated the relationship between homocysteine levels and the risk of periprocedural MI in patients undergoing percutaneous coronary intervention (PCI), and this is therefore the aim of the current study. METHODS: In 1150 patients undergoing PCI, homocysteinemia was assessed at admission. Cardiac biomarkers were measured at intervals from 8 to 48 h after PCI. Periprocedural myonecrosis was defined by a troponin I increase to three times the upper limit of normal (ULN) or by 50% if elevated at the time of the procedure. PMI was defined as a CK-MB increase to three times the ULN or of 50% if elevated at the time of the procedure. RESULTS: We grouped patients according to tertile values of homocysteine. Higher homocysteine levels were associated with older age (P < 0.001), male sex (P = 0.02), arterial hypertension (P = 0.007), diabetes (P = 0.04), renal failure (P < 0.001), higher creatinine levels (P = 0.01), previous MI (P = 0.02), previous PCI (P = 0.04) and previous cerebrovascular accidents (P = 0.01). Homocysteine was associated with lower ejection fraction (P < 0.001), treatment with angiotensin receptor blockers (P < 0.001), nitrates (P = 0.008) and diuretics (P < 0.001) and acetylsalicylic acid (P = 0.01). Homocysteine levels were directly related with the extent of coronary disease (P = 0.04) and coronary calcifications (P < 0.001) but inversely with type C lesions (P = 0.001), TIMI 3 flow pre-PCI (P = 0.02), stenosis severity (P = 0.01) and thrombus (P = 0.004). In addition, they are associated with higher rates of balloon predilatation (P = 0.02), lower use of thrombectomy (P = 0.01) and periprocedural administration of GPIIbIIIa inhibitors (P = 0.02). Ageing, male sex, diabetes, renal failure, creatinine levels, diuretics use, coronary calcifications and type C lesions were independently related to homocysteine. Homocysteine did not affect the risk of PMI [adjusted odds ratio (OR) 1.14 (0.91-1.42), P = 0.26], or periprocedural myonecrosis [adjusted OR 1.17 (0.98-1.39), P = 0.08]. Similar results were found after propensity score adjustment [adjusted OR 1.19 (0.95-1.48), P = 0.14 for PMI and adjusted OR 1.18 (0.99-1.4), P = 0.07 for myonecrosis] and at subgroup analysis in higher risk subsets of patients. CONCLUSION: In patients undergoing PCI, the risk of PMI is not influenced by hyperhomocysteinemia. PMID- 24625567 TI - Quality end-of-life care for dementia: What have family carers told us so far? A narrative synthesis. AB - BACKGROUND: People with dementia do not always receive good quality end-of-life care, with undertreated pain, aggressive medical interventions and limited access to hospice care being common. Family carers often provide the majority of informal care for people with dementia, therefore may be best placed to comment on quality of care. AIM: We explored what quality end-of-life care for dementia is from the perspective of family carers. DESIGN: A review of qualitative evidence taking a systematic approach using a narrative synthesis with tabulation, textual description of studies and thematic analysis as tools, following the guidelines from the Economic and Social Research Council. DATA SOURCES: Keywords and subject headings were searched in MEDLINE, EMBASE, CINAHL, SCIE and PsycINFO for studies from 1990 in April 2012 and updated in May 2013. Reference lists were checked and citation searches undertaken. RESULTS: Eight studies were included. There was an overarching theme of 'A family's belief of death and their choice of treatment'. Three further themes were then identified to explain family carers' beliefs: the relationship with professionals as a core component of care quality; emotional and commitment pressures of caring and finally, family carers' ability to think about death and dying. CONCLUSION: It is difficult to define what constitutes high-quality end-of-life care for people with dementia from the perspective of family carers. Their views expressed in the literature appear to demonstrate more variation of preference of care and treatment and their uncertainty of this. PMID- 24625568 TI - Cortisol release in response to UVB exposure in Xiphophorus fish. AB - Xiphophorus fishes are comprised of 26 known species. Interspecies hybridization between select species has been utilized to produce experimental models to study melanoma development. Xiphophorus melanoma induction protocols utilize ultraviolet light (UVB) to induce DNA damage and associated downstream tumorigenesis. However, the impact of induced stress caused by the UVB treatment of the experimental animals undergoing tumor induction protocols has not been assessed. Stress is an adaptive physiological response to excessive or unpredictable environmental stimuli. The stress response in fishes may be measured by an assay of cortisol released into the water. Here, we present results from investigations of stress response during an experimental treatment and UVB exposure in Xiphophorus maculatus Jp 163 B, Xiphophorus couchianus, and F1 interspecies hybrids produced from the mating X. maculatus Jp 163 B*X. couchianus. Overall, cortisol release rates for males and females after UVB exposure showed no statistical differences. At lower UVB doses (8 and 16kJ/m(2)), X. couchianus exhibited 2 fold higher levels of DNA damage then either X. maculatus or the F1 hybrid. However, based on the cortisol release rates, none of the fish types tested induced a primary stress response at the UVB lower doses (8 and 16kJ/m(2)). In contrast, at a very high UVB dose (32kJ/m(2)) both X. maculatus and the F1 hybrid showed a 5 fold increase in the cortisol release rate. To determine the effect of pigmentation on UVB induced stress, wild type and albino Xiphophorus hellerii were exposed to UVB (32kJ/m(2)). Albino X. hellerii exhibited 3.7 fold increase in the cortisol release while wild type X. hellerii did not exhibit a significant cortisol response to UVB. Overall, the data suggest the rather low UVB doses often employed in tumor induction protocols do not induce a primary stress response in Xiphophorus fishes. PMID- 24625569 TI - Survival of free and encapsulated human and rat islet xenografts transplanted into the mouse bone marrow. AB - Bone marrow was recently proposed as an alternative and potentially immune privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation. PMID- 24625570 TI - Cell-penetrating peptide (CPP)-conjugated proteins is an efficient tool for manipulation of human mesenchymal stromal cells. AB - Delivery of proteins has been regarded as the safest and most useful application in therapeutic application of stem cells, because proteins can regulate gene expression transiently without any genomic alteration. However, it is difficult to accurately measure efficiency or quantity of intracellular protein uptake. Here, we performed a comparison study of cell-penetrating peptide (CPP) conjugated protein delivery system using seven arginine and Streptolysin O (SLO) mediated system. To compare CPP- and SLO-mediated protein delivery systems, we used GFP and ESRRB protein, which is known to regulate pluripotency-related genes, for delivery into human bone marrow stromal cells (hBMSCs) and human testicular stromal cells (hTSCs). We found that CPP-conjugated protein delivery was more efficient, lower cytotoxicity, and higher biological activity than SLO mediated protein delivery system. These results suggest that delivery of CPP conjugated proteins is an efficient tool for introducing biologically active proteins into cells and may have important implications in clinical cell-based therapy. PMID- 24625571 TI - Heart rate variability reflects the natural history of physiological development in healthy children and is not associated with quality of life. AB - BACKGROUND: Quality of life (QoL), being the sum expression of diverse influencing factors, is not easy to determine. A clinically relevant option would be to identify and measure quality of life on the basis of physiological parameters which correlate plausibly and statistically with psychometrically measured QoL. Analysis of heart rate variability (HRV) offers readily measurable physiological parameters which could be of use here. A correlation of HRV with both course of disease and QoL has been reported in patients with chronic illness. Various psychometric instruments have been developed for use in paediatric oncology. The aim of this study was to obtain data on HRV and QoL and their correlations, initially in healthy children. METHODS: Holter ECG and quality of life were examined in 160 children and adolescents (72 male) aged between 8 and 18 years. QoL was determined with the established questionnaire PEDQoL. Standard parameters of HRV from the frequency domain were calculated and correlated with QoL domains using Spearman (nonparametric) correlation analysis. RESULTS: Minor but significant associations were revealed only with regard to the PEDQoL domain "autonomy" on the one hand and heart rate and HRV (e.g. MRR, MRRn, MRRd, HRV_ULF, SDNN) parameters which evidently reflect distinct physiological functions on the other. CONCLUSIONS: In healthy children and adolescents we have a first indication that there is a correlation between parameters of HRV and QoL. However, to a greater extent, HRV reflects associated physiological processes of the autonomic nervous system. A higher correlation is more likely to be found in chronically ill children. PMID- 24625572 TI - Molecular evidence of demographic expansion of the chagas disease vector Triatoma dimidiata (Hemiptera, Reduviidae, Triatominae) in Colombia. AB - BACKGROUND: Triatoma dimidiata is one of the most significant vectors of Chagas disease in Central America and Colombia, and, as in most species, its pattern of genetic variation within and among populations is strongly affected by its phylogeographic history. A putative origin from Central America has been proposed for Colombian populations, and high genetic differentiation among three biographically different population groups has recently been evidenced. Analyses based on putatively neutral markers provide data from which past events, such as population expansions and colonization, can be inferred. We analyzed the genealogies of the nicotinamide adenine dinucleotide dehydrogenase 4 (ND4) and the cytochrome oxidase subunit 1-mitochondrial genes, as well as partial nuclear ITS-2 DNA sequences obtained across most of the eco-geographical range in Colombia, to assess the population structure and demographic factors that may explain the geographical distribution of T. dimidiata in this country. RESULTS: The population structure results support a significant association between genetic divergence and the eco-geographical location of population groups, suggesting that clear signals of demographic expansion can explain the geographical distribution of haplotypes of population groups. Additionally, empirical date estimation of the event suggests that the population's expansion can be placed after the emergence of the Panama Isthmus, and that it was possibly followed by a population fragmentation process, perhaps resulting from local adaptation accomplished by orographic factors such as geographical isolation. CONCLUSION: Inferences about the historical population processes in Colombian T. dimidiata populations are generally in accordance with population expansions that may have been accomplished by two important biotic and orographic events such as the Great American Interchange and the uplift of the eastern range of the Andes mountains in central Colombia. PMID- 24625573 TI - Electrophysiological characteristics of six mutations in hClC-1 of Korean patients with myotonia congenita. AB - ClC-1 is a member of a large family of voltage-gated chloride channels, abundantly expressed in human skeletal muscle. Mutations in ClC-1 are associated with myotonia congenita (MC) and result in loss of regulation of membrane excitability in skeletal muscle. We studied the electrophysiological characteristics of six mutants found among Korean MC patients, using patch clamp methods in HEK293 cells. Here, we found that the autosomal dominant mutants S189C and P480S displayed reduced chloride conductances compared to WT. Autosomal recessive mutant M128I did not show a typical rapid deactivation of Cl(-) currents. While sporadic mutant G523D displayed sustained activation of Cl(-) currents in the whole cell traces, the other sporadic mutants, M373L and M609K, demonstrated rapid deactivations. V1/2 of these mutants was shifted to more depolarizing potentials. In order to identify potential effects on gating processes, slow and fast gating was analyzed for each mutant. We show that slow gating of the mutants tends to be shifted toward more positive potentials in comparison to WT. Collectively, these six mutants found among Korean patients demonstrated modifications of channel gating behaviors and reduced chloride conductances that likely contribute to the physiologic changes of MC. PMID- 24625574 TI - Tat-fused recombinant human SAG prevents dopaminergic neurodegeneration in a MPTP induced Parkinson's disease model. AB - Excessive reactive oxygen species (ROS) generated from abnormal cellular process lead to various human diseases such as inflammation, ischemia, and Parkinson's disease (PD). Sensitive to apoptosis gene (SAG), a RING-FINGER protein, has anti apoptotic activity and anti-oxidant activity. In this study, we investigate whether Tat-SAG, fused with a Tat domain, could protect SH-SY5Y neuroblastoma cells against 1-methyl-4-phenylpyridinium (MPP(+)) and dopaminergic (DA) neurons in the substantia nigra (SN) against 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP) toxicity. Western blot and immunohistochemical analysis showed that, unlike SAG, Tat-SAG transduced efficiently into SH-SY5Y cells and into the brain, respectively. Tat-SAG remarkably suppressed ROS generation, DNA damage, and the progression of apoptosis, caused by MPP(+) in SH-SY5Y cells. Also, immunohistochemical data using a tyrosine hydroxylase antibody and cresyl violet staining demonstrated that Tat-SAG obviously protected DA neurons in the SN against MPTP toxicity in a PD mouse model. Tat-SAG-treated mice showed significant enhanced motor activities, compared to SAG- or Tat-treated mice. Therefore, our results suggest that Tat-SAG has potential as a therapeutic agent against ROS-related diseases such as PD. PMID- 24625575 TI - The non-canonical effect of N-acetyl-D-glucosamine kinase on the formation of neuronal dendrites. AB - N-acetylglucosamine kinase (GlcNAc kinase or NAGK; EC 2.7.1.59) is a N acetylhexosamine kinase that belong to the sugar kinase/heat shock protein 70/actin superfamily. In this study, we investigated both the expression and function of NAGK in neurons. Immunohistochemistry of rat brain sections showed that NAGK was expressed at high levels in neurons but at low levels in astrocytes. Immunocytochemistry of rat hippocampal dissociate cultures confirmed these findings and showed that NAGK was also expressed at low levels in oligodendrocytes. Furthermore, several NAGK clusters were observed in the nucleoplasm of both neuron and glia. The overexpression of EGFP- or RFP (DsRed2) tagged NAGK in rat hippocampal neurons (DIV 5-9) increased the complexity of dendritic architecture by increasing the numbers of primary dendrites and dendritic branches. In contrast, knockdown of NAGK by shRNA resulted in dendrite degeneration, and this was prevented by the co-expression of RFP-tagged NAGK. These results suggest that the upregulation of dendritic complexity is a non canonical function of NAGK. PMID- 24625577 TI - Fungal toenail infections. AB - INTRODUCTION: Fungal infections are reported to cause 23% of foot diseases and 50% of nail conditions in people seen by dermatologists, but are less common in the general population, affecting 3% to 12% of people. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral treatments for fungal toenail infections in adults? What are the effects of topical treatments for fungal toenail infections in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 13 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amorolfine, butenafine, ciclopirox, fluconazole, itraconazole, terbinafine, tioconazole, and topical ketoconazole. PMID- 24625576 TI - The role of macrophage polarization in infectious and inflammatory diseases. AB - Macrophages, found in circulating blood as well as integrated into several tissues and organs throughout the body, represent an important first line of defense against disease and a necessary component of healthy tissue homeostasis. Additionally, macrophages that arise from the differentiation of monocytes recruited from the blood to inflamed tissues play a central role in regulating local inflammation. Studies of macrophage activation in the last decade or so have revealed that these cells adopt a staggering range of phenotypes that are finely tuned responses to a variety of different stimuli, and that the resulting subsets of activated macrophages play critical roles in both progression and resolution of disease. This review summarizes the current understanding of the contributions of differentially polarized macrophages to various infectious and inflammatory diseases and the ongoing effort to develop novel therapies that target this key aspect of macrophage biology. PMID- 24625578 TI - The analysis of factors associated with progression of isolated terminal ileal lesions. AB - OBJECTIVE: To assess the factors associated with the progression of isolated terminal ileal lesions (ITILs) at colonoscopy in Chinese patients. METHODS: Patients diagnosed with ITILs were enrolled. The ileoscopy was performed by two experienced gastroenterologists every 52 weeks. A logistic regression analysis was used to elucidate the factors associated with Crohn's disease (CD) and mucosal healing. A log rank test was used to assess the differences of the cumulative proportion of CD and mucosal healing in different groups at different times. RESULTS: (1) A total of 34 patients were included and no patient had taken nonsteroidal anti-inflammatory drug in the last 6 months; eight (23.5%) patients had a clinical diagnosis of CD, 14 (41.2%) patients achieved mucosal healing, and 12 (35.3%) patients showed no significant changes in the lesions at last follow up. (2) The logistic regression analysis showed that only abdominal pain was a factor in the ITIL disease outcomes. (3) The cumulative proportion of CD in the abdominal pain group after 3 years was statistically higher than that in the non abdominal pain group (42.7% vs. 6.2%, chi2 = 10.129, P = 0.001). However, the cumulative proportion of mucosal healing in the non-abdominal pain group was statistically higher than that in the abdominal pain group (73.3% vs. 5.6%, chi2 = 5.225, P = 0.022). (4) The numbers of lesions observed on the initial colonoscopy exams and the initial histologic findings were not related to the ITIL disease outcomes. CONCLUSIONS: Clinical symptoms may be related to ITIL disease outcomes. Patients with abdominal pain had a high likelihood of CD, whereas those without abdominal pain had a high likelihood of mucosal healing. PMID- 24625579 TI - Association between 9p21 genomic markers and ischemic stroke risk: evidence based on 21 studies. AB - Epidemiological studies indicate a genetic contribution to ischemic stroke risk, but specific genetic variants remain unknown. Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21 (rs10757278 and proxy SNPs). Given that stroke is a common complication after myocardial infarction, several validation studies have been conducted among various ethnic populations to investigate if the same loci was associated with ischemic stroke (IS), but the results have been inconsistent. To investigate this inconsistency and derive a more precise estimation of the relationship, a meta-analysis of 34,128 cases and 153,428 controls from 21 studies was performed. Potential sources of heterogeneity including ethnicity, sample size, control source and ischemic stroke subtypes were also assessed. Overall, the summary odds ratio of IS was 1.11 (95% CI: 1.07-1.15, P<10(-5)) for rs10757278. In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians (3188 cases and 4503 controls; OR = 1.14, 95% CI: 1.07-1.21, P<10(-5)) and Caucasians (30505 cases and 145153controls; OR = 1.08, 95% CI: 1.04-1.12, P<10(-5)) for the polymorphism; while no significant associations were found among African Americans (435 cases and 3772 controls; OR = 0.97, 95% CI: 0.63-1.51, P = 0.90) in all genetic models. In the subgroup analyses by IS subtypes, significant association was detected only in large vessel stroke group, while no significant associations among small vessel or cardioembolic stroke. When stratified by sample size, and control source, significantly increased risks were found for the polymorphism in all genetic models. This meta-analysis provides accurate and comprehensive estimates of the association of genetic variant at chromosome 9p21 and IS, but these associations vary in different ethnic populations. PMID- 24625580 TI - DNA dynamics during early double-strand break processing revealed by non intrusive imaging of living cells. AB - Chromosome breakage is a major threat to genome integrity. The most accurate way to repair DNA double strand breaks (DSB) is homologous recombination (HR) with an intact copy of the broken locus. Mobility of the broken DNA has been seen to increase during the search for a donor copy. Observing chromosome dynamics during the earlier steps of HR, mainly the resection from DSB ends that generates recombinogenic single strands, requires a visualization system that does not interfere with the process, and is small relative to the few kilobases of DNA that undergo processing. Current visualization tools, based on binding of fluorescent repressor proteins to arrays of specific binding sites, have the major drawback that highly-repeated DNA and lengthy stretches of strongly bound protein can obstruct chromatin function. We have developed a new, non-intrusive method which uses protein oligomerization rather than operator multiplicity to form visible foci. By applying it to HO cleavage of the MAT locus on Saccharomyces cerevisiae chromosome III, we provide the first real-time analysis of resection in single living cells. Monitoring the dynamics of a chromatin locus next to a DSB revealed transient confinement of the damaged chromatin region during the very early steps of resection, consistent with the need to keep DNA ends in contact. Resection in a yku70 mutant began ~ 10 min earlier than in wild type, defining this as the period of commitment to homology-dependent repair. Beyond the insights into the dynamics and mechanism of resection, our new DNA labelling and -targeting method will be widely applicable to fine-scale analysis of genome organization, dynamics and function in normal and pathological contexts. PMID- 24625582 TI - Intravitreal thrombin activity is elevated in retinal vein occlusion. AB - To evaluate whether intravitreal thrombin activity is elevated in eyes with branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) in comparison to healthy controls. Prospective clinical case series of 19 patients with BRVO, 13 patients suffering from CRVO and nine participants serving as controls. Vitreous taps were extracted from the central vitreous body, 200 MUl frozen/thawed sample was immediately stabilized with 200 MUl 5% human albumin, and 200 MUl mixture thereof was stabilized with 200 MUl 2.5 mol/l arginine, pH 8.6. Thrombin activity was determined chromogenically. Intravitreal levels of vascular endothelial growth factor (VEGF) as a marker for blood-retina barrier (BRB) breakdown were measured by a commercial chemiluminescent enzyme immuno assay (R&D). Intravitreal thrombin activity and VEGF levels were 1.6 +/- 1.2 mIU/ml (mean value +/- SD; range: 0.2-4.2 mIU/ml) and 554 +/- 568 pg/ml (range: 20-2005 pg/ml) in BRVO-affected eyes, 2.6 +/- 1.2 mIU/ml (range: 0.8-5.2 mIU/ml) and 1332 +/- 1350 pg/ml (range: 58-3943 pg/ml) in eyes suffering from CRVO as well as 0.8 +/- 0.8 mIU/ml (range: 0.2-2.7 mIU/ml) and 115 +/- 120 pg/ml (range: 32-431 pg/ml) in controls. There are significant differences of intravitreal thrombin activity and intravitreal VEGF levels between eyes with BRVO, CRVO, and controls (P = 0.007 and P = 0.003, Kruskal-Wallis test). Intravitreal thrombin activity is significantly correlated with intravitreal VEGF levels (r = 0656; P < 0.001, Pearson correlation). Intravitreal thrombin activity might serve as a new marker for BRB breakdown or macular fibrin deposition in ophthalmology. Significant differences of intravitreal thrombin activity between eyes with BRVO, CRVO, and healthy controls might offer new therapeutic strategies for RVO affected eyes. The effect of oral and intravitrealy injected direct thrombin inhibitors needs to be evaluated in further investigations. PMID- 24625581 TI - High-density lipoprotein cholesterol is a favorable prognostic factor and negatively correlated with C-reactive protein level in non-small cell lung carcinoma. AB - BACKGROUND: Although the alterations of lipid profile in lung cancer have been documented, the prognostic value of serum HDL-C level and its correlation with inflammation in NSCLC remain unknown. SUBJECTS AND METHODS: Levels of preoperative serum lipid concentrations (including HDL-C, LDL-C, TC, and TG) and the inflammatory biomarker C-reactive protein level (CRP) were retrospectively analyzed in 228 patients with NSCLC and in 300 healthy controls. The serum lipid levels in these two populations were compared. Univariate and multivariate cox hazards analyses were performed to investigate the prognostic value of serum lipid levels in NSCLC. The correlation between CRP and lipid profile were also analyzed. RESULTS: Compared with those in normal controls, the serum HDL-C, LDL C, and TC levels were statistically decreased and the TG levels were significantly increased in 228 NSCLC patients. The patients with decreased levels of HDL-C had significantly lower 5-year survival rates than those with normal HDL C, not only in the whole NSCLC cohort but also in the subgroups stratified according to the disease T, N classifications, and metastasis, whereas the other lipid components were not independent prognostic factors for NSCLC. Of the lipid components, a lower HDL-C level was observed more often in patients with a high CRP level than in those with a normal CRP level. Spearman's rank correlation analysis revealed that the HDL-C level presented a negative correlation with the CRP level (r = -0.360, p<0.001). CONCLUSIONS: A decreased level of preoperative HDL-C was found to be associated with poor survival in patients with NSCLC. Serum HDL-C level may be a clinical prognosis factor for NSCLC patients. In addition, a negative correlation was present between the levels of HDL-C and CRP, the well known inflammation biomarker. PMID- 24625583 TI - Long term streptomycin toxicity in the treatment of Buruli Ulcer: follow-up of participants in the BURULICO drug trial. AB - BACKGROUND: Buruli Ulcer (BU) is a tropical infectious skin disease that is currently treated with 8 weeks of intramuscular streptomycin and oral rifampicin. As prolonged streptomycin administration can cause both oto- and nephrotoxicity, we evaluated its long term toxicity by following-up former BU patients that had received either 4 or 8 weeks of streptomycin in addition to other drugs between 2006 and 2008, in the context of a randomized controlled trial. METHODS: Former patients were retrieved in 2012, and oto- and nephrotoxicity were determined by audiometry and serum creatinine levels. Data were compared with baseline and week 8 measurements during the drug trial. RESULTS: Of the total of 151 former patients, 127 (84%) were retrieved. Ototoxicity was present in 29% of adults and 25% of children. Adults in the 8 week streptomycin group had significantly higher hearing thresholds in all frequencies at long term follow-up, and these differences were most prominent in the high frequencies. In children, no differences between the two treatment arms were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2.4% of patients at long term follow-up. CONCLUSIONS: Prolonged streptomycin administration in the adult study subjects caused significant persistent hearing loss, especially in the high frequency range. Nephrotoxicity was also present in both adults and children but appeared to be transient. Streptomycin should be given with caution especially in patients aged 16 or older, and in individuals with concurrent risks for renal dysfunction or hearing loss. PMID- 24625584 TI - Metal catalyst for low-temperature growth of controlled zinc oxide nanowires on arbitrary substrates. AB - Zinc oxide nanowires generated by hydrothermal method present superior physical and chemical characteristics. Quality control of the growth has been very challenging and controlled growth is only achievable under very limited conditions using homogeneous seed layers with high temperature processes. Here we show the controlled ZnO nanowire growth on various organic and inorganic materials without the requirement of a homogeneous seed layer and a high temperature process. We also report the discovery of an important role of the electronegativity in the nanowire growth on arbitrary substrates. Using heterogeneous metal oxide interlayers with low-temperature hydrothermal methods, we demonstrate well-controlled ZnO nanowire arrays and single nanowires on flat or curved surfaces. A metal catalyst and heterogeneous metal oxide interlayers are found to determine lattice-match with ZnO and to largely influence the controlled alignment. These findings will contribute to the development of novel nanodevices using controlled nanowires. PMID- 24625585 TI - Size matters: in labs now and clinics soon, nanotech is a hot ticket. PMID- 24625586 TI - Regulating nanomedicine: new nano tools offer great promise for the future--if regulators can solve the difficulties that hold development back. PMID- 24625587 TI - How nanomaterials are reshaping biomedical technology: a conversation with Eric Keller, Art Coury, and Tarek Fadel. PMID- 24625588 TI - At the interface of disciplines: Jeffrey Karp pulls from nature and nano to transform medicine. PMID- 24625589 TI - Small and bright: nanodiamonds for tissue repair, drug delivery, and biodetection. PMID- 24625590 TI - Miniature medicine: nanobiomaterials for therapeutic delivery and cell engineering applications. PMID- 24625591 TI - On the horizon: instructive nanomaterials hold the potential to mimic tissue complexity. PMID- 24625592 TI - A doctor in the palm of your hand: how the Qualcomm Tricorder X-Prize could help to revolutionize medical diagnosis. PMID- 24625593 TI - The race to build a better shoe: biomechanists now know how to build a healthier shoe. So why aren't shoe companies making them? PMID- 24625594 TI - Costunolide and Dehydrocostuslactone, two natural sesquiterpene lactones, ameliorate the inflammatory process associated to experimental pleurisy in mice. AB - The aim of this study was to investigate the effect of costunolide (CS) and dehydrocostuslactone (DCE) a well-known sesquiterpene lactones contained in many plants, in a model of lung injury induced by carrageenan administration in the mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and increased production of tumour necrosis factor alpha (TNF-alpha). All parameters of inflammation were attenuated by CS and DCE (15mg/kg 10% DMSO i.p.) administered 1h before carrageenan. Carrageenan induced an up regulation of the intracellular adhesion molecules-1 (ICAM-1) and P selectin, as well as nitrotyrosine and poly (ADP-ribose) (PAR) as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM 1, P-selectin, nitrotyrosine and PAR was reduced by CS and DCE. Additionally we show that this inflammatory events were associated with NF-kappaB and STAT3 activation and these sesquiterpenes down-regulated it. Taken together, ours results clearly shown that CS and DCE may offer a novel therapeutic approach for the management of inflammatory diseases. PMID- 24625595 TI - S,S'-dinitrosobucillamine, a new nitric oxide donor, induces a better vasorelaxation than other S-nitrosothiols. AB - S-nitrosothiols (RSNO) are considered as potential drugs for delivering nitric oxide (NO) or related species in cardiovascular disorders associated with decrease in NO bioavailability. We have synthesized a new RSNO, i.e. S,S' dinitrosobucillamine (BUC(NO)2), which combines in its structure two S mononitrosothiols, S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-N acetylcysteine (NACNO). Synthesized BUC(NO)2 was structurally characterized using high-performance liquid chromatography/mass spectrometry (HPLC/MS), (1)H nuclear magnetic resonance ((1)H NMR), infrared (IR) and UV-visible spectroscopies, and thermal analysis; resulting data are consistent with the expected structure. The vasorelaxant effect of BUC(NO)2 was evaluated using isolated rat aortic rings and compared to SNAP, NACNO, and to an equimolar mixture of NACNO plus SNAP in order to mimic the number of NO contained in a BUC(NO)2 molecule. BUC(NO)2 (pD2=7.8+/ 0.1) was more potent in vasorelaxation than NACNO (pD2=6.4+/-0.2), SNAP (pD2=6.7+/-0.1) and the mixture of SNAP plus NACNO (pD2=6.7+/-0.2). The release of NO from BUC(NO)2 was 6-fold that of the basal value and significantly higher than the release of NO from the SNAP plus NACNO mixture (4-fold increase versus basal value). Finally, the role of protein disulfide isomerase (PDI) in BUC(NO)2 metabolism was investigated. Vasorelaxant effect (pD2=6.8+/-0.2) and NO release decreased in the presence of a PDI inhibitor (both P<0.05 versus BUC(NO)2). In conclusion, BUC(NO)2 releases a larger amount of NO into the aorta, partially through PDI activation, and induces vasorelaxation at lower concentrations than other RSNO previously reported. PMID- 24625596 TI - Ab initio study of H, He, Li and Be impurity effect in tungsten Sigma3{1 1 2} and Sigma27{5 5 2} grain boundaries. AB - Density functional theory calculations were performed to investigate the effect of H, He, Li and Be impurities on the intergranular cohesion of W Sigma3<1 1 0>{1 1 2} and Sigma27<1 1 0>{5 5 2} grain boundaries (GBs). A rigorous search of unique interstices was performed to reveal a range of impurity behaviors. It was found that He exhibits the largest defect formation energy, however it is Li that shows the strongest tendency to segregate towards the GBs. The embrittling potency was studied using the ideal GB fracture energy (Rice-Wang) criterion (Rice and Wang 1989 Mater. Sci. Eng. A 107 23). The potency was found to depend significantly on the local atomic environment. A site-dependent concentration was used as the weighing factor to obtain an average potency as a function of temperature. It was found that the potency depends only weakly on temperature. In Sigma3 H, He, Li and Be decrease fracture energy by 4%, 27%, 30% and 14%, respectively. In Sigma27 H, He and Li also decrease cohesion, albeit less severely: 3%, 14% and 7%. On the other hand, Be increases cohesion in Sigma27 by 3%. PMID- 24625597 TI - Magnetic resonance 4D flow reveals unusual hemodynamics associated with aneurysm formation and a possible cause of cryptogenic stroke in a patient with aortic dissection. AB - Four-dimensional flow is a magnetic resonance technology that has undergone significant technical improvements in recent years. With increasingly rapid acquisition times and new postprocessing tools, it can provide a tool for demonstrating and visualizing cardiovascular flow phenomena, which may offer new insights into disease. We present an interesting clinical case in which 4 dimensional flow demonstrates potential etiologies for 2 interesting phenomena in the same patient: (1) development of an unusual aneurysm and (2) cryptogenic stroke. PMID- 24625598 TI - Catheter insertion for intravenous (IV) contrast infusion in multidetector-row computed tomography (MDCT): defining how catheter caliber selection affects procedure of catheter insertion, IV contrast infusion rate, complication rate, and MDCT image quality. AB - PURPOSE: This study evaluated the effect of intravenous (IV) catheter gauge size on catheter placement, contrast infusion, and image quality for patients undergoing IV contrast-enhanced multidetector computed tomography (MDCT). MATERIALS AND METHODS: One thousand consecutive adult outpatients undergoing IV contrast-enhanced MDCT and 10 IV insertion CT nurses were observed from IV catheter selection through IV removal. Patients' demographics, number of sticks required, catheter gauge during each attempt, time for catheter placement, IV nurses' assessment of vein quality and contrast infusion parameters were recorded. Scan quality was assessed subjectively. RESULTS: Subjects included 547 men and 453 women, with a mean age 59.2 years (range, 19-92 years). Median number of catheter attempts was 1 per patient (range, 1-9). Catheters were successfully placed in 98%. First and final catheters were most commonly 20 gauge (59% and 56%, respectively), followed by 22 gauge (34% for both), 18 gauge (6% for both), and 24 gauge (2% and 3%, respectively). Mean infusion rate correlated with catheter gauge: 5.3 mL/s for 18 gauge; 3.5 mL/s for 20 gauge; 2.3 mL/s for 22 gauge; and 1.7 mL/s for 24 gauge (P < 0.0001). Target infusion rate of >= 3 mL/s was related to catheter gauge (100% of 18 gauge, 71% of 20 gauge, 11% of 22 gauge, and 0% of 24 gauge; P < 0.0001). Nine hundred sixty-eight subjects underwent imaging. Most of the CT examinations (935/968 [97%]) were of acceptable quality. CONCLUSION: Experienced IV starters usually achieve IV access in one attempt by tailoring IV catheter gauge to vein quality; however, target infusion rates are not likely to be achieved with 22- and 24-gauge catheters, used in nearly 1/3 of the patients in this study. PMID- 24625599 TI - Diagnostic accuracy of coronary CT angiography: comparison of filtered back projection and iterative reconstruction with different strengths. AB - PURPOSE: To investigate the diagnostic accuracy of coronary computed tomographic (CT) angiography (CCTA) using filtered back projection (FBP) and sinogram affirmed iterative reconstruction (SAFIRE) of different strength factors with invasive coronary angiography as the reference standard. MATERIALS AND METHODS: Fifty consecutive patients (32 men and 18 women) prospectively underwent electrocardiogram-triggered CCTA on a dual-source CT system. The acquisition window was set depending on the heart rate (HR): HR of less than 60 beats per minute (bpm) at the 70% RR interval, 61 to 80 bpm at 30% to 80% RR interval, and greater than 80 bpm at 30% to 50% RR interval; 100 kV and 359 to 377 mA s for patients with a body mass index of less than 24 kg/m, and 410 to 438 mA s at 120 kV for patients with a body mass index of 24 kg/m or greater. Image data were reconstructed using both FBP and SAFIRE. Sinogram-affirmed iterative reconstruction series were reconstructed using 3 different strength factors. Two blinded observers independently assessed the image quality and image impression of each coronary segment using a 4-point scale (1, non-diagnostic; and 4, excellent). Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured. Filtered back projection and all SAFIRE series were independently evaluated for coronary artery stenosis (>50%), and their diagnostic accuracy was compared with invasive coronary angiography. RESULTS: Statistically significant increases in SNR and CNR were obtained when higher strength factors were used. The highest SNR and CNR were found with the highest SAFIRE strength factor of 5; however, this strength also resulted in a more unfamiliar, "plasticlike" image appearance. Imaging quality scores of FBP and different SAFIRE strengths were 3.37 +/- 0.49, 3.41 +/- 0.47, 3.52 +/- 0.30, and 3.48 +/- 0.35, respectively (P < 0.001). The diagnostic accuracies were 92.91%, 93.76%, 95.28%, and 94.94% on per-segment level, respectively (P = 0.993). A tendency toward higher diagnostic performance was observed with SAFIRE strength factor 3 on per-segment analysis, albeit without reaching statistical significance. The effective radiation dose equivalent was 5.7 +/- 1.6 mSv. CONCLUSION: Sinogram affirmed iterative reconstruction provides significant improvements in image noise, SNR, and CNR compared with FBP, which are progressive with increasing SAFIRE strength factors. Sinogram-affirmed iterative reconstruction strength factor 3 or 5 is recommended for use with CCTA. PMID- 24625600 TI - Magnetic resonance imaging spectrum of solid pseudopapillary neoplasm of the pancreas. AB - OBJECTIVE: To describe the magnetic resonance imaging spectrum of solid pseudopapillary tumors (SPTs), with an emphasis on solid SPTs. METHODS: Thirty two patients with proven SPTs with preoperative magnetic resonance were included. The SPTs were classified into 3 types: solid, cystic, and mixed; and 2 radiologists analyzed the images regarding the morphologic features and enhancement pattern. RESULTS: Of 11 solid SPTs, 9 SPTs (81.8%) were less than 3 cm. Alternatively, of the 18 mixed SPTs and 3 cystic SPTs, 15 SPTs (71.4%) were larger than 3 cm. The predominant imaging features were homogeneous hypoenhancement with a gradually incremental enhancement pattern showing a sharp margin without hemorrhage, whereas those of the mixed SPTs were heterogeneous enhancement showing a sharp margin with internal hemorrhage. CONCLUSION: Solid SPTs frequently present as small, well-defined tumors with a gradual enhancement and without hemorrhage or necrosis, and with features that differ from those of mixed or cystic SPTs. PMID- 24625601 TI - Combination of increased flip angle, radial k-space trajectory, and free breathing acquisition for improved detection of a biliary variant at living donor liver transplant evaluation using gadoxetic acid-enhanced MRCP. AB - Gadoxetic acid-enhanced magnetic resonance cholangiopancreatography (MRCP) was performed for evaluation of living donor liver transplantation. T2-weighted MRCP and hepatobiliary-phase postcontrast MRCP showed an aberrant right posterior bile duct, although the precise variant was uncertain. Optimized hepatobiliary-phase MRCP was obtained using 3 sequence modifications: increased flip angle to improve contrast between the biliary tree and surrounding tissues; radial k-space sampling to minimize motion artifact; and free-breathing acquisition to improve signal-to-noise ratio and, in turn, spatial resolution (resolution of 1.28 * 1.28 * 1.5 mm). The optimized sequence demonstrated that the right posterior bile duct drained into the cystic duct, consistent with type 3C biliary variant, thus modifying surgical planning. PMID- 24625602 TI - Detection and characterization of tendon abnormalities with multidetector computed tomography. AB - With recent advances in multidetector computed tomography (MDCT) acquisition and reconstruction options, MDCT can now be used successfully for evaluating tendon abnormalities. In this article, MDCT protocol optimization for the imaging of tendons is underscored, and applications of MDCT for assessing tendon pathology are highlighted. Although our retrospective experience of CT imaging with 2 dimensional multiplanar reconstructions and 3-dimensional postprocessing techniques is reviewed, potential applications for newer CT technologies, including dual-energy CT and 4-dimensional CT imaging of the peripheral tendons, are also discussed. PMID- 24625603 TI - Usefulness of adding SPECT/CT to 99mTc-hexamethylpropylene amine oxime (HMPAO) labeled leukocyte imaging for diagnosing prosthetic joint infections. AB - OBJECTIVE: This study evaluated the usefulness of adding single-photon emission computed tomography (SPECT)/computed tomography (CT) (SPECT/CT) to technetium Tc 99m (Tc) hexamethylpropylene amine oxime (HMPAO)-labeled leukocyte imaging for diagnosing infections in hip or knee joint prostheses. METHODS: The Tc-HMPAO labeled leukocyte scans of 164 patients (71 with hip prostheses and 93 with knee prostheses) with clinically suspected prosthetic infections were reviewed retrospectively. Planar images were taken 4 to 6 and 21 to 26 hours after injecting the labeled leukocytes and SPECT/CT images were obtained 4 to 6 hours after the injection. The final diagnosis of infection was based on pathologic findings (n = 70), bacteriological data (n = 61), or clinical follow-up (n = 33). RESULTS: Of the 164 patients, 89 patients had a diagnosis of prosthetic joint infections. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the planar images alone were 82.0%, 88.0%, 89.0%, 80.5%, and 84.8%, respectively. When the planar images were combined with SPECT, the sensitivity, specificity, PPV, NPV, and diagnostic accuracy were 91.0%, 88.0%, 90.0%, 89.2%, and 89.6%, respectively. When the planar images were combined with SPECT/CT, these values increased further to 93.3%, 93.3%, 94.3%, 92.1%, and 93.3%, respectively. Adding CT to SPECT resulted in a greater increase in sensitivity and specificity for hip prosthesis infections than for knee prosthesis infections. SPECT/CT mainly contributed by precisely localizing the anatomical site of the active inflammatory lesion and by delineating the extent of the lesion after diagnosis with SPECT. CONCLUSIONS: Single-photon emission computed tomography/CT combined with Tc-HMPAO-labeled leukocyte imaging was useful for diagnosing prosthesis infections, particularly in hip prosthesis infections, as it improved diagnostic accuracy and provided anatomical localization data. PMID- 24625604 TI - Size of the semicircular canals measured by multidetector computed tomography in different age groups. AB - PURPOSE: The purpose of the study was to obtain reference values for the sizes of the semicircular canals (SCCs) on multidetector computed tomographic (CT) images in different age groups. METHODS: Computed tomographic images of the temporal bone of 210 patients, a total of 420 ears without inner ear pathology, have been evaluated. These patients were divided into 4 groups by age: young children (<7 years), older children and adolescents (8-17 years), adults (18-59 years), and the elderly patients (>60 years). The inner diameter, maximum height, and width of the SCCs were measured. RESULTS: There was no significant difference in the size of SCC among the 4 age groups. The inner diameter measurements of the anterior SCC, lateral SCC, and posterior SCC were 0.101 +/- 0.016, 0.135 +/- 0.033, and 0.124 +/- 0.021 cm, respectively. The height measurements of the anterior SCC, lateral SCC, and posterior SCC were 0.535 +/- 0.086, 0.349 +/- 0.090, and 0.490 +/- 0.109 cm, respectively. The width measurements of the anterior SCC, lateral SCC, and posterior SCC were 0.567 +/- 0.080, 0.302 +/- 0.082, and 0.472 +/- 0.099 cm, respectively. CONCLUSIONS: The size of SCCs remains constant from children to the elderly people, unlike the other human organs. The reference values provided by multidetector CT can serve as an aid for the interpretation of CT images. PMID- 24625605 TI - Procedure-oriented sectional anatomy of the knee. AB - This is the fifth in a series of articles related to procedure-oriented joint anatomy. This article reviews the anatomy of the knee and its relationship to procedures in the clinical setting with or without ultrasound/electromyographic guidance. Anatomically correct axial schematics allow injections to be envisioned relative to clinically important anatomy for common knee procedures. Cross sectional schematics for the knee were drawn as they appear in imaging projections. The levels and planes of cross section were selected to highlight important anatomic landmarks for injection. It is hoped that these schematics allow for safer and more accurate needle procedures in the knee area. PMID- 24625606 TI - Features suggestive of gallbladder malignancy: analysis of T1, T2, and T3 tumors on cross-sectional imaging. AB - OBJECTIVES: Gallbladder cancer carries an extremely high mortality rate, with a 5 year survival rate as low as 12%. Survival is dependent on the diagnosis of these tumors in their earliest stages. This study sought to describe the clinical and imaging features of stages T1, T2, and T3 gallbladder tumors and to illustrate features that may allow radiologists to make an early diagnosis. MATERIALS AND METHODS: After approval from the institutional review board, a search of the pathology department database yielded 18 patients with surgically proven T1, T2, and T3 gallbladder cancers with available preoperative computed tomography (CT) or magnetic resonance imaging. The imaging was reviewed for lesional morphology (focal polyploid mass, focal wall thickening, circumferential wall thickening), enhancement characteristics, liver invasion, locoregional lymphadenopathy, and distant metastatic disease. The electronic medical record was also searched for demographic information and clinical presentation. RESULTS: There were 10 women and 8 men with a mean age of 69 years. Virtually all patients were symptomatic, with most patients demonstrating symptoms suggestive of underlying malignancy (including jaundice, weight loss, and chronic abdominal pain). Tumors on CT and MRI included 6 polyploid masses, 9 tumors with focal wall thickening, and 3 with circumferential wall thickening. The mean attenuation of those tumors imaged with CT was 59.4 Hounsfield units (HUs) on the arterial phase and 86.5 HUs on the venous phase, with a mean increase in Hounsfield attenuation between the arterial and venous phases of 28.2 HUs. Twelve of the 18 patients were correctly diagnosed prospectively on CT. CONCLUSIONS: The imaging findings of gallbladder cancer can be subtle, regardless of whether the tumor presents as a discrete mass, focal wall thickening, or circumferential diffuse wall thickening, and radiologists should be aware of the wide range of different possible appearances. Moreover, the vast majority of these patients had clinical symptoms suggestive of an underlying malignancy, and this should precipitate a careful evaluation of the gallbladder in all such cases. PMID- 24625607 TI - Differentiation of gastric true leiomyoma from gastric stromal tumor based on biphasic contrast-enhanced computed tomographic findings. AB - The objective of this study was to identify the computed tomographic criteria that differentiate gastric true leiomyoma from gastric stromal tumor. MATERIALS AND METHODS: Computed tomographic images of gastric true leiomyoma (n = 11) and gastric stromal tumor (n=30) were reviewed. The location, contour, growth pattern, enhancement pattern, necrosis, and ulceration were analyzed. Long diameter (LD), short diameter (SD), LD/SD ratio, and enhancement degree were measured and calculated. The Fisher exact test, grouped t test, rank sum test, and receiver operating characteristic curve were analyzed. Sensitivity and specificity were also calculated. RESULTS: Cardial location, round/ovoid contour, intraluminal growth, homogeneous enhancement, absence of necrosis, less than 3.35 cm in LD and less than 2.3 cm in SD, enhancement degree of less than 12.5 Hounsfield units in the arterial phase versus less than 31.5 Hounsfield units in the portal venous phase were found to be significant variables for differentiating gastric true leiomyoma from gastric stromal tumor (P < 0.05). CONCLUSIONS: These 9 computed tomographic criteria are helpful to differentiate gastric true leiomyoma from gastric stromal tumor. PMID- 24625609 TI - Primary small cell neuroendocrine carcinoma of the mediastinum: computed tomography and histopathological correlation. AB - OBJECTIVES: The objectives of this study were to describe the computed tomographic (CT) and histopathological characteristics of neuroendocrine carcinomas of the mediastinum and to improve the diagnostic accuracy for these tumors. MATERIALS AND METHODS: We retrospectively analyzed 9 patients with histopathologically confirmed primary small cell neuroendocrine carcinoma of the mediastinum. RESULTS: Of the 9 tumors, 6 (67%) were located in the anterior middle mediastinum; 2, in the anterior-middle-posterior mediastinum; and 1, in the middle-mediastinum. Eight tumors appeared inhomogeneous on CT, with large areas of necrosis, whereas 1 tumor had a uniform density. Four tumors (44%) had scattered punctate calcifications. Moderate, heterogeneous enhancement (range, 21 34 Hounsfield units) was present in 8 patients. All tumors compressed or invaded the adjacent mediastinal structures. Hematoxylin and eosin staining results revealed small tumor cells, with little cytoplasm, pale chromatin, and inconspicuous or absent nucleoli. Immunohistochemical analysis results showed that the tumor cells were positive for chromogranin A, synaptophysin, and neuron specific enolase. CONCLUSIONS: A large tumor located in the anterior-middle mediastinum, showing scattered punctate calcifications and compressing or invading the adjacent mediastinal structures, should arouse suspicion for a small cell neuroendocrine carcinoma. However, the diagnosis of such tumors requires a combination of pathological and immunohistochemical examination. PMID- 24625610 TI - Multidetector computed tomographic study of amulets, jewelry, and other foreign objects in royal Egyptian mummies dated from the 18th to 20th dynasties. AB - OBJECTIVE: The objective of this study was to study the role of multidetector computed tomography (MDCT) in the analysis of foreign objects found within or on the royal Egyptian mummies. METHODS: We studied MDCT images of 15 royal Egyptian mummies (1493-1156 BC) for the presence of foreign objects. We studied each found object for its location, morphology, dimensions, and density in correlation with the archeologic literature. RESULTS: We detected 14 objects in 6 mummies: a heart amulet, 3 Eye of Horus, 4 Sons of Horus, a crowned-Osiris amulet, 2 bracelets, 2 sets of beads/stones, and an arrowhead that may be linked to injury. The MDCT images suggested the material of the objects to be metal (n = 6), semiprecious stone (n = 1), quartzlike (faience) (n = 2), and fired clay (n = 5). Placement of an amulet within the heart supports our knowledge that its funeral purpose was meant for the purpose of protection. CONCLUSIONS: Multidetector computed tomography offers a detailed noninvasive analysis of objects on/in mummies and differentiates funerary objects from those that may be related to cause of death. PMID- 24625611 TI - Coronary artery assessment on electrocardiogram-gated thoracoabdominal multidetector computed tomographic angiography for aortic evaluation. AB - OBJECTIVE: The objective of this study was to evaluate coronary image quality, stenosis grade, and diagnostic confidence in patients undergoing electrocardiogram-gated thoracoabdominal multidetector computed tomographic angiography (CTA) for aortic evaluation. METHODS: Seventy-five consecutive patients underwent retrospectively electrocardiogram-gated thoracoabdominal CTA reconstructed at each 12.5% of the R wave to R wave (R-R) interval. Two observers in consensus scored the coronary arteries per segment (15-segment American Heart Association model) for image quality, stenosis grade, and stenosis-assessment confidence. RESULTS: Nondiagnostic image quality prohibited coronary evaluation in 14 patients. In the remaining patients, 2% of segments was scored absent, 24% was scored nondiagnostic, 12% was scored diagnostically limited, and 61% was scored at least acceptable. Acceptable or higher image quality was seen in 82% of the proximal and middle segments. Significant stenosis (>50%) was seen in 57% of the patients. Stenosis-severity scoring confidence was moderate to high in 79% of 673 assessable segments. CONCLUSIONS: Electrocardiogram-gated thoracoabdominal CTA allows concomitant assessment of the proximal and middle coronary arteries and may serve as a combined tool for aortic-disease workup. Aortic CTA showed significant coronary artery stenosis in 57% of the patients evaluated for aortic pathology. PMID- 24625612 TI - The prevalence of superior semicircular canal dehiscence in conductive and mixed hearing loss in the absence of other pathology using submillimetric temporal bone computed tomography. AB - OBJECTIVE: The objective of this study was to assess the relationship between superior semicircular canal dehiscence (SSCD) and hearing impairment. METHODS: We retrospectively compared the prevalence of SSCD in the ears classified as conductive hearing loss (CHL), mixed hearing loss (MHL), and normal hearing status using submillimetric temporal bone computed tomography (TBCT) on the basis of coronal and additional reformatted planes dedicated to SSCD. RESULTS: From the patients with CHL (n = 127) and MHL (n = 45), the overall prevalence of SSCD in the ears classified as CHL, MHL, and normal hearing status were 6.6%, 7.2%, and 3.0%, respectively. Furthermore, the odds ratio for SSCD in the absence of any cause of hearing loss (eg, dysfunction of the tympanic membrane or middle ear, TBCT abnormalities, otosclerosis, trauma, surgery) was 5.35 in MHL (4/27; P = 0.037, 95% confidence interval, 1.1-25.81) and 3.31 in CHL (5/61; P = 0.115, 95% confidence interval, 0.75-14.63), compared with normal hearing status. CONCLUSIONS: Bony covering of the SSC should be specifically evaluated in patients with hearing impairment using submillimetric TBCT. PMID- 24625613 TI - Clear cell meningioma: clinical features, CT, and MR imaging findings in 23 patients. AB - BACKGROUND: Clear cell meningioma (CCM) is a rare meningioma, with radiologic features not well characterized in literature. The purpose of this study was to describe and characterize the clinical features and imaging findings of CCM. MATERIALS AND METHODS: The computed tomography (n = 16) and magnetic resonance (n = 23) images of 23 patients (12 men and 11 women; mean age, 34.6 years) were retrospectively reviewed. All of the patients underwent surgical resection. Follow-up was performed through clinical observations. RESULTS: Cerebellopontine angle was the most frequently presenting location (n = 10). The tumors were isointense (n = 12) or hypointense but associated with isointense (n = 7) appearance to gray matter on T1-weighted images. However, the tumors seemed to be isointense (n = 6) or isointense and hyperintense (n = 13) on T2-weighted images. On gadolinium-enhanced T1-weighted images, heterogeneous enhancement was seen in 14 lesions. Four lesions had amorphous calcifications, 18 showed peritumoral edema, 14 had cystic areas, 2 had bone hyperostosis, and 8 manifested bone destruction. On initial surgery, 17 patients underwent complete resection, whereas 5 patients underwent subtotal resection of their tumors. The operative result for the remaining patient was unknown. Follow-up was possible in 22 patients. Eleven patients had recurrence and 2 had died. CONCLUSIONS: Clear cell meningioma is a rare subtype of meningioma that occurs in younger patients and often recurs. Cerebellopontine angle is the most affected area in this series. The extent of initial surgical resection is the most important prognostic factor. In radiological studies, CCM tends to have marked heterogeneous enhancement, prominent peritumoral edema, intratumoral cystic components, and involvement of the adjacent bone. PMID- 24625614 TI - Imaging Crohn disease: MR enterography. AB - Magnetic resonance enterography in Crohn disease management has been rapidly growing in importance during recent years. Being familiar to this technique is essential for radiologists and also, to some extent, for gastroenterologists. Our aim is to study and describe the imaging findings in magnetic resonance enterography in Crohn disease to develop a comprehensive and useful review article and imaging atlas. PMID- 24625615 TI - Pulmonary pseudoemboli: a new artifact arising from a commercial metal artifact reduction algorithm for computed tomographic image reconstruction. AB - Metal artifact reduction algorithms for computed tomographic (CT) image reconstruction have recently become commercially available on modern CT scanners for reducing artifacts from orthopedic hardware. However, we have observed that a commercial orthopedic metal artifact reduction algorithm can produce the appearance of artifactual pulmonary emboli when applied to spinal hardware in contrast-enhanced CT scans of the chest. We provide 4 case examples demonstrating this previously undescribed artifact. PMID- 24625616 TI - Tumor volumes measured from static and dynamic 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan: comparison of different methods using magnetic resonance imaging as the criterion standard. AB - OBJECTIVE: The objective of this study was to compare the accuracy of calculating the primary tumor volumes using a gradient-based method and fixed threshold methods on the standardized uptake value (SUV) maps and the net influx of FDG (Ki) maps from positron emission tomography-computed tomography (PET-CT) images. MATERIALS AND METHODS: Newly diagnosed patients with head and neck cancer were recruited, and dynamic PET-CT scan and T2-weighted magnetic resonance imaging were performed. The maps of Ki and SUV were calculated from PET-CT images. The tumor volumes were calculated using a gradient-based method and a fixed threshold method at 40% of maximal SUV or maximal Ki. Four kinds of volumes, VOLKi-Gra (from the Ki maps using the gradient-based method), VOLKi-40% (from the Ki maps using the threshold of 40% maximal Ki), VOLSUV-Gra (from the SUV maps using the gradient-based method), and VOLSUV-40% (from the SUV maps using the threshold of 40% maximal SUV), were acquired and compared with VOLMRI (the volumes acquired on T2-weighted images) using the Pearson correlation, paired t test, and similarity analysis. RESULTS: Eighteen patients were studied, of which 4 had poorly defined tumors (PDT). The positron emission tomography-derived volumes were as follows: VOLSUV-40%, 2.1 to 41.2 cm (mean [SD], 12.3 [10.6]); VOLSUV-Gra, 2.2 to 28.1 cm (mean [SD], 13.2 [8.4]); VOLKi-Gra, 2.4 to 17.0 cm (mean [SD], 9.5 [4.6]); and VOLKi-40%, 2.7 to 20.3 cm (mean [SD], 12.0 [6.0]). The VOLMRI ranged from 2.9 to 18.1 cm (mean [SD], 9.1 [3.9]). The VOLKi-Gra significantly correlated with VOLMRI with the highest correlation coefficient (PDT included, R = 0.673, P = 0.002; PDT excluded, R = 0.841, P < 0.001) and presented no difference from VOLMRI (P = 0.672 or 0.561, respectively, PDT included and excluded). The difference between VOLKi-Gra and VOLMRI was also the smallest. CONCLUSIONS: The tumor volumes delineated on the Ki maps using the gradient-based method are more accurate than those on the SUV maps and using the fixed threshold methods. PMID- 24625619 TI - Fast range switching of passively scattered proton beams using a modulation wheel and dynamic beam current modulation. AB - In proton radiotherapy, the range of particles in the patient body is determined by the energy of the protons. For most systems, the energy selection time is on the order of a few seconds, which becomes a serious obstacle for continuous dose delivery techniques requiring adaptive range modulation. This work analyses the feasibility of using the range modulation wheel, an element in the beamline used to form the spread-out Bragg peak (SOBP), to produce near-instantaneous changes not only in the modulation, but also in the range of the beam. While delivering proton beams in double scattering mode, the beam current can be synchronized with the range modulation wheel rotation by defining a current modulation pattern. Different current modulation patterns were computed from Monte Carlo simulations of our double scattering nozzle to range shift an SOBP of initial range 15 cm by varying degrees of up to ~9 cm. These patterns were passed to the treatment control system at our institution and the resulting measured depth-dose distributions were analysed in terms of flatness, distal penumbra and relative irradiation time per unit mid-SOBP dose. Suitable SOBPs were obtained in all cases, with the maximum range shift being limited only by the maximum thickness of the wheel. The distal dose fall-off (80% to 20%) of the shifted peaks was broadened to about 1 cm, from the original 0.5 cm, and the predicted overhead in delivery time showed a linear increase with the amount of the shift. By modulating the beam current in clinical scattered proton beams equipped with a modulation wheel, it is possible to dynamically modify the in-patient range of the SOBP without adding any specific hardware or compensators to the beamline. A compromise between sharper distal dose fall-off and lower delivery time can be achieved and is subject to optimization. PMID- 24625618 TI - Reduction of the HIV protease inhibitor-induced ER stress and inflammatory response by raltegravir in macrophages. AB - BACKGROUND: HIV protease inhibitor (PI), the core component of highly active antiretroviral treatment (HAART) for HIV infection, has been implicated in HAART associated cardiovascular complications. Our previous studies have demonstrated that activation of endoplasmic reticulum (ER) stress is linked to HIV PI-induced inflammation and foam cell formation in macrophages. Raltegravir is a first-in its-class HIV integrase inhibitor, the newest class of anti-HIV agents. We have recently reported that raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of hepatic lipid metabolism by inhibiting ER stress. However, little information is available as to whether raltegravir would also prevent HIV PI-induced inflammatory response and foam cell formation in macrophages. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we examined the effect of raltegravir on ER stress activation and lipid accumulation in cultured mouse macrophages (J774A.1), primary mouse macrophages, and human THP-1-derived macrophages, and further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed activation of inflammatory response and foam cell formation. The results indicated that raltegravir did not induce ER stress and inflammatory response in macrophages. Even more interestingly, HIV PI-induced ER stress, oxidative stress, inflammatory response and foam cell formation were significantly reduced by raltegravir. High performance liquid chromatography (HPLC) analysis further demonstrated that raltegravir did not affect the uptake of HIV PIs in macrophages. CONCLUSION AND SIGNIFICANCE: Raltegravir could prevent HIV PI induced inflammatory response and foam cell formation by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the cardiovascular complications associated with current HAART. PMID- 24625620 TI - From eutrophic to mesotrophic: modelling watershed management scenarios to change the trophic status of a reservoir. AB - Management decisions related with water quality in lakes and reservoirs require a combined land-water processes study approach. This study reports on an integrated watershed-reservoir modeling methodology: the Soil and Water Assessment Tool (SWAT) model to estimate the nutrient input loads from the watershed, used afterwards as boundary conditions to the reservoir model, CE-QUAL-W2. The integrated modeling system was applied to the Torrao reservoir and drainage basin. The objective of the study was to quantify the total maximum input load that allows the reservoir to be classified as mesotrophic. Torrao reservoir is located in the Tamega River, one of the most important tributaries of the Douro River in Portugal. The watershed is characterized by a variety of land uses and urban areas, accounting for a total Waste Water Treatment Plants (WWTP) discharge of ~100,000 p.e. According to the criteria defined by the National Water Institute (based on the WWTP Directive), the Torrao reservoir is classified as eutrophic. Model estimates show that a 10% reduction in nutrient loads will suffice to change the state to mesotrophic, and should target primarily WWTP effluents, but also act on diffuse sources. The method applied in this study should provide a basis for water environmental management decision-making. PMID- 24625621 TI - Use of neuroenhancement drugs: prevalence, frequency and use expectations in Switzerland. AB - OBJECTIVE: The present study investigates the use expectations, prevalence and frequency of neuroenhancement drug (ND) use among the Swiss male population, separating college students from others. METHODS: Young Swiss men were invited to participate in the Cohort Study on Substance Use Risk Factors. A total of 5,967 participants responded to questions on six types of NDs (wakefulness medication, antidepressants, Alzheimer's disease medication, Parkinson's disease medication, attention deficit-hyperactivity disorder (ADHD) medication, and beta-blockers). The frequency of use depending on five expectations (to enhance wakefulness, attention, memory, concentration and stress reduction) was analyzed for a twelve month period. RESULTS: (1) About 3% of the sample indicated use of at least one ND; (2) ADHD medication was the most prevalent; (3) The type of ND preferred differed depending on academic status (4). Quantitatively, over the year, college student users used ND much less frequently than other users. CONCLUSIONS: Prevalence of ND use is low in Switzerland relative to other countries such as the United States. Patterns of ND use differed depending on academic status, suggesting that while college student ND users tended to do so rarely (probably to enhance cognitive abilities for exams), non-college male users used other NDs more frequently (probably to "get high"). PMID- 24625623 TI - Time-dependent propensity score for assessing the effect of vaccine exposure on pregnancy outcomes through pregnancy exposure cohort studies. AB - Women are advised to be vaccinated for influenza during pregnancy and may receive vaccine at any time during their pregnancy. In observational studies evaluating vaccine safety in pregnancy, to account for such time-varying vaccine exposure, a time-dependent predictor can be used in a proportional hazards model setting for outcomes such as spontaneous abortion or preterm delivery. Also, due to the observational nature of pregnancy exposure cohort studies and relatively low event rates, propensity score (PS) methods are often used to adjust for potential confounders. Using Monte Carlo simulation experiments, we compare two different ways to model the PS for vaccine exposure: (1) logistic regression treating the exposure status as binary yes or no; (2) Cox regression treating time to exposure as time-to-event. Coverage probability of the nominal 95% confidence interval for the exposure effect is used as the main measure of performance. The performance of the logistic regression PS depends largely on how the exposure data is generated. In contrast, the Cox regression PS consistently performs well across the different data generating mechanisms that we have considered. In addition, the Cox regression PS allows adjusting for potential time-varying confounders such as season of the year or exposure to additional vaccines. The application of the Cox regression PS is illustrated using data from a recent study of the safety of pandemic H1N1 influenza vaccine during pregnancy. PMID- 24625622 TI - Effects of OEF/OIF-related physical and emotional co-morbidities on associative learning: concurrent delay and trace eyeblink classical conditioning. AB - This study examined the performance of veterans and active duty personnel who served in Operation Enduring Freedom and/or Operation Iraqi Freedom (OEF/OIF) on a basic associative learning task. Eighty-eight individuals participated in this study. All received a comprehensive clinical evaluation to determine the presence and severity of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). The eyeblink conditioning task was composed of randomly intermixed delay and trace conditioned stimulus (CS) and unconditioned stimulus (US) pairs (acquisition) followed by a series of CS only trials (extinction). Results revealed that those with a clinical diagnosis of PTSD or a diagnosis of PTSD with comorbid mTBI acquired delay and trace conditioned responses (CRs) to levels and at rates similar to a deployed control group, thus suggesting intact basic associative learning. Differential extinction impairment was observed in the two clinical groups. Acquisition of CRs for both delay and trace conditioning, as well as extinction of trace CRs, was associated with alcoholic behavior across all participants. These findings help characterize the learning and memory function of individuals with PTSD and mTBI from OEF/OIF and raise the alarming possibility that the use of alcohol in this group may lead to more significant cognitive dysfunction. PMID- 24625624 TI - Sensitivity of Oncomelania hupensis to niclosamide: a nation-wide survey in China. AB - Schistosomiasis japonica, transmitted by the intermediate host snail Oncomelania hupensis of the causative agent Schistosoma japonicum, remains a major public health concern in China, and control of this snail is one of the major approaches used in attempts to interrupt the transmission of this neglected tropical disease. Niclosamide is currently the only commercial molluscicide available for the control of O. hupensis snails in China. The purpose of this study was to evaluate the current sensitivity of O. hupensis to niclosamide in China. O. hupensis snails derived from 17 sampling sites from eight schistosomiasis-endemic provinces of China were used for the molluscicidal tests. Active adult snails (10 for each drug concentration), were immersed in solutions of 1, 0.5, 0.25, 0.125, 0.063, 0.032, 0.016 and 0.008 mg/L of 50% wettable powder of niclosamide ethanolamine salt (WPN) for 24 and 48 h at 25 degrees C, and then the snail mortality was estimated and LC50 values were calculated. All field-derived O. hupensis snails were dead following immersion in 0.5 and 1 mg/L WPN for 24 h, whereas no death was observed after immersion in 0.008 mg/L WPN for 24 h. Immersion in 0.5, 0.25, 0.125, 0.063, 0.032 and 0.016 mg/L WPN for 24 h resulted in 80%-100%, 63.33%-100%, 0%-85%, 0%-50%, 0%-15%, and 0%-5% snail mortalities, respectively. The 24 h WPN LC50 values for the O. hupensis snails derived from the 17 sampling sites in China ranged from 0.0743 to 0.2285 mg/L, and no significant difference was detected by the Kolmogorov-Smirnov test (p = 0.2). The results indicate that there is no regional variation in the current susceptibility to niclosamide in O. hupensis populations in China. It is suggested that the current sensitivity of niclosamide against O. hupensis remains high and has not changed after more than two decades of repeated, extensive application for snail control in the main endemic areas of China. PMID- 24625625 TI - Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti inflammatory drugs in the treatment of knee or hip osteoarthritis pain. AB - OBJECTIVE: To evaluate whether subjects with knee or hip osteoarthritis (OA) pain on non-steroidal anti-inflammatory drugs (NSAIDs) received greater benefit when tanezumab monotherapy replaced or was coadministered with NSAIDs. METHODS: Subjects (N=2700) received intravenous tanezumab (5 or 10 mg) or placebo every 8 weeks with or without oral naproxen 500 mg twice daily or celecoxib 100 mg twice daily. Efficacy was assessed as change from baseline to week 16 in three co primary endpoints: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and Patient's Global Assessment (PGA) of OA. Safety assessments included adverse events, physical and neurological examinations, laboratory tests and vital signs. RESULTS: Although all tanezumab treatments provided significant improvements in WOMAC Pain and Physical Function over either NSAID alone, only tanezumab+NSAIDs were significant versus NSAIDs with PGA and met the prespecified definition of superiority. Combination treatment did not substantially improve pain or function over tanezumab monotherapy. Adverse event frequency was higher with tanezumab than with NSAIDs and highest with combination therapy. Higher incidence of all-cause total joint replacements occurred with tanezumab+NSAID versus tanezumab monotherapy or NSAIDs. Rapidly progressive OA incidence was significantly greater versus NSAID in all tanezumab groups except tanezumab 5 mg monotherapy. CONCLUSIONS: Subjects receiving partial symptomatic relief of OA pain with NSAIDs may receive greater benefit with tanezumab monotherapy. While only coadministration of tanezumab with NSAIDs met the definition of superiority, combination treatment did not provide important benefits over tanezumab monotherapy; small differences in efficacy were negated by treatment-limiting or irreversible safety outcomes. TRIAL REGISTRATION NUMBER: NCT00809354. PMID- 24625626 TI - Osteoarthritis research priorities: a report from a EULAR ad hoc expert committee. AB - Osteoarthritis (OA) currently affects over 40 million Europeans, with its associated personal suffering and significant economic burden for health systems set to dramatically escalate in a rapidly ageing Europe. Given the very limited effective therapeutic options for OA, the European League Against Rheumatism (EULAR) created an ad hoc committee of OA researchers, clinicians and patients to consider a research agenda focussed on the areas of epidemiology, pathogenesis, imaging and biomarkers, and therapies. The committee deliberated and listed research needs in these areas and also established some cross-area priority themes: predictors of OA progression, especially where this might enable stratified interventions; understanding mechanisms of OA pain; improved understanding of tissue communication in a process where multiple tissue pathologies are common; developing concepts of, and consequently interventions for, early OA where both pain and structural processes may be more effectively targeted than in typical clinical presentations; and the need for new treatment strategies, with examples discussed on pathology-targeted therapies and optimal combinations of therapies. This research agenda should provide useful guidance for all researchers in this field and hopefully lead to improved OA care. PMID- 24625627 TI - GIMAP and Behcet disease: no association in the European population. PMID- 24625628 TI - Early aortic clamping in the surgical treatment of splenic artery aneurysm rupture. PMID- 24625629 TI - Side effects of proton-pump inhibitors: another reason to indicate anti-reflux surgery for Barrett's esophagus? PMID- 24625630 TI - A comparative analysis of prenatal care and fetal growth in eight South American countries. AB - There has been little work that comprehensively compared the relationship between prenatal care and infant health across multiple countries using similar data sources and analytical models. Such comparative analyses are useful for understanding the background of differences in infant health between populations. We evaluated the association between prenatal care visits and fetal growth measured by birth weight (BW) in grams or low birth weight (<2500 grams; LBW) adjusted for gestational age in eight South American countries using similarly collected data across countries and the same analytical models. OLS and logistic regressions were estimated adjusting for a large set of relevant infant, maternal, and household characteristics and birth year and hospital fixed effects. Birth data were acquired from 140 hospitals that are part of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network. The analytical sample included 56,014 live-born infants (~69% of total sample) with complete data born without congenital anomalies in the years 1996-2011 in Brazil, Argentina, Chile, Venezuela, Ecuador, Colombia, Bolivia, and Uruguay. Prenatal care visits were significantly (at p<.05) and positively associated with BW and negatively associated with LBW for all countries. The OLS coefficients ranged from 9 grams per visit in Bolivia to 36 grams in Uruguay. The association with LBW was strongest for Chile (OR = 0.87 per visit) and lowest for Argentina and Venezuela (OR = 0.95). The association decreased in the recent decade compared to earlier years. Our findings suggest that estimates of association between prenatal care and fetal growth are population-specific and may not be generalizable to other populations. Furthermore, as one of the indicators for a country's healthcare system for maternal and child health, prenatal care is a highly variable indicator between countries in South America. PMID- 24625631 TI - A cross-sectional study to assess the long-term health status of patients with lower respiratory tract infections, including Q fever. AB - Patients with a lower respiratory tract infection (LRTI) might be at risk for long-term impaired health status. We assessed whether LRTI patients without Q fever are equally at risk for developing long-term symptoms compared to LRTI patients with Q fever. The study was a cross-sectional cohort design. Long-term health status information of 50 Q fever-positive and 32 Q fever-negative LRTI patients was obtained. Health status was measured by the Nijmegen Clinical Screening Instrument. The most severely affected subdomains of the Q fever positive group were 'general quality of life' (40%) and 'fatigue' (40%). The most severely affected subdomains of the Q fever-negative group were 'fatigue' (64%) and 'subjective pulmonary symptoms' (35%). Health status did not differ significantly between Q fever-positive LRTI patients and Q fever-negative LRTI patients for all subdomains, except for 'subjective pulmonary symptoms' (P = 0.048). PMID- 24625632 TI - Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4,576 general population individuals with repeat measurements 10 years apart. AB - Cross-sectional studies have associated short telomere length with smoking, body weight, physical activity, and possibly alcohol intake; however, whether these associations are due to confounding is unknown. We tested these hypotheses in 4,576 individuals from the general population cross-sectionally, and with repeat measurement of relative telomere length 10 years apart. We also tested whether change in telomere length is associated with mortality and morbidity in the general population. Relative telomere length was measured with quantitative polymerase chain reaction. Cross-sectionally at the first examination, short telomere length was associated with increased age (P for trend across quartiles = 3 * 10(-77)), current smoking (P = 8 * 10(-3)), increased body mass index (P = 7 * 10(-14)), physical inactivity (P = 4 * 10(-17)), but not with increased alcohol intake (P = 0.10). At the second examination 10 years later, 56% of participants had lost and 44% gained telomere length with a mean loss of 193 basepairs. Change in leukocyte telomere length during 10 years was associated inversely with baseline telomere length (P<1 * 10(-300)) and age at baseline (P = 1 * 10(-27)), but not with baseline or 10-year inter-observational tobacco consumption, body weight, physical activity, or alcohol intake. Prospectively during a further 10 years follow-up after the second examination, quartiles of telomere length change did not associate with risk of all-cause mortality, cancer, chronic obstructive pulmonary disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease. In conclusion, smoking, increased body weight, and physical inactivity were associated with short telomere length cross-sectionally, but not with telomere length change during 10 years observation, and alcohol intake was associated with neither. Also, change in telomere length did not associate prospectively with mortality or morbidity in the general population. PMID- 24625633 TI - Production of squalene in Synechocystis sp. PCC 6803. AB - In recent years, there has been an increased interest in the research and development of sustainable alternatives to fossil fuels. Using photosynthetic microorganisms to produce such alternatives is advantageous, since they can achieve direct conversion of carbon dioxide from the atmosphere into the desired product, using sunlight as the energy source. Squalene is a naturally occurring 30-carbon isoprenoid, which has commercial use in cosmetics and in vaccines. If it could be produced sustainably on a large scale, it could also be used instead of petroleum as a raw material for fuels and as feedstock for the chemical industry. The unicellular cyanobacterium Synechocystis PCC 6803 possesses a gene, slr2089, predicted to encode squalene hopene cyclase (Shc), an enzyme converting squalene into hopene, the substrate for forming hopanoids. Through inactivation of slr2089 (shc), we explored the possibility to produce squalene using cyanobacteria. The inactivation led to accumulation of squalene, to a level over 70 times higher than in wild type cells, reaching 0.67 mg OD750(-1) L(-1). We did not observe any significant growth deficiency in the Deltashc strain compared to the wild type Synechocystis, even at high light conditions, suggesting that the observed squalene accumulation was not detrimental to growth, and that formation of hopene by Shc is not crucial for growth under normal conditions, nor for high light stress tolerance. Effects of different light intensities and growth stages on squalene accumulation in the Deltashc strain were investigated. We also identified a gene, sll0513, as a putative squalene synthase in Synechocystis, and verified its function by inactivation. In this work, we show that it is possible to use the cyanobacterium Synechocystis to generate squalene, a hydrocarbon of commercial interest and a potential biofuel. We also report the first identification of a squalene hopene cyclase, and the second identification of squalene synthase, in cyanobacteria. PMID- 24625634 TI - Yellow Fever outbreaks in unvaccinated populations, Brazil, 2008-2009. AB - Due to the risk of severe vaccine-associated adverse events, yellow fever vaccination in Brazil is only recommended in areas considered at risk for disease. From September 2008 through June 2009, two outbreaks of yellow fever in previously unvaccinated populations resulted in 21 confirmed cases with 9 deaths (case-fatality, 43%) in the southern state of Rio Grande do Sul and 28 cases with 11 deaths (39%) in Sao Paulo state. Epizootic deaths of non-human primates were reported before and during the outbreak. Over 5.5 million doses of yellow fever vaccine were administered in the two most affected states. Vaccine-associated adverse events were associated with six deaths due to acute viscerotropic disease (0.8 deaths per million doses administered) and 45 cases of acute neurotropic disease (5.6 per million doses administered). Yellow fever vaccine recommendations were revised to include areas in Brazil previously not considered at risk for yellow fever. PMID- 24625636 TI - The left and right ventricle in the grip of protein degradation: similarities and unique patterns in regulation. PMID- 24625635 TI - Cardiac fibroblast in development and wound healing. AB - Cardiac fibroblasts are the most abundant cell type in the mammalian heart and comprise approximately two-thirds of the total number of cardiac cell types. During development, epicardial cells undergo epithelial-mesenchymal-transition to generate cardiac fibroblasts that subsequently migrate into the developing myocardium to become resident cardiac fibroblasts. Fibroblasts form a structural scaffold for the attachment of cardiac cell types during development, express growth factors and cytokines and regulate proliferation of embryonic cardiomyocytes. In post natal life, cardiac fibroblasts play a critical role in orchestrating an injury response. Fibroblast activation and proliferation early after cardiac injury are critical for maintaining cardiac integrity and function, while the persistence of fibroblasts long after injury leads to chronic scarring and adverse ventricular remodeling. In this review, we discuss the physiologic function of the fibroblast during cardiac development and wound healing, molecular mediators of activation that could be possible targets for drug development for fibrosis and finally the use of reprogramming technologies for reversing scar. This article is part of a Special Issue entitled "Myocyte Fibroblast Signalling in Myocardium." PMID- 24625637 TI - Depression and anxiety in prostate cancer: a systematic review and meta-analysis of prevalence rates. AB - OBJECTIVES: To systematically review the literature pertaining to the prevalence of depression and anxiety in patients with prostate cancer as a function of treatment stage. DESIGN: Systematic review and meta-analysis. PARTICIPANTS: 4494 patients with prostate cancer from primary research investigations. PRIMARY OUTCOME MEASURE: The prevalence of clinical depression and anxiety in patients with prostate cancer as a function of treatment stage. RESULTS: We identified 27 full journal articles that met the inclusion criteria for entry into the meta analysis resulting in a pooled sample size of 4494 patients. The meta-analysis of prevalence rates identified pretreatment, on-treatment and post-treatment depression prevalences of 17.27% (95% CI 15.06% to 19.72%), 14.70% (95% CI 11.92% to 17.99%) and 18.44% (95% CI 15.18% to 22.22%), respectively. Pretreatment, on treatment and post-treatment anxiety prevalences were 27.04% (95% CI 24.26% to 30.01%), 15.09% (95% CI 12.15% to 18.60%) and 18.49% (95% CI 13.81% to 24.31%), respectively. CONCLUSIONS: Our findings suggest that the prevalence of depression and anxiety in men with prostate cancer, across the treatment spectrum, is relatively high. In light of the growing emphasis placed on cancer survivorship, we consider that further research within this area is warranted to ensure that psychological distress in patients with prostate cancer is not underdiagnosed and undertreated. PMID- 24625638 TI - Lipodystrophy among patients with HIV infection on antiretroviral therapy: a systematic review protocol. AB - INTRODUCTION: Lipodystrophy is a frequent and disfiguring adverse effect of antiretroviral therapy (ART) in patients with HIV. It affects the quality of life of the patient and adherence to treatment, and generates new needs for comprehensive healthcare services. The aim of this study will be to conduct a systematic review of the literature from observational studies and describe lipodystrophy among patients with HIV infection during current or previous use of ART. METHODS AND ANALYSIS: A systematic review of observational studies published in MEDLINE, CINAHL, LILACS, EMBASE and International Pharmaceutical Abstracts will be carried out. Citations of included studies will be checked to identify additional studies not identified in the electronic searches. It will include any observational study that considered lipodystrophy as the primary or secondary outcome and that had enrolled adolescent and adult patients with HIV infection who were on current or previous ART for at least 6 months. Data extraction and analysis will be performed independently by two reviewers. The extracted data will be discussed, decisions documented and, where necessary, the authors of the studies will be contacted for clarification. Measures of frequency, prevalence and incidence of lipodystrophy will be stratified according to definition, method of diagnosis and risk factors of the outcome. ETHICS AND DISSEMINATION: Ethics is not required given this is a protocol for a systematic review. The findings of this study will be widely disseminated through peer-reviewed publications and conference presentations. Updates of the review will be conducted to inform and guide healthcare practice. PROTOCOL REGISTRATION: PROSPERO-42013005450. PMID- 24625639 TI - Interaction of sleep quality and sleep duration on impaired fasting glucose: a population-based cross-sectional survey in China. AB - OBJECTIVES: To explore the interactions of sleep quality and sleep duration and their effects on impaired fasting glucose (IFG) in Chinese adults. DESIGN: Cross sectional survey. SETTING: Community-based investigation in Xuzhou, China. PARTICIPANTS: 15 145 Chinese men and women aged 18-75 years old who fulfilled the inclusion criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: The Pittsburgh Sleep Quality Index was used to produce sleep quality categories of good, common and poor. Fasting blood glucose levels were assessed for IFG. Sleep duration was measured by average hours of sleep per night, with categories of <6, 6-8 and >8 h. The products of sleep and family history of diabetes, obesity and age were added to the logistic regression model to evaluate the addictive interaction and relative excess risk of interaction (RERI) on IFG. The attributable proportion (AP) of the interaction and the synergy index (S) were applied to evaluate the additive interaction of two factors. Bootstrap measures were used to calculate 95% CI of RERI, AP and S. RESULTS: The prevalence of IFG was greatest in those with poor sleep quality and short sleep duration (OR 6.37, 95% CI 4.66 to 8.67; p<0.001) compared with those who had good sleep quality and 6-8 h sleep duration, after adjusting for confounders. After adjusting for potential confounders RERI, AP and S values (and their 95% CI) were 1.69 (0.31 to 3.76), 0.42 (0.15 to 0.61) and 2.85 (2.14 to 3.92), respectively, for the interaction between poor sleep quality and short sleep duration, and 0.78 (0.12 to 1.43), 0.61 (0.26 to 0.87) and -65 (-0.94 to -0.27) for the interaction between good sleep quality and long sleep duration. CONCLUSIONS: The results suggest that there are additive interactions between poor sleep quality and short sleep duration. PMID- 24625640 TI - Mapping patient safety: a large-scale literature review using bibliometric visualisation techniques. AB - BACKGROUND: The amount of scientific literature available is often overwhelming, making it difficult for researchers to have a good overview of the literature and to see relations between different developments. Visualisation techniques based on bibliometric data are helpful in obtaining an overview of the literature on complex research topics, and have been applied here to the topic of patient safety (PS). METHODS: On the basis of title words and citation relations, publications in the period 2000-2010 related to PS were identified in the Scopus bibliographic database. A visualisation of the most frequently cited PS publications was produced based on direct and indirect citation relations between publications. Terms were extracted from titles and abstracts of the publications, and a visualisation of the most important terms was created. The main PS-related topics studied in the literature were identified using a technique for clustering publications and terms. RESULTS: A total of 8480 publications were identified, of which the 1462 most frequently cited ones were included in the visualisation. The publications were clustered into 19 clusters, which were grouped into three categories: (1) magnitude of PS problems (42% of all included publications); (2) PS risk factors (31%) and (3) implementation of solutions (19%). In the visualisation of PS-related terms, five clusters were identified: (1) medication; (2) measuring harm; (3) PS culture; (4) physician; (5) training, education and communication. Both analysis at publication and term level indicate an increasing focus on risk factors. CONCLUSIONS: A bibliometric visualisation approach makes it possible to analyse large amounts of literature. This approach is very useful for improving one's understanding of a complex research topic such as PS and for suggesting new research directions or alternative research priorities. For PS research, the approach suggests that more research on implementing PS improvement initiatives might be needed. PMID- 24625641 TI - Impact of lattice mismatch and stoichiometry on the structure and bandgap of (Fe,Cr)2O3 epitaxial thin films. AB - The structural properties of phase-pure epitaxial (Fe1-xCrx)2O3 thin films deposited on alpha-Al2O3(0 0 0 1) substrates by oxygen-plasma-assisted molecular beam epitaxy are investigated across the composition range using x-ray photoelectron spectroscopy, high-resolution x-ray diffraction, scanning transmission electron microscopy and electron energy loss spectroscopy, and non Rutherford resonant elastic scattering measurements. The films possess a columnar grain structure with uniform mixing of cations on the nanometer scale. Fe-rich films are relaxed and appear to be slightly oxygen-rich, while Cr-rich films remain partially strained to the Al2O3 substrate and are found to be oxygen deficient. A model is proposed to explain the oxygen stoichiometry results based on the energetics of oxygen defect formation and rate of oxygen diffusion in the corundum lattice, and the dependence on the cation composition. Deliberately introducing residual compressive biaxial strain into (Fe1-xCrx)2O3 thin films (x = 0, 0.41, 0.52) by employing a Cr2O3 buffer layer is shown to narrow the optical bandgap, from 1.80(1) eV for relaxed (Fe0.47Cr0.53)2O3 to 1.77(1) eV for partially strained (Fe0.48Cr0.52)2O3. The relationships which are elucidated between epitaxial film structure and optical properties can be applied to bandgap optimization in the (Fe,Cr)2O3 system. PMID- 24625642 TI - Unique function of a chemosensory protein in the proboscis of two Helicoverpa species. AB - Chemosensory proteins (CSPs) are soluble proteins found only in arthropods. Some of them fill the lumen of chemosensilla and are believed to play a role similar to that of odorant-binding proteins in the detection of semiochemicals. Other members of the CSP family have been reported to perform different functions, from delivery of pheromones to development. This report is focused on a member (CSP4) of the family that is highly and almost exclusively present in the proboscis of two sibling noctuid species, Helicoverpa armigera and H. assulta. We expressed the protein in bacteria and measured binding to terpenoids and related compounds. Using specific antibodies, we found that when the moths suck on a sugar solution, CSP4 is partly extruded from the proboscis. A solution of protein can also fill a hydrophobic tube of same length and diameter as the proboscis by capillary action. On this basis, we suggest that CSP4 acts as a wetting agent to reduce the surface tension of aqueous solutions and consequently the pressure involved in sucking. PMID- 24625643 TI - Skeletal muscle fuel selection occurs at the mitochondrial level. AB - Mammals exponentially increase the rate of carbohydrate oxidation as exercise intensity rises, while birds combust lipid almost exclusively while flying at high percentages of aerobic capacity. The fuel oxidized by contracting muscle depends on many factors: whole-body fuel storage mass, mobilization, blood transport, cellular uptake, and substrate selection at the level of the mitochondrion. We examined the fuel preferences of mitochondria isolated from mammalian and avian locomotory muscles using two approaches. First, the influence of substrates on the kinetics of respiration (Km,ADP and Vmax) was evaluated. For all substrates and combinations, Km,ADP was generally twofold higher in avian mitochondria. Second, fuel competition between pyruvate, glutamate and/or palmitoyl-l-carnitine at three levels of ATP free energy was determined using the principle of mass balance and the measured rates of O2 consumption and metabolite accumulation/utilization. Avian mitochondria strongly spared pyruvate from oxidation when another substrate was available and fatty acid was the dominant substrate, regardless of energy state. Mammalian mitochondria exhibited some preference for fatty acid over pyruvate at lower flux (higher energy state), but exhibited a much greater tendency to select pyruvate and glutamate when available. Studies in sonicated mitochondria revealed twofold higher electron transport chain electron conductance in avian mitochondria. We conclude that substantial fuel selection occurs at the level of the mitochondrial matrix and that avian flight muscle mitochondria are particularly biased toward the selection of fatty acid, possibly by facilitating high beta-oxidation flux by maintaining a more oxidized matrix. PMID- 24625644 TI - Evolutionary capacity of upper thermal limits: beyond single trait assessments. AB - Thermal tolerance is an important factor influencing the distribution of ectotherms, but we still have limited understanding of the ability of species to evolve different thermal limits. Recent studies suggest that species may have limited capacity to evolve higher thermal limits in response to slower, more ecologically relevant rates of warming. However, these conclusions are based on univariate estimates of adaptive capacity. To test these findings within an explicitly multivariate context, we used a paternal half-sibling breeding design to estimate the multivariate evolutionary potential for upper thermal limits in Drosophila melanogaster. We assessed heat tolerance using static (basal and hardened) and ramping assays. Additive genetic variances were significantly different from zero only for the static measures of heat tolerance. Our G: matrix analysis revealed that any response to selection for increased heat tolerance will largely be driven by static basal and hardened heat tolerance, with minimal contribution from ramping heat tolerance. These results suggest that the capacity to evolve upper thermal limits in nature may depend on the type of thermal stress experienced. PMID- 24625645 TI - The cost of muscle power production: muscle oxygen consumption per unit work increases at low temperatures in Xenopus laevis. AB - Metabolic energy (ATP) supply to muscle is essential to support activity and behaviour. It is expected, therefore, that there is strong selection to maximise muscle power output for a given rate of ATP use. However, the viscosity and stiffness of muscle increases with a decrease in temperature, which means that more ATP may be required to achieve a given work output. Here, we tested the hypothesis that ATP use increases at lower temperatures for a given power output in Xenopus laevis. To account for temperature variation at different time scales, we considered the interaction between acclimation for 4 weeks (to 15 or 25 degrees C) and acute exposure to these temperatures. Cold-acclimated frogs had greater sprint speed at 15 degrees C than warm-acclimated animals. However, acclimation temperature did not affect isolated gastrocnemius muscle biomechanics. Isolated muscle produced greater tetanus force, and faster isometric force generation and relaxation, and generated more work loop power at 25 degrees C than at 15 degrees C acute test temperature. Oxygen consumption of isolated muscle at rest did not change with test temperature, but oxygen consumption while muscle was performing work was significantly higher at 15 degrees C than at 25 degrees C, regardless of acclimation conditions. Muscle therefore consumed significantly more oxygen at 15 degrees C for a given work output than at 25 degrees C, and plastic responses did not modify this thermodynamic effect. The metabolic cost of muscle performance and activity therefore increased with a decrease in temperature. To maintain activity across a range of temperature, animals must increase ATP production or face an allocation trade-off at lower temperatures. Our data demonstrate the potential energetic benefits of warming up muscle before activity, which is seen in diverse groups of animals such as bees, which warm flight muscle before take-off, and humans performing warm ups before exercise. PMID- 24625646 TI - Experimental analysis of the liquid-feeding mechanism of the butterfly Pieris rapae. AB - The butterfly Pieirs rapae drinks liquid using a long proboscis. A high pressure gradient is induced in the proboscis when cibarial pump muscles contract. However, liquid feeding through the long proboscis poses a disadvantage of high flow resistance. Hence, butterflies may possess special features to compensate for this disadvantage and succeed in foraging. The main objective of this study is to analyze the liquid-feeding mechanism of butterflies. The systaltic motion of the cibarial pump organ was visualized using the synchrotron X-ray imaging technique. In addition, an ellipsoidal pump model was established based on synchrotron X-ray micro-computed tomography. To determine the relationship between the cyclic variation of the pump volume and the liquid-feeding flow, velocity fields of the intake flow at the tip of the proboscis were measured using micro-particle image velocimetry. Reynolds and Womersley numbers of liquid feeding flow in the proboscis were ~1.40 and 0.129, respectively. The liquid feeding flow could be characterized as a quasi-steady state laminar flow. Considering these results, we analyzed the dimensions of the feeding apparatus on the basis of minimum energy consumption during the liquid-feeding process. The relationship between the proboscis and the cibarial pump was determined when minimum energy consumption occurs. As a result, the volume of the cibarial pump is proportional to the cube of the radius of the proboscis. It seems that the liquid-feeding system of butterflies and other long-proboscid insects follow the cube relationship. The present results provide insights into the feeding strategies of liquid-feeding butterflies. PMID- 24625647 TI - Can bees see at a glance? AB - Primates can analyse visual scenes extremely rapidly, making accurate decisions for presentation times of only 20 ms. We asked whether bumblebees, despite having potentially more limited processing power, could similarly detect and discriminate visual patterns presented for durations of 100 ms or less. Bumblebees detected stimuli and discriminated between differently oriented and coloured stimuli when presented as briefly as 25 ms but failed to identify ecologically relevant shapes (predatory spiders on flowers) even when presented for 100 ms. This suggests an important difference between primate and insect visual processing, so that while primates can capture entire visual scenes 'at a glance', insects might have to rely on continuous online sampling of the world around them, using a process of active vision, which requires longer integration times. PMID- 24625648 TI - Intracellular pH and its response to CO2-driven seawater acidification in symbiotic versus non-symbiotic coral cells. AB - Regulating intracellular pH (pHi) is critical for optimising the metabolic activity of corals, yet the mechanisms involved in pH regulation and the buffering capacity within coral cells are not well understood. Our study investigated how the presence of symbiotic dinoflagellates affects the response of pHi to PCO2-driven seawater acidification in cells isolated from Pocillopora damicornis. Using the fluorescent dye BCECF-AM, in conjunction with confocal microscopy, we simultaneously characterised the pHi response in host coral cells and their dinoflagellate symbionts, in symbiotic and non-symbiotic states under saturating light, with and without the photosynthetic inhibitor DCMU. Each treatment was run under control (pH 7.8) and CO2-acidified seawater conditions (decreasing pH from 7.8 to 6.8). After 105 min of CO2 addition, by which time the external pH (pHe) had declined to 6.8, the dinoflagellate symbionts had increased their pHi by 0.5 pH units above control levels when in the absence of DCMU. In contrast, in both symbiotic and non-symbiotic host coral cells, 15 min of CO2 addition (0.2 pH unit drop in pHe) led to cytoplasmic acidosis equivalent to 0.3 0.4 pH units irrespective of whether DCMU was present. Despite further seawater acidification over the duration of the experiment, the pHi of non-symbiotic coral cells did not change, though in host cells containing a symbiont cell the pHi recovered to control levels when photsynthesis was not inhibited. This recovery was negated when cells were incubated with DCMU. Our results reveal that photosynthetic activity of the endosymbiont is tightly coupled with the ability of the host cell to recover from cellular acidosis after exposure to high CO2/low pH. PMID- 24625649 TI - Undulatory locomotion of flexible foils as biomimetic models for understanding fish propulsion. AB - An undulatory pattern of body bending in which waves pass along the body from head to tail is a major mechanism of creating thrust in many fish species during steady locomotion. Analyses of live fish swimming have provided the foundation of our current understanding of undulatory locomotion, but our inability to experimentally manipulate key variables such as body length, flexural stiffness and tailbeat frequency in freely swimming fish has limited our ability to investigate a number of important features of undulatory propulsion. In this paper we use a mechanical flapping apparatus to create an undulatory wave in swimming flexible foils driven with a heave motion at their leading edge, and compare this motion with body bending patterns of bluegill sunfish (Lepomis macrochirus) and clown knifefish (Notopterus chitala). We found similar swimming speeds, Reynolds and Strouhal numbers, and patterns of curvature and shape between these fish and foils, suggesting that flexible foils provide a useful model for understanding fish undulatory locomotion. We swam foils with different lengths, stiffnesses and heave frequencies while measuring forces, torques and hydrodynamics. From measured forces and torques we calculated thrust and power coefficients, work and cost of transport for each foil. We found that increasing frequency and stiffness produced faster swimming speeds and more thrust. Increasing length had minimal impact on swimming speed, but had a large impact on Strouhal number, thrust coefficient and cost of transport. Foils that were both stiff and long had the lowest cost of transport (in mJ m(-1) g(-1)) at low cycle frequencies, and the ability to reach the highest speed at high cycle frequencies. PMID- 24625650 TI - A viral aphrodisiac in the cricket Gryllus texensis. AB - We identified the insect iridovirus IIV-6/CrIV as a pathogen of the cricket Gryllus texensis using electron microscopy (EM) and polymerase chain reaction (PCR) analysis. EM showed that the virus attacks the fat body, an organ important for protein production, immune function and lipid storage. During infection the fat body hypertrophied, but egg production withered, leaving the lateral oviducts empty of eggs; the females were effectively sterile. EM of the testis of infected males suggests that the testis was not invaded by the virus, although sperm taken from the spermatophores of infected males showed little or no motility. Nevertheless, males and females continued to mate when infected. In fact, infected males were quicker to court females than uninfected controls. The virus benefits from the continued sexual behaviour of its host; transmission studies show that the virus can be spread through sexual contact. Sickness behaviour, the adaptive reduction of feeding and sexual behaviour that is induced by an activated immune system, was absent in infected crickets. Total haemolymph protein was reduced, as was phenoloxidase activity, suggesting a reduction in immune protein production by the fat body. The evidence suggests that during IIV 6/CrIV infection, the immune signal(s) that induces sickness behaviour is absent. Curtailment of a host's sickness behaviour may be necessary for any pathogen that is spread by host sexual behaviour. PMID- 24625651 TI - The effect of water temperature and flow on respiration in barnacles: patterns of mass transfer versus kinetic limitation. AB - In aquatic systems, physiological processes such as respiration, photosynthesis and calcification are potentially limited by the exchange of dissolved materials between organisms and their environment. The nature and extent of physiological limitation is, therefore, likely to be dependent on environmental conditions. Here, we assessed the metabolic sensitivity of barnacles under a range of water temperatures and velocities, two factors that influence their distribution. Respiration rates increased in response to changes in temperature and flow, with an interaction where flow had less influence on respiration at low temperatures, and a much larger effect at high temperatures. Model analysis suggested that respiration is mass transfer limited under conditions of low velocity (<7.5 cm ( 1)) and high temperature (20-25 degrees C). In contrast, limitation by uptake reaction kinetics, when the biotic capacity of barnacles to absorb and process oxygen is slower than its physical delivery by mass transport, prevailed at high flows (40-150 cm s(-1)) and low temperatures (5-15 degrees C). Moreover, there are intermediate flow-temperature conditions where both mass transfer and kinetic limitation are important. Behavioral monitoring revealed that barnacles fully extend their cirral appendages at low flows and display abbreviated 'testing' behaviors at high flows, suggesting some form of mechanical limitation. In low flow-high temperature treatments, however, barnacles displayed distinct 'pumping' behaviors that may serve to increase ventilation. Our results suggest that in slow-moving waters, respiration may become mass transfer limited as temperatures rise, whereas faster flows may serve to ameliorate the effects of elevated temperatures. Moreover, these results underscore the necessity for approaches that evaluate the combined effects of multiple environmental factors when examining physiological and behavioral performance. PMID- 24625652 TI - Defective skeletogenesis and oversized otoliths in fish early stages in a changing ocean. AB - Early life stages of many marine organisms are being challenged by rising seawater temperature and CO2 concentrations, but their physiological responses to these environmental changes still remain unclear. In the present study, we show that future predictions of ocean warming (+4 degrees C) and acidification (DeltapH=0.5 units) may compromise the development of early life stages of a highly commercial teleost fish, Solea senegalensis. Exposure to future conditions caused a decline in hatching success and larval survival. Growth, metabolic rates and thermal tolerance increased with temperature but decreased under acidified conditions. Hypercapnia and warming amplified the incidence of deformities by 31.5% (including severe deformities such as lordosis, scoliosis and kyphosis), while promoting the occurrence of oversized otoliths (109.3% increase). Smaller larvae with greater skeletal deformities and larger otoliths may face major ecophysiological challenges, which might potentiate substantial declines in adult fish populations, putting in jeopardy the species' fitness under a changing ocean. PMID- 24625654 TI - Characterization of Salmonella Enteritidis strains isolated from poultry and farm environments in Brazil. AB - Salmonella Enteritidis is a major causative agent of foodborne outbreaks worldwide. Using enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) and pulsed-field gel electrophoresis (PFGE), this study assessed the genetic relatedness, the pathogenic potential, and antimicrobial resistance in 60 strains isolated from chickens and the farm environment in Brazil between 2004 and 2010. The resulting concatenated dendrogram of the two methodologies distinguished the strains into two clusters. Some strains isolated from the two sources were indistinguishable. All the strains contained the 13 virulence markers investigated. Forty-four strains were resistant to nalidixic acid. Quinolone resistance presented by many strains suggests that quinolones may have been used to treat chickens. The high prevalence of virulence markers highlights the importance of poultry as vehicles of S. Enteritidis strains that have the potential to cause disease. PMID- 24625653 TI - Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation. AB - Localization of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells to lymphoid and non-lymphoid tissue is instrumental for the effective control of immune responses. Compared with conventional T cells, Treg cells constitute a minute fraction of the T-cell repertoire. Despite this numeric disadvantage, Tregs efficiently migrate to sites of immune responses reaching an optimal number for the regulation of T effector (Teff) cells. The array and levels of adhesion and chemokine receptor expression by Tregs do not explain their powerful migratory capacity. Here we show that recognition of self-antigens expressed by endothelial cells in target tissue is instrumental for efficient Treg recruitment in vivo. This event relies upon IFN-gamma-mediated induction of MHC-class-II molecule expression by the endothelium and requires optimal PI3K p110delta activation by the T-cell receptor. We also show that, once in the tissue, Tregs inhibit Teff recruitment, further enabling a Teff:Treg ratio optimal for regulation. PMID- 24625656 TI - Performance of blood pressure-to-height ratio at a single screening visit for the identification of hypertension in children. AB - BACKGROUND: The diagnosis of hypertension in children is difficult because of the multiple sex-, age-, and height-specific thresholds to define elevated blood pressure (BP). Blood pressure-to-height ratio (BPHR) has been proposed to facilitate the identification of elevated BP in children. OBJECTIVE: We assessed the performance of BPHR at a single screening visit to identify children with hypertension that is sustained elevated BP. METHOD: In a school-based study conducted in Switzerland, BP was measured at up to three visits in 5207 children. Children had hypertension if BP was elevated at the three visits. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the identification of hypertension were assessed for different thresholds of BPHR. The ability of BPHR at a single screening visit to discriminate children with and without hypertension was evaluated with receiver operating characteristic (ROC) curve analyses. RESULTS: The prevalence of systolic/diastolic hypertension was 2.2%. Systolic BPHR had a better performance to identify hypertension compared with diastolic BPHR (area under the ROC curve: 0.95 vs. 0.84). The highest performance was obtained with a systolic BPHR threshold set at 0.80 mmHg/cm (sensitivity: 98%; specificity: 85%; PPV: 12%; and NPV: 100%) and a diastolic BPHR threshold set at 0.45 mmHg/cm (sensitivity: 79%; specificity: 70%; PPV: 5%; and NPV: 99%). The PPV was higher among tall or overweight children. CONCLUSION: BPHR at a single screening visit had a high performance to identify hypertension in children, although the low prevalence of hypertension led to a low PPV. PMID- 24625655 TI - Extrarenal atherosclerotic disease blunts renal recovery in patients with renovascular hypertension. AB - BACKGROUND: Atherosclerotic renovascular disease (ARVD) is associated with high rates of coronary events and predicts mortality among patients with coronary artery disease (CAD). However, the impact of coronary atherosclerosis on renal outcomes after revascularization of ARVD is unclear. We hypothesized that CAD negatively impacts renal functional outcomes among patients with ARVD undergoing renal artery revascularization. METHODS: Patients with ARVD who underwent echocardiography at Mayo Clinic, Rochester, Minnesota, USA between 2004 and 2012 were identified retrospectively and included if they had ejection fraction more than 50%. Renal and overall outcomes were compared among atherosclerotic renovascular disease patients with coronary artery disease (ARVD-C, n = 75) and without coronary artery disease (ARVD, n = 56), within 1 year from initial revascularization and included blood pressure control, renal function, and incident cardiovascular/cerebrovascular events. RESULTS: Degree of renal artery stenosis was similar in both groups. ARVD-C had higher prevalence of diabetes, peripheral artery disease (PAD), and cerebrovascular disease, and lower baseline renal function. Risk of developing end-stage renal disease was higher in ARVD-C (11 vs. 2%, P = 0.05). Despite better control of blood pressure and cholesterol levels, renal function postrevascularization worsened in 15% of ARVD-C compared with 2% of ARVD (P = 0.01). Differences in clinical outcomes remained statistically significant after adjustment for covariables, including sex, baseline blood pressure, renal function, underlying diabetes, cholesterol levels, and medications. Similar differences in clinical outcomes were also associated with PAD and cerebrovascular disease. CONCLUSION: CAD in patients with ARVD is a predictor of worse outcomes after renal revascularization, likely reflecting diffuse atherosclerotic disease. Further studies are needed to develop strategies to manage patients with vascular comorbidities and improve their outcomes. PMID- 24625657 TI - Where Do Self-Concordant Goals Come From? The Role of Domain-Specific Psychological Need Satisfaction. AB - Previous research has shown that self-concordant goals are more likely to be attained. But what leads someone to adopt a self-concordant goal in the first place? The present research addresses this question by looking at the domains in which goals are set, focusing on the amount of psychological need satisfaction experienced in these domains. Across three experimental studies, we demonstrate that domain-related need satisfaction predicts the extent to which people adopt self-concordant goals in a given domain, laying the foundation for successful goal pursuit. In addition, we show that need satisfaction influences goal self concordance because in need-satisfying domains people are both more likely to choose the most self-concordant goal (among a set of comparable choices), and are more likely to internalize the possible goals. The implications of this research for goal setting and pursuit as well as for the importance of examining goals within their broader motivational framework are discussed. PMID- 24625658 TI - More Diverse Yet Less Tolerant? How the Increasingly Diverse Racial Landscape Affects White Americans' Racial Attitudes. AB - Recent Census Bureau projections indicate that racial/ethnic minorities will comprise over 50% of the U.S. population by 2042, effectively creating a so called "majority-minority" nation. Across four experiments, we explore how presenting information about these changing racial demographics influences White Americans' racial attitudes. Results reveal that exposure to the changing demographics evokes the expression of greater explicit and implicit racial bias. Specifically, Whites exposed to the racial demographic shift information preferred interactions/settings with their own ethnic group over minority ethnic groups; expressed more negative attitudes toward Latinos, Blacks, and Asian Americans; and expressed more automatic pro-White/anti-minority bias. Perceived threat to Whites' societal status mediated the effects of the racial shift information on explicit racial attitudes. These results suggest that rather than ushering in a more tolerant future, the increasing diversity of the nation may instead yield intergroup hostility. Implications for intergroup relations and media framing of the racial shift are discussed. PMID- 24625660 TI - Top- and bottom-emission-enhanced electroluminescence of deep-UV light-emitting diodes induced by localised surface plasmons. AB - We report localised-surface-plasmon (LSP) enhanced deep-ultraviolet light emitting diodes (deep-UV LEDs) using Al nanoparticles for LSP coupling. Polygonal Al nanoparticles were fabricated on the top surfaces of the deep-UV LEDs using the oblique-angle deposition method. Both the top- and bottom-emission electroluminescence of deep-UV LEDs with 279 nm multiple-quantum-well emissions can be effectively enhanced by the coupling with the LSP generated in the Al nanoparticles. The primary bottom-emission wavelength is longer than the primary top-emission wavelength. This difference in wavelength can be attributed to the substrate-induced Fano resonance effect. For resonance modes with shorter wavelengths, the radiation fraction directed back into the LEDs is largest in the direction that is nearly parallel to the surface of the device and results in total reflection and re-absorption in the LEDs. PMID- 24625659 TI - Intravenous phosphate loading increases fibroblast growth factor 23 in uremic rats. AB - Oral phosphate loading and calcitriol stimulate Fibroblast growth factor 23 (FGF23) secretion, but the mechanisms underlying the stimulation of FGF23 remain to be studied. We compared the effect of intravenous phosphate loading with that of oral loading on FGF23 levels in normal and 5/6 nephrectomized uremic rats. Uremic rats (Nx) and sham-operated rats were fed a normal phosphate diet for 2 weeks and then divided into 3 groups: 1) with the same phosphate diet (NP), 2) with a high phosphate diet (HP), and 3) NP rats with intravenous phosphate infusion using a microinfusion pump (IV). Blood and urine were obtained 1 day (early phase) and 7 days (late phase) after the interventions. In the early and late phases, serum phosphate levels and fractional excretion of phosphate (FEP) were comparable in the HP and IV groups in both Sham and Nx rats. Serum phosphate levels in the HP and IV groups were equally and significantly higher than those in the NP group only in the late phase in Nx rats. In the early phase, FGF23 levels were comparable in the NP, HP, and IV groups, but were significantly higher in the HP and IV groups compared to the NP group in the late phase in Nx rats. 1alpha-hydroxylase and sodium dependent phosphate co-transporter 2a expression levels in the kidney in Nx rats were equally and significantly decreased in the HP and IV groups compared with the NP group, while 24 hydroxylase expression was equally and significantly increased. These results show that chronic intravenous phosphate loading increases bioactive FGF23, indicating that an alternative pathway for FGF23 regulation, in addition to the dietary route, may be present. This pathway is clearer under conditions produced by a kidney injury in which phosphate is easily overloaded. PMID- 24625662 TI - Comparative proteomic analysis of differential responses of Pinus massoniana and Taxus wallichiana var. mairei to simulated acid rain. AB - Acid rain (AR), a serious environmental issue, severely affects plant growth and development. As the gymnosperms of conifer woody plants, Pinus massoniana (AR sensitive) and Taxus wallichiana var. mairei (AR-resistant) are widely distributed in southern China. Under AR stress, significant necrosis and collapsed lesions were found in P. massoniana needles with remarkable yellowing and wilting tips, whereas T. wallichiana var. mairei did not exhibit chlorosis and visible damage. Due to the activation of a large number of stress-related genes and the synthesis of various functional proteins to counteract AR stress, it is important to study the differences in AR-tolerance mechanisms by comparative proteomic analysis of tolerant and sensitive species. This study revealed a total of 65 and 26 differentially expressed proteins that were identified in P. massoniana and T. wallichiana var. mairei, respectively. Among them, proteins involved in metabolism, photosynthesis, signal transduction and transcription were drastically down-regulated in P. massoniana, whereas most of the proteins participating in metabolism, cell structure, photosynthesis and transcription were increased in T. wallichiana var. mairei. These results suggest the distinct patterns of protein expression in the two woody species in response to AR, allowing a deeper understanding of diversity on AR tolerance in forest tree species. PMID- 24625664 TI - Intratumoral decorin gene delivery by AAV vector inhibits brain glioblastomas and prolongs survival of animals by inducing cell differentiation. AB - Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors. PMID- 24625666 TI - Which reasons do doctors, nurses, and patients have for hospital discharge? A mixed-methods study. AB - BACKGROUND: The decision to discharge a patient from a hospital is a complex process governed by many medical and non-medical factors, while the actual reasons for discharge frequently remain ill-defined. AIM: To define relevant discharge criteria as perceived by doctors, nurses and patients for the development of a standard hospital discharge policy, we collected actual reasons and most pivotal medical and organisational criteria for discharge among all stakeholders. SETTING: A tertiary referral university teaching hospital. METHODS: We conducted a mixed methods analysis, using patient questionnaires, interviews and a focus group with caregivers, and observations during the daily rounds of doctors, nurses and patients during their hospital stay. Fourteen wards of the Surgery, Paediatrics and Neurology departments contributed. RESULTS: We observed 426 patients during their hospital stay. Forty doctors and nurses were interviewed, and 7 senior nurses attended a focus group. The most commonly used discharge criteria were clinical factors, organisational discharge issues and patient-related factors. A total of 269 patients returned their questionnaires. About one third of the adult patients and nearly half of the children (or their parents) felt their personal situation and assistance needed at home was insufficiently taken into account before discharge. Patients were least satisfied with the information given about what they were allowed to do or should avoid after discharge and their involvement in the planning of their discharge. Thus, besides obvious medical reasons for discharge, several non-medical reasons were signalled by all stakeholders as important issues to be improved. CONCLUSIONS: A set of discharge criteria could be defined that is useful for a more uniform hospital discharge policy that may help reduce unnecessary length of stay and improve patient satisfaction. PMID- 24625665 TI - Carvacrol and trans-cinnamaldehyde reduce Clostridium difficile toxin production and cytotoxicity in vitro. AB - Clostridium difficile is a nosocomial pathogen that causes a serious toxin mediated enteric disease in humans. Reducing C. difficile toxin production could significantly minimize its pathogenicity and improve disease outcomes in humans. This study investigated the efficacy of two, food-grade, plant-derived compounds, namely trans-cinnamaldehyde (TC) and carvacrol (CR) in reducing C. difficile toxin production and cytotoxicity in vitro. Three hypervirulent C. difficile isolates were grown with or without the sub-inhibitory concentrations of TC or CR, and the culture supernatant and the bacterial pellet were collected for total toxin quantitation, Vero cell cytotoxicity assay and RT-qPCR analysis of toxin encoding genes. The effect of CR and TC on a codY mutant and wild type C. difficile was also investigated. Carvacrol and TC substantially reduced C. difficile toxin production and cytotoxicity on Vero cells. The plant compounds also significantly down-regulated toxin production genes. Carvacrol and TC did not inhibit toxin production in the codY mutant of C. difficile, suggesting a potential codY-mediated anti-toxigenic mechanism of the plant compounds. The antitoxigenic concentrations of CR and TC did not inhibit the growth of beneficial gut bacteria. Our results suggest that CR and TC could potentially be used to control C. difficile, and warrant future studies in vivo. PMID- 24625668 TI - Accuracy in interpreting the paediatric ECG: a UK-wide study and the need for improvement. AB - BACKGROUND: Paediatric ECG interpretation is significant for informed treatment of several conditions. Formal training in paediatric ECG is rarely undertaken. METHODS: A prospective survey based study module of UK-wide paediatricians registered with the UK Royal College of Paediatricians and Child Health (RCPCH) was conducted. 10 common clinical conditions seen in paediatrics for which there are recognisable ECGs had to be interpreted. After provision of an educational page, 10 further ECGs were presented. FINDINGS: 8450 RCPCH members were emailed a link to the online survey-study module, of whom 764 participated. Of these, 493 interpreted the first 10 ECGs, and 385 interpreted both sets of ECGs. The accuracy for the first ECGs was 61.5% (63.5% for those who participated in the whole survey), and after use of the educational page increased to 73.3%. This was independent from previous ECG training. CONCLUSIONS: The use of an easily accessible online educational page improved the accuracy of paediatric ECG interpretation significantly. Internet based education can improve the accuracy of paediatric ECG interpretation and should be developed further. PMID- 24625667 TI - Making ambulatory blood pressure monitoring accessible in pharmacies. AB - OBJECTIVES: Ambulatory blood pressure measurement (ABPM), although recommended for the diagnosis and management of hypertension, has limited availability. The objective of this study was to show that if the characteristics of patients attending pharmacies for ABPM are similar to those attending primary care, the technique can be made more widely available to patients through pharmacies. PATIENTS AND METHODS: A comparative study using a software program that allowed central collection, analysis and comparison of ABPM data from patients attending primary care and pharmacies for assessment of hypertension in Ireland. RESULTS: ABPM data from 46 978 patients attending primary care were compared with 1698 attending pharmacies between 2007 and 2013. The age, sex and blood pressure characteristics of patients attending primary care and pharmacies were similar. The mean pressures in all categories, except for systolic blood pressure recorded in primary care, were higher in men. The first ABPM measurements recorded in pharmacies were slightly higher than those in primary care (150.8 +/- 19.5/88.7 +/- 13.7 vs. 149.6 +/- 20.7/88.0 +/- 14.4 mmHg). More patients attending primary care were normotensive than those attending pharmacies (19.5 vs. 16.4%), whereas more patients attending pharmacies were hypertensive than those attending primary care (62.8 vs. 60.7%), particularly female patients (61.0 vs. 56.4%). White-coat hypertension was similar in patients attending primary care and pharmacies (19.8 vs. 20.8%), but it was more prevalent in men attending pharmacies (22.0 vs. 17.4%) and in women attending primary care (21.9 vs. 19.7%). There were more dippers in pharmacy then primary care ABPMs (84.7 vs. 79.4%). A preference for having ABPM on Fridays and Saturdays was evident in patients attending pharmacies (19.6 vs. 6.6%), whereas there was a preference for early morning recording in primary care (4.1 vs. 1.1%). CONCLUSION: This study, which is the first to report on ABPM data from the pharmacy setting, shows that the blood pressure characteristics of patients with ABPMs recorded in pharmacies are similar to those recorded in primary care practices. It is feasible, therefore, to perform ABPM in pharmacies, which can be utilized to make ABPM more accessible to the large number of patients in the population with hypertension. PMID- 24625663 TI - Sphingolipids: key regulators of apoptosis and pivotal players in cancer drug resistance. AB - Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a) counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b) increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c) modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (alphaNeu5Ac(2 8)alphaNeu5Ac(2-3)betaGal(1-4)betaGlc(1-1)Cer) or N-glycolyl GM3 (alphaNeu5Ac (2 3)betaGal(1-4)betaGlc(1-1)Cer) and de-N-acetyl GM3 (NeuNH(2)betaGal(1-4)betaGlc(1 1)Cer) endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy. PMID- 24625669 TI - High rates of potentially infectious tuberculosis and multidrug-resistant tuberculosis (MDR-TB) among hospital inpatients in KwaZulu Natal, South Africa indicate risk of nosocomial transmission. AB - BACKGROUND: Nosocomial transmission has been implicated as a key factor in the outbreak of extensively drug resistant (XDR) and multidrug-resistant (MDR-TB) tuberculosis at Church of Scotland Hospital (CoSH), in KwaZulu-Natal (KZN), South Africa. The aim of this study was to quantify the burden of potentially infectious tuberculosis and the proportion of drug resistance among hospital inpatients throughout the province of KZN. METHODS: Inpatients with current cough, capable of producing sputum were selected from 19 public hospitals in KZN. After informed consent, demographic and clinical data, and sputum samples were collected. Samples were processed for fluorescent microscopy, liquid culture and first and second-line anti-tuberculosis drug susceptibility testing. RESULTS: There were a total of 2,964 inpatients where sampling was done. About 1,585 inpatients (53%) had a current cough and sufficient microbiological and clinical data for inclusion. Mycobacterium tuberculosis was isolated from 543 inpatients (34% of those tested and 18% of all inpatients). Eighty-four (15%) inpatients with TB were found to be MDR-TB infected and 16 (3%) had XDR-TB. There was no association between the prevalence of MDR-TB and proximity to CoSH. Among patients with microbiologically confirmed TB, MDR/XDR-TB was associated with male sex, a longer length of stay between hospital admission and date of sample collection, and current or previous TB treatment. CONCLUSIONS: One in five inpatients had potentially infectious TB. This is an underestimate since patients without current cough were not tested. MDR-TB was frequently observed and was found in nearly one in six active TB inpatients. While present at lower levels than the original outbreak report at CoSH, XDR-TB was detected in hospitals throughout KZN. The high burden of potentially infectious TB and confirmed MDR TB, much of it undiagnosed, indicates a serious risk for nosocomial transmission and the need for intensified infection control within the inpatient setting. PMID- 24625671 TI - Protection against experimental aspergillosis by heat-killed yeast is not antibody dependent. AB - Previously we showed heat-killed yeast (HKY) of Saccharomyces cerevisiae administered as a vaccine are protective against systemic murine aspergillosis (and other mycoses) and that HKY induces antibody and cellular responses. To determine the role of antibodies in this protection, male antibody knockout mice (KO; strain B6.129S2-Igh-6 (tm1Cgn)/J) and C57BL/6 wild-type (WT) mice were vaccinated subcutaneously with 6 * 10(7) HKY or phosphate buffered saline (PBS) given three or four times. Mice were infected intravenously with 6 * 10(6) viable conidia of Aspergillus fumigatus 10AF and mortality tallied through 12 days post infection. HKY vaccination given four times proved protective in the prolongation of survival of WT and KO mice vs. the respective PBS-treated controls. In one study, survival was prolonged in vaccinated WT or KO mice (P < 0.0001). A second study confirmed these results (P < 0.0001). Additionally, a three-dose regimen of HKY was also effective, prolonging survival of WT or KO mice vs. controls (P = 0.0002); no difference was found when the effectiveness of three- or four-dose regimens was compared. No significant differences in survival were found between HKY-vaccinated WT and KO mice, nor were PBS-treated KO mice more susceptible to infection than PBS-treated WT mice. Similar results were noted in another study in which a higher infectious inoculum and a three-dose regimen were used. Overall, antibodies do not appear to play a significant role in HKY-induced prolongation of survival in systemic aspergillosis, nor do antibodies appear to play a role in the innate resistance of the mice to aspergillosis. PMID- 24625670 TI - Estimation of sensitivity and specificity of bacteriology, histopathology and PCR for the confirmatory diagnosis of bovine tuberculosis using latent class analysis. AB - Bacteriology and histopathology are the most commonly used tests used for official confirmatory diagnosis of bovine tuberculosis (bTB) in cattle in most countries. PCR is also being used increasingly because it allows a fast diagnosis. This test could be applied as a supplement to or replacement for current bTB confirmatory diagnostic tests but its characteristics have first to be evaluated. The aim of this study was to estimate and compare sensitivities and specificities of bacteriology, histopathology and PCR under French field conditions, in the absence of a gold standard using latent class analysis. The studied population consisted of 5,211 animals from which samples were subjected to bacteriology and PCR (LSI VetMAXTM Mycobacterium tuberculosis Complex PCR Kit, Life Technologies) as their herd of origin was either suspected or confirmed infected with bTB or because bTB-like lesions were detected during slaughterhouse inspection. Samples from 697 of these animals (all with bTB-like lesions) were subjected to histopathology. Bayesian models were developed, allowing for dependence between bacteriology and PCR, while assuming independence from histopathology. The sensitivity of PCR was higher than that of bacteriology (on average 87.7% [82.5-92.3%] versus 78.1% [72.9-82.8%]) while specificity of both tests was very good (on average 97.0% for PCR [94.3-99.0%] and 99.1% for bacteriology [97.1-100.0%]). Histopathology was at least as sensitive as PCR (on average 93.6% [89.9-96.9%]) but less specific than the two other tests (on average 83.3% [78.7-87.6%]). These results suggest that PCR has the potential to replace bacteriology to confirm bTB in samples submitted from suspect cattle. PMID- 24625672 TI - In vitro and in vivo activity of a killer peptide against Malassezia pachydermatis causing otitis in dogs. AB - In order to overcome the limitations inherent in current pharmacological treatments for Malassezia pachydermatis, the cause of otitis externa in dogs, the efficacy of a killer decapeptide (KP) was evaluated in vitro and in vivo. Sixteen dogs with naturally occurring M. pachydermatis otitis externa were enrolled, and the in vitro fungicidal activity of KP was evaluated using yeasts recovered from these animals. The therapeutic activity was evaluated in four groups of four animals each. The dogs were topically treated with KP (150 MUl, 2 mg/ml) three times per week (group A) or every day (group B), treated with a scramble peptide every day (group C), or left untreated (group D). Assessment of clinical signs (pruritus, erythema, and lichenification and/or hyperpigmentation), expressed as mean of the total clinical index score (mTCIS), the population size of M. pachydermatis at the cytological examination (mean number of yeast cells at 40* magnification [mYC]), and culture testing (mean number of log10 CFU/swab [mCFU]), were conducted daily from the first day of treatment (T0) until two consecutive negative cultures (mCFU <= 2). KP showed an in vitro fungicidal effect against M. pachydermatis isolates, with an MFC90 value of 1 MUg/ml. The mTCIS, mYC and mCFU were negative only in animals in group B after T8. Daily administration of KP for 8 days was safe and effective in controlling both clinical signs and the population size of M. pachydermatis causing otitis externa, thus offering an alternative to the currently available therapeutic or prophylactic protocols for recurrent cases of Malassezia otitis in dogs. PMID- 24625673 TI - Is catheter-related candidemia a polyclonal infection? AB - Diagnosis of catheter-related candidemia (CRC) requires the simultaneous isolation of Candida spp. from both blood and catheter samples. We previously observed that in most CRC cases, the genotype of the yeast found in catheter samples is also recovered from blood. However, it is not clear whether CRC is a polyclonal infection. We prospectively studied 20 patients with CRC caused by Candida albicans, C. parapsilosis, or C. glabrata to analyze whether their infections were polyclonal. As many as 10 colonies per sample (n = 475) isolated from blood (n = 220) and catheter (n = 255) specimens were studied using species specific microsatellite markers. Genotyping always revealed matches between the Candida spp. from blood and catheter samples. However, 15% of patients had a polyclonal pattern of infection or catheter colonization that was species specific. An additional genotype was found exclusively in the catheters of two patients infected with C. albicans, whereas an additional genotype was noted in the blood culture of a patient infected with C. parapsilosis. Considering only the presence of different genotypes in blood samples, 5% of patients had polyclonal infections. We conclude that most cases of CRC are caused by a single genotype. PMID- 24625674 TI - Molecular diagnosis of Pneumocystis jirovecii in patients with malignancy: clinical significance of quantitative polymerase chain reaction. AB - Pneumocystis jirovecii pneumonia (PJP) is increasingly seen in association with the use of new and potent immunosuppressive therapies in populations not infected with human immunodeficiency virus. Today, molecular methods are widely used to improve diagnostic yield; however, the relationship between clinical findings and quantitative polymerase chain reaction (qPCR) results is undefined. Our objective was to describe characteristics of PJP in patients with malignancies and determine if qPCR results were correlated with clinical findings. From 2007 to 2012, all patients at the Peter MacCallum Cancer Centre with positive Pneumocystis PCR were identified from a microbiology database. Clinical, radiological, and microbiological records were reviewed. PJP was defined as the presence of positive PCR for Pneumocystis on a respiratory specimen, radiological abnormalities consistent with a pneumonic process, and receipt of targeted PJP treatment. qPCR was performed on all diagnostic specimens, and values were reported according to clinical findings. Forty-five patients fulfilled inclusion criteria: 44.4% had underlying solid organ tumors and 55.6% had hematological malignancies. Nonsmall cell lung carcinoma and lymphoma were the most frequent predispositions. Shortness of breath, cough, and fever were reported in 64.4%, 48.9%, and 42.2% of the patients, respectively. Admission to the intensive care unit and mortality rates were lower than in previous reports. Overall, a relationship between other clinical features and qPCR results was not identified. In the era of routine molecular diagnostics, patients with malignancy and PJP have improved outcomes. However, there was no demonstrable relationship between qPCR results and clinical features or PCR data and outcomes. PMID- 24625675 TI - A family of glutathione peroxidases contributes to oxidative stress resistance in Candida albicans. AB - Candida albicans is a well-adapted human commensal but is also a facultative pathogen that can cause superficial and systemic infections. Its remarkable capacity to thrive within the human host relies on its ability to adapt and respond to the local environment of different niches. C. albicans is able to cope with oxidative stress in a coordinated fashion via upregulation of different protective mechanisms. Here, we unravel the role of a family of glutathione peroxidase (GPx), designated Gpx31, Gpx32, and Gpx33, in oxidative stress resistance. We show that GPx activity in C. albicans is induced upon exposure to peroxides and that this enzymatic activity is required for full resistance to oxidative stress. The GPx activity relies on the presence of GPX31, with no apparent contribution from GPX32 and GPX33 during in vitro short-term (3 h) exposure to peroxides. However, a triple gpx31-33Delta/Delta mutant exhibited a more pronounced sensitivity than a single gpx31Delta/Delta mutant on solid media in the presence of oxidants, suggesting that GPX32 and GPX33 may be involved in long-term adaptation to oxidative stress. Interestingly, reintegration of a single allele of GPX31 was sufficient to restore the wild-type phenotype in both the single and triple mutants. We found that mutants lacking GPX31-33 were more susceptible to killing by phagocytic cells, suggesting that GPxs are required for full resistance to innate immune effector cells. Despite the sensitivity to oxidative stress and phagocytes, these mutants were not affected in their virulence in the chicken embryo model of candidiasis. PMID- 24625676 TI - Cat favus caused by Microsporum incurvatum comb. nov.: the clinical and histopathological features and molecular phylogeny. AB - Favus is a distinctive form of infection that is caused by exclusively dermatophytes. Its clinical presentation is characterized by scutula, which are concave, thick fungal crusts. The best-known examples of human scalp favus are caused by Trichophyton schoenleinii and those of mouse favus are caused by T. quinckeanum. However, other dermatophytes, such as T. violaceum, T. verrucosum, Microsporum audouinii, M. gallinae, M. gypseum, and M. canis, have been reported sporadically to cause favic lesions. Favus on cats has rarely been mentioned in the literature, and the pathogens with which it has been associated are, for the most part, unknown. Here, we examine four cat favus cases, focusing on clinical presentations and histopathological features. In all cases the etiologic agent was identified as M. incurvatum based on its morphological characteristics and sequences of internal transcribed spacers (ITS) of nuclear ribosomal DNA. Phylogenetic analysis using the neighbor-joining method, which is based on ITS, showed that these four isolates belonged to two strains of M. incurvatum; one strain was a new combination from the basionym Nannizzia incurvata. PMID- 24625677 TI - Comparative adherence of Candida albicans and Candida dubliniensis to human buccal epithelial cells and extracellular matrix proteins. AB - Candida albicans and Candida dubliniensis are very closely related pathogenic yeast species. Despite their close relationship, C. albicans is a far more successful colonizer and pathogen of humans. The purpose of this study was to determine if the disparity in the virulence of the two species is attributed to differences in their ability to adhere to human buccal epithelial cells (BECs) and/or extracellular matrix proteins. When grown overnight at 30 degrees C in yeast extract peptone dextrose, genotype 1 C. dubliniensis isolates were found to be significantly more adherent to human BECs than C. albicans or C. dubliniensis genotypes 2-4 (P < 0.001). However, when the yeast cells were grown at 37 degrees C, no significant difference between the adhesion of C. dubliniensis genotype 1 and C. albicans to human BECs was observed, and C. dubliniensis genotype 1 and C. albicans adhered to BECs in significantly greater numbers than the other C. dubliniensis genotypes (P < 0.001). Using surface plasmon resonance analysis, C. dubliniensis isolates were found to adhere in significantly greater numbers than C. albicans to type I and IV collagen, fibronectin, laminin, vitronectin, and proline-rich peptides. These data suggest that C. albicans is not more adherent to epithelial cells or matrix proteins than C. dubliniensis and therefore other factors must contribute to the greater levels of virulence exhibited by C. albicans. PMID- 24625678 TI - Microsporum aenigmaticum sp. nov. from M. gypseum complex, isolated as a cause of tinea corporis. AB - An undescribed Microsporum species was isolated from skin scales recovered from a 40-mm large, annular, scaling lesion on the wrist of a 46-year-old woman. The risk factors for dermatophyte infection in the patient were frequent work in the garden, hunting, and contact with dogs and horses. Direct microscopic examination of the scales revealed the presence of dermatophyte hyphae; when the samples were cultured, a morphologically similar fungus grew on all slants in pure culture. Both of these findings strongly suggested that the isolate was the true causal agent of infection. The possible geophilic nature of the species was based on phylogenetic analysis (internal transcribed spacer region of rDNA and beta tubulin gene) that placed it in between species of the M. gypseum complex. However, its divergencies from all other Microsporum species exceeded 4% base pairs. Based on beta-tubulin phylogeny, the isolated species is a sister to M. gypseum. The species produces abundant chlamydospores and clumps of hyphae similar to those of ascomatal primordia but no conidia and ascospores. The species was unable to grow at 37 degrees C and does not grow on T6 basal medium, which is unlike other Microsporum species; hair perforation and urease tests were positive. The addition of histidine to the T6 medium resulted in rapid growth of the fungus. The phylogenetic evidence, morphology, growth parameters, and physiology justified the proposal that the isolate is a new species, M. aenigmaticum, sp. nov. PMID- 24625680 TI - Evaluation of the SF6 tracer technique for estimating methane emission rates with reference to dairy cows using a mechanistic model. AB - A dynamic, mechanistic model of the sulfur hexafluoride (SF6) tracer technique, used for estimating methane (CH4) emission rates from ruminants, was constructed to evaluate the accuracy of the technique. The model consists of six state variables and six zero-pools representing the quantities of SF6 and CH4 in rumen and hindgut fluid, in rumen and hindgut headspace, and in blood and collection canister. The model simulates flows of CH4 and SF6 through the body, subsequent eructation and exhalation and accumulation in a collection canister. The model predicts CH4 emission by multiplying the SF6 release rate of a permeation device in the rumen by the ratio of CH4:SF6 in collected air. This prediction is compared with the actual CH4 production rate, assumed to be continuous and used as a driving variable in the model. A sensitivity analysis was conducted to evaluate the effect of changes in several parameters. The predicted CH4 emission appeared sensitive to parameters affected by the difference in CH4:SF6 ratio in exhaled and eructed air respectively, viz., hindgut fractional passage rate and hindgut CH4 production. This is caused by the difference in solubility of CH4 and SF6 and by hindgut CH4 production. In addition, the predicted CH4 emission rate appeared sensitive to factors that affect proportions of exhaled and eructed air sampled, i.e., eructation time fraction, exhalation time fraction, and distance from sampling point to mouth/nostrils. Changes in rumen fractional passage rate, eructation rate, SF6 release rate, background values and air sampling rate did not noticeably affect the predicted CH4 emission. Simulations with (13)CH4 as an alternative tracer show that the differences and sensitivity to parameters greatly disappear. The model is considered a useful tool to evaluate critical points in the SF6 technique. Data from in vivo experiments are needed to further evaluate model simulations. PMID- 24625679 TI - Lsd1 restricts the number of germline stem cells by regulating multiple targets in escort cells. AB - Specialized microenvironments called niches regulate tissue homeostasis by controlling the balance between stem cell self-renewal and the differentiation of stem cell daughters. However the mechanisms that govern the formation, size and signaling of in vivo niches remain poorly understood. Loss of the highly conserved histone demethylase Lsd1 in Drosophila escort cells results in increased BMP signaling outside the cap cell niche and an expanded germline stem cell (GSC) phenotype. Here we present evidence that loss of Lsd1 also results in gradual changes in escort cell morphology and their eventual death. To better characterize the function of Lsd1 in different cell populations within the ovary, we performed Chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq). This analysis shows that Lsd1 associates with a surprisingly limited number of sites in escort cells and fewer, and often, different sites in cap cells. These findings indicate that Lsd1 exhibits highly selective binding that depends greatly on specific cellular contexts. Lsd1 does not directly target the dpp locus in escort cells. Instead, Lsd1 regulates engrailed expression and disruption of engrailed and its putative downstream target hedgehog suppress the Lsd1 mutant phenotype. Interestingly, over expression of engrailed, but not hedgehog, results in an expansion of GSC cells, marked by the expansion of BMP signaling. Knockdown of other potential direct Lsd1 target genes, not obviously linked to BMP signaling, also partially suppresses the Lsd1 mutant phenotype. These results suggest that Lsd1 restricts the number of GSC-like cells by regulating a diverse group of genes and provide further evidence that escort cell function must be carefully controlled during development and adulthood to ensure proper germline differentiation. PMID- 24625681 TI - Surveillance for yellow Fever virus in non-human primates in southern Brazil, 2001-2011: a tool for prioritizing human populations for vaccination. AB - In Brazil, epizootics among New World monkey species may indicate circulation of yellow fever (YF) virus and provide early warning of risk to humans. Between 1999 and 2001, the southern Brazilian state of Rio Grande do Sul initiated surveillance for epizootics of YF in non-human primates to inform vaccination of human populations. Following a YF outbreak, we analyzed epizootic surveillance data and assessed YF vaccine coverage, timeliness of implementation of vaccination in unvaccinated human populations. From October 2008 through June 2009, circulation of YF virus was confirmed in 67 municipalities in Rio Grande do Sul State; vaccination was recommended in 23 (34%) prior to the outbreak and in 16 (24%) within two weeks of first epizootic report. In 28 (42%) municipalities, vaccination began more than two weeks after first epizootic report. Eleven (52%) of 21 laboratory-confirmed human YF cases occurred in two municipalities with delayed vaccination. By 2010, municipalities with confirmed YF epizootics reported higher vaccine coverage than other municipalities that began vaccination. In unvaccinated human populations timely response to epizootic events is critical to prevent human yellow fever cases. PMID- 24625683 TI - A comparative first-principles study of martensitic phase transformations in TiPd2 and TiPd intermetallics. AB - Martensitic phase transformations in TiPd2 and TiPd alloys are studied employing density-functional, first-principles calculations. We examine the transformation of tetragonal C11b TiPd2 to the low-temperature orthorhombic phase (C11b -> oI6), and the transformation of cubic B2 TiPd under orthorhombic (B2->B19) and subsequent monoclinic transformations (B19->B19') as the system is cooled. We employ a theoretical approach based on a phenomenological Landau theory of the structural phase transitions and a mean-field approximation for the free energy, utilizing first-principles calculations to obtain the deformation energy as a function of strains and to deduce parameters for constructing the free energy. The predicted transition temperature for the TiPd2 C11b -> oI6 transition is in good agreement with reported experimental results. To investigate the TiPd B2 >B19 transformation, we employ both the Cauchy-Born rule and a soft-mode-based approach, and elucidate the importance of the coupling between lattice distortion and atomic displacements (i.e. shuffling) in the formation of the final structure. The calculated B2->B19 transition temperature for TiPd alloy agrees well with the experimental results. We also find that there exists a very small but finite (0.0005 eV/atom) energy barrier of B19 TiPd under monoclinic deformation for B19->B19' structural phase transformation. PMID- 24625682 TI - Assessment of insulin-like growth factor-1 (IGF-I) level in patients with rheumatic mitral stenosis. AB - OBJECTIVES: Insulin-like growth factor-1 may serve some regulatory function in the immune system. Rheumatic mitral stenosis is related to autoimmune heart valve damage after streptococcal infection. The aim of this study was to assess the level of insulin-like growth factor-1 and its correlation with the Wilkins score in patients with rheumatic mitral stenosis. METHODS: A total of 65 patients with rheumatic mitral stenosis and 62 age- and sex-matched control subjects were enrolled in this study. All subjects underwent transthoracic echocardiography. The mitral valve area and Wilkins score were evaluated for all patients. Biochemical parameters and serum insulin-like growth factor-1 levels were measured. RESULTS: Demographic data were similar in the rheumatic mitral stenosis and control groups. The mean mitral valve area was 1.6+/-0.4 cm2 in the rheumatic mitral stenosis group. The level of insulin-like growth factor-1 was significantly higher in the rheumatic mitral stenosis group than in the control group (104 (55.6-267) versus 79.1 (23.0-244.0) ng/ml; p=0.039). There was a significant moderate positive correlation between insulin-like growth factor-1 and thickening of leaflets score of Wilkins (r=0.541, p<0.001). CONCLUSIONS: The present study demonstrated that serum insulin-like growth factor-1 levels were significantly higher in the rheumatic mitral stenosis group compared with control subjects and that insulin-like growth factor-1 level was also correlated with the Wilkins score. It can be suggested that there may be a link between insulin-like growth factor-1 level and immune pathogenesis of rheumatic mitral stenosis. PMID- 24625684 TI - PI3Kdelta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. AB - Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kdelta) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kdelta inhibition confers protection in ischaemia/reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kdelta inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kdelta (p110delta(D910A/D910A)) or wild-type mice pre- or post-treated with the PI3Kdelta inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kdelta as a potential therapeutic target in ischaemic stroke. PMID- 24625685 TI - Pharmacokinetic study in mice of galphimine-A, an anxiolytic compound from Galphimia glauca. AB - The aim of this study was to obtain pharmacokinetic data for the anxiolytic compound galphimine-A (G-A) from Galphimia glauca. G-A is the most abundant anxiolytic compound in this plant, while Galphimine-E (G-E) is the most abundant galphimine, but inactive. G-E was transformed chemically into G-A. The pharmacokinetic study was carried out in ICR mice, which were orally administered a single 200 mg/kg dose of G-A. Samples of blood and brain were taken at different times after administration of G-A. Previously, we established the validation of methods for determining the concentration of G-A. The G-A was detected in plasma 5 min after oral administration, and its concentration reached 2.47 MUg/mL. Data from concentration-time curves allowed us to establish the main pharmacokinetic parameters in two models: one- and/or two-compartment. C(max) values were 3.33 and 3.42 MUg/mL respectively, likewise AUC(0->1440 min) were 1,951.58 and 1,824.95 MUg/mL.min. The G-A in brain tissue was noted to cross the blood-brain barrier, reaching C(max) 2.74 MUg/mL, T(max) 81.6 min, and then drop gradually to 0.32 MUg/mL detected at 24 h. The presence of G-A in brain tissue, confirmed that this anxiolytic compound can access the target organ and acts directly on the CNS. PMID- 24625687 TI - Effect of treatment with interferon beta-1a on changes in voxel-wise magnetization transfer ratio in normal appearing brain tissue and lesions of patients with relapsing-remitting multiple sclerosis: a 24-week, controlled pilot study. AB - BACKGROUND: This pilot study investigated changes in remyelinating and demyelinating activity in normal appearing brain tissue (NABT) and lesions, by using voxel-wise magnetization transfer ratio (VW-MTR), in patients with relapsing-remitting multiple sclerosis (RRMS) receiving interferon beta-1a 44 mcg subcutaneously (IFN beta-1a SC) three times weekly versus healthy controls (HCs) (NCT01085318). METHODS: Increasing (suggestive of remyelination) and decreasing (suggestive of demyelination) VW-MTR changes in NABT and in T2, T1 and gadolinium (Gd)-enhancing lesion volume were measured over 24 weeks in 23 patients treated with IFN beta-1a SC and in 15 HCs (where applicable). VW-MTR changes were tested using the Wilcoxon signed-rank or Wilcoxon rank-sum test. RESULTS: A trend for greater volume of NABT with increasing VW-MTR at 24 weeks was observed for patients versus HCs (median [range] 1206 [0-15278]; 342 [0-951] mm3; p = 0.061). NABT volume with increasing VW-MTR at 12 weeks was significantly greater in patients than in HCs (852 [6-11577]; 360 [0-1755] mm3; p = 0.028). Similar findings were detected for lesion volumes. Two patients with notably high numbers of Gd-enhancing lesions at baseline had a markedly greater volume of tissue with increasing VW-MTR compared with other patients. Volume of NABT tissue with decreasing VW-MTR was significantly greater in patients versus HCs at 24 weeks (942 [0-6141]; 297 [0-852] mm3; p<0.001). CONCLUSIONS: The significant change in NABT volume with increasing VW-MTR at 12 weeks suggests that active remyelination in patients with RRMS may occur during treatment with IFN beta-1a SC. Findings from two patients with the highest number of Gd-enhancing lesions at baseline suggest that extensive remyelination in NABT may occur in patients with high disease activity. Tissue volume with decreasing VW-MTR was greater in patients than in HCs, despite treatment, validating the sensitivity of this technique for detecting MS disease activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01085318. PMID- 24625688 TI - The impact of no-reflow phenomena after primary percutaneous coronary intervention: a time-dependent analysis of mortality. AB - BACKGROUND: The no-reflow phenomenon is a potential complication of primary percutaneous coronary intervention (PCI). Predictors of the no-reflow phenomenon and the impact on long-term mortality remain unclear. METHODS: Two thousand and seventeen patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary PCI were consecutively enrolled in the multicentre Acute Myocardial Infarction registry of Korea. The no-reflow phenomenon was diagnosed on the basis of angiographic criteria. The primary outcome was all-cause mortality. RESULTS: The no-reflow phenomenon was diagnosed in 262 patients (13.0%). Independent predictors of no-reflow were older age, high Killip class, reduced pre-PCI thrombolysis in myocardial infarction flow grade, and longer stent length in the culprit vessel. During a median follow-up period of 4.1 years (interquartile range: 3.0-5.2 years), patients with no-reflow showed a higher rate of mortality than that observed in patients with reflow (30.2 vs. 18.3%, P<0.001). The multivariate Cox proportional hazards model identified the no reflow phenomenon as an independent correlate of long-term mortality [adjusted hazard ratio (HR): 1.45; 95% confidence interval (CI): 1.12-1.86; P=0.004]. Time period-specific analyses demonstrated that the association between no-reflow and mortality was significant and stronger for short-term (<30 days) mortality (adjusted HR: 3.11; 95% CI: 1.91-5.05; P<0.001) but was not significant for longer-term mortality (>=30 days; adjusted HR: 1.12; 95% CI: 0.82-1.52; P=0.47). CONCLUSION: In patients with STEMI who had undergone primary PCI, the no-reflow phenomenon was an independent predictor of short-term but not long-term mortality. PMID- 24625689 TI - Relationship between CT features and high preoperative serum carcinoembryonic antigen levels in early-stage lung adenocarcinoma. AB - AIM: To assess the relationship between thin-section computed tomography (CT) features of primary tumour and high preoperative serum carcinoembryonic antigen (CEA) levels that reportedly suggest poor prognoses in early-stage lung adenocarcinoma. MATERIALS AND METHODS: Two hundred and seventy-five consecutive patients who underwent resection of pathological stage I (T1-2aN0M0) adenocarcinomas with a maximum diameter of <= 3 cm (144 men, 131 women; mean age 67.8 years) were enrolled. CT features of the primary tumours and clinical characteristics of these patients were statistically evaluated to identify the factors associated with high serum CEA levels (>5 ng/ml). RESULTS: Eighty-one patients (29.5%) had high serum CEA levels. In univariate analysis, lower ground glass opacity ratio (p < 0.001), lower tumour shadow disappearance rate (TDR: the ratio of tumour area in mediastinal window to that of lung window, p < 0.001), presence of notch (p = 0.015), and coexistence with bullae or honeycomb cysts (p < 0.001) were observed more frequently in the group with high serum CEA levels than that of the group with normal levels. TDR [odds ratio (OR) 0.984; 95% confidence interval (CI): 0.976-0.993; p < 0.001] and coexistence with bullae or honeycomb cysts (OR = 3.08; 95% CI: 1.55-6.12; p = 0.001) remained significant, even after adjusting patients' age, gender, and smoking status. CONCLUSIONS: Adenocarcinomas with lower TDR and coexisting with bullae or honeycomb cysts are associated with high preoperative serum CEA levels. Although some CEA elevations may be due to benign pulmonary diseases, such tumours are suspected to have poor prognoses, even for early-stage diseases. PMID- 24625690 TI - Endovascular coil embolization in internal carotid artery bifurcation aneurysms. AB - AIM: To present the clinical and radiological results of coil embolization in internal carotid artery (ICA) bifurcation aneurysms (BA). MATERIALS AND METHODS: The records of 65 patients with 66 ICA BA were retrieved from data prospectively accrued between September 1999 and July 2013. Clinical and morphological outcomes of the aneurysms were assessed, including technical aspects of treatment. RESULTS: The aneurysms under study were directed either superiorly (41/66, 62.1%), anteriorly (24/66, 36.4%), or posteriorly (1/66, 1.5%), and all were devoid of perforators. Aneurysmal necks were situated symmetrically at the terminal ICA (37/66, 56.1%) or slightly deviated to the proximal A1 segment (29/66, 43.9%). The steam-shaped S microcatheter (73.8%) was most commonly used to select the aneurysms, and the single microcatheter technique was most commonly applied (56.1%) to perform coil embolization, followed by balloon remodelling (21.2%), multiple microcatheter (15.1%), and stent-protection (7.6%). Successful aneurysmal occlusion was achieved in 100% of cases, with no procedure-related morbidity or mortality. Imaging performed in the course of follow-up (mean duration 27.3 months) confirmed stable occlusion of most lesions (47/53, 88.7%). CONCLUSION: Through tailored technical strategies, ICA BA are amenable to safe and effective endovascular coil embolization, with a tendency for stable occlusion long-term. PMID- 24625691 TI - MRI findings before and after abdominal radical trachelectomy (ART) for cervical cancer: a prospective study and review of the literature. AB - AIM: To report the authors' experience with dedicated pelvic magnetic resonance imaging (MRI) in young women with early-stage cervical cancer treated with abdominal radical trachelectomy (ART). MATERIALS AND METHODS: During a 5-year period, 21 patients, with biopsy-confirmed cervical carcinoma, International Federation of Gynaecology and Obstetrics (FIGO) stage <=IB1, were considered for trachelectomy. All patients underwent pelvic MRI within 30 days prior to surgery. Tumour size, endocervical extension, extrauterine spread, and nodal status were noted. Postoperative MRI findings were reviewed in 16 patients. RESULTS: Nineteen of the 21 patients were treated with ART. In two patients, trachelectomy was aborted intraoperatively and radical hysterectomy was performed; preoperative MRI findings were consistent with surgicopathological examination in both patients. MRI correctly assessed tumour size in 18/21 patients, coming within 5 mm of the surgical specimen. Tumour size was underestimated in two cases because of circumferential growth (n = 1) or technical difficulties (n = 1). False-positive MRI result was due to post-biopsy inflammation (n = 1). MRI accurately identified absence of internal os involvement in 17/19 ART patients; false-positive MRI for internal os involvement were due to endocervical polyp (n = 1) and coexisting Nabothian cysts (n = 1). No trachelectomy patient had extrauterine disease or malignant nodes at MRI or final histology. Post-trachelectomy complications included hydrosalpinges (n = 3), lymphocysts (n = 2), isthmic stenosis (n = 1), and tumour relapse (n = 2). CONCLUSIONS: Dedicated pelvic MRI is helpful in assessing tumour size and endocervical extension in young women, candidates for ART. Hydrosalpinx may occur after ART and it may influence fertility potential. PMID- 24625692 TI - Role of diffusion-weighted MRI in differentiation of hepatic abscesses from non infected fluid collections. AB - AIM: To evaluate the role of diffusion-weighted magnetic resonance imaging (DW MRI) in the differentiation of hepatic abscesses from non-infected fluid collections. MATERIALS AND METHODS: In this retrospective study, 22 hepatic abscesses and 27 non-infected hepatic fluid collections were examined in 27 patients who underwent abdominal MRI including DW-MRI. Two independent observers reviewed T2-weighted + DW-MRI and T2-weighted + contrast-enhanced T1-weighted (CET1W) images in two sessions. Detection rates and confidence levels were calculated and compared using McNemar's and Wilcoxon's signed rank tests, respectively. Apparent diffusion coefficient (ADC) values of abscesses and non infected fluid collections were compared using the t-test. Receiver operating characteristic (ROC) curves were constructed. RESULTS: There was no statistically significant difference in the accuracy of detecting abscesses using T2-weighted + DW-MRI (both observers: 21/22, 95.5%) versus T2-weighted + CET1W images (observer 1: 21/22, 95.5%; observer 2: 22/22, 100%; p < 0.01). Mean ADC values were significantly lower with abscesses versus non-infected fluid collections (0.83 +/ 0.24 versus 2.25 +/- 0.61 * 10(-3) mm(2)/s; p < 0.001). With ROC analysis there was good discrimination of abscess from non-infected fluid collections at a threshold ADC value of 1.36 * 10(-3) mm(2)/s. CONCLUSION: DW-MRI allows qualitative and quantitative differentiation of abscesses from non-infected fluid collections in the liver. PMID- 24625693 TI - DW-MRI of liver lesions: can a single ADC-value represent the entire lesion? AB - AIM: To evaluate whether focal liver lesions (FLLs) exhibit a homogeneous appearance on apparent diffusion coefficient (ADC) maps and whether there is inter-section variation in the calculated ADC values of FLLs (inter-section range). MATERIALS AND METHODS: Eighty-eight patients with 128 FLLs (70 benign, 58 malignant) who underwent abdominal magnetic resonance imaging (MRI) including diffusion-weighted (DW)-MRI were included. Two observers evaluated variation of signal intensity of each FLL within each ADC map image (intra-section) and among different ADC map images through the lesion (inter-section). ADC values of each FLL and neighbouring liver parenchyma were measured on all sections. The inter section range of FLLs was compared with the neighbouring liver parenchyma. RESULTS: Intra-section inhomogeneity was noted in 39.8% (97/244 sections) and 38.9% (95/244) of benign lesions, and 61% (114/187 sections) and 61.5% (115/187) of malignant lesions, by observer 1 and observer 2, respectively. Inter-section inhomogeneity was noted in 25.7% (18/70) and 27.1% (19/70) of benign lesions, and 51.7% (30/58) and 50% (29/58) of malignant lesions, by observer 1 and observer 2, respectively. The inter-section range for both benign (0.28 * 10(-3) mm(2)/s) and malignant (0.25 * 10(-3) mm(2)/s) FLLs were significantly greater than that of liver parenchyma surrounding benign (0.16 * 10(-3) mm(2)/s, p < 0.001) and malignant (0.14 * 10(-3) mm(2)/s, p = 0.01) FLLs. CONCLUSION: Due to intra-/inter section variations in ADC values of benign and malignant FLLs, a single ADC value may not reliably represent the entire lesion. PMID- 24625694 TI - Are radiologists the contemporary anatomists? PMID- 24625695 TI - Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease. AB - Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-beta accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 +/- 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 +/- 7.8 years), neurologically normal elderly without amyloid-beta accumulation (normal ageing; n = 13, age at death: 82.9 +/- 10.8 years) and neurologically normal elderly with extensive cortical amyloid-beta deposits (pathological ageing; n = 15; age at death: 92.7 +/- 5.9 years). The levels of amyloid-beta40, amyloid-beta42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-beta metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-beta42 accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid-beta42 accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-beta metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-beta metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-beta42 accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the regional distribution of APP as well as beta C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-beta42 accumulation in familial Alzheimer's disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-beta (especially amyloid beta40) accumulation in both sporadic and familial Alzheimer's disease. Familial Alzheimer's disease had greater striatal tau pathology than sporadic Alzheimer's disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer's disease compared with sporadic Alzheimer's disease. These results suggest that disproportionate amyloid-beta42 accumulation in cortical areas in sporadic Alzheimer's disease may be mediated by synaptic processes, whereas disproportionate amyloid-beta42 accumulation in subcortical areas in familial Alzheimer's disease may be driven by APP and its processing. Region-specific amyloid-beta42 accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer's disease. PMID- 24625696 TI - DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation. AB - The Duffy antigen/receptor for chemokines, DARC, belongs to the family of atypical heptahelical chemokine receptors that do not couple to G proteins and therefore fail to transmit conventional intracellular signals. Here we show that during experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, the expression of DARC is upregulated at the blood-brain barrier. These findings are corroborated by the presence of a significantly increased number of subcortical white matter microvessels staining positive for DARC in human multiple sclerosis brains as compared to control tissue. Using an in vitro blood-brain barrier model we demonstrated that endothelial DARC mediates the abluminal to luminal transport of inflammatory chemokines across the blood-brain barrier. An involvement of DARC in experimental autoimmune encephalomyelitis pathogenesis was confirmed by the observed ameliorated experimental autoimmune encephalomyelitis in Darc(-/-) C57BL/6 and SJL mice, as compared to wild-type control littermates. Experimental autoimmune encephalomyelitis studies in bone marrow chimeric Darc(-/-) and wild-type mice revealed that increased plasma levels of inflammatory chemokines in experimental autoimmune encephalomyelitis depended on the presence of erythrocyte DARC. However, fully developed experimental autoimmune encephalomyelitis required the expression of endothelial DARC. Taken together, our data show a role for erythrocyte DARC as a chemokine reservoir and that endothelial DARC contributes to the pathogenesis of experimental autoimmune encephalomyelitis by shuttling chemokines across the blood-brain barrier. PMID- 24625698 TI - The multiple strategies of an insect herbivore to overcome plant cyanogenic glucoside defence. AB - Cyanogenic glucosides (CNglcs) are widespread plant defence compounds that release toxic hydrogen cyanide by plant beta-glucosidase activity after tissue damage. Specialised insect herbivores have evolved counter strategies and some sequester CNglcs, but the underlying mechanisms to keep CNglcs intact during feeding and digestion are unknown. We show that CNglc-sequestering Zygaena filipendulae larvae combine behavioural, morphological, physiological and biochemical strategies at different time points during feeding and digestion to avoid toxic hydrolysis of the CNglcs present in their Lotus food plant, i.e. cyanogenesis. We found that a high feeding rate limits the time for plant beta glucosidases to hydrolyse CNglcs. Larvae performed leaf-snipping, a minimal disruptive feeding mode that prevents mixing of plant beta-glucosidases and CNglcs. Saliva extracts did not inhibit plant cyanogenesis. However, a highly alkaline midgut lumen inhibited the activity of ingested plant beta-glucosidases significantly. Moreover, insect beta-glucosidases from the saliva and gut tissue did not hydrolyse the CNglcs present in Lotus. The strategies disclosed may also be used by other insect species to overcome CNglc-based plant defence and to sequester these compounds intact. PMID- 24625699 TI - Segmentation of neuronal structures using SARSA (lambda)-based boundary amendment with reinforced gradient-descent curve shape fitting. AB - The segmentation of structures in electron microscopy (EM) images is very important for neurobiological research. The low resolution neuronal EM images contain noise and generally few features are available for segmentation, therefore application of the conventional approaches to identify the neuron structure from EM images is not successful. We therefore present a multi-scale fused structure boundary detection algorithm in this study. In the algorithm, we generate an EM image Gaussian pyramid first, then at each level of the pyramid, we utilize Laplacian of Gaussian function (LoG) to attain structure boundary, we finally assemble the detected boundaries by using fusion algorithm to attain a combined neuron structure image. Since the obtained neuron structures usually have gaps, we put forward a reinforcement learning-based boundary amendment method to connect the gaps in the detected boundaries. We use a SARSA (lambda) based curve traveling and amendment approach derived from reinforcement learning to repair the incomplete curves. Using this algorithm, a moving point starts from one end of the incomplete curve and walks through the image where the decisions are supervised by the approximated curve model, with the aim of minimizing the connection cost until the gap is closed. Our approach provided stable and efficient structure segmentation. The test results using 30 EM images from ISBI 2012 indicated that both of our approaches, i.e., with or without boundary amendment, performed better than six conventional boundary detection approaches. In particular, after amendment, the Rand error and warping error, which are the most important performance measurements during structure segmentation, were reduced to very low values. The comparison with the benchmark method of ISBI 2012 and the recent developed methods also indicates that our method performs better for the accurate identification of substructures in EM images and therefore useful for the identification of imaging features related to brain diseases. PMID- 24625700 TI - Functional neuroimaging changes subsequent to electroconvulsive therapy in unipolar depression: a review of the literature. AB - Electroconvulsive therapy (ECT) is an effective treatment for major depressive episodes; however, the neural mechanisms underlying its therapeutic effects remain largely unknown. This review summarizes the findings of functional neuroimaging studies on the effects of the ECT treatment in patients with unipolar depression. Functional neuroimaging studies show that ECT induces changes in cerebral metabolism, blood flow, neurotransmitter activity, neuronal metabolites, and brain functional connectivity. Nevertheless, most of these studies are cross-sectional, with small sample sizes, and the findings across these studies are inconsistent and often contradictory. The levels of brain functional changes are seldom correlated with alleviation of depressive symptoms. Based on the results of current functional neuroimaging studies, one cannot draw any conclusions about the exact neural mechanisms of the antidepressant effect of ECT. Additional multicenter, large-sample, unified-protocol studies with long term follow-up and multiple observational markers are needed to clarify and cross validate the neural mechanisms of the antidepressant effect of ECT and to explore validated neuroimaging markers for predicting and evaluating the clinical efficacy of ECT treatment. PMID- 24625701 TI - Electroconvulsive therapy in patients with deep brain stimulators. AB - The scope of functional neurosurgery is expanding, and deep brain stimulation (DBS) indications with comorbid depressive disorders that are challenging to manage, such as movement disorders, are common. There is limited research or clinical experience on the safety and efficacy of electroconvulsive therapy (ECT) in patients with DBS electrodes. We present a case illustrating the challenges when faced with ECT for treatment-resistant depression in the context of preexisting DBS electrodes, and establish a database to collect cases of ECT in DBS patients. PMID- 24625702 TI - Electroconvulsive therapy in Croatia. PMID- 24625703 TI - Mechanisms of ECT: reviewing the science and dismissing the myths. PMID- 24625704 TI - Low-frequency repetitive transcranial magnetic stimulation in the right prefrontal cortex combined with partial sleep deprivation in treatment-resistant depression: a randomized sham-controlled trial. AB - INTRODUCTION: Sham-controlled low-frequency repetitive transcranial magnetic stimulation (rTMS) was used in patients with pharmacoresistant major depression as an added treatment along with partial sleep deprivation (PSD). In addition, the potential predictive role of brain-derived neurotrophic factor genetic polymorphism on treatment response was analyzed. METHODS: We recruited 19 female patients (48.3 +/- 8.6 years old) with treatment-resistant unipolar major depression (Hamilton Depression Rating Scale [HDRS] score >=20) who were on a stable antidepressant treatment. They received either 1-Hz rTMS or sham stimulation over the right dorsolateral prefrontal cortex (intensity of 110% of the threshold; 3000 stimuli per protocol; and 10 daily sessions). Additionally, PSD was applied once per week during the treatment. The patients were evaluated (HDRS and Clinical Global Impression Scale) by a blind rater at baseline (B) and after 2 and 3 weeks (W2 and W3) of treatment for short-term outcome. Long-term evaluations were performed after 12 (W12) and 24 weeks (W24) for patients who received active stimulation. RESULTS: Eleven patients in the active group showed a significant HDRS score reduction from 30.09 +/- 3.53 (B) to 16.73 +/- 5.71 (W3) compared to the lack of therapeutic response in the sham-treated patients. The long-term follow-up for the active group included 64% of the responders at W12 and 55% at W24. Full remission (HDRS <=10) was achieved in 5 of 11 patients. Four of these 5 patients with long-term sustained remission expressed the Val66Val genotype. CONCLUSION: Our study suggests a clinically relevant response, persisting for up to 6 months, from 1-Hz rTMS over the right dorsolateral prefrontal cortex and PSD in patients with pharmacoresistant major depression. The brain-derived neurotrophic factor Val66Val homozygous genotype may be related to a better treatment outcome. PMID- 24625705 TI - Is electroconvulsive therapy use among young-old and old-old adults comparable? A 10-year population-level analysis of service provision. AB - OBJECTIVES: Existing research on electroconvulsive therapy (ECT) in older adults has largely examined its efficacy and safety in treating depression, but there are few population-level studies of its use in this patient group. Our objective was to provide a comprehensive 10-year picture of ECT use among adults aged 65 years and older in the State of Victoria, Australia. We focused especially on comparing patterns of ECT use between young-old and old-old individuals, to better inform practicing physicians, policy makers, and researchers about ECT practices in this diverse range of patients. METHODS: We analyzed statewide ECT service provision data from 1998 to 2007 provided by the Office of the Chief Psychiatrist of Victoria. RESULTS: Age-adjustment of crude data revealed that old old adults had the highest rate of ECT use overall (especially women) as well as the highest utilization rates for depression and public sector treatment. Although the highest rate of exclusively involuntary treatment under the Mental Health Act was also observed among old-old adults, most of the old-old patients were treated on an exclusively voluntary basis. The number of ECT treatments administered to young-old and old-old patients did not differ. CONCLUSIONS: The higher ECT utilization rates we previously reported in older adults as a whole were further accentuated in old-old individuals. Old-old adults may have medical comorbidities and personal care needs that have implications for ECT technique and service delivery. Our findings underscore the need for greater inclusion of old-old patients in future ECT research to increase its clinical applicability. PMID- 24625706 TI - Predictors of remission in 208 drug-resistant depressive patients treated with electroconvulsive therapy. AB - OBJECTIVES: This study aimed to explore predictors of remission to electroconvulsive therapy (ECT) in a sample of depressive patients resistant to pharmacological treatments. METHODS: Two hundred eight patients, 31 of whom had major depressive disorder, 101 had bipolar disorder II (BP II), and 76 had bipolar disorder I (BP I), diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were treated with bilateral ECT on a twice-a-week schedule. All patients included were undergoing a depressive episode, excluding patients with mixed and manic episodes. Patients were assessed before (baseline) and a week after the ECT course (final score) using the Hamilton Rating Scale for Depression-17 items (HAM-D-17), the Young Mania Rating Scale (YMRS), the Brief Psychiatric Rating Scale, and the Clinical Global Impression-Improvement (CGI-I). RESULTS: At the end of the ECT course, 56 patients (26.9%) were considered nonresponders, and 80 patients (38.4%) were considered responders (HAM-D score of at least 50% and CGI-I subscale rating of 2, "much improved") and 72 remitters (34.6%) (HAM-D scores <=8 and a CGI-I subscale rating of 1). On backward stepwise logistic regression length of current episode, Bipolar Disorder and baseline YMRS total mean scores were statistically significant predictors of nonresponders versus remitters. Among the YMRS items at basal evaluation 8 (thought content), 10 (appearance), and 11 (insight), the mean scores were significantly lower in the remitters than in the responders and nonresponders. CONCLUSION: Major depressive disorder, short duration of the current episode, absence of psychotic symptoms, preserved insight, and adequate personal care are associated with complete remission in our sample of drug resistant depressive patients treated with ECT. PMID- 24625707 TI - Trends in use of electroconvulsive therapy in South London from 1949 to 2006. AB - OBJECTIVES: Electroconvulsive therapy (ECT) remains the most acutely effective treatment for severe depression, but its use has declined since its introduction more than 70 years ago. To provide some historical perspective on changes in ECT practice, the objective of the present study was to identify trends in ECT practice in selected teaching hospitals in South London, UK, between 1949 and 2006. METHODS: Annual rates of ECT for 1949-1970 were estimated from the contemporary hospital reports of the Maudsley and Bethlem Royal hospitals in South London, UK. Case notes were also retrospectively reviewed to calculate annual rates of ECT administration and extract demographic and clinical information for approximately every 5 years between 1987 and 2006. RESULTS: The annual rate of ECT peaked at 35% of total admission in 1956 and declined gradually thereafter to 10.8% by 1970 and fell below 2.2% from 1991 onward. Depressed and female patients were more likely to receive ECT. Compared to previous years, patients were more severely ill and treatment resistant in 2006, whereas ethnic minorities made up 30% of patients receiving ECT compared to approximately 14% in the preceding years. CONCLUSIONS: Currently, ECT seems to be provided increasingly late in more severe illness episodes. The ethnicity of patients receiving ECT in South London may be becoming more representative of the background population, but ECT is being used relatively more frequently for nonaffective disorders in ethnic minorities. PMID- 24625709 TI - Teaching therapeutic seizure criteria to psychiatrists. AB - OBJECTIVES: Following on from our previous work looking at the interrater reliability of assessing seizure adequacy for electroconvulsive therapy (ECT), we sought to examine whether a specific teaching module could improve the reliability of visual inspection of electroencephalography (EEG) recordings for specific features of seizure length, presence of polyspike, delta wave activity, and post-ictal suppression. METHODS: Twelve medical practitioners at varying levels of training and ECT experience rated 15 EEG traces after minimal training and a further set of 15 EEG traces after a more detailed training. Results were analyzed to examine the interrater reliability of the EEG features and the overall assignment of traces as meeting "old" (1995) or "new" (2005) Royal College of Psychiatrists criteria for therapeutic seizures compared with the agreed ratings of 2 experienced ECT practitioners ("standard ratings"). RESULTS: There was evidence for a specific training effect for the "old" criteria with an improvement in the interrater reliability (generalized kappa, 0.590 vs 0.813) associated with a significantly better estimation of seizure length as assessed by comparison of the root mean square difference from the standard ratings (mean, 7.83 vs 4.49; P < 0.003). The interrater reliability for the new criteria did not improve (generalized kappa, 0.599 vs 0.581) but was already at quite a good standard. Examination of individual features did demonstrate improvement in the rating of delta activity (generalized kappa, 0.564 vs 0.655) and post-ictal suppression (generalized kappa, 0.553 vs 0.611) after the training. When these 2 criteria were grouped together (delta suppression), interrater reliability was shown to be significantly improved after the training (generalized kappa, 0.568 vs 0.659). Although not statistically significant, the participants reported that the training improved their confidence in using both criteria for therapeutic seizures (old: 49% vs 67%; new: 27% vs 48%). CONCLUSIONS: The reliability of assessments of seizure length, presence of delta activity, and post-ictal suppression can be measurably improved with a specific teaching module. Using the delta suppression criteria together with the accurate estimation of seizure length on EEG may have greater clinical utility when it comes to instructing trainees in ECT administration, assessment of therapeutic seizures, and developing protocols for dose adjustment. PMID- 24625708 TI - Fetal spasms after the administration of electroconvulsive therapy in pregnancy: our experience. AB - OBJECTIVES: Most psychotropic drugs are not approved for use during pregnancy. Electroconvulsive therapy (ECT) might be an effective and safe treatment option for several psychiatric disorders in pregnant women. This study assessed ECT for treating major psychoses during pregnancy, taking all possible adverse effects into account. METHODS: We scrutinized all biomedical reviews on ECT during pregnancy published within the past 10 years, and present our experience with 3 patients in different phases of pregnancy that were treated with ECT between December 2009 and July 2012. Four to 5 ECT sessions were administered to pregnant women (10th to 28th week of pregnancy) with severe psychoses, and fetal heartbeat and movements were monitored during ECT and for 2 hours afterward. RESULTS: Bizarre fetal spasms occurred in pregnant women treated with ECT. The authors are not aware of any similar description in the published reviews on this topic, to date. Still, all 3 women had successful deliveries, and the infants remained healthy during follow-ups ranging from 1 to 3.5 years. These data fill a lacking gap in the literature regarding long-term infant outcomes after ECT administration to pregnant women. This supports the theory that ECT may be an excellent treatment solution for pregnant women with certain severe mental disorders. CONCLUSIONS: Electroconvulsive therapy may be an acceptable approach for preventing pharmacotherapy risks or danger arising from injuries associated with mental illnesses in pregnant women. Nonetheless, careful monitoring of both mother and baby is absolutely necessary when considering ECT during pregnancy. PMID- 24625710 TI - Remission of treatment-resistant depression with electroconvulsive therapy and ketamine. PMID- 24625711 TI - Ketamine as an electroconvulsive therapy anesthetic agent. PMID- 24625712 TI - Electroconvulsive therapy after division and repair of strap muscle and anterior jugular vein. PMID- 24625713 TI - New evidence for seizure quality improvement by hyperoxia and mild hypocapnia. AB - INTRODUCTION: Preoxygenation and hyperventilation (with oxygen) in electroconvulsive therapy (ECT) may improve not only safety but also seizure quality. METHODS: We retrospectively examined transcutaneous tissue partial pressure of oxygen (tcpO2) and carbon dioxide (tcpCO2) in 441 ECT sessions of 37 consecutive patients. All patients received standard face mask airway management. In parallel, seizure quality markers such as seizure duration, seizure amplitude, central inhibition, interhemispheric coherence, and sympathetic activation were documented and used to build up a seizure quality sum score. RESULTS: Mean (SD) tcpO2 was 289 (123) mm Hg and for tcpCO2 41 (11) mm Hg. A multivariate repeated measurement regression analysis revealed that the ratio of tcpO2/tcpCO2 had a significant influence on the seizure quality sum score (P = 0.033). Furthermore, a corresponding regression analysis with charge ("stimulation energy") as a dependent variable showed a significant influence of tcpO2 (P = 0.019) and of tcpO2/tcpCO2 (P = 0.03), too. CONCLUSIONS: We observed, in our typical clinical ECT sample of 37 patients, a significant and synergistic influence of tcpO2/tcpCO2 on seizure quality. Partial pressure of oxygen covaried with lower stimulation energy. The ratio tcpO2/tcpCO2 was associated with lower stimulation energy and still better seizure quality. PMID- 24625697 TI - Association of brain amyloid-beta with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment. AB - Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-beta pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-beta with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-beta accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-beta negative controls and -positive subjects in different diagnostic groups, and if amyloid-beta had different associations with cerebral blood flow and grey matter volume. Global amyloid-beta load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-beta load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-beta-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-beta with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-beta being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-beta pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-beta pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages. PMID- 24625714 TI - The seizure, not electricity, is essential in convulsive therapy: the flurothyl experience. AB - BACKGROUND: For more than 50 years, research in convulsive therapy has been focused on the impact of electricity and seizures on memory and not on brain chemistry or neurophysiology. Brief pulse and ultra-brief pulse currents replaced sinusoidal currents. Electrode placements were varied, energy dosing was altered, and electricity was replaced by magnetic currents. METHOD: The published experiences and archival records of seizures induced by camphor, pentylenetetrazol, and flurothyl are reviewed and compared with the changes induced by electricity. FINDINGS: The clinical efficacy of chemically induced seizures is equal to that of electrical inductions. Seizure durations are longer, and impairment of cognition and memory is less. Electroconvulsive therapy replaced chemical treatments for ease of use, not for greater efficacy or safety. CONCLUSIONS: The brain seizure, not the method of induction, is the essential element in the efficacy of convulsive therapy. Seizure induction with chemicals avoids the direct effects of electricity on brain functions with lesser effects on cognition. Reexamination of chemical inductions of seizures as replacements for electricity is encouraged. PMID- 24625715 TI - Takotsubo cardiomyopathy in a young man after maintenance electroconvulsive therapy and clozapine initiation: a case report. PMID- 24625716 TI - A 10-year descriptive study of electroconvulsive therapy at the Neuropsychiatric Hospital, Aro, Abeokuta. AB - OBJECTIVES: Evidence supports the use of electroconvulsive therapy (ECT) in current practice, and good quality of care is related to adherence to evidence based guidelines. However, there are no guidelines for the practice of ECT in Nigeria and there is no regulatory body for its standards. The objective of this study therefore was to examine the practice of ECT between 2001 and 2010 at the Neuropsychiatric Hospital, Aro, Abeokuta, regarding consent procedures, staffing, training, indications, and administration with the goal of informing the development of guidelines locally. METHODS: Data were extracted from 154 complete ECT treatment records in the register and from the patients' case files. The data were qualitatively analyzed and described. RESULTS: The mean age of patients who received ECT was 35.5 years and the majority were female. Bilateral electrode placement was invariable for all treatments. The major diagnosis of the patients receiving ECT was schizophrenia, whereas poor response to medication and psychomotor retardation were commonly stated indications. Treatments were largely unmodified during the first 3 years of the review, with a gradual reversal of this pattern in the latter years. The mean number of treatments per patient was 6.6, and only 1 patient received continuation ECT. CONCLUSIONS: Although the procedure of ECT in this center is generally similar to what is obtained in many other countries in Asia and Africa, aspects such as that of informed consent require attention. Regular audits of the practice are desirable. PMID- 24625718 TI - Depth of anesthesia appropriate for electroconvulsive therapy: the lash reflex need not be abolished. PMID- 24625717 TI - No change in neuropsychological functioning after receiving repetitive transcranial magnetic stimulation treatment for major depression. AB - Early studies of transcranial magnetic stimulation (TMS) have shown no adverse effects on neuropsychological function. However, further research using higher TMS intensities as well as a greater number of TMS pulses and with larger sample sizes is needed. We studied 68 patients with major depressive disorder who were randomized to receive either 15 sessions of sham or real TMS at 110% of the estimated prefrontal cortex threshold to the left dorsolateral prefrontal cortex. Each session consisted of 32 5-second trains of 10-Hz repetitive TMS at 110% adjusted motor threshold. A total of 24,000 pulses were given. Neuropsychological function was assessed before and immediately after TMS treatment with a battery of 8 tests. Using a higher TMS intensity as well as a greater number of pulses and having a larger sample size compared with most previous studies, this study found no negative neuropsychological effects of TMS. Changes in neuropsychological function were unrelated to changes in depression. PMID- 24625719 TI - Learning to rank figures within a biomedical article. AB - Hundreds of millions of figures are available in biomedical literature, representing important biomedical experimental evidence. This ever-increasing sheer volume has made it difficult for scientists to effectively and accurately access figures of their interest, the process of which is crucial for validating research facts and for formulating or testing novel research hypotheses. Current figure search applications can't fully meet this challenge as the "bag of figures" assumption doesn't take into account the relationship among figures. In our previous study, hundreds of biomedical researchers have annotated articles in which they serve as corresponding authors. They ranked each figure in their paper based on a figure's importance at their discretion, referred to as "figure ranking". Using this collection of annotated data, we investigated computational approaches to automatically rank figures. We exploited and extended the state-of the-art listwise learning-to-rank algorithms and developed a new supervised learning model BioFigRank. The cross-validation results show that BioFigRank yielded the best performance compared with other state-of-the-art computational models, and the greedy feature selection can further boost the ranking performance significantly. Furthermore, we carry out the evaluation by comparing BioFigRank with three-level competitive domain-specific human experts: (1) First Author, (2) Non-Author-In-Domain-Expert who is not the author nor co-author of an article but who works in the same field of the corresponding author of the article, and (3) Non-Author-Out-Domain-Expert who is not the author nor co-author of an article and who may or may not work in the same field of the corresponding author of an article. Our results show that BioFigRank outperforms Non-Author-Out Domain-Expert and performs as well as Non-Author-In-Domain-Expert. Although BioFigRank underperforms First Author, since most biomedical researchers are either in- or out-domain-experts for an article, we conclude that BioFigRank represents an artificial intelligence system that offers expert-level intelligence to help biomedical researchers to navigate increasingly proliferated big data efficiently. PMID- 24625720 TI - Reaching out to young investigators. PMID- 24625721 TI - Neutrophils cast NETs in atherosclerosis: employing peptidylarginine deiminase as a therapeutic target. PMID- 24625722 TI - Sialyltransferase activity and atherosclerosis. PMID- 24625723 TI - Inhibition of the cardiomyocyte-specific troponin I-interacting kinase limits oxidative stress, injury, and adverse remodeling due to ischemic heart disease. AB - Ischemia-reperfusion injury is strongly associated with increased oxidative stress, mitochondrial dysfunction, and cell death. These processes are diminished in an animal model of ischemia-reperfusion by the genetic loss or pharmacological inhibition of troponin I-interacting kinase. PMID- 24625724 TI - How to get a K award: it is not just about the science. PMID- 24625725 TI - Blind dates in sciences: dealing with rejection in peer review. PMID- 24625726 TI - Role of the autonomic nervous system in modulating cardiac arrhythmias. AB - The autonomic nervous system plays an important role in the modulation of cardiac electrophysiology and arrhythmogenesis. Decades of research has contributed to a better understanding of the anatomy and physiology of cardiac autonomic nervous system and provided evidence supporting the relationship of autonomic tone to clinically significant arrhythmias. The mechanisms by which autonomic activation is arrhythmogenic or antiarrhythmic are complex and different for specific arrhythmias. In atrial fibrillation, simultaneous sympathetic and parasympathetic activations are the most common trigger. In contrast, in ventricular fibrillation in the setting of cardiac ischemia, sympathetic activation is proarrhythmic, whereas parasympathetic activation is antiarrhythmic. In inherited arrhythmia syndromes, sympathetic stimulation precipitates ventricular tachyarrhythmias and sudden cardiac death except in Brugada and J-wave syndromes where it can prevent them. The identification of specific autonomic triggers in different arrhythmias has brought the idea of modulating autonomic activities for both preventing and treating these arrhythmias. This has been achieved by either neural ablation or stimulation. Neural modulation as a treatment for arrhythmias has been well established in certain diseases, such as long QT syndrome. However, in most other arrhythmia diseases, it is still an emerging modality and under investigation. Recent preliminary trials have yielded encouraging results. Further larger-scale clinical studies are necessary before widespread application can be recommended. PMID- 24625727 TI - PCSK9: a key modulator of cardiovascular health. AB - Since the discovery of proprotein convertase subtilisin kexin 9 (PCSK9) in 2003, this PC has attracted a lot of attention from the scientific community and pharmaceutical companies. Secreted into the plasma by the liver, the proteinase K like serine protease PCSK9 binds the low-density lipoprotein (LDL) receptor at the surface of hepatocytes, thereby preventing its recycling and enhancing its degradation in endosomes/lysosomes, resulting in reduced LDL-cholesterol clearance. Surprisingly, in a nonenzymatic fashion, PCSK9 enhances the intracellular degradation of all its target proteins. Rare gain-of-function PCSK9 variants lead to higher levels of LDL-cholesterol and increased risk of cardiovascular disease; more common loss-of-function PCSK9 variants are associated with reductions in both LDL-cholesterol and risk of cardiovascular disease. It took 9 years to elaborate powerful new PCSK9-based therapeutic approaches to reduce circulating levels of LDL-cholesterol. Presently, PCSK9 monoclonal antibodies that inhibit its function on the LDL receptor are evaluated in phase III clinical trials. This review will address the biochemical, genetic, and clinical aspects associated with PCSK9's biology and pathophysiology in cells, rodent and human, with emphasis on the clinical benefits of silencing the expression/activity of PCSK9 as a new modality in the treatment of hypercholesterolemia and associated pathologies. PMID- 24625728 TI - Evolution of transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement emerged ~20 years ago and changed the landscape of structural interventional cardiology. The first experiments in animal models provided proofs of the concept and the substrate for the first percutaneous valve implantation in patients. The initial promising results in a clinical setting drew the attention of the industry and of the scientific community, and an effort was made for the past 12 years to address the limitations of the technology, facilitate the procedure, minimize the risk of complications, and broaden the applications of transcatheter aortic valve replacement. This article reviews the evolution of transcatheter aortic valve replacement, presents the first steps in this field, cites the evidence from registries and clinical trials, highlights the limitations of this treatment, and discusses the future perspectives and the developments proposed to address the current pitfalls. PMID- 24625729 TI - Gigantic business: titin properties and function through thick and thin. AB - The giant protein titin forms a unique filament network in cardiomyocytes, which engages in both mechanical and signaling functions of the heart. TTN, which encodes titin, is also a major human disease gene. In this review, we cover the roles of cardiac titin in normal and failing hearts, with a special emphasis on the contribution of titin to diastolic stiffness. We provide an update on disease associated titin mutations in cardiac and skeletal muscles and summarize what is known about the impact of protein-protein interactions on titin properties and functions. We discuss the importance of titin-isoform shifts and titin phosphorylation, as well as titin modifications related to oxidative stress, in adjusting the diastolic stiffness of the healthy and the failing heart. Along the way we distinguish among titin alterations in systolic and in diastolic heart failure and ponder the evidence for titin stiffness as a potential target for pharmacological intervention in heart disease. PMID- 24625730 TI - Letter to the editor on Nagendran et al. PMID- 24625731 TI - Response to Lazarus. PMID- 24625733 TI - BH3-mimetic gossypol-induced autophagic cell death in mutant BRAF melanoma cells with high expression of p21Cip1.). AB - AIMS: The aim of the present study was to identify the potential therapeutic effects of BH3-mimetic gossypol on melanoma cells with acquired resistance to BRAF inhibitors. MAIN METHODS: The IC50 values of gossypol were determined using MTT assays in three melanoma cell lines with different resistances to BRAF inhibitor. The effects of gossypol on three melanoma cell lines were further examined by immunoblotting analysis, cell cycle analysis, flow cytometric apoptotic assay and autophagy assay. The functional role of autophagy in gossypol induced growth inhibition was investigated using siRNA-mediated knockdown of Beclin-1. KEY FINDINGS: Gossypol retained its efficacy in BRAF-V600E melanoma clones with acquired resistance to BRAF inhibitors through a mechanism independent of MEK-ERK inhibition. Gossypol caused G2/M arrest in both BRAF mutant A375P and A375P/Mdr cells with high expression of p21(Cip1), regardless of their drug resistance. Interestingly, we determined that the lack of gossypol induced mitotic arrest in BRAF-WT-harboring SK-MEL-2 cells was associated with a low level of p21(Cip1) expression. In addition, gossypol preferentially induced autophagy and apoptosis in the gossypol-sensitive cells and not in the gossypol resistant SK-MEL-2 cells. In particular, alleviation of autophagy by knockdown of Beclin-1 partially caused a resistance to gossypol-induced cell cycle arrest at G2/M in BRAF-V600E cells with a concomitant decreased induction of apoptosis. SIGNIFICANCE: Taken together, these results suggest that gossypol may exhibit potential for the treatment of BRAF inhibitor-resistant tumors, but a functional p21(Cip1) is a prerequisite for a positive response to its clinical application. PMID- 24625734 TI - Disaster Research/Evaluation Frameworks, Part 1: An Overview. AB - Note: Many of the concepts and some of the text and content provided in this paper were developed in association with Knut Ole Sundnes, MD and evolved from the Health Disaster Management: Guidelines for Evaluation and Research in the Utstein Style. * Initial and partial support for this project was provided by the Task Force for Quality Control of Disaster Management. This Project is under the auspices of the World Association for Disaster and Emergency Medicine. Abstract The goals of conducting disaster research are to obtain information to: (1) decrease the human, environmental, and economic losses; (2) decrease morbidity; (3) decrease pain and suffering; and (4) enhance the recovery of the affected population. Two principal, but inter-related, branches of disaster research are: (1) Epidemiological; and (2) Interventional. In response to the need for the discipline of disaster health to build its science on data that are generalizable and comparable, a set of five Frameworks have been developed to structure the information and research of the health aspects of disasters: (1) Conceptual; (2) Longitudinal; (3) Transectional Societal; (4) Relief-Recovery; and (5) Risk Reduction. These Frameworks provide a standardized format for studying and comparing the epidemiology of disasters as well as evaluating the interventions (responses) provided prior to, during, and following a disaster, especially as they relate to the health status of the people affected or at-risk. Critical to all five Frameworks is the inclusion of standardized definitions of the terms used to describe factors that lead to and affect the occurrence and severity of a disaster. The Conceptual Framework describes the progression of a hazard that becomes an event, which causes structural damage and a decrease or loss of function (functional damage), that, in turn, produces needs that lead to a disaster. The Longitudinal Framework describes this chronological progression as phases in order of their appearance in time, even though some of them occur concurrently. In order to study and compare the effects of an event on the complex amalgam that constitutes a society, the essential functions of a society have been deconstructed into 13 Basic Societal Systems that comprise the Transectional Societal Framework. These diverse, but inter-related Basic Societal Systems interface with each other through a 14th system called Coordination and Control. Epidemiological research studies the relationships and occurrences that influence and result from a disaster. Interventional research involves the evaluation of interventions, whether they are directed at relief, recovery, hazard mitigation, capacity building, or performance. The Relief-Recovery and Risk-Reduction Frameworks are based on a Disaster Logic Model. The Relief Recovery Framework provides the structure necessary to systematically evaluate specific interventions provided during the Relief and Recovery phases of a disaster. The Risk-Reduction Framework details the processes involved in mitigating the risk that a hazard will produce a destructive event and/or that capacity building will augment the resilience of a community to the consequences of such an event. It incorporates a cascade of risks that lead from the presence of a hazard to the development of a disaster. Risk is described as the likelihood that each of the steps leading from a hazard to a disaster will take place; it also includes the probable consequences of the occurrence of each of the elements in the Conceptual Framework. The Conceptual, Longitudinal, and Transectional Societal Frameworks are useful in epidemiological research, i.e., the study of the incidence of, and factors influencing events and disasters. The Relief Recovery and Risk-Reduction Frameworks are added to the Conceptual, Longitudinal, and Transectional Societal Frameworks for conducting and reporting of interventional research/evaluations. Examples of the application of these Frameworks are provided. Birnbaum ML , Daily EK , O'Rourke AP , Loretti A . Disaster research/evaluation frameworks, part 1: an overview. Prehosp Disaster Med. 2014;29(2):1-12 . PMID- 24625736 TI - Subpixelic measurement of large 1D displacements: principle, processing algorithms, performances and software. AB - This paper presents a visual measurement method able to sense 1D rigid body displacements with very high resolutions, large ranges and high processing rates. Sub-pixelic resolution is obtained thanks to a structured pattern placed on the target. The pattern is made of twin periodic grids with slightly different periods. The periodic frames are suited for Fourier-like phase calculations leading to high resolution-while the period difference allows the removal of phase ambiguity and thus a high range-to-resolution ratio. The paper presents the measurement principle as well as the processing algorithms (source files are provided as supplementary materials). The theoretical and experimental performances are also discussed. The processing time is around 3 us for a line of 780 pixels, which means that the measurement rate is mostly limited by the image acquisition frame rate. A 3-sigma repeatability of 5 nm is experimentally demonstrated which has to be compared with the 168 um measurement range. PMID- 24625737 TI - Energy-efficient boarder node medium access control protocol for wireless sensor networks. AB - This paper introduces the design, implementation, and performance analysis of the scalable and mobility-aware hybrid protocol named boarder node medium access control (BN-MAC) for wireless sensor networks (WSNs), which leverages the characteristics of scheduled and contention-based MAC protocols. Like contention based MAC protocols, BN-MAC achieves high channel utilization, network adaptability under heavy traffic and mobility, and low latency and overhead. Like schedule-based MAC protocols, BN-MAC reduces idle listening time, emissions, and collision handling at low cost at one-hop neighbor nodes and achieves high channel utilization under heavy network loads. BN-MAC is particularly designed for region-wise WSNs. Each region is controlled by a boarder node (BN), which is of paramount importance. The BN coordinates with the remaining nodes within and beyond the region. Unlike other hybrid MAC protocols, BN-MAC incorporates three promising models that further reduce the energy consumption, idle listening time, overhearing, and congestion to improve the throughput and reduce the latency. One of the models used with BN-MAC is automatic active and sleep (AAS), which reduces the ideal listening time. When nodes finish their monitoring process, AAS lets them automatically go into the sleep state to avoid the idle listening state. Another model used in BN-MAC is the intelligent decision-making (IDM) model, which helps the nodes sense the nature of the environment. Based on the nature of the environment, the nodes decide whether to use the active or passive mode. This decision power of the nodes further reduces energy consumption because the nodes turn off the radio of the transceiver in the passive mode. The third model is the least-distance smart neighboring search (LDSNS), which determines the shortest efficient path to the one-hop neighbor and also provides cross-layering support to handle the mobility of the nodes. The BN-MAC also incorporates a semi synchronous feature with a low duty cycle, which is advantageous for reducing the latency and energy consumption for several WSN application areas to improve the throughput. BN-MAC uses a unique window slot size to enhance the contention resolution issue for improved throughput. BN-MAC also prefers to communicate within a one-hop destination using Anycast, which maintains load balancing to maintain network reliability. BN-MAC is introduced with the goal of supporting four major application areas: monitoring and behavioral areas, controlling natural disasters, human-centric applications, and tracking mobility and static home automation devices from remote places. These application areas require a congestion-free mobility-supported MAC protocol to guarantee reliable data delivery. BN-MAC was evaluated using network simulator-2 (ns2) and compared with other hybrid MAC protocols, such as Zebra medium access control (Z-MAC), advertisement-based MAC (A-MAC), Speck-MAC, adaptive duty cycle SMAC (ADC-SMAC), and low-power real-time medium access control (LPR-MAC). The simulation results indicate that BN-MAC is a robust and energy-efficient protocol that outperforms other hybrid MAC protocols in the context of quality of service (QoS) parameters, such as energy consumption, latency, throughput, channel access time, successful delivery rate, coverage efficiency, and average duty cycle. PMID- 24625735 TI - Genetic dissection of photoreceptor subtype specification by the Drosophila melanogaster zinc finger proteins elbow and no ocelli. AB - The elbow/no ocelli (elb/noc) complex of Drosophila melanogaster encodes two paralogs of the evolutionarily conserved NET family of zinc finger proteins. These transcriptional repressors share a conserved domain structure, including a single atypical C2H2 zinc finger. In flies, Elb and Noc are important for the development of legs, eyes and tracheae. Vertebrate NET proteins play an important role in the developing nervous system, and mutations in the homolog ZNF703 human promote luminal breast cancer. However, their interaction with transcriptional regulators is incompletely understood. Here we show that loss of both Elb and Noc causes mis-specification of polarization-sensitive photoreceptors in the 'dorsal rim area' (DRA) of the fly retina. This phenotype is identical to the loss of the homeodomain transcription factor Homothorax (Hth)/dMeis. Development of DRA ommatidia and expression of Hth are induced by the Wingless/Wnt pathway. Our data suggest that Elb/Noc genetically interact with Hth, and we identify two conserved domains crucial for this function. Furthermore, we show that Elb/Noc specifically interact with the transcription factor Orthodenticle (Otd)/Otx, a crucial regulator of rhodopsin gene transcription. Interestingly, different Elb/Noc domains are required to antagonize Otd functions in transcriptional activation, versus transcriptional repression. We propose that similar interactions between vertebrate NET proteins and Meis and Otx factors might play a role in development and disease. PMID- 24625738 TI - A computational model for path loss in wireless sensor networks in orchard environments. AB - A computational model for radio wave propagation through tree orchards is presented. Trees are modeled as collections of branches, geometrically approximated by cylinders, whose dimensions are determined on the basis of measurements in a cherry orchard. Tree canopies are modeled as dielectric spheres of appropriate size. A single row of trees was modeled by creating copies of a representative tree model positioned on top of a rectangular, lossy dielectric slab that simulated the ground. The complete scattering model, including soil and trees, enhanced by periodicity conditions corresponding to the array, was characterized via a commercial computational software tool for simulating the wave propagation by means of the Finite Element Method. The attenuation of the simulated signal was compared to measurements taken in the cherry orchard, using two ZigBee receiver-transmitter modules. Near the top of the tree canopies (at 3 m), the predicted attenuation was close to the measured one-just slightly underestimated. However, at 1.5 m the solver underestimated the measured attenuation significantly, especially when leaves were present and, as distances grew longer. This suggests that the effects of scattering from neighboring tree rows need to be incorporated into the model. However, complex geometries result in ill conditioned linear systems that affect the solver's convergence. PMID- 24625739 TI - Quorum sensing activity of Serratia fonticola strain RB-25 isolated from an ex landfill site. AB - Quorum sensing is a unique bacterial communication system which permits bacteria to synchronize their behaviour in accordance with the population density. The operation of this communication network involves the use of diffusible autoinducer molecules, termed N-acylhomoserine lactones (AHLs). Serratia spp. are well known for their use of quorum sensing to regulate the expression of various genes. In this study, we aimed to characterized the AHL production of a bacterium designated as strain RB-25 isolated from a former domestic waste landfill site. It was identified as Serratia fonticola using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis and this was confirmed by 16S ribosomal DNA sequencing. High resolution triple quadrupole liquid chromatography-mass spectrometry analysis of S. fonticola strain RB-25 spent culture supernatant indicated the existence of three AHLs namely: N-butyryl L-homoserine lactone (C4-HSL), N-hexanoyl-L-homoserine lactone (C6-HSL) and N-(3 oxohexanoyl) homoserine-lactone (3-oxo-C6 HSL). This is the first report of the production of these AHLs in S. fonticola. PMID- 24625740 TI - Time-frequency methods for structural health monitoring. AB - Detection of early warning signals for the imminent failure of large and complex engineered structures is a daunting challenge with many open research questions. In this paper we report on novel ways to perform Structural Health Monitoring (SHM) of flood protection systems (levees, earthen dikes and concrete dams) using sensor data. We present a robust data-driven anomaly detection method that combines time-frequency feature extraction, using wavelet analysis and phase shift, with one-sided classification techniques to identify the onset of failure anomalies in real-time sensor measurements. The methodology has been successfully tested at three operational levees. We detected a dam leakage in the retaining dam (Germany) and "strange" behaviour of sensors installed in a Boston levee (UK) and a Rhine levee (Germany). PMID- 24625741 TI - A new direct single-molecule observation method for DNA synthesis reaction using fluorescent replication protein A. AB - Using a single-stranded region tracing system, single-molecule DNA synthesis reactions were directly observed in microflow channels. The direct single molecule observations of DNA synthesis were labeled with a fusion protein consisting of the ssDNA-binding domain of a 70-kDa subunit of replication protein A and enhanced yellow fluorescent protein (RPA-YFP). Our method was suitable for measurement of DNA synthesis reaction rates with control of the sslambdaDNA form as stretched sslambdaDNA (+flow) and random coiled sslambdaDNA (-flow) via buffer flow. Sequentially captured photographs demonstrated that the synthesized region of an sslambdaDNA molecule monotonously increased with the reaction time. The DNA synthesis reaction rate of random coiled sslambdaDNA (-flow) was nearly the same as that measured in a previous ensemble molecule experiment (52 vs. 50 bases/s). This suggested that the random coiled form of DNA (-flow) reflected the DNA form in the bulk experiment in the case of DNA synthesis reactions. In addition, the DNA synthesis reaction rate of stretched sslambdaDNA (+flow) was approximately 75% higher than that of random coiled sslambdaDNA (-flow) (91 vs. 52 bases/s). The DNA synthesis reaction rate of the Klenow fragment (3'-5'exo-) was promoted by DNA stretching with buffer flow. PMID- 24625742 TI - Design and experimentation with sandwich microstructure for catalytic combustion type gas sensors. AB - The traditional handmade catalytic combustion gas sensor has some problems such as a pairing difficulty, poor consistency, high power consumption, and not being interchangeable. To address these issues, integrated double catalytic combustion of alcohol gas sensor was designed and manufactured using silicon micro-electro mechanical systems (MEMS) technology. The temperature field of the sensor is analyzed using the ANSYS finite element analysis method. In this work, the silicon oxide-PECVD-oxidation technique is used to manufacture a SiO2-Si3N2-SiO2 microstructure carrier with a sandwich structure, while wet etching silicon is used to form a beam structure to reduce the heat consumption. Thin-film technology is adopted to manufacture the platinum-film sensitive resistance. Nano Al2O3-ZrO-ThO is coated to format the sensor carrier, and the sensitive unit is dipped in a Pt-Pd catalyst solution to form the catalytic sensitive bridge arm. Meanwhile the uncoated catalyst carrier is considered as the reference unit, realizing an integrated chip based on a micro double bridge and forming sensors. The lines of the Pt thin-film resistance have been observed with an electronic microscope. The compensation of the sensitive material carriers and compensation materials have been analyzed using an energy spectrum. The results show that the alcohol sensor can detect a volume fraction between 0 and 4,500 * 10(-6) and has good linear output characteristic. The temperature ranges from -20 to +40 degrees C. The humidity ranges from 30% to 85% RH. The zero output of the sensor is less than +/-2.0% FS. The power consumption is <=0.2 W, and both the response and recovery time are approximately 20 s. PMID- 24625743 TI - A polarization control system for intensity-resolved guided mode resonance sensors. AB - In this study, a polarization-control setup for intensity-resolved guided mode resonance sensors is proposed and demonstrated experimentally. The experimental results are in good agreement with the simulation data based on rigorous coupled wave approach calculations. The proposed intensity-resolved measurement setup transfers polarization ellipses, which are produced from guided mode resonance to a linear polarization state under a buffer solution condition, and then suppresses the signals to dark using a polarization-control set. Hence, any changes in the refractive index results in an increase in the intensity signals. Furthermore, no wavelength-resolved or angular-resolved measurement is needed in this scheme. According to the experimental results, a wide linear detection range of 0.014 refractive index units is achieved and the limit of detection is 1.62E-4 RIU. PMID- 24625744 TI - Force sensor attachable to thin fiberscopes/endoscopes utilizing high elasticity fabric. AB - An endoscope/fiberscope is a minimally invasive tool used for directly observing tissues in areas deep inside the human body where access is limited. However, this tool only yields visual information. If force feedback information were also available, endoscope/fiberscope operators would be able to detect indurated areas that are visually hard to recognize. Furthermore, obtaining such feedback information from tissues in areas where collecting visual information is a challenge would be highly useful. The major obstacle is that such force information is difficult to acquire. This paper presents a novel force sensing system that can be attached to a very thin fiberscope/endoscope. To ensure a small size, high resolution, easy sterilization, and low cost, the proposed force visualization-based system uses a highly elastic material-panty stocking fabric. The paper also presents the methodology for deriving the force value from the captured image. The system has a resolution of less than 0.01 N and sensitivity of greater than 600 pixels/N within the force range of 0-0.2 N. PMID- 24625745 TI - Olfaction-inspired sensing using a sensor system with molecular recognition and optimal classification ability for comprehensive detection of gases. AB - In this study, we examined the comprehensive detection of numerous volatile molecules based on the olfactory information constructed by using olfaction inspired sensor technology. The sensor system can simultaneously detect multiple odors by the separation and condensation ability of molecularly imprinted filtering adsorbents (MIFAs), where a MIP filter with a molecular sieve was deposited on a polydimethylsiloxane (PDMS) substrate. The adsorption properties of MIFAs were evaluated using the solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS). The results demonstrated that the system embedded with MIFAs possesses high sensitivity and specific selectivity. The digitization and comprehensive classification of odors were accomplished by using artificial odor maps constructed through this system. PMID- 24625746 TI - Characteristic two-dimensional Fermi surface topology of high-Tc iron-based superconductors. AB - Unconventional Cooper pairing originating from spin or orbital fluctuations has been proposed for iron-based superconductors. Such pairing may be enhanced by quasi-nesting of two-dimensional electron and hole-like Fermi surfaces (FS), which is considered an important ingredient for superconductivity at high critical temperatures (high-Tc). However, the dimensionality of the FS varies for hole and electron-doped systems, so the precise importance of this feature for high-Tc materials remains unclear. Here we demonstrate a phase of electron-doped CaFe2As2 (La and P co-doped CaFe2As2) with Tc = 45 K, which is the highest Tc found for the AEFe2As2 bulk superconductors (122-type; AE = Alkaline Earth), possesses only cylindrical hole- and electron-like FSs. This result indicates that FS topology consisting only of two-dimensional sheets is characteristic of both hole- and electron-doped 122-type high-Tc superconductors. PMID- 24625747 TI - Risk factors and outcomes stratified by severity of acute kidney injury in malaria. AB - Severe acute kidney injury (AKI) is known to have prognostic value for in hospital outcomes in malaria. However, little is known about the association of AKI of lesser severity with malarial risk factors and outcomes--and such a gap is becoming increasingly relevant with the upsurge in the incidence of AKI due to Plasmodium falciparum malaria and Plasmodium vivax malaria over the last decade. We aimed to identify risk factors of AKI in malaria and assessed in-hospital outcomes stratified by severity of AKI. We performed an observational study of 1,191 hospitalized malaria patients enrolled between 2007 and 2011 in a tertiary care academic center in India. Patients were categorized based on peak serum creatinine into one of three groups: no AKI (<1.6 mg/dL), mild AKI (1.6-3.0 mg/dL), and severe AKI (>3 mg/dL). Plasmodium vivax was the predominant species (61.41%), followed by Plasmodium falciparum (36.41%) and mixed infections with both the species (2.18%). Mild and severe AKI were detected in 12% and 5.6% of patients, respectively. Mild AKI due to Plasmodium vivax (49%) and Plasmodium falciparum (48.5%) was distributed relatively equally within the sample population; however, cases of severe AKI due to Plasmodium falciparum (80%) and Plasmodium vivax (13%) was significantly different (P<0.001). On history and physical examination, risk factors for AKI were age, absence of fever, higher heart rate, lower diastolic blood pressure, icterus, and hepatomegaly. The only laboratory parameter associated with risk of AKI on multivariate analysis was direct bilirubin. Patients with mild and severe AKI had greater organ complications, supportive requirements, longer duration of hospital stay and in hospital mortality in a dose-dependent relationship, than patients with no AKI. Mild AKI is associated with significant (P<0.05) morbidity compared to no AKI, and future studies should assess strategies for early diagnosis of AKI and prevent AKI progression. PMID- 24625749 TI - The diagnostic value of both troponin T and creatinine kinase isoenzyme (CK-MB) in detecting combined renal and myocardial injuries in asphyxiated infants. AB - BACKGROUND: Troponin T (cTnT) and Creatinine Kinase Isoenzyme (CK-MB) are both markers of myocardial injuries. However, CK-MB is also elevated in acute kidney injury. OBJECTIVE: The diagnostic value of both cTnT and cardiac CK-MB in combined myocardial and acute kidney injuries (AKI) in asphyxiated neonates was evaluated. METHOD: 40 asphyxiated infants and 40 non-asphyxiated controls were consecutively recruited. Serum levels of cTnT, CK-MB and creatinine were measured. Myocardial injury and AKI were defined as cTnT >95th percentile of the control and serum creatinine >1.0 mg/dl respectively. RESULTS: Of the 40 subjects, 9 (22.50%), 8 (20.00%) and 4 (10.00%) had myocardial injury, AKI and combined AKI and myocardial injuries respectively. The mean cTnT and CK-MB values were highest in infants with combined AKI and myocardial injuries. The Mean cTnT in infants with AKI, myocardial injury and combined AKI and myocardial injuries were 0.010+/-0.0007 ng/ml, 0.067+/-0.040 ng/ml and 0.084+/-0.067 ng/ml respectively, p = 0.006. The mean CK-MB in infants with AKI, myocardial injury and combined AKI and myocardial injuries were 2.78+/-0.22 ng/ml, 1.28+/-0.11 ng/ml and 4.58+/-0.52 ng/ml respectively, p = <0.0001. CONCLUSION: In severe perinatal asphyxia, renal and myocardial injuries could co-exist. Elevated cTnT signifies the presence of myocardial injury. Elevated CK-MB indicates either myocardial injury, AKI or both. Therefore renal injury should be excluded in asphyxiated infants with elevated CK-MB. PMID- 24625748 TI - Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation. AB - The ability of acetylcholine (ACh) to alter specific functional properties of the cortex endows the cholinergic system with an important modulatory role in memory formation. For example, an increase in ACh release occurs during novel stimulus processing, indicating that ACh activity is critical during early stages of memory processing. During novel taste presentation, there is an increase in ACh release in the insular cortex (IC), a major structure for taste memory recognition. There is extensive evidence implicating the cholinergic efferents of the nucleus basalis magnocellularis (NBM) in cortical activity changes during learning processes, and new evidence suggests that the histaminergic system may interact with the cholinergic system in important ways. However, there is little information as to whether changes in cholinergic activity in the IC are modulated during taste memory formation. Therefore, in the present study, we evaluated the influence of two histamine receptor subtypes, H1 in the NBM and H3 in the IC, on ACh release in the IC during conditioned taste aversion (CTA). Injection of the H3 receptor agonist R-alpha-methylhistamine (RAMH) into the IC or of the H1 receptor antagonist pyrilamine into the NBM during CTA training impaired subsequent CTA memory, and simultaneously resulted in a reduction of ACh release in the IC. This study demonstrated that basal and cortical cholinergic pathways are finely tuned by histaminergic activity during CTA, since dual actions of histamine receptor subtypes on ACh modulation release each have a significant impact during taste memory formation. PMID- 24625750 TI - Sequencing of a patient with balanced chromosome abnormalities and neurodevelopmental disease identifies disruption of multiple high risk loci by structural variation. AB - Balanced chromosome abnormalities (BCAs) occur at a high frequency in healthy and diseased individuals, but cost-efficient strategies to identify BCAs and evaluate whether they contribute to a phenotype have not yet become widespread. Here we apply genome-wide mate-pair library sequencing to characterize structural variation in a patient with unclear neurodevelopmental disease (NDD) and complex de novo BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (LINC00299, NUP205, PSMD14) that gave rise to abnormal mRNAs and could be assumed as disease-causing. However, unbiased genome-wide analysis of the sequencing data for cryptic structural variation was key to reveal an additional submicroscopic inversion that truncates the schizophrenia- and bipolar disorder-associated brain transcription factor ZNF804A as an equally likely NDD driving gene. Deep sequencing of fluorescent-sorted wild-type and derivative chromosomes confirmed the clinically undetected BCA. Moreover, deep sequencing further validated a high accuracy of mate-pair library sequencing to detect structural variants larger than 10 kB, proposing that this approach is powerful for clinical-grade genome-wide structural variant detection. Our study supports previous evidence for a role of ZNF804A in NDD and highlights the need for a more comprehensive assessment of structural variation in karyotypically abnormal individuals and patients with neurocognitive disease to avoid diagnostic deception. PMID- 24625751 TI - Anisotropic plasmon-coupling dimerization of a pair of spherical electron gases. AB - We have discovered a novel feature in the plasmon excitations for a pair of Coulomb-coupled non-concentric spherical two-dimensional electron gases (S2DEGs). Our results show that the plasmon excitations for such pairs depend on the orientation with respect to the external electromagnetic probe field. The origin of this anisotropy of the inter-sphere Coulomb interaction is due to the directional asymmetry of the electrostatic coupling of electrons in excited states which depend on both the angular momentum quantum number L and its projection M on the axis of quantization taken as the probe E-field direction. We demonstrate the anisotropic inter-sphere Coulomb coupling in space and present semi-analytic results in the random-phase approximation both perpendicular and parallel to the axis of quantization. For the incidence of light with a finite orbital or spin angular momentum, the magnetic field generated from an induced oscillating electric dipole on one sphere can couple to an induced magnetic dipole on another sphere in a way that is dependent on whether the direction is parallel or perpendicular to the probe E field. Such an effect from the plasmon spatial correlation is expected to be experimentally observable by employing circularly polarized light or a helical light beam for incidence. The S2DEG serves as a simple model for fullerenes as well as metallic dimers, when the energy bands are far apart. PMID- 24625752 TI - Hippocampal--prefrontal BDNF and memory for fear extinction. AB - Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories. PMID- 24625753 TI - The impact of MIR137 on dorsolateral prefrontal-hippocampal functional connectivity in healthy subjects. AB - A recent mega-analysis combining genome-wide association study data revealed that a variant of microRNA 137 (MIR137) exhibits the most significant association with schizophrenia. Other biological evidence also consistently suggests that MIR137 may have a pivotal role in the pathogenesis of schizophrenia. However, the underlying neural mechanism remains unclear. As the disrupted dorsolateral prefrontal cortex (DLPFC) coupling with the hippocampal formation (HF) has been widely observed in schizophrenia patients, DLPFC-HF dysconnectivity can therefore be thought of as a pivotal intermediate phenotype that links genetic variants of psychiatric risk genes to schizophrenia. This study used resting-state functional magnetic resonance imaging to test whether the MIR137 variant (rs1625579) impacts DLPFC-HF functional connectivity and cognitive performance in 290 young, healthy Han Chinese individuals. To identify functional connectivity between DLPFC and HF, a seed-based functional connectivity analysis was used. The association between DLPFC-HF connectivity and working memory performance was further examined in individuals with different MIR137 genotypes. The individuals who are homozygous for the MIR137 risk allele (TT), which confers a high risk for schizophrenia, exhibited significantly different DLPFC-HF functional connectivity compared with TG individuals. Moreover, the DLPFC-HF connectivity could predict the working memory performance in MIR137 TG individuals, but not in TT individuals. The current findings obtained in a large sample of healthy participants identified potential neural mechanisms linking MIR137 with the risk of developing schizophrenia via the intermediate phenotype of DLPFC-HF connectivity. PMID- 24625754 TI - A soluble form of the giant cadherin Fat1 is released from pancreatic cancer cells by ADAM10 mediated ectodomain shedding. AB - In pancreatic cancer, there is a clear unmet need to identify new serum markers for either early diagnosis, therapeutic stratification or patient monitoring. Proteomic analysis of tumor cell secretomes is a promising approach to indicate proteins released from tumor cells in vitro. Ectodomain shedding of transmembrane proteins has previously been shown to contribute significant fractions the tumor cell secretomes and to generate valuable serum biomarkers. Here we introduce a soluble form of the giant cadherin Fat1 as a novel biomarker candidate. Fat1 expression and proteolytic processing was analyzed by mass spectrometry and Western blotting using pancreatic cancer cell lines as compared to human pancreatic ductal epithelial cells. RNA expression in cancer tissues was assessed by in silico analysis of publically available microarray data. Involvement of ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in Fat1 ectodomain shedding was analyzed by chemical inhibition and knockdown experiments. A sandwich ELISA was developed to determine levels of soluble Fat1 in serum samples. In the present report we describe the release of high levels of the ectodomain of Fat1 cadherin into the secretomes of human pancreatic cancer cells in vitro, a process that is mediated by ADAM10. We confirm the full-length and processed heterodimeric form of Fat1 expressed on the plasma membrane and also show the p60 C-terminal transmembrane remnant fragment corresponding to the shed ectodomain. Fat1 and its sheddase ADAM10 are overexpressed in pancreatic adenocarcinomas and ectodomain shedding is also recapitulated in vivo leading to increased Fat1 serum levels in some pancreatic cancer patients. We suggest that soluble Fat1 may find an application as a marker for patient monitoring complementing carbohydrate antigen 19-9 (CA19-9). In addition, detailed analysis of the diverse processed protein isoforms of the candidate tumor suppressor Fat1 can also contribute to our understanding of cell biology and tumor behavior. PMID- 24625755 TI - Effects of woodsmoke exposure on airway inflammation in rural Guatemalan women. AB - BACKGROUND: More than two-fifths of the world's population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD) among women in developing countries. OBJECTIVE: To assess whether lower woodsmoke exposure from use of a stove with a chimney, compared to open fires, is associated with lower markers of airway inflammation in young women. DESIGN: We carried out a cross-sectional analysis on a sub-cohort of participants enrolled in a randomized controlled trial in rural Guatemala, RESPIRE. PARTICIPANTS: We recruited 45 indigenous women at the end of the 18-month trial; 19 women who had been using the chimney stove for 18-24 months and 26 women still using open fires. MEASUREMENTS: We obtained spirometry and induced sputum for cell counts, gene expression of IL-8, TNF alpha, MMP-9 and 12, and protein concentrations of IL-8, myeloperoxidase and fibronectin. Exhaled carbon monoxide (CO) and 48-hr personal CO tubes were measured to assess smoke exposure. RESULTS: MMP-9 gene expression was significantly lower in women using chimney stoves. Higher exhaled CO concentrations were significantly associated with higher gene expression of IL-8, TNF-alpha, and MMP-9. Higher 48-hr personal CO concentrations were associated with higher gene expression of IL-8, TNF- alpha, MMP-9 and MMP-12; reaching statistical significance for MMP-9 and MMP-12. CONCLUSIONS: Compared to using an open wood fire for cooking, use of a chimney stove was associated with lower gene expression of MMP-9, a potential mediator of airway remodeling. Among all participants, indoor biomass smoke exposure was associated with higher gene expression of multiple mediators of airway inflammation and remodeling; these mechanisms may explain some of the observed association between prolonged biomass smoke exposure and COPD. PMID- 24625756 TI - Genetic determinants influencing human serum metabolome among African Americans. AB - Phenotypes proximal to gene action generally reflect larger genetic effect sizes than those that are distant. The human metabolome, a result of multiple cellular and biological processes, are functional intermediate phenotypes proximal to gene action. Here, we present a genome-wide association study of 308 untargeted metabolite levels among African Americans from the Atherosclerosis Risk in Communities (ARIC) Study. Nineteen significant common variant-metabolite associations were identified, including 13 novel loci (p<1.6 * 10(-10)). These loci were associated with 7-50% of the difference in metabolite levels per allele, and the variance explained ranged from 4% to 20%. Fourteen genes were identified within the nineteen loci, and four of them contained non-synonymous substitutions in four enzyme-encoding genes (KLKB1, SIAE, CPS1, and NAT8); the other significant loci consist of eight other enzyme-encoding genes (ACE, GATM, ACY3, ACSM2B, THEM4, ADH4, UGT1A, TREH), a transporter gene (SLC6A13) and a polycystin protein gene (PKD2L1). In addition, four potential disease-associated paths were identified, including two direct longitudinal predictive relationships: NAT8 with N-acetylornithine, N-acetyl-1-methylhistidine and incident chronic kidney disease, and TREH with trehalose and incident diabetes. These results highlight the value of using endophenotypes proximal to gene function to discover new insights into biology and disease pathology. PMID- 24625757 TI - HPV E6/E7 RNA in situ hybridization signal patterns as biomarkers of three-tier cervical intraepithelial neoplasia grade. AB - Cervical lesion grading is critical for effective patient management. A three tier classification (cervical intraepithelial neoplasia [CIN] grade 1, 2 or 3) based on H&E slide review is widely used. However, for reasons of considerable inter-observer variation in CIN grade assignment and for want of a biomarker validating a three-fold stratification, CAP-ASCCP LAST consensus guidelines recommend a two-tier system: low- or high-grade squamous intraepithelial lesions (LSIL or HSIL). In this study, high-risk HPV E6/E7 and p16 mRNA expression patterns in eighty-six CIN lesions were investigated by RNAscope chromogenic in situ hybridization (CISH). Specimens were also screened by immunohistochemistry for p16INK4a (clone E6H4), and by tyramide-based CISH for HPV DNA. HPV genotyping was performed by GP5+/6+ PCR combined with cycle-sequencing. Abundant high-risk HPV RNA CISH signals were detected in 26/32 (81.3%) CIN 1, 22/22 (100%) CIN 2 and in 32/32 (100%) CIN 3 lesions. CIN 1 staining patterns were typified (67.7% specimens) by abundant diffusely staining nuclei in the upper epithelial layers; CIN 2 lesions mostly (66.7%) showed a combination of superficial diffuse-stained nuclei and multiple dot-like nuclear and cytoplasmic signals throughout the epithelium; CIN 3 lesions were characterized (87.5%) by multiple dot-like nuclear and cytoplasmic signals throughout the epithelial thickness and absence/scarcity of diffusely staining nuclei (trend across CIN grades: P<0.0001). These data are consistent with productive phase HPV infections exemplifying CIN 1, transformative phase infections CIN 3, whereas CIN 2 shows both productive and transformative phase elements. Three-tier data correlation was not found for the other assays examined. The dual discernment of diffuse and/or dot-like signals together with the assay's high sensitivity for HPV support the use of HPV E6/E7 RNA CISH as an adjunct test for deciding lesion grade when CIN 2 grading may be beneficial (e.g. among young women) or when 'LSIL vs. HSIL' assignment is equivocal. PMID- 24625759 TI - Using a drug-word Stroop task to differentiate recreational from dependent drug use. AB - Distinguishing dependent from recreational drug use can be a surprisingly difficult task, and the current means for identifying substance abuse can be inadequate or even misleading. In subjective self-reports, those who are most at risk may down play their consumption, not admitting to the full extent of their habit, and measures purely of quantity of use rarely capture the true nature of an individual's relationship to the drug, such as a psychological dependence on the substance. This trend is particularly true for heavy stimulant use, which is absent of the physical withdrawal symptoms that can help identify opiate or alcohol dependence. As such, a simple objective measure to help identify substance abuse, particularly in individuals who might not otherwise raise suspicion, would be a valuable tool in both clinical and experimental settings. We propose that the drug-word Stroop task, an objective assessment of attentional bias and distraction to salient drug-related stimuli, would be a valuable tool in helping to make these categorizations. This measure has been shown to correlate with drug craving, as well as to successfully distinguish dependent from recreational stimulant users and to help to predict outcomes in treatment-seeking individuals. Here, we survey prior literature on the drug-word Stroop task and provide a perspective on using the assessment as a potential diagnostic for drug use severity. PMID- 24625761 TI - Re: defining progression in nonmuscle invasive bladder cancer: it is time for a new, standard definition. D. Lamm, R. Persad, M. Brausi, R. Buckley, J. A. Witjes, J. Palou, A. Bohle, A. M. Kamat, M. Colombel and M. Soloway J Urol 2014;191:20-27. PMID- 24625758 TI - Specific non-local interactions are not necessary for recovering native protein dynamics. AB - The elastic network model (ENM) is a widely used method to study native protein dynamics by normal mode analysis (NMA). In ENM we need information about all pairwise distances, and the distance between contacting atoms is restrained to the native value. Therefore ENM requires O(N2) information to realize its dynamics for a protein consisting of N amino acid residues. To see if (or to what extent) such a large amount of specific structural information is required to realize native protein dynamics, here we introduce a novel model based on only O(N) restraints. This model, named the 'contact number diffusion' model (CND), includes specific distance restraints for only local (along the amino acid sequence) atom pairs, and semi-specific non-local restraints imposed on each atom, rather than atom pairs. The semi-specific non-local restraints are defined in terms of the non-local contact numbers of atoms. The CND model exhibits the dynamic characteristics comparable to ENM and more correlated with the explicit solvent molecular dynamics simulation than ENM. Moreover, unrealistic surface fluctuations often observed in ENM were suppressed in CND. On the other hand, in some ligand-bound structures CND showed larger fluctuations of buried protein atoms interacting with the ligand compared to ENM. In addition, fluctuations from CND and ENM show comparable correlations with the experimental B-factor. Although there are some indications of the importance of some specific non-local interactions, the semi-specific non-local interactions are mostly sufficient for reproducing the native protein dynamics. PMID- 24625762 TI - In-vitro neurotoxicity of two Malaysian krait species (Bungarus candidus and Bungarus fasciatus) venoms: neutralization by monovalent and polyvalent antivenoms from Thailand. AB - Bungarus candidus and Bungarus fasciatus are two species of krait found in Southeast Asia. Envenoming by these snakes is often characterized by neurotoxicity and, without treatment, causes considerable morbidity and mortality. In this study, the in vitro neurotoxicity of each species, and the effectiveness of two monovalent antivenoms and a polyvalent antivenom, against the neurotoxic effects of the venoms, were examined in a skeletal muscle preparation. Both venoms caused concentration-dependent inhibition of indirect twitches, and attenuated responses to exogenous nicotinic receptor agonists, in the chick biventer preparation, with B. candidus venom being more potent than B. fasciatus venom. SDS-PAGE and western blot analysis indicated different profiles between the venoms. Despite these differences, most proteins bands were recognized by all three antivenoms. Antivenom, added prior to the venoms, attenuated the neurotoxic effect of the venoms. Interestingly, the respective monovalent antivenoms did not neutralize the effects of the venom from the other Bungarus species indicating a relative absence of cross-neutralization. Addition of a high concentration of polyvalent antivenom, at the t90 time point after addition of venom, partially reversed the neurotoxicity of B. fasciatus venom but not B. candidus venom. The monovalent antivenoms had no significant effect when added at the t90 time point. This study showed that B. candidus and B. fasciatus venoms display marked in vitro neurotoxicity in the chick biventer preparation and administration of antivenoms at high dose is necessary to prevent or reverse neurotoxicity. PMID- 24625763 TI - Identification of a key residue for oligomerisation and pore-formation of Clostridium perfringens NetB. AB - Necrotic enteritis toxin B (NetB) is a beta-pore-forming toxin produced by Clostridium perfringens and has been identified as a key virulence factor in the pathogenesis of avian necrotic enteritis, a disease causing significant economic damage to the poultry industry worldwide. In this study, site-directed mutagenesis was used to identify amino acids that play a role in NetB oligomerisation and pore-formation. NetB K41H showed significantly reduced toxicity towards LMH cells and human red blood cells relative to wild type toxin. NetB K41H was unable to oligomerise and form pores in liposomes. These findings suggest that NetB K41H could be developed as a genetic toxoid vaccine to protect against necrotic enteritis. PMID- 24625764 TI - A method for predicting protein-protein interaction types. AB - Protein-protein interactions (PPIs) govern basic cellular processes through signal transduction and complex formation. The diversity of those processes gives rise to a remarkable diversity of interactions types, ranging from transient phosphorylation interactions to stable covalent bonding. Despite our increasing knowledge on PPIs in humans and other species, their types remain relatively unexplored and few annotations of types exist in public databases. Here, we propose the first method for systematic prediction of PPI type based solely on the techniques by which the interaction was detected. We show that different detection methods are better suited for detecting specific types. We apply our method to ten interaction types on a large scale human PPI dataset. We evaluate the performance of the method using both internal cross validation and external data sources. In cross validation, we obtain an area under receiver operating characteristic (ROC) curve ranging from 0.65 to 0.97 with an average of 0.84 across the predicted types. Comparing the predicted interaction types to external data sources, we obtained significant agreements for phosphorylation and ubiquitination interactions, with hypergeometric p-value = 2.3e(-54) and 5.6e( 28) respectively. We examine the biological relevance of our predictions using known signaling pathways and chart the abundance of interaction types in cell processes. Finally, we investigate the cross-relations between different interaction types within the network and characterize the discovered patterns, or motifs. We expect the resulting annotated network to facilitate the reconstruction of process-specific subnetworks and assist in predicting protein function or interaction. PMID- 24625765 TI - Impact of axis-I comorbidity and suicidal behavior disorders on sensitivity and specificity of the Mood Disorder Questionnaire in complex depressed inpatients. AB - OBJECTIVE: This study assessed the psychometric performance of the Mood Disorder Questionnaire (MDQ) and its modified MDQ7 version, to screen for bipolar disorders (BD) in depressive inpatients according to depression severity, number of current axis I psychiatric comorbidities and suicidal behavior disorders. METHODS: Depressed adult inpatients (n=195) were consecutively enrolled. Psychiatric diagnoses were made using the standardized DSM-IV-TR structured interview MINI 5.0.0 and medical case notes. Depression severity was assessed with the Beck Depression Inventory and the Hamilton Depression Scale. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each MDQ version were evaluated in the whole sample and according to depression severity, current axis I psychiatric comorbidities and suicidal behavior. RESULTS: The occurrence and the number of axis I disorders affected performance of both versions. Among depressed patients with two or more comorbidities, PPV and NPV of the MDQ were 65% and 80%, respectively, and they were respectively 56.2% and 87.9% with MDQ7. Current suicidal behavior disorders also dramatically reduced the PPV of MDQ (from 81.2% to 63.3%) and MDQ7 (from 72.2% to 52.6%) but the NPV remained above 80%. The performance of both versions of the MDQ tended to improve with the severity of depression. CONCLUSION: The MDQ is not a suitable screening instrument to diagnose BD in subjects with a complex major depressive episode and/or a current history of suicidal behavior. Nevertheless MDQ particularly in its modified version may be useful for ruling out the presence of BD among these complex patients. PMID- 24625766 TI - The relationship between impulsivity and lipid levels in bipolar patients: does temperament explain it? AB - BACKGROUND: The aim of this study was to investigate whether there was a relationship between impulsivity and lipid levels in patients with bipolar disorder (BD) and to examine the correlation of impulsivity and lipid levels with temperament subtypes. METHODS: For this purpose, one hundred patients who were admitted to our out-patient unit for routine controls, had been in remission for at least 8weeks, and diagnosed as BD according to the DSM-IV were evaluated consecutively. Impulsivity and temperament were evaluated with the BIS-11 and the TEMPS-A. Blood samples were obtained to measure levels of lipids (cholesterol, triglyceride, high density lipoprotein-HDL, low density lipoprotein-LDL). RESULTS: A weak correlation was found between impulsivity scores and triglyceride levels (r=0.190, p=0.050). Correlation was found between impulsivity scores and depressive, anxious, cyclothymic, and irritable temperaments (r=0.371, p<0.001; r=0.458, p<0.001; r=0.541, p<0.001; r=0.530, p<0.001), while triglyceride levels were only related with depressive and anxious temperaments (r=0.485, p=0.001 and r=0.391, p=0.006). CONCLUSIONS: Temperament is an important mediator of the relationship between lipid levels and trait impulsivity in patients with BD. PMID- 24625767 TI - Feasibility of using central registry data to assess timeliness of breast cancer care in Delaware. AB - Studies have shown that timely screening, diagnosis, and treatment of breast cancer reduces mortality rates. The objective of this study was to determine if data collected by the Delaware Cancer Registry (DCR) could be used to access the timeliness of diagnosis and treatment for breast cancer patients, using the Centers for Disease Control and Prevention (CDC) recommendations of 60 days maximum for screening to diagnosis and 60 days maximum for diagnosis to treatment. This study analyzed DCR data for female Delawarean breast cancer patients diagnosed in 2004; data were included that had a valid screening, diagnosis, and treatment date. Calculations of 3 time intervals were performed: screening to diagnosis (time interval A), diagnosis to treatment (time interval B), and screening to treatment (time interval C). Results of this study show that, while not captured as an independent variable, screening dates could be extracted from text fields to calculate appropriate time intervals. The mean and median for time intervals A (23.2 days, 20.0 days), B (2.1 days, 0.0 days), and C (40.1 days, 37.0 days) met CDC recommendations. This study shows that it is possible to utilize DCR data to conduct a timeliness of breast cancer treatment providing the ability to benchmark Delaware breast cancer treatment timelines to national recommendations. PMID- 24625768 TI - Construction of a comorbidity index for prostate cancer patients linking state cancer registry with inpatient and outpatient data. AB - INTRODUCTION: Identifying clinically relevant comorbid conditions might lead to effective control of prostate cancer- specific risk factors and provide opportunities to improve patient care and outcomes. There are challenges in assessing comorbidity using linked databases such as statewide hospital administrative data and state cancer registry. The objective was to compile a comprehensive list of clinically relevant comorbid conditions for patients with prostate cancer using registry and statewide diagnosis databases. METHODS: Florida Cancer Data System cases were linked with the inpatient/ outpatient diagnosis information. The Elixhauser Comorbidity Index was used as a reference. Conditions not captured by Elixhauser were identified, and grouped into clinically meaningful categories. Descriptive analysis was performed on comorbidity conditions and major study population variables. Associations of comorbidity with selected demographic and disease characteristics were examined. RESULTS: Twenty-nine Elixhauser and 16 additional categories were examined within the 1 record per patient data set. Statistically significant association was found between comorbidity with race, stage, and age. Blacks had a higher mean number of conditions compared to whites. A higher proportion of blacks had at least 1 comorbid condition compared to whites. Additional conditions identified by this research capture more comorbidities for white men. Distinct trends towards larger number of comorbidities with older age at diagnosis and advanced disease stage were observed. CONCLUSIONS: The Elixhauser Comorbidity Index captured the majority of comorbidities in the study population while the additional conditions identified by this research add more information. This study offers important insights into the challenges and process to identify relevant comorbidities for prostate cancer patients. PMID- 24625769 TI - Registry data quality improvement by identifying discrepancies between assigned codes and text descriptions of birth defects. AB - INTRODUCTION: Birth defects surveillance programs support efforts to prevent and address population health. For 30 years, the New York State (NYS) Department of Health (DOH) Congenital Malformations Registry (CMR) has been receiving reports of children with birth defects diagnosed from birth to age 2 years as required by NYS DOH regulation. Our objective in this effort was to improve the accuracy of British Pediatric Association (BPA) codes assigned to case reports in the NYS CMR. METHODS: From 1998 forward, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code and a text description for reported birth defects have been entered into the CMR database. Upon receipt, CMR staff use reported descriptions and ICD-9-CM codes to recode all birth defects into BPA codes to improve surveillance specificity. To improve CMR data completeness and accuracy for birth years 1998-2010, computer programming was used to identify possible mismatches between birth defect descriptions and BPA codes. First, descriptions were reviewed for text strings related to specific BPA codes, and common spellings, misspellings and abbreviations were identified. Next, 1998-2010 case reports were flagged if they had either the identified text strings or the related BPA codes but not both. All flagged records were reviewed manually by registry staff and necessary data corrections were made. This quality control process was evaluated, overall and for 78 targeted birth defect groups, using frequency and percent. The number of records flagged for possible discrepancy between BPA codes and text strings, percent reviewed and percent corrected are presented. These findings helped us understand which BPA codes or birth defects required the most attention. RESULTS: A total of 164,726 records were scanned for discrepancies between BPA code and text strings related to 78 birth defects. Of the records scanned, approximately 10 percent were found to have discrepancies and were flagged for manual review and approximately 8 percent required correction. Among case records for the targeted birth defects, 24.8 percent were reviewed and 19 percent were corrected. Of the records reviewed, 76.8 percent were corrected. CONCLUSIONS: This approach to data quality improvement was effective in identifying and resolving inaccuracies in the NYS CMR. High quality data is valuable for monitoring birth defects trends, allowing interstate comparisons of specific defects, and supporting birth defects research. As a result, prevention efforts and policy decisions aimed at improving public health will be better informed. PMID- 24625770 TI - Using cancer registries to assess the accuracy of primary liver or intrahepatic bile duct cancer as the underlying cause of death, 1999-2010. AB - Inaccuracies in primary liver cancer (ie, excluding intrahepatic bile duct [IHBD]) or IHBD cancer as the underlying cause of death on the death certificate vs the cancer site in a cancer registry should be considered in surveillance of mortality rates in the population. Concordance between cancer site on the death record (1999-2010) and diagnosis (1973-2010) in the database for 9 cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program was examined for decedents with only 1 cancer recorded. Overreporting of deaths coded to liver cancer (ie, lack of confirmation in SEER) was largely balanced by underreporting (ie, a cancer site other than liver cancer in SEER). For IHBD cancer, overreporting was much more frequent than underreporting. Using modified rates, based on the most accurate numerators available, had little impact on trends for liver cancer in the SEER population, which were similar to trends for the entire US population based on routine statistics. An increase in the death rate for IHBD cancer, however, was no longer evident after modification. The findings support the use of routine data on underlying cause of death for surveillance of trends in death rates for liver cancer but not for IHBD cancer. Additional population-based cancer registries could potentially be used for surveillance of recent and future trends in mortality rates from these cancers. PMID- 24625771 TI - Enhancement and validation of an Arab surname database. AB - OBJECTIVES: Arab Americans constitute a large, heterogeneous, and quickly growing subpopulation in the United States. Health statistics for this group are difficult to find because US governmental offices do not recognize Arab as separate from white. The development and validation of an Arab- and Chaldean American name database will enhance research efforts in this population subgroup. METHODS: A previously validated name database was supplemented with newly identified names gathered primarily from vital statistic records and then evaluated using a multistep process. This process included 1) review by 4 Arabic- and Chaldean-speaking reviewers, 2) ethnicity assessment by social media searches, and 3) self-report of ancestry obtained from a telephone survey. RESULTS: Our Arab- and Chaldean-American name algorithm has a positive predictive value of 91 percent and a negative predictive value of 100 percent. CONCLUSIONS: This enhanced name database and algorithm can be used to identify Arab Americans in health statistics data, such as cancer and hospital registries, where they are often coded as white, to determine the extent of health disparities in this population. PMID- 24625772 TI - Impact of race/ethnicity and socioeconomic status on adjuvant chemotherapy use among elderly patients with stage III colon cancer. AB - BACKGROUND: It is well recognized that stage III colon cancer patients who received chemotherapy postoperatively can have a reduced risk of recurrence and an improved survival rate. This study examined the impact of race/ethnicity and socioeconomic status (SES) on receipt of chemotherapy within 4 months after resection among stage III colon cancer patients enrolling in Medicare Parts A and B and trends of utilizing adjuvant chemotherapy. METHODS: Stage III colon cancer patients diagnosed between 2000 and 2007 were obtained from the Surveillance, Epidemiology, and End Results-Medicare data. Multilevel logistic regression was used to estimate the association between predictor variables and adjuvant chemotherapy, and the Cochran-Armitage test was used to assess for linear trends. RESULTS: Of 13,608 stage III colon cancer patients aged 66 and older, 56 percent received adjuvant chemotherapy within 4 months of surgical resection. Blacks or patients residing in the least affluent areas were less likely to receive the adjuvant chemotherapy within 4 months after resection, both before and after adjusting for race/ethnicity and other independent variables. A significantly decreasing trend was observed, from 58 percent in 2000 to 53 percent in 2007, for all patients combined. Trends of receiving chemotherapy within 4 months after resection were varied more in racial/ethnic groups than in SES groups. CONCLUSIONS: After adjusting for demographic and clinical factors, there are persistent racial/ethnic and SES disparities in the use of adjuvant chemotherapy among Medicare-insured elderly patients with stage III colon cancer. The shortage of chemotherapy drugs and the change of Medicare drug administration reimbursement could be attributive factors in the decline of using adjuvant chemotherapy within 4 months of surgical resection. PMID- 24625773 TI - Using the cancer registry to meet the Commission on Cancer clinical trials accrual standard. AB - Clinical trials are an important tool for innovation in cancer treatments. Therefore, accrual into trials has been highlighted for Commission on Cancer (CoC)-accredited hospital programs. The current Standard 5.21 and Standard 1.92 which take effect in 2015 require a minimum percentage of patient enrollment for compliance, as well as an opportunity for commendation at a higher percentage. The standards do not define a role for the hospital cancer registry staff but, at C/NET Solutions, we believe that the data collection and management efforts of the registry can be leveraged to effectively screen patients for clinical trials accrual. PMID- 24625774 TI - Optical coherence tomography shape analysis of the peripapillary retinal pigment epithelium layer in presumed optic nerve sheath meningiomas. AB - BACKGROUND: Geometric morphometrics (GM) was used to compare the shape of the peripapillary retinal pigment epithelium-Bruch's membrane (ppRPE) layer imaged on spectral domain optical coherence tomography (SD-OCT) of patients with presumed optic nerve sheath meningiomas (pONSM) and normal subjects. METHODS: We compared 2 groups: 30 normals to 10 patients (11 eyes) with pONSM. We digitized 20 equidistant semi-landmarks on OCT images of the ppRPE-layer, spanning 2500 MUm on each side of the neural canal opening (NCO). Data were analyzed using standard GM techniques including a generalized least squares Procrustes superimposition, principal component analysis (PCA), thin-plate spline, and permutation statistical analysis to evaluate differences in shape. We also analyzed other variables with respect to shape including tumor size-proximity to the globe, age, retinal nerve fiber layer, and optic disc height. RESULTS: All pONSM patients were female (age 37-66 years); 10 had unilateral and 1 had bilateral optic nerve involvement. Ten of the eyes had optic disc edema at presentation, 4 went on to develop shunt vessels, and 4 had optic atrophy. The ppRPE-layer bordering the NCO in normals is V-shaped pointing away from the vitreous; the ppRPE-layer in pONSM is indented causing an inverted-U shaped deformation skewed nasally toward the vitreous. PCA showed a significant difference between normals and pONSM (permutation, n = 10,000, P = 0.001). The size and proximity of the tumor to the globe correlates with the shape of the ppRPE-layer (r = 0.75, P = 0.04). Correlation between shape variables and RNFL thickening (r = 0.51), optic disc height (r = 0.67), and age (r = 0.67) were not statistically significant. CONCLUSION: The shape of the RPE layer in pONSM is characterized by an inverted-U shape or indentation that differs significantly from normals. It is indistinguishable from the shape we previously reported in papilledema and is not caused by disc edema. The mechanism in pONSM is unknown but may involve a change in the compliance of the nerve and/or localized sequestration of cerebrospinal fluid in the distal optic nerve sheath. PMID- 24625775 TI - Reversal of pupillary atonia after removal of an encircling band. AB - : We describe a patient who developed an atonic pupil after placement of an encircling band during retinal detachment surgery. When the band was removed 18 months later, the pupil signs showed partial recovery demonstrating a degree of reversibility of the parasympathetic paresis. We speculate that in this case mechanical deformation of the sclera by the encircling band had produced a conduction block of the short posterior ciliary nerve fibers as they pass forward in the underlying suprachoroidal space. PMID- 24625776 TI - Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. AB - Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or "personalized") medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR. PMID- 24625777 TI - Refining gold from existing data. AB - PURPOSE OF REVIEW: The purpose is to review the arguments for increasing use of existing data in health research. RECENT FINDINGS: The reuse of data in observational, exploratory and outcome studies, as well as in confirming other findings, is being justified on epistemological grounds as the major path to new knowledge and to the generalizing of findings to 'real world' populations. It is also justified on the grounds of cost, power, and efficiency, even though data reuse comes with real informatics, scientific culture, societal, and regulatory issues. SUMMARY: Data reuse is becoming more compelling. When contemplating new research for any purpose other than RCTs for efficacy, it is prudent to consider whether partnership with existing data holders should be part of the optimal research plan. PMID- 24625778 TI - Germline transgenesis in rodents by pronuclear microinjection of Sleeping Beauty transposons. AB - We describe a protocol for high-efficiency germline transgenesis and sustained transgene expression in two important biomedical models, the mouse and the rat, by using the Sleeping Beauty transposon system. The procedure is based on co injection of synthetic mRNA encoding the SB100X hyperactive transposase, together with circular plasmid DNA carrying a transgene construct flanked by binding sites for the transposase, into the pronuclei of fertilized oocytes. Upon translation of the transposase mRNA, enzyme-mediated excision of the transgene cassettes from the injected plasmids followed by permanent genomic insertion produces stable transgenic animals. Generation of a germline-transgenic founder animal by using this protocol takes ~3 months. Transposon-mediated transgenesis compares favorably in terms of both efficiency and reliable transgene expression with classic pronuclear microinjection, and it offers comparable efficacies to lentiviral approaches without limitations on vector design, issues of transgene silencing, and the toxicity and biosafety concerns of working with viral vectors. PMID- 24625779 TI - Germline transgenesis in rabbits by pronuclear microinjection of Sleeping Beauty transposons. AB - The laboratory rabbit (Oryctolagus cuniculus) is widely used as a model for a variety of inherited and acquired human diseases. In addition, the rabbit is the smallest livestock animal that is used to transgenically produce pharmaceutical proteins in its milk. Here we describe a protocol for high-efficiency germline transgenesis and sustained transgene expression in rabbits by using the Sleeping Beauty (SB) transposon system. The protocol is based on co-injection into the pronuclei of fertilized oocytes of synthetic mRNA encoding the SB100X hyperactive transposase together with plasmid DNA carrying a transgene construct flanked by binding sites for the transposase. The translation of the transposase mRNA is followed by enzyme-mediated excision of the transgene cassette from the plasmids and its permanent genomic insertion to produce stable transgenic animals. Generation of a germline-transgenic founder animal by using this protocol takes ~2 months. Transposon-mediated transgenesis compares favorably in terms of both efficiency and reliable transgene expression with classic pronuclear microinjection, and it offers comparable efficacies (numbers of transgenic founders obtained per injected embryo) to lentiviral approaches, without limitations on vector design, issues of transgene silencing, and the toxicity and biosafety concerns of working with viral vectors. PMID- 24625780 TI - Germline transgenesis in pigs by cytoplasmic microinjection of Sleeping Beauty transposons. AB - The pig has emerged as an important large animal model in biomedical and pharmaceutical research. We describe a protocol for high-efficiency germline transgenesis and sustained transgene expression in pigs by using the Sleeping Beauty (SB) transposon system. The protocol is based on co-injection of a plasmid encoding the SB100X hyperactive transposase, together with a second plasmid carrying a transgene flanked by binding sites for the transposase, into the cytoplasm of porcine zygotes. The transposase mediates excision of the transgene cassette from the plasmid vector and its permanent insertion into the genome to produce stable transgenic animals. This method compares favorably in terms of both efficiency and reliable transgene expression to classic pronuclear microinjection or somatic cell nuclear transfer (SCNT), and it offers comparable efficacies to lentiviral approaches, without limitations on vector design, issues of transgene silencing and the toxicity and biosafety concerns of working with viral vectors. Microinjection of the vectors into zygotes and transfer of the embryos to recipient animals can be performed in 1 d; generation of germline transgenic lines by using this protocol takes ~1 year. PMID- 24625781 TI - Quantitative analysis of ribonucleoside modifications in tRNA by HPLC-coupled mass spectrometry. AB - Post-transcriptional modification of RNA is an important determinant of RNA quality control, translational efficiency, RNA-protein interactions and stress response. This is illustrated by the observation of toxicant-specific changes in the spectrum of tRNA modifications in a stress-response mechanism involving selective translation of codon-biased mRNA for crucial proteins. To facilitate systems-level studies of RNA modifications, we developed a liquid chromatography mass spectrometry (LC-MS) technique for the quantitative analysis of modified ribonucleosides in tRNA. The protocol includes tRNA purification by HPLC, enzymatic hydrolysis, reversed-phase HPLC resolution of the ribonucleosides, and identification and quantification of individual ribonucleosides by LC-MS via dynamic multiple reaction monitoring (DMRM). In this approach, the relative proportions of modified ribonucleosides are quantified in several micrograms of tRNA in a 15-min LC-MS run. This protocol can be modified to analyze other types of RNA by modifying the steps for RNA purification as appropriate. By comparison, traditional methods for detecting modified ribonucleosides are labor- and time intensive, they require larger RNA quantities, they are modification-specific or require radioactive labeling. PMID- 24625782 TI - Tracking the sources of blood meals of parasitic arthropods using shotgun proteomics and unidentified tandem mass spectral libraries. AB - Identifying the species on which hematophagous arthropods feed is crucial for studying the factors that affect pathogen distributions and that can aid public health. Here we describe a protocol to identify the species a parasitic arthropod has previously fed upon by identifying the source of the remnants of a previous blood meal via shotgun proteomics and spectral matching. The protocol is a nontargeted approach that uses the entire detected blood proteome for source identification; it does not require a priori knowledge of genome or protein sequences. Instead, reference spectral libraries are compiled from the blood of multiple host species by using SpectraST, which takes ~4 d; the identification of the species from which a previous blood meal of a hematophagous arthropod was taken is achieved with spectral matching against the reference spectral libraries, which takes approximately another 4 d. This method is robust against random degradation of the blood meal and can identify unknown blood remnants months after the feeding event. PMID- 24625783 TI - Marble game with optimal ferroelectric switching. AB - A low coercivity and, consequently, low hysteresis loss are desired properties for ferroelectric materials used in high-power and high-frequency actuators. The coercive field required for the onset of ferroelectric switching is shown to develop a strong directional anisotropy due to peculiarities of an energy surface associated with the polarization rotation. It is found that the ferroelectric anisotropy exhibits 'hard' and 'easy' switching axes similar to magnetic materials. The hard axis corresponds to 180 degrees polarization reversal, whereas the easy axis favors 90 degrees switching. Our results suggest that the intrinsic low coercivity and the full polarization reversal may not be achieved at the same time under uniaxial excitation. A rotating electric field excitation is proposed in order to circumvent this limitation and to guide the polarization switching along a curved path. PMID- 24625784 TI - Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. AB - RATIONALE: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)(high) and reparative Ly-6C(low) monocytes/macrophages (Mo/MPhi). According to 1 model, Mo/MPhi heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C(low) monocyte production but dispensable to Ly-6C(low) macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity. OBJECTIVE: This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/MPhi accumulation scenarios. METHODS AND RESULTS: We show that Ly-6C(high) monocytes infiltrate the infarcted myocardium and, unlike Ly-6C(low) monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C(high) monocytes accrue in response to a brief C-C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C(high) monocytes give rise to reparative Ly-6C(low) F4/80(high) macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C(high) monocytes express heightened levels of C-C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function. CONCLUSIONS: Ly-6C(high) monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression. PMID- 24625785 TI - Stimulus-induced reversal of information flow through a cortical network for animacy perception. AB - Decades of research have demonstrated that a region of the right fusiform gyrus (FG) and right posterior superior temporal sulcus (pSTS) responds preferentially to static faces and biological motion, respectively. Despite this view, both regions activate in response to both stimulus categories and to a range of other stimuli, such as goal-directed actions, suggesting that these regions respond to characteristics of animate agents more generally. Here we propose a neural model for animacy detection composed of processing streams that are initially differentially sensitive to cues signaling animacy, but that ultimately act in concert to support reasoning about animate agents. We use dynamic causal modeling, a measure of effective connectivity, to demonstrate that the directional flow of information between the FG and pSTS is initially dependent on the characteristics of the animate agent presented, a key prediction of our proposed network for animacy detection. PMID- 24625786 TI - Is my voice just a familiar voice? An electrophysiological study. AB - It is not clear whether self-stimuli are processed by the brain as highly familiar overlearned stimuli or as self-specific stimuli. This study examined the neural processes underlying discrimination of one's own voice (OV) compared with a familiar voice (FV) using electrophysiological methods. Event-related potentials were recorded while healthy subjects (n = 15) listened passively to oddball sequences composed of recordings of the French vowel /a/ pronounced either by the participant her/himself, or by a familiar person or an unknown person. The results indicated that, although mismatch negativity displayed similar peak latency and amplitude in both conditions, the amplitude of the subsequent P3a was significantly smaller in response to OV compared with a FV. This study therefore indicated that fewer pre-attentional processes are involved in the discrimination of one's OV than in the discrimination of FVs. PMID- 24625787 TI - Evaluating the impact of the Baby-Friendly Hospital Initiative on breast-feeding rates: a multi-state analysis. AB - OBJECTIVE: To evaluate the impact of the Baby-Friendly Hospital Initiative (BFHI) on breast-feeding initiation and duration overall and according to maternal education. DESIGN: Quasi-experimental study using data from five states (Alaska, Maine, Nebraska, Ohio, Washington) that participated in the Pregnancy Risk Assessment Monitoring System from 1999 to 2009. Using differences-in-differences models that included year and hospital fixed effects, we compared rates of breast feeding initiation and duration (any and exclusive breast-feeding for >=4 weeks) before and after BFHI accreditation between mothers who gave birth in hospitals that were accredited or became accredited and mothers from matched non-BFHI facilities. We stratified analyses into lower and higher education groups. SETTING: Thirteen BFHI hospitals and nineteen matched non-BFHI facilities across five states in the USA. SUBJECTS: Mothers (n 11 723) who gave birth in BFHI hospitals and mothers (n 13 604) from nineteen matched non-BFHI facilities. RESULTS: Although we did not find overall differences in breast-feeding initiation between birth facilities that received BFHI accreditation compared with non-Baby-Friendly facilities (adjusted coefficient = 0.024; 95 % CI -0.00, 0.51), breast-feeding initiation increased by 3.8 percentage points among mothers with lower education who delivered in Baby-Friendly facilities (P = 0.05), but not among mothers with higher education (adjusted coefficient = 0.002; 95 % CI 0.04, 0.05). BFHI accreditation also increased exclusive breast-feeding for >=4 weeks by 4.5 percentage points (P = 0.02) among mothers with lower education who delivered in BFHI facilities. CONCLUSIONS: By increasing breast-feeding initiation and duration among mothers with lower education, the BFHI may reduce socio-economic disparities in breast-feeding. PMID- 24625788 TI - Cell cycle kinetics, apoptosis rates, DNA damage and TP53 gene expression in bladder cancer cells treated with allyl isothiocyanate (mustard essential oil). AB - Allyl isothiocyanate (AITC) is present in plants of the cruciferous family and is abundant in mustard seed. Due to its high bioavailability in urine after ingestion, AITC has been considered a promising antineoplastic agent against bladder cancer. Because TP53 mutations are the most common alterations in bladder cancer cells and are frequently detected in in situ carcinomas, in this study, we investigated whether the AITC effects in bladder cancer cells are dependent on the TP53 status. Two bladder transitional carcinoma cell lines were used: RT4, with wild-type TP53; and T24, mutated TP53 gene. AITC was tested at concentrations of 0.005, 0.0625, 0.0725, 0.0825, 0.0925, 0.125 and 0.25 MUM in cytotoxicity, cell and clonogenic survival assays, comet and micronucleus assays and for its effects on cell cycle and apoptosis by flow cytometry and on TP53 gene expression. The data showed increased primary DNA damage in both cell lines; however, lower concentrations of AITC were able to induce genotoxicity in the mutant cells for the TP53 gene. Furthermore, the results demonstrated increased apoptosis and necrosis rates in the wild-type cells, but not in mutated TP53 cells, and cell cycle arrest in the G2 phase for mutated cells after AITC treatment. No significant differences were detected in TP53 gene expression in the two cell lines. In conclusion, AITC caused cell cycle arrest, increased apoptosis rates and varying genotoxicity dependent on the TP53 status. However, we cannot rule out the possibility that those differences could reflect other intrinsic genetic alterations in the examined cell lines, which may also carry mutations in genes other than TP53. Therefore, further studies using other molecular targets need to be performed to better understand the mechanisms by which AITC may exert its antineoplastic properties against tumor cells. PMID- 24625790 TI - The ABI4-induced Arabidopsis ANAC060 transcription factor attenuates ABA signaling and renders seedlings sugar insensitive when present in the nucleus. AB - Seedling establishment is inhibited on media containing high levels (~ 6%) of glucose or fructose. Genetic loci that overcome the inhibition of seedling growth on high sugar have been identified using natural variation analysis and mutant selection, providing insight into sugar signaling pathways. In this study, a quantitative trait locus (QTL) analysis was performed for seedling sensitivity to high sugar in a Col/C24 F2 population of Arabidopsis thaliana. A glucose and fructose-sensing QTL, GSQ11, was mapped through selective genotyping and confirmed in near-isogenic lines in both Col and C24 backgrounds. Allelism tests and transgenic complementation showed that GSQ11 lies within the ANAC060 gene. The Col ANAC060 allele confers sugar insensitivity and was dominant over the sugar-sensitive C24 allele. Genomic and mRNA analyses showed that a single nucleotide polymorphism (SNP) in Col ANAC060 affects the splicing patterns of ANAC060 such that 20 additional nucleotides are present in the mRNA. The insertion created a stop codon, resulting in a truncated ANAC60 protein lacking the transmembrane domain (TMD) that is present in the C24 ANAC060 protein. The absence of the TMD results in the nuclear localization of ANAC060. The short version of the ANAC060 protein is found in ~ 12% of natural Arabidopsis accessions. Glucose induces GSQ11/ANAC060 expression in a process that requires abscisic acid (ABA) signaling. Chromatin immunoprecipitation-qPCR and transient expression analysis showed that ABI4 directly binds to the GSQ11/ANAC060 promoter to activate transcription. Interestingly, Col ANAC060 reduced ABA sensitivity and Glc-induced ABA accumulation, and ABI4 expression was also reduced in Col ANAC060 lines. Thus, the sugar-ABA signaling cascade induces ANAC060 expression, but the truncated Col ANAC060 protein attenuates ABA induction and ABA signaling. This negative feedback from nuclear ANAC060 on ABA signaling results in sugar insensitivity. PMID- 24625789 TI - Genetic characterization of hepatitis C virus in long-term RNA replication using Li23 cell culture systems. AB - BACKGROUND: The most distinguishing genetic feature of hepatitis C virus (HCV) is its remarkable diversity and variation. To understand this feature, we previously performed genetic analysis of HCV in the long-term culture of human hepatoma HuH 7-derived HCV RNA-replicating cell lines. On the other hand, we newly established HCV RNA-replicating cell lines using human hepatoma Li23 cells, which were distinct from HuH-7 cells. METHODOLOGY/PRINCIPAL FINDINGS: Li23-derived HCV RNA replicating cells were cultured for 4 years. We performed genetic analysis of HCVs recovered from these cells at 0, 2, and 4 years in culture. Most analysis was performed in two separate parts: one part covered from the 5'-terminus to NS2, which is mostly nonessential for RNA replication, and the other part covered from NS3 to NS5B, which is essential for RNA replication. Genetic mutations in both regions accumulated in a time-dependent manner, and the mutation rates in the 5'-terminus-NS2 and NS3-NS5B regions were 4.0-9.0*10(-3) and 2.7-4.0*10(-3) base substitutions/site/year, respectively. These results suggest that the variation in the NS3-NS5B regions is affected by the pressure of RNA replication. Several in-frame deletions (3-105 nucleotides) were detected in the structural regions of HCV RNAs obtained from 2-year or 4-year cultured cells. Phylogenetic tree analyses clearly showed that the genetic diversity of HCV was expanded in a time-dependent manner. The GC content of HCV RNA was significantly increased in a time-dependent manner, as previously observed in HuH-7-derived cell systems. This phenomenon was partially due to the alterations in codon usages for codon optimization in human cells. Furthermore, we demonstrated that these long-term cultured cells were useful as a source for the selection of HCV clones showing resistance to anti-HCV agents. CONCLUSIONS/SIGNIFICANCE: Long-term cultured HCV RNA-replicating cells are useful for the analysis of evolutionary dynamics and variations of HCV and for drug-resistance analysis. PMID- 24625791 TI - Accumulation of non-traditional risk factors for coronary heart disease is associated with incident coronary heart disease hospitalization and death. AB - BACKGROUND: Assessing multiple traditional risk factors improves prediction for late-life diseases, including coronary heart disease (CHD). It appears that non traditional risk factors can also predict risk. The objective was to investigate contributions of non-traditional risk factors to coronary heart disease risk using a deficit accumulation approach. METHODS: Community-dwelling adults with no known history of CHD (n = 2195, mean age 46.9+/-18.7 years, 51.8% women) participated in the 1995 Nova Scotia Health Survey. Three risk factor indices were constructed to quantify the proportion of deficits present in individuals: 1) a 17-item Non-Traditional Risk Factor Index (e.g. sinusitis, arthritis); 2) a 9-item Traditional Risk Factor Index (e.g. hypertension, diabetes); and 3) a frailty index (25 items combined from the other two index measures). Ten-year risks of CHD events (defined as CHD-related hospitalization and CHD-related mortality) were evaluated. RESULTS: The Non-Traditional Risk Factor Index, made up of health deficits unrelated to CHD, was independently associated with incident CHD events over 10 years after controlling for age, sex, and the Traditional Risk Factor Index [adjusted {adj.} Hazard Ratio {HR} = 1.31; Confidence Interval {CI} 1.14-1.51]. When all health deficits, both those related and unrelated to CHD, were included in a frailty index the corresponding adjusted hazard ratio was 1.61; CI 1.40-1.85. CONCLUSION: Both traditional and non traditional risk factor indices are independently associated with incident CHD events. CHD risk assessment may benefit from consideration of general health information as well as from traditional risk factors. PMID- 24625793 TI - Pyruvate carboxylase and pentose phosphate fluxes are reduced in AbetaPP-PS1 mouse model of Alzheimer's disease: a 13C NMR study. AB - Although pyruvate dehydrogenase (PDH) is the major pathway of glucose metabolism and source for energy production, pyruvate carboxylase (PC) and pentose phosphate pathway (PPP) account for a significant fraction of glucose oxidation in the mature central nervous system. Flux through the PDH pathway has been reported to be reduced in Alzheimer's disease (AD) patients as well as in animal models of AD. However, fluxes through the PPP and PC pathways have not been explored under conditions of AD. The present study investigates the fluxes of PC and PPP in a 20 month-old AbetaPP-PS1 mouse model of AD using 13C NMR spectroscopy together with an infusion of [2-13C]glucose. Mice were also administered [1,6-13C2]glucose or [1-13C]glucose for 10 or 90 min, respectively, to investigate PDH flux. AbetaPP PS1 mice exhibit a significant reduction in the level of NAA and increase in level of myo-inositol. The flux through PDH was found to be significantly lower in the cerebral cortex (AbetaPP-PS1 0.39 +/- 0.08; control 0.77 +/- 0.08 MUmol/g/min), hippocampus (AbetaPP-PS1 0.31 +/- 0.04; control 0.64 +/- 0.12 MUmol/g/min), and striatum (AbetaPP-PS1 0.34 +/- 0.06; control 0.56 +/- 0.03 MUmol/g/min) of AbetaPP-PS1 as compared with control mice. The fluxes through PC (AbetaPP-PS1 0.037 +/- 0.006, control 0.079 +/- 0.013 MUmol/g/min) and PPP (AbetaPP-PS1 0.024 +/- 0.005; control 0.062 +/- 0.022 MUmol/g/min) were found to be significantly reduced in AbetaPP-PS1 mice when compared with age-matched controls. The reduction in the fluxes of PC and PPP may lead to a weakened neural defense system of ammonia detoxification and antioxidant reserve in AbetaPP-PS1 mice, which may be responsible for the compromised neuronal viability and functions in AD. PMID- 24625794 TI - The Subjective Cognitive Decline Questionnaire (SCD-Q): a validation study. AB - BACKGROUND: Subjective cognitive decline (SCD) is gaining importance as a focus of investigation, but adequate tools are needed for its quantification. OBJECTIVE: To develop and validate a questionnaire to quantify SCD, termed the Subjective Cognitive Decline Questionnaire (SCD-Q). METHODS: 124 controls (CTR), 144 individuals with SCD, 83 mild cognitive impairment subjects, 46 Alzheimer's disease patients, and 397 informants were included. The SCD-Q contains: part I, named MyCog, which is answered by the subject; and part II, TheirCog, which includes the same questions and is answered by the informant or caregiver. The 24 SCD-Q items assess the perceived subjective decline in memory, language, and executive functions in the last two years. RESULTS: The MyCog scores of controls differed significantly from those of the other groups (p < 0.05) and there were significant differences in TheirCog scores between all groups. The optimal TheirCog cut-off score for discriminating between individuals with and without cognitive impairment was 7/24 (sensitivity 85%, specificity 80%). MyCog scores correlated significantly with anxiety and depression (r = 0.29, r = 0.43, p < 0.005), but no correlations were found with neuropsychological tests. TheirCog scores correlated significantly with most of the neuropsychological tests (p < 0.05). Informants' depression and anxiety influenced TheirCog scores in controls and SCD groups. CONCLUSION: Self-perceived cognitive decline, measured by the SCD Q part I (MyCog), discriminated SCD from CTR. Part II (TheirCog) was strongly related to subjects' objective cognitive performance, and discriminated between subjects with or without cognitive impairment. The SCD-Q is a useful tool to measure self-perceived cognitive decline incorporating the decliner and the informant perspective. PMID- 24625795 TI - Altered serum levels of adipokines and insulin in probable Alzheimer's disease. AB - Cerebral hypometabolism of glucose, weight loss, and decreased food intake are characteristic features of sporadic Alzheimer's disease (AD). A systematic study on the serum levels of adipokines and insulin, the major hormones regulating energy metabolism, food intake, and body weight, in sporadic AD is necessary. The present study compares the serum levels of leptin, adiponectin, and insulin, measured by commercially available immuno-assay kits, between controls and sporadic AD subjects. The results show a conspicuous decrease in the level of leptin, a dramatic rise in the level of adiponectin, and also a statistically significant increase in insulin level, in the blood of AD subjects, with respect to controls. The changes in the serum levels of adiponectin and insulin in AD are positively correlated with the severity of dementia. Likewise, the serum level of leptin in AD subjects is negatively correlated with the degree of dementia. The changes in the levels of adipokines and insulin have implications in the amyloid pathology, neurodegeneration, and hypometabolism of glucose existing in the AD brain. PMID- 24625796 TI - Mortality risk after dementia diagnosis by dementia type and underlying factors: a cohort of 15,209 patients based on the Swedish Dementia Registry. AB - BACKGROUND: Knowledge on survival in dementia is crucial for patients and public health planning. Most studies comparing mortality risk included few different dementia diagnoses. OBJECTIVES: To compare mortality risk in the most frequent dementia disorders in a large cohort of patients with an incident diagnosis, adjusting for potential confounding factors. METHODS: 15,209 patients with dementia from the national quality database, Swedish Dementia Registry (SveDem), diagnosed in memory clinics from 2008 to 2011, were included in this study. The impact of age, gender, dementia diagnosis, baseline Mini-Mental State Examination (MMSE), institutionalization, coresidency, and medication on survival after diagnosis were examined using adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: During a mean follow-up of 2.5 years, 4,287 deaths occurred, with 114 (95% CI 111-117) deaths/1,000 person-years. Adjusted HR of death for men was 1.56 (95% CI 1.46-1.66) compared to women. Low MMSE, institutionalization, and higher number of medications were associated with higher HR of death. All dementia diagnoses demonstrated higher HR compared to Alzheimer's disease, with vascular dementia presenting the highest crude HR. After adjusting, frontotemporal dementia had the highest risk with a HR of 1.91 (95% CI 1.52-2.39), followed by Lewy body dementia (HR 1.64; 95% CI 1.39-1.95), vascular dementia (HR 1.55; 95% CI 1.42-1.69), Parkinson's disease dementia (HR 1.47; 95% CI 1.17-1.84), and mixed Alzheimer's disease and vascular dementia (HR 1.32; 95% CI 1.22-1.44). CONCLUSION: Worse cognition, male gender, higher number of medications, institutionalization, and age were associated with increased death risk after dementia diagnosis. Adjusted risk was lowest in Alzheimer's disease patients and highest in frontotemporal dementia subjects. PMID- 24625797 TI - Severe diabetic retinal disease and dementia risk in type 2 diabetes. AB - BACKGROUND: Persons with type 2 diabetes are at an increased risk of dementia compared to those without, but the etiology of this increased risk is unclear. OBJECTIVE: Cerebral microvascular disease may mediate the link between diabetes and dementia. Given the anatomical and physiological similarities between cerebral and retinal microvessels, we examined the longitudinal association between diabetic retinal disease and dementia in patients with type 2 diabetes. METHODS: Longitudinal cohort study of 29,961 patients with type 2 diabetes aged >=60 years. Electronic medical records were used to collect diagnoses and treatment of severe diabetic retinal disease (i.e., diabetic proliferative retinopathy and macular edema) between 1996-1998 and dementia diagnoses for the next ten years (1998-2008). The association between diabetic retinal disease and dementia was evaluated by Cox proportional hazard models adjusted for sociodemographics, as well as diabetes-specific (e.g., diabetes duration, pharmacotherapy, HbA1c, hypoglycemia, hyperglycemia) and vascular (e.g., vascular disease, smoking, body mass index) factors. RESULTS: 2,008 (6.8%) patients had severe diabetic retinal disease at baseline and 5,173 (17.3%) participants were diagnosed with dementia during follow-up. Those with diabetic retinal disease had a 42% increased risk of incident dementia (demographics adjusted Hazards Ratio (HR) = 1.42, 95% Confidence Interval (CI) 1.27, 1.58); further adjustment for diabetes-specific (HR 1.29; 95% CI 1.14, 1.45) and vascular-related disease conditions (HR 1.35; 95% CI 1.21, 1.52) attenuated the relation slightly. CONCLUSION: Diabetic patients with severe diabetic retinal disease have an increased risk of dementia. This may reflect a causal link between microvascular disease and dementia. PMID- 24625798 TI - Synergistic inhibition of synaptic signaling in cortical cultures by subcytotoxic levels of oligomerized amyloid-beta and iron: alleviation by zinc. AB - Iron exacerbates amyloid-beta (Abeta) toxicity, while zinc alleviates it. We examined the impact of these metals on Abeta-induced signaling inhibition. Murine embryonic cortical neurons on multi-electrode arrays received 0.1 MUM FeCl2 0.1 MUM zinc acetate and/or 10 nM oligomerized Abeta(1-42). No toxicity was observed. Spontaneous signaling was not altered by iron or Abeta individually, but was inhibited by both. Zinc did not impact signaling alone, but prevented inhibition by iron plus Abeta. Abeta can be detected years before cognitive decline. Subcytotoxic iron levels may potentiate Abeta-induced impairment of synaptic activity during these early stages; zinc supplementation may alleviate this potentiation. PMID- 24625799 TI - Apolipoprotein E genotype and cerebrovascular alterations can influence conversion to dementia in patients with mild cognitive impairment. AB - The presence of apolipoprotein E (APOE) epsilon4 allele is the only recognized genetic risk factor for the sporadic form of Alzheimer's disease. The aim of this study was to investigate the relationship between APOE genotype and the functional and anatomic status of cerebral vessels in patients with mild cognitive impairment (MCI). Moreover, we explored whether the possible correlation between APOE genotype and cerebrovascular parameters influences the risk of conversion from MCI to dementia. 75 MCI patients underwent a complete neuropsychological battery at baseline and after 24 months to evaluate the possible conversion to dementia. Ultrasound assessment of neck and intracranial vessels was performed to assess common carotid artery intima-media thickness (IMT), plaque index, and cerebrovascular reactivity (breath-holding index, BHI). APOE genotype was determined to classify patients as carriers (APOE epsilon4+) and non-carriers (APOE epsilon4-). Pathologic values of BHI and IMT were significantly more common in epsilon4 carriers than in non-carriers [OR 6.603 (95% CI: 1.678-25.997), p < 0.05 and OR 5.195 (95% CI 1.319-20.464), p < 0.05; logistic regression adjusted model]. The risk of conversion to dementia was significantly higher in APOE epsilon4+ patients than in APOE epsilon4- ones (OR: 6.818; 95% CI:1.894-24.545, p = 0.003). A path-analysis model showed that APOE genotype influences the progression to dementia directly and indirectly by increasing the risk of pathologic values of IMT or BHI. Our data, besides confirming an increased susceptibility of MCI patients with APOE epsilon4 to develop dementia, show an association between functional and anatomic impairment of the cerebral vessels and APOE epsilon4+ genotype. PMID- 24625801 TI - Postural sway, falls, and cognitive status: a cross-sectional study among older adults. AB - BACKGROUND: Cognitive impairment-related changes in postural sway increase fall risk among older adults. Better understanding this association could be helpful for fall prevention. OBJECTIVE: To examine the center-of-pressure (COP) velocity association with cognitive status and history of falls, in cognitively healthy individuals (CHI), patients with mild cognitive impairment (MCI), and with mild to-moderate Alzheimer's disease (MMAD). METHODS: Six hundred and eleven older community-dwellers (77.2 +/- 7.9 years; 51.8% men) were separated into CHI, MCI, and MMAD participants. By computing the average absolute maximal velocity (AAMV), the bounding limits of COP velocity dynamics were determined while participants were asked to maintain quiet stance on a force platform with eyes open or with eyes closed. Age, gender, history of falls, body mass index, medications, handgrip strength, Timed Up & Go score were used as covariates. RESULTS: The multivariate ANCOVA, with AAMV in eyes open and eyes closed conditions as dependent variables, showed that the highest AAMVs that bound the COP velocity dynamics of postural sway were associated with cognitive impairment (p = 0.048) (i.e., lowest limits in CHI and MCI as compared with MMAD) and falls (p = 0.033) (i.e., highest limits in fallers). CONCLUSIONS: These findings identified the bounding limits of COP velocity as a hallmark feature of cognitive impairment related changes in postural sway, in particular for MMAD. This point is of special interest for clinical balance assessment and fall prevention in MMAD patients in order to plan long-term targeted fall-prevention programs. PMID- 24625800 TI - Strikingly reduced amyloid burden and improved behavioral performance in Alzheimer's disease mice immunized with recombinant chimeric vaccines by hexavalent foldable Abeta1-15 fused to toxin-derived carrier proteins. AB - Targeting on the amyloid-beta (Abeta) is a promising immunotherapeutic strategy for Alzheimer's disease (AD). However, Abeta(1-15) sequence alone induces low antibody response and poor protection against AD. We describe here the immunological characterization and protective efficacy of several recombinant chimeric vaccines with hexavalent foldable Abeta(1-15) (6Abeta15) fused to PADRE or toxin-derived carrier proteins. Immunization with these chimeric antigens generated robust Th2 immune responses with high anti-Abeta42 antibody titers in different mice, which recognized neurotoxic Abeta42 oligomers, but did not stimulate Abeta42-specific T cell responses. These 6Abeta15 chimeric vaccines markedly reduced Abeta pathology and prevented development of behavioral deficits in immunized older AD mice. Importantly, toxin-derived carrier proteins as molecular adjuvants of chimeric vaccines could substantially boost immune responses and overcome Abeta- and old age-associated hypo-responsiveness, and elicit long-term Abeta-specific antibody response, which in turn inhibited Abeta mediated pathology and improved acquisition and retention of spatial memory in immunized AD mice. These data indicate that toxin fragments as molecular adjuvants are promising new tools for the rational design and development of prototype chimeric vaccines for AD and this type of chimeric vaccine design has the added advantage of overcoming hypo-responsiveness in elderly AD patients with pre-existing memory Th cells from tetanus toxin. PMID- 24625802 TI - Qualification of a surrogate matrix-based absolute quantification method for amyloid-beta42 in human cerebrospinal fluid using 2D UPLC-tandem mass spectrometry. AB - The primary aims of this work were to: 1) establish a calibrator surrogate matrix for quantification of amyloid-beta (Abeta)42 in human cerebrospinal fluid (CSF) and preparation of quality control samples for LC-MS-MS methodology, 2) validate analytical performance of the assay, and 3) evaluate its diagnostic utility and compare it with the AlzBio3 immunoassay. The analytical methodology was based on a 2D-UPLC-MS-MS platform. Sample pretreatment used 5 M guanidine hydrochloride and extraction on MUElution SPE columns as previously described. A column cleaning procedure involved gradual removal of aqueous solvents by acetonitrile assured consistent long-term chromatography performance. Receiver-operator characteristic (ROC) curve and correlation analyses evaluated the diagnostic utility of UPLC-MS-MS compared to AlzBio3 immunoassay for detection of Alzheimer's disease (AD). The surrogate matrix, artificial CSF containing 4 mg/mL of BSA, provides linear and reproducible calibration comparable to human pooled CSF as calibration matrix. Appropriate cleaning of the trapping and analytical columns provided every-day, trouble-free runs. Analyses of CSF Abeta42 showed that UPLC-MS-MS distinguished neuropathologically-diagnosed AD subjects from healthy controls with at least equivalent diagnostic utility to AlzBio3. Comparison of ROC curves for these two assays showed no statistically significant difference (p = 0.2229). Linear regression analysis of Abeta42 concentrations measured by this mass spectrometry-based method compared to the AlzBio3 immunoassay showed significantly higher but highly correlated results. In conclusion, the newly established surrogate matrix for 2D-UPLC-MS-MS measurement of Abeta42 provides selective, reproducible, and accurate results. The documented analytical performance and diagnostic performance for AD versus controls supports consideration as a candidate reference method. PMID- 24625803 TI - Adenosine triphosphate (ATP) reduces amyloid-beta protein misfolding in vitro. AB - Alzheimer's disease (AD) is a devastating disease of aging that initiates decades prior to clinical manifestation and represents an impending epidemic. Two early features of AD are metabolic dysfunction and changes in amyloid-beta protein (Abeta) levels. Since levels of ATP decrease over the course of the disease and Abeta is an early biomarker of AD, we sought to uncover novel linkages between the two. First and remarkably, a GxxxG motif is common between both Abeta (oligomerization motif) and nucleotide binding proteins (Rossmann fold). Second, ATP was demonstrated to protect against Abeta mediated cytotoxicity. Last, there is structural similarity between ATP and amyloid binding/inhibitory compounds such as ThioT, melatonin, and indoles. Thus, we investigated whether ATP alters misfolding of the pathologically relevant Abeta42. To test this hypothesis, we performed computational and biochemical studies. Our computational studies demonstrate that ATP interacts strongly with Tyr10 and Ser26 of Abeta fibrils in solution. Experimentally, both ATP and ADP reduced Abeta misfolding at physiological intracellular concentrations, with thresholds at ~500 MUM and 1 mM respectively. This inhibition of Abeta misfolding is specific; requiring Tyr10 of Abeta and is enhanced by magnesium. Last, cerebrospinal fluid ATP levels are in the nanomolar range and decreased with AD pathology. This initial and novel finding regarding the ATP interaction with Abeta and reduction of Abeta misfolding has potential significance to the AD field. It provides an underlying mechanism for published links between metabolic dysfunction and AD. It also suggests a potential role of ATP in AD pathology, as the occurrence of misfolded extracellular Abeta mirrors lowered extracellular ATP levels. Last, the findings suggest that Abeta conformation change may be a sensor of metabolic dysfunction. PMID- 24625804 TI - Caveolin-1 mediates Salmonella invasion via the regulation of SopE-dependent Rac1 activation and actin reorganization. AB - Caveolar endocytosis has an important function in the cellular uptake of some bacterial toxins, viruses, and circulating proteins. However, the molecular machinery involved in caveolae-dependent bacterial endocytosis is poorly defined. In the present study, we identify a new molecular mechanism for the caveolin-1 dependent entry of Salmonella into host cells via the direct regulation of actin reorganization. In contrast to the interaction of caveolae with other pathogens, the caveolae did not form Salmonella-containing vesicles or endosomes in the host cells. Instead, the caveolae rapidly moved to the apical plasma membrane upon actin condensation during early invasion. Interestingly, the injected bacterial protein SopE interacted with Rac1 to regulate actin reorganization, and both proteins colocalized and directly interacted with caveolin-1 in caveolae during early invasion. After the complete internalization of Salmonella, SopE levels decreased both in the caveolae and in the host cytoplasm; Rac1 activity was also decreased. Downregulation of caveolin-1 by siRNA treatment led to reduction of Salmonella invasion compared with control siRNA-treated cells. These results suggest a new model in which caveolin-1 might be involved in Salmonella entry via its interaction with SopE and Rac1, leading to enhanced membrane ruffling for phagocytosis into host cells. PMID- 24625805 TI - A booster dose of an inactivated enterovirus 71 vaccine in chinese young children: a randomized, double-blind, placebo-controlled clinical trial. AB - BACKGROUND: A significant waning of enterovirus 71 (EV71) antibody titer after priming immunization with an inactivated EV71 vaccine implied the potential need for a booster dose. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, we recruited participants who had received at least 1 dose of priming EV71 vaccine in an early phase 2 clinical trial that was conducted in healthy infants and children aged 6-35 months. All participants were grouped according to the priming EV71 vaccine formulations (160 U, 320 U, and 640 U with adjuvant and 640 U without adjuvant) and then randomly assigned (ratio, 2:1) to receive a booster dose of vaccine or placebo within each formulation group. The primary end point was the geometric mean titer 28 days after the booster dose. RESULTS: A total of 773 participants were enrolled. Significantly greater immunological responses were induced by the booster shot of all 4 formulations of EV71 vaccine, compared with that induced by placebo (P < .0001). The frequencies of adverse reactions were similar between vaccine and placebo groups within each formulation group. CONCLUSIONS: A booster dose of EV71 vaccine 1 year after the priming EV71 immunization shows excellent immunogenicity and good safety profile. Clinical Trials Registration: NCT01734408. PMID- 24625806 TI - Antibiotics help control rotavirus infections and enhance antirotaviral immunity: are you serious? PMID- 24625807 TI - A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori-induced metaplasia in the stomach. AB - Carriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gastric adenocarcinoma. To our knowledge, we are the first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and inflammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cagPAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA(+) background. PMID- 24625808 TI - High-risk oral human papillomavirus load in the US population, National Health and Nutrition Examination Survey 2009-2010. AB - We investigated the association of demographic and behavioral factors with oral human papillomavirus (HPV) load for 18 high-risk types among 211 individuals with prevalent high-risk HPV within the National Health and Nutrition Examination Survey 2009-2010. Factors independently associated with HPV load above the median included older age (odds ratio, 1.04 per year increase [95% confidence interval, 1.01-1.07]; P = .004) and intensity of current smoking (P for trend <.001). A marginally greater percentage of men than women had an HPV load above the median (55.7% vs 32.8%; P = .069), and HPV load increased marginally with increasing alcohol use (P for trend = .062). In conclusion, older age and current smoking are associated with a high oral load of high-risk HPV types among individuals with a prevalent infection. PMID- 24625809 TI - Long-term tracking of the central corneal endothelial mosaic. AB - PURPOSE: When comparing follow-up endothelial cell (EC) density measurements it is only possible to demonstrate cell loss in large cohorts or in pronounced cases due to the standard deviation of measurements. However, especially in clinical studies or refractive surgery patients, EC stability is an important factor. Thus we developed a computer program to achieve cell-by-cell alignment of conventional specular non-contact EC photographs. This is a pilot study to evaluate whether this new diagnostic technique is applicable in postoperative patients. METHODS: Digitized endothelial cell photos of 30 eyes following implantation of a phakic posterior chamber intraocular lens for correction of high myopia were analyzed. All EC centroids were dotted on each image, and early and late follow-up pictures were automatically aligned on the basis of these centroids. The tracking results were confirmed via alternating image presentation of the corresponding image areas, and were reviewed for loss of individual cells. In addition, conventional EC density measurements were performed. RESULTS: Mean time interval between first and second postoperative EC image was 1.4 years (range 3 months-2.2 years), with early images taken at a median of 5.5 months after IOL implantation (lower/upper quartile 1.2-12.3 months). Extrapolated central EC density was 2812+/-500/mm2 at the first time point, and 2797+/-524/mm2 at the second time point. In 26 out of 30 image pairs, the EC mosaic was successfully retraced; cell loss in this area was excluded via photo flickering. Only in 4 image pairs, the EC mosaic could not be matched. CONCLUSIONS: We demonstrate that the corneal EC mosaic of clinical routine non-contact microscope pictures can be superimposed and compared on single cell level over time with our new computer based program. This new method is valuable to judge on EC stability even in small cohorts since it does not require mean values and standard deviations. PMID- 24625810 TI - Human cytomegalovirus US28 facilitates cell-to-cell viral dissemination. AB - Human cytomegalovirus (HCMV) encodes a number of viral proteins with homology to cellular G protein-coupled receptors (GPCRs). These viral GPCRs, including US27, US28, UL33, and UL78, have been ascribed numerous functions during infection, including activating diverse cellular pathways, binding to immunomodulatory chemokines, and impacting virus dissemination. To investigate the role of US28 during virus infection, two variants of the clinical isolate TB40/E were generated: TB40/E-US28(YFP) expressing a C-terminal yellow fluorescent protein tag, and TB40/E-FLAG(YFP) in which a FLAG-YFP cassette replaces the US28 coding region. The TB40/E-US28(YFP) protein localized as large perinuclear fluorescent structures at late times post-infection in fibroblasts, endothelial, and epithelial cells. Interestingly, US28(YFP) is a non-glycosylated membrane protein throughout the course of infection. US28 appears to impact cell-to-cell spread of virus, as the DUS28 virus (TB40/E-FLAG(YFP)) generated a log-greater yield of extracellular progeny whose spread could be significantly neutralized in fibroblasts. Most strikingly, in epithelial cells, where dissemination of virus occurs exclusively by the cell-to-cell route, TB40/E-FLAG(YFP) (DUS28) displayed a significant growth defect. The data demonstrates that HCMV US28 may contribute at a late stage of the viral life cycle to cell-to-cell dissemination of virus. PMID- 24625811 TI - Viral metagenomics: analysis of begomoviruses by illumina high-throughput sequencing. AB - Traditional DNA sequencing methods are inefficient, lack the ability to discern the least abundant viral sequences, and ineffective for determining the extent of variability in viral populations. Here, populations of single-stranded DNA plant begomoviral genomes and their associated beta- and alpha-satellite molecules (virus-satellite complexes) (genus, Begomovirus; family, Geminiviridae) were enriched from total nucleic acids isolated from symptomatic, field-infected plants, using rolling circle amplification (RCA). Enriched virus-satellite complexes were subjected to Illumina-Next Generation Sequencing (NGS). CASAVA and SeqMan NGen programs were implemented, respectively, for quality control and for de novo and reference-guided contig assembly of viral-satellite sequences. The authenticity of the begomoviral sequences, and the reproducibility of the Illumina-NGS approach for begomoviral deep sequencing projects, were validated by comparing NGS results with those obtained using traditional molecular cloning and Sanger sequencing of viral components and satellite DNAs, also enriched by RCA or amplified by polymerase chain reaction. As the use of NGS approaches, together with advances in software development, make possible deep sequence coverage at a lower cost; the approach described herein will streamline the exploration of begomovirus diversity and population structure from naturally infected plants, irrespective of viral abundance. This is the first report of the implementation of Illumina-NGS to explore the diversity and identify begomoviral-satellite SNPs directly from plants naturally-infected with begomoviruses under field conditions. PMID- 24625813 TI - High-field magnetization and magnetoelasticity of single crystalline HoFe5Al7. AB - Magnetization and ultrasound measurements have been performed in pulsed magnetic fields up to 60 T on a ferrimagnetic HoFe5Al7 single crystal (Curie temperature TC = 216 K, compensation point Tcomp = 65 K) with a tetragonal crystal structure of the ThMn12-type. The compound exhibits a high magnetic anisotropy of the easy plane type. A large anisotropy is also observed within the basal plane having an easy-magnetization direction along the [110] axis with the spontaneous magnetic moment Ms = 2 uB/f.u. at T = 2 K. Along the easy axis, two first-order field induced magnetic transitions are observed. At both transitions sharp anomalies in the acoustic properties are found. The critical fields of the transitions depend on temperature in a different manner. Within molecular-field theory and using the high-field magnetization data the Ho-Fe inter-sublattice exchange parameter has been determined to be nHoFe ~ 4 T/uB. The magnetoelasticity has also been probed by magnetization measurements under hydrostatic pressure. TC decreases with a rate dTC/dp = -10 K/GPa, whereas Tcomp increases with dTcomp/dp = 3.5 K/GPa. PMID- 24625817 TI - WITHDRAWN: Evaluation of potential gender-related differences in behavioral and cognitive alterations following pilocarpine-induced status epilepticus in C57BL/6 mice. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24625812 TI - NOD2/RICK-dependent beta-defensin 2 regulation is protective for nontypeable Haemophilus influenzae-induced middle ear infection. AB - Middle ear infection, otitis media (OM), is clinically important due to the high incidence in children and its impact on the development of language and motor coordination. Previously, we have demonstrated that the human middle ear epithelial cells up-regulate beta-defensin 2, a model innate immune molecule, in response to nontypeable Haemophilus influenzae (NTHi), the most common OM pathogen, via TLR2 signaling. NTHi does internalize into the epithelial cells, but its intracellular trafficking and host responses to the internalized NTHi are poorly understood. Here we aimed to determine a role of cytoplasmic pathogen recognition receptors in NTHi-induced beta-defensin 2 regulation and NTHi clearance from the middle ear. Notably, we observed that the internalized NTHi is able to exist freely in the cytoplasm of the human epithelial cells after rupturing the surrounding membrane. The human middle ear epithelial cells inhibited NTHi-induced beta-defensin 2 production by NOD2 silencing but augmented it by NOD2 over-expression. NTHi-induced beta-defensin 2 up-regulation was attenuated by cytochalasin D, an inhibitor of actin polymerization and was enhanced by alpha-hemolysin, a pore-forming toxin. NOD2 silencing was found to block alpha-hemolysin-mediated enhancement of NTHi-induced beta-defensin 2 up regulation. NOD2 deficiency appeared to reduce inflammatory reactions in response to intratympanic inoculation of NTHi and inhibit NTHi clearance from the middle ear. Taken together, our findings suggest that a cytoplasmic release of internalized NTHi is involved in the pathogenesis of NTHi infections, and NOD2 mediated beta-defensin 2 regulation contributes to the protection against NTHi induced otitis media. PMID- 24625818 TI - MiR-27a targets sFRP1 in hFOB cells to regulate proliferation, apoptosis and differentiation. AB - MicroRNAs (miRNAs) play a key role in the regulation of almost all the physiological and pathological processes, including bone metabolism. Recent studies have suggested that miR-27 might play a key role in osteoblast differentiation and bone formation. Increasing evidence indicates that the canonical Wnt signaling pathway contributes to different stages of bone formation. In this study, we identify miR-27a can promote osteoblast differentiation by repressing a new target, secreted frizzled-related proteins 1 (sFRP1) expression at the transcriptional level. Here, 21 candidate targets of miR-27a involved in canonical Wnt/beta-catenin signaling were predicted, and a significant decrease in sFRP1 luciferase activity was observed both in 293T and MG63 cells co-transfected with the matched luciferase reporter constructs and miR 27a mimic. Furthermore, the presence of exogenous miR-27a significantly decreased sFRP1 mRNA and protein expression in hFOB1.19 cells during both proliferation and osteogenic differentiation. The over-expression of miR-27a or knockdown sFRP1 significantly increased the percentage of apoptotic hFOBs, the percentage of cells in the G2-M phase of the cell cycle and the expression of key osteoblastic markers, including ALP, SPP1, RUNX2 and ALP activity. Over-expression of miR-27a or knockdown of endogenous sFRP1 led to an accumulation of beta-catenin in hFOBs. In the present study, we demonstrate that miR-27a induced gene silencing effect is a vital mechanism contributing to bone metabolism in hFOB cells in vitro, which is partly affected by the post-transcriptional regulation of sFRP1, during osteoblast proliferation, apoptosis and differentiation. PMID- 24625820 TI - The Vacuum of the Mind: A Self-Report on the Phenomenology of Autistic, Obsessive Compulsive, and Depressive Comorbidity. PMID- 24625819 TI - Macro advances in microRNAs and myocardial regeneration. AB - PURPOSE OF REVIEW: Myocardial injury and disease often result in heart failure, a major cause of death worldwide. To achieve myocardial regeneration and foster development of efficient therapeutics for cardiac injury, it is essential to uncover molecular mechanisms that will promote myocardial regeneration. In this review, we examine the latest progress made in elucidation of the roles of small non-coding RNAs called microRNAs (miRs) in myocardial regeneration. RECENT FINDINGS: Promising progress has been made in studying cardiac regeneration. Several miRs, which include miR-590, miR-199a, miR-17-92 cluster, miR-199a-214 cluster, miR-34a, and miR-15 family, have been recently shown to play an essential role in myocardial regeneration by regulating different processes during cardiac repair, including cell death, proliferation, and metabolism. For example, miR-590 promotes cardiac regeneration through activating cardiomyocyte proliferation, whereas miR-34a inhibits cardiac repair through inducing apoptosis. SUMMARY: These recent findings shed new light on our understanding of myocardial regeneration and suggest potential novel therapeutic targets to treat cardiac disease. PMID- 24625821 TI - Surgical sutures filled with adipose-derived stem cells promote wound healing. AB - Delayed wound healing and scar formation are among the most frequent complications after surgical interventions. Although biodegradable surgical sutures present an excellent drug delivery opportunity, their primary function is tissue fixation. Mesenchymal stem cells (MSC) act as trophic mediators and are successful in activating biomaterials. Here biodegradable sutures were filled with adipose-derived mesenchymal stem cells (ASC) to provide a pro-regenerative environment at the injured site. Results showed that after filling, ASCs attach to the suture material, distribute equally throughout the filaments, and remain viable in the suture. Among a broad panel of cytokines, cell-filled sutures constantly release vascular endothelial growth factor to supernatants. Such conditioned media was evaluated in an in vitro wound healing assay and showed a significant decrease in the open wound area compared to controls. After suturing in an ex vivo wound model, cells remained in the suture and maintained their metabolic activity. Furthermore, cell-filled sutures can be cryopreserved without losing their viability. This study presents an innovative approach to equip surgical sutures with pro-regenerative features and allows the treatment and fixation of wounds in one step, therefore representing a promising tool to promote wound healing after injury. PMID- 24625822 TI - Energy-optimal electrical-stimulation pulses shaped by the Least-Action Principle. AB - Electrical stimulation (ES) devices interact with excitable neural tissue toward eliciting action potentials (AP's) by specific current patterns. Low-energy ES prevents tissue damage and loss of specificity. Hence to identify optimal stimulation-current waveforms is a relevant problem, whose solution may have significant impact on the related medical (e.g. minimized side-effects) and engineering (e.g. maximized battery-life) efficiency. This has typically been addressed by simulation (of a given excitable-tissue model) and iterative numerical optimization with hard discontinuous constraints--e.g. AP's are all-or none phenomena. Such approach is computationally expensive, while the solution is uncertain--e.g. may converge to local-only energy-minima and be model-specific. We exploit the Least-Action Principle (LAP). First, we derive in closed form the general template of the membrane-potential's temporal trajectory, which minimizes the ES energy integral over time and over any space-clamp ionic current model. From the given model we then obtain the specific energy-efficient current waveform, which is demonstrated to be globally optimal. The solution is model independent by construction. We illustrate the approach by a broad set of example situations with some of the most popular ionic current models from the literature. The proposed approach may result in the significant improvement of solution efficiency: cumbersome and uncertain iteration is replaced by a single quadrature of a system of ordinary differential equations. The approach is further validated by enabling a general comparison to the conventional simulation and optimization results from the literature, including one of our own, based on finite-horizon optimal control. Applying the LAP also resulted in a number of general ES optimality principles. One such succinct observation is that ES with long pulse durations is much more sensitive to the pulse's shape whereas a rectangular pulse is most frequently optimal for short pulse durations. PMID- 24625823 TI - Trial watch: Bone-building antibody outshines current treatments in osteoporosis trial. PMID- 24625824 TI - The COPD pipeline. PMID- 24625826 TI - Local evolution of seed flotation in Arabidopsis. AB - Arabidopsis seeds rapidly release hydrophilic polysaccharides from the seed coat on imbibition. These form a heavy mucilage layer around the seed that makes it sink in water. Fourteen natural Arabidopsis variants from central Asia and Scandinavia were identified with seeds that have modified mucilage release and float. Four of these have a novel mucilage phenotype with almost none of the released mucilage adhering to the seed and the absence of cellulose microfibrils. Mucilage release was modified in the variants by ten independent causal mutations in four different loci. Seven distinct mutations affected one locus, coding the MUM2 beta-D-galactosidase, and represent a striking example of allelic heterogeneity. The modification of mucilage release has thus evolved a number of times independently in two restricted geographical zones. All the natural mutants identified still accumulated mucilage polysaccharides in seed coat epidermal cells. Using nuclear magnetic resonance (NMR) relaxometry their production and retention was shown to reduce water mobility into internal seed tissues during imbibition, which would help to maintain seed buoyancy. Surprisingly, despite released mucilage being an excellent hydrogel it did not increase the rate of water uptake by internal seed tissues and is more likely to play a role in retaining water around the seed. PMID- 24625825 TI - Aquaporins: important but elusive drug targets. AB - The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators. PMID- 24625827 TI - Lateralized readiness potentials reveal properties of a neural mechanism for implementing a decision threshold. AB - Many perceptual decision making models posit that participants accumulate noisy evidence over time to improve the accuracy of their decisions, and that in free response tasks, participants respond when the accumulated evidence reaches a decision threshold. Research on the neural correlates of these models' components focuses primarily on evidence accumulation. Far less attention has been paid to the neural correlates of decision thresholds, reflecting the final commitment to a decision. Inspired by a model of bistable neural activity that implements a decision threshold, we reinterpret human lateralized readiness potentials (LRPs) as reflecting the crossing of a decision threshold. Interestingly, this threshold crossing preserves signatures of a drift-diffusion process of evidence accumulation that feeds in to the threshold mechanism. We show that, as our model predicts, LRP amplitudes and growth rates recorded while participants performed a motion discrimination task correlate with individual differences in behaviorally estimated prior beliefs, decision thresholds and evidence accumulation rates. As such LRPs provide a useful measure to test dynamical models of both evidence accumulation and decision commitment processes non-invasively. PMID- 24625828 TI - Rapid diagnosis of aneuploidy using segmental duplication quantitative fluorescent PCR. AB - The aim of this study was use a simple and rapid procedure, called segmental duplication quantitative fluorescent polymerase chain reaction (SD-QF-PCR), for the prenatal diagnosis of fetal chromosomal aneuploidies. This method is based on the co-amplification of segmental duplications located on two different chromosomes using a single pair of fluorescent primers. The PCR products of different sizes were subsequently analyzed through capillary electrophoresis, and the aneuploidies were determined based on the relative dosage between the two chromosomes. Each primer set, containing five pairs of primers, was designed to simultaneously detect aneuploidies located on chromosomes 21, 18, 13, X and Y in a single reaction. We applied these two primer sets to DNA samples isolated from individuals with trisomy 21 (n = 36); trisomy 18 (n = 6); trisomy 13 (n = 4); 45, X (n = 5); 47, XXX (n = 3); 48, XXYY (n = 2); and unaffected controls (n = 40). We evaluated the performance of this method using the karyotyping results. A correct and unambiguous diagnosis with 100% sensitivity and 100% specificity, was achieved for clinical samples examined. Thus, the present study demonstrates that SD-QF-PCR is a robust, rapid and sensitive method for the diagnosis of common aneuploidies, and these analyses can be performed in less than 4 hours for a single sample, providing a competitive alternative for routine use. PMID- 24625831 TI - Kinematic analysis in patients with Parkinson's disease and SWEDD. AB - BACKGROUND AND OBJECTIVES: The differential diagnosis between mild Parkinson's disease (PD) and Scan Without Evidence of Dopaminergic Deficit(SWEDD) is challenging. Progressive reduction in amplitude and speed of finger tapping (sequence effect) has been considered as the most useful sign for discriminating PD from SWEDD. However, a video analysis reported that sequence effect is a major confounding factor for the misdiagnosis of PD. Our objective was to perform a kinematic analysis of finger tapping to explore parameters for distinguishing between patients with PD and SWEDD. METHODS: We enrolled 14 patients with PD, 17 patients with SWEDD and 18 age- and sex-matched healthy controls. Amplitude, speed and frequency of finger tapping were measured using gyroscopes, and the means, decrement and variability in kinematic parameters for specific tapping duration were calculated. RESULTS: Compared to SWEDD group, PD group showed more decrement in amplitude and speed of the first 20 taps, more decrement in frequency after 20 taps and more variability in speed of 15 seconds of taps. However, none of parameters was a practically useful indicator distinguishing individual patients with PD from those with SWEDD. CONCLUSIONS: Analysis of finger tapping, even using an apparatus, is not useful for distinguishing mild PD and SWEDD. PMID- 24625830 TI - Olfactory dysfunction and dementia in Parkinson's disease. AB - Dementia is one of the most debilitating symptoms of Parkinson's disease (PD), but the development of dementia is still difficult to predict at early stages of the disease. We recently found that hyposmia, one of the most typical non-motor features of PD, was a predictive feature of Parkinson's disease with dementia (PDD). In that work, multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in scores on the odor stick identification test for Japanese (OSIT-J). We also found an association between severe hyposmia and a specific pattern of cerebral metabolic decline, which was identical to findings observed in PDD. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and atrophy of focal brain structures, including the amygdala and other limbic structures. Our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of PDD. We have now started a randomized, double-blind study using donepezil for the PD group with severe hyposmia. We hope that this clinical trial will allow us to establish a therapeutic intervention that can improve the prognosis of advanced PD. PMID- 24625829 TI - Intracellular gold nanoparticles increase neuronal excitability and aggravate seizure activity in the mouse brain. AB - Due to their inert property, gold nanoparticles (AuNPs) have drawn considerable attention; their biological application has recently expanded to include nanomedicine and neuroscience. However, the effect of AuNPs on the bioelectrical properties of a single neuron remains unknown. Here we present the effect of AuNPs on a single neuron under physiological and pathological conditions in vitro. AuNPs were intracellularly applied to hippocampal CA1 neurons from the mouse brain. The electrophysiological property of CA1 neurons treated with 5- or 40-nm AuNPs was assessed using the whole-cell patch-clamp technique. Intracellular application of AuNPs increased both the number of action potentials (APs) and input resistance. The threshold and duration of APs and the after hyperpolarization (AHP) were decreased by the intracellular AuNPs. In addition, intracellular AuNPs elicited paroxysmal depolarizing shift-like firing patterns during sustained repetitive firings (SRF) induced by prolonged depolarization (10 sec). Furthermore, low Mg2+-induced epileptiform activity was aggravated by the intracellular AuNPs. In this study, we demonstrated that intracellular AuNPs alter the intrinsic properties of neurons toward increasing their excitability, and may have deleterious effects on neurons under pathological conditions, such as seizure. These results provide some considerable direction on application of AuNPs into central nervous system (CNS). PMID- 24625833 TI - The reamer-irrigator-aspirator as a device for harvesting bone graft compared with iliac crest bone graft: union rates and complications. AB - OBJECTIVES: This study was performed to compare patient outcomes after Reamer Irrigator-Aspirator (RIA)-harvested bone grafting with the current gold standard, either anterior or posterior iliac crest bone graft (ICBG). DESIGN: Prospective randomized controlled trial. SETTING: Multicenter study at 3 geographically separate Level 1 trauma centers. PATIENTS/PARTICIPANTS: One hundred thirty-three patients with nonunion or posttraumatic segmental bone defect requiring operative intervention. INTERVENTION: Patients were prospectively randomized to receive ICBG or RIA autograft. Supplemental internal fixation was performed per surgeon preference. MAIN OUTCOME MEASUREMENTS: Operative data included amount of graft, time of harvest, and associated surgical costs. The Short Musculoskeletal Functional Assessment and the Visual Analog Scale were used to document baseline and postoperative function and pain. Clinical and radiographic union was the defined end point; patients considered to have failed treatment if they either developed an infection requiring operative treatment or had a persistent nonunion of the grafted extremity. RESULTS: One hundred thirteen of the 133 enrolled patients were followed until union and included in the final analysis. Intraoperative data showed anterior ICBG to yield 20.7 +/- 12.8 (5-60) cm of autograft with an average harvest time of 33.2 +/- 16.2 minutes, posterior ICBG yielded 36.1 +/- 21.3 (20-100) cm of autograft in 40.6 +/- 11.2 minutes, and RIA yielded 37.7 +/- 12.9 (5-90) cm in 29.4 +/- 15.1 minutes. Anterior ICBG produced significantly less bone graft than either RIA or posterior ICBG (P < 0.001). The RIA harvest was completed in significantly less operative time compared with posterior ICBG (P = 0.005). At $738, the RIA setup was considerably more expensive than the ~$100 cost of a bone graft tray; however, when compared with posterior ICBG, the longer operative time required for a posterior harvest came at an additional incremental cost of $990-1880, making RIA the less expensive option. Patients were followed for an average of 56.9 +/- 42.1 (11-250) weeks. Forty-nine of 57 patients (86.0%) who received ICBG united in an average of 22.5 +/- 13.2 weeks; 46 of 56 patients (82.1%) who received RIA healed in an average of 25.8 +/- 17.0 weeks. Union rates and time to union were comparable between the 2 procedures. There was no difference in complications requiring reoperation for persistent nonunion or infection at the grafted site, nor there was any difference in donor-site complications. Postoperative follow-up showed that RIA patients had significantly lower donor-site pain scores throughout follow-up. CONCLUSIONS: When compared with autograft obtained from the iliac crest, autograft harvested using the RIA technique achieves similar union rates with significantly less donor-site pain. RIA also yields a greater volume of graft compared with anterior ICBG and has a shorter harvest time compared with posterior ICBG. For larger volume harvests, cost analysis favors using RIA. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 24625832 TI - An improved canine genome and a comprehensive catalogue of coding genes and non coding transcripts. AB - The domestic dog, Canis familiaris, is a well-established model system for mapping trait and disease loci. While the original draft sequence was of good quality, gaps were abundant particularly in promoter regions of the genome, negatively impacting the annotation and study of candidate genes. Here, we present an improved genome build, canFam3.1, which includes 85 MB of novel sequence and now covers 99.8% of the euchromatic portion of the genome. We also present multiple RNA-Sequencing data sets from 10 different canine tissues to catalog ~175,000 expressed loci. While about 90% of the coding genes previously annotated by EnsEMBL have measurable expression in at least one sample, the number of transcript isoforms detected by our data expands the EnsEMBL annotations by a factor of four. Syntenic comparison with the human genome revealed an additional ~3,000 loci that are characterized as protein coding in human and were also expressed in the dog, suggesting that those were previously not annotated in the EnsEMBL canine gene set. In addition to ~20,700 high confidence protein coding loci, we found ~4,600 antisense transcripts overlapping exons of protein coding genes, ~7,200 intergenic multi-exon transcripts without coding potential, likely candidates for long intergenic non-coding RNAs (lincRNAs) and ~11,000 transcripts were reported by two different library construction methods but did not fit any of the above categories. Of the lincRNAs, about 6,000 have no annotated orthologs in human or mouse. Functional analysis of two novel transcripts with shRNA in a mouse kidney cell line altered cell morphology and motility. All in all, we provide a much-improved annotation of the canine genome and suggest regulatory functions for several of the novel non-coding transcripts. PMID- 24625834 TI - MicroRNA-dependent regulation of transcription in non-small cell lung cancer. AB - Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies. PMID- 24625836 TI - Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding. AB - Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to <1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 MUg/g in the lungs of ethanol-fed mice as compared to 1.5 MUg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol requiring enzyme-1alpha and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease. PMID- 24625837 TI - Monomethylarsonous acid inhibited endogenous cholesterol biosynthesis in human skin fibroblasts. AB - Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 human skin fibroblasts following acute MMA(III) exposure. Among the ~6500 unique proteins quantified, ~300 displayed significant changes in expression after exposure with 2 MUM MMA(III) for 24 h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content. PMID- 24625838 TI - Trends in stunting and overweight in Peruvian pre-schoolers from 1991 to 2011: findings from the Demographic and Health Surveys. AB - OBJECTIVE: To examine trends in stunting and overweight in Peruvian children, using 2006 WHO Multicentre Growth Reference Study criteria. DESIGN: Trend analyses using nationally representative cross-sectional surveys from Demographic and Health Surveys (1991-2011). We performed logistic regression analyses of stunting and overweight trends in sociodemographic groups (sex, age, urban-rural residence, region, maternal education and household wealth), adjusted for sampling design effects (strata, clusters and sampling weights). SETTING: Peru. SUBJECTS: Children aged 0-59 months surveyed in 1991-92 (n 7999), 1996 (n 14 877), 2000 (n 11 754), 2007-08 (n 8232) and 2011 (n 8186). RESULTS: Child stunting declined (F(1, 5149) = 174.8, P <= 0.00) and child overweight was stable in the period 1991-2011 (F(1, 5147) = 0.4, P <= 0.54). Over the study period, levels of stunting were highest in rural compared with urban areas, the Andean and Amazon regions compared with the Coast, among children of low-educated mothers and among children living in households in the poorest wealth quintile. The trend in overweight rose among males in coastal areas (F(1, 2250) = 4.779, P <= 0.029) and among males in the richest wealth quintile (F(1, 1730) = 5.458, P <= 0.020). CONCLUSIONS: The 2011 levels of stunting and overweight were eight times and three and a half times higher, respectively, than the expected levels from the 2006 WHO growth standards. The trend over the study period in stunting declined in most sociodemographic subgroups. The trend in overweight was stable in most sociodemographic subgroups. PMID- 24625839 TI - Too little or too much are inadequate. PMID- 24625840 TI - Intracranial arterial variations: a comprehensive evaluation using CT angiography. AB - Background Intracranial arterial variations are a frequent finding in the general population. Knowledge of these vascular variations has significant clinical impact because some of them predispose patients to development of an aneurysm or cerebrovascular ischemic disease. The purpose of this study was to evaluate the frequency of intracranial vascular variations and associated vascular lesions on computed tomography angiography (CTA) examinations. Material and Methods CTA examinations performed by 16-detector computed tomography were prospectively reviewed in 455 patients for the presence of fenestrations, duplications, hypoplasia, aplasia, aneurysms, and other vascular lesions. Results Arterial fenestrations were found in 2.4% of patients, with the vertebrobasilar system as the most common location. The remaining fenestrations were located on the middle cerebral artery M1 segment (0.2%), anterior communicating artery (0.4%), and anterior cerebral artery A1 segment (0.6%). No associated aneurysms were noted in these patients. The prevalence of an azygos anterior cerebral artery was 1.5%. Bihemispheric anterior cerebral artery was found in 0.9%, hypoplastic A1 segment in 17.6%, and congenital absence of A1 segment in 0.4% of patients. Fetal origin of the posterior cerebral artery was found in 37% of cases. Hypoplastic vertebral artery terminating as posterior inferior cerebellar artery was observed in 9 patients, while transversal anastomosis between vertebral arteries was seen in only 1 patient. Conclusions CTA precisely demonstrates the diversity of intracranial arterial variations, whose overall frequency in this study is similar to previous radiological reports. Furthermore, our results do not show significant association between the frequency of aneurysms and cerebral arterial anomalies. PMID- 24625842 TI - Antiviral immunity: editing HLA-E expression. PMID- 24625841 TI - The production and regulation of IgE by the immune system. AB - IgE not only provides protective immunity against helminth parasites but can also mediate the type I hypersensitivity reactions that contribute to the pathogenesis of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Despite the importance of IgE in immune biology and allergic pathogenesis, the cells and the pathways that produce and regulate IgE are poorly understood. In this Review, we summarize recent advances in our understanding of the production and the regulation of IgE in vivo, as revealed by studies in mice, and we discuss how these findings compare to what is known about human IgE biology. PMID- 24625843 TI - Innate lymphoid cells: support for indie B cells. PMID- 24625844 TI - Neutrophils: nanoparticles targeting the bad guys. PMID- 24625845 TI - Inflammation: TNF snuffs out steroids. PMID- 24625846 TI - [The EUROMAX study]. PMID- 24625847 TI - [Role of emergent coronary angiography in post-cardiac arrest care: from literature review to clinical practice]. AB - Out-of-hospital cardiac arrest is a relatively common event. Acute coronary thrombotic events are the main trigger of sudden cardiac arrest. Mortality of patients, in whom return of spontaneous circulation is obtained, is still high, mainly due to anoxic brain injury and progressive cardiac failure. In the last years, the implementation of "post-cardiac arrest care" led to a significant improvement of hospital survival of these patients. Mild therapeutic hypothermia has become the foundation for improvement of survival with good neurological outcome after cardiac arrest. Recently, there is a growing interest in emergent invasive coronary strategies, including emergent coronary angiography and subsequent percutaneous coronary interventions when indicated. Emergent coronary angiography is strongly recommended in patients with ST-segment elevation on the ECG performed after return of spontaneous circulation. Conversely, whether patients without ST-segment elevation on ECG or patients who remain unconscious after return of spontaneous circulation should always undergo emergent coronary angiography is still unclear. Recent observational stud ies have shown that emergent invasive coronary strategies may improve hospital survival also in this patient subset. This suggests that resuscitated cardiac arrest victims without an obvious non-cardiac etiology should always undergo emergent coronary angiography, in association with therapeutic hypothermia if indicated. PMID- 24625848 TI - [Upstream administration of oral antiplatelet agents in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention]. AB - Current guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) recommend the administration of dual antiplatelet therapy with aspirin and an ADP receptor blocker "as early as possible" before angiography (upstream), though this suggestion is not based on the results of randomized clinical trials designed to investigate pre-hospital rather than in-hospital drug administration. The present review analyzed randomized clinical trials, registries and observational studies that assessed clopidogrel, prasugrel and ticagrelor administration in STEMI patients undergoing primary PCI to evaluate if their upstream use may be justified in clinical practice. A significant difference favoring early clopidogrel administration has been demonstrated in observational studies. No evidence is available for prasugrel and ticagrelor; however, the initial delay of their antiplatelet effect in STEMI patients could support an upstream strategy to obtain complete platelet inhibition in the first hours after PCI and prevent major adverse events (e.g., stent thrombosis) despite an increased risk of major bleeding, particularly in case of urgent bypass surgery. Data from specifically designed randomized clinical trials are warranted to establish whether early administration of prasugrel and ticagrelor may favor reperfusion and improve clinical outcome with an acceptable risk-benefit ratio. PMID- 24625850 TI - [A high-volume single center experience of no-reflow post-percutaneous coronary intervention]. AB - BACKGROUND: The no-reflow (NR) phenomenon is frequent in patients with ST elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). However, its real incidence and prognostic significance, so far derived from relatively small patient cohorts, remain poorly defined. METHODS: We have retrospectively analyzed 19 290 consecutive PCI performed at our hospital between January 1998 and November 2010. NR was defined as a TIMI flow <=2 at the end of the PCI. RESULTS: In the 1257 patients with STEMI, NR occurred in 9.4% of cases and was more common when the left anterior descending coronary artery was the culprit vessel. STEMI-NR patients had longer ischemic times and more frequently multivessel disease. In the STEMI-NR group, glycoprotein IIb/IIIa inhibitors were used in 60.2%, nitroprusside in 39.6%, thrombus aspiration in 10.7% and adenosine in 8.7%. In the remaining 18033 patients without STEMI undergoing PCI, the NR phenomenon occurred only in 0.2% of cases. STEMI-NR patients had lower left ventricular ejection fraction at discharge (50.3 +/- 7.2 vs 44.9 +/- 8.4%; p<0.01) and showed higher rates of adverse events (death, non fatal myocardial infarction, coronary revascularization, new hospital admission for heart failure: 67.8 vs 36.9%, p=0.001), death (25.4 vs 13.2%, p<0.01), myocardial infarction (13.6 vs 4.8%, p<0.01) and hospitalizations for heart failure (13.6 vs 4.8%, p<0.001). CONCLUSIONS: Our data, derived from a large cohort of patients from a single center, allow a more correct estimate of the occurrence and prognostic significance of NR. The NR phenomenon is more common in STEMI patients undergoing primary PCI and has an important negative prognostic value. PMID- 24625849 TI - [Management of thromboembolic risk in patients with atrial fibrillation in Italy: baseline data from the PREFER in AF European Registry]. AB - BACKGROUND: Atrial fibrillation (AF) is a common heart rhythm disorder associated with an increased risk of stroke, heart failure and death. Although available evidence supports the administration of oral anticoagulants with respect to other treatment options to prevent thromboembolism, the use of oral anticoagulation therapy remains suboptimal. The PREFER in AF registry was conducted to evaluate patterns of prescriptions and patient adherence to guidelines, clinical features, quality of life and treatment satisfaction. METHODS: The PREFER in AF registry enrolled consecutive patients with AF recruited in high-volume cardiology centers, with AF documented during the previous 12 months. Patients were assessed at baseline and at 1-year follow-up. The present report provides Italian baseline data compared with data from other European countries participating in the registry. RESULTS: The registry enrolled 1888 Italian patients (out of 7243 in Europe), with an average age of 70.9 years. Main comorbidities included hypertension (73.5%), dyslipidemia (38.7%) and obesity (21.9%). The risk of thromboembolism was assessed using the CHA2DS2-VASc score, according to which only 4.7% of Italian patients scored 0, whereas 11.3% scored 1 and 84% scored >=2. Italy is the Western European country with the lowest use of vitamin K antagonists (71.6%; average rate in Europe: 78.3%) and the highest average INR measurements, whereas time in therapeutic range is 72.2%, lower than in any other Western European country with the exception of Spain. Most Italian patients are unsatisfied with treatment, and only 36% report no difficulties in taking anticoagulation therapy compared with 70.3% of patients in other Western European countries. CONCLUSIONS: Among Western European countries included in the registry, Italy has the lowest prescription rate of vitamin K antagonists and the highest rate of INR measurements. Italian patients also report lower levels of satisfaction with treatment and a higher subjective difficulty in managing anticoagulation therapy. The new oral anticoagulants may favor treatment management, thus having the potential of improving medication adherence and persistence as well as quality of life. PMID- 24625851 TI - [CircuLite Synergy ventricular assist device: a new approach to end-stage congestive heart failure]. AB - BACKGROUND: The Synergy system, a miniature partial circulatory support device, is implanted by an off-pump, minimally invasive surgical approach. The system has been optimized to improve performance in an EU clinical trial for chronic ambulatory heart failure. This therefore offers the possibility of treating elderly chronic heart failure patients who might not usually be considered for long-term circulatory support. METHODS: From June 2007 to December 2012, 63 patients were implanted with the Synergy system (12 patients >=70 years) using four different releases of the device. Briefly, the system draws blood through the inflow cannula from the left atrium into the micro-pump (placed in a right subclavicular pocket) and pumps it through an outflow graft to the right subclavian artery. In this paper, we present an intermediate analysis of the clinical trial as performed on April 30, 2013, leading to the placing of the CE mark. RESULTS: Mean duration of support is ongoing at 230 days (range 23-1387). Follow-up showed improved hemodynamic response, with additional improvements in 6 min walk distance (299 +/- 144 to 420 +/- 119 m) and Minnesota Living with Heart Failure Questionnaire (69.5 +/- 20.4 to 49.2 +/- 24.3). Older patients had longer mean durations of support (337 vs 188 days). On average, elderly and younger patients showed similar improvements in hemodynamics and 6-min walk distance (107 +/- 120 vs 130 +/- 121 m). Major adverse cardiac events included bleeding (n=4) with one bleeding related to renal failure resulting in death. CONCLUSIONS: Clinical use of the Synergy device was associated with a significant functional improvement. Very low adverse event rates were reported with the latest device release. Older patients had smaller body sizes and worse renal function than younger patients. Both groups experienced similar hemodynamic benefits and functional improvements. The risk of bleeding and renal dysfunction appears to be increased in the elderly, though still within acceptable ranges compared to other full support devices. Minimally invasive long-term circulatory support devices, like Synergy, offer a new treatment option that might be available even for the elderly chronic heart failure population. PMID- 24625853 TI - [Great expectations]. PMID- 24625852 TI - [Oral anticoagulation for atrial fibrillation in Italy: where do we stand?]. PMID- 24625854 TI - [Double mitro-aortic valve replacement in a high-risk patient: the sutureless way]. AB - The mitro-aortic disease in high-risk patients is a challenge for the cardiac surgeon because minimally invasive techniques are difficult to apply. We report the first case in the literature of a 78-year-old woman affected by severe rheumatic steno-insufficiency of aortic and mitral valves at high surgical risk. The patient was successfully treated by mitral valve replacement with a biological prosthesis and concomitant aortic valve replacement with a sutureless prosthesis. PMID- 24625855 TI - [Massive destruction of heart fibrous skeleton due to peptostreptococcus endocarditis]. PMID- 24625857 TI - 25th silver anniversary of perspectives in vascular surgery and endovascular therapy. PMID- 24625858 TI - Vernet's syndrome after carotid endarterectomy. AB - Unilateral paresis of cranial nerves IX to XI is defined as Vernet's syndrome. We retrospectively assessed cranial nerve symptoms from the clinical records of 143 carotid endarterectomy patients. A flexible nasolaryngoscope was used to examine vocal fold movements in 73 patients. If vocal fold paresis (VFP) was confirmed, the patient also underwent magnifying laryngoscopy (for correct diagnosis of injury to the glossopharyngeal and vagus nerves). It was found from clinical records that 8 patients (6%) were confirmed to have cranial nerve symptoms corresponding to Vernet's syndrome; 7 patients (9 %) had VFP on nasolaryngoscopy. In 2 patients, magnifying laryngoscopy confirmed ipsilateral VFP, pharyngeal paresis, pharyngeal wall hypesthesia, and ipsilateral pharyngeal wall swelling. These 2 patients also had symptoms of injury to the accessory nerve. Damage to cranial nerves IX to XI probably occurred in the parapharyngeal space, based on the existence of posterior pharyngeal wall edema or swelling after carotid endarterectomy. PMID- 24625859 TI - Real-space renormalization group method for quantum 1/2 spins on the pyrochlore lattice. AB - A simple phenomenological real-space renormalization group method for quantum Heisenberg spins with nearest and next nearest neighbour interactions on a pyrochlore lattice is presented. Assuming a scaling law for the order parameter of two clusters of different sizes, a set of coupled equations that gives the fixed points of the renormalization group transformation and, thus, the critical temperatures and ordered phases of the system is found. The particular case of spins 1/2 is studied in detail. Furthermore, to simplify the mathematical details, from all the possible phases arising from the renormalization group transformation, only those phases in which the magnetic lattice is commensurate with a subdivision of the crystal lattice into four interlocked face-centred cubic sublattices are considered. These correspond to a quantum spin liquid, ferromagnetic order, or non-collinear order in which the total magnetic moment of a tetrahedral unit is zero. The corresponding phase diagram is constructed and the differences with respect to the classical model are analysed. It is found that this method reproduces fairly well the phase diagram of the pyrochlore lattice under the aforementioned constraints. PMID- 24625860 TI - [Necrotizing vasculitis induced by cocaine]. PMID- 24625861 TI - Platypnea-orthodeoxia syndrome. PMID- 24625862 TI - Sex chromosome turnover contributes to genomic divergence between incipient stickleback species. AB - Sex chromosomes turn over rapidly in some taxonomic groups, where closely related species have different sex chromosomes. Although there are many examples of sex chromosome turnover, we know little about the functional roles of sex chromosome turnover in phenotypic diversification and genomic evolution. The sympatric pair of Japanese threespine stickleback (Gasterosteus aculeatus) provides an excellent system to address these questions: the Japan Sea species has a neo-sex chromosome system resulting from a fusion between an ancestral Y chromosome and an autosome, while the sympatric Pacific Ocean species has a simple XY sex chromosome system. Furthermore, previous quantitative trait locus (QTL) mapping demonstrated that the Japan Sea neo-X chromosome contributes to phenotypic divergence and reproductive isolation between these sympatric species. To investigate the genomic basis for the accumulation of genes important for speciation on the neo-X chromosome, we conducted whole genome sequencing of males and females of both the Japan Sea and the Pacific Ocean species. No substantial degeneration has yet occurred on the neo-Y chromosome, but the nucleotide sequence of the neo-X and the neo-Y has started to diverge, particularly at regions near the fusion. The neo-sex chromosomes also harbor an excess of genes with sex-biased expression. Furthermore, genes on the neo-X chromosome showed higher non-synonymous substitution rates than autosomal genes in the Japan Sea lineage. Genomic regions of higher sequence divergence between species, genes with divergent expression between species, and QTL for inter-species phenotypic differences were found not only at the regions near the fusion site, but also at other regions along the neo X chromosome. Neo-sex chromosomes can therefore accumulate substitutions causing species differences even in the absence of substantial neo-Y degeneration. PMID- 24625863 TI - Dynamic light scattering on bioconjugated laser generated gold nanoparticles. AB - Gold nanoparticles (AuNPs) conjugated to DNA are widely used for biomedical targeting and sensing applications. DNA functionalization is easily reached on laser generated gold nanoparticles because of their unique surface chemistry, not reproducible by other methods. In this context, we present an extensive investigation concerning the attachment of DNA to the surface of laser generated nanoparticles using Dynamic Light Scattering and UV-Vis spectroscopy. The DNA conjugation is highlighted by the increase of the hydrodynamic radius and by the UV-Vis spectra behavior. Our investigation indicates that Dynamic Light Scattering is a suitable analytical tool to evidence, directly and qualitatively, the binding between a DNA molecule and a gold nanoparticle, therefore it is ideal to monitor changes in the conjugation process when experimental conditions are varied. PMID- 24625864 TI - Whole Genome Sequence of the Probiotic Strain Lactobacillus paracasei N1115, Isolated from Traditional Chinese Fermented Milk. AB - Lactobacillus paracasei N1115 is a new strain with probiotic properties isolated from traditional homemade dairy products in Inner Mongolia, China. Here, we report the complete genome sequence of L. paracasei N1115, which shows high similarity to the well-studied probiotic Lactobacillus rhamnosus GG, and 3 structures turned out to be inversions, according to the colinearity analysis of the BLAST alignment. PMID- 24625865 TI - Draft Genome Sequence of Campylobacter coli Strain IPSID-1 Isolated from a Patient with Immunoproliferative Small Intestinal Disease. AB - The genome sequence and annotation of Campylobacter coli strain IPSID-1 are reported here. This bacterial isolate is the first to be cultured from a patient with immunoproliferative small intestinal disease (IPSID). The draft genome sequence is 1.683 Mb long, comprises 64 contigs, and has 31.26% G+C content. PMID- 24625866 TI - Complete genome sequence of Swine hepatitis e virus prevalent in southwest china. AB - Hepatitis E virus (HEV) is an important public health concern in the world, especially in developing countries of Africa and Asia, including China. Hepatitis E is recognized as a zoonotic disease, which is transmitted across species, including between humans and swine. HEV is highly endemic in China, but the complete sequence of HEV in southwestern China is lacking. Swine HEV strain KM01 was isolated from a village in rural Kunming, Yunnan province, China, where swine are housed with humans. Here, we report the complete genome sequence of the swine HEV strain KM01. The sequence and phylogenetic analyses reveal that swine HEV is closely related to the strain isolated from Xinjiang (CHN-XJ-SW13). The genome of the KM01 strain will facilitate further study of HEV molecular epidemiology and genetic diversity in China. PMID- 24625867 TI - Genome Sequences of Four Italian Streptococcus thermophilus Strains of Dairy Origin. AB - This report describes the genome sequences of four Streptococcus thermophilus strains, namely, TH982, TH985, TH1477, and 1F8CT, isolated from different dairy environments from the Campania and the Veneto regions in Italy. These data are aimed at increasing the genomic information available on this species, which is of paramount importance for the dairy industry. PMID- 24625868 TI - Complete Genome Sequence of Vibrio parahaemolyticus Environmental Strain UCM V493. AB - Vibrio parahaemolyticus is the leading bacterial cause of seafood-related gastroenteritis in the world. Here, we report the complete genome sequence and annotation of an environmental strain of V. parahaemolyticus, UCM-V493, with the aim of understanding the differences between the clinical and environmental isolates of the bacteria. We also make some preliminary sequence comparisons with the clinical strain RIMD2210633. PMID- 24625869 TI - Genome Sequence of the Acute Urethral Catheter Isolate Pseudomonas aeruginosa MH38. AB - Pseudomonas aeruginosa is a major nosocomial bacterial pathogen causing complicated catheter-associated urinary tract infections (CAUTIs). Here, we present the 6.9-Mb draft genome sequence of P. aeruginosa MH38 isolated from an acute nosocomial CAUTI. It exhibits resistance to several antibiotics but revealed low-level production of virulence factors. PMID- 24625870 TI - Genome Sequence of Pseudomonas aeruginosa Strain LCT-PA220, Which Was Selected after Space Flight by Using Biolog's Powerful Carbon Source Utilization Technology. AB - To explore the changes of Pseudomonas aeruginosa in space flight, we present the draft genome sequence of P. aeruginosa strain LCT-PA220, which originated from a P. aeruginosa strain, ATCC 27853, that traveled on the Shenzhou-VIII spacecraft. PMID- 24625871 TI - High-Quality Draft Whole-Genome Sequences of Three Strains of Enterobacter Isolated from Jamaican Dioscorea cayenensis (Yellow Yam). AB - Here we report the whole-genome sequences of three endophytic bacteria, Enterobacter sp. strain DC1, Enterobacter sp. strain DC3, and Enterobacter sp. strain DC4, from root tubers of the yellow yam plant, Dioscorea cayenensis. Preliminary analyses suggest that the genomes of the three bacteria contain genes involved in acetoin and indole-3-acetic acid metabolism. PMID- 24625872 TI - Complete Genome Sequence of Magnetospirillum gryphiswaldense MSR-1. AB - We report the complete genomic sequence of Magnetospirillum gryphiswaldense MSR-1 (DSM 6361), a type strain of the genus Magnetospirillum belonging to the Alphaproteobacteria. Compared to the reported draft sequence, extensive rearrangements and differences were found, indicating high genomic flexibility and "domestication" by accelerated evolution of the strain upon repeated passaging. PMID- 24625873 TI - Genome Sequences of Sequence Type 45 (ST45) Persistent Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia Strain 300-169 and ST45 Resolving MRSA Bacteremia Strain 301-188. AB - Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (positive blood cultures after >=7 days) represents a challenging subset of invasive MRSA infections. The comparison of genome sequences of persistent (300 169) and resolving (301-188) MRSA bacteremia isolates with similar genetic background (sequence type 45 [ST45]) will help us to better understand underlying mechanisms of persistent MRSA bacteremia. PMID- 24625874 TI - Complete Genome Sequence of the Extremely Halophilic Archaeon Haloarcula hispanica Strain N601. AB - Haloarcula hispanica has been widely used in haloarchaeal studies, particularly in the isolation of haloviruses. The genome of strain N601, a laboratory derivative of the type strain ATCC 33960, was sequenced. Several potentially significant differences from the published sequence of the type strain (CGMCC 1.2049 = ATCC 33960) were observed. PMID- 24625875 TI - Draft Genome Sequence of Bacillus thuringiensis Serovar Tolworthi Strain Na205-3, an Isolate Toxic for Helicoverpa armigera. AB - We report here the complete annotated 6,510,053-bp draft genome sequence of Bacillus thuringiensis serovar tolworthi strain Na205-3, which is toxic for Helicoverpa armigera. This strain potentially contains nine insecticidal toxin genes homologous to cry1Aa12, cry1Ab1, cry1Ab8, cry1Ba1, cry1Af1, cry1Ia10, vip1Bb1, vip2Ba2, and vip3Aa6. PMID- 24625876 TI - Draft Genome Sequence and Annotation of the Entomopathogenic Bacterium Xenorhabdus szentirmaii Strain DSM16338. AB - We report the genome sequence of Xenorhabdus szentirmaii DSM16338 (4.84 Mb), a symbiont of the entomopathogenic nematode Steinernema rarum. This strain produces antimicrobial activity. PMID- 24625877 TI - Long-term survival of participants in the prostate cancer prevention trial. PMID- 24625878 TI - Effects of natural mineral-rich water consumption on the expression of sirtuin 1 and angiogenic factors in the erectile tissue of rats with fructose-induced metabolic syndrome. AB - Consuming a high-fructose diet induces metabolic syndrome (MS)-like features, including endothelial dysfunction. Erectile dysfunction is an early manifestation of endothelial dysfunction and systemic vascular disease. Because mineral deficiency intensifies the deleterious effects of fructose consumption and mineral ingestion is protective against MS, we aimed to characterize the effects of 8 weeks of natural mineral-rich water consumption on the structural organization and expression of vascular growth factors and receptors on the corpus cavernosum (CC) in 10% fructose-fed Sprague-Dawley rats (FRUCT). Differences were not observed in the organization of the CC either on the expression of vascular endothelial growth factor (VEGF) or the components of the angiopoietins/Tie2 system. However, opposing expression patterns were observed for VEGF receptors (an increase and a decrease for VEGFR1 and VEGFR2, respectively) in FRUCT animals, with these patterns being strengthened by mineral rich water ingestion. Mineral-rich water ingestion (FRUCTMIN) increased the proportion of smooth muscle cells compared with FRUCT rats and induced an upregulatory tendency of sirtuin 1 expression compared with the control and FRUCT groups. Western blot results were consistent with the dual immunofluorescence evaluation. Plasma oxidized low-density lipoprotein and plasma testosterone levels were similar among the experimental groups, although a tendency for an increase in the former was observed in the FRUCTMIN group. The mineral-rich water treated rats presented changes similar to those observed in rats treated with MS protective polyphenol-rich beverages or subjected to energy restriction, which led us to hypothesize that the effects of mineral-rich water consumption may be more vast than those directly observed in this study. PMID- 24625879 TI - Neurovascular bundle dissection for Nesbit procedure in congenital penile curvature patients: medial or lateral? AB - The objective of this study was to compare the outcomes of the modified Nesbit procedure using different techniques for dissecting the neurovascular bundle (NVB) to correct ventral congenital penile curvatures (CPCs). The bundle was mobilized using the medial and lateral dissection technique in 21 (Group 1) and 13 (Group 2) patients, respectively. In the medial technique, Buck's fascia is opened at the dorsal side of the penis, the deep dorsal vein is removed at the most prominent site of the curvature and a diamond-shaped tunica albuginea (TA) is excised from the midline of the penis. In the lateral technique, the bundle is mobilized using a longitudinal lateral incision of the Buck's fascia above the urethra at the 5 and 7 o'clock positions via a bilateral approach. The localization and degree of curvature was evaluated using the combined intracavernous injection stimulation test or from the patients' photographs. The mean patient age and degree of curvature were similar between groups. The mean operation time was longer for Group 2 (P = 0.01). In Group 1, nine patients (42.8%) required one diamond excision, 10 (47.6%) required two diamond excisions and two (9.5%) required more than two excisions; in Group 2, six patients (46.2%) required two diamond excisions and seven patients (53.8%) required more than two diamond excisions (P = 0.019). The differences in penile shortening, penile straightening and numbness of the glans penis were not statistically significant. Medial dissection of the bundle for the modified Nesbit procedure reduces the number of diamond-shaped removals of TA and thus shortens operation time in comparison with its lateral counterpart. PMID- 24625880 TI - Phosphorylated p70S6K in noninvasive low-grade urothelial carcinoma of the bladder: correlation with tumor recurrence. AB - We investigated whether inhibiting phosphorylated p70S6K (p-p70S6K) suppresses the proliferation and growth of noninvasive low-grade urothelial carcinoma (LG URCa) in vitroand whether p-p70S6K can serve as a predictive biomarker for the recurrence of noninvasive LG-URCa of the bladder in patients. We constructed a tissue microarray (TMA) for 95 LG-URCa and 35 benign urothelium samples and performed immunohistochemical staining for p-p70S6K and p-4E-BP1. A Cox regression model was used to investigate the predictive factors for recurrence of LG-URCa. We investigated the dose-dependent antiproliferative effect of rapamycin, its antiproliferative effect and the growth-inhibition effect of p70S6K siRNA transfection in RT4 and 253J cell lines. The pT1 staged group (P < 0.05; hazard ratio (HR), 2.415) and the high p-p70S6K staining group (P < 0.05; HR, 2.249) were independent factors for predicting recurrence. Rapamycin inhibited RT4 and 253J cell proliferation in a dose-dependent manner (r = -0.850, P< 0.001 in RT4 cells; r = -0.835, P< 0.001 in 253J cells). RT4 and 253J cell proliferation and growth were inhibited by the transfection of p70S6K siRNA and rapamycin, respectively (P < 0.05). Transfection of p70S6K siRNA resulted in inhibitory effects on cell proliferation and growth that were similar to those of rapamycin. Our results suggest that inhibiting p70S6K phosphorylation is important to prevent recurrence and that p70S6K phosphorylation can be used as a molecular biomarker to predict recurrence of certain LG-URCa of the bladder. PMID- 24625881 TI - Glucocorticoids and prostate cancer treatment: friend or foe? AB - Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo- and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of defining their contribution to the biology of prostate cancer. PMID- 24625882 TI - Clinical features and an atypical WT1 mutant site in a child with incomplete Denys-Drash syndrome. PMID- 24625883 TI - Decline of semen quality during IVF is not associated with subjective male stress. AB - The aim of the present study was to assess if semen quality declines during in vitro fertilization (IVF) and whether or not this phenomenon is triggered by chronic male stress. In order to test this hypothesis, we first investigated a retrospective cohort of 155 male IVF patients (testing cohort). Subsequently, we started a prospective cohort study in men undergoing their first IVF and assessed semen quality and subjective male chronic stress using a validated tool, i.e. the Fertility Problem Inventory (FPI) questionnaire. The association between stress and sperm quality decline measured 4-6 weeks before the start of IVF (T1) and at the day of oocyte retrieval (T2) was the primary outcome. Live birth rate, first trimester abortion and rate of poor responders were secondary outcomes. In the testing cohort, mean progressive motility, but not mean sperm density significantly declined. There were 78/154 (51%) men who showed a decline in semen density and 50/154 (32%) men who showed a decline in progressive motility. In the validation cohort, progressive motility declined, whereas, sperm density increased from T1 to T2. Of 78 men, 27 men had increased stress (FPI-score > 146). Sperm density and progressive motility were not significantly different in men with and without stress. However, in the presence of male stress, couples had a higher rate of poor responders, miscarriages and a lower rate of live births. Subjective stress is not associated with a decline in semen quality observed during IVF but may be associated with adverse pregnancy outcome. PMID- 24625884 TI - The influence of prostate volume on cancer detection in the Chinese population. AB - In western populations, prostate volume (PV) has been proven to be one of the strongest predictors of detecting prostate cancer (PCa) in biopsies. We performed this study in a biopsy cohort, to evaluate associations among the prostate volume, prostate-specific antigen (PSA) and PCa detection in the Chinese population. Between the years, 2007-13, 1486 men underwent prostate biopsy at Huashan Hospital, Fudan University, Shanghai, China. The study population was divided into two groups for analysis according to total PSA (tPSA) range (4 ng ml 1 < tPSA <= 20 ng ml-1 and tPSA > 20 ng ml-1 ). PV, age, tPSA, digital rectal examination (DRE) and transrectal ultrasound (TRUS) results were also included in the analysis. Although the positive biopsy rates decreased in both tPSA range groups, the downtrend was more pronounced in the 4 ng ml-1 < tPSA <= 20 ng ml-1 group; therefore, we focused on 853 men in this group with increasing PV. In multivariate logistic regression analysis, only DRE was found to be associated with PCa in four PV groups (P < 0.05) and tPSA did not show a good predictive ability when PV exceeded 50 ml (P > 0.05). Further, it may suggest that with increasing PV, the cancer detection rate decreased in men with different tPSA, DRE and TRUS nodule statuses (all P values for trends were <0.001). Our study indicates that in tPSA ranging from 4 to 20 ng ml-1 , the use of PV ranges of 0 35 ml, 35-50 ml and > 50 ml might be taken into consideration for the biopsy decision-making in the Chinese population. PMID- 24625885 TI - The Xu's chart for prostate biopsy: a visual presentation of the added value of biomarkers to prostate-specific antigen for estimating detection rates of prostate cancer. PMID- 24625886 TI - Male circumcision is not associated with an increased prevalence of erectile dysfunction. PMID- 24625887 TI - Synthesis, spectroscopic characterization, X-ray structure, and DFT calculations of some new 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxamides. AB - A series of novel 1,4-dihydro-2,6- dimethyl-3,5-pyridinedicarboxamides were synthesized and characterized by infrared absorption spectrum (IR), proton nuclear magnetic resonance (1H NMR), elemental analysis, ultraviolet spectrum (UV), and fluorescence techniques, together with X-ray single crystal diffraction. The results of density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations provided a reasonable explanation on the molecular structures, the molecular frontier orbital, and the spectra of electronic absorption and emission. The present work will be helpful to systematically understanding of the structures and the optical properties of 1,4 dihydropyridines for studying the structure-activity relationship and to develop new drugs and their analytical methods. PMID- 24625888 TI - The role of education and verbal abilities in altering the effect of age-related gray matter differences on cognition. AB - Evidence suggests that individual variability in lifetime exposures influences how cognitive performance changes with advancing age. Brain maintenance and cognitive reserve are theories meant to account for preserved performance despite advancing age. These theories differ in their causal mechanisms. Brain maintenance predicts more advantageous lifetime exposures will reduce age-related neural differences. Cognitive reserve predicts that lifetime exposures will not directly reduce these differences but minimize their impact on cognitive performance. The present work used moderated-mediation modeling to investigate the contributions of these mechanisms at explaining variability in cognitive performance among a group of 39 healthy younger (mean age (standard deviation) 25.9 (2.92) and 45 healthy older adults (65.2 (2.79)). Cognitive scores were computed using composite measures from three separate domains (speed of processing, fluid reasoning, and memory), while their lifetime exposures were estimated using education and verbal IQ measures. T1-weighted MR images were used to measure cortical thickness and subcortical volumes. Results suggest a stronger role for cognitive reserve mechanisms in explaining age-related cognitive variability: even with age-related reduced gray matter, individuals with greater lifetime exposures could perform better given their quantity of brain measures. PMID- 24625893 TI - Targeting virulence: can we make evolution-proof drugs? AB - Antivirulence drugs are a new type of therapeutic drug that target virulence factors, potentially revitalising the drug-development pipeline with new targets. As antivirulence drugs disarm the pathogen, rather than kill or halt pathogen growth, it has been hypothesized that they will generate much weaker selection for resistance than traditional antibiotics. However, recent studies have shown that mechanisms of resistance to antivirulence drugs exist, seemingly damaging the 'evolution-proof' claim. In this Opinion article, we highlight a crucial distinction between whether resistance can emerge and whether it will spread to a high frequency under drug selection. We argue that selection for resistance can be reduced, or even reversed, using appropriate combinations of target and treatment environment, opening a path towards the development of evolutionarily robust novel therapeutics. PMID- 24625894 TI - Validation of a commercial insulated isothermal PCR-based POCKIT test for rapid and easy detection of white spot syndrome virus infection in Litopenaeus vannamei. AB - Timely pond-side detection of white spot syndrome virus (WSSV) plays a critical role in the implementation of bio-security measures to help minimize economic losses caused by white spot syndrome disease, an important threat to shrimp aquaculture industry worldwide. A portable device, namely POCKITTM, became available recently to complete fluorescent probe-based insulated isothermal PCR (iiPCR), and automatic data detection and interpretation within one hour. Taking advantage of this platform, the IQ PlusTM WSSV Kit with POCKIT system was established to allow simple and easy WSSV detection for on-site users. The assay was first evaluated for its analytical sensitivity and specificity performance. The 95% limit of detection (LOD) of the assay was 17 copies of WSSV genomic DNA per reaction (95% confidence interval [CI], 13 to 24 copies per reaction). The established assay has detection sensitivity similar to that of OIE-registered IQ2000TM WSSV Detection and Protection System with serial dilutions of WSSV positive Litopenaeus vannamei DNA. No cross-reaction signals were generated from infectious hypodermal and haematopoietic necrosis virus (IHHNV), monodon baculovirus (MBV), and hepatopancreatic parvovirus (HPV) positive samples. Accuracy analysis using 700 L. vannamei of known WSSV infection status shows that the established assayhassensitivity93.5% (95% CI: 90.61-95.56%) and specificity 97% (95% CI: 94.31-98.50%). Furthermore, no discrepancy was found between the two assays when 100 random L. vannamei samples were tested in parallel. Finally, excellent correlation was observed among test results of three batches of reagents with 64 samples analyzed in three different laboratories. Working in a portable device, IQ PlusTM WSSV Kit with POCKIT system allows reliable, sensitive and specific on-site detection of WSSV in L. vannamei. PMID- 24625895 TI - A graph-theoretic approach for identifying non-redundant and relevant gene markers from microarray data using multiobjective binary PSO. AB - The purpose of feature selection is to identify the relevant and non-redundant features from a dataset. In this article, the feature selection problem is organized as a graph-theoretic problem where a feature-dissimilarity graph is shaped from the data matrix. The nodes represent features and the edges represent their dissimilarity. Both nodes and edges are given weight according to the feature's relevance and dissimilarity among the features, respectively. The problem of finding relevant and non-redundant features is then mapped into densest subgraph finding problem. We have proposed a multiobjective particle swarm optimization (PSO)-based algorithm that optimizes average node-weight and average edge-weight of the candidate subgraph simultaneously. The proposed algorithm is applied for identifying relevant and non-redundant disease-related genes from microarray gene expression data. The performance of the proposed method is compared with that of several other existing feature selection techniques on different real-life microarray gene expression datasets. PMID- 24625892 TI - The cryptic sexual strategies of human fungal pathogens. AB - Sexual reproduction is a pervasive attribute of eukaryotic species and is now recognized to occur in many clinically important human fungal pathogens. These fungi use sexual or parasexual strategies for various purposes that can have an impact on pathogenesis, such as the formation of drug-resistant isolates, the generation of strains with increased virulence or the modulation of interactions with host cells. In this Review, we examine the mechanisms regulating fungal sex and the consequences of these programmes for human disease. PMID- 24625896 TI - Bile acids and the gut microbiome. AB - PURPOSE OF REVIEW: We examine the latest research on the emerging bile acid-gut microbiome axis and its role in health and disease. Our focus revolves around two key microbial pathways for degrading bile salts, and the impact of bile acid composition in the gut on the gut microbiome and host physiology. RECENT FINDINGS: Bile acid pool size has recently been shown to be a function of microbial metabolism of bile acids in the intestines. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. Bile acids are emerging as regulators of the gut microbiome at the highest taxonomic levels. The role of bile acids as hormones and potentiators of liver cancer is also emerging. SUMMARY: The host and microbiome appear to regulate bile acid pool size. The host produces a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in intestine and liver. Members of the microbiome utilize bile acids and their conjugates resulting in agonism of FXR in intestine and liver resulting in a smaller, unconjugated hydrophobic bile acid pool. Hydrophilicity of the bile acid pool is associated with disease states. Reduced bile acid levels in the gut are associated with bacterial overgrowth and inflammation. Diet, antibiotic therapy, and disease states affect the balance of the microbiome-bile acid pool. PMID- 24625897 TI - Hepatitis C virus therapy in the direct acting antiviral era. AB - PURPOSE OF REVIEW: The evolution of treatment for patients with chronic hepatitis C virus (HCV) is evolving at a rapid pace. Two new oral antiviral agents, simeprevir and sofosbuvir, have already been approved and are now available for treatment of patients with chronic HCV. Other antiviral agents will be available during 2014. RECENT FINDINGS: The protease inhibitor simeprevir was recently approved for use with peginterferon (PEGINF) and ribavirin (RBV) in patients with chronic genotype 1. About 80% of patients achieve a rapid virologic response and can be treated for 24 weeks. The sustained virologic response (SVR) in treatment naive patients is about 80%. Sofosbuvir, the first polymerase inhibitor, is effective in all HCV genotypes. When utilized with peginterferon and RBV for 12 weeks in treatment-naive patients with genotypes 1, 4, 5 and 6, an SVR of 90% is observed. Sofosbuvir and RBV have also been studied without interferon and represent the first interferon-free therapy for chronic HCV. SUMMARY: It is now possible to cure chronic HCV in the vast majority of patients with chronic HCV and in many patients without interferon. PMID- 24625898 TI - Fibrate treatment for primary biliary cirrhosis. AB - PURPOSE OF REVIEW: Primary biliary cirrhosis (PBC) can lead to end-stage liver disease and death. Ursodeoxycholic acid (UDCA) treatment can normalize serum liver enzymes in PBC, and such UDCA-responsive patients have a similar life expectancy as age and sex-matched controls. Nearly up to 50% of the patients with PBC, depending on sex and age at diagnosis, show an incomplete biochemical response to UDCA and require additional/alternative treatment. The purpose of this review is to critically evaluate the molecular mechanisms and clinical benefit of fibrate treatment in these patients. RECENT FINDINGS: Fibrates have anticholestatic, anti-inflammatory, and antifibrotic effects in animal and in vitro studies. The mechanisms that underlie these effects are complementary, and largely mediated through activation of peroxisome proliferator activated receptors. Fibrate treatment ameliorated liver biochemical tests in UDCA unresponsive patients, either as mono-therapy or in combination with UDCA. These results, however, were obtained in case series and small pilot studies. The results of phase III studies, such as the Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis (BEZURSO) trial, are currently awaited. SUMMARY: A considerable body of observational evidence supports the safety and efficacy of fibrate treatment in PBC patients with an incomplete response to UDCA. These results encourage the evaluation of its effects on liver related morbidity and mortality in larger clinical trials. PMID- 24625900 TI - [Climate changes, floods, and health consequences]. AB - In the European Region, floods are the most common natural disaster, causing extensive damage and disruption. In Italy, it has been estimated that over 68% of municipalities are at high hydrogeological risk and with the recent intense rainfall events local populations have been facing severe disruptions. The health consequences of floods are wide ranging and are dependent upon the vulnerability of the environment and the local population. Health effects can be a direct or indirect consequence of flooding. The immediate health impacts of floods include drowning, heart attacks, injuries and hypothermia. The indirect effects include, injuries and infections, water-borne infectious disease, mental health problems, respiratory disease and allergies in both the medium and long term after a flood. Future efforts should be addressed to integrate health preparedness and prevention measures into emergency flood plans and hydrological warning systems. PMID- 24625901 TI - [Beyond the disease: a qualitative survey about (in)formative needs of hypertensive patients]. AB - Despite the rising prevalence of hypertension, the subsequent increase in incidence of cardiovascular, cerebrovascular, and renal events attributable to high blood pressure (BP), and the availability of effective treatment, BP control rates remain low. Although there are many causes of poor BP control, patients' lack of awareness of the consequences of uncontrolled hypertension and patients' lack of adherence to treatment continue to create significant barriers which prevent successful hypertension management. The objective of this study is to evaluate the hypertensive patients' (in)formative needs in order to develop an educational intervention aimed at improving the adherence to hypertension treatment. Questionnaire and focus group are used to collect patients' needs. Results suggest the development of an educational intervention consisting of group sessions where patients can share opinions and feelings together with one to-one session, based on patients' needs assessment. PMID- 24625902 TI - [TAVI in degenerative aortic stenosis treatment: state of the art and future perspectives]. AB - Degenerative aortic stenosis is the most common form of heart valve disease in developed countries and predominantly affects the elderly. Aortic valve replacement (AVR) has been the gold standard, but recently, transcatheter aortic valve implantation has emerged as an effective therapeutic alternative to conventional AVR for high-risk patients. This review analyzed the literature about AVR, with the objective of evaluating the outcomes of transcatheter aortic valve implantation in patients who are not eligible for surgery showing an improvement in quality of life and middle-term outcomes. The crucial point is the lack of studies with long-term follow-up that could give therapeutic importance to percutaneous valve replacement. PMID- 24625903 TI - [Mild therapeutic hypothermia for the treatment of cardiac arrest and acute myocardial infarction]. AB - Mild therapeutic hypothermia improves neurological outcomes after cardiac arrest by preserving brain function. It is currently under discussion the possibility that hypothermia may also provide a protective effect on cardiac function, in particular, by reducing the infarct size in patients with acute myocardial infarction complicated by cardiac arrest. Despite encouraging experimental and clinical data obtained so far may suggest a potential future indication in this population, routine use of therapeutic hypothermia in acute myocardial infarction patients needs further investigation and it is not currently recommended. PMID- 24625904 TI - [Haemostatic abnormalities and thyroid disorders: the prospective observational MITH study]. AB - Haemostatic abnormalities are a common phenomenon in patients with thyroid diseases. On one hand the condition of hyperthyroidism is associated with an increased risk of thrombotic events, on the other in severe hypothyroidism can be found a haemorrhagic tendency, as opposed to the subclinical hypothyroidism seems to correlate with increased thrombotic risk. The prospective, single center, observational MITH study (Mantua Investigation on Thyroid and Haemostasis), whose results are presented, aims to evaluate coagulation parameters in patients with thyroid disease, to establish the prevalence of haemostatic abnormalities in various conditions, to analyse the implications and clinical response to therapy established. PMID- 24625905 TI - [Relationship between hypothyroidism and cholesterol out of the records of 1756 patients]. AB - BACKGROUND: Subclinical hypothyroidism (SH) is settled whenever high levels of serum thyroid-stimulating hormone (TSH) are detected, whereas free thyroid hormone levels are within the normal range. Benefits and risks of therapy for SH have been debated for 2 decades. However, consensus has not yet been achieved. Besides preventing the progression to overt hypothyroidism, the decision of undertaking replacement therapy in SH is made mainly by basing on the risk of metabolic (dyslypidemia) and subsequent cardiovascular complications. MATERIALS AND METHODS: A series, made up of 1756 patients (mean age 42,8+/-16,8, range 0,5 94) and filed from 1984 to 2013, was studied retrospectively. 169 patients were affected by clinical (overt) hypothyroidism (IC: TSH >40). 1587 patients were affected by SH, out of whom 1121 were mild (TSH <10) and 466 medium (TSH >= 10 <=40). The series of patients was properly followed-up. The mean follow-up time was 6 years. In all patients TSH, Ft4, and total cholesterol were evaluated basally and after appropriate (TSH normalized) medical therapy. RESULTS: By medical replacement treatment, clinical hypothyroidism (CI) related hypercholesterolemia decreased significantly in 28%. In SH, the baseline serum cholesterol levels were wide. However, replacement treatment did not reduce such levels. No major cardiovascular accident occurred to any patient over the follow up period. CONCLUSIONS: Hypercholesterolemia is certainly due to CI, therapy reduces cholesterol levels that not always fall below 200 mg/dl and this condition persists over time. SH is not characterized by hypercholesterolemia. Cholesterol levels in these patients are variable equal to the normal people and can not be reduced with thyroxine. PMID- 24625906 TI - [Severe hypercalcemia secondary to primary hyperparathyroidism]. AB - Primary hyperparathyroidism is a common endocrinopathy which is nowadays diagnosed incidentally. Calcium levels range from "normal" to extremely high which can be life-threatening. We report the case of a female patient who was admitted to hospital for unspecific symptoms ultimately referable to severe hypercalcemia secondary to a large parathyroid tumor. After an intensive medical treatment (hydration, diuretics, steroids, bisphosphonate) leading to reduction of calcium levels, the patient underwent surgery with exeresis of the parathyroid mass proved an adenoma and normalization of calcium levels; nevertheless a few days after discharge symptomatic hypocalcemia occurred and was successfully managed by means of calcium and vitamin D therapy which is still required three months after surgery. PMID- 24625907 TI - [Medicine and literature: an anthology]. PMID- 24625908 TI - [DSM-5: a diagnosis and a drug should not be denied to anyone]. AB - In May 2013 the American Psychiatric Association approved the 5th revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), that since 1958 has been a reference document for the classification of psychiatric conditions. Even before its publication the DSM-5 has raised a controversy widely covered by media, the strongest argument of its critics being the fact that DSM-5 favors the medicalization of conditions that belong to ordinary human experiences. Using DSM-5 as a diagnostic tool in clinical practice may favor over diagnosis and over-treatment, for example by labeling many healthy people experiencing forgetfulness as affected by "cognitive impairment", while grieving after the death of a loved one may be diagnosed as a "major depressive disorder". Moreover, the scientific integrity of the committee that produced the DSM-5 has been questioned, arguing that the tendency to expand the boundaries of mental illness may have been driven by financial and intellectual conflicts of interest and by ties with drug companies of some of its members. PMID- 24625909 TI - ADHD and growth: questions still unanswered. AB - Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed childhood psychiatric disorders. It is manifested in every part of an affected child's behavior, with multiple symptomatology and heterogenous etiology. Published studies report that ADHD children may show changes in growth and development. Most of the studies on ADHD have been focused on connections between medication and growth changes and describe growth delays associated with medication. However, recent research results point to the low significance of the changes accompanying pharmacological treatment. Changes in growth may not only be a secondary effect of the treatment, but may also be specific characteristics of ADHD. PMID- 24625910 TI - Association between serum testosterone levels, body mass index (BMI) and insulin in male patients with schizophrenia treated with atypical antipsychotics- olanzapine or risperidone. AB - OBJECTIVE: A sufficient amount of testosterone (T) is essential for adequate sexual functioning but also for cognitive and psychological well-being. Most recent studies have demonstrated that higher BMI and other symptoms of metabolic syndrome are associated with alterations in sex steroid hormone concentrations. Although, neuroleptics are known to cause a significant and sustained weight excess, the relationships between body mass index and the level of testosterone in psychiatric patients have not been thoroughly studied. The main purpose of the present study was to examine the correlations between testosterone, estradiol BMI, and insulin in male patients diagnosed with schizophrenia and treated with olanzapine or risperidone. METHODS: The study included 78 males diagnosed with schizophrenia according to the DSM-IV diagnostic classification hospitalized in psychiatric inpatient units (42 on risperidone and 36 on olanzapine). The initial and final evaluation of testosterone (T), estradiol, prolactin (PRL) and insulin serum levels were performed at week 3 and 8 after the onset of the new treatment, respectively. RESULTS: At week 3, the mean serum prolactin was markedly higher, whereas testosterone level was lower in risperidone patients compared to those treated with olanzapine. T level was negatively affected by the studied medication (risperidone), increased prolactin and a higher BMI. At week 8, the mean serum prolactin level was markedly higher in risperidone patients. Higher values of BMI and serum insulin were the most prominent factors independently associated with decreased plasma testosterone levels at that measurement point. Individual changes of T level between week 3 and 8 were positively correlated with the corresponding changes in estradiol levels. CONCLUSIONS: T serum levels appear to be independently linked with BMI, insulin and prolactin in both investigated neuroleptics. Further research is needed to elucidate the relationship between reproductive hormones and metabolic parameters in patients with schizophrenia under neuroleptic treatment. PMID- 24625911 TI - BDNF attenuates IL-1beta-induced F-actin remodeling by inhibiting NF-kappaB signaling in hippocampal neurons. AB - OBJECTIVES: To examine the effect of BDNF on F-actin during the stimulation of IL 1beta in hippocampal neurons. MATERIALS & METHODS: We cultured hippocampal neurons from rat embryos. Cell stimulation was induced by IL-1beta. Cell culture success was evaluated by an activity analysis of CCK-8, staining of gliocyte by immunohistochemistry. Changes in F-actin, BDNF and NF-KB were examined using molecular analyses. RESULTS: Our results demonstrate that a high concentration of IL-1beta exaggerates the stimulation-induced degradation of F-actin by BDNF, whereas a low concentration of IL-1beta protects F-actin against this degradation. These beneficial effects might be associated with the inhibition or exaggeration of the NF-KB signaling cascade. CONCLUSIONS: Taken together, our findings indicate that BDNF acts as an F-actin-protective regulator during stimulation by IL-1beta and that this function largely occurs via the regulation of NF- KB signaling. These results suggest that interventions targeting the BDNF signaling system may be of therapeutic value against major depressive disorder (MDD). PMID- 24625912 TI - Combat-training stress in soldiers increases S100B, a marker of increased blood brain-barrier permeability, and induces immune activation. AB - BACKGROUND: Experimental data suggest stress-related cognitive dysfunction may be associated with increased blood-brain-barrier (BBB) permeability secondary to immune activation. METHODS: We investigated the relationship between prolonged and intense physical and psychological combat-training stress, immune activation and blood-brain-barrier permeability in 37 healthy male army medical rapid response troops. RESULTS: Soldiers during intense combat training showed greater self-reported stress, anxiety and depression levels than at rest, as assessed by specific questionnaires. S100B, a marker of BBB permeability, as well as serum cortisol, IL-6 and TNF-alpha concentrations, were significantly increased in soldiers during combat training compared to rest (all p<0.05). Serum S100B correlated negatively with morning serum cortisol in soldiers during combat training, but not during the rest period (r=-0.387, p<0.05). CONCLUSION: We conclude that combat training inducing significant levels of stress, depression and anxiety is accompanied by evidence of increased blood-brain barrier permeability and by increases in systemic pro-inflammatory mediators. PMID- 24625913 TI - Difference of neuro- and immunomodulatory steroids and selected hormone and lipid concentrations between Toxoplasma-free and Toxoplasma-infected but not CMV-free and CMV-infected schizophrenia patients. AB - OBJECTIVES: Toxoplasma gondii, the protozoan parasite infecting about 30% population worldwide, is suspected to be the etiological agent of certain form of schizophrenia disease. Toxoplasma is known to change levels of certain neurotransmitters, cytokines and several hormones in both infected animals and humans. A common feature of toxoplasmosis and schizophrenia is a disorder of immune system. METHODS: Here we studied the levels of five neuro- and immunomodulatory steroids, selected hormones and lipids in sera of 173 schizophrenia patients. RESULTS: Toxoplasma infected schizophrenia patients expressed only insignificantly lower concentration of neuro- and immunomodulatory DHEA metabolites. Infected women had higher concentration of glucose while infected men had higher concentration of cholesterol and LDL cholesterol. No significant effect of human cytomegalovirus infection on the concentration of the above parameters was observed. The difference in the concentration of DHEA metabolites faded with the decrease of the concentration of anti-Toxoplasma IgG antibodies (i.e. with the duration of Toxoplasma infection) while the difference in the concentration of cholesterol and LDL-cholesterol increased with the decrease of the concentration of anti-Toxoplasma IgG antibodies. The prevalence of toxoplasmosis in male (53.2%) but not female (29.8%) schizophrenia patients was unusually high in comparison with prevalence of toxoplasmosis in a general population. CONCLUSION: Our results provided an explanation for seemingly decreasing prevalence of toxoplasmosis in schizophrenia patients observed in current studies (increased concerns about the rights of patients resulting in absence of non-cooperative Toxoplasma-positive patients in the study population) and suggest possible explanation for reported positive correlation between prevalence of toxoplasmosis and incidence of cardiovascular diseases (accelerated atherosclerotic development due to increased level of cholesterol and LDL in Toxoplasma infected humans). PMID- 24625914 TI - Do different assays for human acylated ghrelin concentrations provide comparable results? AB - BACKGROUND: Different assays have been used in investigations on human ghrelin blood concentrations. The range of human ghrelin blood concentrations varies markedly between different studies. The variance of reported ghrelin concentrations might be due to patient specific factors, differences in sample processing, different analytical methods and different manufacturers of the assays. It is unknown how well ghrelin concentrations measured by different analytical methods are comparable and few data exist on the validity (for external consistency) of ghrelin assays. METHODS: We analyzed 256 human plasma samples for acylated ghrelin concentrations with a commercially available enzyme linked immunoassay (ELISA) and a multiplex analysis kit using Luminex((r)) technology. RESULTS: Both methods yielded ghrelin concentration within the same range. Concentrations measured by ELISA were systematically higher (median 1.4 fold). The measured concentrations of both methods correlated well as shown by a high Pearson's correlation coefficient (0.753, p<0.01). Bland-Altman plotting revealed complementary aspects concerning the agreement of the two tested methods at low and high concentrations. CONCLUSIONS: We conclude that the two investigated techniques yield results with an acceptable agreement. The agreement of both measurements indicates a good external consistency and reliability of both analytical methods. In the absence of a gold standard for ghrelin measurement, our data are a cross-validation for both methods. PMID- 24625915 TI - Inverse relationship between leptin increase and improvement in depressive symptoms in anorexia nervosa. AB - OBJECTIVES: Anorexia nervosa (AN) often presents with comorbid depressive symptoms and is characterized by low levels of neuroimmunomodulatory hormone - leptin. Treatment-induced weight gain tends to normalize those variables. The aim of the study was the longitudinal assessment of the relationship between leptin levels and depressive symptoms in patients with AN, since previous cross sectional studies in different populations brought conflicting results. METHODS: Thirty AN inpatients were assessed twice - at admission and after mean body mass index (BMI) increase of 3.2 kg/m(2). Physical parameters were measured, blood samples for leptin levels drawn and depression evaluated with both clinician - (Hamilton Depression Rating Scale - HDRS) and self - (Beck Depression Inventory - BDI) rated scales at the same morning. Correlation coefficients between changes in assessed variables, and linear regression for changes in depression scores were calculated. RESULTS: BMI and leptin levels showed significant increase after treatment, respectively 14.45+/-0.90 vs. 17.61+/-0.87 and 1.87+/-1.14 vs. 7.47+/ 4.65, whereas severity of depressive symptoms measured with BDI and HDRS was significantly reduced: 18.69+/-12.65 vs. 11.62+/-11.59; 12.76+/-6.90 vs. 5.66+/ 4.91, respectively. In linear regression analysis decrease of the clinician-rated depression score (HDRS) was directly associated with decrease in the self assessed depressive symptoms (BDI) (standardized Beta=0.45; t=2.60; p<0.05) and inversely related to the increase in leptin level (standardized Beta=-0.33; t= 2.08; p<0.05). CONCLUSIONS: These results may suggest, that increase in leptin levels during weight recovery in patients with AN is associated with objectively measured depressive symptoms. Longitudinal studies in other populations are warranted to establish whether this relationship is valid across the weight spectrum. PMID- 24625916 TI - Levels of FSH, LH and testosterone, and sperm DNA fragmentation. AB - OBJECTIVE: Having an offspring is the most important human biological goal, which is necessary for survival of the human species. Lack of offspring is a phenomenon concerning approximately 15% of married couples in Poland. In a half of the cases, a causative agent is the male factor infertility problem. There is evidence that certain male fertility problems are related with disorders of the process of spermatogenesis. The course of normal spermatogenesis depends on proper pituitary secretion of folliculostimulin (FSH), luteinizing hormone (LH), as well as testicular secretion of testosterone. It is considered that in approximately 20% of patients with idiopathic infertility an elevated level of sperm DNA fragmentation may be the cause of failure in reproduction. The objective of the present study was determination of the relationship between FSH, LH and testosterone levels, and the occurrence of sperm DNA fragmentation. METHODS: The present study was conducted in the year 2012 in the Non-Public Health Care Unit 'Ovum Reproduction and Andrology' in Lublin, and covered 186 men treated for infertility. For inclusion into the study group we qualified males aged 25-35, who have been treated for infertility for more than 1 year, with no pathological features observed in the female partner. The structure of sperm chromatin was evaluated using the technique of flow cytometry-Sperm Chromatin Structure assay (SCSA). The result of the examination was a sperm DNA Fragmentation Index (DFI), i.e., the percentage of sperm with DNA lesions (DNA fragmentation). A morning blood sample (5 mL volume) was obtained and sent to an authorized laboratory to assess serum levels of testosterone, LH and FSH. RESULTS: An intensified sperm DNA fragmentation co-occurred with both extremely low and extremely high levels of FSH and LH. Sperm DNA fragmentation was negatively correlated with testosterone level. PMID- 24625917 TI - Plasma homocysteine in Alzheimer's disease with or without co-morbid depressive symptoms. AB - OBJECTIVE: Elevated homocysteine is associated with a variety of diseases, including Alzheimer's disease (AD) and depressive disorder. This study was designed to detect an association between plasma homocysteine and AD with or without co-morbid depressive symptoms. METHODS: Plasma homocysteine concentrations were measured in 85 AD patients (36 of them with depressive symptoms), 33 non-AD patients with a depression diagnosis and 44 healthy controls, all aged above 50 years. RESULTS: Positive correlation between age and homocysteine was confirmed. Significantly higher mean plasma homocysteine was found in AD patients, but not in depressive patients, when compared with controls. We confirmed significant correlation between homocysteine concentration and the degree of cognitive impairment in AD patients. There was no incremental effect of concurrent depressive symptoms on homocysteine concentration in AD patients. CONCLUSION: The association of high homocysteine with degree of cognitive impairment or stage of dementia in AD indicate potential role of high plasma homocysteine as a biomarker of the disease and/or indicator of brain damage during the progression of AD dementia. PMID- 24625918 TI - Stereotactic radiosurgery in intraocular malignant melanoma--retrospective study. AB - OBJECTIVE: One day session linear accelerator based stereotactic radiosurgery of intraocular malignant melanoma is a method of "conservative" attitude to treat posterior uveal melanoma. MATERIAL AND METHODS: Retrospective clinic-based study of patients with posterior uveal melanoma in stage T2/T3 who underwent stereotactic radiosurgery at linear accelerator in period 2001-2011. Immobilization of the affected eye was achieved by mechanical fixation to the stereotactic Leibinger frame. The stereotactic treatment planning after fusion of computed tomography and magnetic resonance imaging was optimized according to the critical structures (lenses, optic nerves, chiasm). RESULTS: In group of 96 patients with posterior uveal melanoma treated with one day session stereotactic radiosurgery, patient age ranged from 25 to 80 years with a median of 54 years. Median tumor volume at baseline was 0.6 cm(3) (with range from 0.2 to 1.0 cm(3)). Median maximal dose applied was 49.0 Gy (range from 37.0 to 52.0 Gy). Secondary enucleation was necessary in 11 patients (11.5%) due to complications like irradiation neuropathy and secondary glaucoma. Tumor local control was successful in 95% of patients in 3 years interval after stereotactic radiosurgery and in 85% of patients in 5 years interval after stereotactic radiosurgery. CONCLUSION: One step LINAC based stereotactic radiosurgery with a single dose 35.0 Gy is one of treatment options to treat T2 or T3 stage posterior uveal melanoma. PMID- 24625919 TI - The effect of procyanidin on expression of STAT1 in type 2 diabetes mellitus SD rats with focal cerebral ischemia. AB - OBJECTIVES: Diabetes with cerebral infarction is a common disease that severely impacts health. This study investigated the effect of procyanidin (PC) on the expression of signal transducers and activators of transcription (STAT1) in type 2 diabetes mellitus SD rats with focal cerebral ischemia. We then explored the protective mechanisms of PC in type 2 diabetes mellitus SD rats with focal cerebral ischemia, to provide theory evidence for its clinical application. METHODS: We set up a type 2 diabetes mellitus-MCAO model, evaluated neurological function, and used immunohistochemistry methods to measure the activity of STAT1. RESULTS: The brain expression of STAT1 in rats of the sham-operation group was low, but more STAT1 positive cells were found in normal rats with ischemia and in rats with both type 2 diabetes and ischemia when groups were compared with the sham-operation group (p<0.01). Compared with rats that had type 2 diabetes and ischemia, the numbers of STAT1 positive cells after low, medium and high-doses of PC were all decreased (p<0.01), whereby the mid and high-dose groups showed a more substantial decrease (p<0.01) and with no variance between the two groups (p>0.05). CONCLUSIONS: These results indicate that PC has a neuroprotective effect on type 2 diabetes mellitus-MCAO; this may be through decreasing the expression of STAT1, which influences the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway that may inhibit apoptosis to relieve neurological impairment. PMID- 24625920 TI - The effects of subclinical hypothyroidism on serum lipid level and TLR4 expression of monocyte in peripheral blood of rats. AB - OBJECTIVE: To observe effect of subclinical hypothyroidism (SCH) on serum lipid level and expression of toll-like receptor 4 (TLR4) in rats' peripheral blood mononuclear cells (PBMC). METHODS: Fifty Wistar female rats were divided into three groups: normal control (NC group; n=10), sham group (n=10), and L-T-4 (L thyroxine) group (n=30, with thyroidectomy, fed with rich-calcium water after operation. 5 weeks later, abdominal subcutaneous injection of L-T-4: 0.95 MUg/100g/d). 8 weeks later, the rats were killed then the peripheral blood was collected to determine the levels of serum thyroid-stimulating hormone (TSH), total thyroid hormone (TT4), total cholesterol (TC) and low density lipoprotein cholesterin (LDL-C). Rats in L-T-4 group were divided into normal lipid (NL) group) and high lipid (HL) group) according to lipid value of NC group. Monocytes were separated from blood to determine TLR4 expression by flow cytometry. RESULTS: In NL and HL groups TSH were higher than in NC and Sham groups (p<0.05). TT4 have no significant differences (p>0.05). TLR4, TLR4 mRNA, NF-kappaB (p65) were increased (p<0.05). TNF-alpha, IL-6 and IL-1beta were higher than in NC and sham groups (p<0.01). There were no significant differences of TLR4, TLR4 mRNA, NF-kappaB (p65), TNF-alpha, IL-6 and IL-1beta expression between NL and HL groups (p>0.05). CONCLUSION: TLR4, TLR4 mRNA, NF-kappaB (p65) of PBMC and TNF-alpha, IL 6, IL-1beta expression in serum were all increased in SCH rats, which was not related to serum dyslipidemia. PMID- 24625921 TI - The non-antidepressant effects of citalopram: a clinician's perspective. AB - The authors present an overview of the most often discussed questions concerning citalopram, i.e. its proven effect on the QT interval and related dose reductions. They discuss citalopram's antiplatelet effect including the most recent data and draw attention to serotonin syndrome as its incidence is still underestimated. They go on to discuss hyponatremia pointing out that this condition may develop even in those taking low doses of citalopram. Finally, the authors provide a brief overview of the latest findings on osteoporosis and the serotonergic mechanism inducing it in individuals treated with a selective serotonin reuptake inhibitor. PMID- 24625922 TI - Indomethacin prophylaxis for heterotopic ossification after acetabular fracture surgery increases the risk for nonunion of the posterior wall. AB - OBJECTIVES: To determine if indomethacin has a positive clinical effect for the prophylaxis of heterotopic ossification (HO) after acetabular fracture surgery. To determine whether indomethacin affects the union rate of acetabular fractures. DESIGN: Prospective randomized double-blinded trial. SETTING: Level 1 regional trauma center. PATIENTS: Skeletally mature patients treated operatively for an acute acetabular fracture through a Kocher-Langenbeck approach. INTERVENTION: Patients were randomly allocated to 1 of 4 groups comparing placebo (group 1) to 3 days (group 2), 1 week (group 3), and 6 weeks (group 4) of indomethacin treatment. MAIN OUTCOME MEASUREMENTS: Factors analyzed included the overall incidence, Brooker class and volume of HO, radiographic union of the acetabular fracture, and pain. Patients were followed clinically and radiographically at 6 weeks, 3 months, 6 months, and 1 year. Serum levels of indomethacin were drawn at 1 month to assess compliance. Computed tomographic scans were performed at 6 months to assess healing and volume of HO. RESULTS: Ninety-eight patients were enrolled into this study, 68 completed the follow-up and had the 6-month computed tomographic scan, and there was a 63% compliance rate with the treatment regimen. Overall incidence of HO was 67% for group 1, 29% for group 2 (P = 0.04), 29% for group 3 (P = 0.019), and 67% for group 4. The volume of HO formation was 17,900 mm for group 1, 33,800 mm for group 2, 6300 mm for group 3 (P = 0.005), and 11,100 mm for group 4. The incidence of radiographic nonunion was 19% for group 1, 35% for group 2, 24% for group 3, and 62% for group 4 (P = 0.012). Seventy seven percent of the nonunions involved the posterior wall segment. Pain visual analog scores (VASs) were significantly higher for patients with radiographic nonunion (VAS 4 vs. VAS 1, P = 0.002). CONCLUSIONS: Treatment with 6 weeks of indomethacin does not appear to have a therapeutic effect for decreasing HO formation after acetabular fracture surgery and appears to increase the incidence of nonunion. Treatment with 1 week of indomethacin may be beneficial for decreasing the volume of HO formation without increasing the incidence of nonunion. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 24625923 TI - Investigating processes of nanocrystal formation and transformation via liquid cell TEM. AB - Recent ex situ observations of crystallization in both natural and synthetic systems indicate that the classical models of nucleation and growth are inaccurate. However, in situ observations that can provide direct evidence for alternative models have been lacking due to the limited temporal and spatial resolution of experimental techniques that can observe dynamic processes in a bulk solution. Here we report results from liquid cell transmission electron microscopy studies of nucleation and growth of Au, CaCO3, and iron oxide nanoparticles. We show how these in situ data can be used to obtain direct evidence for the mechanisms underlying nanoparticle crystallization as well as dynamic information that provide constraints on important energetic parameters not available through ex situ methods. PMID- 24625925 TI - Cycling for transport and recreation: associations with socio-economic position, environmental perceptions, and psychological disposition. AB - OBJECTIVE: Interest is growing in promoting utility cycling (i.e., for transport) as a means of incorporating daily physical activity (PA) into people's lives, but little is known about correlates of utility cycling. Our primary aim was to examine cross-sectional relationships between socio-economic characteristics, neighborhood environment perceptions and psychological disposition with utility cycling (with or without additional recreational cycling). A secondary aim was to compare these relationships with those for recreation-only cycling. METHOD: Baseline survey data (2007) from 10,233 participants in HABITAT, a multilevel longitudinal study of PA, sedentary behavior, and health in Brisbane adults aged 40-65years, were analyzed using multinomial regression modeling. RESULTS: Greater income, habitual PA, and positive beliefs about PA were associated with utility and recreation-only cycling (p<0.05). Always having vehicle access and not in the labor force were associated with recreation-only cycling (p<0.05). Some or no vehicle access, part-time employment, and perceived environmental factors (little crime, few cul-de-sacs, nearby transport and recreational destinations) were associated with utility cycling (p<0.05). CONCLUSION: Our findings suggest differences in associations between socio-economic, neighborhood perceptions and psychological factors and utility and recreation-only cycling in Brisbane residents aged 40-65years. Tailored approaches appear to be required to promote utility and recreational cycling. PMID- 24625924 TI - Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate. AB - Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders. PMID- 24625927 TI - Hydrologic regulation of chemical weathering and the geologic carbon cycle. AB - Earth's temperature is thought to be regulated by a negative feedback between atmospheric CO2 levels and chemical weathering of silicate rocks that operates over million-year time scales. To explain variations in the strength of the weathering feedback, we present a model for silicate weathering that regulates climatic and tectonic forcing through hydrologic processes and imposes a thermodynamic limit on weathering fluxes, based on the physical and chemical properties of river basins. Climate regulation by silicate weathering is thus strongest when global topography is elevated, similar to the situation today, and lowest when global topography is more subdued, allowing planetary temperatures to vary depending on the global distribution of topography and mountain belts, even in the absence of appreciable changes in CO2 degassing rates. PMID- 24625926 TI - Polyhedra self-assembled from DNA tripods and characterized with 3D DNA-PAINT. AB - DNA self-assembly has produced diverse synthetic three-dimensional polyhedra. These structures typically have a molecular weight no greater than 5 megadaltons. We report a simple, general strategy for one-step self-assembly of wireframe DNA polyhedra that are more massive than most previous structures. A stiff three-arm junction DNA origami tile motif with precisely controlled angles and arm lengths was used for hierarchical assembly of polyhedra. We experimentally constructed a tetrahedron (20 megadaltons), a triangular prism (30 megadaltons), a cube (40 megadaltons), a pentagonal prism (50 megadaltons), and a hexagonal prism (60 megadaltons) with edge widths of 100 nanometers. The structures were visualized by means of transmission electron microscopy and three-dimensional DNA-PAINT super-resolution fluorescent microscopy of single molecules in solution. PMID- 24625928 TI - A bacterial tyrosine phosphatase inhibits plant pattern recognition receptor activation. AB - Innate immunity relies on the perception of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) located on the host cell's surface. Many plant PRRs are kinases. Here, we report that the Arabidopsis receptor kinase EF-TU RECEPTOR (EFR), which perceives the elf18 peptide derived from bacterial elongation factor Tu, is activated upon ligand binding by phosphorylation on its tyrosine residues. Phosphorylation of a single tyrosine residue, Y836, is required for activation of EFR and downstream immunity to the phytopathogenic bacterium Pseudomonas syringae. A tyrosine phosphatase, HopAO1, secreted by P. syringae, reduces EFR phosphorylation and prevents subsequent immune responses. Thus, host and pathogen compete to take control of PRR tyrosine phosphorylation used to initiate antibacterial immunity. PMID- 24625930 TI - Dysplasia epiphysealis hemimelica: a diagnostic dilemma for orthopedic surgeons and a nightmare for parents. PMID- 24625929 TI - Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. AB - The intestinal microbiota and tissue-resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte-macrophage colony-stimulating factor (GM CSF) production altered mononuclear phagocyte effector functions and led to reduced regulatory T cell (T(reg)) numbers and impaired oral tolerance. We observed that RORgammat(+) innate lymphoid cells (ILCs) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin-1beta. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine. PMID- 24625931 TI - Persistent arthralgia among Chikungunya patients and associated risk factors in Chennai, South India. AB - CONTEXT: Chikungunya (CHIK) fever is viral disease characterized by joint pain for prolonged duration in various settings. However, there are no reports of long term follow-up of the CHIK patients from India. AIMS: We conducted a cohort study to describe the clinical manifestations, incidence of persistent arthralgia, and the associated risk factors among patients with CHIK identified during an outbreak in a suburb of Chennai, India. MATERIALS AND METHODS: We conducted a retrospective cum prospective cohort study in Gowripet, Avadi, Chennai. We included all adult CHIK case patients identified during the outbreak. We conducted a nested case-control study to identify the risk factors for persistent arthralgia defined as a CHIK case experiencing arthralgia for more than 15 days from the date of onset of illness. We included all 81 patients and 81 randomly selected controls. RESULTS: All 403 case patients had joint pain. Approximately 40% suffered joint pain for up to 1 month and 7% had it beyond 1 year. The most commonly affected types of joints were knee (96%), wrist (80%), and ankle (77%) joints. Regarding the number of types of joints affected, 36% had six types of joints, 23% had five types of joints, and 14% had three types of joints affected. The overall incidence of persistent arthralgia was 80%. High-grade fever, involvement of four or more types of joints, and joint swelling were significantly associated with persistent arthralgia. CONCLUSIONS: High prevalence of persistent arthralgia indicates the need for appropriate treatment strategies to reduce the severity and duration of joint pain. PMID- 24625932 TI - Health-related quality of life in patients with chronic obstructive pulmonary disease in North India. AB - BACKGROUND AND OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major health problem in India and constitutes an important cause of mortality and morbidity. A cross-sectional study was undertaken to assess health-related quality of life (HRQL) and its determinants in patients with COPD from India. MATERIALS AND METHODS: A total of 126 patients (73.81% male) were enrolled using convenient sampling prospectively in this cross-sectional study. Eligible patients were assessed for socioeconomic status, anthropometric measures, COPD severity, dyspnea and health status using the Hindi version of St George's Respiratory Questionnaire (SGRQ). Linear regression model was used to examine the association between risk factors and HRQL score (a higher score indicating poorer HRQL), adjusting for age and sex. RESULTS: The mean total score for SGRQ in the patients was 52.66 +/- 12.89, indicating a marked impairment of HRQL. Impairment was associated with the severity of airway obstruction, but within each Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, the variation (SD) was wide [stage I: 47.8 +/- 12.3 (n = 14); stage II: 49.28 +/- 11.69 (n = 47); stage III: 53.47 +/- 11.69 (n = 44); stage IV: 61.75 +/- 14.14 (n = 21)]. A regression analysis showed that body mass index, forced expiratory volume in 1 s (FEV 1 ), dyspnea grade, and depression were associated with poor HRQL. CONCLUSION: HRQL of COPD patients was significantly impaired across stages. Marked impairment of HRQL was found even in patients with mild disease. PMID- 24625933 TI - Medical professionalism from a socio-cultural perspective: evaluating medical residents communicative attitudes during the medical encounter in malaysia. AB - CONTEXT: The practice of medicine requires good communication skills to foster excellent rapport in doctor patient relationship. Reports on communication skills learning attitude among medical professionals are key essentials toward improving patient safety and quality of care. AIMS: We aimed to determine factors affecting communication skills learning attitudes among medical residents in Malaysia. SETTINGS AND DESIGN: Cross-sectional survey, in a Malaysian public health hospital. MATERIALS AND METHODS: A total of 191 medical residents across medical and surgical based rotations were included. We assessed the validated communication skills attitude scale among medical residents from different rotations. STATISTICAL ANALYSIS: Statistical Package of Social Sciences (SPSS(r)) (version 16.0, IBM, Armonk, NY) was used. Cronbach's alpha was used to test the internal consistency of the scale. Descriptive analysis was conducted for all variables. Bivariate analysis was employed across the socio-demographic variables. RESULTS: Majority of the residents believed that communication skills training should be made compulsory in Malaysia (78.5%). Medical residents agreed that acquiring good communication skills is essential to be a good doctor. However, the majority cited time pressures for not being able to learn communication skills. Significant differences in communication skills learning attitude scores were found between Malays and Chinese. CONCLUSION: The majority of medical residents had a positive attitude toward communication skills learning. Socio-demographic factors influenced communication skills learning attitude among medical residents. Incorporating communicative skills modules during hospital Continuous Medical Education for medical residents is essential to cultivate communicative skills attitudes for effective doctor-patient relationship during the routine medical encounters. PMID- 24625935 TI - Patient-physician trust among adults of rural Tamil Nadu: a community-based survey. AB - BACKGROUND: Trust is the acceptance of a vulnerable situation in which the truster believes that the trustee will act in the truster's best interests. The cornerstone of the patient-physician relationship is "trust". Despite the intensity and importance of trust relationship of patients toward their physician, the phenomenon is rarely studied in developing countries. OBJECTIVE: Our study aimed to explore the concept of patient-physician trust among adults of rural Tamil Nadu to assess the factors affecting patient-physician trust relationship and patient satisfaction. MATERIALS AND METHODS: A cross-sectional descriptive household survey was carried out on 112 individuals selected by a multistage random sampling method. Men and women aged above 40 years who have visited a health care service at least once during the last 5 years were included in the study. Thom et al's modification of the Anderson and Dedrick Physician Trust scale was used to measure patient trust in physician. RESULTS: Trust is a one-dimensional construct in the surveyed population as revealed by an exploratory factor analysis which extracted one component explaining 50% of the overall variance. Trust influences patient's self-reported satisfaction (beta coefficient of 0.048; P < 0.001) and remains independent of all the other factors assessed in the study such as, age, gender, education, self-reported health status, time spent with the physician, physician's gender, physician's age, and medical specialty that the physician belongs to. Physician's gender, physician's age, self-reported health status, and time spent with the physician were significantly associated with satisfaction with the physician. CONCLUSION: Trust in physicians seems to not depend on any of the assessed factors and largely seems to be implicit in the physician-patient relationship. Trust in physician is associated with patient satisfaction. Further studies are needed to assess trust in physicians in developing country settings. PMID- 24625934 TI - Comparative evaluation of prophylactic use of pregabalin, gabapentin and diclofenac sodium for prevention of succinylcholine-induced myalgia: a randomized, double-blinded study. AB - CONTEXT: Succinylcholine a depolarizing muscle relaxant with rapid onset, predictable course and short duration of action is associated with myalgia. AIM: The aim of this study is to evaluate the efficacy of pregabalin, gabapentin and diclofenac on the incidence and severity of succinylcholine-induced myalgia. SETTINGS AND DESIGN: Tertiary Care Teaching Hospital. MATERIALS AND METHODS: A total of 120 patients undergoing laparoscopic cholecystectomy were randomly assigned into three groups: Pregabalin group received 150 mg of pregabalin, gabapentin group received 600 mg of gabapentin and diclofenac group received 100 mg of diclofenac sodium orally 2 h prior to surgery. Anesthesia was induced with fentanyl 3 MUg/kg, propofol 2-2.5 mg/kg and succinylcholine 1.5 mg/kg and was maintained with oxygen with sevoflurane in the air and intermittent vecuronium bromide. A blinded observer recorded post-operative pain scores on visual analog scale at different time intervals and myalgia at 24 h. Post-operative pain relief was provided with fentanyl based patient-controlled analgesia. Fentanyl consumption in 24 h was recorded as a primary outcome. STATISTICAL ANALYSIS: Patients' characteristics and total fentanyl consumption were compared using one way ANOVA followed by post-hoc test. Pain score was compared amongst the groups using Kruskal Wallis test. RESULTS: The myalgia occurred in 15, 14 and 13 patients in pregabalin, gabapentin and diclofenac sodium group respectively (P > 0.85). Patients in diclofenac group had significantly higher fentanyl consumption (674.85 +/- 115.58 MUg) compared with pregabalin group (601.87 +/- 129.57 MUg) (95% confidence interval [CI] = 34.8-120.7) and gabapentin group (612.29 +/- 105.12 MUg) (95% CI = 14.9-170.5). However, there was no significant difference in fentanyl consumption between pregabalin and gabapentin groups (95% CI = -34.8 120.7). There was a significant difference in visual analog score at time points 12, 18 and 24 h among the study groups. CONCLUSION: Pre-treatment with pregabalin, gabapentin and diclofenac had equal efficacy in reducing the incidence and severity of succinylcholine-induced myalgia. However, pre-treatment with pregabalin and gabapentin decreased post-operative pain scores and fentanyl consumption. PMID- 24625936 TI - Efficacy of pralidoxime in organophosphorus poisoning: revisiting the controversy in Indian setting. AB - CONTEXT: Poisoning with organophosphorus (OP) compounds constitutes a global public health problem. Standard treatment of OP poisoning involves use of atropine and pralidoxime. While efficacy of atropine is well-established, clinical experience with pralidoxime in management of OP poisoning is controversial. AIMS: To explore the efficacy of add-on pralidoxime with atropine over atropine alone in the management of OP poisoning. SETTINGS AND DESIGN: An open-label, parallel-group, randomized clinical trial was conducted in a tertiary care district hospital in West Bengal. MATERIALS AND METHODS: Patients presenting with features of OP poisoning were randomly allocated to receive atropine or atropine-plus-pralidoxime. Efficacy was assessed by analyzing mortality, requirement for ventilator support and the duration of stay in hospital. STATISTICAL ANALYSIS: Chi-square test was done to compare the efficacy parameters between the two groups. A two-tailed P-value <0.05 was considered as statistically significant. RESULTS: During the study period, 150 patients were screened following which 120 patients were randomized to either of the treatment arms. Add-on pralidoxime therapy did not offer any appreciable benefit over atropine alone in terms of reducing mortality (18.33% (11/60) versus 13.33% (8/60)) and ventilator requirement (5% (3/60) versus 8.33% (5/60)). However, patients randomized in the add-on pralidoxime arm experienced longer duration of hospital stay (7.02 +/- 1.12 days) than those receiving atropine-alone therapy (5.68 +/- 1.87 days) (P < 0.001). CONCLUSION: The present study suggested that add-on pralidoxime with atropine therapy did not offer any appreciable benefit over atropine alone in management of OP poisoning. However, further trials are needed to explore different dosing regimens of pralidoxime in order to determine its efficacy in OP poisoning. PMID- 24625937 TI - Diabetic peripheral neuropathy and its evaluation in a clinical scenario: a review. AB - Diabetes mellitus is not only a clinical syndrome characterizing hyperglycemia, but is also a cause of debilitating problem known as peripheral neuropathy (PN). This review addresses the importance of diagnosing PN in a clinical setting as PN causes pain and discomfort in lower extremities, loss or absence of protective sensations in the lower extremities leading to balance problems, risk of foot ulcerations, and a reduced quality of life in adults with type 2 diabetes. A variety of modalities or methods are available to evaluate both subjective and objective measures of peripheral nerve functions, and have been discussed in detail in this review. It is of utmost importance to understand that evaluating PN as a routine practice in a simple way may also play a vitally important role in preventing foot ulcers or fall-related morbidity and mortality in adults with type 2 diabetes. PMID- 24625938 TI - Role of inhaled amphotericin in allergic bronchopulmonary aspergillosis. AB - Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by immune reactions mounted against the ubiquitous fungus Aspergillus fumigatus. The disease clinically manifests with poorly controlled asthma, hemoptysis, systemic manifestations like fever, anorexia and weight loss, fleeting pulmonary opacities and bronchiectasis. The natural course of the disease is characterized by repeated episodes of exacerbations. Almost 30-40% of the patients require prolonged therapy, which currently consists of corticosteroids and anti-fungal azoles; both these agents have significant adverse reactions. Amphotericin B administered via the inhaled route can achieve a high concentration in the small airways with minimal systemic side-effects. Nebulized amphotericin B has been used in the management of invasive pulmonary aspergillosis. The aim of this review is to study the utility of inhaled amphotericin in ABPA. PMID- 24625939 TI - Projects not initiated by investigators: a retrospective analysis of the queries raised by the institutional ethics committees of a teaching hospital. AB - BACKGROUND: Some investigators on receiving queries from Institutional Ethics Committee (IEC), either leave the queries unanswered or withdraw their studies. The present study was conducted to assess the queries raised by two IECs after reviewing studies that were not initiated and to identify reasons for the same. Clinical Trials Registry-India (CTRI) website was checked to review approval status of these studies at other sites. MATERIALS AND METHODS: A retrospective analysis of studies (submitted between January 2006 and December 2011) not initiated by investigators on receiving queries from IECs were identified. The nature of of these studies: whether sponsored (pharmaceutical industry (pharma)/government/investigator initiated), single-centre/multi-centric, and queries raised were analyzed. Status of multi-centric trials; not initiated at our site was checked at CTRI. Data was analyzed using descriptive statistics. RESULTS: A total of 219/2075 (11%) studies were not initiated. The proportions in pharma sponsored, investigator initiated, and government sponsored were 33%. 7.4%, and 8%, respectively. Out of a total of 1676 queries, the maximum queries were related to ethics (42%) and the least were administrative (7%). The largest proportion of queries in the pharma studies was ethical (47%), whereas majority were scientific queries (45.5%) for the investigator initiated studies. Twenty one of the 94 multi-centric studies not initiated at our site were found registered at the CTRI and were ongoing or completed at 2-55 sites. CONCLUSION: Inability of investigators to defend studies due to lack of good clinical research practice (GCP) and research methodology training or unwillingness of sponsors to comply with local IEC requirements could be potential reasons for studies remaining uninitiated. Continued GCP training of investigators and IEC members and development of uniform ethical review standards across IECs are strongly recommended. PMID- 24625940 TI - Serum 25 hydroxyvitamin D profile after single large oral doses of cholecalciferol (vitamin D3) in medical staff in North India: a pilot study. AB - BACKGROUND: Vitamin D deficiency is widely prevalent in India and subjects who have almost no exposure to sunlight are severely deficient. Daily oral doses of cholecalciferol (vitamin D3) are costly as compared to stoss doses and further, take a long time for the serum levels to reach a plateau. Compliance to supplementation may also be better if a regimen involves single oral doses of vitamin D at specified intervals rather than daily doses. Evidence-based guidelines regarding the dosing and the frequency of dosing for prophylactic intermittent supplementation (stoss doses) in severely-deficient subjects are few. MATERIALS AND METHODS: In a prospective intervention study, we serially assessed 30 asymptomatic healthy medical staff for serum 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH); (a) at baseline; (b) monthly for 3 months after single oral 60,000 units (U) cholecalciferol; (c) monthly for 3 months after 120,000 (or 180,000 for those with elevated alkaline phosphatase) U cholecalciferol; and, (d) subsequently, at 3 months after a repeat dose of 60,000 U cholecalciferol by repeated measures analysis of variance. RESULTS: The baseline serum 25(OH)D was 7.1 +/- 5.4 ng/mL (< 10 ng/mL in 85% subjects) which increased to 18.7 +/- 8.9 ng/mL at 1 month after 60,000 U of cholecalciferol (P < 0.001) and decreased to 11.1 +/- 5.3 ng/mL by the 3 rd month. The higher dose of 120,000 (or 180,000) U increased mean 25(OH)D to 28.9 +/- 9.9 ng/mL at the end of 1 st month, declining to 17.9 +/- 4.9 ng/mL (P < 0.001) at 3 months. With the subsequent 60,000 U the serum 25(OH)D was 18.4 +/- 3.9 ng/mL at 3 months. PTH showed a corresponding negative trend. No hypercalcemia was observed. CONCLUSIONS: Vitamin D deficiency is highly prevalent amongst medical staff in Northern India. An initial dose of 120,000-180,000 U of cholecalciferol is required to elevate 25(OH)D out of the deficiency range. Maintenance dose is needed at 2 months. PMID- 24625941 TI - Evaluation of normal abdominal aortic diameters in the Indian population using computed tomography. AB - OBJECTIVES: The aim of this study was to establish normal diameters for the suprarenal and infrarenal abdominal aorta measured at T12 and L3 vertebral levels in the Indian population and to study the variation in aortic diameters with age, sex, height, weight, body mass index (BMI), and body surface area (BSA). MATERIALS AND METHODS: One hundred and forty-two patients who underwent helical contrast-enhanced computed tomography (CT) scans of the abdomen for non cardiovascular reasons were recruited.. The mean internal diameters of the suprarenal and infrarenal abdominal aorta (maximum anteroposterior and transverse diameter) were measured at T12 and L3 vertebral levels and tabulated according to various age groups for both men and women. Pearson correlation coefficient was used to evaluate the correlation between aortic diameters, height, weight, BSA, and BMI. RESULTS: The mean diameters of the suprarenal and infrarenal abdominal aorta measured at T12 and L3 vertebral levels, in men were 19.0 +/- 2.3 and 13.8 +/- 1.9 mm and in women 17.1 +/- 2.3 and 12.0 +/- 1.6 mm, respectively. The aortic diameter progressively increased in caliber with increasing age of the patients and was smaller in women than men. A significant positive correlation was found in men between the suprarenal and infrarenal aortic diameters and weight, BSA, and BMI. In women, this correlation was significant in the infrarenal aorta but not in the suprarenal aorta. CONCLUSION: We obtained a set of normal values for the abdominal aorta in the Indian population. The aortic diameters correlated with age, gender, and body size of the patients as seen with previously published data in the Western population. A brief comparison of data between Indian and Western population showed that the values obtained were less than published elsewhere and hence, this should be considered while formulating intervention protocols. PMID- 24625942 TI - A mysterious back pain. AB - IgG4-related disease is a fibroinflammatory condition that affects many different organs. The common pathological findings of this disease include storiform fibrosis and dense infiltration of lymphocytes rich in IgG4-positive plasma cells. We herein presents the diagnosis and treatment of a case with a newly recognized condition - IgG4-related pachymeningitis. PMID- 24625943 TI - Xanthoma disseminatum: a progressive case with multisystem involvement. AB - Xanthoma disseminatum (XD) is a rare, benign, non-Langerhans cell histiocytic disorder. The pathogenesis is not clear. It manifests with multiple, grouped, red brown to yellow papules and nodules involving the skin, mucous membranes, and internal organs. We present a case of progressive XD in a 10-year-old male child. The patient presented with progressive, bilateral and symmetrical, reddish-brown, coalescent papules on the neck, around both eyes and all over his trunk and extremities. Skin lesions were accompanied by blurred vision and hoarseness of voice. Examination revealed xanthomatous infiltration of cornea, oral, pharyngeal, and laryngeal mucosae. The patient had diabetes insipidus that was diagnosed 2 years before the appearance of skin lesions. Medical treatment with corticosteroids (20 mg/day) and azathioprine (2 mg/kg/day) did not stop the disease progression. PMID- 24625944 TI - Luffa echinata: healer plant or potential killer. AB - Bristly luffa (Luffa echinata), a member of the cucurbitaceae family is an Ayurvedic medicinal plant, which has been used in the traditional system of medicine for variety of symptoms. The active constituents like cucurbitacin, saponin, echinatin, beta-Sitosterol, oleanolic acid and flavonoids have important pathophysiological effects on human body. However, there is no earlier published report of any toxicity on humans. We report a case of a 50-year-old gentleman, who presented with gastrointestinal bleeding, deranged liver function and shock following consumption of dried fruits of Luffa echinata soaked overnight in water. He had antral gastritis and duodenal erosions on upper gastrointestinal endoscopy and was managed conservatively and recovered completely. PMID- 24625945 TI - Beware of parotitis induced by iodine-containing contrast media. AB - Carotid stenting is being increasingly used for revascularization of the moderate to severe carotid stenosis and thus its complications are increasingly being recognized. We report a rare complication of induced by iodine contrast in a patient undergoing carotid stenting. s. A 51 year old man after the second stenting developed multiple small infarcts in spite of the distal device. He also had painful parotid swelling which improved within a week. One should be aware of iodine parotitis s in the patients undergoing iodinated contrast study. PMID- 24625946 TI - Valgus deformity caused by dysplasia epiphysealis hemimelica in the knee. AB - A rare case of dysplasia epiphysealis hemimelica in the left knee which caused valgus deformity and dysfunction of the limb is presented in this article. Subtotal excision of the lesion, distal femoral medial wedge osteotomy, and reconstruction of the medial collateral ligament were performed for treatment. Cannulated screws and plaster casts were used to stabilize the ligament and distal femur. Two years after removal and reconstruction, the knee was symptom free. The left knee laxity was restored and the mechanical axis of the distal femur was realigned. PMID- 24625947 TI - Unusual way of loosened total hip arthroplasty treatment with an Austin Moore endoprosthesis. AB - A 65-year-old female patient with aseptic loosening of total cemented hip endoprosthesis and pathologic fracture of the femur at the level of the stem of endoprosthesis was presented. As no appropriate endoprosthesis was available due to the war in Croatia and war priority, the problem was managed by femur osteosynthesis and implantation of a partial Austin Moore hip endoprosthesis. The endoprosthesis is still functioning well (for 20 years).To the best of the author's knowledge, nobody has ever treated problem like this using this alternative, an unconventional method, with an Austin Moore endoprosthesis. PMID- 24625948 TI - Therapy-related acute promyelocytic leukemia following etoposide-based chemotherapy in non-seminomatous germ cell tumor. AB - Therapy related AML (t- AML) accounts for 10-20% of all cases of AML. Cytotoxic agents implicated are alkylating agents, topoisomerase II inhibitors and rarely anti metabolites and anti tubulin agents. A growing incidence of therapy related acute promyelocytic leukemia (t-APL) has been reported over the last few decades in malignant and non malignant conditions. To the best of our knowledge this is the first t-APL case report to be reported in NSGCT post etoposide based therapy. PMID- 24625949 TI - Post ablation urethral stricture in posterior urethral valve. PMID- 24625950 TI - Methanol poisoning with blindness and putaminal necrosis - was metabolic acidosis missed? PMID- 24625951 TI - Different epidemiology of candidemia in intensive care unit patients at a hospital in Taiwan. PMID- 24625952 TI - Posterior reversible encephalopathy syndrome in a patient of snake bite. PMID- 24625953 TI - Risk factors for drug induced hepatitis with first-line antituberculosis drugs in hospitalized patients of pulmonary tuberculosis. PMID- 24625954 TI - Hypothyroidism, a rare cause of cerebellar folial calcification. PMID- 24625955 TI - Matching in case-control studies - a comment on, 'do geriatrics require dose titration for antidiabetic agents?'. PMID- 24625956 TI - Comment: association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. PMID- 24625957 TI - Comment on: association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. PMID- 24625959 TI - Circulation of a Meaban-like virus in yellow-legged gulls and seabird ticks in the western Mediterranean basin. AB - In recent years, a number of zoonotic flaviviruses have emerged worldwide, and wild birds serve as their major reservoirs. Epidemiological surveys of bird populations at various geographical scales can clarify key aspects of the eco epidemiology of these viruses. In this study, we aimed at exploring the presence of flaviviruses in the western Mediterranean by sampling breeding populations of the yellow-legged gull (Larus michahellis), a widely distributed, anthropophilic, and abundant seabird species. For 3 years, we sampled eggs from 19 breeding colonies in Spain, France, Algeria, and Tunisia. First, ELISAs were used to determine if the eggs contained antibodies against flaviviruses. Second, neutralization assays were used to identify the specific flaviviruses present. Finally, for colonies in which ELISA-positive eggs had been found, chick serum samples and potential vectors, culicid mosquitoes and soft ticks (Ornithodoros maritimus), were collected and analyzed using serology and PCR, respectively. The prevalence of flavivirus-specific antibodies in eggs was highly spatially heterogeneous. In northeastern Spain, on the Medes Islands and in the nearby village of L'Escala, 56% of eggs had antibodies against the flavivirus envelope protein, but were negative for neutralizing antibodies against three common flaviviruses: West Nile, Usutu, and tick-borne encephalitis viruses. Furthermore, little evidence of past flavivirus exposure was obtained for the other colonies. A subset of the Ornithodoros ticks from Medes screened for flaviviral RNA tested positive for a virus whose NS5 gene was 95% similar to that of Meaban virus, a flavivirus previously isolated from ticks of Larus argentatus in western France. All ELISA-positive samples subsequently tested positive for Meaban virus neutralizing antibodies. This study shows that gulls in the western Mediterranean Basin are exposed to a tick-borne Meaban-like virus, which underscores the need of exploring the spatial and temporal distribution of this flavivirus as well as its potential pathogenicity for animals and humans. PMID- 24625962 TI - Phylogenomics and the dynamic genome evolution of the genus Streptococcus. AB - The genus Streptococcus comprises important pathogens that have a severe impact on human health and are responsible for substantial economic losses to agriculture. Here, we utilize 46 Streptococcus genome sequences (44 species), including eight species sequenced here, to provide the first genomic level insight into the evolutionary history and genetic basis underlying the functional diversity of all major groups of this genus. Gene gain/loss analysis revealed a dynamic pattern of genome evolution characterized by an initial period of gene gain followed by a period of loss, as the major groups within the genus diversified. This was followed by a period of genome expansion associated with the origins of the present extant species. The pattern is concordant with an emerging view that genomes evolve through a dynamic process of expansion and streamlining. A large proportion of the pan-genome has experienced lateral gene transfer (LGT) with causative factors, such as relatedness and shared environment, operating over different evolutionary scales. Multiple gene ontology terms were significantly enriched for each group, and mapping terms onto the phylogeny showed that those corresponding to genes born on branches leading to the major groups represented approximately one-fifth of those enriched. Furthermore, despite the extensive LGT, several biochemical characteristics have been retained since group formation, suggesting genomic cohesiveness through time, and that these characteristics may be fundamental to each group. For example, proteolysis: mitis group; urea metabolism: salivarius group; carbohydrate metabolism: pyogenic group; and transcription regulation: bovis group. PMID- 24625961 TI - A phylogenomic view of ecological specialization in the Lachnospiraceae, a family of digestive tract-associated bacteria. AB - Several bacterial families are known to be highly abundant within the human microbiome, but their ecological roles and evolutionary histories have yet to be investigated in depth. One such family, Lachnospiraceae (phylum Firmicutes, class Clostridia) is abundant in the digestive tracts of many mammals and relatively rare elsewhere. Members of this family have been linked to obesity and protection from colon cancer in humans, mainly due to the association of many species within the group with the production of butyric acid, a substance that is important for both microbial and host epithelial cell growth. We examined the genomes of 30 Lachnospiraceae isolates to better understand the origin of butyric acid capabilities and other ecological adaptations within this group. Butyric acid production-related genes were detected in fewer than half of the examined genomes with the distribution of this function likely arising in part from lateral gene transfer (LGT). An investigation of environment-specific functional signatures indicated that human gut-associated Lachnospiraceae possess genes for endospore formation, whereas other members of this family lack key sporulation-associated genes, an observation supported by analysis of metagenomes from the human gut, oral cavity, and bovine rumen. Our analysis demonstrates that adaptation to an ecological niche and acquisition of defining functional roles within a microbiome can arise through a combination of both habitat-specific gene loss and LGT. PMID- 24625963 TI - Association of variable number of tandem repeats in the coding region of the FAM46A gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with susceptibility to tuberculosis. AB - We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio = 2.42, 95% Confidence Interval = 1.34-4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval = 1.26-9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease. PMID- 24625965 TI - Molecular cloning of Ra-sHSPI, a novel member of the HSP20 family from Rhipicephalus annulatus salivary glands. AB - Infestation of cattle by ticks of Rhipicephalus spp. results in severe veterinary and economical losses. Identification of novel proteins from tick salivary glands will enhance our understanding of several aspects of tick physiology and will aid in the development of anti-tick vaccines. Small heat shock proteins (HSPs) have important roles in infection and immunity, especially between invertebrate vectors and mammalian hosts while initially performing their molecular chaperone activity. Here, we report the identification of a small HSP gene from the salivary glands of Rhipicephalus annulatus ticks through immunoscreening of the corresponding cDNA expression library. The identified cDNA contained a 742bp sequence with 543bp open reading frame. It was subsequently cloned, expressed and successfully purified under both native and denaturing conditions. Sequence analysis and functional investigations showed that the protein belongs to the HSP20 family, hence the annotated name Ra-sHSPI. Indeed, recombinant Ra-sHSPI showed two typical in vitro activities of holdase chaperones, including thermal protection of bacterial cellular extracts and the recombinant HindIII at elevated temperatures. Moreover, the recombinant Ra-sHSPI showed strong immunogenic effect in animal model. These results pave the way toward further investigation of Ra sHSPI role in ticks feeding and its potential use as protective antigen. PMID- 24625964 TI - Nonproteolytic roles of 19S ATPases in transcription of CIITApIV genes. AB - Accumulating evidence shows the 26S proteasome is involved in the regulation of gene expression. We and others have demonstrated that proteasome components bind to sites of gene transcription, regulate covalent modifications to histones, and are involved in the assembly of activator complexes in mammalian cells. The mechanisms by which the proteasome influences transcription remain unclear, although prior observations suggest both proteolytic and non-proteolytic activities. Here, we define novel, non-proteolytic, roles for each of the three 19S heterodimers, represented by the 19S ATPases Sug1, S7, and S6a, in mammalian gene expression using the inflammatory gene CIITApIV. These 19S ATPases are recruited to induced CIITApIV promoters and also associate with CIITA coding regions. Additionally, these ATPases interact with elongation factor PTEFb complex members CDK9 and Hexim-1 and with Ser5 phosphorylated RNA Pol II. Both the generation of transcripts from CIITApIV and efficient recruitment of RNA Pol II to CIITApIV are negatively impacted by siRNA mediated knockdown of these 19S ATPases. Together, these results define novel roles for 19S ATPases in mammalian gene expression and indicate roles for these ATPases in promoting transcription processes. PMID- 24625966 TI - Massive Hematemesis as Presentation of Congenital Aortic Coarctation With Superinfected Aneurysm and Aortoesophageal Fistula. PMID- 24625967 TI - Pediatric UC drug development: a GREAT idea now needs a GRAND conversation. PMID- 24625968 TI - Is it necessary to assess for fat-soluble vitamin deficiencies in pediatric patients with newly diagnosed celiac disease? AB - BACKGROUND: The purpose of this study was to identify the frequency of fat soluble vitamin deficiencies in children with celiac disease (CD) and to determine the value of routine testing for these deficiencies. METHODS: We conducted a retrospective medical record review of patients with a confirmed diagnosis of CD and fat-soluble vitamin levels measured at diagnosis between 1995 and 2012 at Mayo Clinic. Patients' demographics, fat-soluble vitamin levels, and pertinent clinical factors at the time of diagnosis were collected. RESULTS: Eighty-three patients were included in the final analysis: 51 girls and 32 boys, with an average age at diagnosis of 12.8 years in girls and 13.0 years in boys. The most commonly reported symptoms were abdominal pain in 49 patients and diarrhea in 30 patients. Family history of CD was reported in 32 patients. Average vitamin levels for vitamin E, 25-hydroxyvitamin D (25 (OH) D), and vitamin A were 7.5 mg/L, 32.8 ng/mL, and 334.5 MUg/dL, respectively. No patients had vitamin A deficiency, 2 patients had vitamin E deficiency, and 9 patients had mild-to-moderate vitamin D deficiency (none had severe deficiency). Both patients with vitamin E deficiency were symptomatic and had complete villous atrophy. Thirty-one patients had insufficiency of 25 (OH) D, which was less than the reported frequency of vitamin D insufficiency in the general pediatric population in the United States in 2004. None of the patients were receiving vitamin supplements at the time of diagnosis. CONCLUSIONS: Fat-soluble vitamin deficiencies are uncommon in children with new diagnosis of CD. Routine measuring of fat-soluble vitamins levels may not be necessary. PMID- 24625969 TI - Inhibition of p38 mitogen-activated protein kinase attenuates butyrate-induced intestinal barrier impairment in a Caco-2 cell monolayer model. AB - OBJECTIVES: Butyrate is well known to induce apoptosis in differentiating intestinal epithelial cells. The present study was designed to examine the role of p38 mitogen-activated protein kinase (MAPK) in butyrate-induced intestinal barrier impairment. METHODS: The intestinal barrier was determined by measuring the transepithelial electrical resistance (TER) in a Caco-2 cell monolayer model. The permeability was determined by measuring transepithelial passage of fluorescein isothiocyanate-conjugated inulin (inulin-FITC). The morphology of the monolayers was examined with scanning electron microscopy. The apoptosis status was determined by annexin V-FITC labeling and flow cytometry. The activity of p38 MAPK was determined by the phosphorylation status of p38 with Western blotting. RESULTS: Butyrate at 5 mM increases the apoptosis rate of Caco-2 cells and induces impairment of intestinal barrier functions as determined by decreased TER and increased inulin-FITC permeability. Butyrate treatment activates p38 MAPK in a concentration- and time-dependent manner. SB203580, a specific p38 inhibitor, inhibits butyrate-induced Caco-2 cell apoptosis. Treatment of SB203580 significantly attenuates the butyrate-induced impairment of barrier functions in the Caco-2 cell monolayer model. CONCLUSIONS: p38 MAPK can be activated by butyrate and is involved in the butyrate-induced apoptosis and impairment of intestinal barrier function. Inhibition of p38 MAPK can significantly attenuate butyrate-induced intestinal barrier dysfunction. PMID- 24625970 TI - Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer. AB - Phenothiazines are a family of heterocyclic compounds whose clinical utility includes treatment of psychiatric disorders as well as chemotherapy-induced emesis. Various studies have demonstrated that these compounds possess cytotoxic activities in tumor cell lines of different origin. However, there is considerable confusion regarding the molecular basis of phenothiazine-induced cell death. Lung cancer (LC) remains one of the most prevalent and deadly malignancies worldwide despite considerable efforts in the development of treatment strategies, especially new targeted therapies. In this work, we evaluated the potential utility of phenothiazines in human LC. We show that phenothiazines as single treatment decreased cell viability and induced cell death preferentially in small cell lung carcinoma (SCLC) over non small cell lung carcinoma (NSCLC) cell lines. Sensitivity to phenothiazines was not correlated with induction of apoptosis but due to phenothiazine-induced lysosomal dysfunction. Interestingly, the higher susceptibility of SCLC cells to phenothiazine-induced cell death correlated with an intrinsically lower buffer capacity in response to disruption of lysosomal homeostasis. Importantly, this effect in SCLC occurred despite mutation in p53 and was not influenced by intrinsic sensitivity/resistance toward conventional chemotherapeutic agents. Our data thus uncovered a novel context-dependent activity of phenothiazines in SCLC and suggest that phenothiazines could be considered as a treatment regimen of this disease, however, extended cell line analyses as well as in vivo studies are needed to make such conclusion. PMID- 24625971 TI - Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin. AB - Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells. PMID- 24625972 TI - BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis. AB - Endoplasmic reticulum (ER) stress is considered one of the pathological mechanisms of idiopathic pulmonary fibrosis (IPF). Therefore, we examined whether an ER stress regulator, Bax inhibitor-1 (BI-1), regulates collagen accumulation, which is both a marker of fibrosis and a pathological mechanism of fibrosis. The presence of BI-1 inhibited the transforming growth factor-beta1-induced epithelial-mesenchymal transition of epithelial pulmonary cells and bleomycin induced pulmonary fibrosis in a mouse model by enhancing collagen degradation, most likely by enhanced activation of the lysosomal V-ATPase through glycosylation. We also found a correlation between post-translational glycosylation of the V-ATPase and its associated chaperone, calnexin, in BI-1 overexpressing cells. BI-1-induced degradation of collagen through lysosomal V ATPase glycosylation and the involvement of calnexin were confirmed in a bleomycin-induced fibrosis mouse model. These results highlight the regulatory role of BI-1 in IPF and reveal for the first time the role of lysosomal V-ATPase glycosylation in IPF. PMID- 24625973 TI - Feedback loops blockade potentiates apoptosis induction and antitumor activity of a novel AKT inhibitor DC120 in human liver cancer. AB - The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca(2+) via Ca(2+)/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment. PMID- 24625974 TI - NK cell intrinsic regulation of MIP-1alpha by granzyme M. AB - Granzymes are generally recognized for their capacity to induce various pathways of perforin-dependent target cell death. Within this serine protease family, Granzyme M (GrzM) is unique owing to its preferential expression in innate effectors such as natural killer (NK) cells. During Listeria monocytogenes infection, we observed markedly reduced secretion of macrophage inflammatory protein-1 alpha (MIP-1alpha) in livers of GrzM-deficient mice, which resulted in significantly impaired NK cell recruitment. Direct stimulation with IL-12 and IL 15 demonstrated that GrzM was required for maximal secretion of active MIP 1alpha. This effect was not due to reduced protein induction but resulted from heightened intracellular accumulation of MIP-1alpha, with reduced release. These results demonstrate that GrzM is a critical mediator of innate immunity that can regulate chemotactic networks and has an important role in the initiation of immune responses and pathogen control. PMID- 24625975 TI - A stress-induced cellular aging model with postnatal neural stem cells. AB - Aging refers to the physical and functional decline of the tissues over time that often leads to age-related degenerative diseases. Accumulating evidence implicates that the senescence of neural stem cells (NSCs) is of paramount importance to the aging of central neural system (CNS). However, exploration of the underlying molecular mechanisms has been hindered by the lack of proper aging models to allow the mechanistic examination within a reasonable time window. In the present study, we have utilized a hydroxyurea (HU) treatment protocol and effectively induced postnatal subventricle NSCs to undergo cellular senescence as determined by augmented senescence-associated-beta-galactosidase (SA-beta-gal) staining, decreased proliferation and differentiation capacity, increased G0/G1 cell cycle arrest, elevated reactive oxygen species (ROS) level and diminished apoptosis. These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70. Further proteomic analysis suggests that multiple pathways are involved in the HU-induced NSC senescence, including genes related to DNA damage and repair, mitochondrial dysfunction and the increase of ROS level. Intriguingly, compensatory mechanisms may have also been initiated to interfere with apoptotic signaling pathways and to minimize the cell death by downregulating Bcl2-associated X protein (BAX) expression. Taken together, we have successfully established a cellular model that will be of broad utilities to the molecular exploration of NSC senescence and aging. PMID- 24625976 TI - D-ribosylation induces cognitive impairment through RAGE-dependent astrocytic inflammation. AB - Non-enzymatic glycation of proteins by reducing saccharides for instance D glucose is an important post-translational modification regulating protein function. Already two centuries ago, D-glucose (Glc) was identified in the urine of diabetic patients. Recently, abnormally high level of D-ribose (Rib) in the urine of type 2 diabetics has been discovered, which is highly active in protein glycation, resulting in the production of advanced glycation end products (AGEs). Accumulation of AGEs leads to altered cellular function, for example AGE accumulation in the nervous system impairs cognitive ability, yet the mechanisms mediating this process for Rib are unknown. Here we found that treatment with Rib accelerated AGE formation in U251 and U87MG astrocytoma cells and in mouse brain, inducing upregulation of receptor for AGEs (RAGE). Astrocytoma cells with elevated levels of RAGE displayed enhanced activity of the proinflammatory nuclear transcription factor kappaB and increased expression of tumor necrosis factor alpha and glial fibrillary acidic protein. Moreover, injection of Rib induced astrocyte activation in mouse hippocampus and impaired spatial learning and memory abilities. These results indicate that mouse spatial cognitive impairment caused by Rib-derived AGEs is correlated with activation of an astrocyte-mediated, RAGE-dependent inflammatory response. This study may provide insights into the mechanism of Rib-involved cognitive impairments and diabetic encephalopathy. PMID- 24625977 TI - Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells. AB - Mortalin (mot-2) induces inactivation of the tumor suppressor p53's transcriptional and apoptotic functions by cytoplasmic sequestration of p53 in select cancers. The mot-2-dependent cytoprotective function enables cancer cells to support malignant transformation. Abrogating the p53-mot-2 interaction can control or slow down the growth of cancer cells. In this study, we report the discovery of a ubiquitin-like (UBX)-domain-containing protein, UBXN2A, which binds to mot-2 and consequently inhibits the binding between mot-2 and p53. Genetic analysis showed that UBXN2A binds to mot-2's substrate binding domain, and it partly overlaps p53's binding site indicating UBXN2A and p53 likely bind to mot-2 competitively. By binding to mot-2, UBXN2A releases p53 from cytosolic sequestration, rescuing the tumor suppressor functions of p53. Biochemical analysis and functional assays showed that the overexpression of UBXN2A and the functional consequences of unsequestered p53 trigger p53-dependent apoptosis. Cells expressing shRNA against UBXN2A showed the opposite effect of that seen with UBXN2A overexpression. The expression of UBXN2A and its apoptotic effects were not observed in normal colonic epithelial cells and p53-/- colon cancer cells. Finally, significant reduction in tumor volume in a xenograft mouse model in response to UBXN2A expression was verified in vivo. Our results introduce UBXN2A as a home defense response protein, which can reconstitute inactive p53 dependent apoptotic pathways. Inhibition of mot-2-p53 interaction by UBXN2A is an attractive therapeutic strategy in mot-2-elevated tumors. PMID- 24625978 TI - Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress. AB - In Alzheimer's disease (AD), different types of neurons and different brain areas show differential patterns of vulnerability towards neurofibrillary degeneration, which provides the basis for a highly predictive profile of disease progression throughout the brain that now is widely accepted for neuropathological staging. In previous studies we could demonstrate that in AD cortical and subcortical neurons are constantly less frequently affected by neurofibrillary degeneration if they are enwrapped by a specialized form of the hyaluronan-based extracellular matrix (ECM), the so called 'perineuronal net' (PN). PNs are basically composed of large aggregating chondroitin sulphate proteoglycans connected to a hyaluronan backbone, stabilized by link proteins and cross-linked via tenascin-R (TN-R). Under experimental conditions in mice, PN-ensheathed neurons are better protected against iron-induced neurodegeneration than neurons without PN. Still, it remains unclear whether these neuroprotective effects are directly mediated by the PNs or are associated with some other mechanism in these neurons unrelated to PNs. To identify molecular components that essentially mediate the neuroprotective aspect on PN-ensheathed neurons, we comparatively analysed neuronal degeneration induced by a single injection of FeCl3 on four different mice knockout strains, each being deficient for a different component of PNs. Aggrecan, link protein and TN-R were identified to be essential for the neuroprotective properties of PN, whereas the contribution of brevican was negligible. Our findings indicate that the protection of PN-ensheathed neurons is directly mediated by the net structure and that both the high negative charge and the correct interaction of net components are essential for their neuroprotective function. PMID- 24625980 TI - Taking into account the gender issue in cell death studies. PMID- 24625979 TI - PDR-1/hParkin negatively regulates the phagocytosis of apoptotic cell corpses in Caenorhabditis elegans. AB - Apoptotic cell death is an integral part of cell turnover in many tissues, and proper corpse clearance is vital to maintaining tissue homeostasis in all multicellular organisms. Even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. In Caenorhabditis elegans, two parallel and partly redundant conserved pathways act in cell corpse engulfment. The pathway for cytoskeletal rearrangement requires the small GTPase CED-10 Rac1 acting for an efficient surround of the dead cell. The CED-10 Rac pathway is also required for the proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. Parkin, the mammalian homolog of the C. elegans PDR-1, interacts with Rac1 in aged human brain and it is also implicated with actin dynamics and cytoskeletal rearrangements in Parkinsons's disease, suggesting that it might act on engulfment. Our genetic and biochemical studies indicate that PDR-1 inhibits apoptotic cell engulfment and DTC migration by ubiquitylating CED-10 for degradation. PMID- 24625981 TI - Two combined photosensitizers: a goal for more effective photodynamic therapy of cancer. AB - Photodynamic therapy (PDT) is a clinically approved therapeutic modality for the treatment of diseases characterized by uncontrolled cell proliferation, mainly cancer. It involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species upon irradiation with light, leading to tumor regression. Here a synergistic cell photoinactivation is reported based on the simultaneous administration of two PSs, zinc(II) phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N methylpyridyl)porphine (TMPyP) in three cell lines (HeLa, HaCaT and MCF-7), using very low doses of PDT. We detected changes from predominant apoptosis (without cell detachment) to predominant necrosis, depending on the light dose used (2.4 and 3.6 J/cm(2), respectively). Analysis of changes in cytoskeleton components (microtubules and F-actin), FAK protein, as well as time-lapse video microscopy evidenced that HeLa cells were induced to undergo apoptosis, without losing adhesion to the substrate. Moreover, 24 h after intravenous injection into tumor bearing mice, ZnPc and TMPyP were preferentially accumulated in the tumor area. PDT with combined treatment produced significant retardation of tumor growth. We believe that this combined and highly efficient strategy (two PSs) may provide synergistic curative rates regarding conventional photodynamic treatments (with one PS alone). PMID- 24625982 TI - Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells. AB - Lysosomes are acidic organelles that have a crucial role in degrading intracellular macromolecules and organelles during the final stage of autophagy. Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, was reported as an autophagy activator. Here, in contrast with previous studies, we show that Tet is a potent lysosomal deacidification agent and is able to block autophagic flux in the degradation stage. Single-agent Tet induces significant apoptosis both in vitro and in xenograft models. In the presence of Tet, apoptosis was preceded by a robust accumulation of autophagosomes and an increased level of microtubule associated protein 1 light chain 3, type II (LC3-II). However, Tet increased the level of sequestosome 1 and decreased the turnover of LC3, indicating the blockade of autophagic flux in the degradation stage. As blockade of autophagic flux decreases the recycling of cellular fuels, Tet reduces the uptake of glucose in cancer cells. These effects lead to insufficient substrates for tricarboxylic acid (TCA) cycle and impaired oxidative phosphorylation. Blunting autophagosome formation using 3-methyladenine or genetic knockdown of Beclin-1 failed to rescue cells upon Tet treatment. By contrast, addition of methyl pyruvate to supplement TCA substrates protected Tet-treated tumor cells. These results demonstrate that energetic impairment is required in Tet-induced apoptosis. Tet, as a potent lysosomal inhibitor, is translatable to the treatment of malignant tumor patients. PMID- 24625983 TI - The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity. AB - Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta cell destruction in type 2 diabetes. PMID- 24625984 TI - Pivotal role of protein tyrosine phosphatase 1B (PTP1B) in the macrophage response to pro-inflammatory and anti-inflammatory challenge. AB - Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been suggested as an attractive target to improve insulin sensitivity in different cell types. In the present work, we have investigated the effect of PTP1B deficiency on the response of human and murine macrophages. Using in vitro and in vivo approaches in mice and silencing PTP1B in human macrophages with specific siRNAs, we have demonstrated that PTP1B deficiency increases the effects of pro-inflammatory stimuli in both human and rodent macrophages at the time that decreases the response to alternative stimulation. Moreover, the absence of PTP1B induces a loss of viability in resting macrophages and mainly after activation through the classic pathway. Analysis of early gene expression in macrophages treated with pro-inflammatory stimuli confirmed this exacerbated inflammatory response in PTP1B-deficient macrophages. Microarray analysis in samples from wild-type and PTP1B-deficient macrophages obtained after 24 h of pro-inflammatory stimulation showed an activation of the p53 pathway, including the excision base repair pathway and the insulin signaling pathway in the absence of PTP1B. In animal models of lipopolysaccharide (LPS) and D-galactosamine challenge as a way to reveal in vivo inflammatory responses, animals lacking PTP1B exhibited a higher rate of death. Moreover, these animals showed an enhanced response to irradiation, in agreement with the data obtained in the microarray analysis. In summary, these results indicate that, although inhibition of PTP1B has potential benefits for the treatment of diabetes, it accentuates pro-inflammatory responses compromising at least macrophage viability. PMID- 24625985 TI - URI regulates tumorigenicity and chemotherapeutic resistance of multiple myeloma by modulating IL-6 transcription. AB - Unconventional prefoldin RPB5 interactor (URI), which acts as an oncoprotein in solid tumors, is associated with RNA polymerase II subunit 5. However, its impact on multiple myeloma (MM) has not been determined. We demonstrate here that URI is overexpressed in MM compared with plasma cells derived from healthy volunteers. Side population (SP) cells sorted from MM cells showed a much higher level of URI than non-SP cells. Using lentivirus-delivered shRNA, we established stable URI knockdown MM cell lines. URI inhibition significantly attenuated the proliferation of MM cells and decreased colony formation compared with the control cells. Tumor growth assays in NOD/SCID mice further confirmed the promotion role of URI during MM development in vivo. Furthermore, URI knockdown markedly reduced the abundance of SP in MM cell lines and enhanced the chemotherapeutic sensitivity of MM towards bortezomib. Mechanically, URI appears to be critically involved in modulating STAT3 activity through regulating interleukin (IL)-6 transcription via interaction with NFkappaBp65. In conclusion, URI may have an important role in the development of MM and chemotherapeutic resistance through activating the IL-6/STAT3 pathway. PMID- 24625986 TI - BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton. AB - BNIP3 is an atypical BH3-only member of the BCL-2 family of proteins with reported pro-death as well as pro-autophagic and cytoprotective functions, depending on the type of stress and cellular context. In line with this, the role of BNIP3 in cancer is highly controversial and increased BNIP3 levels in cancer patients have been linked with both good as well as poor prognosis. In this study, using small hairpin RNA (shRNA) lentiviral transduction to stably knockdown BNIP3 (BNIP3-shRNA) expression levels in melanoma cells, we show that BNIP3 supports cancer cell survival and long-term clonogenic growth. Although BNIP3-shRNA increased mitochondrial mass and baseline levels of reactive oxygen species production, which are features associated with aggressive cancer cell behavior, it also prevented cell migration and completely abolished the ability to form a tubular-like network on matrigel, a hallmark of vasculogenic mimicry (VM). We found that this attenuated aggressive behavior of these melanoma cells was underscored by severe changes in cell morphology and remodeling of the actin cytoskeleton associated with loss of BNIP3. Indeed, BNIP3-silenced melanoma cells displayed enhanced formation of actin stress fibers and membrane ruffles, while lamellopodial protrusions and filopodia, tight junctions and adherens junctions were reduced. Moreover, loss of BNIP3 resulted in re-organization of focal adhesion sites associated with increased levels of phosphorylated focal adhesion kinase. Remarkably, BNIP3 silencing led to a drop of the protein levels of the integrin-associated protein CD47 and its downstream signaling effectors Rac1 and Cdc42. These observations underscore that BNIP3 is required to maintain steady state levels of intracellular complexes orchestrating the plasticity of the actin cytoskeleton, which is integral to cell migration and other vital processes stimulating cancer progression. All together these results unveil an unprecedented pro-tumorigenic role of BNIP3 driving melanoma cell's aggressive features, like migration and VM. PMID- 24625987 TI - PUMA mediates ER stress-induced apoptosis in portal hypertensive gastropathy. AB - Mucosal apoptosis has been demonstrated to be an essential pathological feature in portal hypertensive gastropathy (PHG). p53-upregulated modulator of apoptosis (PUMA) was identified as a BH3-only Bcl-2 family protein that has an essential role in apoptosis induced by a variety of stimuli, including endoplasmic reticulum (ER) stress. However, whether PUMA is involved in mucosal apoptosis in PHG remains unclear, and whether PUMA induces PHG by mediating ER stress remains unknown. The aim of the study is to investigate whether PUMA is involved in PHG by mediating ER stress apoptotic signaling. To identify whether PUMA is involved in PHG by mediating ER stress, gastric mucosal injury and apoptosis were studied in both PHG patients and PHG animal models using PUMA knockout (PUMA-KO) and PUMA wild-type (PUMA-WT) mice. The induction of PUMA expression and ER stress signaling were investigated, and the mechanisms of PUMA-mediated apoptosis were analyzed. GES-1 and SGC7901 cell lines were used to further identify whether PUMA mediated apoptosis was induced by ER stress in vitro. Epithelial apoptosis and PUMA were markedly induced in the gastric mucosa of PHG patients and mouse PHG models. ER stress had a potent role in the induction of PUMA and apoptosis in PHG models, and the apoptosis was obviously attenuated in PUMA-KO mice. Although the targeted deletion of PUMA did not affect ER stress, mitochondrial apoptotic signaling was downregulated in mice. Meanwhile, PUMA knockdown significantly ameliorated ER stress-induced mitochondria-dependent apoptosis in vitro. These results indicate that PUMA mediates ER stress-induced mucosal epithelial apoptosis through the mitochondrial apoptotic pathway in PHG, and that PUMA is a potentially therapeutic target for PHG. PMID- 24625988 TI - Chemical state information of bulk specimens obtained by SEM-based soft-X-ray emission spectrometry. AB - Electron-beam-induced soft-X-ray emission spectroscopy (SXES) that uses a grating spectrometer has been introduced to a conventional scanning electron microscope (SEM) for characterizing desired specimen areas of bulk materials. The spectrometer was designed as a grazing incidence flat-field optics by using aberration corrected (varied line spacing) gratings and a multichannel plate detector combined with a charge-coupled device camera, which has already been applied to a transmission electron microscope. The best resolution was confirmed as 0.13 eV at Mg L-emission (50 eV), which is comparable with that of recent dedicated electron energy-loss spectroscopy instruments. This SXES-SEM instrument presents density of states of simple metals of bulk Mg and Li. Apparent band structure effects have been observed in Si L-emission of Si wafer, P L-emission of GaP wafer, and Al L-emissions of intermetallic compounds of AlCo, AlPd, Al2Pt, and Al2Au. PMID- 24625989 TI - Chronic kidney disease and the aging population. PMID- 24625990 TI - An update on sickle cell nephropathy. AB - Sickle cell disease (SCD) is a major health problem in many countries. Sickle cell nephropathy (SCN) is now a well-characterized entity with specific manifestations, risk factors and prognosis. The presence of sickled erythrocytes in the renal medullary vessels is the hallmark of the disease with a variety of renal complications. Renal manifestations of SCD include renal ischemia, microinfarcts, renal papillary necrosis and renal tubular abnormalities with variable clinical presentations. Proximal tubule dysfunction generally impairs urinary concentration, while more distal tubule dysfunction may impair potassium excretion, leading to hyperkalemia. Glomerular disease with proteinuria may develop due to ischemia and results in a compensatory increase in the renal blood flow and glomerular filtration rate; such hyperfiltration, combined with glomerular hypertrophy, probably contributes to glomerulosclerosis. Acute and chronic kidney disease are the expected outcomes of the disease. Both dialysis and kidney transplantation are effective renal replacement therapies for end stage renal disease due to SCN, with a higher advantage for transplantation. Whether bone marrow transplantation in the early stage of the disease can halt the progression of SCN is unknown and awaits clinical studies. PMID- 24625991 TI - The impact of genetic polymorphisms on time required to attain the target tacrolimus levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients. AB - Recent pharmacogenetic studies involving various transplant recipients in diverse ethnic populations revealed contradictory findings regarding the impact of CYP3A5 and multidrug resistance-1 (MDR1) single nucleotide polymorphisms (SNPs) on the pharmacodynamics of tacrolmius (TAC). The aim of the current study was to evaluate the impact of these SNPs on the time required to attain target TAC levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013, and MDR1 C3435T. Notably, none of the patients expressing CYP3A5 FNx011FNx011 or FNx011FNx013 achieved the target concentration of 10-20 ng/mL within the first 2 weeks or even the first month after transplant. However, 34.4% of CYP3A5 FNx013FNx013 achieved and maintained the target goal within the first and second weeks (P <0.05). In contrast, C3435T polymorphism had no significant influence on the proportion of patients achieving target TAC levels. An examination of the impact of genotype combinations on clinical outcomes revealed an increased incidence of acute, chronic rejection and graft loss in patients carrying heterozygous MDR1 C3435T alleles (CT); this indicates the possibility of an additive effect of this SNP on its concurrent combination with a FNx013FNx013 SNP. In conclusion, our study revealed trends toward unwanted outcomes in CYP3A5 non-expressers with an unexplained correlation with MDR1 C3435T polymorphisms. Recommending routine pharmacogenetic testing of the individual SNPs in renal transplant patients is not yet feasible as the relationship of cost-effectiveness to ultimate impact on graft or patient survival must be justified by further prospective clinical trials. PMID- 24625992 TI - Oral manifestations of allograft recipients before and after renal transplantation. AB - Renal transplantation is considered the best treatment option for patients with end-stage renal disease. In this study, the prevalence of oral lesions was studied in a cohort of renal transplant recipients before and after transplantation. Fifty-nine kidney transplant recipients were examined one week before and four months after transplantation. The information gathered included age, sex, smoking history, duration on dialysis, drugs and their doses. There were 41 males (69.5%) and 18 females (30.5%) with a mean age of 37 years. Before surgery, two patients had non-specific lesions and two other patients had leukoedema. Following transplantation, 24 patients (40.7%) did not have any specific lesion. In six patients, we observed non-specific erythematous lesions (10.2%). Other recorded observations are as follows: Gingival hyperplasia in five patients (8.5%), oral candidiasis of the erythematous type in five patients (8.5%), hairy leukoplakia in four patients (6.8%) and leukoedema in seven patients (11.9%). In our study patients, the prevalence of oral lesions increased after transplantation, although it was lower than that reported in other studies. This could be due to the differences in sample size, differences between Iranian race and other races and different pharmaceutical formulation of the drug produced in Iran. PMID- 24625993 TI - Occurrence of the polyomavirus among kidney transplant recipients: a single center study. AB - Polyoma virus-associated nephropathy is an increasingly recognized cause of graft dysfunction among kidney transplant recipients and could be the result of use of potent immunosuppression following transplantation. Because there is no safe and effective anti-viral therapy available presently, screening-based prevention and pre-emptive strategy are recommended. This study, which was conducted at the Nephrology Unit, Internal Medicine Department, Alexandria University, consisted of two phases: Phase 1 was a cross-sectional study and phase 2 was a 6-month follow-up study only for polyoma virus-positive cases. Phase 1 included 75 renal allograft recipients from living donors. Urine cytology for decoy cells and quantitative real-time blood polymerase chain reaction (PCR) for the BK virus (BKV) were performed on all the study patients. Renal biopsy was performed only in patients with deteriorating renal function associated with positive urine cytology. Patients who showed positive urine cytology for decoy cells and/or positive quantitative BKV PCR assay were followed-up for six months. During follow-up, the serum creatinine level, with or without urine cytology for decoy cells, and BKV PCR viral load assay were performed. Among the 75 kidney transplant recipients studied, eight were positive for decoy cells (11%), three showed viremia by quantitative PCR for BKV (4.1%), while two others showed nephropathy (2.7%) in the form of tubulointerstitial nephritis with intra-nuclear inclusions in the tubular cells. Cases with stable renal function and positive decoy cells or viremia cleared the virus spontaneously during follow-up without any intervention. Only one case with biopsyproven nephropathy and deteriorating graft function, with undetectable BKV in blood, lost the graft while another case with viremia died during follow-up due to septicemia. Our study suggests that polyoma virus should be considered as a cause of nephropathy in renal transplant recipients. Further research is required to understand this entity better. PMID- 24625994 TI - Protective effect of everolimus on renal ischemia reperfusion injury in rats. AB - The aim of this study was to determine the effect of everolimus and tacrolimus pretreatments on renal morphology and function in a rat ischemia reperfusion (I/R) model. Twenty-eight male Sprague-Dawley rats were randomly assigned to saline + sham operation, saline + I/R (IR), tacrolimus + I/R (TRL + I/R) and everolimus + I/R (ERL + I/R) groups. Saline and active treatments were administered intraperitoneally for seven consecutive days before the surgery. The suprarenal aorta was clamped to achieve warm ischemia, except in the sham group. Right nephrectomy was performed in all animals and histology was examined. Renal function was assessed on post-operative Day 7 by Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy, glomerular filtration rate (GFR) and serum biochemistry. Both everolimus and tacrolimus preserved serum creatinine and blood urea nitrogen levels, but only everolimus preserved GFR (0.74 +/- 0.36, 1.20 +/- 0.37 and 2.24 +/- 0.32 mL/min for I/R, TRL + I/R and ERL + I/R, respectively, P < 0.001). %ID values for sham, I/R, TRL + I/R and ERL + I/R were 55 +/- 3, 47 +/- 4, 45 +/- 6 and 62 +/- 7 (P < 0.001). On histologic evaluation, ERL + I/R showed less tubular damage and necrosis than I/R, as well as TRL + I/R. Within the confines of this rat warm ischemia model, everolimus pre-treatment was useful in preserving renal function following I/R injury. The possibility of using everolimus as a pre conditioning agent for I/R injury in kidney transplantation should be further explored. PMID- 24625995 TI - Obesity and urologic complications after renal transplantation. AB - Although obesity has been associated with improved survival on dialysis, its short-and long-term effects on renal transplantation outcomes remain unclear. Herein, we evaluate the short-term and intermediate long-term effects of obesity on first-time renal transplant patients. A retrospective analysis was performed on 180 consecutive renal transplant recipients from living unrelated donors during 2006-2008 in a major transplantation center in Tehran, Iran. Among these, 34 (18%) patients were found to be obese (body mass index >=30 kg/m 2 ). Obese patients were more likely to develop post-transplant renal artery stenosis (RAS) (17.6% vs. 2.8%, P <0.001), hematoma (47.9% vs. 17.6, P = 0.009), surgical wound complications (64.7% vs. 9.6%, P <0.001) and renal vein thrombosis (2% vs. 0%, P <0.001). However, the incidence of delayed graft function, lymphocele, urologic complications of ureterovesical junction stenosis or urinary leakage, surgical complications of excessive bleeding or renal artery thrombosis and duration of hospitalization were similar between the two groups. The two-year patient and graft survival were also statistically not different. Renal transplantation in obese recipients is associated with a higher incidence of post-transplant RAS, hematoma, surgical wound complications and renal vein thrombosis, but similar two year patient and graft survival. PMID- 24625996 TI - Utility of color Doppler ultrasound in the evaluation of renal artery stenosis in comparison with contrast-enhanced magnetic resonance angiography. AB - Renal artery stenosis (RAS) is one of the main correctable causes of secondary systemic arterial hypertension. Color Doppler ultrasound (DUS), a non-invasive imaging modality, has been used to diagnose RAS in hypertensive patients. This study was conducted in the period between June 2008 and March 2010 to compare the sensitivity, specificity, accuracy and predictive values of DUS using contrast enhanced magnetic resonance angiography (CEMRA) as the gold standard for the diagnosis of RAS. Fifty-seven consecutive patients with clinical findings suggestive of RAS (32 males and 25 females) with a mean age of 56 years (+/-7.92 years) were referred to the University Kebangsaan Medical Center to be screened for RAS using DUS and CEMRA. RAS was considered significant if the reduction in diameter was >60%. A total of 114 arteries were assessed, 65 in males (57%) and 49 in females (43%). On DUS, the parameters measured were the peak systolic velocity at the proximal main renal artery (PSV-P), distal main renal artery (PSV D) and the suprarenal aorta (PSV-A) at the level of the renal hila and the acceleration time (AT) at the main renal artery. The renal-renal ratio (RRR), which is the value of PSV-P/PSV-D, and the renal-aortic ratio (RAR), which is the value of PSV-P/PSV-A, were then calculated. The accuracy, sensitivity, specificity and positive and negative predictive values of DUS in the detection of significant RAS were determined. All measured DUS parameters were positive for the detection of RAS, with an accuracy of 98.3%. On retrospective review, all the arteries that showed significant stenosis on CEMRA demonstrated an irregular outline on DUS. We conclude that DUS is accurate in the diagnosis of significant RAS but is not very sensitive as a screening tool. PMID- 24625997 TI - Allopurinol reduces cardiovascular risks and improves renal function in pre dialysis chronic kidney disease patients with hyperuricemia. AB - To determine the effect of hyperuricemia and allopurinol therapy on renal functions in chronic kidney disease (CKD) stage 3-4, we studied 96 patients in stage 3-4 CKD (57% male, age 65.3 +/- 12.4 years). The mean estimated glomerular filtration rate (GFR) was 44.62 +/- 14.38 iriL/ min/1.73 m 2 . The study patients were divided into non-allopurinol users (n = 47) and those using allopurinol (n = 49) in the last 12 months. Serum uric acid (UA) and C-reactive protein levels decreased after allopurinol therapy (P = 0.00 and P = 0.04, respectively), but no change was observed in the control group during the study period. In the allopurinol group, the mean GFR increased 3.3 +/-1.2 mL/min/1.73 m 2 /year, while it decreased 1.3 +/- 0.6 mL/min/1.73 m 2 in the control group during the follow up period (P = 0.04); the patients in the allopurinol group exhibited lower levels of serum potassium, serum low-density lipoprotein (LDL) and renal resistance index (RRI) (P-values were <0.05). The patients with stable renal functions or GFR change <10% (n = 25) at the end of 12 months had significantly lower LDL and RRI values and more allopurinol users than the group with decreasing GFR (74% vs. 48%, P <0.05). In the regression analysis, UA and RRI were found as independent variables (r 2 = 0.68, P <0.01; r 2 = 0.25, P <0.01) that affected loss of renal function. We conclude that our study suggests a role for allopurinol, an effective agent in lowering serum UA levels, as a reliable therapeutic option in controlling renal progression in pre-dialysis CKD patients. PMID- 24625999 TI - Nephrocalcinosis in pre-term neonates: a study of incidence and risk factors. AB - The objective of this study was to determine the incidence and risk factors of nephrocalcinosis (NC) in pre-term neonates in the neonatal intensive care unit (NICU) at the Al-Minya University, Egypt. The study included 97 pre-term neonates with a gestational age 34 weeks. Data on duration of hospitalization, sex, gestation, birth weight, family history of renal stone, need for respiratory support, intake of calcium and use of total parenteral nutrition (TPN) and nephrotoxic drugs were collected. Blood urea nitrogen, serum creatinine, sodium, potassium, calcium and phosphate were measured within the first week of life and again at term. Blood gases, urinary pH, urinary calcium/creatinine (U Ca/Cr) ratio and urinary oxalate/creatinine (U Ox/Cr) ratio were measured once at term. Three renal ultrasound (US) scans were performed; one before the first week of life, the second at term and the third at a corrected age of one year. Of the 97 infants studied, 14 (14.4%) developed NC diagnosed by renal US at term. NC was bilateral in 11 infants. Factors significantly associated with NC were gestational age, need for respiratory support, high calcium intake, TPN, use of post-natal dexamethasone, furosemide, theophylline, and/or aminoglycosides and U Ca/Cr ratio and U Ox/Cr ratio (all P < 0.05). Low gestational age (P = 0.004), use of respiratory support (P = 0.005), furosemide therapy (P = 0.002) and increased U Ca/Cr ratio (P = 0.001) were the strongest independent risk factors after logistic regression analysis. Eight of the 14 infants (57.1%) with NC had spontaneous resolution of calcification at a corrected age of one year. Screening at term with a renal US scan and long-term follow-up of renal function is needed for early diagnosis and better management of NC. Future research pertaining to prevention of NC in pre-term neonates is required. PMID- 24625998 TI - Comparison of slope-intercept with single plasma sample methods in estimating glomerular filtration rate using radionuclides. AB - To evaluate the accuracy of different single plasma sample methods (SPSM) 99m Tc DTPA clearances and to test whether the SPSM can replace the dual plasma samples method (DPSM) in the measurement of glomerular filtration rate (GFR), we studied 430 subjects counting renal patients and donors (240 male, 190 female; mean age 43.40 +/- 16.30 years). All the subjects underwent dynamic renal scintigraphy after injection of 99m Tc-DTPA; the GFR was calculated by seven SPSMs in addition to DPSM as a reference. Each of the SPSM clearance was compared with the DPSM measurement. There was a high correlation of all the SPSMs and the DPSM. The limits of agreement (95%) were found between the DPSM and all the SPSMs. Overall, the best method among the SPSMs, which is closest to the DPSM, is Fleming's single method as it has a statistically significant low mean difference (bias), low standard error, close mean +/- SD to the reference method, good limits of agreement and high correlation co-efficient. This study concludes that, among the SPSMs, Fleming can reflect GFR more accurately than other methods, particularly when the expected serum creatinine is normal. PMID- 24626000 TI - The protective effect of theophyline in cisplatin nephrotoxicity. AB - Cisplatin is a potent and a major anti-neoplastic drug in the treatment of a broad spectrum of malignancies. However, its clinical use is limited by renal tubular dysfunction that occurs in a significant percent of patients. The aim of the present study was to evaluate the possible protective effect of theophyline in the prevention of cisplatin-induced nephrotoxicity. The trial design was prospective, randomized, double-blinded and placebo controlled. Chemotherapeutic patients who received cisplatin at a dosage of at least 50 mg/m 2 alone or in combination with other chemotherapy agent(s) were included in the study. There were a total of 76 patients who were randomly divided into two groups. In group 1 (n = 38), placebo was advised; in group 2 (n = 38), patients received 4 mg/kg aminophyline as an intravenous loading dose, followed by theophyline in a dose of 200 mg three times daily orally for four consecutive days. The placebo group had 22 males and 16 females and the theophyline group had 26 males and 12 females. The mean age was 51 +/- 17.6 years and the mean dose of cisplatin was 86.71 +/- 43.18 mg. The prevalence of cisplatin nephrotoxicity in groups 1 and 2 was 7.9 and 5.3%, respectively, and the difference was not significant (P = 1). In addition, there was no significant association of cisplatin nephrotoxicity with age (P = 0.1), gender (P = 0.64) and mean dose of cisplatin (P = 0.8). These results indicate that prophy-lactic application of aminophyline and theophyline does not have a protective effect against cisplatin nephrotoxicity. PMID- 24626001 TI - A clinical study of bilateral non-obstructive acute pyelonephritis with acute kidney injury in patients of type 2 diabetes mellitus. AB - The aim of our study was to study the clinical profile of type 2 diabetes mellitus patients admitted with the diagnosis of acute kidney injury (AKI) due to bilateral acute non-obstructive pyelonephritis. The bilateral involvement was identified on various imaging modalities (ultrasound, computed tomography, nuclear scintigrapy). All the patients had AKI. Those with severe AKI underwent hemodialysis. The factors associated with the severity of illness were identified. Twenty-five patients of type 2 diabetes mellitus admitted with the diagnosis of AKI due to bilateral acute non-obstructive pyelonephritis were identified. On ultrasound, bilateral involvement was found in 12 patients and in 17 patients on computed tomography and eight patients on nuclear scintigraphy. Fourteen of them needed dialysis support. Bilateral acute pyelonephritis needs to be considered while evaluating the AKI in type 2 diabetes mellitus patients. PMID- 24626002 TI - Incidence and predictive factors of Balkan endemic nephropathy: a longitudinal study. AB - Balkan endemic nephropathy (BEN) is a chronic kidney disease that progresses slowly. There are no known clinical markers to identify an early disease development. We evaluated the relationship between parental history of BEN and clinical markers as predictors of new occurrences of BEN. A 5-year prospective study in the offsprings of BEN and control patients was conducted in Vratza, Bulgaria, between 2003 and 2009 using markers in years one and three to predict new cases of BEN in the year five. We defined incident cases of BEN based on parental history, reduced kidney size and reduced kidney function, distinguishing probable and definite BEN, both combined as total incidence. The data were analyzed by Cox regression models using age as time scale and controlling for gender. We estimated hazard ratios and their 95% confidence intervals. The incidence of BEN was 17.4%. Paternal history was strongly associated with all three incidence groups (hazards ratio: 27-68, P <0.05). A reduction of kidney size of 1 mm resulted in a 5% increased hazard. However, taking parental history of BEN into account, these associations lost their significance. No kidney function measures were associated with new onset of BEN. A parental history of BEN is more important than clinical markers predicting the incidence of BEN. Without this information, kidney length forecasts probable BEN and the total incidence, while none of any clinical markers was related to definite BEN. PMID- 24626003 TI - Localization of post-transplant lymphoproliferative disorders to the stomach might be associated with favorable outcome: a systematic review. AB - Gastric localization of post-transplant lymphoproliferative disorders (PTLDs) is very rare. In this study, we aimed to accumulate existing data in the current literature to reveal the clinical, histopathological and prognostic specificities associated with gastric PTLDs and to find the best treatment strategies in this patient population. A comprehensive search was conducted for the available data in the current literature using Pubmed and Google scholar search engines for reports on gastric PTLD in renal transplant recipients. Data of different studies were standardized and entered into a database and analyzed. No statistically significant difference was found between gastric and non-gastric PTLD. Gastric PTLD was relatively more prevalent in female patients (P = 0.08) and showed a trend toward better outcome (P = 0.1) and less metastasis (P = 0.07). Surgical intervention and rituximab therapy were associated with a more favorable outcome (17% mortality). Our study showed that organ transplant recipients having gastric PTLD develop metastasis less frequently and tend to have a relatively more favorable outcome. Prospective studies with larger patient populations are needed to confirm or modify our results. PMID- 24626004 TI - Effect of kidney transplantation on early and late post-transplant prostate specific antigen levels. AB - The aim of this study was to determine the effect of kidney transplantation on serum prostate-specific antigen (PSA) levels. Forty patients who were on peritoneal dialysis or hemodialysis underwent kidney transplantation at our department. The immunosuppressive protocol was uniform during the study period. The creatinine and prostate specific antigen (PSA) levels, both free and total, were measured by immunofluorometric assays immediately before transplantation and on post-transplant Days 1, 7, 90 and 180. The mean age of the patients was 49.97 +/- 4.4 years. After transplantation, there was a significant decrease in free PSA, but there was no correlation between total PSA and serum creatinine. Free PSA levels were significantly decreased after kidney transplantation but total PSA remained unchanged. This was observed in post-transplant patients irrespective of whether they had delayed graft function, slow graft function or immediate graft function during the observed period. Therefore, total PSA can be used as a marker for prostate cancer screening after kidney transplantation. PMID- 24626005 TI - Renal transplantation in a child with thrombosed inferior vena cava. AB - The external iliac vein is commonly used in renal transplantation for vascular anastomosis of the allograft renal vein. However, there are rare instances when the transplant surgeon may encounter thrombosis of the ilio-caval vein during surgery, making renal transplantation a challenge. Often, these patients are considered unsuitable for renal transplantation. We report a case of thrombosis of the inferior vena cava in an asymptomatic pediatric patient in whom the splenic vein was used, at transplantation, for venous drainage. This case highlights that pre-operative Doppler screening should be performed in all potential renal transplant recipients. PMID- 24626006 TI - Renal allograft tuberculosis with infected lymphocele transmitted from the donor. AB - Transmission of tuberculosis (TB) from a donor through renal transplantation is a rare incident. We are reporting a 53-year-old Qatari woman diagnosed with renal allograft TB infection. The disease was confirmed by isolation of Mycobacterium tuberculosis from fluid from the lymphocele and demonstration of caseating granuloma in graft biopsy with acid-fast bacilli seen on Ziehl-Neelsen staining. The diagnosis was made quite early post-transplantation. The presence of the granuloma, which is unusual with patients on intensive immunosuppressant medications, suggests that transmission of the infection occurred from the donor rather than from the activation of latent infection. In reviewing the literature, we found ten case reports of TB in transplanted kidney with transmission of TB infection from the donor. The presence of TB in lymphocele in association with the infected transplant by TB, to the best of our knowledge, was reported only once in the literature. Our case had unfavorable outcome and ended by renal allograft nephrectomy and hemodialysis. We are presenting this case of TB infection of renal allograft and lymphocele diagnosed early post-transplantation transmitted from the donor and pertinent review from the literature. PMID- 24626007 TI - Neonatal adrenal hematoma with urinary tract infection: risk factor or a chance association? AB - Neonatal adrenal hematoma is a rare finding that can be discovered incidentally or presents with various symptoms. However, urinary tract infection (UTI) has not been reported in association with this condition. We report on a 4-week old child with massive unilateral adrenal hematoma discovered incidentally during a routine abdominal ultrasound scan for UTI. The mass resolved spontaneously after several months with no complications. The diagnosis and management of infantile suprarenal mass and the possible link between this child's UTI and the adrenal hematoma are discussed. PMID- 24626008 TI - Sodium hypochlorite-induced acute kidney injury. AB - Sodium hypochlorite (bleach) is commonly used as an irrigant during dental procedures as well as a topical antiseptic agent. Although it is generally safe when applied topically, reports of accidental injection of sodium hypochlorite into tissue have been reported. Local necrosis, pain and nerve damage have been described as a result of exposure, but sodium hypo-chlorite has never been implicated as a cause of an acute kidney injury (AKI). In this report, we describe the first case of accidental sodium hypochlorite injection into the infraorbital tissue during a dental procedure that precipitated the AKI. We speculate that oxidative species induced by sodium hypochlorite caused AKI secondary to the renal tubular injury, causing mild acute tubular necrosis. PMID- 24626009 TI - Giant renal artery pseudoaneurysm caused by rupture of renal angiomyolipoma following pregnancy: endovascular treatment and review of the literature. AB - Renal angiomyolipoma is a hamartomatous, benign tumor composed of blood vessels, fatty tissue and smooth muscle cells, and is often detected incidentally. It can also be associated with the tuberous-sclerosis complex (TSC). Pregnancy and use of oral contraceptives are known to be associated with an increased risk of tumoral rupture and bleeding. Herein, we report a unique case of renal angiomyolipoma associated with TSC who presented with hypovolemic shock as a result of spontaneous rupture of a giant renal pseudoaneurysm, immediately after pregnancy. Emergency endovascular treatment was successful with sparing of most of the affected kidney as demonstrated by follow-up computed tomography imaging. PMID- 24626010 TI - Piperazine side-effects in a patient with pre-existing renal insufficiency. AB - Piperazine as an antihelminth has many adverse effects, especially on patients with renal insufficiency. We report the use of piperazine in a girl with a moderately severe kidney disease due to Biedl Bardet syndrome. She developed coma and acute kidney injury due to acute interstitial nephritis (AIN), anemia and thrombocytopenia. The presence of fever, proteinuria, acidosis, anemia, sterile pyuria and non-oliguric renal failure strongly suggested AIN. Her problems abated mostly by discontinuing of piperazine and supportive therapy, except anemia and thrombocytopenia. PMID- 24626011 TI - Chronic tubulo-interstitial nephritis in common variable immunodeficiency: a rare association. AB - Common variable immunodeficiency (CVID) is characterized by reduced serum immunoglobulin levels and repeated serious bacterial infections involving different organ systems. Chronic kidney disease (CKD) is an uncommon association with CVID. Chronic tubulo-interstitial nephritis in a case of CVID that progressed to CKD is distinctly rare. PMID- 24626012 TI - Intussusception in two pediatric patients associated with nephrotic syndrome. AB - We report two cases of intussusception in two Jordanian boys during a relapse of nephrotic syndrome. The first patient had minimal change disease and the second patient had diffuse mesangial sclerosis. The most prominent symptom was abdominal pain, but the other classic sign of currant jelly stool was absent. In spite of the fact that both patients could have had other causes of abdominal pain, intussusception was suspected and confirmed by ultrasound and was treated successfully. Intussusception should be considered in the differential diagnosis in nephrotic patients presenting with abdominal pain. PMID- 24626013 TI - Crescentic glomerulonephritis in non-asthmatic Churg-Strauss syndrome. AB - A 58-year-old male presented with sensory motor polyneuropathy and rapidly progressive renal failure. Investigations revealed marked peripheral eosinophilia and elevated perinuclear antineutrophil cytoplasmic antibody titers. Renal biopsy showed pauci-immune cre-scentic glomerulonephritis with interstitial eosinophil infiltrates. He had no history of asthma. Computed tomography of the chest and X ray of the paranasal sinuses were normal. On Day 1, the patient developed ileal perforation. Resected ileal segments showed small vessel vasculitis with extravascular eosinophils. A diagnosis of non-asthmatic variant of Churg-Strauss syndrome was made. Renal recovery was achieved in 12 weeks with a combination therapy of corticosteroid and cyclophosphamide. The patient has been relapse-free for 12 months on oral prednisolone therapy. PMID- 24626014 TI - Use of a pelvic kidney for living transplantation. PMID- 24626015 TI - Urinary cytopathologic findings in renal allograft recipients in Sudan: trends, outcome and challenges. PMID- 24626016 TI - Aluminum overload: still as a source of concern in hemodialysis patients. PMID- 24626018 TI - Encapsulating peritoneal sclerosis in a patient with Alport's syndrome on long term peritoneal dialysis. PMID- 24626017 TI - Successful management of recurrent atrio-ventricular nodal re-entrant tachycardia with radiofrequency ablation in a patient on maintenance hemodialysis. PMID- 24626019 TI - Frequency and prognosis of acute kidney injury in burned patients. PMID- 24626020 TI - Renal histopathological study of human immunodeficiency virus - positive patients with clinical evidence of renal disease in Benin City, Nigeria. PMID- 24626021 TI - Pulmonary tuberculosis in patients with chronic renal failure. PMID- 24626022 TI - Impact of demographic and comorbid conditions on quality of life of hemodialysis patients: a cross-sectional study. AB - To assess the quality of life (QOL) of Saudi Arabian patients undergoing hemo dialysis (HD) and to determine the impact of gender, age, education and comorbidities on the QOL of these patients, we conducted a cross-sectional study and used the short form-36 (SF-36) questionnaire, a generic instrument for measuring QOL. This questionnaire is composed of eight scales that summarize the physical component scale (PCS) and mental component scale (MCS) of health status. We calculated the PCS and MCS scores for each patient. We studied 205 HD patients (123 men; ages 18-75 years) from the King Fahd General Hospital, Jeddah, Saudi Arabia. The mean SF-36 score was 59.4 +/- 21.7 in men and 41.9 +/- 20.9 in women (P <0.0001). Patients older than 60 years had the worst score (41.5 +/- 21.2), followed by patients aged 40-59 years (53.6 +/- 22.8); patients aged 18-39 years had the best SF-36 score (57.5 +/- 22.5; P <0.0001). Education had a positive impact on QOL (P <0.0001), whereas comorbid conditions had a negative impact. Peripheral vascular disease was associated with the worst outcome (SF-36 score, 40.4 +/- 23.0; P <0.0001), followed by dyslipidemia (42.9 +/- 22.4; P = 0.001) and diabetes mellitus (45.0 +/- 22.0; P = 0.012). Among the comorbid conditions, hypertension was associated with the best SF-36 score (50.6 +/- 22.7; P = 0.034). We conclude that old age, female gender, poor education and comorbid conditions have a negative impact on the QOL of HD patients in Saudi Arabia. These findings indicate a general need for social support for female patients on HD and early diagnosis and management of comorbid conditions. PMID- 24626023 TI - Assessment of adequacy of hemodialysis dose at a Palestinian hospital. AB - Adequacy of hemodialysis improves patient survival, quality of life and biochemical outcomes and minimizes disease complications and hospitalizations. This study was an observational cross-sectional study that was conducted in July 2012. Blood tests, weight and blood pressure were measured before and after hemodialysis. Single-pool Kt/V and urea reduction ratio (URR) were calculated. The targets based on the National Kidney Foundation Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines were Kt/V >= 1.2 and URR >= 65%. Of the 64 patients, 41 (64.1%) were males. The mean age of the patients was 58.13 +/- 17.2 years. The mean body mass index (BMI) was 25.04 +/- 5.01 kg/m 2 . The mean Kt/V and URR were 1.06 +/- 0.05 and 54.4 +/- 19.3, respectively. There was no significant difference between men and women (1.06 +/- 0.47 versus 1.04 +/- 0.55, P = 0.863) and (54.7 +/- 19.59 versus 53.81 +/- 19.17, P = 0.296). Only 25 (39.1%) patients achieved the Kt/V goal and only 22 (34.4%) had target URR, and there was no significant association between hemodialysis adequacy and any of the variables such as sex, age, presence of chronic diseases or BMI. Serum potassium levels post-dialysis were significantly lower in patients who reached the target Kt/V (mean = 3.44 +/- 0.48 versus 3.88 +/- 0.48, P = 0.001). Most patients were inadequately dialyzed and a large percentage of the patients did not attain the targets. Attempts to achieve the desired goals are necessary. It is important to calculate Kt/V or URR and individualize the dialysis doses for each patient. PMID- 24626024 TI - Clinico-pathological study of glomerular diseases in patients with significant proteinuria in North India. AB - Proteinuria is a common manifestation of renal disease. The present study was carried out to analyze the clinic-pathological correlation, assess the value of histopathology and immunofluorescence (IF) as well as note the spectrum of renal diseases in patients with significant proteinuria. Fifty consecutive patients having proteinuria >1 g/24 h underwent ultrasound-guided percutaneous renal biopsy. Clinical information was correlated with the pathological findings and the results were analyzed. The patients were in the age range of 12-79 years. Males (60%) outnumbered females (40%) in all the disease categories except lupus nephritis and IgA nephropathy. The most common clinical presentation was the nephrotic syndrome, seen in 31 cases (62%). Primary glomerular diseases (72%) were more common than secondary glomerular diseases (24%) and tubulointerstitial diseases (4%). Overall, the most common pathological diagnosis was focal and segmental glomerulosclerosis (FSGS) (20%), followed by membranous glomerulonephritis (MGN) (18%). In young patients (age <20 years), minimal change disease (36.4%) was the most common diagnosis while in adults it was MGN (23.5%) and in elderly patients (age >60 years) it was FSGS (60%). IF modified the diagnosis in 12% of the cases. The concordance between clinical diagnosis and pathological diagnosis was 66%. The difference between clinical diagnosis and final diagnosis was statistically significant. Our study further reinforces the knowledge that renal biopsy helps in accurate diagnosis and, thus, helps in appropriate management of the patients. IF provides additional information that can make the morphologic diagnosis considerably more precise. PMID- 24626025 TI - Acute renal failure in pregnancy: our experience. AB - Acute renal failure (ARF) is a serious medical complication during pregnancy, and, in the post-partum period, is associated with significant maternal morbidity and mortality as well as fetal loss. The objective of our study is to find the etiology and maternal outcome of ARF during pregnancy. The study was conducted at the Obstetrics and Gynecology Department of the Institute of Kidney Disease and Research Center, Ahmedabad, India from January 2009 to January 2011. Fifty previously healthy patients who developed ARF, diagnosed on oliguria and serum creatinine >2 mg%, were included in the study. Patients with a known history of renal disease, diabetes and hypertension were excluded from the study. All patients were followed-up for a period of six months. Patient re-cords, demographic data, urine output on admission and preceding history of antepartum hemorrhage (APH), post-partum hemorrhage (PPH), septicemia, operative interventions and retained product of conception were noted and need for dialysis was considered. Patients were thoroughly examined and baseline biochemical investigations and renal and obstetrical ultrasound were performed on each patient and bacterial culture sensitivity on blood, urine or vaginal swabs were performed in selected patients. The age range was 19-38 years (mean 26 +/- 3.8). The first trimester, second trimester and puerperal groups comprised of four (8%), 25 (50%) and 21 patients (42%), respectively. Hemorrhage was the etiology for ARF in 15 (30%), APH in ten (20%) and PPH in five (10%) patients. Eleven (22%) patients had lower segment cesarian section (LSCS) while 36 (78%) patients had normal vaginal delivery. In 20 (40%) patients, puerperal sepsis was the etiological factor, while pre-eclampsia, eclampsia and HELLP syndrome accounted for 18 (36%) patients. Two (4%) patients had disseminated intravascular coagulation on presentation while one (2%) patient was diagnosed with hemolytic uremic syndrome. Maternal mortality was 12% (n = 6). Of the 38 (88%) surviving patients, 21 (42%) had complete recovery of renal function, eight (16%) patients had partial and 15 (30%) patients required dialysis on a long-term basis. ARF in pregnancy is associated with poor maternal and renal outcome if not detected and treated in time. PMID- 24626026 TI - Iridium interdigital transducers for high-temperature surface acoustic wave applications. AB - Iridium is investigated as a potential metal for interdigital transducers (IDTs) in SAW devices operating at high temperatures. SAW delay lines based on such IDTs and langasite (LGS) substrate are fabricated and electrically characterized. The results show reliable frequency responses up to 1000 degrees C. The strong increase of insertion losses beyond this temperature, leading to the vanishing of the signal between 1140 and 1200 degrees C, is attributed to surface transformation of the LGS crystal, consisting of relevant gallium and oxygen losses, as evidenced by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and secondary ion mass spectroscopy. PMID- 24626027 TI - Scaling issues in ferroelectric barium strontium titanate tunable planar capacitors. AB - We report on the geometric limits associated with tunability of interdigitated capacitors, specifically regarding the impact of a parasitic non-tunable component that necessarily accompanies a ferroelectric surface capacitor, and can dominate the voltage-dependent response as capacitor dimensions are reduced to achieve the small capacitance values required for impedance matching in the X band. We present a case study of simple gap capacitors prepared and characterized as a function of gap width (i.e., the distance between electrodes) and gap length (i.e., the edge-to-edge gap distance). Our series of measurements reveals that for gap widths in the micrometer range, as gap lengths are reduced to meet sub picofarad capacitance values, the non-tunable parasitic elements limit the effective tunability. These experimental measurements are supported by a companion set of microwave models that clarify the existence of parallel parasitic elements. PMID- 24626028 TI - An improved phase-locked loop method for automatic resonance frequency tracing based on static capacitance broadband compensation for a high-power ultrasonic transducer. AB - The phase-locked loop (PLL) method is widely used for automatic resonance frequency tracing (ARFT) of high-power ultrasonic transducers, which are usually vibrating systems with high mechanical quality factor (Qm). However, a heavily loaded transducer usually has a low Qm because the load has a large mechanical loss. In this paper, a series of theoretical analyses is carried out to detail why the traditional PLL method could cause serious frequency tracing problems, including loss of lock, antiresonance frequency tracing, and large tracing errors. The authors propose an improved ARFT method based on static capacitance broadband compensation (SCBC), which is able to address these problems. Experiments using a generator based on the novel method were carried out using crude oil as the transducer load. The results obtained have demonstrated the effectiveness of the novel method, compared with the conventional PLL method, in terms of improved tracing accuracy (+/-9 Hz) and immunity to antiresonance frequency tracing and loss of lock. PMID- 24626029 TI - Improvement of the frequency stability below the Dick limit with a continuous atomic fountain clock. AB - The frequency instability of a shot-noise limited atomic fountain clock is inversely proportional to its signal-tonoise ratio. Therefore, increasing the atomic flux is a direct way to improve the stability. Nevertheless, in pulsed operation, the local oscillator noise limits the performance via the Dick effect. We experimentally demonstrate here that a continuous atomic fountain allows one to overcome this limitation. In this work, we take advantage of two-laser optical pumping on a cold cesium beam to increase the useful fountain flux and, thus, to reduce the frequency instability below the Dick limit. A stability of 6 * 10( 14)tau(-1/2) has been measured with the continuous cesium fountain FOCS-2. PMID- 24626030 TI - Reconstruction algorithm for improved ultrasound image quality. AB - A new algorithm is proposed for reconstructing raw RF data into ultrasound images. Previous delay-and-sum beamforming reconstruction algorithms are essentially one-dimensional, because a sum is performed across all receiving elements. In contrast, the present approach is two-dimensional, potentially allowing any time point from any receiving element to contribute to any pixel location. Computer-intensive matrix inversions are performed once, in advance, to create a reconstruction matrix that can be reused indefinitely for a given probe and imaging geometry. Individual images are generated through a single matrix multiplication with the raw RF data, without any need for separate envelope detection or gridding steps. Raw RF data sets were acquired using a commercially available digital ultrasound engine for three imaging geometries: a 64-element array with a rectangular field-of- view (FOV), the same probe with a sector shaped FOV, and a 128-element array with rectangular FOV. The acquired data were reconstructed using our proposed method and a delay- and-sum beamforming algorithm for comparison purposes. Point spread function (PSF) measurements from metal wires in a water bath showed that the proposed method was able to reduce the size of the PSF and its spatial integral by about 20 to 38%. Images from a commercially available quality-assurance phantom had greater spatial resolution and contrast when reconstructed with the proposed approach. PMID- 24626031 TI - Detailed investigations of polymer/metal multilayer matching layer and backing absorber structures for wideband ultrasonic transducers. AB - Detailed investigations of multilayer front and back matching layers and a novel backing absorber have been conducted, the detailed theory for which was presented in a previous paper. To design useful structures using the simple proposed equations, the material parameters of the constituent layers must be identified. Therefore, polyimide (for the matching layer) and adhesive-backed copper tape (for the absorber) were characterized by bonding them to polyvinylidene fluoride trifluoroethylene P(VDF-TrFE) copolymer ultrasonic transducers and then applying a parameter-fitting algorithm to the resulting impedance data. A double matching layer was designed using an 11-MUm PVDF (inner) and 23-MUm copper (outer) multilayer construction in the first matching section followed by a 75-MUm polyimide layer as a typical quarter-wavelength material in the second (outermost) matching section. This structure was bonded to 330-MUm PZT with air backing and the reflection waveform from a short pulse was captured. The FFT frequency response showed a 3.1-MHz bandwidth centered at 6.4 MHz, which agreed with the Mason's model analysis. The use of multiple layers of copper tape as a backing absorber was also investigated. At 3 MHz, the measured impedance was 4 MRayl, attenuation was 220 dB/cm, and velocity was 890 m/s, which agreed with the design theory. The 4-MRayl copper-tape structure was bonded to a back matching structure made from one layer of polyimide and one layer of brass (multilayer matching), and the effectiveness of the backing absorber made of 10 layers of copper tape on a 3-MHz transducer was confirmed. PMID- 24626032 TI - Multi-channel pre-beamformed data acquisition system for research on advanced ultrasound imaging methods. AB - The lack of open access to the pre-beamformed data of an ultrasound scanner has limited the research of novel imaging methods to a few privileged laboratories. To address this need, we have developed a pre-beamformed data acquisition (DAQ) system that can collect data over 128 array elements in parallel from the Ultrasonix series of research-purpose ultrasound scanners. Our DAQ system comprises three system-level blocks: 1) a connector board that interfaces with the array probe and the scanner through a probe connector port; 2) a main board that triggers DAQ and controls data transfer to a computer; and 3) four receiver boards that are each responsible for acquiring 32 channels of digitized raw data and storing them to the on-board memory. This system can acquire pre-beamformed data with 12-bit resolution when using a 40-MHz sampling rate. It houses a 16 GB RAM buffer that is sufficient to store 128 channels of pre-beamformed data for 8000 to 25 000 transmit firings, depending on imaging depth; corresponding to nearly a 2-s period in typical imaging setups. Following the acquisition, the data can be transferred through a USB 2.0 link to a computer for offline processing and analysis. To evaluate the feasibility of using the DAQ system for advanced imaging research, two proof-of-concept investigations have been conducted on beamforming and plane-wave B-flow imaging. Results show that adaptive beamforming algorithms such as the minimum variance approach can generate sharper images of a wire cross-section whose diameter is equal to the imaging wavelength (150 MUm in our example). Also, planewave B-flow imaging can provide more consistent visualization of blood speckle movement given the higher temporal resolution of this imaging approach (2500 fps in our example). PMID- 24626033 TI - Sound-speed image reconstruction in sparse-aperture 3-D ultrasound transmission tomography. AB - The paper is focused on sound-speed image reconstruction in 3-D ultrasound transmission tomography. Along with ultrasound reflectivity and the attenuation coefficient, sound speed is an important parameter which is related to the type and pathological state of the imaged tissue. This is important in the intended application, breast cancer diagnosis. In contrast to 2-D ultrasound transmission tomography systems, a 3-D system can provide an isotropic spatial resolution in the x-, y-, and z-directions in reconstructed 3-D images of ultrasound parameters. Several challenges must, however, be addressed for 3-D systems namely, a sparse transducer distribution, low signal-to-noise ratio, and higher computational complexity. These issues are addressed in terms of sound-speed image reconstruction, using edge-preserving regularized algebraic reconstruction in combination with synthetic aperture focusing. The critical points of the implementation are also discussed, because they are crucial to enable a complete 3-D image reconstruction. The methods were tested on a synthetic data set and on data sets measured with the Karlsruhe 3-D ultrasound computer tomography (USCT) I prototype using phantoms. The sound-speed estimates in the reconstructed volumes agreed with the reference values. The breast-phantom outlines and the lesion mimicking objects were also detectable in the resulting sound-speed volumes. PMID- 24626034 TI - Surface acoustic wave response to optical absorption by graphene composite film. AB - Propagation of surface acoustic waves in YZ LiNbO3 overlaid with graphene flakes has been investigated and its optical response to illumination by 633-nm light from a He-Ne laser was studied. The heating of the sample surface caused by optical absorption by the graphene led to a downshift in the transmitted SAW phase caused by the wave velocity's dependence on temperature. The proposed simple model based on optothermal SAW phase modulation was found to be in good agreement with the experimental results. PMID- 24626035 TI - A blind deconvolution approach to ultrasound imaging. AB - In this paper, a single-input multiple-output (SIMO) channel model is introduced for the deconvolution process of ultrasound imaging; the ultrasound pulse is the single system input and tissue reflectivity functions are the channel impulse responses. A sparse regularized blind deconvolution model is developed by projecting the tissue reflectivity functions onto the null space of a cross relation matrix and projecting the ultrasound pulse onto a low-resolution space. In this way, the computational load is greatly reduced and the estimation accuracy can be improved because the proposed deconvolution model contains fewer variables. Subsequently, an alternating direction method of multipliers (ADMM) algorithm is introduced to efficiently solve the proposed blind deconvolution problem. Finally, the performance of the proposed blind deconvolution method is examined using both computer-simulated data and practical in vitro and in vivo data. The results show a great improvement in the quality of ultrasound images in terms of signal-to-noise ratio and spatial resolution gain. PMID- 24626036 TI - Effects of mismatched electrodes on an AT-cut quartz resonator. AB - We study thickness-shear and thickness-twist free vibrations of a finite AT-cut quartz resonator with mismatched electrodes. The equations of anisotropic elasticity are used with the omission of the small elastic constant c56. An analytical solution is obtained using Fourier series from which the resonant frequencies, mode shapes, and vibration confinement resulting from the electrode inertia are calculated and examined. PMID- 24626037 TI - Determination and experimental verification of high-temperature SAW orientations on langatate. AB - Langatate (LGT) is a member of the langasite family of crystals appropriate for high-temperature frequency control and sensing applications. This paper identifies multiple LGT SAW orientations for use at high temperature, specifically in the 400 degrees C to 900 degrees C range. Orientations with low sensitivity to temperature are desired for frequency control devices and many sensors, conversely large temperature sensitivity is a benefit for temperature sensors. The LGT SAW temperature behavior has been calculated for orientations sweeping the Euler angles (0 degrees , Theta, psi), (90 degrees , Theta, psi), and (psi, 90 degrees , psi), based on newly identified high-temperature elastic constants and temperature coefficients for this material. The temperature coefficient of delay (TCD) and total frequency change over the temperature range were analyzed from 400 degrees C to 900 degrees C. Multiple SAW orientations were identified with zero-TCD between 400 degrees C and 500 degrees C. Although no orientations that have turn-over temperatures above 500 degrees C were identified, several have low frequency variation with temperature, of the order of -0.8% over the range 400 degrees C to 800 degrees C. Temperature-sensitive orientations with TCD up to 75 ppm/ degrees C at 900 degrees C were identified, with potential for high-temperature sensor applications. The reported predictions are shown to agree with measured behavior of LGT SAW delay lines fabricated along 6 orientations in the (90 degrees , 23 degrees , psi) plane. In addition, this work demonstrates that concurrently operated LGT SAW devices fabricated on the same wafer provide means of temperature sensing. In particular, the measured frequency difference between delay lines oriented along (90 degrees , 23 degrees , 0 degrees ) and (90 degrees , 23 degrees , 48 degrees ) has fractional temperature sensitivity that ranges from -172 ppm/ degrees C at 25 degrees C to 205 ppm/ degrees C at 900 degrees C. PMID- 24626038 TI - Langasite surface acoustic wave sensors: fabrication and testing. AB - We report on the development of harsh-environment surface acoustic wave sensors for wired and wireless operation. Surface acoustic wave devices with an interdigitated transducer emitter and multiple reflectors were fabricated on langasite substrates. Both wired and wireless temperature sensing was demonstrated using radar-mode (pulse) detection. Temperature resolution of better than +/-0.5 degrees C was achieved between 200 degrees C and 600 degrees C. Oxygen sensing was achieved by depositing a layer of ZnO on the propagation path. Although the ZnO layer caused additional attenuation of the surface wave, oxygen sensing was accomplished at temperatures up to 700 degrees C. The results indicate that langasite SAW devices are a potential solution for harsh environment gas and temperature sensing. PMID- 24626039 TI - Estimating elastogram series of different resolutions using a multiresolution strain computation method. AB - The techniques used to estimate axial elastogram usually present a trade-off between elastogram resolution and noise level. It is advantageous to format a series of elastograms of various resolutions because each can provide different information about tissue stiffness. This goal is traditionally achieved by generating displacement fields using various window lengths, which increases computation load significantly. In this study, we achieve the same goal by using a multiresolution strain computation method based on Savitzky-Golay digital differentiators of different lengths, which requires calculating the displacement field only once. Simulation and experimental results show that the elastograms estimated by the proposed method are comparable to those estimated by traditional methods in terms of resolution, elastographic signal-to-noise ratio, and elastographic contrast-to-noise ratio, but the proposed method requires significantly less computational time. PMID- 24626040 TI - Temperature coefficients of elastic constants of trigonal, hexagonal, and tetragonal crystals. AB - Temperature coefficients of elastic constants (TC(IJ)) for trigonal, hexagonal, and tetragonal crystals have been obtained. The TC(IJ) of several trigonal, hexagonal, and tetragonal crystals have been calculated and compared with known experimental data. The nature of the anomalous TC66 of quartz has been discussed in detail. PMID- 24626041 TI - High-frequency (>50 MHz) medical ultrasound linear arrays fabricated from micromachined bulk PZT materials. AB - This paper describes the development and characterization of a high-frequency (65 MHz) ultrasound transducer linear array. The array was built from bulk PZT which was etched using an optimized chlorine-based plasma dry-etching process. The median etch rate of 8 u m/h yielded a good profile (wall) angle (>83 degrees ) and a reasonable processing time for etch depths up to 40 MUm (which corresponds to a 50-MHz transducer). A backing layer with an acoustic impedance of 6 MRayl and a front-end polymer matching layer yielded a transducer bandwidth of 40%. The major parameters of the transducer have been characterized. The two-way insertion loss and crosstalk between adjacent channels at the center frequency are 26.5 and -25 dB, respectively. PMID- 24626042 TI - Air-coupled ultrasonic resonant spectroscopy for the study of the relationship between plant leaves' elasticity and their water content. AB - Air-coupled wideband ultrasonic piezoelectric transducers are used in the frequency range 0.3 to 1.3 MHz to excite and sense first-order thickness resonances in the leaves of four different tree species at different levels of hydration. The phase and magnitude spectra of these resonances are measured, and the inverse problem solved; that is, leaf thickness and density, ultrasound velocity, and the attenuation coefficient are obtained. The elastic constant in the thickness direction (c33) is then determined from density and velocity data. The paper focuses on the study of c33, which provides a unique, fast, and noninvasive ultrasonic method to determine leaf elasticity and leaf water content. PMID- 24626043 TI - Transcriptional regulation of arterial differentiation via Wnt, Sox and Notch. AB - PURPOSE OF REVIEW: The development of a functionally and anatomically correct vascular network is a complex phenomenon that requires the combined activity of different signaling pathways and transcription factors. Notch signaling activation, for instance, is crucial for arterial specification. Here, we discuss the current knowledge on how other signaling pathways cooperate with Notch to orchestrate arterial differentiation of embryonic and postnatal vasculature. RECENT FINDINGS: The role of Notch in vascular development and arterial differentiation is well known. However, it was found that canonical Wnt signaling may act upstream of Notch, upregulating Dll4 and inducing endothelial cells to acquire arterial characteristics. Furthermore, the transcription factor Sox17 may act as a link between Wnt and Notch in the induction of a correct arterio/venous differentiation. SUMMARY: In the past years, the research on vascular development was mostly focused on the mechanisms that regulate vessel growth. We now understand that in order to interfere with several vascular diseases (e.g. aneurysm, cerebral ischemia and stroke) or tumor vascularization, we need to understand the signals that direct arterio/venous specification. Here, we discuss the interplay between Notch, Wnt and Sox that exert a combined positive action on arterial differentiation. PMID- 24626044 TI - Abnormal red cell features associated with hereditary neurodegenerative disorders: the neuroacanthocytosis syndromes. AB - PURPOSE OF REVIEW: This review discusses the mechanisms involved in the generation of thorny red blood cells (RBCs), known as acanthocytes, in patients with neuroacanthocytosis, a heterogenous group of neurodegenerative hereditary disorders that include chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). RECENT FINDINGS: Although molecular defects associated with neuroacanthocytosis have been identified recently, their pathophysiology and the related RBC abnormalities are largely unknown. Studies in ChAc RBCs have shown an altered association between the cytoskeleton and the integral membrane protein compartment in the absence of major changes in RBC membrane composition. In ChAc RBCs, abnormal Lyn kinase activation in a Syk-independent fashion has been reported recently, resulting in increased band 3 tyrosine phosphorylation and perturbation of the stability of the multiprotein band 3-based complexes bridging the membrane to the spectrin-based membrane skeleton. Similarly, in MLS, the absence of XK-protein, which is associated with the spectrin-actin-4.1 junctional complex, is associated with an abnormal membrane protein phosphorylation state, with destabilization of the membrane skeletal network resulting in generation of acanthocytes. SUMMARY: A novel mechanism in generation of acanthocytes involving abnormal Lyn activation, identified in ChAc, expands the acanthocytosis phenomenon toward protein-protein interactions, controlled by phosphorylation related abnormal signaling. PMID- 24626045 TI - Integrin function in vascular biology: a view from 2013. AB - PURPOSE OF REVIEW: This review considers recent developments concerning the role of integrins in vascular biology with a specific emphasis on integrin activation, and the crosstalk between integrins and growth factor receptors. RECENT FINDINGS: Recent studies have shown leukocytes can mediate direct transfer of molecules into endothelial cells, how specific integrins can be used to transduce signaling events, in particular in vascular beds, and how endothelial cell integrins can be targeted with specific ligands for the delivery of therapeutics. Kindlin and talin are both essential for integrin activation based on in-vivo studies of mice and humans in which the genes encoding for these proteins have been inactivated. Recent studies have attempted to translate these in-vivo realities into in-vitro models with mixed results. SUMMARY: Mechanisms and consequences of integrin ligand interactions on blood and vascular cells remain a major topic of hematological research. Crucial to the ligand binding function of integrins are two intracellular binding partners, talin and kindlin. In seeking to define the molecular basis for 'integrin activation', a mechanism must be envisioned in which both proteins talin and kindlin are required to produce a productive functional response, be it platelet aggregation or leukocyte extravasation. On endothelial cells, integrins and vascular endothelial growth factor receptor 2 influence the activation of one another by virtue of their direct physical interaction. It has been shown that this bidirectional communication is subject to regulation during angiogenesis. PMID- 24626046 TI - Fever burden is an independent predictor for prognosis of traumatic brain injury. AB - OBJECTIVE: To evaluate fever burden as an independent predictor for prognosis of traumatic brain injury (TBI). METHODS: This retrospective study involved 355 TBI patients with Glasgow Coma Scale (GCS) <=14, who presented at the emergency department of our hospital between November 2010 and October 2012. At 6 months follow-up, patients were divided into 5 groups based on Glasgow Outcome Scale (GOS) and dichotomized to GOS score (high (4 to 5) vs. low (1 to 3)). The relationship between fever burden and GOS was assessed. RESULTS: Fever burden increased as GOS scores decreased from 5 to 2, except for score 1 of GOS, which corresponded to a significant lower fever burden. Following dichotomization, patients in the high GOS group were younger, and showed less abnormal pupil reactivity (P<0.001), a higher median GCS score (P<0.001), and a lower median fever burden (P<0.001), compared with patients in the low GOS group. Univariate logistic regression analysis revealed that poor TBI prognosis was related to age, GCS, pupil reactivity, and fever burden (OR: 1.166 [95% CI: 1.117-1.217] P<0.0001). Multivariate logistic regression analysis identified fever burden as an independent predictor of poor prognosis after TBI (OR 1.098; 95% CI: 1.031 1.169; P = 0.003). These observations were confirmed by evaluation of the receiver operating characteristic (ROC) curve for fever burden (area under the curve [AUC] 0.73 [95% CI: 0.663-0.760]). CONCLUSION: Fever burden might be an independent predictor for prognosis of TBI. High fever burden in the early stage of the disease course associated with TBI could increase the risk of poor prognosis. PMID- 24626047 TI - Persistent stapedial artery. PMID- 24626048 TI - Critical analysis of robotic surgery for laryngeal tumours. AB - In recent years, transoral robotic surgery (TORS) with the Da Vinci robot has been used for the removal of laryngeal cancers with the objective to improve functional and aesthetic outcomes without worsening survival. The advantages of TORS are described in this article. However, its disadvantages, mainly high cost amongst others, do not make robotic surgery the current treatment of choice for laryngeal tumours; transoral laser surgery is superior in most cases. Major technical improvements are expected. Smaller, more ergonomic, new-generation robots better adapted to the head and neck will probably be available in the near future. PMID- 24626049 TI - Direct solution of the Chemical Master Equation using quantized tensor trains. AB - The Chemical Master Equation (CME) is a cornerstone of stochastic analysis and simulation of models of biochemical reaction networks. Yet direct solutions of the CME have remained elusive. Although several approaches overcome the infinite dimensional nature of the CME through projections or other means, a common feature of proposed approaches is their susceptibility to the curse of dimensionality, i.e. the exponential growth in memory and computational requirements in the number of problem dimensions. We present a novel approach that has the potential to "lift" this curse of dimensionality. The approach is based on the use of the recently proposed Quantized Tensor Train (QTT) formatted numerical linear algebra for the low parametric, numerical representation of tensors. The QTT decomposition admits both, algorithms for basic tensor arithmetics with complexity scaling linearly in the dimension (number of species) and sub-linearly in the mode size (maximum copy number), and a numerical tensor rounding procedure which is stable and quasi-optimal. We show how the CME can be represented in QTT format, then use the exponentially-converging hp-discontinuous Galerkin discretization in time to reduce the CME evolution problem to a set of QTT-structured linear equations to be solved at each time step using an algorithm based on Density Matrix Renormalization Group (DMRG) methods from quantum chemistry. Our method automatically adapts the "basis" of the solution at every time step guaranteeing that it is large enough to capture the dynamics of interest but no larger than necessary, as this would increase the computational complexity. Our approach is demonstrated by applying it to three different examples from systems biology: independent birth-death process, an example of enzymatic futile cycle, and a stochastic switch model. The numerical results on these examples demonstrate that the proposed QTT method achieves dramatic speedups and several orders of magnitude storage savings over direct approaches. PMID- 24626050 TI - Determinants beyond both complementarity and cleavage govern microR159 efficacy in Arabidopsis. AB - Plant microRNAs (miRNAs) are critical regulators of gene expression, however little attention has been given to the principles governing miRNA silencing efficacy. Here, we utilize the highly conserved Arabidopsis miR159-MYB33/MYB65 regulatory module to explore these principles. Firstly, we show that perfect central complementarity is not required for strong silencing. Artificial miR159 variants with two cleavage site mismatches can potently silence MYB33/MYB65, fully complementing a loss-of-function mir159 mutant. Moreover, these miR159 variants can cleave MYB33/MYB65 mRNA, however cleavage appears attenuated, as the ratio of cleavage products to full length transcripts decreases with increasing central mismatches. Nevertheless, high levels of un-cleaved MYB33/MYB65 transcripts are strongly silenced by a non-cleavage mechanism. Contrary to MIR159a variants that strongly silenced endogenous MYB33/MYB65, artificial MYB33 variants with central mismatches to miR159 are not efficiently silenced. We demonstrate that differences in the miRNA:target mRNA stoichiometry underlie this paradox. Increasing miR159 abundance in the MYB33 variants results in a strong silencing outcome, whereas increasing MYB33 transcript levels in the MIR159a variants results in a poor silencing outcome. Finally, we identify highly conserved nucleotides that flank the miR159 binding site in MYB33, and demonstrate that they are critical for efficient silencing, as mutation of these flanking nucleotides attenuates silencing at a level similar to that of central mismatches. This implies that the context in which the miRNA binding site resides is a key determinant in controlling the degree of silencing and that a miRNA "target site" encompasses sequences that extend beyond the miRNA binding site. In conclusion, our findings dismiss the notion that miRNA:target complementarity, underpinned by central matches, is the sole dictator of the silencing outcome. PMID- 24626051 TI - Comments on the paper "synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3',5' monophosphate accumulation and adenosine 3'5' triphosphate release from human erythrocytes". PMID- 24626052 TI - Reply by the authors to the comments of Mortimer Lorber, MD. PMID- 24626053 TI - Etiologies and resistance profiles of bacterial community-acquired pneumonia in Cambodian and neighboring countries' health care settings: a systematic review (1995 to 2012). AB - OBJECTIVES: Community-acquired pneumonia (CAP) is one of the most important causes of morbidity and mortality worldwide. Etiological data for Cambodia is scarce. We aimed to describe the main etiological agents causing CAP, and their resistance patterns in Cambodia and the greater Mekong region. METHODS: A review of bacterial etiologies of CAP and antimicrobial resistance in Cambodia and neighboring countries was conducted via: (1) a systematic review of published literature in all NCBI databases using Pubmed, Google scholar, EMBASE, the World Health Organization and the Cambodian Ministry of Health libraries; (2) a review of unpublished data from Cambodia provided by national and international stakeholders working at different tiers of the healthcare system. RESULTS: Twenty three articles and five data sources reported etiologies for 5919 CAP patients diagnosed between May 1995 and December 2012, including 1421 (24.0%), 3571 (60.3%) and 927 (15.7%) from Cambodia, Thailand and Vietnam, respectively. Streptococcus pneumoniae and Haemophilus influenzae were the most common pathogens ranking among the five most prevalent in 12 and 10 studies, respectively. Gram-negative bacteria such as Burkholderia pseudomallei and Klebsiella pneumoniae were also frequently diagnosed, particularly in bacteremic CAP in Thai adults and Cambodian children. In Thailand and Vietnam, Mycoplasma pneumoniae and Chlamydia pneumoniae were frequently identified in settings using indirect laboratory testing. CONCLUSIONS: Based on this analysis, CAP data in Cambodia seems to present etiological and resistance profiles comparable to those of neighboring countries. Findings have been shared with the national authorities upon the revision of the national therapeutic guidelines and were disseminated using a specially created website. PMID- 24626054 TI - A novel algicide: evidence of the effect of a fatty acid compound from the marine bacterium, Vibrio sp. BS02 on the harmful dinoflagellate, Alexandrium tamarense. AB - Alexandrium tamarense is a notorious bloom-forming dinoflagellate, which adversely impacts water quality and human health. In this study we present a new algicide against A. tamarense, which was isolated from the marine bacterium Vibrio sp. BS02. MALDI-TOF-MS, NMR and algicidal activity analysis reveal that this compound corresponds to palmitoleic acid, which shows algicidal activity against A. tamarense with an EC50 of 40 MUg/mL. The effects of palmitoleic acid on the growth of other algal species were also studied. The results indicate that palmitoleic acid has potential for selective control of the Harmful algal blooms (HABs). Over extended periods of contact, transmission electron microscopy shows severe ultrastructural damage to the algae at 40 MUg/mL concentrations of palmitoleic acid. All of these results indicate potential for controlling HABs by using the special algicidal bacterium and its active agent. PMID- 24626055 TI - 18F-FDG and 18F-FLT-PET imaging for monitoring everolimus effect on tumor-growth in neuroendocrine tumors: studies in human tumor xenografts in mice. AB - INTRODUCTION: The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging. METHODS: The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with 18F-FDG or 18F-FLT and then treated with either placebo or everolimus (5 mg/kg daily) for 10 days. PET/CT scans were repeated at day 1,3 and 10. RESULTS: Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126+/-6% vs. 152+/-6%; p = 0.016), day 7 (164+/-7% vs. 226+/-13%; p<0.001) and at day 10 (194+/-10% vs. 281+/-18%; p<0.001). Uptake of 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034), 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019) and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001) and day 10 (r2 = 0.58; P = 0.027). CONCLUSION: Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders. PMID- 24626056 TI - Single-center retrospective study of the incidence of, and risk factors for, non C. albicans invasive candidiasis in hospitalized patients in China. AB - The aims of this study were to establish the incidence of invasive candidiasis (IC) in a Beijing hospital, to identify risk factors associated with IC caused by non-C. albicans Candida (NAC), and to determine risk factors for infection caused by NAC species not susceptible to fluconazole. Clinical data from 141 patients admitted to Beijing Chaoyang Hospital (from 2001-2010) diagnosed with IC were retrospectively analyzed. The incidence of IC increased during the 10-year period, but the proportion due to NAC did not change significantly in that of 141 cases, 55 (39%) were due to NAC and 86 (61%) to C. albicans (CA). The NAC species isolated included C. tropicalis (25 of 141, 18%), C. glabrata (14 of 141, 9.9%), C. parapsilosis (eight of 141, 5.7%), C. krusei (three of 141, 2.1%) and C. lusitaniae (one of 141, 0.71%); other Candida species accounted for four of the 141 cases (2.8%). Twenty-one isolates (38%) of NAC were not susceptible to fluconazole. Total parenteral nutrition (TPN) (OR 4.2; 95% CI 3.5-58; P < 0.001) and previous fluconazole therapy (OR 7.7; 95% CI 2.2-27; P = 0.001) were risk factors for invasive NAC candidiasis, whereas patient age >=65 years (OR 0.37; CI 0.16-0.88; P = 0.025) and invasive mechanical ventilation (OR 0.22; CI 0.069 0.70; P =0.010) were connected with invasive CA candidiasis. Prior fluconazole therapy was a risk factor (P = 0.007) for infections caused by NAC not susceptible to fluconazole. In conclusion, TPN and prior fluconazole therapy are independent risk factors for NAC infection, while prior fluconazole therapy is a risk factor for infection due to NAC not susceptible to fluconazole. PMID- 24626058 TI - Epidemiology of undiagnosed trichomoniasis in a probability sample of urban young adults. AB - T. vaginalis infection (trichomoniasis) is the most common curable sexually transmitted infection (STI) in the U.S. It is associated with increased HIV risk and adverse pregnancy outcomes. Trichomoniasis surveillance data do not exist for either national or local populations. The Monitoring STIs Survey Program (MSSP) collected survey data and specimens which were tested using nucleic acid amplification tests to monitor trichomoniasis and other STIs in 2006-09 among a probability sample of young adults (N = 2,936) in Baltimore, Maryland--an urban area with high rates of reported STIs. The estimated prevalence of trichomoniasis was 7.5% (95% CI 6.3, 9.1) in the overall population and 16.1% (95% CI 13.0, 19.8) among Black women. The overwhelming majority of infected men (98.5%) and women (73.3%) were asymptomatic. Infections were more common in both women (OR = 3.6, 95% CI 1.6, 8.2) and men (OR = 9.0, 95% CI 1.8, 44.3) with concurrent chlamydial infection. Trichomoniasis did not vary significantly by age for either men or women. Women with two or more partners in the past year and women with a history of personal or partner incarceration were more likely to have an infection. Overall, these results suggest that routine T vaginalis screening in populations at elevated risk of infection should be considered. PMID- 24626059 TI - 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier integrity through a mechanism involving P2X7 receptors. AB - The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1beta levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug. Adult male Dark Agouti rats were treated with MDMA (10 mg/kg, i.p.) and killed at several time-points in order to evaluate MMP-9 and MMP-3 activity in the hippocampus and laminin and collagen-IV expression and IgG extravasation in the dentate gyrus. Microglial activation, P2X7R expression and localization were also determined in the dentate gyrus. Separate groups were treated with MDMA and the P2X7R antagonists Brilliant Blue G (BBG; 50 mg/kg, i.p.) or A-438079 (30 mg/kg, i.p.). MDMA increased MMP-3 and MMP-9 activity, reduced laminin and collagen-IV expression and increased IgG immunoreactivity. In addition, MDMA increased microglial activation and P2X7R immunoreactivity in these cells. BBG suppressed the increase in MMP-9 and MMP-3 activity, prevented basal lamina degradation and IgG extravasation into the brain parenchyma. A-438079 also prevented the MDMA induced reduction in laminin and collagen-IV immunoreactivity. These results indicate that MDMA alters BBB permeability through an early P2X7R-mediated event, which in turn leads to enhancement of MMP-9 and MMP-3 activity and degradation of extracellular matrix. PMID- 24626060 TI - Chronic allograft nephropathy or interstitial fibrosis and tubular atrophy: what is in a name? AB - PURPOSE OF REVIEW: Chronic allograft nephropathy has fallen into disfavor as a morphologic term to describe parenchymal scarring in the renal allograft, with a recommendation that this be replaced by the more descriptive term 'interstitial fibrosis and tubular atrophy'. However, neither term addresses the underlying cause of the scarring. This review focuses on whether all interstitial fibrosis and tubular atrophy in the renal allograft has the same implications for long term graft survival, and whether there are specific features of interstitial fibrosis and tubular atrophy that can be used to identify its underlying cause. RECENT FINDINGS: Results from a number of studies indicate that interstitial fibrosis and tubular atrophy, when associated with interstitial inflammation, is a strong predictor of graft loss, much more so than interstitial fibrosis and tubular atrophy alone. Most notably, findings from the multicenter Long-Term Deterioration of Kidney Allograft Function study, designed to identify the causes of late allograft dysfunction, showed interstitial inflammation in the areas of interstitial fibrosis and tubular atrophy (i-IF/TA) was predictive of reduced time to graft failure, even after adjustment for serum creatinine. In addition, the presence of i-IF/TA correlates with increased acute kidney injury gene transcripts. However, neither interstitial fibrosis and tubular atrophy nor i IF/TA is associated with any specific cause of chronic graft injury. SUMMARY: Although (i-IF/TA), especially when widespread, is clearly associated with reduced renal allograft survival and molecular markers of active graft injury and repair, there is presently no reliable way, using either morphology alone, immunohistochemistry, or molecular techniques, to differentiate i-IF/TA (or interstitial fibrosis and tubular atrophy alone) resulting from different causes. PMID- 24626061 TI - Pregnancy outcomes decline in recipients over age 44: an analysis of 27,959 fresh donor oocyte in vitro fertilization cycles from the Society for Assisted Reproductive Technology. AB - OBJECTIVE: To use a large and recent national registry to provide an updated report on the effect of recipient age on the outcome of donor oocyte in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort study. SETTING: United States national registry for assisted reproductive technology. PATIENT(S): Recipients of donor oocyte treatment cycles between 2008 and 2010, with cycles segregated into five age cohorts: <=34, 35 to 39, 40 to 44, 45 to 49, and >=50 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, live-birth, and miscarriage rates. RESULT(S): In donor oocyte IVF cycles, all age cohorts <=39 years had similar rates of implantation, clinical pregnancy, and live birth when compared with the 40- to 44-year-old reference group. Patients in the two oldest age groups (45 to 49, >=50 years) experienced statistically significantly lower rates of implantation, clinical pregnancy, and live birth compared with the reference group. Additionally, all outcomes in the >=50-year-old group were statistically significantly worse than the 45- to 49 year-old group, demonstrating progressive decline with advancing age. CONCLUSION(S): Recent national registry data suggest that donor oocyte recipients have stable rates of pregnancy outcomes before age 45, after which there is a small but steady and significant decline. PMID- 24626062 TI - 14-3-3 eta depletion sensitizes glioblastoma cells to irradiation due to enhanced mitotic cell death. AB - 14-3-3 proteins have important roles in several cellular processes such as cell cycle progression, the DNA-damage checkpoint and apoptosis. We have shown previously that depleting 14-3-3eta, a 14-3-3 isoform, enhances mitotic cell death, and that combining it with microtubule agents is more effective for anticancer therapeutics. In this study, we investigated whether depleting 14-3 3eta can be combined with radiotherapy to enhance its therapeutic efficacy. We found that depleting 14-3-3eta resulted in a synergistic radiosensitizing effect when combined with radiotherapy in several glioblastoma cell lines, where its specific expression and correlation of its expression level with malignancy have been reported. The radiosensitizing effect was associated with enhanced mitotic cell death by 14-3-3eta depletion but not with mitotic catastrophe, which is one of the major cell death mechanisms observed in response to irradiation of most solid tumors. These results suggest that 14-3-3eta may be a therapeutic target to overcome radioresistance in glioblastoma. PMID- 24626063 TI - A qualitative analysis of barriers to accessing HIV/AIDS-related services among newly diagnosed HIV-positive men who have sex with men in China. AB - In China, specific HIV/AIDS-related services have been in place since 2004. However, utilisation of these services remains limited among people living with HIV. We explored barriers to accessing HIV/AIDS-related services from the perspective of newly diagnosed HIV-positive men who have sex with men. We conducted repeated in-depth interviews with 31 newly diagnosed HIV-positive men who have sex with men, using the socio-ecological framework and thematic content analysis. Multiple barriers for utilisation of HIV/AIDS-related services were identified, including perceptions of subjective health and poor quality of services, mental and emotional health problems, lack of trust and understanding of the services on offer, low economic status, lack of insurance, and high medical fees, being refused access to services, and restrictive attendance policies. The findings provide information on potential multi-level obstacles preventing newly diagnosed HIV-positive men who have sex with men to use services that they need. It is recommended that policy makers should create a trustful and non-discriminating environment and services integrating physical and mental healthcare. PMID- 24626064 TI - Proteolytic enzymes in embryonated chicken eggs sustain the replication of egg grown low-pathogenicity avian influenza viruses in cells in the absence of exogenous proteases. AB - Low pathogenic influenza viruses grow readily in embryonated chicken eggs but require the addition of exogenous proteases to grow in MDCK cell culture. In this study, we found that the influenza viruses propagated previously in eggs, can grow for up to two passages in cell culture without the addition of exogenous proteolytic enzymes. These results indicate that the reason for virus propagation in cells during the first two passages may be due to proteases from egg allantoic fluid carried over from egg culture. The ability of influenza viruses to grow in cells in the absence of trypsin is currently considered as a hallmark of highly pathogenic influenza viruses. Our data indicate that differentiating between high and low pathogenicity using cell culture only is not appropriate and other indicators such as sequence analysis and in vitro pathogenicity index should be performed. PMID- 24626065 TI - Cognitive complexity of the medical record is a risk factor for major adverse events. AB - CONTEXT: Patients in tertiary care hospitals are more complex than in the past, but the implications of this are poorly understood as "patient complexity" has been difficult to quantify. OBJECTIVE: We developed a tool, the Complexity Ruler, to quantify the amount of data (as bits) in the patient's medical record. We designated the amount of data in the medical record as the cognitive complexity of the medical record (CCMR). We hypothesized that CCMR is a useful surrogate for true patient complexity and that higher CCMR correlates with risk of major adverse events. DESIGN: The Complexity Ruler was validated by comparing the measured CCMR with physician rankings of patient complexity on specific inpatient services. It was tested in a case-control model of all patients with major adverse events at a tertiary care pediatric hospital from 2005 to 2006. MAIN OUTCOME MEASURES: The main outcome measure was an externally reported major adverse event. We measured CCMR for 24 hours before the event, and we estimated lifetime CCMR. RESULTS: Above empirically derived cutoffs, 24-hour and lifetime CCMR were risk factors for major adverse events (odds ratios, 5.3 and 6.5, respectively). In a multivariate analysis, CCMR alone was essentially as predictive of risk as a model that started with 30-plus clinical factors. CONCLUSIONS: CCMR correlates with physician assessment of complexity and risk of adverse events. We hypothesize that increased CCMR increases the risk of physician cognitive overload. An automated version of the Complexity Ruler could allow identification of at-risk patients in real time. PMID- 24626066 TI - Immunomodulatory agents and risk of postpartum multiple sclerosis relapses. AB - OBJECTIVE: To determine whether treatment with an interferon beta or glatiramer acetate shortly after delivery reduces the otherwise increased risk of postpartum relapses of multiple sclerosis. METHODS: In a retrospective cohort of 112 women with multiple sclerosis and live births from Kaiser Permanente Southern California, complete medical and pharmacy records of the mothers and infants were reviewed. Propensity score-adjusted hazard ratios (HR) of time to first postpartum relapse were calculated. RESULTS: Of 80 women who breastfed little or not at all, 55 (69%) resumed treatment within 1 year postpartum, of whom 26 (47%) relapsed within 6 months postpartum. Resuming treatment within 2 weeks postpartum did not decrease the risk of relapse in the 2 years postpartum compared with women who resumed treatment later in the postpartum year (propensity score adjusted HR = 1.3, 95% confidence interval = 0.5-3.4, p = 0.6). There was no difference in relapse rates between the groups in the first 6 months postpartum. However, later in the postpartum year those who resumed treatment early had fewer relapses (p = 0.08, Poisson regression). CONCLUSIONS: Among women who breastfeed little or not at all, starting treatment with interferon beta or glatiramer acetate within two weeks postpartum does not reduce the risk of postpartum relapse of multiple sclerosis but may reduce the risk of subsequent relapses in the postpartum year. PMID- 24626067 TI - Accuracy of national surgery quality improvement program models in predicting postoperative morbidity in patients undergoing colectomy. AB - BACKGROUND: The National Surgery Quality Improvement Program (NSQIP) is the standard for assessment of acuity-adjusted outcomes in surgery. The validity of NSQIP has not been well established in colorectal surgery. Technical and process variables, which NSQIP may not consider, affect morbidity rate. OBJECTIVE: A retrospective observational study was undertaken to determine the accuracy of NSQIP models in predicting morbidity for patients undergoing laparoscopic or open colectomy. METHODS: NSQIP participant use files for 2005 to 2008 were obtained. Data were selected using Current Procedural Terminology coding for open or laparoscopic colectomy. NSQIP-generated predicted morbidities were used to create area under the receiver operator curves (AUROCs). RESULTS: AUROCs demonstrated an accurate predictive model if the value was above 0.8 and indicated a marginal predictor mode if below 0.7. The AUROC for the general NSQIP model was 0.817 (confidence interval [CI] = 0.815-0.819, p < 0.001). AUROC for the combined laparoscopic and open colectomy group was 0.703 (CI = 0.698-0.709, p value < 0.001). AUROCs for the individual laparoscopic and open colectomy groups were 0.627 (CI = 0.615-0.640, p < 0.001) and 0.701 (CI = 0.695-0.707, p < 0.001). CONCLUSION: This study demonstrates that although NSQIP-generated morbidities used to create AUROCs are accurate for patients in an overall surgical model, predictive models for morbidity are marginal for laparoscopic and open abdominal colectomies. NSQIP risk models tend to emphasize comorbidities rather than intraoperative details or technical aspects of colonic resections. PMID- 24626068 TI - Effect of transcendental meditation on employee stress, depression, and burnout: a randomized controlled study. AB - CONTEXT: Workplace stress and burnout are pervasive problems, affecting employee performance and personal health. OBJECTIVE: To evaluate the effects of the Transcendental Meditation program on psychological distress and burnout among staff at a residential therapeutic school for students with severe behavioral problems. DESIGN: A total of 40 secondary schoolteachers and support staff at the Bennington School in Vermont, a therapeutic school for children with behavioral problems, were randomly assigned to either practice of the Transcendental Meditation program or a wait-list control group. The Transcendental Meditation course was provided by certified instructors. MAIN OUTCOME MEASURES: Outcome measures were assessed at baseline and four months, and included perceived stress, depression, and burnout. A multivariate analysis of covariance was used to determine overall effects. RESULTS: Analysis of the 4-month intervention data indicated a significant improvement in the main outcomes of the study resulting from practice of the Transcendental Meditation program compared with controls (Wilks Lambda [3,28] = 0.695; p = 0.019). Results of univariate F tests indicated a significant reduction of all main outcome measures: perceived stress (F[1,32] = 13.42; p = < 0.001); depression (F[1,32] = 6.92; p = 0.013); and overall teacher burnout (F[1,32] = 6.18; p = 0.018). Effect sizes ranged from 0.40 to 0.94. CONCLUSIONS: The Transcendental Meditation program was effective in reducing psychological distress in teachers and support staff working in a therapeutic school for students with behavioral problems. These findings have important implications for employees' job performance as well as their mental and physical health. PMID- 24626069 TI - Weight patterns before and after total joint arthroplasty and characteristics associated with weight change. AB - CONTEXT: Although prevalence of obesity and incidence of total joint arthroplasty (TJA) have dramatically increased over the last two decades in the U.S., little is known of the preoperative and postoperative weight patterns of patients undergoing TJA. OBJECTIVE: To describe the preoperative and postoperative weight patterns of patients undergoing TJA and evaluate characteristics associated with these patterns. DESIGN: Retrospective cohort study. A cohort of patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) between January 1, 2008, and December 31, 2010, was identified. Using weight obtained at patient encounters, patients were categorized into gainers (increased weight by 5%), losers (decreased weight by 5%), or remained the same (changed < 5%) for the preoperative and postoperative periods. Patients were characterized by sex, age, and race. MAIN OUTCOME MEASURES: Weight change before and after TJA. RESULTS: Of 30,632 patients with TJA identified, 34.5% underwent THA and 65.5% had TKA. Most patients remained the same weight during the year before (THA, 71.5%; TKA, 75.7%) and after the procedure (64.0% and 68.5%, respectively). Before and after THA, men were less likely to lose or gain weight than were women. Older patients were less likely to gain weight. Among patients undergoing TKA, men were less likely to lose weight preoperatively or postoperatively, or gain weight postoperatively, and older patients were less likely to gain weight before or after arthroplasty. Some racial associations with weight patterns were observed. CONCLUSIONS: Specific groups are more susceptible to weight change and could benefit from weight management interventions. PMID- 24626070 TI - Highly reliable procedural teams: the journey to spread the universal protocol in diagnostic imaging. AB - CONTEXT: The Joint Commission's Universal Protocol has been widely implemented in surgical settings since publication in 2003. The elements improved patient safety in operating rooms, and the same rigor is being applied to procedures occurring in other health care arenas, in particular, diagnostic imaging. OBJECTIVE: In 2011, Kaiser Permanente West Los Angeles's Diagnostic Imaging Department desired to adapt previous work on Universal Protocol implementation to improve patient safety in interventional radiology and mammography procedures. DESIGN: The teams underwent human factors training and then adapted key interventions used in surgical suites to their workflows. Time-out posters, use of whiteboards, "glitch books," and regular audits provided structure to overcome the risks that human factors present. MAIN OUTCOME MEASURES: Staff and physician perceptions of the teamwork and safety climates in their modalities were measured using the Safety Attitudes Questionnaire at baseline and at 18 months after training. Unusual Occurrence Reports were also reviewed to identify events and near misses that could be prevented. Implementation of key process changes were identified as process measures. RESULTS: Perception of the safety climate improved 25% in interventional radiology and 4.5% in mammography. Perception of the teamwork climate decreased 5.4% in interventional radiology and 16.6% in mammography. Unusual occurrences were underreported at baseline, and there is ongoing reluctance to document near misses. CONCLUSION: This work provides important considerations of the impact of departmental cultures for the implementation of the Universal Protocol in procedural areas. It also reveals unexpected challenges, and requires long-term effort and focus. PMID- 24626071 TI - Complex case conferences associated with reduced hospital admissions for high risk patients with multiple comorbidities. AB - OBJECTIVES: Reducing avoidable hospital readmissions presents an opportunity to improve health care quality and reduce avoidable costs. We studied the effect person-focused care may have on reducing avoidable admissions to the hospital. METHODS: Among patients with heart failure discharged from the hospital, we evaluated the effect on 30-day readmissions of transitions-in-care interventions: home health visits, follow-up phone calls, and physician office visits. We also used a standardized diagnostic tool to interview readmitted patients to identify social reasons that may have contributed to the readmission. Finally, we used the learnings from both interventions to develop a new intervention: a single complex disease case conference that included the entire health care team. We measured hospital admissions for 21 patients during the 6 months before and after their complex case conferences. RESULTS: Observed-over-expected hospital readmission rates were lowest for patients receiving a postdischarge visit with a home health nurse and a follow-up visit with their physician (0.54), compared with solely a physician visit (0.81), home health visit (1.2), or phone call (1.55). Various social issues may contribute to hospital readmissions, including caregiver knowledge, ability to care for oneself at home, and issues related to medications (adherence, ability to pay, and knowledge about potential side effects). Substantially fewer hospital admissions occurred after complex case conferences. CONCLUSIONS: Complex case conferences with disease-focused and person-focused interventions may be associated with reduced hospital admissions for patients with heart failure and multiple comorbidities. PMID- 24626072 TI - Early detection of breast cancer using a self-referral mammography process: the Kaiser Permanente Northwest 20-year history. AB - OBJECTIVES: Breast cancer is the most common malignancy in women in the Kaiser Permanente Northwest Region. Ninety-five percent of women later found to have breast cancer were seen an average of 5 times in the medical offices in the year preceding diagnosis. Until 1991, screening mammography depended on clinician ordering. However, 20% of at-risk women were left out of the process because they had no clinician visit in the preceding year. Self-referral mammography was introduced as one of a number of processes to provide more comprehensive screening. METHODS: The Region's tumor registry database was examined to assess the effect of self-referral screening on early diagnosis, stage of disease, and family history. RESULTS: From 1991 to 2010, more than 995,000 mammograms were performed and 8752 breast cancers were diagnosed. By 2011, almost 50% of all mammograms were scheduled using the self-referral process, with more than 25% of cancers diagnosed through this process that year. The tumor registry provided both active and passive roles in the quality of cancer screening. DISCUSSION: The expected result of improving access to screening has been demonstrated over the last two decades. Beginning with the self-referral mammography program, each successive effort enhanced overall organizational effectiveness of care for the average-risk patient but failed to translate into any improvements for the higher risk patients. As the number of screening tests done is used as the sole measure of screening effectiveness, segments of the at-risk population are likely to be missed, compromising overall early detection efforts. PMID- 24626073 TI - Relationship between tumor necrosis factor-alpha inhibitors and cardiovascular disease in psoriasis: a review. AB - Psoriasis, a cutaneous disease that is increasingly recognized as a systemic inflammatory process, is associated with an increased risk for the development of cardiovascular disease. Although use of tumor necrosis factor-alpha inhibitors for the treatment of psoriasis has also been associated with decreased incidence of major adverse cardiac events, the precise mechanism by which these agents lower cardiovascular risk remains uncertain. Speculated mechanisms include the suppression of systemic inflammation or improvement of cardiovascular risk factors. Here we review the evidence in support of the beneficial effects of tumor necrosis factor-alpha inhibitors on cardiovascular health. Larger, future studies of patients treated with biologic agents will provide data to more definitively quantify the risk reduction of these agents on major adverse cardiac events. PMID- 24626074 TI - The role of eye movement desensitization and reprocessing (EMDR) therapy in medicine: addressing the psychological and physical symptoms stemming from adverse life experiences. AB - BACKGROUND: A substantial body of research shows that adverse life experiences contribute to both psychological and biomedical pathology. Eye movement desensitization and reprocessing (EMDR) therapy is an empirically validated treatment for trauma, including such negative life experiences as commonly present in medical practice. The positive therapeutic outcomes rapidly achieved without homework or detailed description of the disturbing event offer the medical community an efficient treatment approach with a wide range of applications. METHODS: All randomized studies and significant clinical reports related to EMDR therapy for treating the experiential basis of both psychological and somatic disorders are reviewed. Also reviewed are the recent studies evaluating the eye movement component of the therapy, which has been posited to contribute to the rapid improvement attributable to EMDR treatment. RESULTS: Twenty-four randomized controlled trials support the positive effects of EMDR therapy in the treatment of emotional trauma and other adverse life experiences relevant to clinical practice. Seven of 10 studies reported EMDR therapy to be more rapid and/or more effective than trauma-focused cognitive behavioral therapy. Twelve randomized studies of the eye movement component noted rapid decreases in negative emotions and/or vividness of disturbing images, with an additional 8 reporting a variety of other memory effects. Numerous other evaluations document that EMDR therapy provides relief from a variety of somatic complaints. CONCLUSION: EMDR therapy provides physicians and other clinicians with an efficient approach to address psychological and physiologic symptoms stemming from adverse life experiences. Clinicians should therefore evaluate patients for experiential contributors to clinical manifestations. PMID- 24626075 TI - Pay for performance for salaried health care providers: methodology, challenges, and pitfalls. AB - Pay for performance has been recommended by the Institute of Medicine as an incentive to improve the quality of health care. Traditional quality-improvement methods may be adapted to evaluate performance of salaried providers, but it is important to separate provider contributions from other influencing factors within the health care system. Accurate recording, extraction, and analysis of data together with careful selection and measurement of indicators of performance are crucial for meaningful assessment. If appropriate methodology is not used, much time, effort, and money may be expended gathering data that may be potentially misleading or even useless, with the possibility that good performance may go unrecognized and mediocre performance rewarded. PMID- 24626076 TI - Eluding meaninglessness: a note to self in regard to Camus, critical care, and the absurd. AB - Here I present a medical narrative, as a catharsis, regarding Albert Camus's The Myth of Sisyphus in an attempt to elude meaninglessness in my difficult everyday practice of critical care medicine. It is well documented that physicians who practice critical care medicine are subject to burnout. The sense of despair that occasionally overwhelms me prompted my rereading of Camus's classic text and caused me to recount his arguments that life is meaningless unless one is willing to take a leap of faith to the divine or, alternately, to commit suicide. This set up the examination of his third alternative, acceptance of a life without prima facie evidence of purpose and meaning, a view that may truly have some bearing on my professional life in the intensive care unit. PMID- 24626077 TI - Person-focused care at Kaiser Permanente. AB - Patient-focused care has been described as an extension of patient-centered care, recognizing that patients' medical needs are best understood and addressed in the context of their entire lives, including their life goals and social, economic, emotional, and spiritual functioning. Kaiser Permanente is expanding its ability to care for members as whole persons, not just as patients, with sensitivity to nonmedical factors in planning and delivering care. We describe emerging examples in several areas: interdisciplinary care planning, behavior change, social care, patient-reported outcome measures, and Total Health. Realizing the vision of person-focused care requires taking every opportunity to fully recognizing that each patient we serve is first and foremost a person. PMID- 24626079 TI - The economic impact of hospitalization for diabetic foot infections in a Caribbean nation. AB - CONTEXT: Foot infection is the most common complication of diabetes mellitus in the Caribbean. Diabetic foot infections place a heavy burden on health care resources in the Caribbean. OBJECTIVE: To evaluate the treatment-related costs for diabetic foot infections in a Caribbean nation. METHODS: We identified all patients with diabetic foot infections in a 730-bed hospital serving a catchment population of approximately 400,000 persons from June 1, 2011 through July 31, 2012. The following data were collected: details of infection, antibiotic usage, investigations performed, number of physician consultations, details of operative treatment, and duration of hospitalization. Total charges were tallied to determine the final cost for inhospital treatment of diabetic foot infections. RESULTS: There were 446 patients hospitalized with diabetic foot infections, yielding approximately 0.75% annual risk for patients with diabetes to develop foot infections. The mean duration of hospitalization was 22.5 days. Sixteen patients (3.6%) were treated conservatively without an operative procedure and 430 (96.4%) required some form of operative intervention. There were 885 debridements, 193 minor amputations and 60 major amputations, 7102 wound dressings, 2763 wound cultures, and 27,015 glucometer measurements. When the hospital charges were tallied, a total of US $13,922,178 (mean, US $31,216) were spent to treat diabetic foot infections in these 446 patients during 1 year at this hospital. CONCLUSIONS: Each year, the government of Trinidad and Tobago spends US $85 million, or 0.4% of their gross domestic product, solely to treat patients hospitalized for diabetic foot infections. With this level of national expenditure and the anticipated increase in the prevalence of diabetes, it is necessary to revive the call for investment in preventive public health strategies. PMID- 24626080 TI - Plantar fasciitis: a concise review. AB - One challenge in the treatment of plantar fasciitis is that very few high-quality studies exist comparing different treatment modalities to guide evidence-based management. Current literature suggests a change to the way that plantar fasciitis is managed. This article reviews the most current literature on plantar fasciitis and showcases recommended treatment guidelines. This serves to assist physicians in diagnosing and treating heel pain with plantar fasciitis. PMID- 24626081 TI - Self-reported activities and outcomes of ambulatory care staff registered nurses: an exploration. AB - CONTEXT: Ambulatory care is a growing field of nursing practice. As ambulatory registered nurse (RN) practice grows, there has been an ongoing effort to identify the desired role of the staff RN in outpatient care and to provide linkages to preferred outcomes. OBJECTIVE: This study sought to describe the perceived impact of components of the staff RN role on specific activities and outcomes, as guided by the structures, processes, and outcomes of the Nursing Role Effectiveness Model. DESIGN: This exploratory research study used a descriptive, self-report survey design. RESULTS: Survey respondents were ambulatory care staff RNs from various primary and specialty care clinics (n = 187) in an integrated health care organization in Southern California. The most frequently reported activities included patient assessment, nurse advice during message management, and completion of patient triage. Reported patient outcomes most frequently affected by RN activities were patient satisfaction, normalization of laboratory values, receiving the correct level of medical treatment, and prevention of complications. Respondents expressed that "emergency situations" periodically occur in the ambulatory setting. CONCLUSIONS: This research study supports what ambulatory care RNs say they are doing: daily, diverse, and complex patient care activities that influence multiple relevant patient outcomes. Future research studies could reveal best practices related to message management, in addition to activities and outcomes unique to specialty care populations. PMID- 24626082 TI - Image diagnosis: Sudden paraplegia in abdominal aortic thrombosis. PMID- 24626083 TI - Image diagnosis: Spontaneous hematoma from scurvy. PMID- 24626084 TI - ECG diagnosis: The effect of ionized serum calcium levels on electrocardiogram. AB - High and low levels of ionized serum calcium concentration can produce characteristic changes on the electrocardiogram. These changes are almost entirely limited to the duration of the ST segment, with no change in the QRS complexes or T waves. High ionized serum calcium shortens the ST segment, and low ionized serum calcium prolongs the ST segment. Two common clinical scenarios are presented. PMID- 24626085 TI - Think of salt in preventing falls in the geriatric population. PMID- 24626086 TI - Spodick's sign: a helpful electrocardiographic clue to the diagnosis of acute pericarditis. PMID- 24626087 TI - Assessment of quality of life in patients with chronic oral mucosal diseases: a questionnaire-based study. AB - CONTEXT: A validated discipline-specific questionnaire has been developed recently to assess the quality of life (QOL) in patients with chronic oral mucosal diseases. OBJECTIVE: Use the Chronic Oral Mucosal Diseases Questionnaire for evaluating a diverse group of patients with chronic oral mucosal disease after therapy. DESIGN: Prospective convenience sample. MAIN OUTCOME MEASURE: Quality of life. METHODS: Seventy patients seen in the Department of Oral Medicine and Radiology with oral lichen planus, recurrent aphthous ulcers, pemphigus, and other chronic oral mucosal diseases were included in the study. Patients completed the questionnaire after undergoing treatment of their oral mucosal disease to assess their QOL. RESULTS: Patients older than age 35 years reported significantly lower QOL (p = 0.015) in the domain of social and emotional status. Significant age-related differences in QOL were not observed in other domains. Older individuals also reported a significantly lower overall QOL. Men reported significantly better oral health-related QOL than women did in pain and functional limitation: 16.14 +/- 8.94 vs 21.44 +/- 7.696, respectively (p = 0.010). Significant differences were not observed between sexes for other domains. Significant differences were observed between the disease groups only for recurrent aphthous ulcers and pemphigus (p = 0.005). Patients with pemphigus had the worst overall QOL (73.6 +/- 5.6). CONCLUSION: Even after treatment, chronic oral mucosal diseases negatively affect patients' QOL. Use of the Chronic Oral Mucosal Diseases Questionnaire may allow physicians to more effectively care for their patients with these diseases. PMID- 24626089 TI - KLF5 regulates the integrity and oncogenicity of intestinal stem cells. AB - The intestinal epithelium maintains homeostasis by a self-renewal process involving resident stem cells, including Lgr5(+) crypt-base columnar cells, but core mechanisms and their contributions to intestinal cancer are not fully defined. In this study, we examined a hypothesized role for KLF5, a zinc-finger transcription factor that is critical to maintain the integrity of embryonic and induced pluripotent stem cells, in intestinal stem-cell integrity and cancer in the mouse. Klf5 was indispensable for the integrity and oncogenic transformation of intestinal stem cells. In mice, inducible deletion of Klf5 in Lgr5(+) stem cells suppressed their proliferation and survival in a manner associated with nuclear localization of beta-catenin (Catnb), generating abnormal apoptotic cells in intestinal crypts. Moreover, production of lethal adenomas and carcinomas by specific expression of an oncogenic mutant of beta-catenin in Lgr5(+) stem cells was suppressed completely by Klf5 deletion in the same cells. Given that activation of the Wnt/beta-catenin pathway is the most frequently altered pathway in human colorectal cancer, our results argue that KLF5 acts as a fundamental core regulator of intestinal oncogenesis at the stem-cell level, and they suggest KLF5 targeting as a rational strategy to eradicate stem-like cells in colorectal cancer. PMID- 24626088 TI - The rise and fall of HIV in high-prevalence countries: a challenge for mathematical modeling. AB - Several countries with generalized, high-prevalence HIV epidemics, mostly in sub Saharan Africa, have experienced rapid declines in transmission. These HIV epidemics, often with rapid onsets, have generally been attributed to a combination of factors related to high-risk sexual behavior. The subsequent declines in these countries began prior to widespread therapy or implementation of any other major biomedical prevention. This change has been construed as evidence of behavior change, often on the basis of mathematical models, but direct evidence for behavior changes that would explain these declines is limited. Here, we look at the structure of current models and argue that the common "fixed risk per sexual contact" assumption favors the conclusion of substantial behavior changes. We argue that this assumption ignores reported non linearities between exposure and risk. Taking this into account, we propose that some of the decline in HIV transmission may be part of the natural dynamics of the epidemic, and that several factors that have traditionally been ignored by modelers for lack of precise quantitative estimates may well hold the key to understanding epidemiologic trends. PMID- 24626090 TI - CHD7 expression predicts survival outcomes in patients with resected pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment. PMID- 24626091 TI - Maintaining glycogen synthase kinase-3 activity is critical for mTOR kinase inhibitors to inhibit cancer cell growth. AB - mTOR kinase inhibitors that target both mTORC1 and mTORC2 are being evaluated in cancer clinical trials. Here, we report that glycogen synthase kinase-3 (GSK3) is a critical determinant for the therapeutic response to this class of experimental drugs. Pharmacologic inhibition of GSK3 antagonized their suppressive effects on the growth of cancer cells similarly to genetic attenuation of GSK3. Conversely, expression of a constitutively activated form of GSK3beta sensitized cancer cells to mTOR inhibition. Consistent with these findings, higher basal levels of GSK3 activity in a panel of human lung cancer cell lines correlated with more efficacious responses. Mechanistic investigations showed that mTOR kinase inhibitors reduced cyclin D1 levels in a GSK3beta-dependent manner, independent of their effects on suppressing mTORC1 signaling and cap binding. Notably, selective inhibition of mTORC2 triggered proteasome-mediated cyclin D1 degradation, suggesting that mTORC2 blockade is responsible for GSK3-dependent reduction of cyclin D1. Silencing expression of the ubiquitin E3 ligase FBX4 rescued this reduction, implicating FBX4 in mediating this effect of mTOR inhibition. Together, our findings define a novel mechanism by which mTORC2 promotes cell growth, with potential implications for understanding the clinical action of mTOR kinase inhibitors. PMID- 24626092 TI - Tumor endothelial markers define novel subsets of cancer-specific circulating endothelial cells associated with antitumor efficacy. AB - Circulating endothelial cells (CEC) are derived from multiple sources, including bone marrow (circulating endothelial progenitors; CEP), and established vasculature (mature CEC). Although CECs have shown promise as a biomarker for patients with cancer, their utility has been limited, in part, by the lack of specificity for tumor vasculature and the different nonmalignant causes that can impact CEC. Tumor endothelial markers (TEM) are antigens enriched in tumor versus nonmalignant endothelia. We hypothesized that TEMs may be detectable on CEC and that these circulating TEM(+) endothelial cells (CTEC) may be a more specific marker for cancer and tumor response than standard CEC. We found that tumor bearing mice had a relative increase in numbers of circulating CTEC, specifically with increased levels of TEM7 and TEM8 expression. Following treatment with various vascular-targeting agents, we observed a decrease in CTEC that correlated with the reductions in tumor growth. We extended these findings to human clinical samples and observed that CTECs were present in patients with esophageal cancer and non-small cell lung cancer (N = 40), and their levels decreased after surgical resection. These results demonstrate that CTECs are detectable in preclinical cancer models and patients with cancer. Furthermore, they suggest that CTECs offer a novel cancer-associated marker that may be useful as a blood based surrogate for assessing the presence of tumor vasculature and antiangiogenic drug activity. PMID- 24626093 TI - Curcumin promotes autophagic survival of a subset of colon cancer stem cells, which are ablated by DCLK1-siRNA. AB - Curcumin is known to induce apoptosis of cancer cells by different mechanisms, but its effects on cancer stem cells (CSC) have been less investigated. Here, we report that curcumin promotes the survival of DCLK1-positive colon CSCs, potentially confounding application of its anticancer properties. At optimal concentrations, curcumin greatly reduced expression levels of stem cell markers (DCLK1/CD44/ALDHA1/Lgr5/Nanog) in three-dimensional spheroid cultures and tumor xenografts derived from colon cancer cells. However, curcumin unexpectedly induced proliferation and autophagic survival of a subset of DCLK1-positive CSCs. Spheroid cultures were disintegrated by curcumin in vitro but regrew within 30 to 40 days of treatment, suggesting a survival benefit from autophagy, permitting long-term persistence of colorectal cancer. Notably, RNA interference-mediated silencing of DCLK1 triggered apoptotic cell death of colon cancer cells in vitro and in vivo, and abolished colorectal cancer survival in response to curcumin; combination of DCLK1-siRNA and curcumin dramatically reversed CSC phenotype, contributing to attenuation of the growth of spheroid cultures and tumor xenografts. Taken together, our findings confirm a role of DCLK1 in colon CSCs and highlight DCLK1 as a target to enhance antitumor properties of curcumin. PMID- 24626094 TI - WEE1 inhibition alleviates resistance to immune attack of tumor cells undergoing epithelial-mesenchymal transition. AB - Aberrant expression of the T-box transcription factor brachyury in human carcinomas drives the phenomenon of epithelial-mesenchymal transition (EMT), a phenotypic modulation that facilitates tumor dissemination and resistance to conventional therapies, including chemotherapy and radiotherapy. By generating isogenic cancer cell lines with various levels of brachyury expression, we demonstrate that high levels of brachyury also significantly reduce the susceptibility of cancer cells to lysis by both antigen-specific T cells and natural killer cells. Our results indicated that resistance of brachyury-high tumor cells to immune-mediated attack was due to inefficient caspase-dependent apoptosis, manifested as inefficient nuclear lamin degradation in the presence of activated effector caspases. We correlated this phenomenon with loss of cell cycle-dependent kinase 1 (CDK1), which mediates lamin phosphorylation. In support of a causal connection, pretreatment of tumor cells with a specific inhibitor of WEE1, a negative regulator kinase of CDK1, could counter the defective apoptosis of tumor cells expressing high levels of brachyury. Thus, our findings suggested that reconstituting CDK1 activity to threshold levels may be sufficient to restore immunosurveillance of mesenchymal-like cancer cells that have escaped previous immune detection or eradication. PMID- 24626097 TI - Dietary quercetin reduces chemotherapy-induced fatigue in mice. AB - PURPOSE: While fatigue is the most commonly reported symptom of chemotherapy, there are currently no effective treatments for chemotherapy-induced fatigue (CIF). We used a mouse model to examine the benefits of quercetin on CIF as measured by voluntary wheel running activity and sought to determine whether quercetin may be associated with a decrease in inflammation and/or anemia. METHODS: Mice were assigned to 1 of 4 groups: placebo-vehicle (Plac-PBS), placebo 5-fluorouracil (Plac-5FU), quercetin-vehicle (Quer-PBS), or quercetin-5 fluorouracil (Quer-5FU). All mice were given a daily injection of either 60 mg/kg of 5-FU or phosphate buffered saline (PBS) for 5 days. Quercetin (0.02%) treatment was administered in the food 3 days prior to 5-FU administration and for the duration of the experiment (ie, days -2 to 14). A second group of mice was sacrificed at 5 and 14 days post initial injection for assessment of monocyte chemoattractant protein-1 (MCP-1) and anemia. RESULTS: Voluntary wheel running was reduced in both the Plac-5FU and Quer-5FU groups following 5-FU injection (P < .05). However, the Quer-5FU group recovered to baseline levels by approximately day 7, whereas the Plac-5FU group remained suppressed. MCP-1 was significantly elevated at 14 days in Plac-5FU (P < .001), but no changes were seen with Quer 5FU. Treatment with 5-FU resulted in anemia at both 5 days and 14 days; however, quercetin blocked this effect at 14 days (P < .001). CONCLUSION: These results demonstrate the beneficial effect of quercetin on improving recovery of voluntary physical activity following 5-FU treatment, which may be linked to a decrease in inflammation and anemia. PMID- 24626098 TI - Deformation of the patellofemoral joint caused by synovial hemangioma: a case report. AB - A 15-year-old girl with synovial hemangioma of the knee joint presented with gait pain and occasional sudden swelling for over 7 years. Plain radiographs showed an irregular joint line and a lateral shift of the patella caused by malformation of the patellar groove. Arthroscopy was performed to resect the tumor and to release the lateral patellar retinaculum. If the synovial hemangioma exists in the patellofemoral joint during the growth period, we propose that early surgical treatment is necessary to avoid the deformation of the joint. PMID- 24626099 TI - Endochondral ossification in a case of progressive osseous heteroplasia in a young female child. AB - Progressive osseous heteroplasia (POH) (OMIM 166350) is a rare autosomal dominant condition, characterized by heterotopic ossification of the skin, subcutaneous fat, and deep connective tissue. This condition is distinct from Albright's hereditary osteodystrophy or McCune Albright syndrome (OMIM 103580) and fibrodysplasia ossificans progressiva (OMIM 135100). We present an unusual presentation of POH in a 7-year-old female child. The clinical features included a painful swelling on the left foot, with mechanical complaints. There was no congenital hallux valgus. Family anamnesis was positive in the father. There were subcutaneous ossifications of his left upper arm, right-sided thorax, and lateral side of the right ankle. The father did not allow any radiographs or further examinations. Radiographic examination of the patient revealed ossified subcutaneous plaques on the left foot, lumbar spine, and left scapulae. Additional blood samples were analyzed, revealing no pseudohypoparathyroidism. Sequence analysis of the gene associated with POH, the GNAS1 gene, revealed the heterozygote mutation c.565_568del, previously found in Albright's hereditary osteodystrophy. Histopathological examination of the subcutaneous ossification showed presence of chondrocyte clusters, a feature usually found in fibrodysplasia ossificans progressiva. The combination of the clinical features, the absence of pseudohypoparathyroidism, histology revealing chondrocyte clusters, and the specific GNAS mutation in this patient makes this a truly unusual presentation of POH. The findings in the described case might denote subdivisions of POH. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, and recurrence if excised. We hope to inform pediatricians and orthopedic surgeons to create more awareness of this disorder so that unnecessary treatments can be avoided and proper counseling offered. PMID- 24626100 TI - Retrosternal displacement of the clavicle after medial physeal fracture in an adolescent: MRI. AB - Retrosternal displacement of the medial clavicular metaphysis after a medial physeal fracture is a rare and potentially fatal injury because of possible damage of neurovascular structures, trachea and oesophagus. As the medial clavicular epiphysis does not ossify until 18-20 years of age and the medial clavicular physis is the last to close, around 22-25 years of age, this injury is difficult to demonstrate with plain radiographs in younger patients and is often mistaken for a sternoclavicular joint dislocation. We report on a 16-year-old boy with a fracture of the medial clavicular physis with retrosternal displacement of the metaphysis that was diagnosed with MRI, and discuss the diagnostic tools and treatment options in this rare injury. PMID- 24626101 TI - Partial nail matricectomy with carbon dioxide laser. PMID- 24626102 TI - Update on allergic contact dermatitis due to methylchloroisothiazolinone/methylisothiazolinone and methylisothiazolinone. AB - The combination of methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) is widely used as a preservative in cosmetics, household, and industrial products. Furthermore, MI at a concentration of 100 ppm has been permitted in cosmetic products since 2005. Recently, a considerable increase in cases of contact dermatitis to both MCI and MI have been noted, and this warrants closer monitoring by relevant authorities and, probably, stricter legislation. In fact, MI at a test concentration of 2000 ppm was recently included in the European baseline patch test series. The clinical manifestations of allergy to MCI/MI and MI are highly variable and diagnosis is often missed. In the standard patch test series of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC), MCI/MI is tested at 100 ppm, but at this concentration, up to 50% of cases might go undetected. Furthermore, our data indicate that MCI/MI at 200 ppm would make it possible to diagnose more cases of contact allergy to MI. To improve the diagnosis of contact allergy to MCI/MI and MI, we believe that the test concentration of MCI/MI should be increased to 200 ppm in the GEIDAC standard series and that MI should be added in the GEIDAC standard series. PMID- 24626103 TI - Patch testing in patients with perianal eczema. AB - INTRODUCTION AND OBJECTIVES: Reports show that between 25% and 78% of patients with anogenital dermatitis have positive patch test results. Consequently, patch testing would appear to be warranted in patients presenting with eczema in the anogenital region. The objectives of the present study were to identify the most common allergens in patients with perianal eczema and to determine which allergen series are most useful for patch testing in patients with this condition. MATERIAL AND METHODS: We performed a retrospective review of patch test results in patients with only perianal eczema between 2001 and 2012. RESULTS: Of the 37 patients with perianal eczema, 16 had a positive reaction; methylchloroisothiazolinone/methylisothiazolinone was the main allergen involved. With the exception of 1 case of sensitization to gentamicin, all the positive results with present relevance were to allergens from the standard series of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) or to the patient's own products. CONCLUSIONS: In our experience, methylchloroisothiazolinone/methylisothiazolinone is the main allergen involved in perianal eczema, and sensitization often results from using wet wipes. Patch testing in perianal eczema should be based on the GEIDAC standard series and the patient's own products. PMID- 24626104 TI - Multidisciplinary teams for psoriatic arthritis: on aims and approaches. PMID- 24626105 TI - A slow-growing pedunculated lesion. PMID- 24626106 TI - Interobserver reliability of store-and-forward teledermatology in a clinical practice setting. AB - INTRODUCTION AND OBJECTIVES: Although many studies have evaluated the diagnostic reliability of store-and-forward (SF) teledermatology, the reliability of the technique for the diagnosis of general skin conditions in a clinical practice setting has never been demonstrated. We evaluated the reliability of SF teledermatology in clinical practice by analyzing the diagnostic agreement achieved in a subgroup of patients from the DERMATEL-2 study. MATERIAL AND METHODS: Patients referred from primary care settings were randomized to 3 groups: SF, a combination of videoconferencing and SF technology (VC-SF), and a control group. This article focuses on the SF group. Clinical data were recorded and photographs taken by primary care physicians, who forwarded the data electronically. Each SF consultation package was assessed by 3 dermatologists (D1,D2,D3). Subsequently all the patients were assessed by a single dermatologist (D1) in a face-to-face consultation. Finally, 2 other dermatologists (D4,D5) assessed the agreement between the diagnoses obtained by SF and FF. RESULTS: In total, 457 patients (200 males and 257 females) aged between 2 months and 86 years were randomized (192 to SF, 176 to VC-SF, and 89 to the control group). The diagnostic categories were as follows: tumors (49.4%), inflammatory (25.7%), adnexal (11%), infectious (9.4%) and other processes (4.4%) Since 170 patients had consultations deemed valid for analysis, the study included a total of 510 SF assessments. Most of the images and clinical records were of high quality (71.2% and 91.2% respectively), and diagnostic confidence was high in 81.4% of the cases studied. In 58.4% of cases the condition was managed exclusively by teledermatology. Levels of complete and aggregate interobserver agreement between SF and face-to-face evaluators were 0,72 and 0.90, respectively, for diagnosis and 0.61 and 0.80 for treatment. Diagnostic agreement correlated with the image quality (P < .001), diagnostic confidence (P<.001), felt need for conventional consultation (P<.001), and the quality of the clinical record (P=.013). CONCLUSION: The interobserver reliability of SF diagnosis in clinical practice is good. Dermatologists are able to predict errors in diagnosis by analyzing their own diagnostic confidence and evaluating the quality of the images. PMID- 24626107 TI - Stolt's f-k migration for plane wave ultrasound imaging. AB - Ultrafast ultrasound is an emerging modality that offers new perspectives and opportunities in medical imaging. Plane wave imaging (PWI) allows one to attain very high frame rates by transmission of planar ultrasound wave-fronts. As a plane wave reaches a given scatterer, the latter becomes a secondary source emitting upward spherical waves and creating a diffraction hyperbola in the received RF signals. To produce an image of the scatterers, all the hyperbolas must be migrated back to their apexes. To perform beamforming of plane wave echo RFs and return high-quality images at high frame rates, we propose a new migration method carried out in the frequency-wavenumber (f-k) domain. The f-k migration for PWI has been adapted from the Stolt migration for seismic imaging. This migration technique is based on the exploding reflector model (ERM), which consists in assuming that all the scatterers explode in concert and become acoustic sources. The classical ERM model, however, is not appropriate for PWI. We showed that the ERM can be made suitable for PWI by a spatial transformation of the hyperbolic traces present in the RF data. In vitro experiments were performed to outline the advantages of PWI with Stolt's f-k migration over the conventional delay-and-sum (DAS) approach. The Stolt's f-k migration was also compared with the Fourier-based method developed by J.-Y. Lu. Our findings show that multi-angle compounded f-k migrated images are of quality similar to those obtained with a stateof- the-art dynamic focusing mode. This remained true even with a very small number of steering angles, thus ensuring a highly competitive frame rate. In addition, the new FFT-based f-k migration provides comparable or better contrast-to-noise ratio and lateral resolution than the Lu's and DAS migration schemes. Matlab codes for the Stolt's f-k migration for PWI are provided. PMID- 24626109 TI - School-based health education targeting intestinal worms-further support for integrated control. PMID- 24626108 TI - Hepcidin and the iron enigma in HCV infection. AB - An estimated 30-40% of patients with chronic hepatitis C have elevated serum iron, transferrin saturation, and ferritin levels. Clinical data suggest that iron is a co-morbidity factor for disease progression following HCV infection. Iron is essential for a number of fundamental metabolic processes in cells and organisms. Mammalian iron homeostasis is tightly regulated and this is maintained through the coordinated action of sensory and regulatory networks that modulate the expression of iron-related proteins at the transcriptional and/or posttranscriptional levels. Disturbances of iron homeostasis have been implicated in infectious disease pathogenesis. Viruses, similarly to other pathogens, can escape recognition by the immune system, but they need iron from their host to grow and spread. Hepcidin is a 25-aa peptide, present in human serum and urine and represents the key peptide hormone, which modulates iron homeostasis in the body. It is synthesized predominantly by hepatocytes and its mature form is released in circulation. In this review, we discuss recent advances in the exciting crosstalk of molecular mechanisms and cell signaling pathways by which iron and hepcidin production influences HCV-induced liver disease. PMID- 24626110 TI - Validation of anthropometric indices of adiposity against whole-body magnetic resonance imaging--a study within the German European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts. AB - BACKGROUND: In epidemiological studies, measures of body fat generally are obtained through anthropometric indices such as the body mass index (BMI), waist (WC), and hip circumferences (HC). Such indices, however, can only provide estimates of a person's true body fat content, overall or by adipose compartment, and may have limited accuracy, especially for the visceral adipose compartment (VAT). OBJECTIVE: To determine the extent to which different body adipose tissue compartments are adequately predicted by anthropometry, and to identify anthropometric measures alone, or in combination to predict overall adiposity and specific adipose tissue compartments, independently of age and body size (height). METHODS: In a sub-study of 1,192 participants of the German EPIC (European Prospective Investigation into Cancer and Nutrition) cohorts, whole body MRI was performed to determine adipose and muscle tissue compartments. Additional anthropometric measurements of BMI, WC and HC were taken. RESULTS: After adjusting for age and height, BMI, WC and HC were better predictors of total body volume (TBV), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) than for VAT, coronary adipose tissue (CAT) and skeletal muscle tissue (SMT). In both sexes, BMI was the best predictor for TBV (men: r = 0.72 [0.68-0.76], women: r = 0.80 [0.77-0.83]) and SMT (men: r = 0.52 [0.45-0.57], women: r = 0.48 [0.41-0.54]). WC was the best predictor variable for TAT (r = 0.48 [0.41-0.54]), VAT (r = 0.44 [0.37-0.50]) and CAT (r = 0.34 [0.26-0.41]) (men), and for VAT (r = 0.42 [0.35-0.49]) and CAT (r = 0.29 [0.22-0.37]) (women). BMI was the best predictor for TAT (r = 0.49 [0.43-0.55]) (women). HC was the best predictor for SAT (men (r = 0.39 [0.32-0.45]) and women (r = 0.52 [0.46 0.58])). CONCLUSIONS: Especially the volumes of internal body fat compartments are poorly predicted by anthropometry. A possible implication may be that associations of chronic disease risks with the sizes of internal body fat as measured by BMI, WC and HC may be strongly underestimated. PMID- 24626112 TI - The role of emergency physicians in tobacco cessation and British Columbia's Smoking Cessation Program. PMID- 24626111 TI - Drosophila SNAP-29 is an essential SNARE that binds multiple proteins involved in membrane traffic. AB - Each membrane fusion event along the secretory and endocytic pathways requires a specific set of SNAREs to assemble into a 4-helical coiled-coil, the so-called trans-SNARE complex. Although most SNAREs contribute one helix to the trans-SNARE complex, members of the SNAP-25 family contribute two helixes. We report the characterization of the Drosophila homologue of SNAP-29 (dSNAP-29), which is expressed throughout development. Unlike the other SNAP-25 like proteins in fruit fly (i.e., dSNAP-25 and dSNAP-24), which form SDS-resistant SNARE complexes with their cognate SNAREs, dSNAP-29 does not participate in any SDS-resistant complexes, despite its interaction with dsyntaxin1 and dsyntaxin16 in vitro. Immunofluorescence studies indicated that dSNAP-29 is distributed in various tissues, locating in small intracellular puncta and on the plasma membrane, where it associates with EH domain-containing proteins implicated in the endocytic pathway. Overexpression and RNAi studies suggested that dSNAP-29 mediates an essential process in Drosophila development. PMID- 24626114 TI - Computerized interpretation of the prehospital electrocardiogram: predictive value for ST segment elevation myocardial infarction and impact on on-scene time. AB - INTRODUCTION: Computerized interpretation of the prehospital electrocardiogram (ECG) is increasingly being used in the basic life support (BLS) ambulance setting to reduce delays to treatment for patients suspected of ST segment elevation myocardial infarction (STEMI). OBJECTIVES: To estimate 1) predictive values of computerized prehospital 12-lead ECG interpretation for STEMI and 2) additional on-scene time for 12-lead ECG acquisition. METHODS: Over a 2-year period, 1,247 ECGs acquired by primary care paramedics for suspected STEMI were collected. ECGs were interpreted in real time by the GE-Marquette 12SL ECG analysis program. Predictive values were estimated with a bayesian latent class model incorporating the computerized ECG interpretations, consensus ECG interpretations by study cardiologists, and hospital diagnosis. On-scene time was compared for ambulance-transported patients with (n = 985) and without (n = 5,056) prehospital ECGs who received prehospital aspirin and/or nitroglycerin. RESULTS: The computer's positive and negative predictive values for STEMI were 74.0% (95% credible interval [CrI] 69.6-75.6) and 98.1% (95% CrI 97.8-98.4), respectively. The sensitivity and specificity were 69.2% (95% CrI 59.0-78.5) and 98.9% (95% CrI 98.1-99.4), respectively. Prehospital ECGs were associated with a mean increase in on-scene time of 5.9 minutes (95% confidence interval 5.5-6.3). CONCLUSIONS: The predictive values of the computerized prehospital ECG interpretation appear to be adequate for diversion programs that direct patients with a positive result to hospitals with angioplasty facilities. The estimated 26.0% chance that a positive interpretation is false is likely too high for activation of a catheterization laboratory from the field. Acquiring prehospital ECGs does not substantially increase on-scene time in the BLS setting. PMID- 24626115 TI - Development and validation of a prediction rule for early discharge of low-risk emergency department patients with potential ischemic chest pain. AB - OBJECTIVES: Current guidelines emphasize that emergency department (ED) patients at low risk for potential ischemic chest pain cannot be discharged without extensive investigations or hospitalization to minimize the risk of missing acute coronary syndrome (ACS). We sought to derive and validate a prediction rule that permitted 20 to 30% of ED patients without ACS safely to be discharged within 2 hours without further provocative cardiac testing. METHODS: This prospective cohort study enrolled 1,669 chest pain patients in two blocks in 2000-2003 (development cohort) and 2006 (validation cohort). The primary outcome was 30-day ACS diagnosis. A recursive partitioning model incorporated reliable and predictive cardiac risk factors, pain characteristics, electrocardiographic findings, and cardiac biomarker results. RESULTS: In the derivation cohort, 165 of 763 patients (21.6%) had a 30-day ACS diagnosis. The derived prediction rule was 100.0% sensitive and 18.6% specific. In the validation cohort, 119 of 906 patients (13.1%) had ACS, and the prediction rule was 99.2% sensitive (95% CI 95.4-100.0) and 23.4% specific (95% CI 20.6-26.5). Patients have a very low ACS risk if arrival and 2-hour troponin levels are normal, the initial electrocardiogram is nonischemic, there is no history of ACS or nitrate use, age is < 50 years, and defined pain characteristics are met. The validation of the rule was limited by the lack of consistency in data capture, incomplete follow up, and lack of evaluation of the accuracy, comfort, and clinical sensibility of this clinical decision rule. CONCLUSION: The Vancouver Chest Pain Rule may identify a cohort of ED chest pain patients who can be safely discharged within 2 hours without provocative cardiac testing. Further validation across other centres with consistent application and comprehensive and uniform follow-up of all eligible and enrolled patients, in addition to measuring and reporting the accuracy of and comfort level with applying the rule and the clinical sensibility, should be completed prior to adoption and implementation. PMID- 24626116 TI - Derivation of a risk scale and quantification of risk factors for serious adverse events in adult emergency department syncope patients. AB - BACKGROUND: Determining the appropriate disposition of emergency department (ED) syncope patients is challenging. Previously developed decision tools have poor diagnostic test characteristics and methodological flaws in their derivation that preclude their use. We sought to develop a scale to risk-stratify adult ED syncope patients at risk for serious adverse events (SAEs) within 30 days. METHODS: We conducted a medical record review to include syncope patients age >= 16 years and excluded patients with ongoing altered mental status, alcohol or illicit drug use, seizure, head injury leading to loss of consciousness, or severe trauma requiring admission. We collected 105 predictor variables (demographics, event characteristics, comorbidities, medications, vital signs, clinical examination findings, emergency medical services and ED electrocardiogram/monitor characteristics, investigations, and disposition variables) and information on the occurrence of predefined SAEs. Univariate and multiple logistic regression analyses were performed. RESULTS: Among 505 enrolled patient visits, 49 (9.7%) suffered an SAE. Predictors of SAE and their resulting point scores were as follows: age >= 75 years (1), shortness of breath (2), lowest ED systolic blood pressure < 80 mm Hg (2), Ottawa Electrocardiographic Criteria present (2), and blood urea nitrogen > 15 mmol/L (3). The final score calculated by addition of the individual scores for each variable (range 0-10) was found to accurately stratify patients into low risk (score < 1, 0% SAE risk), moderate risk (score 1, 3.7% SAE risk), or high risk (score > 1, >= 10% SAE risk). CONCLUSION: We derived a risk scale that accurately predicts SAEs within 30 days in ED syncope patients. If validated, this will be a potentially useful clinical decision tool for emergency physicians, may allow judicious use of health care resources, and may improve patient care and safety. PMID- 24626117 TI - Can emergency physicians accurately rule out clinically important cervical spine injuries by using computed tomography? AB - OBJECTIVE: Emergency physicians are expected to rule out clinically important cervical spine injuries using clinical skills and imaging. Our objective was to determine whether emergency physicians could accurately rule out clinically important cervical spine injuries using computed tomographic (CT) imaging of the cervical spine. METHOD: Fifteen emergency physicians were enrolled to interpret a sample of 50 cervical spine CT scans in a nonclinical setting. The sample contained a 30% incidence of cervical spine injury. After a 2-hour review session, the participants interpreted the CT scans and categorized them into either a suspected cervical spine injury or no cervical spine injury. Participants were asked to specify the location and type of injury. The gold standard interpretation was the combined opinion of two staff radiologists. RESULTS: Emergency physicians correctly identified 182 of the 210 abnormal cases with cervical spine injury. The sensitivity of emergency physicians was 87% (95% confidence interval [CI] 82-91), and the specificity was 76% (95% CI 74-77). The negative likelihood ratio was 0.18 (95% CI 0.12-0.25). CONCLUSION: Experienced emergency physicians successfully identified a large proportion of cervical spine injuries on CT; however, they were not sufficiently sensitive to accurately exclude clinically important injuries. Emergency physicians should rely on a radiologist review of cervical spine CT scans prior to discontinuing cervical spine precautions. PMID- 24626118 TI - Cohort study on the prevalence and risk factors for delayed pulmonary complications in adults following minor blunt thoracic trauma. AB - OBJECTIVES: The objectives of this study are to determine the prevalence, risk factors, and time to onset of delayed hemothorax and pneumothorax in adults who experienced a minor blunt thoracic trauma. METHOD: A prospective cohort of 450 consecutive patients was recruited. Eligible patients had to be over 16 years of age, consulted within 72 hours for a trauma, and available for outpatient follow up at 2, 7, and 14 days posttrauma. The clinical outcome investigated was the presence of delayed pneumothorax or hemothorax on the follow-up chest x-ray. OUTCOMES: Delayed hemothorax occurred in 11.8% (95% CI 8.8-14.8), and delayed pneumothorax occurred in 0.9% (95% CI 0.2-2.3) of participants. During the 14-day follow-up period, 87.0% of these delayed complications developed in the first week. In the multivariate analysis, the only statistically significant risk factor for delayed complications was the location of fractures on the x-ray of the hemithorax. The adjusted odds ratio was 1.52 (95% CI 0.62-3.73) for the lower ribs (tenth to twelfth rib), 3.11 (95% CI 1.60-6.08) for the midline ribs (sixth to ninth rib), and 5.05 (95% CI 1.80-14.19) for the upper ribs (third to fifth rib) versus patients with no fractures. CONCLUSION: The presence of at least one rib fracture between the third and ninth rib on the x-ray of the hemithorax is a significant risk factor for delayed hemothorax and pneumothorax. PMID- 24626119 TI - Validity and reliability of an in-training evaluation report to measure the CanMEDS roles in emergency medicine residents. AB - BACKGROUND: There is a question of whether a single assessment tool can assess the key competencies of residents as mandated by the Royal College of Physicians and Surgeons of Canada CanMEDS roles framework. OBJECTIVE: The objective of the present study was to investigate the reliability and validity of an emergency medicine (EM) in-training evaluation report (ITER). METHOD: ITER data from 2009 to 2011 were combined for residents across the 5 years of the EM residency training program. An exploratory factor analysis with varimax rotation was used to explore the construct validity of the ITER. A total of 172 ITERs were completed on residents across their first to fifth year of training. RESULTS: A combined, 24-item ITER yielded a five-factor solution measuring the CanMEDs role Medical Expert/Scholar, Communicator/Collaborator, Professional, Health Advocate and Manager subscales. The factor solution accounted for 79% of the variance, and reliability coefficients (Cronbach alpha) ranged from alpha = 0.90 to 0.95 for each subscale and alpha = 0.97 overall. The combined, 24-item ITER used to assess residents' competencies in the EM residency program showed strong reliability and evidence of construct validity for assessment of the CanMEDS roles. CONCLUSION: Further research is needed to develop and test ITER items that will differentiate each CanMEDS role exclusively. PMID- 24626120 TI - Epinephrine compared to placebo in cardiac arrest resuscitation. AB - CLINICAL QUESTION: Does epinephrine (adrenaline) used in the context of out-of hospital cardiac arrest improve outcomes? ARTICLE CHOSEN: Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: a randomised double-blind placebo-controlled trial. Resuscitation 2011;82:1138-43. OBJECTIVE: To determine the effect of epinephrine in out-of hospital cardiac arrest on patient survival to hospital discharge, prehospital return of spontaneous circulation, and neurologic outcomes. PMID- 24626121 TI - Oral rivaroxaban for the treatment of symptomatic pulmonary embolism: are we ready? AB - CLINICAL QUESTION: Can an oral regimen of rivaroxaban be used for the treatment of symptomatic pulmonary embolism? ARTICLE CHOSEN: Buller H, Prins M, Lensing A, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97. OBJECTIVE: To determine the effectiveness and safety of oral rivaroxaban in the treatment of symptomatic pulmonary embolism when compared to current standard therapy. PMID- 24626122 TI - Progressive bruising in an otherwise healthy child: immune thrombocytopenia purpura. PMID- 24626123 TI - There will be an answer; let it bleed. PMID- 24626124 TI - Lateral medullary syndrome: a diagnostic approach illustrated through case presentation and literature review. AB - Patients with lateral medullary syndrome classically present with crossed hemisensory disturbance, ipsilateral Horner syndrome, and cerebellar signs, all of which are attributable to infarction of the lateral medulla. However, variability in the presentation of this syndrome is the rule, as illustrated in this case presentation and literature review. We propose an approach to diagnosis and management of the lateral medullary syndrome and illustrate the need to integrate clinical information with an understanding of brainstem anatomy with the goal of determining which patients require urgent neuroimaging and acute stroke therapies. The importance of recognition of this condition in the emergency department is underscored by the association between lateral medullary infarction and vertebral artery dissection. With optimal therapy, the prognosis for recovery from lateral medullary syndrome is good. PMID- 24626125 TI - "Bath salts" intoxication: a new recreational drug that presents with a familiar toxidrome. AB - It is important for emergency physicians to be aware of new psychoactive agents being used as recreational drugs. "Bath salts," which include 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone, are the newest recreational stimulants to appear in Canada. There are currently more than 12 synthetic cathinones marketed as bath salts and used with increasing frequency recreationally. Although these drugs are now illegal in Canada, they are widely available online. We present a case report and discuss bath salts intoxication and its anticipated sympathomimetic toxidrome, treatment strategies, and toxicologic analysis, Treatment should not rely on laboratory confirmation. Since the laboratory identification of such drugs varies by institution and toxicologic assay, physicians should not misconstrue a negative toxicology screen as evidence of no exposure to synthetic cathinones. Illicit bath salts represent an increasing public health concern that involves risk to the user, prehospital personnel, and health care providers. PMID- 24626126 TI - Clinical and economic burden of bone metastasis and skeletal-related events in prostate cancer. AB - PURPOSE OF REVIEW: We review the clinical trials and observational studies literature regarding the clinical and economic burden of bone metastasis and skeletal-related events (SREs) in prostate cancer, and discuss current gaps in understanding the impact of bone metastasis in this disease. RECENT FINDINGS: Trial data indicate that SREs occur in half of prostate cancer patients with bone metastasis in the absence of treatment, and 30-45% among those who receive bone modifying agents. In the United States, the cost of SRE ranged from $7553 per radiation episode to $88 838 per bone surgery episode. Prevalence of SRE, time to SRE occurrence, and cost of SRE varied across studies because of differences in study populations, follow-up period, and the algorithm used to measure SRE. There is limited evidence on the clinical and economic impact by SRE subtype. Information regarding patient-reported outcomes and costs from the patient's perspective is lacking. SUMMARY: Bone metastasis and SREs in prostate cancer patients are associated with considerable morbidity, reduced survival, and substantial economic burden. Consistent study methodology, particularly the measurement of SREs, is necessary to allow comparison of estimates across studies. The inclusion of patient-centered clinical and economic outcomes in future research will provide pertinent information regarding the burden of bone metastasis and SREs. PMID- 24626127 TI - Oropharyngeal squamous cell carcinoma treatment: current standards and future directions. AB - PURPOSE OF REVIEW: To discuss the changing landscape and significant developments in the diagnosis and management of oropharyngeal squamous cell carcinoma. RECENT FINDINGS: High-risk human papilloma viruses (HPVs) have been recognized as important causative factors for oropharyngeal cancer. The diagnosis is established with type-specific and broad-spectrum in-situ hybridization probes and/or p16 immunohistochemistry assays on fresh frozen paraffin-embedded tissue blocks. HPV-associated tumors have superior response and outcomes compared with HPV-unrelated tumors. Retrospective studies have been able to stratify oropharyngeal squamous cell carcinoma based on HPV status, tumor stage, nodal stage, and smoking history into risk groups with differing risks of death or distant disease. Selected patients, nonsmokers with less advanced nodal stage, may be overtreated with current treatment paradigms, and deintensification of curative therapy is a current research focus for these patients. Smokers, patients with advanced nodal or tumor stage, and those with HPV-unrelated cancers have a less favorable prognosis and the search for novel targets is particularly important for these patients. SUMMARY: The present review will highlight the current standards and the future direction of novel therapies in both HPV associated and HPV-unrelated cancers. PMID- 24626128 TI - Biomarkers in prostate cancer: what's new? AB - PURPOSE OF REVIEW: This review is intended to provide an overview of the current state of biomarkers for prostate cancer (PCa), with a focus on biomarkers approved by the US Food and Drug Administration (FDA) as well as biomarkers available from Clinical Laboratory Improvement Amendment (CLIA)-certified clinical laboratories within the last 1-2 years. RECENT FINDINGS: During the past 2 years, two biomarkers have been approved by the US FDA. These include proPSA as part of the Prostate Health Index (phi) by Beckman Coulter, Inc and PCA3 as Progensa by Gen Probe, Inc. With the advances in genomic and proteomic technologies, several new CLIA-based laboratory-developed tests have become available. Examples are Oncotype DX from Genomics Health, Inc, and Prolaris from Myriad Genetics, Inc. In most cases, these new tests are based on a combination of multiple genomic or proteomic biomarkers. SUMMARY: Several new tests, as discussed in this review, have become available during the last 2 years. Although the intended use of most of these tests is to distinguish PCa from benign prostatic conditions with better sensitivity and specificity than prostate specific antigen, studies have shown that some of them may also be useful in the differentiation of aggressive from nonaggressive forms of PCa. PMID- 24626129 TI - Therapeutic options and multifaceted treatment paradigms in metastatic castrate resistant prostate cancer. AB - PURPOSE OF REVIEW: The field of prostate cancer therapeutics has undergone a rapid and dramatic change in the last few years. Multiple agents with very distinct mechanisms of actions and unique toxicities and efficacies have become available for clinical use. The focus of this review is to give a summary of clinical perspectives of the indications, including pros and cons of the currently approved regimens. The next generation of novel targets and agents is also highlighted. RECENT FINDINGS: Addition of docetaxel-based chemotherapy to conventional androgen suppression therapy in hormone sensitive advanced prostate cancer demonstrated overall survival benefit in recently released results of ECOG 3805. In castrate-resistant metastatic disease, development of novel immunotherapy (Sipuleucel T), chemotherapy (docetaxel and cabazitaxel), radiation (alpharadin) and hormone therapy (abiraterone and enzalutamide) agents has created a range of choices for treatment, palliation and improved life expectancy. SUMMARY: A paradigm shift has occurred in the management of advanced prostate cancer, with multiple novel agents addressing distinct pathways, and demonstrating powerful efficacy. The judicious use of the available agents, with finesse of sequencing, and concomitant palliative care has prolonged survival and made living with the disease more reasonable and tolerable. PMID- 24626130 TI - Quantitative proteomics of Xenopus laevis embryos: expression kinetics of nearly 4000 proteins during early development. AB - While there is a rich literature on transcription dynamics during the development of many organisms, protein data is limited. We used iTRAQ isotopic labeling and mass spectrometry to generate the largest developmental proteomic dataset for any animal. Expression dynamics of nearly 4,000 proteins of Xenopus laevis was generated from fertilized egg to neurula embryo. Expression clusters into groups. The cluster profiles accurately reflect the major events that mark changes in gene expression patterns during early Xenopus development. We observed decline in the expression of ten DNA replication factors after the midblastula transition (MBT), including a marked decline of the licensing factor XCdc6. Ectopic expression of XCdc6 leads to apoptosis; temporal changes in this protein are critical for proper development. Measurement of expression in single embryos provided no evidence for significant protein heterogeneity between embryos at the same stage of development. PMID- 24626131 TI - Speciation reversal in European whitefish (Coregonus lavaretus (L.)) caused by competitor invasion. AB - Invasion of exotic species has caused the loss of biodiversity and imparts evolutionary and ecological changes in the introduced systems. In northern Fennoscandia, European whitefish (Coregonus lavaretus (L.)) is a highly polymorphic species displaying adaptive radiations into partially reproductively isolated and thus genetically differentiated sympatric morphs utilizing the planktivorous and benthivorous food niche in many lakes. In 1993, Lake Skrukkebukta was invaded by vendace (Coregonus albula (L.)) which is a zooplanktivorous specialist. The vendace displaced the densely rakered whitefish from its preferred pelagic niche to the benthic habitat harbouring the large sparsely rakered whitefish. In this study, we investigate the potential influence of the vendace invasion on the breakdown of reproductive isolation between the two whitefish morphs. We inferred the genotypic and phenotypic differentiation between the two morphs collected at the arrival (1993) and 15 years after (2008) the vendace invasion using 16 microsatellite loci and gill raker numbers, the most distinctive adaptive phenotypic trait between them. The comparison of gill raker number distributions revealed two modes growing closer over 15 years following the invasion. Bayesian analyses of genotypes revealed that the two genetically distinct whitefish morphs that existed in 1993 had collapsed into a single population in 2008. The decline in association between the gill raker numbers and admixture values over 15 years corroborates the findings from the Bayesian analysis. Our study thus suggests an apparent decrease of reproductive isolation in a morph-pair of European whitefish within 15 years (? 3 generations) following the invasion of a superior trophic competitor (vendace) in a subarctic lake, reflecting a situation of "speciation in reverse". PMID- 24626132 TI - Modular composition of gene transcription networks. AB - Predicting the dynamic behavior of a large network from that of the composing modules is a central problem in systems and synthetic biology. Yet, this predictive ability is still largely missing because modules display context dependent behavior. One cause of context-dependence is retroactivity, a phenomenon similar to loading that influences in non-trivial ways the dynamic performance of a module upon connection to other modules. Here, we establish an analysis framework for gene transcription networks that explicitly accounts for retroactivity. Specifically, a module's key properties are encoded by three retroactivity matrices: internal, scaling, and mixing retroactivity. All of them have a physical interpretation and can be computed from macroscopic parameters (dissociation constants and promoter concentrations) and from the modules' topology. The internal retroactivity quantifies the effect of intramodular connections on an isolated module's dynamics. The scaling and mixing retroactivity establish how intermodular connections change the dynamics of connected modules. Based on these matrices and on the dynamics of modules in isolation, we can accurately predict how loading will affect the behavior of an arbitrary interconnection of modules. We illustrate implications of internal, scaling, and mixing retroactivity on the performance of recurrent network motifs, including negative autoregulation, combinatorial regulation, two-gene clocks, the toggle switch, and the single-input motif. We further provide a quantitative metric that determines how robust the dynamic behavior of a module is to interconnection with other modules. This metric can be employed both to evaluate the extent of modularity of natural networks and to establish concrete design guidelines to minimize retroactivity between modules in synthetic systems. PMID- 24626133 TI - Unraveling hepatitis C virus structure. AB - The high variability and the limited knowledge of the structure of the hepatitis C virus (HCV) envelope glycoproteins (GP) are challenging hurdles for vaccine design. Recently, Kong et al. published a new model of HCV E2 GP structure in Science, revealing a globular structure, starkly contrasting from the extended model of class II fusion proteins from other Flaviviridae viruses. PMID- 24626134 TI - Comparative taphonomy, taphofacies, and bonebeds of the Mio-Pliocene Purisima Formation, central California: strong physical control on marine vertebrate preservation in shallow marine settings. AB - BACKGROUND: Taphonomic study of marine vertebrate remains has traditionally focused on single skeletons, lagerstatten, or bonebed genesis with few attempts to document environmental gradients in preservation. As such, establishment of a concrete taphonomic model for shallow marine vertebrate assemblages is lacking. The Neogene Purisima Formation of Northern California, a richly fossiliferous unit recording nearshore to offshore depositional settings, offers a unique opportunity to examine preservational trends across these settings. METHODOLOGY/PRINCIPAL FINDINGS: Lithofacies analysis was conducted to place vertebrate fossils within a hydrodynamic and depositional environmental context. Taphonomic data including abrasion, fragmentation, phosphatization, articulation, polish, and biogenic bone modification were recorded for over 1000 vertebrate fossils of sharks, bony fish, birds, pinnipeds, odontocetes, mysticetes, sirenians, and land mammals. These data were used to compare both preservation of multiple taxa within a single lithofacies and preservation of individual taxa across lithofacies to document environmental gradients in preservation. Differential preservation between taxa indicates strong preservational bias within the Purisima Formation. Varying levels of abrasion, fragmentation, phosphatization, and articulation are strongly correlative with physical processes of sediment transport and sedimentation rate. Preservational characteristics were used to delineate four taphofacies corresponding to inner, middle, and outer shelf settings, and bonebeds. Application of sequence stratigraphic methods shows that bonebeds mark major stratigraphic discontinuities, while packages of rock between discontinuities consistently exhibit onshore-offshore changes in taphofacies. CONCLUSIONS/SIGNIFICANCE: Changes in vertebrate preservation and bonebed character between lithofacies closely correspond to onshore-offshore changes in depositional setting, indicating that the dominant control of preservation is exerted by physical processes. The strong physical control on marine vertebrate preservation and preservational bias within the Purisima Formation has implications for paleoecologic and paleobiologic studies of marine vertebrates. Evidence of preservational bias among marine vertebrates suggests that careful consideration of taphonomic overprint must be undertaken before meaningful paleoecologic interpretations of shallow marine vertebrates is attempted. PMID- 24626136 TI - The relationship between body composition and preseason performance tests of collegiate male lacrosse players. AB - Numerous studies have examined the effects that body composition has on performance in football, soccer, and ice hockey; yet, there are no similar studies examining this relationship in men's lacrosse. The purpose of the study was to examine the physiological profiles and the relationship between body composition and performance in aerobic and anaerobic tests. Fifty-four (19.63 +/- 1.21 years; 178.53 +/- 6.17 cm; 81.66 +/- 14.96 kg) Division III intercollegiate athletes participated. Performance tests, including a 1 repetition maximum power clean (PC), body weight (lbs), bench press repetitions, parallel bar triceps dips to fatigue (DR), two 300-yard shuttles, and a 1-mile run (MT), were completed after the completion of fall preseason practices. Body composition was estimated using air-displacement plethysmography. Correlation coefficients determined relationships between percent body fat (%BF), fat-free mass (FFM), and testing variables. Increased %BF was negatively correlated to DR (r = -0.36, p = 0.01) whereas positively correlated to each 300-yard shuttle time (T1 and T2), total 300-yard shuttle time (TT), and MT (r = 0.64, p = 0.00; r = 0.68, p = 0.00; r = 0.69, p = 0.00; and r = 0.44, p = 0.00, respectively). Increased FFM was positively correlated with PC (r = 0.58, p = 0.00) yet not correlated (p >= 0.05) with other variables. Results indicated that increased %BF might be a detriment to the repetitive anaerobic performance and aerobic capacity vital to on-field lacrosse performance. Body composition also demonstrated a significant relationship to moving internal vs. external resistances. PMID- 24626135 TI - Noise provides new insights on contrast sensitivity function. AB - Sensitivity to luminance difference, or contrast sensitivity, is critical for animals to survive in and interact with the external world. The contrast sensitivity function (CSF), which measures visual sensitivity to spatial patterns over a wide range of spatial frequencies, provides a comprehensive characterization of the visual system. Despite its popularity and significance in both basic research and clinical practice, it hasn't been clear what determines the CSF and how the factors underlying the CSF change in different conditions. In the current study, we applied the external noise method and perceptual template model to a wide range of external noise and spatial frequency (SF) conditions, and evaluated how the various sources of observer inefficiency changed with SF and determined the limiting factors underlying the CSF. We found that only internal additive noise and template gain changed significantly with SF, while the transducer non-linearity and coefficient for multiplicative noise were constant. The 12-parameter model provided a very good account of all the data in the 200 tested conditions (86.5%, 86.2%, 89.5%, and 96.4% for the four subjects, respectively). Our results suggest a re-consideration of the popular spatial vision model that employs the CSF as the front-end filter and constant internal additive noise across spatial frequencies. The study will also be of interest to scientists and clinicians engaged in characterizing spatial vision deficits and/or developing rehabilitation methods to restore spatial vision in clinical populations. PMID- 24626138 TI - Anthropometry and barbell trajectory in the snatch lift for elite women weightlifters. AB - The primary objective of this study was to examine relationships between anthropometry and horizontal barbell displacement during the pulling phase of the snatch lift (SN) in elite women weightlifters. Secondary objectives included description of anthropometric and displacement characteristics, and examinations of SN performance and competitive experience. Thirty-six women weightlifters competing at the 2009 Pan American Championships participated. Participants were measured for standing height, upper limb, trunk, thigh, and shank lengths, and completed a questionnaire about competition and training experience. Horizontal displacement from lift-off to first pull maximum (Dx1) and from first pull to second pull maximum (Dx2) was determined from the heaviest successful SN using 2 dimensional video analysis. Significant correlations (p <= 0.05) existed between thigh and lower-limb lengths and Dx2 in 53 kg participants; lower-limb length and Dx1 in 75 kg participants; and horizontal displacement and body segment ratios involving the upper and lower extremity in multiple weight classes. Correlations between anthropometry and Dx1 also reached significance with participants grouped by barbell trajectory type. Except for the trunk and thigh, body segment lengths were significantly different (p <= 0.05) between weight classes. Significantly different body proportions existed in 48 kg participants compared with all other classes. Multiple thigh and trunk variables were significantly correlated with performance. Horizontal displacement values were similar to previous reports in the literature. Few significant relationships existed between displacement and performance, and none were found for competitive experience. Understanding relationships between anthropometry and barbell trajectory may be useful for optimizing SN technique. PMID- 24626137 TI - Effect of run training and cold-water immersion on subsequent cycle training quality in high-performance triathletes. AB - The purpose of the study was to investigate the effect of cold-water immersion (CWI) on physiological, psychological, and biochemical markers of recovery and subsequent cycling performance after intensive run training. Seven high performance male triathletes (age: 28.6 +/- 7.1 years; cycling VO2peak: 73.4 +/- 10.2 ml . kg(-1) . min(-1)) completed 2 trials in a randomized crossover design consisting of 7 * 5-minute running intervals at 105% of individual anaerobic threshold followed by either CWI (10 +/- 0.5 degrees C) or thermoneutral water immersion (TNI; 34 +/- 0.5 degrees C). Subjects immersed their legs in water 5 times for 60 seconds with 60-second passive rest between each immersion. Nine hours after immersion, inflammatory and muscle damage markers, and perceived recovery measures were obtained before the subjects completed a 5-minute maximal cycling test followed by a high-quality cycling interval training set (6 * 5 minute intervals). Power output, heart rate, blood lactate (La), and rating of perceived exertion (RPE) were also recorded during the cycling time-trial and interval set. Performance was enhanced (change, +/- 90% confidence limits) in the CWI condition during the cycling interval training set (power output [W . kg( 1)], 2.1 +/- 1.7%, La [mmol . L(-1)], 18 +/- 18.1%, La:RPE, 19.8 +/- 17.5%). However, there was an unclear effect of CWI on 5-minute maximal cycling time trial performance, and there was no significant influence on perceptual measures of fatigue/recovery, despite small to moderate effects. The effect of CWI on the biochemical markers was mostly unclear, however, there was a substantial effect for interleukin-10 (20 +/- 13.4%). These results suggest that compared with TNI, CWI may be effective for enhancing cycling interval training performance after intensive interval-running training. PMID- 24626140 TI - Effects of a contrast training program without external load on vertical jump, kicking speed, sprint, and agility of young soccer players. AB - The purpose of this study was to determine the effects of a 12-week contrast training (CT) program (isometric + plyometric), with no external loads, on the vertical jump, kicking speed, sprinting, and agility skills of young soccer players. Thirty young soccer players (age, 15.9 +/- 1.43 years; weight, 65.4 +/- 10.84 kg; height, 171.0 +/- 0.06 cm) were randomized in a control group (n = 13) and an experimental group (n = 17). The CT program was included in the experimental group's training sessions, who undertook it twice a week as a part of their usual weekly training regime. This program included 3 exercises: 1 isometric and 2 plyometric, without external loads. These exercises progressed in volume throughout the training program. Performance in countermovement jump (CMJ), Balsom agility test (BAT), 5-, 10-, 20-, and 30-m sprint, and soccer kick were assessed before and after the training program. A 2-factor (group and time) analysis of variance revealed significant improvements (p < 0.001) in CMJ, BAT, and kicking speed in the experimental group players. Control group remained unchanged in these variables. Both groups significantly reduced sprint times over 5, 10, 20, and 30 m (p <= 0.05). A significant correlation (r = 0.492, p < 0.001) was revealed between DeltaBAT and Deltaaverage kicking speed. Results suggest that a specific CT program without external loads is effective for improving soccer-specific skills such as vertical jump, sprint, agility, and kicking speed in young soccer players. PMID- 24626096 TI - Factors associated with D-dimer levels in HIV-infected individuals. AB - BACKGROUND: Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood. METHODS: In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol. RESULTS: Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL 6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high density lipoprotein cholesterol were negatively correlated with D-dimer levels. CONCLUSIONS: D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels. PMID- 24626141 TI - A comparison of three different start techniques on sprint speed in collegiate linebackers. AB - The purpose of this study was to compare the track block start (BS), rhythm step (false step) (RS), and forward step (FS) on sprint start ability in male Division I collegiate football linebackers. Although the blocks are not practical in the sport of football, they were used as a gold standard for sprint acceleration. Sixteen collegiate football linebackers (age, 20.9 +/- 1.1 years; height, 72 +/- 3.0 in; mass, 97 +/- 4 kg) performed 3 repetitions each of the BS, FS, and RS. Each sprint was videotaped through 5 m. The time from 0 to 2.5 m (t2.5), 0 to 5 m (t5), and 2.5 to 5 m (tsplit) were calculated for each trial using all 3 different techniques, and the best times for each treatment was recorded. Block start resulted in significantly lower t2.5 and t5 compared with RS and FS. Rhythm step had significantly lower t2.5 and t5 compared with FS. There was no difference in tsplit between any of the 3 treatments. The results indicate that using the blocks is optimal for sprint performance through 2.5 and 5 m. Rhythm step outperformed FS through both 2.5 and 5 m, suggesting that for collegiate football linebackers, RS is superior to FS. PMID- 24626142 TI - Multiarticular isokinetic high-load eccentric training induces large increases in eccentric and concentric strength and jumping performance. AB - This study investigated the effects of short-term eccentric exercise training using a custom-made isokinetic leg press device, on concentric and eccentric strength and explosiveness as well as jumping performance. Nineteen healthy males were divided into an eccentric (ECC, n = 10) and a control group (CG, n = 9). The ECC group trained twice per week for 8 weeks using an isokinetic hydraulic leg press machine against progressively increasing resistance ranging from 70 to 90% of maximal eccentric force. Jumping performance and maximal force generating capacity were measured before and after eccentric training. In the ECC group, drop jump (DJ) height and maximal power were increased by 13.6 +/- 3.2% (p < 0.01) and 25.8 +/- 1.2% (p < 0.01), whereas ground contact time was decreased by 17.6 +/- 2.6% (p < 0.01). Changes in ankle, knee, and hip joint angles were also reduced by 33.9 +/- 1.1%, 31.1 +/- 1.0%, and 32.4 +/- 1.6% (all p < 0.01), respectively, indicating an increase in muscle stiffness during the DJ. Maximal eccentric and concentric leg press force was increased by 64.9 +/- 5.5% (p < 0.01) and 32.2 +/- 8.8% (p < 0.01), respectively, and explosiveness, measured as force attained in the first 300 milliseconds, was increased by 49.1 +/- 4.8% (p < 0.01) and 77.1 +/- 7.7% (p < 0.01), respectively. The CG did not show any statistically significant changes in all parameters measured. The main findings of this study were that maximal concentric and eccentric force, explosiveness, and DJ performance were markedly increased after only 16 training sessions, possibly because of the high eccentric load attained during the bilateral eccentric leg press exercise performed on this custom-made device. PMID- 24626143 TI - A knowledge generation model via the hypernetwork. AB - The influence of the statistical properties of the network on the knowledge diffusion has been extensively studied. However, the structure evolution and the knowledge generation processes are always integrated simultaneously. By introducing the Cobb-Douglas production function and treating the knowledge growth as a cooperative production of knowledge, in this paper, we present two knowledge-generation dynamic evolving models based on different evolving mechanisms. The first model, named "HDPH model," adopts the hyperedge growth and the hyperdegree preferential attachment mechanisms. The second model, named "KSPH model," adopts the hyperedge growth and the knowledge stock preferential attachment mechanisms. We investigate the effect of the parameters (alpha,beta) on the total knowledge stock of the two models. The hyperdegree distribution of the HDPH model can be theoretically analyzed by the mean-field theory. The analytic result indicates that the hyperdegree distribution of the HDPH model obeys the power-law distribution and the exponent is gamma = 2 + 1/m. Furthermore, we present the distributions of the knowledge stock for different parameters (alpha,beta). The findings indicate that our proposed models could be helpful for deeply understanding the scientific research cooperation. PMID- 24626144 TI - Immunomodulatory of selenium nano-particles decorated by sulfated Ganoderma lucidum polysaccharides. AB - In this study, we employed a one-step method to prepare selenium nanoparticles (SeNPs) decorated by the water-soluble derivative of Ganoderma lucidum polysaccharides (SPS). The SeNPs-SPS complexes were stable, and the diameter of the SeNPs was homogeneous at around 25 nm. We investigated the anti-inflammatory activity of SeNPs-SPS against murine Raw 264.7 macrophage cells induced by LPS. SeNPs-SPS were found to significantly inhibit LPS-stimulated nitric oxide (NO) production against Raw 264.7 macrophages. RT-PCR results reveal the down regulation of mRNA gene expressions for pro-inflammatory cytokines, including inducible NO synthase (iNOS), interleukin (IL)-1 and TNF-alpha in a dose dependent manner. However, the anti-inflammation cytokine IL-10 was markedly increased. In the NF-kappaB signal pathway, SeNPs-SPS significantly inhibited the phosphorylation of Ikappa-Balpha. Similar results were observed for inhibition of the phosphorylation of JNK1/2 and p38 mitogen-activated protein kinase(MAPKs), whereas ERK1/2 MAPK was not apparently affected by SeNPs-SPS. All of these results suggest that SeNPs-SPS complexes have anti-inflammatory potential modulating pro-/anti-inflammation cytokine secretion profiles, and that the mechanism is partially due to inhibition of activations of NF-kappaB, JNK1/2 and p38 MAPKs. PMID- 24626145 TI - Daily Automated Telephone Assessment and Intervention Improved 1-Month Outcome in Paroled Offenders. AB - This randomized trial evaluates whether automated telephony could be used to perform daily assessments in paroled offenders (N = 108) during their first 30 days after leaving prison. All subjects were called daily and answered assessment questions. Based on the content of their daily assessments, subjects in the intervention group received immediate feedback and a recommendation by automated telephony, and their probation officers also received a daily report by email. The outcome variables were analyzed using linear mixed models. The intervention group showed greater improvement than the control group in the summary scores (M = 9.6, 95% confidence interval [CI] = [0.5, 18.7], p = .038), in mental symptoms (M = 4.6, CI = [0.2, 9.0], p = .042), in alcohol drinking (M = 0.8, CI = [0.1, 1.4], p = .031), in drug use (M = 1.0, CI = [0.5, 1.6], p = .000), and in most stressful daily event (M = 1.9, CI = [1.1, 2.7], p = .000). In conclusion, automated telephony may be used to follow up and to give interventions, resulting in reduced stress and drug use, in paroled offenders. PMID- 24626146 TI - Inhibition of KIF22 suppresses cancer cell proliferation by delaying mitotic exit through upregulating CDC25C expression. AB - KIF22 is a microtubule-dependent molecular motor protein with DNA-binding capacity. It is well known that KIF22 plays a critical role in cell mitosis as a motor protein; however, the role of altered KIF22 expression and its transcriptional regulatory function in cancer development have not yet been defined. This study showed that KIF22 was overexpressed in human cancer tissues, and inhibition of KIF22 significantly led to accumulation of cells in the G2/M phases, resulting in suppression of cancer cell proliferation. The investigation of the molecular mechanisms demonstrated that cell division cycle 25C (CDC25C) is a direct transcriptional target of KIF22, and inhibition of KIF22 increased CDC25C expression and cyclin-dependent kinase 1 (CDK1) activity, resulting in delayed mitotic exit. Phosphorylation of KIF22 was required for its transcriptional regulatory function and the reduction of CDK1 activity. Thus, we conclude that inhibition of KIF22 suppresses cancer cell proliferation by delaying mitotic exit through the transcriptional upregulation of CDC25C. PMID- 24626147 TI - Evaluation of systematic assessment of asthma-like symptoms and tobacco smoke exposure in early childhood by well-child professionals: a randomised trial. AB - OBJECTIVES: This study aimed to evaluate the effectiveness of systematic assessment of asthma-like symptoms and environmental tobacco smoke (ETS) exposure during regular preventive well-child visits between age 1 and 4 years by well child professionals. METHODS: Sixteen well-child centres in Rotterdam, the Netherlands, were randomised into 8 centres where the brief assessment form regarding asthma-like symptoms and ETS exposure was used and 8 centres that applied usual care. 3596 and 4179 children (born between April 2002 and January 2006) and their parents visited the intervention and control centres, respectively. At child's age 6 years, physician-diagnosed asthma ever, wheezing, fractional exhaled nitric oxide (FeNO), airway resistance (Rint), health-related quality of life (HRQOL) and ETS exposure at home ever were measured. Linear mixed models were applied. RESULTS: No differences in asthma, wheezing, FeNO, Rint or HRQOL measurements between intervention and control group were found using multilevel regression in an intention-to-treat analysis (p>0.05). Children of whom the parents were interviewed by using the brief assessment form at the intervention well-child centres had a decreased risk on ETS exposure at home ever, compared to children who visited the control well-child centres, in an explorative per-protocol analysis (aOR = 0.71, 95% CI:0.59-0.87). CONCLUSIONS: Systematic assessment and counselling of asthma-like symptoms and ETS exposure in early childhood by well-child care professionals using a brief assessment form was not effective in reducing the prevalence of physician-diagnosed asthma ever and wheezing, and did not improve FeNO, Rint or HRQOL at age 6 years. Our results hold some promise for interviewing parents and using information leaflets at well child centres to reduce ETS exposure at home in preschool children. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN15790308. PMID- 24626148 TI - Congenital malaria in China. AB - BACKGROUND: Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria-endemic regions. It is recognized as a serious problem in Plasmodium falciparum-endemic sub-Saharan Africa, where recent data suggests that it is more common than previously believed. In such regions where malaria transmission is high, neonates may be protected from disease caused by congenital malaria through the transfer of maternal antibodies against the parasite. However, in low P. vivax-endemic regions, immunity to vivax malaria is low; thus, there is the likelihood that congenital vivax malaria poses a more significant threat to newborn health. Malaria had previously been a major parasitic disease in China, and congenital malaria case reports in Chinese offer valuable information for understanding the risks posed by congenital malaria to neonatal health. As most of the literature documenting congenital malaria cases in China are written in Chinese and therefore are not easily accessible to the global malaria research community, we have undertaken an extensive review of the Chinese literature on this subject. METHODS/PRINCIPAL FINDINGS: Here, we reviewed congenital malaria cases from three major searchable Chinese journal databases, concentrating on data from 1915 through 2011. Following extensive screening, a total of 104 cases of congenital malaria were identified. These cases were distributed mainly in the eastern, central, and southern regions of China, as well as in the low-lying region of southwest China. The dominant species was P. vivax (92.50%), reflecting the malaria parasite species distribution in China. The leading clinical presentation was fever, and other clinical presentations were anaemia, jaundice, paleness, diarrhoea, vomiting, and general weakness. With the exception of two cases, all patients were cured with antimalarial drugs such as chloroquine, quinine, artemether, and artesunate. CONCLUSIONS: The symptoms of congenital malaria vary significantly between cases, so clear and early diagnosis is difficult. We suggest that active surveillance might be necessary for neonates born to mothers with a history of malaria. PMID- 24626149 TI - Mean field approximation for biased diffusion on Japanese inter-firm trading network. AB - By analysing the financial data of firms across Japan, a nonlinear power law with an exponent of 1.3 was observed between the number of business partners (i.e. the degree of the inter-firm trading network) and sales. In a previous study using numerical simulations, we found that this scaling can be explained by both the money-transport model, where a firm (i.e. customer) distributes money to its out edges (suppliers) in proportion to the in-degree of destinations, and by the correlations among the Japanese inter-firm trading network. However, in this previous study, we could not specifically identify what types of structure properties (or correlations) of the network determine the 1.3 exponent. In the present study, we more clearly elucidate the relationship between this nonlinear scaling and the network structure by applying mean-field approximation of the diffusion in a complex network to this money-transport model. Using theoretical analysis, we obtained the mean-field solution of the model and found that, in the case of the Japanese firms, the scaling exponent of 1.3 can be determined from the power law of the average degree of the nearest neighbours of the network with an exponent of -0.7. PMID- 24626150 TI - Does stress within a muscle change in response to an acute noxious stimulus? AB - BACKGROUND: Altered muscle activation during pain is thought to redistribute stress within muscles and ultimately decrease the load on painful structures. However, change in muscle stress during pain has not been directly tested. The aim of the present study is to determine whether stress within muscle tissue is reduced during local acute experimental pain. METHODS AND RESULTS: Ten participants attended 2 experimental sessions that each involved isometric knee extension tasks in 2 series of control trials and 1 series of test trials at ~10%MVC. Shear elastic modulus was measured from vastus lateralis using a shear wave elastographic technique (Supersonic Shear Imaging). Prior to the test contractions, a bolus of hypertonic (Pain) or isotonic saline (No-pain) was injected into vastus lateralis. Pain intensity was 5.2+/-1.0 during the painful contractions. The intra-session repeatability of the shear elastic modulus determined between control trials was good (ICC: 0.95 and 0.99; SEM: 5.1 and 9.3 kPa for No-pain and Pain, respectively). Muscle shear elastic modulus did not change systematically during Pain or No-pain contractions (all main effects and interaction P>0.14). Examination of data for individual participants showed that stress either increased or decreased. If the absolute change in modulus is considered between the control and the test trials, the change during Pain (16.2+/-9.5 kPa) was double that observed with No pain (7.9+/-5.9 kPa; P = 0.046). CONCLUSION: This is the first study to directly determine the change in stress within a muscle (change in shear elastic modulus) during pain. We conclude that experimental pain induced by hypertonic saline does not induce a systematic reduction in muscle stress during a single-joint isometric task. Therefore, the changes in muscle activity reported previously during similar tasks are unlikely to systematically reduce load in the painful region. Whether the individual specific increase and decrease are physiologically relevant or purposeful requires further investigation. PMID- 24626151 TI - Secreted Candida parapsilosis lipase modulates the immune response of primary human macrophages. AB - Candida parapsilosis is an important opportunistic pathogen with increasing prevalence. Extracellular lipases have been shown to play an important role in the virulence of pathogenic Candida species. However, studying the role of secreted lipase in C. albicans is challenging due to the lack of a mutant strain deficient in all 10 lipase genes. In contrast, we have previously constructed a lipase mutant C. parapsilosis strain lacking both CpLIP1 and CpLIP2, and shown that it has significantly decreased virulence in various infection models, and is killed more efficiently by mouse macrophages. In the present study, we compared the response of human peripheral blood monocyte-derived macrophages to a wild type (wt) as well as a lipase-deficient (lip(-/-)) C. parapsilosis strain that has been previously established in our lab. Although macrophages phagocytosed both strains with similar efficiency, lipase mutants were killed more efficiently according to fluorescent microscopic analysis. The more efficient killing of lip( /-) cells was confirmed by CFU-determinations. Phagocytosis of wt and lip(-/-)C. parapsilosis was also examined by flow cytometry, revealing that both strains were internelized to the similar extent by macrophages. Additionally, quantitative imaging analysis revealed that the rate of phagolysosome fusion was higher in case of lip(-/-)C. parapsilosis. Interestingly, macrophages stimulated with lip(-/-)C. parapsilosis showed at least 1.5-fold higher expression of TNFalpha, IL-1beta, IL-6, IL-8, and PTGS-2 after 12 h compared with those infected with wt C. parapsilosis, as determined by qRT-PCR. Furthermore, the lip( /-)C. parapsilosis strain induced significantly higher TNFalpha, IL-1beta, IL-6, and IL-10 protein production in macrophages after 24 h compared with the wt strain. These findings confirm the role of fungal lipases as important virulence factors during C. parapsilosis infection. PMID- 24626152 TI - Effect of demecolcine-assisted enucleation on the MPF level and cyclin B1 distribution in porcine oocytes. AB - Demecolcine (DEM) treatment of oocytes induces formation of a membrane protrusion containing a mass of condensed maternal chromosomes, which can be removed with minimal damage prior to somatic cell nuclear transfer (SCNT). However, the effect of this method on the distribution of maturation-promoting factor (MPF) in porcine oocytes has not been reported. Here, the level of MPF and the distribution of cyclin B1 were assessed in porcine oocytes following DEM treatment. In addition, the efficiencies of DEM-assisted and mechanical enucleation were compared, as were the development (in vitro and in vivo) of these oocytes following SCNT. MPF was uniformly distributed in oocytes that had been treated with 0.4 MUg/ml DEM for 1 h. Immunofluorescence microscopy showed that in untreated oocytes, cyclin B1, the regulatory subunit of MPF, accumulated around the spindle, and was lowly detected in the cytoplasm. DEM treatment disrupted spindle microtubules, induced chromosome condensation, and reduced the level of cyclin B1 in the nuclear region. Cyclin B1 was uniformly distributed in DEM-treated oocytes and the level of MPF was increased. The potential of embryos generated from DEM-treated oocytes to develop in vivo was significantly greater than that of embryos generated from mechanically enucleated oocytes. This is the first study to report the effects of DEM-assisted enucleation of porcine oocytes on the distribution of cyclin B1. MPF in mature oocytes is important for the development of reconstructed embryos and for efficient SCNT. PMID- 24626153 TI - Anti-cancer small molecule JP-8g exhibits potent in vivo anti-inflammatory activity. AB - Spirooxindoles are a class of compounds with diverse biological activity. Previously, we identified a series of spirooxindole-pyranopyrimidine compounds that exhibited broad-spectrum anti-cancer activity. In this study, we evaluated one of these compounds, JP-8g, on mouse models and found that it showed potent in vivo anti-inflammatory activity. Further investigation suggested that JP-8g may execute its anti-inflammatory activity through nitric oxide synthase signaling pathways. Our results suggest that these spirooxindole-pyranopyrimidine class compounds have potential for not only cancer treatment but also inflammation therapy. PMID- 24626154 TI - Assembly of Nsp1 nucleoporins provides insight into nuclear pore complex gating. AB - Nuclear pore complexes (NPCs) form gateways for material transfer across the nuclear envelope of eukaryotic cells. Disordered proteins, rich in phenylalanine glycine repeat motifs (FG-nups), form the central transport channel. Understanding how nups are arranged in the interior of the NPC may explain how NPC functions as a selectivity filter for transport of large molecules and a sieve-like filter for diffusion of small molecules (<9 nm or 40 kDa). We employed molecular dynamics to model the structures formed by various assemblies of one kind of nup, namely the 609-aa-long FG domain of Nsp1 (Nsp1-FG). The simulations started from different initial conformations and geometrical arrangements of Nsp1 FGs. In all cases Nsp1-FGs collectively formed brush-like structures with bristles made of bundles of 2-27 nups, however, the bundles being cross-linked through single nups leaving one bundle and joining a nearby one. The degree of cross-linking varies with different initial nup conformations and arrangements. Structural analysis reveals that FG-repeats of the nups not only involve formation of bundle structures, but are abundantly present in cross-linking regions where the epitopes of FG-repeats are highly accessible. Large molecules that are assisted by transport factors (TFs) are selectively transported through NPC apparently by binding to FG-nups through populated FG-binding pockets on the TF surface. Therefore, our finding suggests that TFs bind concertedly to multiple FGs in cross-linking regions and break-up the bundles to create wide pores for themselves and their cargoes to pass. In addition, the cross-linking between Nsp1 FG bundles, arising from simulations, is found to set a molecular size limit of <9 nm (40 kDa) for passive diffusion of molecules. Our simulations suggest that the NPC central channel, near the periphery where tethering of nups is dominant, features brush-like moderately cross-linked bundles, but in the central region, where tethering loses its effect, features a sieve-like structure of bundles and frequent cross-links. PMID- 24626155 TI - Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms. AB - Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents. PMID- 24626156 TI - Fluconazole prophylaxis for prevention of invasive candidiasis in infants. AB - PURPOSE OF REVIEW: Invasive candidiasis is a serious infection in hospitalized infants that results in significant mortality and morbidity. Fluconazole is approved by the US Food and Drug Administration for prophylaxis of invasive candidiasis in patients undergoing bone marrow transplantation but is not approved for use in infants. This review will describe the history of fluconazole use for prophylaxis in infants. RECENT FINDINGS: Limiting fluconazole prophylaxis to infants with risk factors, in addition to low birth weight and early gestational age, reduces the number of infants treated with fluconazole and the duration of fluconazole therapy for each infant. SUMMARY: Fluconazole prophylaxis appears to be well tolerated for use in premature infants. Reduction in the incidence of invasive candidiasis is observed even when prophylaxis is limited to infants with multiple risk factors. Centers with a low incidence of invasive candidiasis may not benefit from fluconazole prophylaxis. Significant short-term and long-term toxicity and increases in fluconazole-resistant organisms have not been observed with fluconazole use in the intensive care nursery. PMID- 24626158 TI - Hydrodynamic delivery of Cre protein to lineage-mark or time-stamp mouse hepatocytes in situ. AB - Cre-responsive fluorescent marker alleles are powerful tools for cell lineage tracing in mice; however their utility is limited by regulation of Cre activity. When targeting hepatocytes, hydrodynamic delivery of a Cre-expression plasmid can convert Cre-responsive alleles without inducing the intracellular or systemic antiviral responses often associated with viral-derived Cre-expression vectors. In this method, rapid high-volume intravenous inoculation induces hepatocyte targeted uptake of extracellular molecules. Here we tested whether hydrodynamic delivery of Cre protein or Cre fused to the HIV-TAT cell-penetrating peptide could convert Cre-responsive reporters in hepatocytes of mice. Hydrodynamic delivery of 2 nmol of either Cre or TAT-Cre protein converted the reporter allele in 5 to 20% of hepatocytes. Neither protein gave detectable Cre activity in endothelia, non-liver organs, or non-hepatocyte cells in liver. Using mice homozygous for a Cre-responsive marker that directs red- (Cre-naive) or green- (Cre-converted) fluorescent proteins to the nucleus, we assessed sub-saturation Cre-activity. One month after hydrodynamic inoculation with Cre protein, 58% of hepatocyte nuclei that were green were also red, indicating that less than half of the hepatocytes that had obtained enough Cre to convert one marker allele to green were able to convert all alleles. For comparison, one month after hydrodynamic delivery of a Cre-expression plasmid with a weak promoter, only 26% of the green nuclei were also red. Our results show that hydrodynamic delivery of Cre protein allows rapid allelic conversion in hepatocytes, but Cre-activity is sub-saturating so many cells will not convert multiple Cre-responsive alleles. PMID- 24626159 TI - Modulation of glycinergic synaptic transmission in the trigeminal and hypoglossal motor nuclei by the nitric oxide-cyclicGMP signaling pathway. AB - In a previous work we found that nitric oxide (NO) and cyclicGMP (cGMP) inhibit glutamatergic synaptic transmission in trigeminal motoneurons (MnV). Here we study the actions of the NO/cGMP signaling pathway on glycinergic synaptic transmission in trigeminal and hypoglossal motoneurons (MnXII) in brain stem slices of neonatal rats. Glycinergic inhibitory postsynaptic currents (IPSCs) were recorded in MnV by stimulation of the supratrigeminal nucleus (SuV) and in MnXII by stimulation of the nucleus of Roller. The NO donor DETA/NONOate (DETA/NO) reduced the amplitude of the IPSC to 58.1+/-4.2% of control values in MnV. In the presence of YC-1, a modulator of guanylate cyclase that acts as a NO sensitizer, lower and otherwise ineffective concentrations of DETA/NO induced a reduction of the IPSC to 47.2+/-15.6%. NO effects were mimicked by 8 bromo cyclicGMP (8BrcGMP). They were accompanied by an increase in the paired pulse facilitation (PPF) and in the failure rate of evoked IPSCs. 8BrcGMP did not modify the glycinergic currents elicited by exogenous glycine. In MnXII the IPSCs were also reduced by NO donors and 8BrcGMP to 52.9+/-6.3% and 45.9+/-4% of control values, respectively. In these neurons, but not in MnV, we also observed excitatory postsynaptic actions of NO donors. We propose that the differences between the two motor pools may be due to a differential development of the nitrergic system in the two nuclei. Our data show that NO, through its second messenger cGMP, reduces inhibitory glycinergic synaptic transmission in both MnV and MnXII. For MnV, evidence in favor of presynaptic inhibition of glycine release is presented. Given our previous data together with the current results, we propose that the NO/cGMP signaling pathway participates pre- and postsynaptically in the combined regulation of MnV and MnXII activities in motor acts in which they participate. PMID- 24626160 TI - Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X. AB - Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only ~10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2(T158A/)(+)) or a nonsense mutation R168X (Mecp2(R168X/+)). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2(T158A/+) and Mecp2(R168X/+) heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild-type controls. Interestingly, the incidence of apnea was much greater in Mecp2(R168X/+) heterozygotes, 189 per hour, than Mecp2(T158A/+) heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT. PMID- 24626161 TI - Genome-wide association study identified copy number variants important for appendicular lean mass. AB - Skeletal muscle is a major component of the human body. Age-related loss of muscle mass and function contributes to some public health problems such as sarcopenia and osteoporosis. Skeletal muscle, mainly composed of appendicular lean mass (ALM), is a heritable trait. Copy number variation (CNV) is a common type of human genome variant which may play an important role in the etiology of many human diseases. In this study, we performed genome-wide association analyses of CNV for ALM in 2,286 Caucasian subjects. We then replicated the major findings in 1,627 Chinese subjects. Two CNVs, CNV1191 and CNV2580, were detected to be associated with ALM (p = 2.26*10(-2) and 3.34*10(-3), respectively). In the Chinese replication sample, the two CNVs achieved p-values of 3.26*10(-2) and 0.107, respectively. CNV1191 covers a gene, GTPase of the immunity-associated protein family (GIMAP1), which is important for skeletal muscle cell survival/death in humans. CNV2580 is located in the Serine hydrolase-like protein (SERHL) gene, which plays an important role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli. In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM. PMID- 24626162 TI - Pointing in visual periphery: is DF's dorsal stream intact? AB - Observations of the visual form agnosic patient DF have been highly influential in establishing the hypothesis that separate processing streams deal with vision for perception (ventral stream) and vision for action (dorsal stream). In this context, DF's preserved ability to perform visually-guided actions has been contrasted with the selective impairment of visuomotor performance in optic ataxia patients suffering from damage to dorsal stream areas. However, the recent finding that DF shows a thinning of the grey matter in the dorsal stream regions of both hemispheres in combination with the observation that her right-handed movements are impaired when they are performed in visual periphery has opened up the possibility that patient DF may potentially also be suffering from optic ataxia. If lesions to the posterior parietal cortex (dorsal stream) are bilateral, pointing and reaching deficits should be observed in both visual hemifields and for both hands when targets are viewed in visual periphery. Here, we tested DF's visuomotor performance when pointing with her left and her right hand toward targets presented in the left and the right visual field at three different visual eccentricities. Our results indicate that DF shows large and consistent impairments in all conditions. These findings imply that DF's dorsal stream atrophies are functionally relevant and hence challenge the idea that patient DF's seemingly normal visuomotor behaviour can be attributed to her intact dorsal stream. Instead, DF seems to be a patient who suffers from combined ventral and dorsal stream damage meaning that a new account is needed to explain why she shows such remarkably normal visuomotor behaviour in a number of tasks and conditions. PMID- 24626164 TI - A regulatory structure for working with genetically modified mosquitoes: lessons from Mexico. PMID- 24626163 TI - Impact of tumour epithelial subtype on circulating microRNAs in breast cancer patients. AB - While a range of miRNAs have been shown to be dysregulated in the circulation of patients with breast cancer, little is known about the relationship between circulating levels and tumour characteristics. The aim of this study was to analyse alterations in circulating miRNA expression during tumour progression in a murine model of breast cancer, and to detemine the clinical relevance of identified miRNAs at both tissue and circulating level in patient samples. Athymic nude mice received a subcutaneous or mammary fat pad injection of MDA-MB 231 cells. Blood sampling was performed at weeks 1, 3 and 6 following tumour induction, and microRNA extracted. MicroRNA microArray analysis was performed comparing samples harvested at week 1 to those collected at week 6 from the same animals. Significantly altered miRNAs were validated across all murine samples by RQ-PCR (n = 45). Three miRNAs of interest were then quantified in the circulation(n = 166) and tissue (n = 100) of breast cancer patients and healthy control individuals. MicroArray-based analysis of murine blood samples revealed levels of 77 circulating microRNAs to be changed during disease progression, with 44 demonstrating changes >2-fold. Validation across all samples revealed miR-138 to be significantly elevated in the circulation of animals during disease development, with miR-191 and miR-106a levels significantly decreased. Analysis of patient tissue and blood samples revealed miR-138 to be significantly up regulated in the circulation of patients with breast cancer, with no change observed in the tissue setting. While not significantly changed overall in breast cancer patients compared to controls, circulating miR-106a and miR-191 were significantly decreased in patients with basal breast cancer. In tissue, both miRNAs were significantly elevated in breast cancer compared to normal breast tissue. The data demonstrates an impact of tumour epithelial subtype on circulating levels of miRNAs, and highlights divergent miRNA profiles between tissue and blood samples from breast cancer patients. PMID- 24626165 TI - Modeling the impact on HIV incidence of combination prevention strategies among men who have sex with men in Beijing, China. AB - OBJECTIVE: To project the HIV/AIDS epidemics among men who have sex with men (MSM) under different combinations of HIV testing and linkage to care (TLC) interventions including antiretroviral therapy (ART) in Beijing, China. DESIGN: Mathematical modeling. METHODS: Using a mathematical model to fit prevalence estimates from 2000-2010, we projected trends in HIV prevalence and incidence during 2011-2020 under five scenarios: (S1) current intervention levels by averaging 2000-2010 coverage; (S2) increased ART coverage with current TLC; (S3) increased TLC/ART coverage; (S4) increased condom use; and (S5) increased TLC/ART plus increased condom use. RESULTS: The basic reproduction number based upon the current level of interventions is significantly higher than 1 (R0 = 2.09; 95% confidence interval (CI), 1.83-2.35), suggesting that the HIV epidemic will continue to increase to 2020. Compared to the 2010 prevalence of 7.8%, the projected HIV prevalence in 2020 for the five prevention scenarios will be: (S1) Current coverage: 21.4% (95% CI, 9.9-31.7%); (S2) Increased ART: 19.9% (95% CI, 9.9-28.4%); (S3) Increased TLC/ART: 14.5% (95% CI, 7.0-23.8%); (S4) Increased condom use: 13.0% (95% CI, 9.8-28.4%); and (S5) Increased TLC/ART and condom use: 8.7% (95% CI, 5.4-11.5%). HIV epidemic will continue to rise (R0 > 1) for S1-S4 even with hyperbolic coverage in the sensitivity analysis, and is expected to decline (R0 = 0.93) for S5. CONCLUSION: Our transmission model suggests that Beijing MSM will have a rapidly rising HIV epidemic. Even enhanced levels of TLC/ART will not interrupt epidemic expansion, despite optimistic assumptions for coverage. Promoting condom use is a crucial component of combination interventions. PMID- 24626167 TI - Ovarian paraganglioma. AB - A rare case of ovarian paraganglioma was incidentally found as a 1.2-cm intraovarian mass in a 68-year-old hypertensive female operated for an endometrial carcinoma. Histologically, it was arranged in characteristic Zellballen composed of polygonal clear cells with a granular cytoplasm that expressed diffusely CAM5.2 cytokeratin, chromogranin, neuron-specific enolase, synaptophysin, and CD56, while S-100 protein was only present in sustentacular cells. We analyzed differential diagnoses with other rare ovarian tumors such as Sertoli cell tumor, with which it may share an immunophenotype expressing cytokeratins, S-100, and other neural markers, and extra-axial ependymoma, which invariably expresses diffusely GFAP, that may be positive only in the sustentacular cells of paraganglioma. However, on simple hematoxylin-eosin inspection, ovarian paraganglioma displays characteristic Zellballen clusters and cells with a granular cytoplasm but lacks the distinctive Sertoli cell tubules and the characteristic rosettes and fibrillary cytoplasm of ependymoma. Pathologists should be aware of the unusual locations of paraganglioma. PMID- 24626166 TI - A model system for studying the transcriptomic and physiological changes associated with mammalian host-adaptation by Leptospira interrogans serovar Copenhageni. AB - Leptospirosis, an emerging zoonotic disease with worldwide distribution, is caused by spirochetes belonging to the genus Leptospira. More than 500,000 cases of severe leptospirosis are reported annually, with >10% of these being fatal. Leptospires can survive for weeks in suitably moist conditions before encountering a new host. Reservoir hosts, typically rodents, exhibit little to no signs of disease but shed large numbers of organisms in their urine. Transmission occurs when mucosal surfaces or abraded skin come into contact with infected urine or urine-contaminated water or soil. In humans, leptospires can cause a variety of clinical manifestations, ranging from asymptomatic or mild fever to severe icteric (Weil's) disease and pulmonary haemorrhage. Currently, little is known about how Leptospira persist within a reservoir host. Prior in vitro studies have suggested that leptospires alter their transcriptomic and proteomic profiles in response to environmental signals encountered during mammalian infection. However, no study has examined gene expression by leptospires within a mammalian host-adapted state. To obtain a more faithful representation of how leptospires respond to host-derived signals, we used RNA-Seq to compare the transcriptome of L. interrogans cultivated within dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats with that of organisms grown in vitro. In addition to determining the relative expression levels of "core" housekeeping genes under both growth conditions, we identified 166 genes that are differentially-expressed by L. interrogans in vivo. Our analyses highlight physiological aspects of host adaptation by leptospires relating to heme uptake and utilization. We also identified 11 novel non-coding transcripts that are candidate small regulatory RNAs. The DMC model provides a facile system for studying the transcriptional and antigenic changes associated with mammalian host-adaptation, selection of targets for mutagenesis, and the identification of previously unrecognized virulence determinants. PMID- 24626169 TI - New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development. AB - To achieve immune homeostasis in such a harsh environment as the intestinal mucosa, both active and quiescent immunity operate simultaneously. Disruption of gut immune homeostasis leads to the development of intestinal immune diseases such as colitis and food allergies. Among various intestinal innate immune cells, mast cells (MCs) play critical roles in protective immunity against pathogenic microorganisms, especially at mucosal sites. This suggests the potential for a novel MC-targeting type of vaccine adjuvant. Dysregulated activation of MCs also results in inflammatory responses in mucosal compartments. The regulation of this yin and yang function of MCs remains to be elucidated. In this review, we focus on the roles of mucosal MCs in the regulation of intestinal allergic reaction, inflammation and their potential as a new target for the development of mucosal adjuvants. PMID- 24626170 TI - Mucosal dendritic cells shape mucosal immunity. AB - Dendritic cells (DCs) are key modulators that shape the immune system. In mucosal tissues, DCs act as surveillance systems to sense infection and also function as professional antigen-presenting cells that stimulate the differentiation of naive T and B cells. On the basis of their molecular expression, DCs can be divided into several subsets with unique functions. In this review, we focus on intestinal DC subsets and their function in bridging the innate signaling and adaptive immune systems to maintain the homeostasis of the intestinal immune environment. We also review the current strategies for manipulating mucosal DCs for the development of efficient mucosal vaccines to protect against infectious diseases. PMID- 24626168 TI - Regulatory T-cell vaccination independent of auto-antigen. AB - To date, efforts to treat autoimmune diseases have primarily focused on the disease symptoms rather than on the cause of the disease. In large part, this is attributed to not knowing the responsible auto-antigens (auto-Ags) for driving the self-reactivity coupled with the poor success of treating autoimmune diseases using oral tolerance methods. Nonetheless, if tolerogenic approaches or methods that stimulate regulatory T (Treg) cells can be devised, these could subdue autoimmune diseases. To forward such efforts, our approach with colonization factor antigen I (CFA/I) fimbriae is to establish bystander immunity to ultimately drive the development of auto-Ag-specific Treg cells. Using an attenuated Salmonella vaccine expressing CFA/I fimbriae, fimbriae-specific Treg cells were induced without compromising the vaccine's capacity to protect against travelers' diarrhea or salmonellosis. By adapting the vaccine's anti-inflammatory properties, it was found that it could also dampen experimental inflammatory diseases resembling multiple sclerosis (MS) and rheumatoid arthritis. Because of this bystander effect, disease-specific Treg cells are eventually induced to resolve disease. Interestingly, this same vaccine could elicit the required Treg cell subset for each disease. For MS-like disease, conventional CD25(+) Treg cells are stimulated, but for arthritis CD39(+) Treg cells are induced instead. This review article will examine the potential of treating autoimmune diseases without having previous knowledge of the auto-Ag using an innocuous antigen to stimulate Treg cells via the production of transforming growth factor-beta and interleukin-10. PMID- 24626172 TI - Recent progress in mucosal immunology and vaccine development. PMID- 24626171 TI - Antigen targeting to M cells for enhancing the efficacy of mucosal vaccines. AB - Vaccination is one of the most successful applications of immunology and for a long time has depended on parenteral administration protocols. However, recent studies have pointed to the promise of mucosal vaccination because of its ease, economy and efficiency in inducing an immune response not only systemically, but also in the mucosal compartment where many pathogenic infections are initiated. However, successful mucosal vaccination requires the help of an adjuvant for the efficient delivery of vaccine material into the mucosa and the breaking of the tolerogenic environment, especially in oral mucosal immunization. Given that M cells are the main gateway to take up luminal antigens and initiate antigen specific immune responses, understanding the role and characteristics of M cells is crucial for the development of successful mucosal vaccines. Especially, particular interest has been focused on the regulation of the tolerogenic mucosal microenvironment and the introduction of the luminal antigen into the lymphoid organ by exploiting the molecules of M cells. Here, we review the characteristics of M cells and the immune regulatory factors in mucosa that can be exploited for mucosal vaccine delivery and mucosal immune regulation. PMID- 24626173 TI - Ion uptake in tall fescue as affected by carbonate, chloride, and sulfate salinity. AB - Turfgrass nutrient uptake may be differentially affected by different salts. The objective of this study was to compare nutrient uptake in tall fescue (Festuca arundinacea Schreb.) as affected by carbonate, chloride, and sulfate under iso osmotic, iso-Na+ strength conditions. 'Tar Heel II' and 'Wolfpack' cultivars were subjected to NaCl, Na2CO3, Na2SO4, CaCl2, NaCl+ CaCl2, Na2CO3+ CaCl2, and Na2SO4+ CaCl2, in the range of 0 to 225 mM. There was no cultivar difference regarding K, Na, Mg, and Mn content in shoots. 'Tar Heel II' had higher shoot Ca content than 'Wolfpack', which were 6.9 and 5.7 g kg(-1), respectively. In general, K+/Na+ ratio decreased with increasing salt concentrations, which reached <1 at about 87.5 mM in Na2CO3 treatment. All salt treatments decreased Mg content in shoot tissues, especially in Na2CO3 and treatments containing CaCl2. Both Ca and Mg content in shoot were higher in the NaCl treatment than the Na2SO4 and Na2CO3 treatments. All salt treatments except Na2CO3 had higher Mn content in shoots compared to the control. In conclusion, nutrient uptake was differently affected by carbonate, chloride, and sulfate which are different in pH, electrical conductivity (EC), and osmotic potential at the same concentration. Adding Ca to the sodium salts increased Ca content and balanced K+/Na+ in shoots, but did not increase Mg content, which was below sufficient level. Maintaining Mg content in shoots under salinity stress was recommended. The physiological impact of elevated Mn content in shoot under salinity stress requires further study. PMID- 24626174 TI - Smooth muscle enfoldment internal sphincter construction after intersphincteric resection for rectal cancer. AB - OBJECTIVE: To assess smooth muscle enfoldment and internal sphincter construction (SMESC) for improvement of continence after intersphincteric resection (ISR) for rectal cancer. METHODS: Twenty-four Bama miniature pigs were randomly divided into a conventional ISR group and experimental SMESC group, with 12 pigs in each group. The proximal sigmoid colon was anastomosed directly to the anus in the ISR group. In the SMESC group, internal sphincter construction was performed. At 12 weeks before and after surgery, rectal resting pressure and anal canal length were assessed. Three-dimensional ultrasound was used to determine the thickness of the internal sphincter. After the animals were sacrificed, the rectum and anus were resected and pathological examinations were performed to evaluate the differences in sphincter thickness and muscle fibers. RESULTS: All 24 animals in the SMESC group and the ISR group survived the surgery. Twelve weeks post surgery, the rectal resting pressure, length of the anal high-pressure zone and the postoperative internal sphincter thickness for the ISR group were significantly lower than for the SMESC group. There was a thickened area (about 2 cm) above the anastomotic stoma among animals from the SMESC group; in addition, the smooth muscles were significantly enlarged and enfolded when compared to the ISR group. CONCLUSION: This animal model study shows that the SMESC procedure achieved acceptable reconstruction of the internal anal neo-sphincter (IAN/S), without increasing surgical risk. However, the findings in this experimental animal model must be confirmed by clinical trials to determine the safety and efficacy of this procedure in clinical practice. PMID- 24626175 TI - Tumor necrosis factor alpha induces a serotonin dependent early increase in ciliary beat frequency and epithelial transport velocity in murine tracheae. AB - The tracheal epithelium prevents via its highly effective clearance mechanism the contamination of the lower airways by pathogens. This mechanism is driven by ciliary bearing cells which are not only in contact with the gas phase; in addition they are also influenced by inflammatory mediators. These mediators can alter the protective function of the epithelium. Since the pro-inflammatoric cytokine tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role within the inflammatory cascade, we investigated its effect onto the tracheal epithelium measured by its ciliary beat frequency and the particle transport velocity. In organ explant experiments the ciliary beat frequency and the particle transport velocity were measured under the application of TNF-alpha using tracheae from male C57BL6J mice. We observed a dose dependent TNF-alpha induced increase of both particle transport velocity and ciliary beat frequency. Knock out mice experiments made evident that the increase was depended on the expression of tumor necrosis factor receptor 1 (TNF-R1). The increases in ciliary beat frequency as well as the accelerated particle transport velocity were either inhibited by the unspecific serotonin antagonist methysergide or by cyproheptadine a specific 5-HT2 receptor antagonist. Thus, acetylcholine antagonists or nitric oxide synthase (NOS) inhibitors failed to inhibit the TNF alpha induced activation. In conclusion, TNF-alpha may play a pivotal role in the protection of lower airways by inducing ciliary activity and increase in particle transport velocity via TNF-R1 and 5-HT2 receptor. PMID- 24626176 TI - Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice. AB - Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition. PMID- 24626177 TI - Transcriptional changes in bone marrow stromal cells of patients with heart failure. AB - It is proposed that patients with heart failure may have not only myocardial dysfunction, but also a reduced regenerative capacity of stem cells. However, very little is known about bone marrow stromal cell (BMSC) characteristics in heart failure and its comorbidities (obesity and/or diabetes). We hypothesized that metabolic alterations associated with the latter will be reflected in altered expression of key genes related to angiogenesis, inflammation, and tissue remodeling in patient-derived BMSCs. We found that BMSCs of heart failure patients with lower body mass index have enhanced expression of genes involved in extracellular matrix remodeling. In particular, body mass index<30 was associated with upregulated expression of genes encoding collagen type I, proteases and protease activators (MMP2, MMP14, uPA), and regulatory molecules (CTGF, ITGbeta5, SMAD7, SNAIL1). In contrast, these transcript levels did not differ significantly between BMSCs from obese heart failure patients and healthy subjects. Comorbidities (including obesity and diabetes) are known to play role in heart failure progression rate and outcome of the disease. We thus suggest that key molecular targets identified in this study should become the target of the subsequent focused studies. In the future, these targets may find some use in the clinical setting. PMID- 24626178 TI - Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. AB - Non-alcohol-related fatty liver disease (NAFLD) encompasses a wide spectrum, ranging from steatosis alone to steatohepatitis and fibrosis. Presence of steatohepatitis and fibrosis are key hallmarks of disease progression. Previous studies have demonstrated an association between hepatocyte p21 expression and fibrosis stage in NAFLD. The aim of this study is to investigate the association between the variants of CDKN1A, which encodes p21, and disease progression in NAFLD. To this end, the relation between CDKN1A polymorphism and liver fibrosis was studied in 2 cohorts of biopsy-proven NAFLD patients from UK (n = 323) and Finland (n = 123). Genotyping was performed using DNA isolated from lymphocytes collected at the time of liver biopsy. The findings of the UK cohort were tested in the Finnish cohort. Both the UK and Finnish cohorts were significantly different from each other in basic demographics. In the UK cohort, rs762623, of the 6 SNPs across CDKN1A tested, was significantly associated with disease progression in NAFLD. This association was confirmed in the Finnish cohort. Despite the influence on fibrosis development, SNPs across CDKN1A did not affect the progression of liver fibrosis. In conclusion, CDKN1A variant rs762623 is associated with the development but not the propagation of progressive liver disease in NAFLD. PMID- 24626179 TI - Specificity of calcium/calmodulin-dependent protein kinases in mouse egg activation. AB - CaMKIIgamma, the predominant CaMKII isoform in mouse eggs, controls egg activation by regulating cell cycle resumption. In this study we further characterize the involvement and specificity of CaMKIIgamma in mouse egg activation. Using exogenous expression of different cRNAs in Camk2g(-/-) eggs, we show that the other multifunctional CaM kinases, CaMKI, and CaMKIV, are not capable of substituting CaMKIIgamma to initiate cell cycle resumption in response to a rise in intracellular Ca (2+). Exogenous expression of Camk2g or Camk2d results in activation of nearly 80% of Camk2g(-/-) MII eggs after stimulation with SrCl 2, which does not differ from the incidence of activation of wild-type eggs expressing exogenous Egfp. In contrast, none of the Camk2g(-/-) MII eggs expressing Camk1 or Camk4 activate in response to SrCl 2 treatment. Expression of a constitutively active form of Camk4 (ca-Camk4), but not Camk1, triggers egg activation. EMI2, an APC/C repressor, is a key component in regulating egg activation downstream of CaMKII in both Xenopus laevis and mouse. We show that exogenous expression of either Camk2g, Camk2d, or ca-Camk4, but not Camk1, Camk4, or a catalytically inactive mutant form of CaMKIIgamma (kinase-dead) in Camk2g(-/ ) mouse eggs leads to almost complete degradation (~90%) of exogenously expressed EMI2 followed by cell cycle resumption. Thus, degradation of EMI2 following its phosphorylation specifically by CaMKII is mechanistically linked to and promotes cell cycle resumption in MII eggs. PMID- 24626180 TI - TopoIIalpha prevents telomere fragility and formation of ultra thin DNA bridges during mitosis through TRF1-dependent binding to telomeres. AB - Telomeres are repetitive nucleoprotein structures at the ends of chromosomes. Like most genomic regions consisting of repetitive DNA, telomeres are fragile sites prone to replication fork stalling and generation of chromosomal instability. In particular, abrogation of the TRF1 telomere binding protein leads to stalled replication forks and aberrant telomere structures known as "multitelomeric signals". Here, we report that TRF1 deficiency also leads to the formation of "ultra-fine bridges" (UFB) during mitosis, and to an increased time to complete mitosis mediated by the spindle assembly checkpoint proteins (SAC). We find that topoisomerase IIalpha (TopoIIalpha), an enzyme essential for resolution of DNA replication intermediates, binds telomeres in a TRF1-mediated manner. Indeed, similar to TRF1 abrogation, TopoIIalpha downregulation leads to telomere fragility and UFB, suggesting that these phenotypes are due to decreased TopoIIalpha at telomeres. We find that SAC proteins bind telomeres in vivo, and that this is disrupted upon TRF1 deletion. These findings suggest that TRF1 links TopoIIalpha and SAC proteins in a pathway that ensures correct telomere replication and mitotic segregation, unveiling how TRF1 protects from telomere fragility and mitotic defects. PMID- 24626181 TI - Identification of the nuclear localization signal of SALL4B, a stem cell transcription factor. AB - SALL4B plays a critical role in maintaining the pluripotency of embryonic stem cells and hematopoietic stem cells. SALL4B primarily functions as a transcription factor, and, thus, its nuclear localization is paramount to its biological activities. To understand the structural basis by which SALL4B was transported and retained in the nucleus, we made a series of SALL4B constructs with deletions or point mutations. We found that K64R mutation resulted in a random distribution of SALL4B within the cell. An analysis of neighboring amino acid sequences revealed that (64)KRLR (67) in SALL4B matches exactly with the canonical nuclear localization signal (K-K/R-x-K/R). SALL4B fragment (a.a. 50-109) that contained KRLR was sufficient for targeting GFP-tagged SALL4B to the nucleus, whereas K64R mutation led to a random distribution of GFP-SALL4B signal within the cell. We further demonstrated that the nuclear localization was essential for transactivating luciferase reporter gene driven by OCT4 promoter, a known transcriptional target of SALL4B. Therefore, our study identifies the KRLR sequence as a bona fide nuclear localization signal for SALL4B. PMID- 24626182 TI - Tumor suppressor roles of CENP-E and Nsl1 in Drosophila epithelial tissues. AB - Depletion of spindle assembly checkpoint (SAC) genes in Drosophila epithelial tissues leads to JNK-dependent programmed cell death and additional blockade of the apoptotic program drives tumorigenesis. A recent report proposes that chromosomal instability (CIN) is not the driving force in the tumorigenic response of the SAC-deficient tissue, and that checkpoint proteins exert a SAC independent tumor suppressor role. This notion is based on observations that the depletion of CENP-E levels or prevention of Bub3 from binding to the kinetochore in Drosophila tissues unable to activate the apoptotic program induces CIN but does not cause hyperproliferation. Here we re-examined this proposal. In contrast to the previous report, we observed that depletion of CENP-E or Nsl1-the latter mediating kinetochore targeting of Bub3-in epithelial tissues unable to activate the apoptotic program induces significant levels of aneuploidy and drives tumor like growth. The induction of the JNK transcriptional targets Wingless, a mitogenic molecule, and MMP1, a matrix metaloproteinase 1 involved in basement membrane degradation was also observed in these tumors. An identical response of the tissue was previously detected upon depletion of several SAC genes or genes involved in spindle assembly, chromatin condensation, and cytokinesis, all of which have been described to cause CIN. All together, these results reinforce the role of CIN in driving tumorigenesis in Drosophila epithelial tissues and question the proposed SAC-independent roles of checkpoint proteins in suppressing tumorigenesis. Differences in aneuploidy rates might explain the discrepancy between the previous report and our results. PMID- 24626183 TI - RASSF6 promotes p21(Cip1/Waf1)-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is a highly aggressive and common pathological subtype of renal cancer. This cancer is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which leads to the accumulation of hypoxia-inducible factors (HIFs). Although therapies targeted at HIFs can significantly improve survival, nearly all patients with advanced ccRCC eventually succumb to the disease. Thus, additional oncogenic events are thought to be involved in the development of ccRCC tumors. In this study, we investigated the role of RASSF6 in ccRCC. Downregulation of RASSF6 was commonly observed in primary tumors relative to matched adjacent normal tissues. Moreover, functional studies established that ectopic re-expression of RASSF6 in ccRCC cells inhibited cell proliferation, clonogenicity, and tumor growth in mice, whereas silencing of RASSF6 dramatically enhanced cell proliferation in vitro and in vivo. Mechanistic investigation suggested that RASSF6 triggers p21(Cip1/Waf1) accumulation to induce G 1 cell cycle arrest and promote apoptosis upon exposure to pro-apoptotic agents, and both of these mechanisms appear to be mediated by activated JNK signaling. Together, these findings suggest that RASSF6 may play a tumor suppressor role in the progression of ccRCC. PMID- 24626184 TI - The RNA helicase/transcriptional co-regulator, p68 (DDX5), stimulates expression of oncogenic protein kinase, Polo-like kinase-1 (PLK1), and is associated with elevated PLK1 levels in human breast cancers. AB - p68 (DDX5) acts both as an ATP-dependent RNA helicase and as a transcriptional co activator of several cancer-associated transcription factors, including the p53 tumor suppressor. p68 is aberrantly expressed in a high proportion of cancers, but the oncogenic drive for, or the consequences of, these expression changes remain unclear. Here we show that elevated p68 expression in a cohort of human breast cancers is associated significantly with elevated levels of the oncogenic protein kinase, Polo-like kinase-1 (PLK1). Patients expressing detectable levels of both p68 and PLK1 have a poor prognosis, but only if they also have mutation in the TP53 gene (encoding p53), suggesting that p68 can regulate PLK1 levels in a manner that is suppressed by p53. In support of this hypothesis, we show that p68 stimulates expression from the PLK1 promoter, and that silencing of endogenous p68 expression downregulates endogenous PLK1 gene expression. In the absence of functional p53, p68 stimulates the expression of PLK1 both at basal levels and in response to the clinically relevant drug, etoposide. In keeping with a role as a transcriptional activator/co-activator, chromatin immuno precipitation analysis shows that p68 is associated with the PLK1 promoter, irrespective of the p53 status. However, its recruitment is stimulated by etoposide in cells lacking p53, suggesting that p53 can oppose association of p68 with the PLK1 promoter. These data provide a model in which p68 and p53 interplay regulates PLK1 expression, and which describes the behavior of these molecules, and the outcome of their interaction, in human breast cancer. PMID- 24626185 TI - Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers. AB - Cells respond to genotoxic stress by activating the DNA damage response (DDR). When injury is severe or irreparable, cells induce apoptosis or cellular senescence to prevent transmission of the lesions to the daughter cells upon cell division. Resistance to apoptosis is a hallmark of cancer that challenges the efficacy of cancer therapy. In this work, the effects of ionizing radiation on apoptosis-resistant E1A + E1B transformed cells were investigated to ascertain whether the activation of cellular senescence could provide an alternative tumor suppressor mechanism. We show that irradiated cells arrest cell cycle at G 2/M phase and resume DNA replication in the absence of cell division followed by formation of giant polyploid cells. Permanent activation of DDR signaling due to impaired DNA repair results in the induction of cellular senescence in E1A + E1B cells. However, irradiated cells bypass senescence and restore the population by dividing cells, which have near normal size and ploidy and do not express senescence markers. Reversion of senescence and appearance of proliferating cells were associated with downregulation of mTOR, activation of autophagy, mitigation of DDR signaling, and expression of stem cell markers. PMID- 24626186 TI - Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. AB - Entry and progression through mitosis has traditionally been linked directly to the activity of cyclin-dependent kinase 1 (Cdk1). In this study we utilized low doses of the Cdk1-specific inhibitor, RO3306 from early G 2 phase onwards. Addition of low doses of RO3306 in G 2 phase induced minor chromosome congression and segregation defects. In contrast, mild doses of RO3306 during G 2 phase resulted in cells entering an aberrant mitosis, with cells fragmenting centrosomes and failing to fully disassemble the nuclear envelope. Cells often underwent cytokinesis and metaphase simultaneously, despite the presence of an active spindle assembly checkpoint, which prevented degradation of cyclin B1 and securin, resulting in the random partitioning of whole chromosomes. This highly aberrant mitosis produced a significant increase in the proportion of viable polyploid cells present up to 3 days post-treatment. Furthermore, cells treated with medium doses of RO3306 were only able to reach the threshold of Cdk1 substrate phosphorylation required to initiate nuclear envelope breakdown, but failed to reach the levels of phosphorylation required to correctly complete pro metaphase. Treatment with low doses of Okadaic acid, which primarily inhibits PP2A, rescued the mitotic defects and increased the number of cells that completed a normal mitosis. This supports the current model that PP2A is the primary phosphatase that counterbalances the activity of Cdk1 during mitosis. Taken together these results show that continuous and subtle disruption of Cdk1 activity from G 2 phase onwards has deleterious consequences on mitotic progression by disrupting the balance between Cdk1 and PP2A. PMID- 24626187 TI - Cdc14 targets the Holliday junction resolvase Yen1 to the nucleus in early anaphase. AB - The only canonical Holliday junction (HJ) resolvase identified in eukaryotes thus far is Yen1/GEN1. Nevertheless, Yen1/GEN1 appears to have a minor role in HJ resolution, and, instead, other structure-specific endonucleases (SSE) that recognize branched DNA play the leading roles, Mus81-Mms4/EME1 being the most important in budding yeast. Interestingly, cells tightly regulate the activity of each HJ resolvase during the yeast cell cycle. Thus, Mus81-Mms4 is activated in G 2/M, while Yen1 gets activated shortly afterwards. Nevertheless, cytological studies have shown that Yen1 is sequestered out of the nucleus when cyclin dependent kinase activity is high, i.e., all of the cell cycle but G 1. We here show that the mitotic master phosphatase Cdc14 targets Yen1 to the nucleus in early anaphase through the FEAR network. We will further show that this FEAR mediated Cdc14-driven event is sufficient to back-up Mus81-Mms4 in removing branched DNA structures, which are especially found in the long chromosome arms upon replication stress. Finally, we found that MEN-driven Cdc14 re-activation in late anaphase is essential to keep Yen1 in the nucleus until the next G 1. Our results highlight the essential role that early-activated Cdc14, i.e., through the FEAR network, has in removing all kind of non-proteinaceous linkages that preclude faithful sister chromatid segregation in anaphase. In addition, our results support the general idea of Yen1 acting as a last resource endonuclease to deal with any remaining HJ that might compromise genetic stability during chromosome segregation. PMID- 24626188 TI - Trichostatin A targets the mitochondrial respiratory chain, increasing mitochondrial reactive oxygen species production to trigger apoptosis in human breast cancer cells. AB - AIM: Histone deacetylase inhibitors (HDACIs)-based therapies have stimulated interest via their anti-tumor activities, including apoptosis induction, cell cycle arrest, cell differentiation, and autophagy. However, the mechanisms of HDACI-associated anti-tumor activity are not yet clearly defined. The aim of this study was to explore the key events of Trichostatin A (TSA), a classic HDACI agent, against breast cancer cells. METHODS: The MCF-7, MDA-MB-231 and MCF-10A cell lines were evaluated with colony-forming and cell viability assays. Apoptosis and cell cycle distribution were detected by flow cytometry. Mitochondrial function was measured with biochemical assays, flow cytometry and transmission electron microscopy. RESULTS: TSA inhibited breast cancer cell viability and proliferation, without affecting MCF-10A cell. TSA-induced breast cancer cell apoptosis was initiated by G2-M arrest and depended on mitochondrial reactive oxygen species (ROS) produced subsequent to reduced mitochondrial respiratory chain activity. The enhanced mitochondrial ROS production and apoptosis in cancer cells were markedly attenuated by antioxidants, such as N acetyl cysteine (NAC), reduced glutathione (GSH) and Vitamin C. CONCLUSION: The present study demonstrated that TSA-induced cell death by arresting cell cycle in G2-M phase and was dependent on production of mitochondria-derived ROS, which was derived from impaired mitochondrial respiratory chain. PMID- 24626190 TI - Design and construction of an equibiaxial cell stretching system that is improved for biochemical analysis. AB - We describe the design and validation of an equibiaxial stretching device in which cells are confined to regions of homogeneous strain. Using this device, we seek to overcome a significant limitation of existing equibiaxial stretching devices, in which strains are not homogeneous over the entire region of cell culture. We cast PDMS in a mold to produce a membrane with a cylindrical wall incorporated in the center, which was used to confine cell monolayers to the central membrane region subjected to homogeneous equibiaxial strain. We demonstrated that the presence of the wall to hold the culture medium did not affect strain homogeneity over the majority of the culture surface and also showed that cells adhered well onto the PDMS membranes. We used our device in cyclic strain experiments and demonstrated strain-dependent changes in extracellular signal-regulated kinase (ERK) and tyrosine phosphorylation upon cell stretching. Furthermore, we examined cell responses to very small magnitudes of strain ranging from 1% to 6% and were able to observe a graduated increase in ERK phosphorylation in response to these strains. Collectively, we were able to study cellular biochemical response with a high degree of accuracy and sensitivity to fine changes in substrate strain. Because we have designed our device along the lines of existing equibiaxial stretching technologies, we believe that our innovations can be incorporated into existing systems. This device would provide a useful addition to the set of tools applied for in vitro studies of cell mechanobiology. PMID- 24626191 TI - 2DEGs at perovskite interfaces between KTaO3 or KNbO3 and stannates. AB - We report density functional studies of electron rich interfaces between KTaO3 or KNbO3 and CaSnO3 or ZnSnO3 and in particular the nature of the interfacial electron gasses that can be formed. We find that depending on the details these may occur on either the transition metal or stannate sides of the interface and in the later case can be shifted away from the interface by ferroelectricity. We also present calculations for bulk KNbO3, KTaO3, CaSnO3, BaSnO3 and ZnSnO3, showing the different transport and optical properties that may be expected on the two sides of such interfaces. The results suggest that these interfaces may display a wide range of behaviors depending on conditions, and in particular the interplay with ferroelectricity suggests that electrical control of these properties may be possible. PMID- 24626189 TI - Bidirectional control of absence seizures by the basal ganglia: a computational evidence. AB - Absence epilepsy is believed to be associated with the abnormal interactions between the cerebral cortex and thalamus. Besides the direct coupling, anatomical evidence indicates that the cerebral cortex and thalamus also communicate indirectly through an important intermediate bridge-basal ganglia. It has been thus postulated that the basal ganglia might play key roles in the modulation of absence seizures, but the relevant biophysical mechanisms are still not completely established. Using a biophysically based model, we demonstrate here that the typical absence seizure activities can be controlled and modulated by the direct GABAergic projections from the substantia nigra pars reticulata (SNr) to either the thalamic reticular nucleus (TRN) or the specific relay nuclei (SRN) of thalamus, through different biophysical mechanisms. Under certain conditions, these two types of seizure control are observed to coexist in the same network. More importantly, due to the competition between the inhibitory SNr-TRN and SNr SRN pathways, we find that both decreasing and increasing the activation of SNr neurons from the normal level may considerably suppress the generation of spike and-slow wave discharges in the coexistence region. Overall, these results highlight the bidirectional functional roles of basal ganglia in controlling and modulating absence seizures, and might provide novel insights into the therapeutic treatments of this brain disorder. PMID- 24626192 TI - Expression of miR-33 from an SREBF2 intron targets the FTO gene in the chicken. AB - The sterol regulatory element binding transcription factor 2 (SREBF2) gene encodes a transcription factor that activates the expression of many genes involved in the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids. Through bioinformatics, we found that intron 16 of the chicken SREBF2 gene might encode the chicken miR-33. Using quantitative RT-PCR, we detected the expression of miR-33 in a variety of chicken tissues including skeletal muscle, adipose tissue, and liver. Three hundred and seventy eight genes were predicted to be potential targets of miR-33 in chickens via miRNA target prediction programs "miRanda" and "TargetScan". Among these targets, the gene FTO (fat mass and obesity associated) encodes a Fe(II)- and 2-oxoglutarate-dependent nucleic acid demethylase that regulates lipid metabolism, and the possibility that its expression is negatively regulated by miR-33 in the chicken liver was therefore further studied. Co-transfection and dual-luciferase reporter assays showed that the expression of luciferase reporter gene linked to the 3' untranslated region (3'UTR) of the chicken FTO mRNA was down-regulated by overexpression of the chicken miR-33 in the C2C12 cells (P<0.05). Furthermore, this down-regulation was completely abolished when the predicted miR-33 target site in the FTO 3'UTR was mutated. In contrast, the expression of FTO mRNA in the primary chicken hepatocytes was up-regulated after transfection with the miR-33 inhibitor LNA-anti-miR-33. Using quantitative RT-PCR, we also found that the expression of miR-33 was increased in the chicken liver from day 0 to day 49 of age, whereas that of the FTO mRNA was decreased during the same age period. These data together suggest that miR-33 might play an important role in lipid metabolism in the chicken liver by negatively regulating the expression of the FTO gene. PMID- 24626193 TI - Increased risk of major depression in the three years following a femoral neck fracture--a national population-based follow-up study. AB - Femoral neck fracture is common in the elderly, and its impact has increased in aging societies. Comorbidities, poor levels of activity and pain may contribute to the development of depression, but these factors have not been well addressed. This study aims to investigate the frequency and risk of major depression after a femoral neck fracture using a nationwide population-based study. The Taiwan Longitudinal Health Insurance Database was used in this study. A total of 4,547 patients who were hospitalized for femoral neck fracture within 2003 to 2007 were recruited as a study group; 13,641 matched non-fracture participants were enrolled as a comparison group. Each patient was prospectively followed for 3 years to monitor the occurrence of major depression. Cox proportional-hazards models were used to compute the risk of major depression between members of the study and comparison group after adjusting for residence and socio-demographic characteristics. The most common physical comorbidities that were present after the fracture were also analyzed. The incidences of major depression were 1.2% (n = 55) and 0.7% (n = 95) in the study and comparison groups, respectively. The stratified Cox proportional analysis showed a covariate-adjusted hazard ratio of major depression among patients with femoral neck fracture that was 1.82 times greater (95% CI, 1.30-2.53) than that of the comparison group. Most major depressive episodes (34.5%) presented within the first 200 days following the fracture. In conclusion, patients with a femoral neck fracture are at an increased risk of subsequent major depression. Most importantly, major depressive episodes mainly occurred within the first 200 days following the fracture. PMID- 24626194 TI - Use of antibiotics within the IMCI guidelines in outpatient settings in Papua New Guinean children: an observational and effectiveness study. AB - INTRODUCTION: There is a need to investigate the effectiveness and appropriateness of antibiotics prescription within the Integrated Management of Childhood Illness (IMCI) strategy in the context of routine outpatient clinics. METHODS: Making use of a passive case detection system established for a malaria prevention trial in outpatient clinics in Papua New Guinea, the appropriateness and effectiveness of the use of antibiotics within the IMCI was assessed in 1605 young children. Main outcomes were prescription of antibiotics and re-attendances within 14 days for mild pneumonia, mild diarrhoea and uncomplicated malaria whether they were managed with or without antibiotics (proxy of effectiveness). Appropriateness was assessed for both mild and severe cases, while effectiveness was assessed only for mild diseases. RESULTS: A total of 6975 illness episodes out of 8944 fulfilled inclusion criteria (no previous attendance <14 days+full medical records). Clinical incidence rates (episodes/child/year; 95% CI) were 0.85 (0.81-0.90) for pneumonia, 0.62 (0.58-0.66) for malaria and 0.72 (0.65-0.93) for diarrhoea. Fifty three percent of 6975 sick children were treated with antibiotics, 11% were not treated with antibiotics when they should have been and in 29% antibiotics were prescribed when they should not have been. Re-attendance rates within 14 days following clinical diagnosis of mild pneumonia were 9% (126/1401) when managed with antibiotics compared to 8% (56/701) when managed without (adjusted Hazard Ratio (aHR) = 1.00 (0.57-1.76), p = 0.98). Rates for mild diarrhoea were 8% (73/874) and 9% (79/866) respectively (aHR = 0.8 (0.42 1.57), p = 0.53). CONCLUSION: Non-adherence to IMCI recommendations for prescription of antibiotics is common in routine settings in Papua New Guinea. Although recommended, the use of antibiotics in young children with mild pneumonia as defined by IMCI criteria did not impact on their outcome. Better tools and new strategies for the identification of bacterial infections that require antibiotics are urgently needed. PMID- 24626195 TI - Clonality of HTLV-2 in natural infection. AB - Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ~8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections. PMID- 24626196 TI - A population-based approach to study the impact of PROP perception on food liking in populations along the Silk Road. AB - Taste is one of the main factors determining food choices. Differences in PROP bitter taste perception have been implicated in individual differences in food preferences and selection. The present study examined associations between, PROP phenotypes, self-reported food liking and TAS2R38 polymorphisms, the major gene implicated in PROP bitterness, in six different populations of the Caucasus and Central Asia, located along the ancient Silk Road. Differences in the distribution of PROP phenotypes across populations were detected, with a higher frequency of super tasters in Tajikistan (31.3%) and Armenia (39.0%) and a higher frequency of non tasters in Georgia (50.9%). While no relationships were observed between PROP phenotypes and food liking using standard statistical tests, we used an approach based on comparison of distance matrices derived from these data. The first matrix compared the food liking ratings of each population to all others pairwise using the Kruskal-Wallis test (at p<0.00063), and the second one compared the distribution of PROP phenotypes across all populations in a similar manner calculating the chi-square statistic as a distance measure. A strong correlation between the two matrices was found (Mantel test: r = 0.67, p-value = 0.03), suggesting that the pattern of food liking across populations was closely related to the distribution of PROP phenotypes. This same relationship was not observed when TAS2R38 genotypes were substituted for PROP phenotypes in this analysis. Our data suggest that a population-based approach utilizing distance matrices is a useful technique for detecting PROP-related differences in food liking and can be applied to other taste phenotypes. PMID- 24626197 TI - Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. AB - Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The u-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas' resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3 isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID- 24626198 TI - Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors. AB - Fibroblast growth factor receptor 3 (FGFR3) activating mutations are drivers of malignancy in several human tissues, including bladder, lung, cervix, and blood. However, in skin, these mutations are associated predominantly with benign, common epidermal growths called seborrheic keratoses (SKs). How epidermis resists FGFR3 mediated transformation is unclear, but previous studies have suggested that FGFR3 activation in skin keratinocytes may serve a tumor-suppressive role by driving differentiation and antagonizing Ras signaling. To define the role of FGFR3 in human normal and neoplastic epidermis, and to directly test the hypothesis that FGFR3 antagonizes Ras, we engineered human skin grafts in vivo with mutant active FGFR3 or shRNA FGFR3 knockdown. We show that FGFR3 active mutants drive mild hyperproliferation, but are insufficient to support benign or malignant tumorigenesis, either alone, or in combination with G 1-S checkpoint release. This suggests that additional cell-intrinsic or stromal cues are required for formation of benign SKs with FGFR3 mutations. Further, FGFR3 activation does not alter the growth kinetics or differentiation status of engineered human epidermal SCCs driven by Ras, and FGFR3 protein itself is dispensable for Ras-driven SCC. To extend these findings to patients, we examined a uniquely informative human tumor in which SCC developed in continuity with a SK, raising the hypothesis that one of the tumors evolved from the other. However, mutational analysis from each tumor indicates that the overlapping SK and SCC evolved independently and supports our conclusion that FGFR3 activation is insufficient to drive SCC. PMID- 24626199 TI - Preventing over-resection by DNA2 helicase/nuclease suppresses repair defects in Fanconi anemia cells. AB - FANCD2 is required for the repair of DNA damage by the FA (Fanconi anemia) pathway, and, consequently, FANCD2-deficient cells are sensitive to compounds such as cisplatin and formaldehyde that induce DNA:DNA and DNA:protein crosslinks, respectively. The DNA2 helicase/nuclease is required for RNA/DNA flap removal from Okazaki fragments during DNA replication and for the resection of DSBs (double-strand breaks) during HDR (homology-directed repair) of replication stress-induced damage. A knockdown of DNA2 renders normal cells as sensitive to cisplatin (in the absence of EXO1) and to formaldehyde (even in the presence of EXO1) as FANCD2(-/-) cells. Surprisingly, however, the depletion of DNA2 in FANCD2-deficient cells rescues the sensitivity of FANCD2(-/-) cells to cisplatin and formaldehyde. We previously showed that the resection activity of DNA2 acts downstream of FANCD2 to insure HDR of the DSBs arising when replication forks encounter ICL (interstrand crosslink) damage. The suppression of FANCD2(-/-) by DNA2 knockdowns suggests that DNA2 and FANCD2 also have antagonistic roles: in the absence of FANCD2, DNA2 somehow corrupts repair. To demonstrate that DNA2 is deleterious to crosslink repair, we used psoralen-induced ICL damage to trigger the repair of a site-specific crosslink in a GFP reporter and observed that "over resection" can account for reduced repair. Our work demonstrates that excessive resection can lead to genome instability and shows that strict regulatory processes have evolved to inhibit resection nucleases. The suppression of FANCD2( /-) phenotypes by DNA2 depletion may have implications for FA therapies and for the use of ICL-inducing agents in chemotherapy. PMID- 24626200 TI - CRABP1 provides high malignancy of transformed mesenchymal cells and contributes to the pathogenesis of mesenchymal and neuroendocrine tumors. AB - CRABP1 (cellular retinoic acid binding protein 1) belongs to the family of fatty acid binding proteins. Retinoic acid binding is the only known functional activity of this protein. The role of CRABP1 in human carcinogenesis remains poorly understood. Here, for the first time we demonstrated pro-metastatic and pro-tumorigenic activity of CRABP1 in mesenchymal tumors. Further functional analysis revealed that the pro-tumorigenic effect of CRABP1 does not depend on retinoic acid binding activity. These results suggest that CRABP1 could have an alternative intracellular functional activity that contributes to the high malignancy of transformed mesenchymal cells. Microarray analysis detected CRABP1 mediated alterations in the expression of about 100 genes, including those encoding key regulatory proteins. CRABP1 is ubiquitously expressed in monophasic synovial sarcomas, while in biphasic synovial sarcomas it is expressed uniquely by the spindle cells of the aggressive mesenchymal component. High level of CRABP1 expression is associated with lymph node metastasis and poor differentiation/high grade of pancreatic neuroendocrine tumors (pNETs). Presented data suggest CRABP1 as a promising biomarker of pNETs' clinical behavior. Our results give the first evidence of pro-tumorigenic and pro-metastatic activity of CRABP1 in mesenchymal and neuroendocrine tumors. PMID- 24626201 TI - Model-based analysis for qualitative data: an application in Drosophila germline stem cell regulation. AB - Discovery in developmental biology is often driven by intuition that relies on the integration of multiple types of data such as fluorescent images, phenotypes, and the outcomes of biochemical assays. Mathematical modeling helps elucidate the biological mechanisms at play as the networks become increasingly large and complex. However, the available data is frequently under-utilized due to incompatibility with quantitative model tuning techniques. This is the case for stem cell regulation mechanisms explored in the Drosophila germarium through fluorescent immunohistochemistry. To enable better integration of biological data with modeling in this and similar situations, we have developed a general parameter estimation process to quantitatively optimize models with qualitative data. The process employs a modified version of the Optimal Scaling method from social and behavioral sciences, and multi-objective optimization to evaluate the trade-off between fitting different datasets (e.g. wild type vs. mutant). Using only published imaging data in the germarium, we first evaluated support for a published intracellular regulatory network by considering alternative connections of the same regulatory players. Simply screening networks against wild type data identified hundreds of feasible alternatives. Of these, five parsimonious variants were found and compared by multi-objective analysis including mutant data and dynamic constraints. With these data, the current model is supported over the alternatives, but support for a biochemically observed feedback element is weak (i.e. these data do not measure the feedback effect well). When also comparing new hypothetical models, the available data do not discriminate. To begin addressing the limitations in data, we performed a model-based experiment design and provide recommendations for experiments to refine model parameters and discriminate increasingly complex hypotheses. PMID- 24626202 TI - Infant exploratory learning: influence on leg joint coordination. AB - A critical issue in the study of infant development is to identify the processes by which task-specific action emerges from spontaneous movement. Emergent leg action has been studied by providing contingent reinforcement to specific leg movements using an overhead infant-activated mobile, however, there is limited information on the strategies used by infants to support the emergence of task specific leg action from spontaneous movement. The purpose of this study is to (1) determine the ability of 3 month old infants to learn, through discovery, the contingency between leg action and mobile activation using a virtual threshold, and (2) identify strategies, defined by variance of the end-effectors (feet) and hip-knee joint coordination, used by infants that learned the contingency. Fourteen 3 month old infants participated in 2 sessions of mobile reinforcement on consecutive days. As a group, infants increased the percentage of mobile activation to meet performance criteria on Day 2, but did not meet memory or learning criteria across days. However, five infants learned the contingency based on individual learning criteria. When interacting with the mobile on Day 2 as compared to spontaneous kicking on Day 1, infants who learned the contingency, but not infants who did not learn the contingency, increased variance of the end effectors (feet) in the vertical, task-specific direction and demonstrated less in-phase hip-knee joint coordination. An important discovery is that infants can discover this very specific contingency, suggesting that this movement behavior (action) can be shaped in future work. This may have implications for the rehabilitation of infants with atypical leg action. PMID- 24626203 TI - Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies. AB - Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4 hydroperoxy-cyclophosphamide, chlorambucil and melphalan) and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine) in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C), followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs). Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP) in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies. PMID- 24626204 TI - The city, its people, their health and tuberculosis. PMID- 24626205 TI - Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013. AB - Zika fever, considered as an emerging disease of arboviral origin, because of its expanding geographic area, is known as a benign infection usually presenting as an influenza-like illness with cutaneous rash. So far, Zika virus infection has never led to hospitalisation. We describe the first case of Guillain-Barre syndrome (GBS) occurring immediately after a Zika virus infection, during the current Zika and type 1 and 3 dengue fever co-epidemics in French Polynesia. PMID- 24626206 TI - Influenza vaccine effectiveness in Spain 2013/14: subtype-specific early estimates using the cycEVA study. AB - Adjusted early estimates of the 2013/14 influenza vaccine effectiveness (VE) in Spain for all age groups was 35% (95% CI: -9 to 62), 33% (95% CI: -33 to 67) and 28% (95% CI: -33 to 61) against any influenza virus type, A(H1N1)pdm09 and A(H3N2) viruses, respectively. For the population targeted for vaccination, the adjusted VE was 44% (95% CI: -11 to 72), 36% (95% CI: -64 to 75) and 42% (95% CI: -29 to 74), respectively. These preliminary results in Spain suggest a suboptimal protective effect of the vaccine against circulating influenza viruses. PMID- 24626207 TI - Interim estimates of 2013/14 influenza clinical severity and vaccine effectiveness in the prevention of laboratory-confirmed influenza-related hospitalisation, Canada, February 2014. AB - During the 2013/14 influenza season in Canada, 631 of 654 hospitalisations for laboratory-confirmed influenza enrolled in sentinel hospitals were due to Influenza A. Of the 375 with known subtype, influenza A(H1N1) accounted for 357. Interim unmatched vaccine effectiveness adjusted for age and presence of one or more medical comorbidities was determined by test-negative case-control design to be 58.5% (90% confidence interval (CI): 43.9-69.3%) overall and 57.9% (90% CI: 37.7-71.5) for confirmed influenza A(H1N1). PMID- 24626208 TI - Epidemiology of tuberculosis in big cities of the European Union and European Economic Area countries. AB - This cross-sectional survey aimed to examine the epidemiology of tuberculosis (TB) in European Union (EU) and European Economic Area (EEA) cities with populations greater than 500,000. National TB programme managers were asked to provide data on big city population size, total number of notified TB cases in big cities and national notification rate for 2009. A rate ratio was calculated using the big city TB notification rate as a numerator and country TB notification rate, excluding big city TB cases and population, as a denominator. Twenty of the 30 EU/EEA countries had at least one big city. Pooled rate ratios were 2.5, 1.0, and 0.7 in low-, intermediate- and high-incidence countries respectively. In 15 big cities, all in low-incidence countries, rate ratios were twice the national notification rate. These data illustrate the TB epidemiology transition, a situation whereby TB disease concentrates in big cities as national incidence falls, most likely as a result of the higher concentration of risk groups found there. This situation requires targeted interventions and we recommend that big city TB data, including information about patients' risk factors, are collected and analysed systematically, and that successful interventions are shared. PMID- 24626209 TI - Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011. AB - On 31 May 2011, after notification of Klebsiella pneumoniae (KP)(OXA-48;CTX-M-15) in two patients, nosocomial transmission was suspected in a Dutch hospital. Hospital-wide infection control measures and an outbreak investigation were initiated. A total of 72,147 patients were categorised into groups based on risk of OXA-48 colonisation or infection, and 7,527 were screened for Enterobacteriaceae(OXA-48) by polymerase chain reaction (PCR). Stored KP isolates (n=408) were retrospectively tested for OXA-48 and CTX-M-1 group extended spectrum beta-lactamases (ESBL). 285 KP isolates from retrospective and prospective patient screening were genotyped by amplified fragment length polymorphism (AFLP). 41 isolates harbouring different Enterobacteriaceae species were analysed by plasmid multilocus sequence typing (pMLST). No nosocomial transmission of Enterobacteriaceae(OXA-48) was detected after 18 July 2011. Enterobacteriaceae(OXA-48) were found in 118 patients (KP (n=99), Escherichia coli (n=56), >=1 Enterobacteriaceae(OXA-48) species (n=52)), of whom 21 had clinical infections. 39/41 (95%) of OXA-48 containing plasmids were identical in pMLST. Minimum inhibitory concentrations (MICs) of KP(OXA-48) and E. coli(OXA-48) for imipenem and meropenem ranged from <=1 to >=16 mg/L, and 153/157 (97%) had MIC >0.25 mg/L for ertapenem. AFLP identified a cluster of 203 genetically linked isolates (62 KP(OXA-48;CTX-M15); 107 KP(CTX-M-15); 34 KP(OXA-48)). The 'oldest' KP(CTX-M-15) and KP(OXA-48) clonal types originated from February 2009 and September 2010, respectively. The last presumed outbreak-related KP(OXA-48) was detected in April 2012. Uncontrolled transmission of KP(CTX-M-15) evolved into a nosocomial outbreak of KP(OXA-48;CTX-M15) with large phenotypical heterogeneity. Although the outbreak was successfully controlled, the contribution of individual containment measures and of the hospital relocating into a new building just before outbreak notification was impossible to quantify. PMID- 24626210 TI - Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement. AB - In low-incidence countries in the European Union (EU), tuberculosis (TB) is concentrated in big cities, especially among certain urban high-risk groups including immigrants from TB high-incidence countries, homeless people, and those with a history of drug and alcohol misuse. Elimination of TB in European big cities requires control measures focused on multiple layers of the urban population. The particular complexities of major EU metropolises, for example high population density and social structure, create specific opportunities for transmission, but also enable targeted TB control interventions, not efficient in the general population, to be effective or cost effective. Lessons can be learnt from across the EU and this consensus statement on TB control in big cities and urban risk groups was prepared by a working group representing various EU big cities, brought together on the initiative of the European Centre for Disease Prevention and Control. The consensus statement describes general and specific social, educational, operational, organisational, legal and monitoring TB control interventions in EU big cities, as well as providing recommendations for big city TB control, based upon a conceptual TB transmission and control model. PMID- 24626214 TI - Enhancement of the cycling performance of Li3V2(PO4)3/C by stabilizing the crystal structure through Zn2+ doping. AB - A series of Li3V(2-2/3x)Zn(x)(PO4)3/C phases were synthesized by carbon thermal reduction assisted by the ball-mill process. Scanning electron microscopy (SEM) showed that the irregular morphology of the pristine Li3V2(PO4)3/C could be transformed to spherical upon doping with a suitable amount of zinc. The structural stability of the pristine and the Zn doped Li3V2(PO4)3/C were investigated via X-ray absorption near edge structure (XANES) spectroscopy and X ray diffraction (XRD). The results revealed that Zn doping not only improves the stability of the VO6 octahedral structures before electrochemical cycling, but also reduces the degree of irreversible expansion of the c axis and the crystal volume upon repeated cycles. Among the Li3V(2-2/3x)Zn(x)(PO4)3/C (0 <=x<= 0.15) series, the sample doped with 0.05 Zn atoms per formula unit showed the best electrochemical performance. Excess Zn doping (x > 0.05) didn't result in further improvement in the electrochemical performance due to the segregation effect and the inactive nature of Zn. PMID- 24626215 TI - The temporal version of the pediatric sepsis biomarker risk model. AB - BACKGROUND: PERSEVERE is a risk model for estimating mortality probability in pediatric septic shock, using five biomarkers measured within 24 hours of clinical presentation. OBJECTIVE: Here, we derive and test a temporal version of PERSEVERE (tPERSEVERE) that considers biomarker values at the first and third day following presentation to estimate the probability of a "complicated course", defined as persistence of >=2 organ failures at seven days after meeting criteria for septic shock, or death within 28 days. METHODS: Biomarkers were measured in the derivation cohort (n = 225) using serum samples obtained during days 1 and 3 of septic shock. Classification and Regression Tree (CART) analysis was used to derive a model to estimate the risk of a complicated course. The derived model was validated in the test cohort (n = 74), and subsequently updated using the combined derivation and test cohorts. RESULTS: A complicated course occurred in 23% of the derivation cohort subjects. The derived model had a sensitivity for a complicated course of 90% (95% CI 78-96), specificity was 70% (62-77), positive predictive value was 47% (37-58), and negative predictive value was 96% (91-99). The area under the receiver operating characteristic curve was 0.85 (0.79-0.90). Similar test characteristics were observed in the test cohort. The updated model had a sensitivity of 91% (81-96), a specificity of 70% (64-76), a positive predictive value of 47% (39-56), and a negative predictive value of 96% (92-99). CONCLUSIONS: tPERSEVERE reasonably estimates the probability of a complicated course in children with septic shock. tPERSEVERE could potentially serve as an adjunct to physiological assessments for monitoring how risk for poor outcomes changes during early interventions in pediatric septic shock. PMID- 24626216 TI - Refolding of beta-stranded class I chitinases of Hippophae rhamnoides enhances the antifreeze activity during cold acclimation. AB - Class I chitinases hydrolyse the beta-1,4-linkage of chitin and also acquire antifreeze activity in some of the overwintering plants during cold stress. Two chitinases, HrCHT1a of 31 kDa and HrCHT1b of 34 kDa, were purified from cold acclimated and non-acclimated seabuckthorn seedlings using chitin affinity chromatography. 2-D gels of HrCHT1a and HrCHT1b showed single spots with pIs 7.0 and 4.6 respectively. N-terminal sequence of HrCHT1b matched with the class I chitinase of rice and antifreeze proteins while HrCHT1a could not be sequenced as it was N-terminally blocked. Unlike previous reports, where antifreeze activity of chitinase was cold inducible, our results showed that antifreeze activity is constitutive property of class I chitinase as both HrCHT1a and HrCHT1b isolated even from non-acclimated seedlings, exhibited antifreeze activity. Interestingly, HrCHT1a and HrCHT1b purified from cold acclimated seedlings, exhibited 4 and 2 times higher antifreeze activities than those purified from non-acclimated seedlings, suggesting that antifreeze activity increased during cold acclimation. HrCHT1b exhibited 23-33% higher hydrolytic activity and 2-4 times lower antifreeze activity than HrCHT1a did. HrCHT1b was found to be a glycoprotein; however, its antifreeze activity was independent of glycosylation as even deglycosylated HrCHT1b exhibited antifreeze activity. Circular dichroism (CD) analysis showed that both these chitinases were rich in unusual beta-stranded conformation (36-43%) and the content of beta-strand increased (~11%) during cold acclimation. Surprisingly, calcium decreased both the activities of HrCHT1b while in case of HrCHT1a, a decrease in the hydrolytic activity and enhancement in its antifreeze activity was observed. CD results showed that addition of calcium also increased the beta-stranded conformation of HrCHT1a and HrCHT1b. This is the first report, which shows that antifreeze activity is constitutive property of class I chitinase and cold acclimation and calcium regulate these activities of chitinases by changing the secondary structure. PMID- 24626217 TI - Quantification of acute vocal fold epithelial surface damage with increasing time and magnitude doses of vibration exposure. AB - Because the vocal folds undergo repeated trauma during continuous cycles of vibration, the epithelium is routinely susceptible to damage during phonation. Excessive and prolonged vibration exposure is considered a significant predisposing factor in the development of vocal fold pathology. The purpose of the present study was to quantify the extent of epithelial surface damage following increased time and magnitude doses of vibration exposure using an in vivo rabbit phonation model. Forty-five New Zealand white breeder rabbits were randomized to nine groups and received varying phonation time-doses (30, 60, or 120 minutes) and magnitude-doses (control, modal intensity phonation, or raised intensity phonation) of vibration exposure. Scanning electron microscopy and transmission electron microscopy was used to quantify the degree of epithelial surface damage. Results revealed a significant reduction in microprojection density, microprojection height, and depth of the epithelial surface with increasing time and phonation magnitudes doses, signifying increased epithelial surface damage risk with excessive and prolonged vibration exposure. Destruction to the epithelial cell surface may provide significant insight into the disruption of cell function following prolonged vibration exposure. One important goal achieved in the present study was the quantification of epithelial surface damage using objective imaging criteria. These data provide an important foundation for future studies of long-term tissue recovery from excessive and prolonged vibration exposure. PMID- 24626218 TI - The circular F-actin bundles provide a track for turnaround and bidirectional movement of mitochondria in Arabidopsis root hair. AB - BACKGROUND: The movement of organelles in root hairs primarily occurs along the actin cytoskeleton. Circulation and "reverse fountain" cytoplasmic streaming constitute the typical forms by which most organelles (such as mitochondria and the Golgi apparatus) in plant root hair cells engage in bidirectional movement. However, there remains a lack of in-depth research regarding the relationship between the distribution of the actin cytoskeleton and turnaround organelle movement in plant root hair cells. RESULTS: In this paper, Arabidopsis seedlings that had been stably transformed with a GFP-ABD2-GFP (green fluorescent protein actin-binding domain 2-green fluorescent protein) construct were utilized to study the distribution of bundles of filamentous (F)-actin and the directed motion of mitochondria along these bundles in root hairs. Observations with a confocal laser scanning microscope revealed that there were widespread circular F actin bundles in the epidermal cells and root hairs of Arabidopsis roots. In root hairs, these circular bundles primarily start at the sub-apical region, which is the location where the turnaround movement of organelles occurs. MitoTracker probes were used to label mitochondria, and the dynamic observation of root hair cells with a confocal laser scanning microscope indicated that turnaround mitochondrial movement occurred along circular F-actin bundles. CONCLUSIONS: Relevant experimental results demonstrated that the circular F-actin bundles provide a track for the turnaround and bidirectional movement of mitochondria. PMID- 24626220 TI - Electroacupuncture-like stimulation at the Baihui (GV20) and Dazhui (GV14) acupoints protects rats against subacute-phase cerebral ischemia-reperfusion injuries by reducing S100B-mediated neurotoxicity. AB - OBJECTIVES: The purpose of this study was to evaluate the effects of electroacupuncture-like stimulation at the Baihui (GV20) and Dazhui (GV14) acupoints (EA at acupoints) during the subacute phase of cerebral ischemia reperfusion (I/R) injury and to establish the neuroprotective mechanisms involved in the modulation of the S100B-mediated signaling pathway. METHODS: The experimental rats were subjected to middle cerebral artery occlusion (MCAo) for 15 min followed by 1 d or 7 d of reperfusion. EA at acupoints was applied 1 d postreperfusion then once daily for 6 consecutive days. RESULTS: We observed that 15 min of MCAo caused delayed infarct expansion 7 d after reperfusion. EA at acupoints significantly reduced the cerebral infarct and neurological deficit scores. EA at acupoints also downregulated the expression of the glial fibrillary acidic protein (GFAP), S100B, nuclear factor-kappaB (NF-kappaB; p50), and tumor necrosis factor-alpha (TNF-alpha), and reduced the level of inducible nitric oxide synthase (iNOS) and apoptosis in the ischemic cortical penumbra 7 d after reperfusion. Western blot analysis showed that EA at acupoints significantly downregulated the cytosolic expression of phospho-p38 MAP kinase (p-p38 MAP kinase), tumor necrosis factor receptor type 1-associated death domain (TRADD), Fas-associated death domain (FADD), cleaved caspase-8, and cleaved caspase-3 in the ischemic cortical penumbra 7 d after reperfusion. EA at acupoints significantly reduced the numbers of GFAP/S100B and S100B/nitrotyrosine double labeled cells. CONCLUSION: Our study results indicate that EA at acupoints initiated 1 d postreperfusion effectively downregulates astrocytic S100B expression to provide neuroprotection against delayed infarct expansion by modulating p38 MAP kinase-mediated NF-kappaB expression. These effects subsequently reduce oxidative/nitrative stress and inhibit the TNF alpha/TRADD/FADD/cleaved caspase-8/cleaved caspase-3 apoptotic pathway in the ischemic cortical penumbra 7 d after reperfusion. PMID- 24626221 TI - The relative effectiveness of signaling systems: relying on external items reduces signaling accuracy while leks increase accuracy. AB - Multiple evolutionary phenomena require individual animals to assess conspecifics based on behaviors, morphology, or both. Both behavior and morphology can provide information about individuals and are often used as signals to convey information about quality, motivation, or energetic output. In certain cases, conspecific receivers of this information must rank these signaling individuals based on specific traits. The efficacy of information transfer associated within a signal is likely related to the type of trait used to signal, though few studies have investigated the relative effectiveness of contrasting signaling systems. I present a set of models that represent a large portion of signaling systems and compare them in terms of the ability of receivers to rank signalers accurately. Receivers more accurately assess signalers if the signalers use traits that do not require non-food resources; similarly, receivers more accurately ranked signalers if all the signalers could be observed simultaneously, similar to leks. Surprisingly, I also found that receivers are only slightly better at ranking signaler effort if the effort results in a cumulative structure. This series of findings suggests that receivers may attend to specific traits because the traits provide more information relative to others; and similarly, these results may explain the preponderance of morphological and behavioral display signals. PMID- 24626222 TI - Cerebral microbleeds are associated with deep white matter hyperintensities, but only in hypertensive patients. AB - Cerebral microbleeds (CMBs) and white matter hyperintensities (WMH) are the most common manifestations of small vessel disease, and often co-occur in patients with cerebral vascular disease. Hypertension is widely accepted as a risk factor for both CMBs and WMH. However, the effect of hypertension on the association between CMBs and WMH remains unclear. We hypothesized that the relationship between CMBs and WMH is determined by hypertension. One hundred forty-eight patients with acute cerebrovascular disease who were admitted to PLA general hospital in Beijing, China from February 2010 to May 2011 were recruited in this study. CMBs on T2*-weighted angiography (SWAN) were assessed using the Brain Observer Microbleed Rating Scale criteria. The severity of the WMH was separately assessed as either peri-ventricular hyperintensities (PVH) or deep white matter hyperintensities (DWMH). The association among CMBs and the severity of WMH, and hypertension were determined. CMBs were found in 65 (43.9%) patients. The frequency of CMBs was related to the severity of DWMH and PVH. CMBs were more frequently observed in patients with hypertension compared to patients without hypertension (51.3% vs. 20.0%, p = 0.001). Hypertension was an independent risk factor for CMBs (odds ratio 5.239, p = 0.001) and DWMH (odds ratio 2.373, p = 0.040). Furthermore, the relationship between the presence of CMBs and the severity of DWMH was only found in patients with hypertension (r = 0.298, p<0.01). However, CMBs were associated with PVH independently of hypertension. This study demonstrated that hypertension determined the association between CMBs and DWMH. PMID- 24626223 TI - Conflicting interests in the pathogen-host tug of war: fungal micronutrient scavenging versus mammalian nutritional immunity. PMID- 24626224 TI - The effect of additional training on motor outcomes at discharge from recovery phase rehabilitation wards: a survey from multi-center stroke data bank in Japan. AB - OBJECTIVES: The purpose of the present study was to examine the potential benefits of additional training in patients admitted to recovery phase rehabilitation ward using the data bank of post-stroke patient registry. SUBJECTS AND METHODS: Subjects were 2507 inpatients admitted to recovery phase rehabilitation wards between November 2004 and November 2010. Participants were retrospectively divided into four groups based upon chart review; patients who received no additional rehabilitation, patients who were added with self initiated off hours training, patients who were added with off hours training by ward staff, patients who received both self-initiated training and training by ward staff. Parameters for assessing outcomes included length of stay, motor/cognitive subscales of functional independent measures (FIM) and motor benefit of FIM calculated by subtracting the score at admission from that at discharge. RESULTS: Participants were stratified into three groups depending on the motor FIM at admission (?28, 29~56, 57?) for comparison. Regarding outcome variables, significant inter-group differences were observed in all items examined within the subgroup who scored 28 or less and between 29 and 56. Meanwhile no such trends were observed in the group who scored 57 or more compared with those who scored less. In a decision tree created based upon Exhaustive Chi-squared Automatic Interaction Detection method, variables chosen were the motor FIM at admission (the first node) additional training (the second node), the cognitive FIM at admission(the third node). CONCLUSIONS: Overall the results suggest that additional training can compensate for the shortage of regular rehabilitation implemented in recovery phase rehabilitation ward, thus may contribute to improved outcomes assessed by motor FIM at discharge. PMID- 24626225 TI - A stem-cell based bioassay to critically assess the pathology of dysfunctional neuromuscular junctions. AB - Pluripotent stem cells can be directed to differentiate into motor neurons and assessed for functionality in vitro. An emerging application of this technique is to model genetically inherited diseases in differentiated motor neurons and to screen for new therapeutic targets. The neuromuscular junction (NMJ) is essential to the functionality of motor neurons and its dysfunction is a primary hallmark of motor neuron disease. However, mature NMJs that possess the functional and morphological characteristics of those formed in vivo have so far not been obtained in vitro. Here we describe the generation and analysis of mature NMJs formed between embryonic stem cell-derived motor neurons (ESCMNs) and primary myotubes. We compared the formation and maturation of NMJs generated by wild-type (NCAM+/+) ESCMNs to those generated by neural cell adhesion molecule null (NCAM-/ ) ESCMNs in order to definitively test the sensitivity of this assay to identify synaptic pathology. We find that co-cultures using NCAM-/- ESCMNs replicate key in vivo NCAM-/- phenotypes and reveal that NCAM influences neuromuscular synaptogenesis by controlling the mode of synaptic vesicle endocytosis. Further, we could improve synapse formation and function in NCAM-/- co-cultures by chronic treatment with nifedipine, which blocks an immature synaptic vesicle recycling pathway. Together, our results demonstrate that this ESCMN/myofiber co-culture system is a highly sensitive bioassay for examining molecules postulated to regulate synaptic function and for screening therapeutics that will improve the function of compromised NMJs. PMID- 24626226 TI - Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. AB - Toxoplasma gondii is an intracellular parasite that infects a wide range of warm blooded species. Rats vary in their susceptibility to this parasite. The Toxo1 locus conferring Toxoplasma resistance in rats was previously mapped to a region of chromosome 10 containing Nlrp1. This gene encodes an inflammasome sensor controlling macrophage sensitivity to anthrax lethal toxin (LT) induced rapid cell death (pyroptosis). We show here that rat strain differences in Toxoplasma infected macrophage sensitivity to pyroptosis, IL-1beta/IL-18 processing, and inhibition of parasite proliferation are perfectly correlated with NLRP1 sequence, while inversely correlated with sensitivity to anthrax LT-induced cell death. Using recombinant inbred rats, SNP analyses and whole transcriptome gene expression studies, we narrowed the candidate genes for control of Toxoplasma mediated rat macrophage pyroptosis to four genes, one of which was Nlrp1. Knockdown of Nlrp1 in pyroptosis-sensitive macrophages resulted in higher parasite replication and protection from cell death. Reciprocally, overexpression of the NLRP1 variant from Toxoplasma-sensitive macrophages in pyroptosis resistant cells led to sensitization of these resistant macrophages. Our findings reveal Toxoplasma as a novel activator of the NLRP1 inflammasome in rat macrophages. PMID- 24626227 TI - De novo assembly of Auricularia polytricha transcriptome using Illumina sequencing for gene discovery and SSR marker identification. AB - Auricularia polytricha (Mont.) Sacc., a type of edible black-brown mushroom with a gelatinous and modality-specific fruiting body, is in high demand in Asia due to its nutritional and medicinal properties. Illumina Solexa sequenceing technology was used to generate very large transcript sequences from the mycelium and the mature fruiting body of A. polytricha for gene discovery and molecular marker development. De novo assembly generated 36,483 ESTs with an N50 length of 636 bp. A total of 28,108 ESTs demonstrated significant hits with known proteins in the nr database, and 94.03% of the annotated ESTs showed the greatest similarity to A. delicata, a related species of A. polytricha. Functional categorization of the Gene Ontology (GO), Clusters of Orthologous Groups (COG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways revealed the conservation of genes involved in various biological processes in A. polytricha. Gene expression profile analysis indicated that a total of 2,057 ESTs were differentially expressed, including 1,020 ESTs that were up-regulated in the mycelium and 1,037 up-regulated in the fruiting body. Functional enrichment showed that the ESTs associated with biosynthesis, metabolism and assembly of proteins were more active in fruiting body development. The expression patterns of homologous transcription factors indicated that the molecular mechanisms of fruiting body formation and development were not exactly the same as for other agarics. Interestingly, an EST encoding tyrosinase was significantly up-regulated in the fruiting body, indicating that melanins accumulated during the processes of the formation of the black-brown color of the fruiting body in A. polytricha development. In addition, a total of 1,715 potential SSRs were detected in this transcriptome. The transcriptome analysis of A. polytricha provides valuable sequence resources and numerous molecular markers to facilitate further functional genomics studies and genetic researches on this fungus. PMID- 24626228 TI - Double trouble at high density: cross-level test of resource-related adaptive plasticity and crowding-related fitness. AB - Population size is often regulated by negative feedback between population density and individual fitness. At high population densities, animals run into double trouble: they might concurrently suffer from overexploitation of resources and also from negative interference among individuals regardless of resource availability, referred to as crowding. Animals are able to adapt to resource shortages by exhibiting a repertoire of life history and physiological plasticities. In addition to resource-related plasticity, crowding might lead to reduced fitness, with consequences for individual life history. We explored how different mechanisms behind resource-related plasticity and crowding-related fitness act independently or together, using the water flea Daphnia magna as a case study. For testing hypotheses related to mechanisms of plasticity and crowding stress across different biological levels, we used an individual-based population model that is based on dynamic energy budget theory. Each of the hypotheses, represented by a sub-model, is based on specific assumptions on how the uptake and allocation of energy are altered under conditions of resource shortage or crowding. For cross-level testing of different hypotheses, we explored how well the sub-models fit individual level data and also how well they predict population dynamics under different conditions of resource availability. Only operating resource-related and crowding-related hypotheses together enabled accurate model predictions of D. magna population dynamics and size structure. Whereas this study showed that various mechanisms might play a role in the negative feedback between population density and individual life history, it also indicated that different density levels might instigate the onset of the different mechanisms. This study provides an example of how the integration of dynamic energy budget theory and individual-based modelling can facilitate the exploration of mechanisms behind the regulation of population size. Such understanding is important for assessment, management and the conservation of populations and thereby biodiversity in ecosystems. PMID- 24626230 TI - VE-cadherin cleavage by LasB protease from Pseudomonas aeruginosa facilitates type III secretion system toxicity in endothelial cells. AB - Infection of the vascular system by Pseudomonas aeruginosa (Pa) occurs during bacterial dissemination in the body or in blood-borne infections. Type 3 secretion system (T3SS) toxins from Pa induce a massive retraction when injected into endothelial cells. Here, we addressed the role of type 2 secretion system (T2SS) effectors in this process. Mutants with an inactive T2SS were much less effective than wild-type strains at inducing cell retraction. Furthermore, secretomes from wild-types were sufficient to trigger cell-cell junction opening when applied to cells, while T2SS-inactivated mutants had minimal activity. Intoxication was associated with decreased levels of vascular endothelial (VE) cadherin, a homophilic adhesive protein located at endothelial cell-cell junctions. During the process, the protein was cleaved in the middle of its extracellular domain (positions 335 and 349). VE-cadherin attrition was T3SS independent but T2SS-dependent. Interestingly, the epithelial (E)-cadherin was unaffected by T2SS effectors, indicating that this mechanism is specific to endothelial cells. We showed that one of the T2SS effectors, the protease LasB, directly affected VE-cadherin proteolysis, hence promoting cell-cell junction disruption. Furthermore, mouse infection with Pa to induce acute pneumonia lead to significant decreases in lung VE-cadherin levels, whereas the decrease was minimal with T2SS-inactivated or LasB-deleted mutant strains. We conclude that the T2SS plays a pivotal role during Pa infection of the vascular system by breaching the endothelial barrier, and propose a model in which the T2SS and the T3SS cooperate to intoxicate endothelial cells. PMID- 24626231 TI - Continuous cardiac troponin I release in Fabry disease. AB - BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disorder also affecting the heart. The aims of this study were to determine the frequency of cardiac troponin I (cTNI) elevation, a sensitive parameter reflecting myocardial damage, in a smaller cohort of FD-patients, and to analyze whether persistent cTNI can be a suitable biomarker to assess cardiac dysfunction in FD. METHODS: cTNI values were determined at least twice per year in 14 FD-patients (6 males and 8 females) regularly followed-up in our centre. The data were related to other parameters of heart function including cardiac magnetic resonance imaging (cMRI). RESULTS: Three patients (21%) without specific vascular risk factors other than FD had persistent cTNI-elevations (range 0.05-0.71 ng/ml, normal: <0.01). cMRI disclosed late gadolinium enhancement (LGE) in all three individuals with cTNI values >=0.01, while none of the 11 patients with cTNI <0.01 showed a pathological enhancement (p<0.01). Two subjects with increased cTNI-values underwent coronary angiography, excluding relevant stenoses. A myocardial biopsy performed in one during this procedure demonstrated substantial accumulation of globotriaosylceramide (Gb3) in cardiomyocytes. CONCLUSION: Continuous cTNI elevation seems to occur in a substantial proportion of patients with FD. The high accordance with LGE, reflecting cardiac dysfunction, suggests that cTNI elevation can be a useful laboratory parameter for assessing myocardial damage in FD. PMID- 24626229 TI - Responses to elevated c-di-GMP levels in mutualistic and pathogenic plant interacting bacteria. AB - Despite a recent burst of research, knowledge on c-di-GMP signaling pathways remains largely fragmentary and molecular mechanisms of regulation and even c-di GMP targets are yet unknown for most bacteria. Besides genomics or bioinformatics, accompanying alternative approaches are necessary to reveal c-di GMP regulation in bacteria with complex lifestyles. We have approached this study by artificially altering the c-di-GMP economy of diverse pathogenic and mutualistic plant-interacting bacteria and examining the effects on the interaction with their respective host plants. Phytopathogenic Pseudomonas and symbiotic Rhizobium strains with enhanced levels of intracellular c-di-GMP displayed common free-living responses: reduction of motility, increased production of extracellular polysaccharides and enhanced biofilm formation. Regarding the interaction with the host plants, P. savastanoi pv. savastanoi cells containing high c-di-GMP levels formed larger knots on olive plants which, however, displayed reduced necrosis. In contrast, development of disease symptoms in P. syringae-tomato or P. syringae-bean interactions did not seem significantly affected by high c-di-GMP. On the other hand, increasing c-di-GMP levels in symbiotic R. etli and R. leguminosarum strains favoured the early stages of the interaction since enhanced adhesion to plant roots, but decreased symbiotic efficiency as plant growth and nitrogen contents were reduced. Our results remark the importance of c-di-GMP economy for plant-interacting bacteria and show the usefulness of our approach to reveal particular stages during plant-bacteria associations which are sensitive to changes in c-di-GMP levels. PMID- 24626233 TI - rAvis: an R-package for downloading information stored in Proyecto AVIS, a citizen science bird project. AB - Citizen science projects store an enormous amount of information about species distribution, diversity and characteristics. Researchers are now beginning to make use of this rich collection of data. However, access to these databases is not always straightforward. Apart from the largest and international projects, citizen science repositories often lack specific Application Programming Interfaces (APIs) to connect them to the scientific environments. Thus, it is necessary to develop simple routines to allow researchers to take advantage of the information collected by smaller citizen science projects, for instance, programming specific packages to connect them to popular scientific environments (like R). Here, we present rAvis, an R-package to connect R-users with Proyecto AVIS (http://proyectoavis.com), a Spanish citizen science project with more than 82,000 bird observation records. We develop several functions to explore the database, to plot the geographic distribution of the species occurrences, and to generate personal queries to the database about species occurrences (number of individuals, distribution, etc.) and birdwatcher observations (number of species recorded by each collaborator, UTMs visited, etc.). This new R-package will allow scientists to access this database and to exploit the information generated by Spanish birdwatchers over the last 40 years. PMID- 24626234 TI - The probabilistic convolution tree: efficient exact Bayesian inference for faster LC-MS/MS protein inference. AB - Exact Bayesian inference can sometimes be performed efficiently for special cases where a function has commutative and associative symmetry of its inputs (called "causal independence"). For this reason, it is desirable to exploit such symmetry on big data sets. Here we present a method to exploit a general form of this symmetry on probabilistic adder nodes by transforming those probabilistic adder nodes into a probabilistic convolution tree with which dynamic programming computes exact probabilities. A substantial speedup is demonstrated using an illustration example that can arise when identifying splice forms with bottom-up mass spectrometry-based proteomics. On this example, even state-of-the-art exact inference algorithms require a runtime more than exponential in the number of splice forms considered. By using the probabilistic convolution tree, we reduce the runtime to O(k log(k)2) and the space to O(k log(k)) where k is the number of variables joined by an additive or cardinal operator. This approach, which can also be used with junction tree inference, is applicable to graphs with arbitrary dependency on counting variables or cardinalities and can be used on diverse problems and fields like forward error correcting codes, elemental decomposition, and spectral demixing. The approach also trivially generalizes to multiple dimensions. PMID- 24626232 TI - Associations of genetic risk score with obesity and related traits and the modifying effect of physical activity in a Chinese Han population. AB - BACKGROUND/OBJECTIVES: Recent large-scale genome-wide association studies have identified multiple loci robustly associated with BMI, predominantly in European ancestry (EA) populations. However, associations of these loci with obesity and related traits have not been well described in Chinese Hans. This study aimed to investigate whether BMI-associated loci are, individually and collectively, associated with adiposity-related traits and obesity in Chinese Hans and whether these associations are modified by physical activity (PA). SUBJECTS/METHODS: We genotyped 28 BMI-associated single nucleotide polymorphisms (SNPs) in a population-based cohort including 2,894 unrelated Han Chinese. Genetic risk score (GRS), EA and East Asian ancestry (EAA) GRSs were calculated by adding BMI increasing alleles based on all, EA and EAA identified SNPs, respectively. Interactions of GRS and PA were examined by including the interaction-term in the regression model. RESULTS: Individually, 26 of 28 SNPs showed directionally consistent effects on BMI, and associations of four loci (TMEM18, PCSK1, BDNF and MAP2K5) reached nominal significance (P<0.05). The GRS was associated with increased BMI, trunk fat and body fat percentages; and increased risk of obesity and overweight (all P<0.05). Effect sizes (0.11 vs. 0.17 kg/m2) and explained variance (0.90% vs. 1.45%) of GRS for BMI tended to be lower in Chinese Hans than in Europeans. The EA GRS and EAA GRS were associated with 0.11 and 0.13 kg/m2 higher BMI, respectively. In addition, we found that PA attenuated the effect of the GRS on BMI (Pinteraction = 0.022). CONCLUSIONS: Our observations suggest that the combined effect of obesity-susceptibility loci on BMI tended to be lower in Han Chinese than in EA. The overall, EA and EAA GRSs exert similar effects on adiposity traits. Genetic predisposition to increased BMI is attenuated by PA in this population of Han Chinese. PMID- 24626236 TI - Pneumonia in the immunocompromised host. AB - PURPOSE OF REVIEW: Novel treatment modalities for previously fatal diseases, including newer chemotherapeutic and biologic agents and the expansion of the indications for solid organ and stem cell transplantation, have resulted in prolonged patient survival and a significant increase in the population of immunocompromised hosts (ICHs). RECENT FINDINGS: This review discusses the increasing spectrum of opportunistic infections in the ICH, the general approach for early diagnosis and treatment of pulmonary infections in this population, and the current and novel diagnostic modalities available to establish a rapid and specific microbiologic diagnosis, focusing on recent controversies and advances. SUMMARY: Early diagnosis and prompt initiation of effective therapy for infection help reduce morbidity in ICHs. Advances in diagnostic assays using nonculture based methods, such as nucleic acid amplification, may allow for earlier targeted therapy. Invasive procedures including bronchoscopy and biopsy remain essential and should be vigorously pursued in ICHs given the broad differential diagnosis of possible pulmonary pathogens in this population, and the need to establish a specific diagnosis to allow accurate targeted therapy. PMID- 24626235 TI - Severe acute respiratory syndrome vs. the Middle East respiratory syndrome. AB - PURPOSE OF REVIEW: This review compares the clinical features, laboratory aspects and treatment options of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). RECENT FINDINGS: Bats are the natural reservoirs of SARS-like coronaviruses (CoVs) and are likely the reservoir of MERS coronavirus (MERS-CoV). Although a small number of camels have been found to have positive nasal swabs by real-time polymerase chain reaction and to carry antibody against MERS-CoV, the transmission route and the intermediary animal source remain uncertain amongst the sporadic primary cases. Both SARS-CoV and MERS-CoV may cause severe respiratory failure and extrapulmonary features such as diarrhoea, whereas mild or asymptomatic cases also occur in both conditions. In comparison with SARS, patients with MERS are older with male predominance, more comorbid illness and relatively lower human-to-human transmission potential. Although the viral kinetics of MERS-CoV remain unknown, nosocomial infections of MERS occur early within the first week of illness of the index case, whereas those of SARS occurred mainly in the second week of illness when the patient's upper airway viral load peaks on day 10 of illness. In-vitro data suggest that interferon (IFN) with or without ribavirin and mycophenolic acid may inhibit MERS CoV, whereas protease inhibitors and IFN have inhibitory activity against SARS CoV. SUMMARY: Although there are some similarities in the clinical features, MERS progresses to respiratory failure much more rapidly than SARS. The higher case fatality rate of MERS is likely related to older age and comorbid illness. More studies are needed to understand MERS-CoV in order to guide public health infection control measures and treatment. PMID- 24626237 TI - Tuberculosis vaccine development at a divide. AB - PURPOSE OF REVIEW: Tuberculosis (TB) remains a major health threat that will only be defeated by a combination of better drugs, diagnostics and vaccines. The only licensed TB vaccine, bacille Calmette-Guerin (BCG), protects against extrapulmonary TB in infants. RECENT FINDINGS: Novel vaccine candidates that could protect against pulmonary TB either in TB naive or in latent TB-infected healthy individuals have been developed and are currently being assessed in clinical trials. Subunit booster vaccines are either based on viral vectors expressing TB-specific antigens or on TB-protein antigens in adjuvants. Subunit vaccines are administered on top of BCG. Replacement vaccines for BCG are recombinant viable BCG or Mycobacterium tuberculosis. Several candidates are undergoing, or will soon start, phase IIb assessment for efficacy. The first vaccine candidate, MVA85A, to complete a phase IIb trial, unfortunately failed to show protection against TB in infants. Therapeutic vaccines composed of killed mycobacterial preparations target patients with complicated TB in adjunct to drug treatment. SUMMARY: With increasing numbers of TB vaccine candidates in clinical trials, financial, regulatory and infrastructural issues arise, which would be best tackled by a global strategy. In addition, selection of the most promising vaccine candidates for further clinical development gains increasing importance. PMID- 24626238 TI - Atypical pneumonia. AB - PURPOSE OF REVIEW: We present the key advances in the infections that clinicians conventionally associate with atypical pneumonia: legionellosis, Mycoplasma pneumonia, Chlamydophila species pneumonia and Q fever. RECENT FINDINGS: There have been significant developments in molecular diagnosis to include Mycoplasma pneumoniae and Chlamydophila pneumoniae in multiplex PCR of respiratory specimens. There are diagnostic challenges in distinguishing carriage from infection, which is recognized in C. pneumoniae and now also evident in M. pneumoniae. Macrolide-resistant M. pneumoniae has emerged in Asia. There are new antimicrobials on the horizon in the ketolide class with activity against typical and atypical pathogens and useful empirical agents. SUMMARY: There are few advances in our knowledge of the epidemiology of atypical pathogens or the effectiveness of antimicrobial therapy--empirical or pathogen specific. However, if molecular testing becomes widely implemented, there will be an increased understanding of the epidemiology and presentation of atypical pneumonia and a shift to more targeted antimicrobial therapy. PMID- 24626239 TI - Dimerization of VirD2 binding protein is essential for Agrobacterium induced tumor formation in plants. AB - The Type IV Secretion System (T4SS) is the only bacterial secretion system known to translocate both DNA and protein substrates. The VirB/D4 system from Agrobacterium tumefaciens is a typical T4SS. It facilitates the bacteria to translocate the VirD2-T-DNA complex to the host cell cytoplasm. In addition to protein-DNA complexes, the VirB/D4 system is also involved in the translocation of several effector proteins, including VirE2, VirE3 and VirF into the host cell cytoplasm. These effector proteins aid in the proper integration of the translocated DNA into the host genome. The VirD2-binding protein (VBP) is a key cytoplasmic protein that recruits the VirD2-T-DNA complex to the VirD4-coupling protein (VirD4 CP) of the VirB/D4 T4SS apparatus. Here, we report the crystal structure and associated functional studies of the C-terminal domain of VBP. This domain mainly consists of alpha-helices, and the two monomers of the asymmetric unit form a tight dimer. The structural analysis of this domain confirms the presence of a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) fold. Biophysical studies show that VBP is a dimer in solution and that the HEPN domain is the dimerization domain. Based on structural and mutagenesis analyses, we show that substitution of key residues at the interface disrupts the dimerization of both the HEPN domain and full-length VBP. In addition, pull-down analyses show that only dimeric VBP can interact with VirD2 and VirD4 CP. Finally, we show that only Agrobacterium harboring dimeric full-length VBP can induce tumors in plants. This study sheds light on the structural basis of the substrate recruiting function of VBP in the T4SS pathway of A. tumefaciens and in other pathogenic bacteria employing similar systems. PMID- 24626241 TI - Modeling group size and scalar stress by logistic regression from an archaeological perspective. AB - Johnson's scalar stress theory, describing the mechanics of (and the remedies to) the increase in in-group conflictuality that parallels the increase in groups' size, provides scholars with a useful theoretical framework for the understanding of different aspects of the material culture of past communities (i.e., social organization, communal food consumption, ceramic style, architecture and settlement layout). Due to its relevance in archaeology and anthropology, the article aims at proposing a predictive model of critical level of scalar stress on the basis of community size. Drawing upon Johnson's theory and on Dunbar's findings on the cognitive constrains to human group size, a model is built by means of Logistic Regression on the basis of the data on colony fissioning among the Hutterites of North America. On the grounds of the theoretical framework sketched in the first part of the article, the absence or presence of colony fissioning is considered expression of not critical vs. critical level of scalar stress for the sake of the model building. The model, which is also tested against a sample of archaeological and ethnographic cases: a) confirms the existence of a significant relationship between critical scalar stress and group size, setting the issue on firmer statistical grounds; b) allows calculating the intercept and slope of the logistic regression model, which can be used in any time to estimate the probability that a community experienced a critical level of scalar stress; c) allows locating a critical scalar stress threshold at community size 127 (95% CI: 122-132), while the maximum probability of critical scale stress is predicted at size 158 (95% CI: 147-170). The model ultimately provides grounds to assess, for the sake of any further archaeological/anthropological interpretation, the probability that a group reached a hot spot of size development critical for its internal cohesion. PMID- 24626240 TI - Proteomic profiling of autophagosome cargo in Saccharomyces cerevisiae. AB - Macroautophagy (autophagy) is a bulk protein-degradation system ubiquitously conserved in eukaryotic cells. During autophagy, cytoplasmic components are enclosed in a membrane compartment, called an autophagosome. The autophagosome fuses with the vacuole/lysosome and is degraded together with its cargo. Because autophagy is important for the maintenance of cellular homeostasis by degrading unwanted proteins and organelles, identification of autophagosome cargo proteins (i.e., the targets of autophagy) will aid in understanding the physiological roles of autophagy. In this study, we developed a method for monitoring intact autophagosomes ex vivo by detecting the fluorescence of GFP-fused aminopeptidase I, the best-characterized selective cargo of autophagosomes in Saccharomyces cerevisiae. This method facilitated optimization of a biochemical procedure to fractionate autophagosomes. A combination of LC-MS/MS with subsequent statistical analyses revealed a list of autophagosome cargo proteins; some of these are selectively enclosed in autophagosomes and delivered to the vacuole in an Atg11 independent manner. The methods we describe will be useful for analyzing the mechanisms and physiological significance of Atg11-independent selective autophagy. PMID- 24626242 TI - Temporomandibular disorder, facial pain and the need for high level information. PMID- 24626244 TI - Is there an association between anxiety/depression and temporomandibular disorders in college students? AB - OBJECTIVE: Considering the high incidence of Temporomandibular Disorders (TMD) in the population aged 15-30 years and the fact that students are exposed to stressful psychosocial factors, the purposes of this study were: to verify clinical symptoms and jaw functionality in college students with TMD according to the anxiety/depression (A/D) level and to evaluate the correlation between A/D and functionality, maximum mouth opening (MMO) and pain and muscle activity. MATERIAL AND METHODS: Nineteen students with TMD diagnosed according to the Research Diagnostic Criteria for Temporomandibular Disorders underwent two assessments during an academic semester. The evaluations were based on questionnaires (MFIQ - Mandibular Function Impairment Questionnaire; HADS - Hospital Anxiety and Depression Scale), clinical measurements (MMO without pain, MMO and assisted MMO; palpation of joint and masticatory muscles), and electromyography. The HADS scores obtained in the two assessments were used to classify all data as either "high" or "low" A/D. Data normality, differences and correlations were tested with the Shapiro-Wilk test, Student's t-test (or the Wilcoxon test), and Spearman test, respectively. The alpha level was set at 0.05. RESULTS: None of the clinical variables were significantly different when comparing low and high A/D data. In low A/D there was a significant correlation between HADS score and: MFIQ (P=0.005, r=0.61), and MMO without pain (P=0.01, r= 0.55). CONCLUSIONS: Variation in A/D level did not change clinical symptoms or jaw functionality in college students with TMD. Apparently, there is a correlation between TMJ functionality and A/D level, which should be further investigated, taking into account the source of the TMD and including subjects with greater functional limitation. PMID- 24626243 TI - TMJ response to mandibular advancement surgery: an overview of risk factors. AB - OBJECTIVE: In order to understand the conflicting information on temporomandibular joint (TMJ) pathophysiologic responses after mandibular advancement surgery, an overview of the literature was proposed with a focus on certain risk factors. METHODS: A literature search was carried out in the Cochrane, PubMed, Scopus and Web of Science databases in the period from January 1980 through March 2013. Various combinations of keywords related to TMJ changes [disc displacement, arthralgia, condylar resorption (CR)] and aspects of surgical intervention (fixation technique, amount of advancement) were used. A hand search of these papers was also carried out to identify additional articles. RESULTS: A total of 148 articles were considered for this overview and, although methodological troubles were common, this review identified relevant findings which the practitioner can take into consideration during treatment planning: 1- Surgery was unable to influence TMJ with preexisting displaced disc and crepitus; 2- Clicking and arthralgia were not predictable after surgery, although there was greater likelihood of improvement rather than deterioration; 3- The amount of mandibular advancement and counterclockwise rotation, and the rigidity of the fixation technique seemed to influence TMJ position and health; 4- The risk of CR increased, especially in identified high-risk cases. CONCLUSIONS: Young adult females with mandibular retrognathism and increased mandibular plane angle are susceptible to painful TMJ, and are subject to less improvement after surgery and prone to CR. Furthermore, thorough evidenced-based studies are required to understand the response of the TMJ after mandibular advancement surgery. PMID- 24626245 TI - Lack of correlation between tubular dentine cement penetration, adhesiveness and leakage in roots filled with gutta percha and an endodontic cement based on epoxy amine resin. AB - OBJECTIVE: To analyze possible correlations among tubular dentine cement penetration, adhesiveness and apical leakage in fillings performed with gutta percha and an endodontic cement based on epoxy amine resin. MATERIAL AND METHODS: Sixty similar, extracted human mandibular central incisors were irrigated, instrumented and filled following the same protocol. First, apical leakage was quantified by fluid filtration tests. Then, these same specimens were sectioned for analysis of tubular dentine cement penetration and the middle thirds were submitted to push-out tests to analyze the adhesiveness of the fillings. RESULTS: In brief, the means and standard deviations with a confidence interval of 95% were as follows: tubular dentine cement penetration (8.875+/-4.540), adhesiveness (4.441+/-2.683) and apical leakage (0.318+/-0.215). The data were confronted using the Pearson's test (P>0.05), and it was possible to prove that there was no correlation between (1) tubular dentine cement penetration and apical leakage (r2: 0.08276), (2) tubular dentine cement penetration and adhesiveness (r2: 0.2412) and (3) adhesiveness and apical leakage (r2: 0.1340). CONCLUSION: After analysis of these data, it could be observed that there exists no correlation among the variables analyzed in this study. PMID- 24626246 TI - Non-cross-linked collagen type I/III materials enhance cell proliferation: in vitro and in vivo evidence. AB - OBJECTIVE: To analyze Mucograft(r)(MG), a recently introduced collagen matrix, in vitro and in vivo, and compare it with BioGide(r)(BG), a well-established collagen membrane, as control. MATERIAL AND METHODS: A detailed analysis of the materials surface and ultra-structure was performed. Cellular growth patterns and proliferation rates of human fibroblasts on MG and BG were analyzed in vitro. In addition, the early tissue reaction of CD-1 mouse to these materials was analyzed by means of histological and histomorphometrical analysis. RESULTS: MG showed a three-fold higher thickness both in dry and wet conditions, when compared to BG. The spongy surface of BG significantly differed from that of MG. Cells showed a characteristic proliferation pattern on the different materials in vitro. Fibroblasts tended to proliferate on the compact layers of both collagens, with the highest values on the compact side of BG. In vivo, at day three both materials demonstrated good tissue integration, with a mononuclear cell sheet of fibroblasts on all surfaces, however, without penetrating into the materials. CONCLUSIONS: The findings of this study showed that MG and BG facilitate cell proliferation on both of their surfaces in vitro. In vivo, these two materials induce a comparable early tissue reaction, while serving as cell occlusive barriers. PMID- 24626247 TI - Effect of fixed orthodontic appliances on salivary microbial parameters at 6 months: a controlled observational study. AB - OBJECTIVE: The aim of this study was to assess the microbial changes in children with fixed orthodontic appliances compared with a control group of children without orthodontic treatment. MATERIAL AND METHODS: Ninety-five children, aged between 12 and 16 years, participated in this study. Forty-eight subjects were fitted with fixed orthodontic appliances and forty-seven were free of any such appliances. The follow-up was 6 months for all children. The association between orthodontic appliances and high levels of Streptococcus mutans and Lactobacillus spp was assessed with logistic regression models, taking age, sex, pH and buffer capacity into account. RESULTS: Differences at baseline between the two groups were not statistically significant. We found that wearing a fixed orthodontic appliance was associated with high levels of Streptococcus mutans and Lactobacillus spp (adjusted OR: 6.65, 95% CI [1.98-22.37]; 9.49, 95% CI [2.57 35.07], respectively), independently of other variables. CONCLUSION: The originality of the present epidemiological study was to evaluate the evolution of salivary microbial parameters in a population of children with fixed orthodontic appliances. Our results show an increase of Streptococcus mutans and Lactobacillus spp values during the follow-up. The whole dental workforce should be aware that preventive measures are of paramount importance during orthodontic treatment. PMID- 24626248 TI - Influence of light-exposure methods and depths of cavity on the microhardness of dual-cured core build-up resin composites. AB - OBJECTIVE: The purpose of this study was to evaluate the Knoop hardness number (KHN) of dual-cured core build-up resin composites (DCBRCs) at 6 depths of cavity after 3 post-irradiation times by 4 light-exposure methods. MATERIAL AND METHODS: Five specimens each of DCBRCs (Clearfil DC Core Plus [DCP] and Unifil Core EM [UCE]) were filled in acrylic resin blocks with a semi-cylindrical cavity and light-cured using an LED light unit (power density: 1,000 mW/cm2)at the top surface by irradiation for 20 seconds (20 s), 40 seconds (40 s), bonding agent plus 20 seconds (B+20 s), or 40 seconds plus light irradiation of both sides of each acrylic resin block for 40 seconds each (120 s). KHN was measured at depths of 0.5, 2.0, 4.0, 6.0, 8.0, and 10.0 mm at 0.5 hours, 24 hours, and 7 days post irradiation. Statistical analysis was performed using repeated measures ANOVA and Tukey's compromise post-hoc test with a significance level of p<0.05. RESULTS: For both DCBRCs, at 0.5 hours post-irradiation, the 20 s and 40 s methods showed the highest KHN at depth of 0.5 mm. The 40 s method showed significantly higher KHN than the 20 s method at all depths of cavity and post-irradiation times, except UCE at depth of 0.5 mm (p<0.05). The 120 s method did not result in significantly different KHN at all depths of cavity and post-irradiation times (p>0.05). In DCP, and not UCE, at 24 hours and 7 days post-irradiation, the B+20 s method showed significantly higher KHN at all depths of cavity, except the depth of 0.5 mm (p<0.05). CONCLUSION: KHN depends on the light-exposure method, use of bonding agent, depth of cavity, post-irradiation time, and material brand. Based on the microhardness behavior, DCBRCs are preferably prepared by the effective exposure method, when used for a greater depth of cavity. PMID- 24626249 TI - Finite element analysis of rapid canine retraction through reducing resistance and distraction. AB - OBJECTIVE: The aims of this study were to compare different surgical approaches to rapid canine retraction by designing and selecting the most effective method of reducing resistance by a three-dimensional finite element analysis. MATERIAL AND METHODS: Three-dimensional finite element models of different approaches to rapid canine retraction by reducing resistance and distraction were established, including maxillary teeth, periodontal ligament, and alveolar. The models were designed to dissect the periodontal ligament, root, and alveolar separately. A 1.5 N force vector was loaded bilaterally to the center of the crown between first molar and canine, to retract the canine distally. The value of total deformation was used to assess the initial displacement of the canine and molar at the beginning of force loading. Stress intensity and force distribution were analyzed and evaluated by Ansys 13.0 through comparison of equivalent (von Mises) stress and maximum shear stress. RESULTS: The maximum value of total deformation with the three kinds of models occurred in the distal part of the canine crown and gradually reduced from the crown to the apex of the canine; compared with the canines in model 3 and model 1, the canine in model 2 had the maximum value of displacement, up to 1.9812 mm. The lowest equivalent (von Mises) stress and the lowest maximum shear stress were concentrated mainly on the distal side of the canine root in model 2. The distribution of equivalent (von Mises) stress and maximum shear stress on the PDL of the canine in the three models was highly concentrated on the distal edge of the canine cervix. . CONCLUSIONS: Removal of the bone in the pathway of canine retraction results in low stress intensity for canine movement. Periodontal distraction aided by surgical undermining of the interseptal bone would reduce resistance and effectively accelerate the speed of canine retraction. PMID- 24626250 TI - Evaluation of cytotoxicity, antimicrobial activity and physicochemical properties of a calcium aluminate-based endodontic material. AB - A calcium aluminate-based endodontic material, EndoBinder, has been developed in order to reduce MTA negative characteristics, preserving its biological properties and clinical applications. OBJECTIVES: The aim of this study was to evaluate the cytotoxicity, antimicrobial activity, pH, solubility and water sorption of EndoBinder and to compare them with those of white MTA (WMTA). MATERIAL AND METHODS: Cytotoxicity was assessed through a multiparametric analysis employing 3T3 cells. Antimicrobial activity against Enterococcus faecalis (ATCC 29212), Staphylococcus aureus. (ATCC 25923) and Candida albicans (ATCC 10556) was determined by the agar diffusion method. pH was measured at periods of 3, 24, 72 and 168 hours. Solubility and water sorption evaluation were performed following ISO requirements. Data were statistically analyzed by ANOVA and Tukey's test with a significance level of 5%. RESULTS: EndoBinder and WMTA were non-cytotoxic in all tested periods and with the different cell viability parameters. There was no statistical differences between both materials (P>.05). All tested materials were inhibitory by direct contact against all microbial strains tested. EndoBinder and WMTA presented alkaline pH in all tested times with higher values of pH for WMTA (P<.05). Both materials showed values complying with the solubility minimum requirements. However, EndoBinder showed lower solubility than WMTA (P<.05). No statistical differences were observed regarding water sorption (P>.05). CONCLUSION: Under these experimental conditions, we concluded that the calcium aluminate-based endodontic material EndoBinder demonstrated suitable biological and physicochemical properties, so it can be suggested as a material of choice in root resorption, perforations and root-end filling. PMID- 24626251 TI - Effect of cariogenic challenge on the stability of dentin bonds. AB - OBJECTIVE: The oral environment is subject to biofilm accumulation and cariogenic challenge, and few studies exist on the effect of these factors on the bond strength of adhesive systems. The aim of this study was to test if the exposure of adhesive interfaces to cariogenic challenge under biofilm accumulation could promote higher degradation than the exposure to biofilm accumulation alone. MATERIAL AND METHODS: Five molars were ground until exposure of medium dentin and then restored (Single Bond 2 and Z250 3M ESPE). The tooth/resin sets were cut to obtain beam-shaped specimens, which were distributed according to the aging conditions (n=20): water for 24 h (control); biofilm under cariogenic challenge for 3, 5 or 10 days; biofilm without cariogenic challenge for 10 days; and water for 3 months. Microcosm biofilms were formed from human saliva and grown in a saliva analogue medium, supplemented or not with sucrose to promote cariogenic challenge. Specimens were tested for microtensile bond strength, and failure modes were classified using light microscopy. Bond strength data were analyzed using ANOVA and failure modes were analyzed using ANOVA on ranks (alpha=0.05). RESULTS: No significant differences in bond strength were detected among the aging methods (P=0.248). The aging period was associated with an increase in the frequency of adhesive failures for the groups aged for 10 days or longer (P<0.001). CONCLUSION: Aging leads to a higher prevalence of interfacial adhesive failures, although this effect is not associated with cariogenic challenge or reduction in bond strengths. PMID- 24626252 TI - Social aspects of dental caries in the context of mother-child pairs. AB - The relationship between mother and child in the context of oral health has traditionally been exposed by the scientific literature in microbiology, which lacks a broad and necessary discussion of health and illness seen as processes, both biological and social. OBJECTIVE: Investigate the family social determinants associated with the caries history of children and the need for dental treatment (NDT) among their mothers was the objective of this study. MATERIAL AND METHODS: This research employed a cross-sectional study of mother-child pairs living in southern Brazil. Data collection occurred in public institutions of early childhood education. The instruments included a structured questionnaire administered to mothers and clinical oral examinations of the mothers and children. The social variables considered were marital status, maternal education, number of children, income, employment status, and frequency of visits to a dental professional. The measured outcomes were the maternal NDT and child caries history. Data were analyzed by the chi-square test (chi2) and by discriminant analysis. RESULTS: The final sample consisted of 272 mother-child pairs and it was found that the greatest need for treatment was among mothers with low educational level and low family income who rarely or never visited a dentist. Tooth decay was less frequent in only child, and most frequent in children of mothers with low educational attainment, and in children in lower income households who rarely or never visited the dentist. The social determinants of caries in children and of the maternal NDT were similar. It follows that the maternal NDT and caries history among children were strongly associated with maternal education (p<0.0001), household income (p<0.0001), and frequency of visits to a dental professional (0.0018). Caries history among children was also associated with number of children in the household (p<0.0001). CONCLUSIONS: The results suggest that the caries experience in children depended less on the family social variables than on the maternal NDT. PMID- 24626253 TI - Relation of plasma tissue kallikrein levels to presence and severity of coronary artery disease in a Chinese population. AB - OBJECTIVES: Tissue kallikrein (TK) has been shown to provide cardiovascular and cerebrovascular protective effects in animal models. The aim of this study was to investigate the relationship of plasma TK levels with the presence and severity of coronary artery disease (CAD) in the Chinese. METHODS: The study involved 898 consecutive CAD patients and 905 ethnically and geographically matched controls. CAD was angiographically confirmed in all the patients, and the severity of CAD was expressed by the number of affected vessel and coronary artery stenosis scores. Plasma TK levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Plasma TK levels were significantly higher in CAD patients than controls (0.347+/-.082 vs. 0.256+/-0.087 mg/L, P<0.001), and elevated plasma TK levels were directly associated with a higher risk of CAD (OR = 3.49, 95% CI 2.90 4.19). One-way ANOVA and multivariable stepwise linear regression analysis demonstrated that TK levels were negatively associated with the severity of CAD according to vessel scores (P<0.001) and stenosis scores (r = -0.211, p<0.001). CONCLUSIONS: Our findings suggest that higher levels of TK in plasma are associated with the presence of CAD and are a predictor of mild coronary arteriosclerosis. PMID- 24626254 TI - Risk of multiple myeloma in rheumatoid arthritis: a meta-analysis of case-control and cohort studies. AB - OBJECTIVES: multiple myeloma is a malignant neoplasm of plasma cells mainly affecting elderly patients. Despite the wealth of information available on therapeutic strategies, the etiology and pathogenesis of myeloma remain unclear. In the current study, a meta-analysis was conducted to assess the possible association between rheumatoid arthritis and myeloma. METHODS: a literature search was conducted with PubMed, EMBASE and Web of Science for relevant studies published by December 25, 2013. Additionally, we searched annual meeting abstracts of the American Society of Hematology from 2004 to 2013. Only original studies that investigated the association between rheumatoid arthritis and myeloma were included. In total, 8 case-control and 10 cohort studies were identified for analysis. RESULTS: the meta-estimate of the association between rheumatoid arthritis and myeloma was 1.14 (95% CI, 0.97-1.33) overall, with significant heterogeneity among studies. The relationship between myeloma and other autoimmune diseases was additionally examined from available data. Our results showed that myeloma risk is increased 1.31 to 1.65-fold in pernicious anemia and 1.36 to 2.30-fold in ankylosing spondylitis patients. CONCLUSION: Rheumatoid arthritis does not appear to alter the risk of myeloma, while between study heterogeneity analyses suggest caution in the interpretation of results. Pernicious anemia and ankylosing spondylitis may be potential risk factors for myeloma development. Future large-scale epidemiological studies with reliable exposure biomarkers are necessary to establish the possible contribution of autoimmune disorders to multiple myeloma. PMID- 24626255 TI - Dimensionality variations in new zirconium iodates: hydrothermal syntheses, structural determination, and characterization of BaZr(IO3)6 and K2Zr(IO3)6. AB - Two new quaternary zirconium iodates, BaZr(IO3)6 and K2Zr(IO3)6, have been synthesized through hydrothermal reactions using BaCO3 (or K2CO3), ZrO2, and HIO3 as reagents. Single crystal and powder X-ray diffraction were used to determine crystal structures of the compounds. BaZr(IO3)6 exhibits infinite bands that are composed of ZrO7 pentagonal bipyramids and IO3 trigonal pyramids, in which Ba(2+) cations are sandwiched by the bands. K2Zr(IO3)6 exhibits a molecular structure that is composed of ZrO6 octahedra and IO3 groups. The dimensionality variations seem to be attributable to the flexible coordination numbers of Zr(4+) cations with large ionic radii as well as the number of counter cations. Both of the materials are thermally stable up to approximately 440-450 degrees C and decompose to the corresponding metal zirconium oxides above these temperatures. The band gaps for BaZr(IO3)6 and K2Zr(IO3)6 are calculated to be 3.1 and 3.0 eV, respectively, using the (K/S)-versus-E plots obtained from the UV-vis diffuse reflectance spectra. Infrared spectra and local dipole moment calculations are also presented. PMID- 24626256 TI - Ethics, regulation, and comparative effectiveness research: time for a change. PMID- 24626257 TI - Chagas disease in the 21st century: a public health success or an emerging threat? AB - Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a major public health burden in Latin America and a potentially serious emerging threat to a number of countries throughout the world. Although public health programs have significantly reduced the prevalence of Chagas disease in Latin America in recent decades, the number of infections in the United States and non-endemic countries in Europe and the Western Pacific Region continues to rise. Moreover, there is still no vaccine or highly effective cure available for the approximately 10 million people currently infected with T. cruzi, a third of which will develop potentially fatal cardiomyopathy and/or severe digestive tract disorders. As Chagas disease becomes an increasingly globalized public health issue in the twenty-first century, continued attentiveness from governmental and health organizations as well as improved diagnostic tools, expanded surveillance and increased research funding will be required to maintain existing public health successes and stymie the spread of the disease to new areas and populations. PMID- 24626258 TI - Functional status of fracture victims four years after the 2008 Wenchuan earthquake. AB - OBJECTIVE: To investigate the functional status of fracture victims 4 years after the 2008 Wenchuan earthquake. METHODS: A total of 374 fracture victims who were admitted to the rehabilitation department of 5 municipal hospitals in the hardest hit areas in 2008 were interviewed face to face in 2012. Functional assessments, including muscle strength, range of motion, pain, activities of daily living and working status, were conducted. RESULTS: Approximately one-third (33.2%) of the fracture victims had decreased muscle strength and 29.4% had limited range of motion. Among the 55.3% of subjects who still experienced pain, the proportions of mild, moderate and severe pain were 65.7%, 28.5% and 5.8%, respectively. The majority (83.4%) of fracture victims were independent in caring for themselves. However, 1.6% of subjects were highly dependent or totally dependent. Single fracture victims had better muscle strength, range of motion, pain and independence than those with multiple fractures. The degrees of pain, muscle strength and dependency were worse in the older age group, and better in those with a higher level of education. In addition 17.1% were jobless and 22.2% received economic support mainly from family members. The mean unemployment rate was significantly higher and the annual household income (USD 3,086 (standard deviation 1,985) was lower than in the general population in rural Sichuan province. CONCLUSION: The prevalence of functional disorders, including pain, limited range of motion, decreased muscle strength and dependency in activities of daily living, remained high among fracture victims 4 years after the Wenchuan earthquake. Unemployment rate was high and annual household income was low in this population. PMID- 24626259 TI - Biochemical and structural characterization of neocartilage formed by mesenchymal stem cells in alginate hydrogels. AB - A popular approach to make neocartilage in vitro is to immobilize cells with chondrogenic potential in hydrogels. However, functional cartilage cannot be obtained by control of cells only, as function of cartilage is largely dictated by architecture of extracellular matrix (ECM). Therefore, characterization of the cells, coupled with structural and biochemical characterization of ECM, is essential in understanding neocartilage assembly to create functional implants in vitro. We focused on mesenchymal stem cells (MSC) immobilized in alginate hydrogels, and used immunohistochemistry (IHC) and gene expression analysis combined with advanced microscopy techniques to describe properties of cells and distribution and organization of the forming ECM. In particular, we used second harmonic generation (SHG) microscopy and focused ion beam/scanning electron microscopy (FIB/SEM) to study distribution and assembly of collagen. Samples with low cell seeding density (1e7 MSC/ml) showed type II collagen molecules distributed evenly through the hydrogel. However, SHG microscopy clearly indicated only pericellular localization of assembled fibrils. Their distribution was improved in hydrogels seeded with 5e7 MSC/ml. In those samples, FIB/SEM with nm resolution was used to visualize distribution of collagen fibrils in a three dimensional network extending from the pericellular region into the ECM. In addition, distribution of enzymes involved in procollagen processing were investigated in the alginate hydrogel by IHC. It was discovered that, at high cell seeding density, procollagen processing and fibril assembly was also occurring far away from the cell surface, indicating sufficient transport of procollagen and enzymes in the intercellular space. At lower cell seeding density, the concentration of enzymes involved in procollagen processing was presumably too low. FIB/SEM and SHG microscopy combined with IHC localization of specific proteins were shown to provide meaningful insight into ECM assembly of neocartilage, which will lead to better understanding of cartilage formation and development of new tissue engineering strategies. PMID- 24626260 TI - Putting fungi to work: harvesting a cornucopia of drugs, toxins, and antibiotics. PMID- 24626261 TI - Peptidomimetics via modifications of amino acids and peptide bonds. AB - Peptidomimetics represent an important field in chemistry, pharmacology and material science as they circumvent the limitations of traditional peptides used in therapy. Self-structural organizations such as turns, helices, sheets and loops can be accessed by chemical modifications of amino acids or peptides. In depth structural and conformational analysis and structure-activity relationships (SAR) offer a way to establish peptidomimetic libraries. Herein, we review recent developments in peptidomimetics that are formed via heteroatom replacement within the native amino acid backbone. Each sub-section describes structural features, utility and preparative methods. PMID- 24626262 TI - Dysfunctional muscle and liver glycogen metabolism in mdx dystrophic mice. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice. RESULTS: Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01)). Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001). Glycogen synthase activity was 12% higher (P<0.05) but glycogen branching enzyme activity was 70% lower (P<0.01) in mdx compared with wild-type mice. The rate limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01) in mdx mice resulting from a 24% reduction in PKA activity (P<0.01). In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001) together with starch-binding domain protein 1 (219% higher; P<0.01). In addition, mdx mice were glucose intolerant (P<0.01) and had 30% less liver glycogen (P<0.05) compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05) as a possible cause of this phenotype. CONCLUSION: We identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen. PMID- 24626263 TI - Lung ultrasound in the evaluation of pleural effusion. PMID- 24626264 TI - Can ultrasound guidance reduce the risk of pneumothorax following thoracentesis? . AB - OBJECTIVE: Thoracentesis is one of the bedside procedures most commonly associated with iatrogenic complications, particularly pneumothorax. Various risk factors for complications associated with thoracentesis have recently been identified, including an inexperienced operator; an inadequate or inexperienced support team; the lack of a standardized protocol; and the lack of ultrasound guidance. We sought to determine whether ultrasound-guided thoracentesis can reduce the risk of pneumothorax and improve outcomes (fewer procedures without fluid removal and greater volumes of fluid removed during the procedures). In our comparison of thoracentesis with and without ultrasound guidance, all procedures were performed by a team of expert pulmonologists, using the same standardized protocol in both conditions. METHODS: A total of 160 participants were randomly allocated to undergo thoracentesis with or without ultrasound guidance (n = 80 per group). The primary outcome was pneumothorax following thoracentesis. Secondary outcomes included the number of procedures without fluid removal and the volume of fluid drained during the procedure. RESULTS: Pneumothorax occurred in 1 of the 80 patients who underwent ultrasound-guided thoracentesis and in 10 of the 80 patients who underwent thoracentesis without ultrasound guidance, the difference being statistically significant (p = 0.009). Fluid was removed in 79 of the 80 procedures performed with ultrasound guidance and in 72 of the 80 procedures performed without it. The mean volume of fluid drained was larger during the former than during the latter (960 +/- 500 mL vs. 770 +/- 480 mL), the difference being statistically significant (p = 0.03). CONCLUSIONS: Ultrasound guidance increases the yield of thoracentesis and reduces the risk of post procedure pneumothorax. (Chinese Clinical Trial Registry identifier: ChiCTR-TRC 12002174 [http://www.chictr.org/en/]). PMID- 24626265 TI - Factors related to the incorrect use of inhalers by asthma patients. AB - OBJECTIVE: To evaluate inhaler technique in outpatients with asthma and to determine associations between the correctness of that technique and the level of asthma control. METHODS: This was a cross-sectional study involving patients > 14 years of age with physician-diagnosed asthma. The patients were recruited from the Asthma Outpatient Clinic of the Hospital de Clinicas de Porto Alegre, in the city of Porto Alegre, Brazil. The patients completed two questionnaires (a general questionnaire and an asthma control questionnaire based on the 2011 Global Initiative for Asthma guidelines), demonstrated their inhaler technique, and performed pulmonary function tests. Incorrect inhaler technique was defined as the incorrect execution of at least two of the predefined steps. RESULTS: We included 268 patients. Of those, 81 (30.2%) showed incorrect inhaler technique, which was associated with poor asthma control (p = 0.002). Logistic regression analysis identified the following factors associated with incorrect inhaler technique: being widowed (OR = 5.01; 95% CI, 1.74-14.41; p = 0.003); using metered dose inhalers (OR = 1.58; 95% CI, 1.35-1.85; p < 0.001); having a monthly family income < 3 times the minimum wage (OR = 2.67; 95% CI, 1.35-1.85; p = 0.008), and having > 2 comorbidities (OR = 3.80; 95% CI, 1.03-14.02; p = 0.045). CONCLUSIONS: In the sample studied, incorrect inhaler technique was associated with poor asthma control. Widowhood, use of metered dose inhalers, low socioeconomic level, and the presence of > 2 comorbidities were associated with incorrect inhaler technique. PMID- 24626266 TI - Morbidity, mortality, and categorization of the risk of perioperative complications in lung cancer patients. AB - OBJECTIVE: To determine morbidity and mortality rates by risk category in accordance with the American College of Chest Physicians guidelines, to determine what role pulmonary function tests play in this categorization process, and to identify risk factors for perioperative complications (PCs). METHODS: This was a historical cohort study based on preoperative and postoperative data collected for cases of lung cancer diagnosed or suspected between 2001 and 2010. RESULTS: Of the 239 patients evaluated, only 13 (5.4%) were classified as being at high risk of PCs. Predicted postoperative FEV1 (FEV1ppo) was sufficient to define the risk level in 156 patients (65.3%); however, cardiopulmonary exercise testing (CPET) was necessary for identifying those at high risk. Lung resection was performed in 145 patients. Overall morbidity and mortality rates were similar to those reported in other studies. However, morbidity and mortality rates for patients at an acceptable risk of PCs were 31.6% and 4.3%, respectively, whereas those for patients at high risk were 83.3% and 33.3%. Advanced age, COPD, lobe resection, and lower FEV1ppo were correlated with PCs. CONCLUSIONS: Although spirometry was sufficient for risk assessment in the majority of the population studied, CPET played a key role in the identification of high-risk patients, among whom the mortality rate was seven times higher than was that observed for those at an acceptable risk of PCs. The risk factors related to PCs coincided with those reported in previous studies. PMID- 24626267 TI - PLATINO, a nine-year follow-up study of COPD in the city of Sao Paulo, Brazil: the problem of underdiagnosis. AB - OBJECTIVE: To determine the underdiagnosis rate in new COPD cases at the end of a nine-year follow-up period-in the study designated "Projeto Latino-Americano de Investigacao em Obstrucao Pulmonar" (PLATINO, Latin-American Pulmonary Obstruction Investigation Project)-and compare that with the underdiagnosis rate during the initial phase of the study, as well as to identify the clinical features exhibited by the subjects who were not diagnosed until the end of the follow-up phase. METHODS: The study population comprised the 1,000 residents of the city of Sao Paulo, Brazil, who took part in the PLATINO study. Of those, 613 participated in the follow-up phase, during which the subjects were assessed with the same instruments and equipment employed in the initial phase of the study. We used the chi-square test or the independent sample t-test to analyze the underdiagnosis rate and to identify the characteristics of the subjects who were not diagnosed until the end of the follow-up phase. RESULTS: The underdiagnosis rate for new COPD cases at the end of the nine-year follow-up period was 70.0%. The underdiagnosis rate during the follow-up phase was 17.5% lower than that reported for the initial phase of the study. The subjects who were not diagnosed until the end of the follow-up phase presented with fewer respiratory symptoms, better pulmonary function, and less severe disease than did those previously diagnosed with COPD. CONCLUSIONS: The underdiagnosis rate for new COPD cases was lower in the follow-up phase of the study than in the initial phase. The subjects who were not diagnosed until the end of the follow-up phase of the PLATINO study presented with the same clinical profile as did those who were not diagnosed in the initial phase. These findings underscore the need for spirometry in order to confirm the diagnosis of COPD and provide early intervention. PMID- 24626268 TI - Incidence of pulmonary embolism during COPD exacerbation. AB - OBJECTIVE: Because pulmonary embolism (PE) and COPD exacerbation have similar presentations and symptoms, PE can be overlooked in COPD patients. Our objective was to determine the prevalence of PE during COPD exacerbation and to describe the clinical aspects in COPD patients diagnosed with PE. METHODS: This was a prospective study conducted at a university hospital in the city of Ankara, Turkey. We included all COPD patients who were hospitalized due to acute exacerbation of COPD between May of 2011 and May of 2013. All patients underwent clinical risk assessment, arterial blood gas analysis, chest CT angiography, and Doppler ultrasonography of the lower extremities. In addition, we measured D dimer levels and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. RESULTS: We included 172 patients with COPD. The prevalence of PE was 29.1%. The patients with pleuritic chest pain, lower limb asymmetry, and high NT-pro-BNP levels were more likely to develop PE, as were those who were obese or immobile. Obesity and lower limb asymmetry were independent predictors of PE during COPD exacerbation (OR = 4.97; 95% CI, 1.775-13.931 and OR = 2.329; 95% CI, 1.127 7.105, respectively). CONCLUSIONS: The prevalence of PE in patients with COPD exacerbation was higher than expected. The association between PE and COPD exacerbation should be considered, especially in patients who are immobile or obese. PMID- 24626269 TI - A new experimental model of cigarette smoke-induced emphysema in Wistar rats. AB - OBJECTIVE: To describe a new murine model of cigarette smoke-induced emphysema. METHODS: Twenty-four male Wistar rats were divided into two groups: the cigarette smoke group, comprising 12 rats exposed to smoke from 12 commercial filter cigarettes three times a day (a total of 36 cigarettes per day) every day for 30 weeks; and the control group, comprising 12 rats exposed to room air three times a day every day for 30 weeks. Lung function was assessed by mechanical ventilation, and emphysema was morphometrically assessed by measurement of the mean linear intercept (Lm). RESULTS: The mean weight gain was significantly (approximately ten times) lower in the cigarette smoke group than in the control group. The Lm was 25.0% higher in the cigarette smoke group. There was a trend toward worsening of lung function parameters in the cigarette smoke group. CONCLUSIONS: The new murine model of cigarette smoke-induced emphysema and the methodology employed in the present study are effective and reproducible, representing a promising and economically viable option for use in studies investigating the pathophysiology of and therapeutic approaches to COPD. PMID- 24626270 TI - Chest compression with a higher level of pressure support ventilation: effects on secretion removal, hemodynamics, and respiratory mechanics in patients on mechanical ventilation. AB - OBJECTIVE: To determine the efficacy of chest compression accompanied by a 10 cmH2O increase in baseline inspiratory pressure on pressure support ventilation, in comparison with that of aspiration alone, in removing secretions, normalizing hemodynamics, and improving respiratory mechanics in patients on mechanical ventilation. METHODS: This was a randomized crossover clinical trial involving patients on mechanical ventilation for more than 48 h in the ICU of the Porto Alegre Hospital de Clinicas, in the city of Porto Alegre, Brazil. Patients were randomized to receive aspiration alone (control group) or compression accompanied by a 10-cmH2O increase in baseline inspiratory pressure on pressure support ventilation (intervention group). We measured hemodynamic parameters, respiratory mechanics parameters, and the amount of secretions collected. RESULTS: We included 34 patients. The mean age was 64.2 +/- 14.6 years. In comparison with the control group, the intervention group showed a higher median amount of secretions collected (1.9 g vs. 2.3 g; p = 0.004), a greater increase in mean expiratory tidal volume (16 +/- 69 mL vs. 56 +/- 69 mL; p = 0.018), and a greater increase in mean dynamic compliance (0.1 +/- 4.9 cmH2O vs. 2.8 +/- 4.5 cmH2O; p = 0.005). CONCLUSIONS: In this sample, chest compression accompanied by an increase in pressure support significantly increased the amount of secretions removed, the expiratory tidal volume, and dynamic compliance. (ClinicalTrials.gov Identifier:NCT01155648 [http://www.clinicaltrials.gov/]). PMID- 24626271 TI - The burden of disease due to tuberculosis in the state of Santa Catarina, Brazil. AB - OBJECTIVE: To estimate the burden of disease due to tuberculosis in the state of Santa Catarina, Brazil, in 2009. METHODS: This was an epidemiological study with an ecological design. Data on tuberculosis incidence and mortality were collected from specific Brazilian National Ministry of Health databases. The burden of disease due to tuberculosis was based on the calculation of disability-adjusted life years (DALYs). The DALYs were estimated by adding the years of life lost (YLLs) and years lived with disability (YLDs). Absolute values were transformed into rates per 100,000 population. The rates were calculated by gender, age group, and health care macroregion. RESULTS: The burden of disease due to tuberculosis was 5,644.27 DALYs (92.25 DALYs/100,000 population), YLLs and YLDs respectively accounting for 78.77% and 21.23% of that total. The highest rates were found in males in the 30-44 and 45-59 year age brackets, although that was not true in every health care macroregion. Overall, the highest estimated burden was in the Planalto Norte macroregion (179.56 DALYs/100,000 population), followed by the Nordeste macroregion (167.07 DALYs/100,000 population). CONCLUSIONS: In the majority of the health care macroregions of Santa Catarina, the burden of disease due to tuberculosis was concentrated in adult males, the level of that concentration varying among the various macroregions. PMID- 24626272 TI - Empyema and bacteremic pneumococcal pneumonia in children under five years of age. AB - We compared bacteremic pneumococcal pneumonia (BPP) and pneumococcal empyema (PE), in terms of clinical, radiological, and laboratory findings, in under fives. A cross-sectional nested cohort study, involving under-fives (102 with PE and 128 with BPP), was conducted at 12 centers in Argentina, Brazil, and the Dominican Republic. Among those with PE, mean age was higher; disease duration was longer; and tachypnea, dyspnea, and high leukocyte counts were more common. Among those with BPP, fever and lethargy were more common. It seems that children with PE can be distinguished from those with BPP on the basis of clinical and laboratory findings. Because both conditions are associated with high rates of morbidity and mortality, prompt diagnosis is crucial. PMID- 24626273 TI - Assessment of ICU readmission risk with the Stability and Workload Index for Transfer score. AB - Patient discharge from the ICU is indicated on the basis of clinical evidence and the result of strategies aimed at improving health care. Nevertheless, some patients might be discharged too early. We attempted to identify risk factors for unplanned ICU readmission, using a score for risk assessment, designated the Stability and Workload Index for Transfer (SWIFT) score. We evaluated 100 patients discharged from an ICU and found that the SWIFT score can be used as a tool for improving the assessment of ICU patients and the appropriateness of ICU discharge, thus preventing readmission. PMID- 24626274 TI - Adalimumab-induced acute interstitial lung disease in a patient with rheumatoid arthritis. AB - The use of immunobiological agents for the treatment of autoimmune diseases is increasing in medical practice. Anti-TNF therapies have been increasingly used in refractory autoimmune diseases, especially rheumatoid arthritis, with promising results. However, the use of such therapies has been associated with an increased risk of developing other autoimmune diseases. In addition, the use of anti-TNF agents can cause pulmonary complications, such as reactivation of mycobacterial and fungal infections, as well as sarcoidosis and other interstitial lung diseases (ILDs). There is evidence of an association between ILD and the use of anti-TNF agents, etanercept and infliximab in particular. Adalimumab is the newest drug in this class, and some authors have suggested that its use might induce or exacerbate preexisting ILDs. In this study, we report the first case of acute ILD secondary to the use of adalimumab in Brazil, in a patient with rheumatoid arthritis and without a history of ILD. PMID- 24626275 TI - Add-on treatment with nebulized hypertonic saline in a child with plastic bronchitis after the Glenn procedure. AB - Plastic bronchitis (PB), although a rare cause of airway obstruction, has mortality rates up to 50% in children after Fontan-type cardiac surgery. We present the case of an 18-month-old female patient with PB following pneumonia. At 6 months of age, the patient underwent the Glenn procedure due to functionally univentricular heart. Fiberoptic bronchoscopy revealed complete blockage of the left bronchus by mucoid casts. Pharmacotherapy consisted of glucocorticosteroids, azithromycin, and enalapril maleate. The child also received nebulized 3% NaCl solution, which proved to be beneficial. In children submitted to Fontan-type procedures, physicians must be alert for PB, which can be triggered by respiratory tract infection. PMID- 24626276 TI - Tiotropium use and pulmonary function in patients with constrictive bronchiolitis. PMID- 24626277 TI - Interstitial pneumonia following exposure to fluorocarbon polymers. PMID- 24626278 TI - Mixed pneumoconiosis due to silicates and hard metals associated with primary Sjogren's syndrome due to silica. PMID- 24626279 TI - Mounier-Kuhn syndrome: a rare and often overlooked cause of bronchial dilation and recurrent respiratory tract infections. PMID- 24626280 TI - Understanding cultural competence in a multicultural nursing workforce: registered nurses' experience in Saudi Arabia. AB - PURPOSE: In Saudi Arabia, the health system is mainly staffed by expatriate nurses from different cultural and linguistic backgrounds. Given the potential risks this situation poses for patient care, it is important to understand how cultural diversity can be effectively managed in this multicultural environment. The purpose of this study was to explore notions of cultural competence with non Saudi Arabian nurses working in a major hospital in Saudi Arabia. DESIGN: Face-to face, audio-recorded, semistructured interviews were conducted with 24 non-Saudi Arabian nurses. Deductive data collection and analysis were undertaken drawing on Campinha-Bacote's cultural competence model. The data that could not be explained by this model were coded and analyzed inductively. FINDINGS: Nurses within this culturally diverse environment struggled with the notion of cultural competence in terms of each other's cultural expectations and those of the dominant Saudi culture. DISCUSSION: The study also addressed the limitations of Campinha Bacote's model, which did not account for all of the nurses' experiences. Subsequent inductive analysis yielded important themes that more fully explained the nurses' experiences in this environment. IMPLICATIONS FOR PRACTICE: The findings can inform policy, professional education, and practice in the multicultural Saudi setting. PMID- 24626281 TI - Intimate partner violence, depression, and barriers to service utilization in Arab American women. AB - How intimate partner violence (IPV), depression, and barriers to services affect Arab American women in the United States is not very well documented. This cross sectional exploratory descriptive study examines (a) the relationship between depression and IPV and (b) whether living in the United States 10 or more years decreases barriers to reporting intimate partner violence and depression in a sample (N = 312) of Arab American women 19 years and older. Findings demonstrate significant relationships between women who were at risk for IPV and depression scores (r = .44, p < .001), and number of years living in the United States and barriers to service (r = .25, p < .001). There was a significant negative relationship between barriers to service and depression (r = -.30, p < .001), and barriers to service and IPV (r = -.23, p < .001), and number of years living in the United States and depression (r = .25, p < .001). Findings underscore the importance of screening referral and follow-up for Arab American women experiencing IPV and depression. PMID- 24626282 TI - The relationship between select demographic characteristics and body mass index among Native Hawaiian and other Pacific Islander caregiving adults. AB - PURPOSE: Native Hawaiian and other Pacific Islanders (NHOPIs) have the highest prevalence of overweight and obesity in the world. We identified the proportion of our NHOPI sample in each body mass index (BMI) category and explored relationships between BMI and demographic characteristics. DESIGN/METHOD: Our descriptive correlational study included 364 NHOPI caregiver adults in Utah (n = 155) and Hawaii (n = 209). We gathered demographic information with a questionnaire. Height and weight were measured for BMI calculations. RESULTS: According to the Centers for Disease Control and Prevention's BMI categories, 84.3% of our sample was overweight or obese. Participants in Utah had significantly higher BMIs than participants in Hawaii. Educational attainment was inversely related with BMI; however, age, gender, and income were not significantly related with BMI. DISCUSSION: NHOPIs on the U.S. mainland may be at greater risk for obesity than those in Hawaii; food price differences between locations may help explain this. NHOPIs in early adulthood had high BMIs; overtime this situation could worsen without intervention. IMPLICATIONS FOR PRACTICE: NHOPIs with low education levels or in areas of low food prices are at increased risk for obesity. Future research should focus on culturally sensitive interventions to reduce NHOPI obesity and associated risks. PMID- 24626283 TI - Factors that influence mammography use among older American Indian and Alaska Native women. AB - INTRODUCTION: American Indian and Alaska Native (AIAN) women have relatively high breast cancer mortality rates despite the availability of free or low-cost screening. PURPOSE: This qualitative study explored issues that influence the participation of older AIAN women in mammography screening through tribally directed National Breast and Cervical Cancer Early Detection Programs (NBCCEDPs). METHODS: We interviewed staff (n = 12) representing five tribal NBCCEDPs and conducted four focus groups with AIAN women ages 50 to 80 years (n = 33). RESULTS: Our analysis identified four main areas of factors that predispose, enable, or reinforce decisions around mammography: financial issues and personal investments, program characteristics including direct services and education, access issues such as transportation, and comfort zone topics that include cultural or community-wide norms regarding cancer prevention. CONCLUSION: This study has implications for nurse education and training on delivering effective mammography services and preventive cancer outreach and education programs in AIAN communities. PMID- 24626284 TI - Environmentally Relevant Level of Aflatoxin B1 Dysregulates Human Dendritic Cells Through Signaling on Key Toll-Like Receptors. AB - Aflatoxins (AFs) are highly hazardous fungal biometabolites usually present in feeds and foods. Aflatoxin B1 (AFB1) is the most toxic and a known carcinogen. Toll-like receptors (TLRs), highly expressed by myeloid dendritic cells (DC), are key innate immune-surveillance molecules. Toll-like receptors not only sense pathogen-associated molecular patterns but also contribute to infections and cancer. To assess AFB1-TLR interactions on human myeloid DC, pure CD11c+ DC were generated from monocytes isolated from healthy individuals and then exposed to relevant level of AFB1 for 2 hours. Both quantitative polymerase chain reaction and flow cytometric assays were used to quantify, respectively, expression of TLR2 and TLR4 at the messenger RNA (mRNA) and protein levels in these DC. Levels of interleukin (IL) 1beta, IL-6, and IL-10 were also analyzed in AFB1- and mock treated DC. Compared to nontreated CD11c+ DC, expression levels of both TLR2 and TLR4 mRNA and proteins were significantly upregulated in AFB1-treated cells. Further, although IL-10 levels in AFB1-treated DC were similar to those in the mock-treated DC, the AFB1-exposed DC secreted higher amounts of IL-1beta and IL 6. Dendritic cells are sensitive to environmentally relevant level of AFB1, and TLR2 and TLR4 are involved in sensing AFB1 Considering the broad roles of TLR2, TLR4, and DC in immunity and infections, our novel findings open a new door to understanding the molecular mechanisms and functional consequences of AFB1 in inducing immunodysregulation, immunotoxicity, and thus (non)infectious diseases in humans. PMID- 24626285 TI - Economic analysis of delivering primary health care services through community health workers in 3 North Indian states. AB - BACKGROUND: We assessed overall annual and unit cost of delivering package of services and specific services at sub-centre level by CHWs and cost effectiveness of Government of India's policy of introducing a second auxiliary nurse midwife (ANM) at the sub-centre compared to scenario of single ANM sub-centre. METHODS: We undertook an economic costing of health services delivered by CHWs, from a health system perspective. Bottom-up costing method was used to collect data on resources spent in 50 randomly selected sub-centres selected from 4 districts. Mean unit cost along with its 95% confidence intervals were estimated using bootstrap method. Multiple linear regression model was used to standardize cost and assess its determinants. RESULTS: Annually it costs INR 1.03 million (USD 19,381), or INR 187 (USD 3.5) per capita per year, to provide a package of preventive, curative and promotive services through community health workers. Unit costs for antenatal care, postnatal care, DOTS treatment and immunization were INR 525 (USD 10) per full ANC care, INR 767 (USD 14) per PNC case registered, INR 974 (USD 18) per DOTS treatment completed and INR 97 (USD 1.8) per child immunized in routine immunization respectively. A 10% increase in human resource costs results in 6% rise in per capita cost. Similarly, 10% increment in the ANC case registered per provider through-put results in a decline in unit cost ranging from 2% in the event of current capacity utilization to 3% reduction in case of full capacity utilization. Incremental cost of introducing 2nd ANM at sub-centre level per unit percent increase ANC coverage was INR 23,058 (USD 432). CONCLUSION: Our estimates would be useful in undertaking full economic evaluations or equity analysis of CHW programs. Government of India's policy of hiring 2nd ANM at sub-centre level is very cost effective from Indian health system perspective. PMID- 24626286 TI - The efficacy of oral non-steroidal anti-inflammatory drugs for rotator cuff tendinopathy: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis on the efficacy of oral non-steroidal anti-inflammatory drugs for rotator cuff tendinopathy. DESIGN: Systematic review. METHOD: A literature search was conducted in 4 databases for randomized controlled trials published until 05/2013, comparing the efficacy of oral anti-inflammatory drugs to any other intervention. Studies characteristics were extracted using a standardized form and the methodological quality was evaluated. Results were summarized qualitatively or quantitatively. RESULTS: The mean methodological score of the 12 included studies was 53.6 +/- 8.8%. The majority of studies included acute cases and were underpowered to detect differences in adverse events. Compared to a placebo, oral non-steroidal anti inflammatory drugs were found to provide short-term pain relief (pooled mean difference: -2.69; 95% confidence interval: -1.96 to -3.41) but not function. Oral anti-inflammatory- drugs and corticosteroids injections have similar short term efficacy in terms of pain reduction as well as in function (pooled standardized mean difference: 0.09; 95% confidence interval: -0.25 to 0.44). CONCLUSION: Low to moderate grade evidence exists regarding the efficacy of non steroidal anti-inflammatory drugs for rotator cuff tendinopathy. Oral anti inflammatory drugs are effective in reducing short-term pain but not function. In terms of pain and function, oral anti-inflammatory drugs in the short term are as effective as corticosteroid injections. PMID- 24626287 TI - A high-resolution genetic map of yellow monkeyflower identifies chemical defense QTLs and recombination rate variation. AB - Genotyping-by-sequencing methods have vastly improved the resolution and accuracy of genetic linkage maps by increasing both the number of marker loci as well as the number of individuals genotyped at these loci. Using restriction-associated DNA sequencing, we construct a dense linkage map for a panel of recombinant inbred lines derived from a cross between divergent ecotypes of Mimulus guttatus. We used this map to estimate recombination rate across the genome and to identify quantitative trait loci for the production of several secondary compounds (PPGs) of the phenylpropanoid pathway implicated in defense against herbivores. Levels of different PPGs are correlated across recombinant inbred lines suggesting joint regulation of the phenylpropanoid pathway. However, the three quantitative trait loci identified in this study each act on a distinct PPG. Finally, we map three putative genomic inversions differentiating the two parental populations, including a previously characterized inversion that contributes to life-history differences between the annual/perennial ecotypes. PMID- 24626288 TI - Bioinformatics analysis of alternative polyadenylation in green alga Chlamydomonas reinhardtii using transcriptome sequences from three different sequencing platforms. AB - Messenger RNA 3'-end formation is an essential posttranscriptional processing step for most eukaryotic genes. Different from plants and animals where AAUAAA and its variants routinely are found as the main poly(A) signal, Chlamydomonas reinhardtii uses UGUAA as the major poly(A) signal. The advance of sequencing technology provides an enormous amount of sequencing data for us to explore the variations of poly(A) signals, alternative polyadenylation (APA), and its relationship with splicing in this algal species. Through genome-wide analysis of poly(A) sites in C. reinhardtii, we identified a large number of poly(A) sites: 21,041 from Sanger expressed sequence tags, 88,184 from 454, and 195,266 from Illumina sequence reads. In comparison with previous collections, more new poly(A) sites are found in coding sequences and intron and intergenic regions by deep-sequencing. Interestingly, G-rich signals are particularly abundant in intron and intergenic regions. The prevalence of different poly(A) signals between coding sequences and a 3'-untranslated region implies potentially different polyadenylation mechanisms. Our data suggest that the APA occurs in about 68% of C. reinhardtii genes. Using Gene Ontolgy analysis, we found most of the APA genes are involved in RNA regulation and metabolic process, protein synthesis, hydrolase, and ligase activities. Moreover, intronic poly(A) sites are more abundant in constitutively spliced introns than retained introns, suggesting an interplay between polyadenylation and splicing. Our results support that APA, as in higher eukaryotes, may play significant roles in increasing transcriptome diversity and gene expression regulation in this algal species. Our datasets also provide useful information for accurate annotation of transcript ends in C. reinhardtii. PMID- 24626289 TI - Genetic diversity analysis of highly incomplete SNP genotype data with imputations: an empirical assessment. AB - Genotyping by sequencing (GBS) recently has emerged as a promising genomic approach for assessing genetic diversity on a genome-wide scale. However, concerns are not lacking about the uniquely large unbalance in GBS genotype data. Although some genotype imputation has been proposed to infer missing observations, little is known about the reliability of a genetic diversity analysis of GBS data, with up to 90% of observations missing. Here we performed an empirical assessment of accuracy in genetic diversity analysis of highly incomplete single nucleotide polymorphism genotypes with imputations. Three large single-nucleotide polymorphism genotype data sets for corn, wheat, and rice were acquired, and missing data with up to 90% of missing observations were randomly generated and then imputed for missing genotypes with three map-independent imputation methods. Estimating heterozygosity and inbreeding coefficient from original, missing, and imputed data revealed variable patterns of bias from assessed levels of missingness and genotype imputation, but the estimation biases were smaller for missing data without genotype imputation. The estimates of genetic differentiation were rather robust up to 90% of missing observations but became substantially biased when missing genotypes were imputed. The estimates of topology accuracy for four representative samples of interested groups generally were reduced with increased levels of missing genotypes. Probabilistic principal component analysis based imputation performed better in terms of topology accuracy than those analyses of missing data without genotype imputation. These findings are not only significant for understanding the reliability of the genetic diversity analysis with respect to large missing data and genotype imputation but also are instructive for performing a proper genetic diversity analysis of highly incomplete GBS or other genotype data. PMID- 24626290 TI - In situ crystal growth of zeolitic imidazolate frameworks (ZIF) on electrospun polyurethane nanofibers. AB - This paper reports for the first time in situ crystal growth of ZIF-8 on electrospun polyurethane (PU) nanofibers. In SEM images, continuous and compact ZIF-8 nanocrystals grow along electrospun PU nanofibers. The highest loading capacity of ZIF-8 on PU reaches 63%. By N2 adsorption-desorption, ZIF-8-PU shows a high surface area of 566 cm(2) g(-1). Combining the good flexibility of PU with the high adsorption properties of ZIF-8, ZIF-8-PU can be easily tailored into clothes or other forms as adsorption material. Furthermore, the gas adsorption ability of ZIF-8-PU was measured for H2, N2, O2 and CO2 at room temperature (20 degrees C) under different pressure gradients. The results show that the adsorption capacity of ZIF-8-PU for CO2 is nearly 11 times that for H2, 50 times that for O2 and 75 times that for N2 at 800 mmHg. PMID- 24626291 TI - Creating natural double eyelids with continuous buried suture and mini-incision technique using subcutaneous absorbable suture for patients with puffy eyelids. AB - IMPORTANCE Incision and buried suture are 2 primary techniques for creating double eyelids. The incision method is suitable for all kinds of eyelids, but operational trauma and prolonged recovery time limit its application. The non incision approach can shape a natural and vivid crease with a relatively short recovery time. However, it is not suitable for patients with puffy eyelids, and in those patients the duration of the supratarsal crease is not long.We propose a method of combining the techniques of continuous buried suture and mini-incision. OBJECTIVE To explore a new kind of double eyelid plasty, a corrective surgical procedure for patients with puffy eyelids. DESIGN, SETTING, AND PARTICIPANTS Observational study of 221 patients with puffy single eyelids who underwent this new blepharoplasty from May 2007 to and March 2012. INTERVENTIONS Combined continuous buried-suture and mini-incision surgery using subcutaneous absorbable suture to create natural double eyelids under local anesthesia. All procedures were performed by the same surgeon. MAIN OUTCOMES AND MEASURES All patients were observed after surgery for a period ranging from 1 to 28 months (mean follow-up, 16 months). Data collection included operative time, postoperative recovery and complications. RESULTS All double eyelids appeared natural after short operative time and rapid postoperative recovery, leaving an invisible scar and long-lasting supratarsal crease. No corneal damage or infection occurred.CONCLUSIONS AND RELEVANCE Combined continuous buried-suture and mini-incision surgery using subcutaneous absorbable suture to create natural double eyelids is a reliable,durable, and less-invasive technique for patients with puffy eyelids. PMID- 24626293 TI - Emerging micro- and nanotechnology based synthetic approaches for insulin delivery. AB - Insulin is essential for type 1 and advanced type 2 diabetics to maintain blood glucose levels and prolong lives. The traditional administration requires frequent subcutaneous insulin injections that are associated with poor patient compliance, including pain, local tissue necrosis, infection, and nerve damage. Taking advantage of emerging micro- and nanotechnologies, numerous alternative strategies integrated with chemical approaches for insulin delivery have been investigated. This review outlines recent developments in the controlled delivery of insulin, including oral, nasal, pulmonary, transdermal, subcutaneous and closed-loop insulin delivery. Perspectives from new materials, formulations and devices at the micro- or nano-scales are specifically surveyed. Advantages and limitations of current delivery methods, as well as future opportunities and challenges are also discussed. PMID- 24626292 TI - Differential sensitivity to apoptosome apparatus activation in non-small cell lung carcinoma and the lung. AB - The intrinsic apoptosis pathway represents an important mechanism of stress induced death of cancer cells. To gain insight into the functional status of the apoptosome apparatus in non-small cell lung carcinoma (NSCLC), we studied its sensitivity to activation, the assembly of apoptosome complexes and stability of their precursors, and the importance of X-linked inhibitor of apoptosis (XIAP) in the regulation of apoptosome activity, using cell-free cytosols from NSCLC cell lines and NSCLC tumours and lungs from 62 surgically treated patients. Treatment of cytosol samples with cytochrome c (cyt-c) and dATP induced proteolytic processing of procaspase-9 to caspase-9, which was followed by procaspase-3 processing to caspase-3, and by generation of caspase-3-like activity in 5 of 7 studied NSCLC cell lines. Further analysis demonstrated formation of high-Mr Apaf 1 complexes associated with cleaved caspase-9 in the (cyt-c + dATP)-responsive COLO-699 and CALU-1 cells. By contrast, in A549 cells, Apaf-1 and procaspase-9 co eluted in the high-Mr fractions, indicating formation of an apoptosome complex unable of procaspase-9 processing. Thermal pre-treatment of cell-free cytosols in the absence of exogenous cyt-c and dATP lead to formation of Apaf-1 aggregates, unable to recruit and activate procaspase-9 in the presence of cyt-c and dATP, and to generate caspase-3-like activity. Further studies showed that the treatment with cyt-c and dATP induced a substantially higher increase of caspase 3-like activity in cytosol samples from NSCLC tumours compared to matched lungs. Tumour histology, grade and stage had no significant impact on the endogenous and the (cyt-c + dATP)-induced caspase-3-like activity. Upon addition into the cytosol, the XIAP-neutralizing peptides AVPIAQK and ATPFQEG only moderately heightened the (cyt-c + dATP)-induced caspase-3-like activity in some NSCLC tumours. Taken together, the present study provides evidence that the apoptosome apparatus is functional in the majority of NSCLCs and that its sensitivity to the (cyt-c + dATP)-mediated activation is often enhanced in NSCLCs compared to lungs. They also indicate that XIAP does not frequently and effectively suppress the activity of apoptosome apparatus in NSCLCs. PMID- 24626294 TI - Capillary micromechanics for core-shell particles. AB - In this work, we have developed a facile, economical microfluidic approach as well as a simple model description to measure and predict the mechanical properties of composite core-shell microparticles made from materials with dramatically different elastic properties. By forcing the particles through a tapered capillary and analyzing their deformation, the shear and compressive moduli can be measured in one single experiment. We have also formulated theoretical models that accurately capture the moduli of the microparticles in both the elastic and the non-linear deformation regimes. Our results show how the moduli of these core-shell structures depend on the material composition of the core-shell microparticles, as well as on their microstructures. The proposed technique and the understanding enabled by it also provide valuable insights into the mechanical behavior of analogous biomaterials, such as liposomes and cells. PMID- 24626297 TI - beta1-adrenergic regulation of rapid component of delayed rectifier K+ currents in guinea-pig cardiac myocytes. AB - Human ether-a-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current (IKr), which is crucial for repolarization of cardiac action potential. Patients with hERG-associated long QT syndrome usually develop tachyarrhythmias during physical and/or emotional stress, both known to stimulate adrenergic receptors. The present study aimed to investigate a putative functional link between beta1-adrenergic stimulation and IKr in guinea-pig left ventricular myocytes and to analyze how IKr is regulated following activation of the beta1-adrenergic signaling pathway. The IKr current was measured using a whole-cell patch-clamp technique. A selective beta1 adrenergic receptor agonist, xamoterol, at concentrations of 0.01-100 uM decreased IKr in a concentration-dependent manner. The 10 uM xamoterol-induced inhibition of IKr was attenuated by the protein kinase A (PKA) inhibitor KT5720, the protein kinase C (PKC) inhibitor chelerythrine, and the phospholipase (PLC) inhibitor U73122, indicating involvement of PKA, PKC and PLC in beta1-adrenergic inhibition of IKr. The results of the present study indicate an association between IKr and the beta1-adrenergic receptor in arrhythmogenesis, involving the activation of PKA, PKC and PLC. PMID- 24626296 TI - Caspase-1-dependent and -independent cell death pathways in Burkholderia pseudomallei infection of macrophages. AB - The cytosolic pathogen Burkholderia pseudomallei and causative agent of melioidosis has been shown to regulate IL-1beta and IL-18 production through NOD like receptor NLRP3 and pyroptosis via NLRC4. Downstream signalling pathways of those receptors and other cell death mechanisms induced during B. pseudomallei infection have not been addressed so far in detail. Furthermore, the role of B. pseudomallei factors in inflammasome activation is still ill defined. In the present study we show that caspase-1 processing and pyroptosis is exclusively dependent on NLRC4, but not on NLRP3 in the early phase of macrophage infection, whereas at later time points caspase-1 activation and cell death is NLRC4- independent. In the early phase we identified an activation pathway involving caspases-9, -7 and PARP downstream of NLRC4 and caspase-1. Analyses of caspase 1/11-deficient infected macrophages revealed a strong induction of apoptosis, which is dependent on activation of apoptotic initiator and effector caspases. The early activation pathway of caspase-1 in macrophages was markedly reduced or completely abolished after infection with a B. pseudomallei flagellin FliC or a T3SS3 BsaU mutant. Studies using cells transfected with the wild-type and mutated T3SS3 effector protein BopE indicated also a role of this protein in caspase-1 processing. A T3SS3 inner rod protein BsaK mutant failed to activate caspase-1, revealed higher intracellular counts, reduced cell death and IL-1beta secretion during early but not during late macrophage infection compared to the wild-type. Intranasal infection of BALB/c mice with the BsaK mutant displayed a strongly decreased mortality, lower bacterial loads in organs, and reduced levels of IL 1beta, myeloperoxidase and neutrophils in bronchoalveolar lavage fluid. In conclusion, our results indicate a major role for a functional T3SS3 in early NLRC4-mediated caspase-1 activation and pyroptosis and a contribution of late caspase-1-dependent and -independent cell death mechanisms in the pathogenesis of B. pseudomallei infection. PMID- 24626295 TI - Diagnostic and prognostic utility of a DNA hypermethylated gene signature in prostate cancer. AB - We aimed to identify a prostate cancer DNA hypermethylation microarray signature (denoted as PHYMA) that differentiates prostate cancer from benign prostate hyperplasia (BPH), high from low-grade and lethal from non-lethal cancers. This is a non-randomized retrospective study in 111 local Asian men (87 prostate cancers and 24 BPH) treated from 1995 to 2009 in our institution. Archival prostate epithelia were laser-capture microdissected and genomic DNA extracted and bisulfite-converted. Samples were profiled using Illumina GoldenGate Methylation microarray, with raw data processed by GenomeStudio. A classification model was generated using support vector machine, consisting of a 55-probe DNA methylation signature of 46 genes. The model was independently validated on an internal testing dataset which yielded cancer detection sensitivity and specificity of 95.3% and 100% respectively, with overall accuracy of 96.4%. Second validation on another independent western cohort yielded 89.8% sensitivity and 66.7% specificity, with overall accuracy of 88.7%. A PHYMA score was developed for each sample based on the state of methylation in the PHYMA signature. Increasing PHYMA score was significantly associated with higher Gleason score and Gleason primary grade. Men with higher PHYMA scores have poorer survival on univariate (p = 0.0038, HR = 3.89) and multivariate analyses when controlled for (i) clinical stage (p = 0.055, HR = 2.57), and (ii) clinical stage and Gleason score (p = 0.043, HR = 2.61). We further performed bisulfite genomic sequencing on 2 relatively unknown genes to demonstrate robustness of the assay results. PHYMA is thus a signature with high sensitivity and specificity for discriminating tumors from BPH, and has a potential role in early detection and in predicting survival. PMID- 24626300 TI - Sudden sensorineural hearing loss associated with iron-deficiency anemia: a population-based study. AB - IMPORTANCE Vascular events play a big part in the development of sudden sensorineural hearing loss (SSNHL), but only those associated with sickle-cell anemia have been previously associated with SSNHL. This study demonstrates an association between SSNHL and prior iron-deficiency anemia (IDA).OBJECTIVE To evaluate the association between IDA and SSNHL using a nationwide population based database.DESIGN, SETTING, AND PARTICIPANTS In this case-control study in Taiwan, participants with SSNHL (n = 4004) were identified, and controls (n = 12 012) were randomly selected.MAIN OUTCOMES AND MEASURES Conditional logistic regression was used to calculate the ORs (95%CIs) for IDA in participants with SSNHL vs controls.RESULTS Of the 16 016 sampled participants, 533 (3.3%) had previously been diagnosed with IDA, including 172 (4.3%) participants with SSNHL and 361 (3.0%) controls. The chi2 test revealed a significant difference (P < .001) in the prevalence of prior IDA between participants with SSNHL and controls. By conditional logistic regression, we found that the OR for previous IDA among the participants with SSNHL was 1.34 (95%CI, 1.11-1.61) (P < .01)after adjusting for monthly income, geographic region, urbanization level, and comorbidities(ie, hypertension, diabetes, hyperlipidemia, renal disease, and coronary heart disease). The significant relationship between SSNHL and prior IDA was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95%CI, 1.35-2.72) (P < .001) for the participants with SSNHL compared with controls, and the strength of this relationship decreased with age.CONCLUSIONS AND RELEVANCE There is an association between SSNHL and prior IDA.Patients with IDA, especially those younger than 60 years, should be more aggressively surveyed and managed to reduce hearing-related morbidities. PMID- 24626299 TI - BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2. AB - An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL) independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2 associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway. PMID- 24626301 TI - Cutaneous leishmaniasis in North Africa: a review. AB - In North African countries, cutaneous leishmaniasis transmission has been increasing since the 1980s, with a significant increase in the incidence of cases and a spread of the geographical distribution. The disease currently represents a major public health problem with a productivity gap and an impediment for development, which results in dramatic socioeconomic and psycho-sanitary impacts. The incidence is more than thousands of cases every year in Algeria, Libya, Morocco, and Tunisia. In Egypt, only a few dozen cases per year are reported, mainly in the Sinai Peninsula. Three Leishmania species, associated with distinct eco-epidemiological and clinical patterns, are involved, namely Leishmania infantum, L. major, and L. tropica. However, L. major is by far the most frequent in Algeria, Libya, and Tunisia, with more than 90% of the registered cases. It is mainly encountered in rural areas under semi-arid, arid and Saharan climates. Leishmania tropica is more prevalent in Morocco, reaching 30-40% of isolates in some districts. Much data is still missing concerning the risk factors of the infection and the lesion development, as well as vector and reservoir ecology and behavior. The knowledge of such parameters, following multidisciplinary and integrated approaches, is crucial for better management and control of the disease, that also faces a lack of resources and efficient control measures. PMID- 24626302 TI - Characterisation of divergent flavivirus NS3 and NS5 protein sequences detected in Rhipicephalus microplus ticks from Brazil. AB - Transcripts similar to those that encode the nonstructural (NS) proteins NS3 and NS5 from flaviviruses were found in a salivary gland (SG) complementary DNA (cDNA) library from the cattle tick Rhipicephalus microplus. Tick extracts were cultured with cells to enable the isolation of viruses capable of replicating in cultured invertebrate and vertebrate cells. Deep sequencing of the viral RNA isolated from culture supernatants provided the complete coding sequences for the NS3 and NS5 proteins and their molecular characterisation confirmed similarity with the NS3 and NS5 sequences from other flaviviruses. Despite this similarity, phylogenetic analyses revealed that this potentially novel virus may be a highly divergent member of the genus Flavivirus. Interestingly, we detected the divergent NS3 and NS5 sequences in ticks collected from several dairy farms widely distributed throughout three regions of Brazil. This is the first report of flavivirus-like transcripts in R. microplus ticks. This novel virus is a potential arbovirus because it replicated in arthropod and mammalian cells; furthermore, it was detected in a cDNA library from tick SGs and therefore may be present in tick saliva. It is important to determine whether and by what means this potential virus is transmissible and to monitor the virus as a potential emerging tick-borne zoonotic pathogen. PMID- 24626303 TI - Peripheral blood fibrocytes: new information to explain the dynamics of Leishmania infection. AB - Fibrocytes are important for understanding the progression of many diseases because they are present in areas where pathogenic lesions are generated. However, the morphology of fibrocytes and their interactions with parasites are poorly understood. In this study, we examined the morphology of peripheral blood fibrocytes and their interactions with Leishmania (L.) amazonensis . Through ultrastructural analysis, we describe the details of fibrocyte morphology and how fibrocytes rapidly internalise Leishmania promastigotes. The parasites differentiated into amastigotes after 2 h in phagolysosomes and the infection was completely resolved after 72 h. Early in the infection, we found increased nitric oxide production and large lysosomes with electron-dense material. These factors may regulate the proliferation and death of the parasites. Because fibrocytes are present at the infection site and are directly involved in developing cutaneous leishmaniasis, they are targets for effective, non-toxic cell-based therapies that control and treat leishmaniasis. PMID- 24626304 TI - A comparative study of the effect of multiple immersions on Aedini (Diptera: Culicidae) mosquito eggs with emphasis on sylvan vectors of yellow fever virus. AB - The effect of multiple immersions on Haemagogus janthinomys , Haemagogus leucocelaenus , Aedes albopictus and Ochlerotatus terrens eggs was studied. Eggs were collected in April, June, October and December of 2011 in Minas Gerais, Brazil. Most of the Aedes and Ochlerotatus eggs hatched upon the first immersion, while Haemagogus eggs showed a varied instalment hatching response. The number of immersions required for hatching increased for eggs collected closer to the dry winter season. PMID- 24626305 TI - Increased frequency of micronuclei in the lymphocytes of patients chronically infected with hepatitis B or hepatitis C virus. AB - In this study, we analysed the frequency of micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) and evaluated mutagen-induced sensitivity in the lymphocytes of patients chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV). In total, 49 patients with chronic viral hepatitis (28 HBV-infected and 21 HCV-infected patients) and 33 healthy, non-infected blood donor controls were investigated. The frequencies (0/00) of MN, NPBs and NBUDs in the controls were 4.41 +/- 2.15, 1.15 +/- 0.97 and 2.98 +/- 1.31, respectively. The frequencies of MN and NPBs were significantly increased (p < 0.0001) in the patient group (7.01 +/- 3.23 and 2.76 +/- 2.08, respectively) compared with the control group. When considered separately, the HBV-infected patients (7.18 +/- 3.57) and HCV-infected patients (3.27 +/- 2.40) each had greater numbers of MN than did the controls (p < 0.0001). The HCV-infected patients displayed high numbers of NPBs (2.09 +/- 1.33) and NBUDs (4.38 +/- 3.28), but only the HBV infected patients exhibited a significant difference (NPBs = 3.27 +/- 2.40, p < 0.0001 and NBUDs = 4.71 +/- 2.79, p = 0.03) in comparison with the controls. Similar results were obtained for males, but not for females, when all patients or the HBV-infected group was compared with the controls. The lymphocytes of the infected patients did not exhibit sensitivity to mutagen in comparison with the lymphocytes of the controls (p = 0.06). These results showed that the lymphocytes of patients who were chronically infected with HBV or HCV presented greater chromosomal instability. PMID- 24626306 TI - Submicroscopic malaria parasite carriage: how reproducible are polymerase chain reaction-based methods? AB - The polymerase chain reaction (PCR)-based methods for the diagnosis of malaria infection are expected to accurately identify submicroscopic parasite carriers. Although a significant number of PCR protocols have been described, few studies have addressed the performance of PCR amplification in cases of field samples with submicroscopic malaria infection. Here, the reproducibility of two well established PCR protocols (nested-PCR and real-time PCR for the Plasmodium 18 small subunit rRNA gene) were evaluated in a panel of 34 blood field samples from individuals that are potential reservoirs of malaria infection, but were negative for malaria by optical microscopy. Regardless of the PCR protocol, a large variation between the PCR replicates was observed, leading to alternating positive and negative results in 38% (13 out of 34) of the samples. These findings were quite different from those obtained from the microscopy-positive patients or the unexposed individuals; the diagnosis of these individuals could be confirmed based on the high reproducibility and specificity of the PCR-based protocols. The limitation of PCR amplification was restricted to the field samples with very low levels of parasitaemia because titrations of the DNA templates were able to detect < 3 parasites/uL in the blood. In conclusion, conventional PCR protocols require careful interpretation in cases of submicroscopic malaria infection, as inconsistent and false-negative results can occur. PMID- 24626307 TI - The use of Mycobacterium tuberculosis HspX and GlcB proteins to identify latent tuberculosis in rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterised by the destruction of articular cartilage and bone damage. The chronic treatment of RA patients causes a higher susceptibility to infectious diseases such as tuberculosis (TB); one-third of the world's population is latently infected (LTBI) with Mycobacterium tuberculosis (Mtb). The tuberculin skin test is used to identify individuals LTBI, but many studies have shown that this test is not suitable for RA patients. The goal of this work was to test the specific cellular immune responses to the Mtb malate synthase (GlcB) and heat shock protein X (HspX) antigens of RA patients and to correlate those responses with LTBI status. The T-helper (Th)1, Th17 and Treg-specific immune responses to the GlcB and HspX Mtb antigens were analysed in RA patients candidates for tumour necrosis factor alpha blocker treatment. Our results demonstrated that LTBI RA patients had Th1 specific immune responses to GlcB and HspX. Patients were followed up over two years and 14.3% developed active TB. After the development of active TB, RA patients had increased numbers of Th17 and Treg cells, similar to TB patients. These results demonstrate that a GlcB and HspX antigen assay can be used as a diagnostic test to identify LTBI RA patients. PMID- 24626308 TI - Evaluation of the WHO classification of dengue disease severity during an epidemic in 2011 in the state of Ceara, Brazil. AB - In 2009, the World Health Organization (WHO) issued a new guideline that stratifies dengue-affected patients into severe (SD) and non-severe dengue (NSD) (with or without warning signs). To evaluate the new recommendations, we completed a retrospective cross-sectional study of the dengue haemorrhagic fever (DHF) cases reported during an outbreak in 2011 in northeastern Brazil. We investigated 84 suspected DHF patients, including 45 (53.6%) males and 39 (46.4%) females. The ages of the patients ranged from five-83 years and the median age was 29. According to the DHF/dengue shock syndrome classification, 53 (63.1%) patients were classified as having dengue fever and 31 (36.9%) as having DHF. According to the 2009 WHO classification, 32 (38.1%) patients were grouped as having NSD [4 (4.8%) without warning signs and 28 (33.3%) with warning signs] and 52 (61.9%) as having SD. A better performance of the revised classification in the detection of severe clinical manifestations allows for an improved detection of patients with SD and may reduce deaths. The revised classification will not only facilitate effective screening and patient management, but will also enable the collection of standardised surveillance data for future epidemiological and clinical studies. PMID- 24626311 TI - Azo-conjugated half-sandwich Rh/Ru complexes for homogeneous water-oxidation catalysis. AB - Herein we report the molecular structures and electronic properties of ionic, hydrophobic, half-sandwich complexes of the formula [eta(5)-Cp*Rh(L)(MeOH)] (1) and [eta(6)-CyRu(L)(H2O)] (2), where L is azo-dye compound of (p-(2-hydroxy-1 naphthylazo)benzenesulfonic acid sodium salt). Both these complexes have been investigated electrochemically and found to display good electronic properties for use as water-oxidation catalysts potentially. PMID- 24626310 TI - Interruption of vector transmission by native vectors and "the art of the possible". AB - In a recent article in the Reader's Opinion, advantages and disadvantages of the certification processes of interrupted Chagas disease transmission (American trypanosomiasis) by native vector were discussed. Such concept, accepted by those authors for the case of endemic situations with introduced vectors, has been built on a long and laborious process by endemic countries and Subregional Initiatives for Prevention, Control and Treatment of Chagas, with Technical Secretariat of the Pan American Health Organization/World Health Organization, to create a horizon target and goal to concentrate priorities and resource allocation and actions. With varying degrees of sucess, which are not replaceable for a certificate of good practice, has allowed during 23 years to safeguard the effective control of transmission of Trypanosoma cruzi not to hundreds of thousands, but millions of people at risk conditions, truly "the art of the possible." PMID- 24626309 TI - Single nucleotide polymorphisms in the interferon gamma gene are associated with distinct types of retinochoroidal scar lesions presumably caused by Toxoplasma gondii infection. AB - The association of single nucleotide polymorphisms (SNPs) in the interferon (IFN) gamma gene ( IFNG ) with different types of retinal scar lesions presumably caused by toxoplasmosis were investigated in a cross-sectional population-based genetic study. Ten SNPs were investigated and after Bonferroni correction, only the associations between SNPs rs2069718 and rs3181035 with retinal/retinochoroidal scar lesions type A (most severe scar lesions) and C (least severe scar lesions), respectively, remained significant. The associations of two different IFNG SNPs with two different types of retinal lesions attributable to toxoplasmosis support the hypothesis that different inflammatory mechanisms underlie the development of these lesions. The in vitro analysis of IFN-gamma secretion by peripheral blood mononuclear cells stimulated with Toxoplasma gondii antigens was also investigated. The association between SNP rs2069718 and type A scar lesions revealed that differential IFN-gamma levels are correlated with distinct genotypes. However, no correlation was observed with IFN gamma secretion levels and the SNP rs3181035 , which was significantly associated with type C scar lesions. Our findings strongly suggest that immunogenetic studies of individuals with congenital or postnatally acquired infection are needed to better understand the role of IFN-gamma and its polymorphisms in the pathogenesis of ocular toxoplasmosis. PMID- 24626313 TI - Versatile reactivity of Pd-catalysts: mechanistic features of the mono-N protected amino acid ligand and cesium-halide base in Pd-catalyzed C-H bond functionalization. AB - The widely used C-H functionalization strategies and some complexities in the Pd catalyzed chemical transformations were analyzed. It was emphasized that in the course of catalysis various Pd-intermediates (including nano-scale Pd-clusters) could act as active catalysts. However, both identification of these catalytically active species and determination of factors controlling the overall catalytic process require more comprehensive and multi-disciplinary approaches. Recent joint computational and experimental approaches were instrumental in: (1) demonstrating that the addition of Pd(OAc)2 as a catalyst precursor to RSeH and RSH reagents forms the [Pd(SeR)2]n and [Pd(SR)2]n clusters, respectively, which show an unprecedented ability for selective synthesis of Markovnikov-type products starting with a mixture of reagents RSH/RSeH and acetylenic hydrocarbons; (2) predicting a valid mechanism of the amino acid ligand-assisted Pd(II)-catalyzed C-H activation that is shown to proceed via the formation of the catalytically active Pd(II) intermediate with a bidentately coordinated dianionic amino acid ligand; (3) demonstrating that the amino acid ligand plays crucial roles in the ligand-assisted Pd(II)-catalyzed C-H activation by acting as: (a) a weakly coordinating ligand to stabilize the desirable Pd(II)-precatalyst, (b) a soft proton donor and a bidentately coordinated dianionic ligand in the catalytically active Pd(II) intermediate, and (c) a proton acceptor accelerating the C-H deprotonation via the CMD mechanism; and (4) revealing the roles of the CsF base (and "cesium effect") in the Pd(0)/PCy3-catalyzed intermolecular arylation of the terminal beta-C(sp(3))-H bond of aryl amide and predicting the unprecedented "Cs2-I-F cluster" assisted mechanism for this reaction. PMID- 24626312 TI - The emerging role of anti-angiogenic therapy in ovarian cancer (review). AB - The introduction of new therapeutic agents into clinical practice of ovarian cancer, in addition to the role of surgery and chemotherapy, has been the subject of numerous studies because this tumor remains worldwide the most lethal gynecological cancer. It is now known that angiogenesis plays a vital role for ovarian physiology, but also in ovarian carcinogenesis and so it has become the main target of ovarian cancer treatment. In this review, the most common molecular pathways of angiogenesis have been investigated leading to the identification of novel targets, including monoclonal antibodies and tyrosine kinase inhibitors. The fundamental targets of anti-angiogenic drugs are vascular endothelial growth factor receptor and its ligand, but also platelet-derived growth factor, fibroblast growth factor and angiopoietin. Moreover, improved knowledge of angiogenic process allowed the discovery of other molecules, such as semaphorins, neuropilins, clusterin, some transcriptional factors, and the identification of features, including stemness, epithelial-mesenchymal transition, downregulation of certain microRNAs, the alteration of immune system, that contribute to angiogenesis and possibly to resistance mechanisms. The following patent and literature review aim to highlight recent findings of approved and novel anti-angiogenic drugs that make the treatment of patients with ovarian cancer a rapidly growing field of oncology. PMID- 24626314 TI - Early immunopathological diagnosis of ichthyosis with confetti in two sporadic cases with new mutations in keratin 10. AB - Ichthyosis with confetti (IC) is a severe non-syndromic ichthyosis due to heterozygous mutations in the KRT10 gene. The disease manifests at birth with erythroderma and scaling and is characterised by the gradual development of numerous confetti-like spots of normal skin. Diagnosis of IC is frequently delayed until adolescence or even adulthood. We report 2 young children who were first diagnosed as having congenital ichthyosiform erythroderma. However, the development of thick, confluent hyperkeratotic plaques together with the histopathological finding of keratinocyte vacuolisation in the suprabasal epidermis evoked IC. Immunofluorescence analysis showed a highly reduced keratin 10 expression within the cytoplasm of suprabasal keratinocytes and its characteristic mislocalisation to the nuclei. The diagnosis was confirmed by the identification of 2 previously unreported mutations in intron 6 and exon 7 of KRT10. Careful clinical examination then showed the presence of the first spots of normal skin in both patients at the age of 2.5 and 5 years, respectively. These cases point to the usefulness of immunofluorescence analysis of keratin 10 expression for an early diagnosis of IC. PMID- 24626315 TI - Improving Foot Examinations in Patients With Diabetes: A Performance Improvement Continuing Medical Education (PI-CME) Project. AB - PURPOSE: The purpose of this project was to determine if a Performance Improvement Continuing Medical Education (PI-CME) project, using the American Medical Association's methodology, would help improve the timeliness and comprehensiveness of foot examinations in patients with diabetes. METHODS: A PI CME project was conducted with the Internal Medicine faculty staff physicians (n = 8) and residents (n = 45). Following the 3 steps of PI-CME, participants received baseline reports about their performance defined by the American Diabetes Association's guidelines for foot examinations (stage A). Each group received an educational intervention (stage B) and a reminder tool for use in the practice. Participants received individualized reports about their performance post intervention (stage C) for comparison with preintervention data and reflection on any changes in compliance. RESULTS: In the faculty and resident clinics, the percentage of patients who received an annual foot examination when due increased significantly. Both clinics also showed improvements in the percentage of patients who received all 3 components of the exam, with the greatest improvement in the resident clinic. CONCLUSIONS: The PI-CME approach can be successfully used both with faculty staff physicians (who receive CME credits) and residents (who do not receive credits) to improve performance on diabetes quality measures. PMID- 24626317 TI - Research to improve outcomes for children and young people with long-term conditions. PMID- 24626316 TI - Proteomic identification of S-nitrosylated proteins in the parasite Entamoeba histolytica by resin-assisted capture: insights into the regulation of the Gal/GalNAc lectin by nitric oxide. AB - Entamoeba histolytica is a gastrointestinal protozoan parasite that causes amebiasis, a disease which has a worldwide distribution with substantial morbidity and mortality. Nitrosative stress, which is generated by innate immune cells, is one of the various environmental challenges that E. histolytica encounters during its life cycle. Although the effects of nitric oxide (NO) on the regulation of gene expression in this parasite have been previously investigated, our knowledge on S-nitrosylated proteins in E.histolytica is lacking. In order to fill this knowledge gap, we performed a large-scale detection of S-nitrosylated (SNO) proteins in E.histolytica trophozoites that were treated with the NO donor, S-nitrosocysteine by resin-assisted capture (RAC). We found that proteins involved in glycolysis, gluconeogenesis, translation, protein transport, and adherence to target cells such as the heavy subunit of Gal/GalNac lectin are among the S-nitrosylated proteins that were enriched by SNO-RAC. We also found that the S-nitrosylated cysteine residues in the carbohydrate recognition domain (CRD) of Gal/GalNAc lectin impairs its function and contributes to the inhibition of E.histolytica adherence to host cells. Collectively, these results advance our understanding of the mechanism of reduced E.histolytica adherence to mammalian cells by NO and emphasize the importance of NO as a regulator of key physiological functions in E.histolytica. PMID- 24626318 TI - Peanut allergy: progress at last. PMID- 24626319 TI - Hypotonic fluids and hyponatraemia. PMID- 24626320 TI - Question 1: does the use of ranitidine increase the risk of NEC in preterm infants? PMID- 24626321 TI - Towards evidence based medicine for paediatricians. PMID- 24626322 TI - Question 2: is there any long-term benefit from injecting botulinum toxin-A into children with cerebral palsy? PMID- 24626324 TI - F-actin cytoskeleton reorganization is associated with hepatic stellate cell activation. AB - The activation of hepatic stellate cells (HSCs) is involved in the development of hepatic fibrosis. Previous studies have indicated that the acquisition of certain properties by activated HSCs is highly dependent on the reorganization of the actin cytoskeleton. However, direct evidence showing that the reorganization of the actin cytoskeleton is responsible for HSC activation is lacking. The aim of the present study was to investigate the role of cytoskeletal reorganization during HSC activation and to clarify the underlying mechanism. HSC-T6 cells were treated either with the F-actin stabilizer jasplakinolide (Jas) or the depolymerizer cytochalasin D (Cyto D). The actin cytoskeleton was evaluated via assessment of stress fiber formation. Furthermore, the activation properties of HSCs, including proliferation, adhesion, migration and the expression of alpha smooth muscle actin (alpha-SMA) and collagen 1, were investigated in vitro. The results showed that Jas and Cyto D affected the actin distribution in HSC-T6 cells. Treatment with Jas resulted in thick actin bundles and a patchy appearance in the cytoplasm in HSC-T6 cells. In parallel, polymerization of actin microfilaments induced by Jas upregulated the expression of alpha-SMA and collagen 1, and also enhanced the migration and adhesion properties of HSC-T6 cells. Furthermore, the activation of HSC-T6 cells induced by the reorganization of the actin cytoskeleton was associated with the p38 mitogen-activated protein kinase (p38 MAPK) pathway. In conclusion, the present study suggests that the reorganization of the F-actin cytoskeleton is associated with HSC activation and that the p38 MAPK pathway is involved in this process. The inhibition of F-actin reorganization may thus be a potential key factor or molecular target for the control of liver fibrosis or cirrhosis. PMID- 24626325 TI - Questionnaire-based survey on the distribution and incidence of canine babesiosis in countries of Western Europe. AB - The incidence of canine babesiosis may vary considerably from one country to another depending on the distribution of the causative parasite species and their specific vectors. The aim of the present study was to evaluate the clinical occurrence of canine babesiosis diagnosed in European veterinary clinics and propose an updated map of the disease distribution in Western Europe. Questionnaires were sent to companion animal veterinary clinics in Spain, France, Benelux, Germany and Austria. The annual number of babesiosis cases in 2010, the number of practitioners in the clinic and the location of the clinic were recorded. The total numbers of dogs and practitioners in each country were used for definition of the reference populations and the annual incidence of canine babesiosis was calculated by dividing the total number of reported babesiosis cases by the total number of dogs in the veterinary practices involved in the study. Data were georeferenced for distribution map construction. The overall annual incidence of clinical babesiosis amongst the investigated dog population was 0.7%, with significant variations amongst countries and regions. Three epidemiological situations were described: (i) Spain, with co-existence of several species of piroplasms and patchy distribution of babesiosis, (ii) France, with overall presence of babesiosis due to Babesia canis and local variations and (iii) Benelux, Germany and Austria, with overall low prevalence of the disease associated with localised description related either to imported cases or to small autochthonous foci of B. canis infection. PMID- 24626326 TI - A new fluorescent probe for gasotransmitter H2S: high sensitivity, excellent selectivity, and a significant fluorescence off-on response. AB - A fluorescent off-on probe for H2S was exploited by coupling the azide-based strategy with the excited-state intramolecular proton transfer (ESIPT) sensing mechanism, which exhibits a considerably high fluorescence enhancement (1150 fold), an extremely low detection limit (0.78 nM), and a relatively fast response time (3-10 min) as well as excellent selectivity. PMID- 24626328 TI - Eosinophils are important for protection, immunoregulation and pathology during infection with nematode microfilariae. AB - Eosinophil responses typify both allergic and parasitic helminth disease. In helminthic disease, the role of eosinophils can be both protective in immune responses and destructive in pathological responses. To investigate whether eosinophils are involved in both protection and pathology during filarial nematode infection, we explored the role of eosinophils and their granule proteins, eosinophil peroxidase (EPO) and major basic protein-1 (MBP-1), during infection with Brugia malayi microfilariae. Using eosinophil-deficient mice (PHIL), we further clarify the role of eosinophils in clearance of microfilariae during primary, but not challenge infection in vivo. Deletion of EPO or MBP-1 alone was insufficient to abrogate parasite clearance suggesting that either these molecules are redundant or eosinophils act indirectly in parasite clearance via augmentation of other protective responses. Absence of eosinophils increased mast cell recruitment, but not other cell types, into the broncho-alveolar lavage fluid during challenge infection. In addition absence of eosinophils or EPO alone, augmented parasite-induced IgE responses, as measured by ELISA, demonstrating that eosinophils are involved in regulation of IgE. Whole body plethysmography indicated that nematode-induced changes in airway physiology were reduced in challenge infection in the absence of eosinophils and also during primary infection in the absence of EPO alone. However lack of eosinophils or MBP 1 actually increased goblet cell mucus production. We did not find any major differences in cytokine responses in the absence of eosinophils, EPO or MBP-1. These results reveal that eosinophils actively participate in regulation of IgE and goblet cell mucus production via granule secretion during nematode-induced pathology and highlight their importance both as effector cells, as damage inducing cells and as supervisory cells that shape both innate and adaptive immunity. PMID- 24626329 TI - Development of Hot and Cold Executive Function in Boys and Girls With ADHD. AB - OBJECTIVE: To investigate the development of executive function with pronounced emotional salience (hot EF) and less pronounced emotional salience (cold EF) in boys and girls with ADHD relative to typically developing (TD) children. METHOD: Seventy-five children with ADHD and 47 TD children were assessed with hot and cold EF tests at baseline and after 2 years. RESULTS: Despite considerable maturation, the ADHD group remained impaired on all cold EF tests relative to TD children after 2 years. There was no effect of gender on cold EF test results. Females with ADHD outperformed TD counterparts on hot EF at baseline. Females with ADHD showed deteriorating hot EF performance, while TD counterparts showed improved hot EF performance across time. CONCLUSION: Enduring cold EF impairments after 2 years may reflect stable phenotypic traits in children with ADHD. Results indicate divergent developmental trajectories of hot EF in girls with ADHD relative to TD counterparts. PMID- 24626330 TI - The Impact of DSM-5 A-Criteria Changes on Parent Ratings of ADHD in Adolescents. AB - OBJECTIVE: Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) A-criteria for ADHD were expanded to include new descriptors referencing adolescent and adult symptom manifestations. This study examines the effect of these changes on symptom endorsement in a sample of adolescents with ADHD (N = 259; age range = 10.72-16.70). METHOD: Parent ratings were collected and Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV TR) and DSM-5 endorsement of ADHD symptoms were compared. RESULTS: Under the DSM 5, there were significant increases in reported inattention, but not hyperactivity/impulsivity (H/I) symptoms, with specific elevations for certain symptoms. The average adolescent met criteria for less than one additional symptom under the DSM-5, but the correlation between ADHD symptoms and impairment was attenuated when using the DSM-5 items. Impulsivity items appeared to represent adolescent deficits better than hyperactivity items. Results were not moderated by demographic factors. CONCLUSION: In a sample of adolescents with well-diagnosed DSM-IV-TR ADHD, developmental symptom descriptors led parents to endorse slightly more symptoms of inattention, but this elevation is unlikely to be clinically meaningful. PMID- 24626331 TI - Overexpression of WRAP53 is associated with development and progression of esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer whose underlying molecular mechanisms are poorly understood. The natural antisense transcript (NAT) WRAP53 regulates p53 expression and WRAP53 protein is a component of telomerase. NATs play key roles in carcinogenesis, and although WRAP53 is known to increase cancer cell survival, its role in ESCC clinicopathology is unknown. The aim of this study was to investigate WRAP53 expression in ESCC and to correlate it with clinicopathological characteristics. METHODS: WRAP53 mRNA and protein expression was measured by quantitative PCR (qRT PCR) and western blotting, respectively, in 4 ESSC cells lines and in 45 paired ESCC and non-neoplastic esophageal mucosa tissues. To correlate WRAP53 protein expression with clinicopathological characteristics, immunohistochemistry (IHC) was performed on 134 ESCC and 85 non-neoplastic esophageal mucosa tissues. RESULTS: Expression of WRAP53 was detected in all ESCC cell lines and was upregulated in the ESCC tissues compared with the corresponding non-neoplastic tissues (P<0.01). More cells expressed WRAP53 protein in the ESCC tissues than in the non-neoplastic tissues (P<0.01). Overexpression of WRAP53 was significantly correlated with tumor infiltration depth (P = 0.000), clinical stage (P = 0.001), and lymph node metastasis (P = 0.025). Wrap53 expression was not correlated with age, gender, or tumor differentiation. CONCLUSION: This report indicates increased expression of WRAP53 in ESCC and that WRAP53 overexpression is correlated with tumor progression. WRAP53 may play a significant role in ESCC; accordingly, WRAP53 could be a useful biomarker for ESCC. PMID- 24626332 TI - Stereoselective formation of a meso-diruthenium(II,II) complex and tuning the properties of its monoruthenium analogues. AB - A novel bis(bidentate) ligand dgpm (dgpm = diguanidylpyrimidine) was synthesized by a catalyst-free C-N bond forming reaction in high yield (90%) by microwave assisted heating. The ligand was coordinated to two [Ru(bpy)2](2+) cores to afford a meso-di-Ru(II,II) complex (1-meso) with high diastereoselectivity over its homochiral form. Three mononuclear ether-functionalized Ru(II) complexes (2: ethoxyether; 3: butoxyether; 4: 2-hydroxy-1-ethoxyether) were also isolated. The ligand and complexes were fully characterized by a variety of techniques including X-ray crystallography. In cyclic voltammetric studies, the complexes exhibit a Ru(III/II) couple, which is ~500 mV less positive than the Ru(III/II) couple in Ru(bpy)3(2+). The (1)MLCT absorption maxima of all the complexes (510 550 nm) are considerably red-shifted as compared to that of Ru(bpy)3(2+) (450 nm). The (3)MLCT emission maxima of complexes 1-meso and 3 are also red-shifted by about 120 nm compared to that of Ru(bpy)3(2+) (620 nm), whereas the corresponding maxima for complexes 2 and 4 are shifted by 75 nm and 25 nm, respectively. These relative trends in redox potentials and (1)MLCT maxima are in good agreement with DFT and TD-DFT calculations, performed for all complexes. Complexes 1-meso and 3 display emission from a Ru(II)-to-bpy (3)MLCT state, which is rarely the emitting state at lambda > 700 nm in [Ru(bpy)2(N-N)](2+) complexes when the ancillary ligand is neutral. PMID- 24626333 TI - Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells. AB - Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-kappaB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-kappaB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs. PMID- 24626334 TI - Increased melanoma risk in individuals with papillary thyroid carcinoma. AB - IMPORTANCE Determining the associated risk between papillary thyroid carcinoma (PTC) and cutaneous malignant melanoma (CM) and the rate of BRAF v600e mutation could help identify a common genetic component of these 2 cancers. OBJECTIVES To define the relative risk of PTC in patients with CM, and vice versa, and their first- through fifth-degree relatives and spouses by using a unique population research database; and to assess the rate of BRAF v600e mutation in a group of patients with both diagnoses. DESIGN, SETTING, AND PARTICIPANTS Retrospective rev iew using the Utah Population Database (which is linked to medical records and the Utah Cancer Registry from 1966 to 2011) and tissue analysis in a tertiary care facility. Included were 4460 patients diagnosed with PTC and 14 569 with CM in Utah between 1966 and 2011 and their first- through fifth-degree relatives and spouses. These were compared at a 5:1 ratio with matched, population-based controls. MAIN OUTCOMES AND MEASURES Statistically significant increased risk of PTC in patients with CM, and vice versa, and any first- through fifth-degree relatives and spouses; and a significantly higher rate of BRAF v600e mutation in patients with both PTC and CM than would be expected for each individual condition alone. RESULTS Patients with CM had a 2.3-fold increased risk (P < .001) of being diagnosed as having PTC compared with population-based matched controls. Conversely, patients with PTC had a 1.8-fold increased risk (P < .001) of developing CM. First- through fifth-degree relatives and spouses of patients with PTC or CM did not show a statistically significant increased risk. Eight patients with both cancer diagnoses had tissue specimens tested, of which 4 (50%) were found to be positive for the BRAF v600e mutation in either their PTC or CM specimen, and 3 (38%) were found positive in both. CONCLUSIONS AND RELEVANCE Patients with either PTC or CMhave an increased risk of developing the other cancer as a second primary malignant neoplasm. Tissue specimens from patients with both cancers show a high rate of BRAF v600e mutation. Translational studies are needed to better define the associated genetic predisposition between PTC and CM and to test the efficacy of and implementation techniques for treatment plans using BRAF mutation as a therapeutic target. PMID- 24626335 TI - Aggregation behavior and electrical properties of amphiphilic pyrrole-tailed ionic liquids in water, from the viewpoint of dielectric relaxation spectroscopy. AB - The self-aggregation behavior of amphiphilic pyrrole-tailed imidazolium ionic liquids (Py(CH2)12mim+Br-: Py = pyrrole, mim = methylimidazolium) in water is investigated by dielectric spectroscopy from 40 Hz to 110 MHz. Dielectric determination shows that the critical micelle concentration (CMC) is 8.5 mM, which is lower than that for traditional ionic surfactants. The thermodynamic parameter of the micellization, the Gibbs free energy DeltaG, was calculated for Py(CH2)12mim+Br- and compared to those of the corresponding C(n)mim+Br- (n = 12, 14). It was found that the main driven forces of the Py(CH2)12mim+Br- aggregation were hydrophobic interaction and pi-pi interactions among the adjacent Py groups. Further, the structure of aggregation was speculated theoretically that Py groups partially insert into the alkyl chains and the staggered arrangement in micelles is formed. When the concentration of Py(CH2)12mim+Br- is higher than CMC, two remarkable relaxations which originated from diffusion of counterions and interfacial polarization between the micelles and solution, were observed at about 1.3 MHz and 55 MHz. The relaxation parameters representing the real properties of the whole system were obtained by fitting the experimental data with Cole-Cole equation. A dielectric model characterizing the structure and electrical properties of spherical micelles was proposed by which the conductivity, permittivity and the volume fraction of micelles as well as electrical properties of solution were calculated from the relaxation parameters. An intriguingly high permittivity of about 150 for the micelle was found to be a direct consequence of the strong orientational order of water molecules inside the core of micelle, and essentially is attributed to the special structure of the micelle. Furthermore, the calculation of the interfacial electrokinetic parameters of the micelles, i.e., the surface conductivity, surface charge density and zeta potential, were also achieved based on the relaxation parameters and phase parameters from higher frequency relaxation. On the basis of the results obtained, the aggregation behaviours and interfacial electrokinetic properties of the special micelles are discussed. PMID- 24626336 TI - WGSQuikr: fast whole-genome shotgun metagenomic classification. AB - With the decrease in cost and increase in output of whole-genome shotgun technologies, many metagenomic studies are utilizing this approach in lieu of the more traditional 16S rRNA amplicon technique. Due to the large number of relatively short reads output from whole-genome shotgun technologies, there is a need for fast and accurate short-read OTU classifiers. While there are relatively fast and accurate algorithms available, such as MetaPhlAn, MetaPhyler, PhyloPythiaS, and PhymmBL, these algorithms still classify samples in a read-by read fashion and so execution times can range from hours to days on large datasets. We introduce WGSQuikr, a reconstruction method which can compute a vector of taxonomic assignments and their proportions in the sample with remarkable speed and accuracy. We demonstrate on simulated data that WGSQuikr is typically more accurate and up to an order of magnitude faster than the aforementioned classification algorithms. We also verify the utility of WGSQuikr on real biological data in the form of a mock community. WGSQuikr is a Whole Genome Shotgun QUadratic, Iterative, K-mer based Reconstruction method which extends the previously introduced 16S rRNA-based algorithm Quikr. A MATLAB implementation of WGSQuikr is available at: http://sourceforge.net/projects/wgsquikr. PMID- 24626337 TI - Prediction of steps in the evolution of variola virus host range. AB - Variola virus, the agent of smallpox, has a severely restricted host range (humans) but a devastatingly high mortality rate. Although smallpox has been eradicated by a World Health Organization vaccination program, knowledge of the evolutionary processes by which human super-pathogens such as variola virus arise is important. By analyzing the evolution of variola and other closely related poxviruses at the level of single nucleotide polymorphisms we detected a hotspot of genome variation within the smallpox ortholog of the vaccinia virus O1L gene, which is known to be necessary for efficient replication of vaccinia virus in human cells. These mutations in the variola virus ortholog and the subsequent loss of the functional gene from camelpox virus and taterapox virus, the two closest relatives of variola virus, strongly suggest that changes within this region of the genome may have played a key role in the switch to humans as a host for the ancestral virus and the subsequent host-range restriction that must have occurred to create the phenotype exhibited by smallpox. PMID- 24626338 TI - Nanostructured hydrotreating catalysts for electrochemical hydrogen evolution. AB - Progress in catalysis is driven by society's needs. The development of new electrocatalysts to make renewable and clean fuels from abundant and easily accessible resources is among the most challenging and demanding tasks for today's scientists and engineers. The electrochemical splitting of water into hydrogen and oxygen has been known for over 200 years, but in the last decade and motivated by the perspective of solar hydrogen production, new catalysts made of earth-abundant materials have emerged. Here we present an overview of recent developments in the non-noble metal catalysts for electrochemical hydrogen evolution reaction (HER). Emphasis is given to the nanostructuring of industrially relevant hydrotreating catalysts as potential HER electrocatalysts. The new syntheses and nanostructuring approaches might pave the way for future development of highly efficient catalysts for energy conversion. PMID- 24626340 TI - Prenatal cocaine exposure uncouples mGluR1 from Homer1 and Gq Proteins. AB - Cocaine exposure during gestation causes protracted neurobehavioral changes consistent with a compromised glutamatergic system. Although cocaine profoundly disrupts glutamatergic neurotransmission and in utero cocaine exposure negatively affects metabotropic glutamate receptor-type 1 (mGluR1) activity, the effect of prenatal cocaine exposure on mGluR1 signaling and the underlying mechanism responsible for the prenatal cocaine effect remain elusive. Using brains of the 21-day-old (P21) prenatal cocaine-exposed rats, we show that prenatal cocaine exposure uncouples mGluR1s from their associated synaptic anchoring protein, Homer1 and signal transducer, Gq/11 proteins leading to markedly reduced mGluR1 mediated phosphoinositide hydrolysis in frontal cortex (FCX) and hippocampus. This prenatal cocaine-induced effect is the result of a sustained protein kinase C (PKC)-mediated phosphorylation of mGluR1 on the serine residues. In support, phosphatase treatment of prenatal cocaine-exposed tissues restores whereas PKC mediated phosphorylation of saline-treated synaptic membrane attenuates mGluR1 coupling to both Gq/11 and Homer1. Expression of mGluR1, Homer1 or Galpha proteins was not altered by prenatal cocaine exposure. Collectively, these data indicate that prenatal cocaine exposure triggers PKC-mediated hyper phosphorylation of the mGluR1 leading to uncoupling of mGluR1 from its signaling components. Hence, blockade of excessive PKC activation may alleviate abnormalities in mGluR1 signaling and restores mGluR1-regulated brain functions in prenatal cocaine-exposed brains. PMID- 24626342 TI - Pediatric vocal fold immobility: natural history and the need for long-term follow-up. AB - IMPORTANCE The clinical course and outcomes of pediatric vocal fold immobility (VFI) vary widely in the literature, and follow-up in these patients varies accordingly. A better understanding of the natural history of pediatric VFI is crucial to improved management. OBJECTIVE To characterize the natural history of pediatric VFI, including symptoms and rates of resolution and surgical intervention. DESIGN, SETTING, AND PARTICIPANTS Retrospective review at an academically affiliated private pediatric otolaryngology practice in a metropolitan area of all patients seen between July 15, 2001, and September 1, 2012, with a diagnosis of complete or partial VFI. After elimination of 92 incomplete or duplicate files, 404 patient records were reviewed for demographic characteristics, etiologies, symptoms, follow-up, resolution, and interventions. Follow-up records were available for 362 patients (89.6%). MAIN OUTCOMES AND MEASURES Resolution of VFI confirmed by repeated laryngoscopy, length of follow up, and surgical intervention rates. RESULTS Among the 404 patients, left VFI was present in 66.8%, right VFI in 7.9%, and bilateral VFI in 25.3%. Median (range) age at presentation was 2.9 (0-528.1) months. Major etiological categories included cardiac surgery in 68.8%, idiopathic immobility in 21.0%, and neurologic disease in 7.4%. At presentation, 61.4%experienced dysphonia, 54.0%respiratory symptoms, and 49.5%dysphagia. Tracheotomy was performed in 25.7%and gastrostomy in 40.8%. Median (range) duration of follow-up among the 89.6%of patients with follow-up was 17.2 (0.2-173.5) months. Resolution evidenced by laryngoscopy was found in 28.0%, with a median (range) time to resolution of 4.3 (0.4-38.7) months. In patients without laryngoscopic resolution, median follow-up was 26.0 months, and 28.9% reported symptomatic resolution. CONCLUSIONS AND RELEVANCE The natural history of pediatric VFI involves substantial morbidity, with lasting symptoms and considerable rates of surgical intervention. In this large database, the majority of patients did not experience resolution. This suggests a need for more regimented follow-up in these patients, a recommendation for which is proposed here. PMID- 24626341 TI - Fha interaction with phosphothreonine of TssL activates type VI secretion in Agrobacterium tumefaciens. AB - The type VI secretion system (T6SS) is a widespread protein secretion system found in many Gram-negative bacteria. T6SSs are highly regulated by various regulatory systems at multiple levels, including post-translational regulation via threonine (Thr) phosphorylation. The Ser/Thr protein kinase PpkA is responsible for this Thr phosphorylation regulation, and the forkhead-associated (FHA) domain-containing Fha-family protein is the sole T6SS phosphorylation substrate identified to date. Here we discovered that TssL, the T6SS inner membrane core component, is phosphorylated and the phosphorylated TssL (p-TssL) activates type VI subassembly and secretion in a plant pathogenic bacterium, Agrobacterium tumefaciens. Combining genetic and biochemical approaches, we demonstrate that TssL is phosphorylated at Thr 14 in a PpkA-dependent manner. Further analysis revealed that the PpkA kinase activity is responsible for the Thr 14 phosphorylation, which is critical for the secretion of the T6SS hallmark protein Hcp and the putative toxin effector Atu4347. TssL phosphorylation is not required for the formation of the TssM-TssL inner-membrane complex but is critical for TssM conformational change and binding to Hcp and Atu4347. Importantly, Fha specifically interacts with phosphothreonine of TssL via its pThr-binding motif in vivo and in vitro and this interaction is crucial for TssL interaction with Hcp and Atu4347 and activation of type VI secretion. In contrast, pThr-binding ability of Fha is dispensable for TssM structural transition. In conclusion, we discover a novel Thr phosphorylation event, in which PpkA phosphorylates TssL to activate type VI secretion via its direct binding to Fha in A. tumefaciens. A model depicting an ordered TssL phosphorylation-induced T6SS assembly pathway is proposed. PMID- 24626344 TI - Genes involved in epithelial differentiation and development are differentially expressed in oral and genital lichen planus epithelium compared to normal epithelium. AB - Lichen planus (LP) is a chronic mucocutaneous disease with unknown cause. Patients with LP often have both oral and genital lesions, but these conditions are often considered as separate diseases and treated accordingly. To find out which genes are differently expressed in mucosal LP compared to normal mucosa and establish whether oral and genital LP are in fact the same disease, whole genome expression analysis was performed on epithelium from 13 patients diagnosed with oral and/or genital LP and normal controls. For confirmation of keratin 4 and corneodesmosin expression, quantitative reverse-transcription PCR and immunohistochemistry were used. Many genes involved in epithelial development and differentiation are differently expressed in epithelium from LP compared to normal epithelium. Several of the differentially expressed genes are common for oral and genital LP and the same biological processes are altered which supports the fact that oral and genital LP are manifestations of the same disease. The change in gene expression indicates that differentiation is altered leading to changes in the epithelial barrier. PMID- 24626345 TI - Halogen-bonding in a new family of tris(haloanilato)metallate(III) magnetic molecular building blocks. AB - Here we report on new tris(haloanilato)metallate(III) complexes with general formula [A]3[M(X2An)3] (A = (n-Bu)4N(+), (Ph)4P(+); M = Cr(III), Fe(III); X2An = 3,6-dihalo derivatives of 2,5-dihydroxybenzoquinone (H4C6O4), chloranilate (Cl2An(2-)), bromanilate (Br2An(2-)) and iodanilate (I2An(2-))), obtained by a general synthetic strategy, and their full characterization. The crystal structures of these Fe(III) and Cr(III) haloanilate complexes consist of anions formed by homoleptic complexes formulated as [M(X2An)3](3-) and (Et)3NH(+), (n Bu)4N(+), or (Ph4)P(+) cations. All complexes exhibit octahedral coordination geometry with metal ions surrounded by six oxygen atoms from three chelate ligands. These complexes are chiral according to the metal coordination of three bidentate ligands, and both Lambda and Delta enantiomers are present in their crystal lattice. The packing of [(n-Bu)4N]3[Cr(I2An)3] (5a) shows that the complexes form supramolecular dimers that are held together by two symmetry related I...O interactions (3.092(8) A), considerably shorter than the sum of iodine and oxygen van der Waals radii (3.50 A). The I...O interaction can be regarded as a halogen bond (XB), where the iodine behaves as the XB donor and the oxygen atom as the XB acceptor. This is in agreement with the properties of the electrostatic potential for [Cr(I2An)3](3-) that predicts a negative charge accumulation on the peripheral oxygen atoms and a positive charge accumulation on the iodine. The magnetic behaviour of all complexes, except 5a, may be explained by considering a set of paramagnetic non-interacting Fe(III) or Cr(III) ions, taking into account the zero-field splitting effect. The presence of strong XB interactions in 5a are able, instead, to promote antiferromagnetic interactions among paramagnetic centers at low temperature, as shown by the fit with the Curie Weiss law, in agreement with the formation of halogen-bonded supramolecular dimers. PMID- 24626343 TI - A pivotal role of the vascular endothelial growth factor signaling pathway in the formation of venous hypertension-induced dural arteriovenous fistulas. AB - Dural arteriovenous fistulas (DAVFs) are associated with venous hypertension. Numerous studies have revealed high expression levels of vascular endothelial growth factor (VEGF) in human DAVF specimens, as well as in animal models of experimental venous hypertension. The objective of the present study was to clarify whether the VEGF signaling pathway is important in the development of DAVFs. Rats (n=216) were randomly divided into six groups. In the rats from five groups (groups A and C-E, n=45 in each group; group B, n=12), experimental venous hypertension was induced by right common carotid artery (CCA)-external jugular vein (EJV) anastomosis, superior sinus occlusion and left transver sinus occlusion, while the remaining group (group F, n=24) underwent sham surgery. The rats in group A received a VEGF recombinant adenovirus injection into the distal section of the right EJV 30 min prior to anastomosis of the CCA and EJV. An equivalent control adenovirus was injected into the right EJV of group B rats prior to anastomosis. The rats in group C received no virus prior to anastomosis and no medicine subsequent to surgery. The group D rats were lavaged with Vatalanib, a VEGF receptor (VEGFR) inhibitor, and the group E rats were lavaged with an equal quantity of saline weekly following surgery. Six rats from groups A E and one rat from group F were sacrificed in the first, second, fourth and twelfth weeks after surgery for immunohistochemical analysis of VEGF expression and analysis of microvessel density. Cerebral angiography was performed on the remaining rats in each group on the twelfth week after surgery. The results revealed that following transfection with VEGF recombinant adenovirus, angiogenesis in the dura mater of venous hypertensive rats was increased subsequent to the increase in the VEGF expression levels of the brain and dura mater. The rate of DAVF induction by venous hypertension was significantly reduced by the VEGFR antagonist due to reduced angiogenesis in the dura mater. In conclusion, VEGF and its receptor may be important in the formation of venous hypertension-induced DAVFs. PMID- 24626346 TI - Leishmania (Leishmania) martiniquensis n. sp. (Kinetoplastida: Trypanosomatidae), description of the parasite responsible for cutaneous leishmaniasis in Martinique Island (French West Indies). AB - The parasite responsible for autochthonous cutaneous leishmaniasis in Martinique island (French West Indies) was first isolated in 1995; its taxonomical position was established only in 2002, but it remained unnamed. In the present paper, the authors name this parasite Leishmania (Leishmania) martiniquensis Desbois, Pratlong & Dedet n. sp. and describe the type strain of this taxon, including its biological characteristics, biochemical and molecular identification, and pathogenicity. This parasite, clearly distinct from all other Euleishmania, and placed at the base of the Leishmania phylogenetic tree, is included in the subgenus Leishmania. PMID- 24626347 TI - Autophagy-related IRGM polymorphism is associated with mortality of patients with severe sepsis. AB - OBJECTIVE: Autophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients. METHODS: The study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes. RESULTS: No significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019). CONCLUSIONS: The data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation. PMID- 24626348 TI - Short-term treatment with glucosamine hydrochloride specifically downregulates hypoxia-inducible factor-1alpha at the protein level in YD-8 human tongue cancer cells. AB - Hypoxia-inducible factor-1 (HIF-1) is a tumor angiogenic transcription factor composed of an alpha and beta subunit. We investigated the effect of glucosamine hydrochloride (GS-HCl) on the expression of HIF-1alpha and HIF-1beta in serum treated YD-8 human tongue cancer cells. While long-term (24 h) treatment with GS HCl strongly repressed the expression of HIF-1alpha and HIF-1beta at both the protein and mRNA levels, short-term (4 h) GS-HCl treatment inhibited HIF-1alpha at the protein level. Short-term GS-HCl treatment also decreased phosphorylation of p70S6K and S6, translation-related proteins. However, the results of subsequent pharmacological inhibition and protein stability analyses indicated that HIF-1alpha protein downregulation induced by short-term GS-HCl treatment was not through modulation of the mTOR/p70S6K/S6 signaling pathways, the 26S proteasomal and lysosomal activities and HIF-1alpha protein stability. Importantly, our further analyses identified that HIF-1alpha protein downregulation induced by short-term GS-HCl treatment was blunted by exogenous administration of the citric acid cycle metabolites citrate and 2-oxoglutarate, but not the glycolytic end byproducts pyruvate and lactate. These findings demonstrate firstly that short-term GS treatment selectively downregulates HIF 1alpha at the protein level in YD-8 cells via interference of production of the citric acid cycle metabolites. It is proposed that short-term GS-HCl exposure may be applied for the treatment of oral tumors with high expression of HIF-1alpha. PMID- 24626350 TI - Innovations to overcome challenges related to internationalization of journals in the field of nursing. PMID- 24626349 TI - Automated detection and measurement of isolated retinal arterioles by a combination of edge enhancement and cost analysis. AB - Pressure myography studies have played a crucial role in our understanding of vascular physiology and pathophysiology. Such studies depend upon the reliable measurement of changes in the diameter of isolated vessel segments over time. Although several software packages are available to carry out such measurements on small arteries and veins, no such software exists to study smaller vessels (<50 um in diameter). We provide here a new, freely available open-source algorithm, MyoTracker, to measure and track changes in the diameter of small isolated retinal arterioles. The program has been developed as an ImageJ plug-in and uses a combination of cost analysis and edge enhancement to detect the vessel walls. In tests performed on a dataset of 102 images, automatic measurements were found to be comparable to those of manual ones. The program was also able to track both fast and slow constrictions and dilations during intraluminal pressure changes and following application of several drugs. Variability in automated measurements during analysis of videos and processing times were also investigated and are reported. MyoTracker is a new software to assist during pressure myography experiments on small isolated retinal arterioles. It provides fast and accurate measurements with low levels of noise and works with both individual images and videos. Although the program was developed to work with small arterioles, it is also capable of tracking the walls of other types of microvessels, including venules and capillaries. It also works well with larger arteries, and therefore may provide an alternative to other packages developed for larger vessels when its features are considered advantageous. PMID- 24626351 TI - [Reasons for non-elective removal of epicutaneous catheters in neonates]. AB - This study aimed to describe the incidence and reasons for nonelective removal of epicutaneous catheters in neonates, identifying its association with the catheter insertion site. This was a prospective cohort study, conducted in a neonatal intensive care unit of a private tertiary hospital in the city of Sao Paulo, Brazil. We analyzed 266 epicutaneous catheter insertions. The incidence of non elective removal was 39.1%. The most frequent post-insertion complications were suspicion of catheter-related bloodstream infection (25%) and rupture (23.1%). Most catheters were inserted through the right side of the body (65%), in upper limbs (77.1%), and using the axillary veins (31.2%). The findings did not suggest association between the incidence of non-elective removal and the insertion site of the epicutaneous catheter in neonates. Nurses should implement strategies to improve care and decrease incidence of non-elective epicutaneous catheter removals among neonates. PMID- 24626352 TI - [Prevalence of nasal septum injury in premature infants using nasal prongs]. AB - The aim of this study was to investigate the prevalence and factors associated with nasal septum injury in preterm infants in the use of noninvasive ventilation. A cross-sectional study with data collection between March and July 2012 and with search for records, interviews with mothers and nasal evaluation of 47 premature in the neonatal unit of a teaching hospital in Recife, Pernambuco, northeastern Brazil. A descriptive bivariate statistical analysis was performed through the chi-square test or Fisher exact test using the SPSS software. The prevalence of nasal lesions was 68.1%, associated with low birth weight and duration of treatment. The prevalence of nasal injury in this population is high and associated with low birth weight and length of stay in noninvasive ventilation. Due to these facts the necessity for preventive actions was noticed, such as continuous care in nursing, suitability of devices and permanent education in service. PMID- 24626353 TI - [Baby-Friendly Hospital: prevalence of exclusive breastfeeding at 6 months and intervening factors]. AB - The objective of this research was to identify the pattern of exclusive breastfeeding (EBF) in the first 6 months of infants born in a Baby-Friendly Hospital and the factors that contribute to early weaning. This was a prospective cohort study with 261 mothers and children. The data were analyzed via the construction of a Kaplan-Meier survival curve, and the log-rank test was used for the univariate analysis. A multivariate analysis was performed using the Cox proportional-hazards regression model. During the 6 months, the percentage of mothers who practiced EBF for 30, 90, 120, 150 and 180 days was 75%, 52%, 33%, 19% and 5.7%, respectively. In the multivariate analysis, the variables that conferred a risk for early weaning were the hospital and the occurrence of a follow-up visit due to mammary complication, improper positioning and the association of both of these factors. The Baby-Friendly Hospital Initiative favored EBF. PMID- 24626354 TI - [Feeding children in the immediate perioperative period after palatoplasty: a comparison between techniques using a cup and a spoon]. AB - This prospective study conducted at the Hospital for the Rehabilitation of Craniofacial Anomalies aimed to compare the best technique - a cup or a spoon - for feeding children immediately after palatoplasty. We assessed 44 children and their caregivers during feeding every 4 hours; this generated 176 evaluations: 88 using a cup and 88 using a spoon. The Fisher exact test and the Mann-Whitney test were used for statistical analysis, with a significance level of 5% (p<0.05). When the spoon was used, the percentage of patients with food escaping through the labial commissure was lower (17%; p=0.024, the portion administrated was higher (12%; p=0.029), and coughing was less frequent (13%; p=0.026) compared with use of a cup. We conclude that using a spoon to administer food after palatoplasty is better than using a cup. PMID- 24626355 TI - School age children with HIV/AIDS: possible discrimination and attitudes against. AB - Survey-based study what purpose was to analyse respondents' opinions about contacts with HIV/AIDS-affected people. It was performed using a paper-pencil method during visits of respondents at primary care centres and on-line through a link to the questionnaire distributed among patients of primary care physicians. The study involved 302 respondents, 80% of whom were women; the average age was 34.48 years. The majority of respondents did not know anyone with HIV/AIDS (89.6%). About 83.3% claimed that they would not decrease contacts with HIV/AIDS affected people. According to 64.1% of respondents, children with HIV/AIDS should go to kindergarten/public or non-public school. We selected a group of respondents, who previously were not but now are inclined to limit such contacts. These respondents can be a potential target group for HIV/AIDS educational programmes. Most respondents think that there is insufficient information about the HIV/AIDS in the mass media. PMID- 24626357 TI - [Nursing diagnoses in patients classified as priority level I and II according to the Manchester protocol]. AB - The aim of this study was to identify possible nursing diagnoses in patients classified as priority level I and II according to the Manchester protocol. This descriptive retrospective study evaluated 40 medical charts classified as priority level I and II. To identify nursing diagnoses, two experts analyzed signs and symptoms registered in medical charts at the time of risk classification. For priority level I patients, the most frequent nursing diagnoses were acute pain (65.0%), respiratory insufficiency (45.0%), and impaired gas exchange (40.0%). For the priority level II patients, the most frequent nursing diagnoses were acute pain (80.0%), nausea (10.0%), and risk for electrolyte imbalance (10.0%). This study suggests that the use of the Manchester protocol enabled identification of defining characteristics and risk factors and supports the elaboration of nursing diagnoses in risk classification. PMID- 24626356 TI - [Cultural adaptation and initial psychometric properties of the DISABKIDS (r) - Cystic Fibrosis Module - Brazilian version]. AB - This study aimed to perform the cultural adaptation and describe the initial psychometric properties of the DISABKIDS(r)-Cystic Fibrosis Module instrument to measure health-related quality of life for children and adolescents and their parents/caregivers. Methodological study of sequential development, including 126 participants in four Brazilian states. Involved translation and back translation of items, semantic and conceptual equivalence, face validity and description of the initial psychometric properties related to the construct and reliability. For semantic equivalence of the adapted version, there were adjustments in the phrasing of an item. The instrument showed satisfactory internal consistency with Cronbach's alpha values between 0.70 and 0.85, convergent validity with correlation values above 0.40 in 85% of the items and divergent validity with scale fit higher than 75%. The Brazilian version of DISABKIDS(r) - CFM will certainly constitute a valid and reliable instrument for measuring the quality of life of Brazilian children and adolescents with cystic fibrosis. PMID- 24626358 TI - [Anxiety and depression among men and women who underwent percutaneous coronary intervention]. AB - A descriptive, cross-sectional, correlational study aimed to investigate the association of sex and the presence of anxiety and depression after hospital discharge in patients who underwent percutaneous coronary intervention (PCI). Fifty-nine patients undergoing PCI and receiving outpatient treatment in the first seven months after hospital discharge were evaluated. To assess the symptoms of anxiety and depression the Hospital Anxiety and Depression Scale (HADS) was used. To test the possible associations between the variables anxiety, depression and sex the Chi-square test was used with a significance level of 5%. The results indicated a greater number of women with depression and the association between the variables sex and depression was statistically significant. In relation to anxiety, cases were more frequent in males and the association between the variables sex and anxiety was not statistically significant. PMID- 24626359 TI - [Cross-cultural adaptation and validation of the World Health Organization Health and Work Performance Questionnaire to Brazilian nurses]. AB - Study aiming to cross-culturally adapt the instrument Health and Work Performance Questionnaire (HPQ) and evaluate the psychometric properties of the Brazilian version for nurses. The adaptation process followed the Process of Translation of World Health Organization. Data for the evaluation of the psychometric properties were collected in a teaching public hospital of Ribeirao Preto in 2011. The evaluated psychometric properties were: face validity and content (group of experts), reliability by Cronbach's alpha and test-retest stability. In the evaluation of psychometric properties, the internal consistency of the HPQ adapted version, Cronbach's alpha was 0.94 for the section A and 0.86 for section B of the instrument. In analyzing the agreement of test-retest stability, the agreements were positive and statistically significant. Thus, the HPQ adapted version proved valid and reliable in the sample studied. PMID- 24626360 TI - [Profile of the elderly who naps]. AB - This study aimed to characterize the elderly who naps according to sociodemographic characteristics and frailty. A descriptive, cross-sectional study part of the multicenter project Frailty in the Elderly Brazilians. We evaluated 1,866 elderly people using a sociodemographic questionnaire. The frailty was assessed using the phenotype proposed by Fried. The data were analyzed with descriptive statistics. The results showed that the profile of the elderly who naps consists predominantly of women, married, retired, pre-frail, with an average age of 73 years, four years of study, with monthly family income of 3.9 minimum salary, with 4,4 children who were living with them only. The elderly reported napping on average 5.9 days per week, lasting 53.5 minutes per nap. Knowing the profile of the elderly who naps contributes to health professionals in the development of actions in relation to sleep problems of the frail/pre-frail elderly, preventing, minimizing or solving these problems. PMID- 24626361 TI - [Therapeutic factors in a group of health promotion for the elderly]. AB - The aim of this study was to identify therapeutic factors presented in a group of health promotion for the elderly. This is a descriptive, exploratory study with a qualitative approach. Data were collected between December 2010 and April 2011 in focal groups that included participants and their coordinators. Results were submitted to content analysis and thematic approach. Findings showed convergence of answers among participants, who indicated resonance and complementarity in identification of the following therapeutic factors: cohesion, introduction of hope, socialization, information sharing, existential factors, altruism, interpersonal relationships, and universal learning. The identification of these factors indicates the therapeutic potential of focal groups, especially for attending to the needs of elderly people, keeping these patients healthy, and strengthening their feelings of love and life, and being part of a social group. PMID- 24626362 TI - [Association between social support and the profiles of family caregivers of patients with disability and dependence]. AB - This is a descriptive cross-sectional study that analyzes the association between dimensions of social support and the profiles of family caregivers. The following instruments were used to interview 110 caregivers: a socio-demographic questionnaire, the Social Network Index, the Medical Outcomes Study, and the Barthel Index. The Mann-Whitney and Kruskal-Wallis tests were used to compare dimensions of social support and the qualitative variables as well as to determine the Spearman correlation for the quantitative variables. Caregivers who could not read or had never studied showed better perception of social support in all dimensions except the affective. In the positive interaction dimension, groups who had a partner and denied being overloaded showed a higher average than others. In addition, the number of family members and friends correlated with all dimensions of social support. Thus, the results indicate that one's social network is important for the perception of support. PMID- 24626363 TI - [Continued care for families of children with chronic diseases: perceptions of Family Health Program teams]. AB - The objective of this study is to characterize how the Family Health Strategy teams in Brazil perceive their role to provide continued care to families of children with chronic diseases. This was a qualitative study that used symbolic interactionism as its theoretical framework, with content analysis for thematic categorical analysis. Focus groups with three Family Health Strategy teams were used for data collection, with a total of 32 study participants. The results were organized into three thematic categories: 1) singularities of families that live with children with chronic diseases; 2) team, family and Family Health Strategy; and 3) limitations of care . The teams' perception is that the design of the Family Health Strategy encourages access to the family experience, allowing the recognition of its specificities. Further, the data reveal team limitations regarding their capacity to provide care, and the need for investments in articulation with different social services, sectors, and equipment. PMID- 24626364 TI - [Effectiveness in the diagnosis of tuberculosis in Foz do Iguacu, the triple border area of Brazil, Paraguay and Argentina]. AB - This study sought to assess the effectiveness of health services in the diagnosis of tuberculosis in Foz do Iguacu-PR, the triple border region of Brazil, Paraguay, and Argentina. In this epidemiologic, cross-sectional study, 101 persons with tuberculosis were interviewed in 2009 by using an instrument based on the Primary Care Assessment Tool . The analysis was based on proportions and respective 95% confidence intervals (95%) and means. Emergency units (37%) and primary health care units (26%) were the most sought units. Access to medical consultation on the same day reached 70%, but tuberculosis was suspected in less than 47% of patients; bacilloscopy was conducted in 50% of patients. We conclude that although these services provide rapid care, they do not determine the true diagnosis and lead the patient to seek specialized services. Specialty services are more effective in establishing the correct diagnosis. In the triple border region, seeking care at a primary health care unit led to extra time and more returns to the hospital for a tuberculosis diagnosis. PMID- 24626365 TI - [I am alone: the experience of nurses delivering care to alcohol and drug users]. AB - The objective of this study was to determine the experience of nurses who care for drug-dependent patients at a medical service of a public hospital in Chile. This is a qualitative study of phenomenological trajectory according to Martin Heidegger's framework. The study question was, What is the experience of taking care of drug-dependent patients admitted to your service? Nurses' reports were based on the concept of situated phenomenon reference by Joel Martins After analyzing the interviews, we identified three themes that expressed this phenomenon: speaking about the drug-dependent patient, taking care of patients in an adverse environment, and dispelling the fear of care. This study shows the need to train health care professionals on dealing with alcohol- and drug dependent patients in order to overcome prejudices and improve care delivered to these patients. PMID- 24626366 TI - [Clinical practice as an arborescent and rhizomorphic practice in surgical nursing work]. AB - A qualitative and exploratory case study was conducted in a surgery unit of a university hospital. The study aimed to analyze the nurses' work from the perspective of health care production and clinical practice. The subjects of the study were six nurses. Non-participant observations, documentary research and in depth interviews were carried out, followed by discursive textual analysis. Nursing work is organized according to two interconnected and interdependent perspectives: a clinical model, which forms the central structure of its practice, and a structure formed by multiple and heterogeneous elements. in this way, the clinical model of health care is organized as a centered structure that enables the fulfillment of biological needs and acts as a basis for connecting disparate knowledge and practices that expand practice through interconnections with the work environment. PMID- 24626367 TI - [Vulnerability of children in adverse situations to their development: proposed analytical matrix]. AB - This theoretical study presents a conceptual matrix built to analyze the vulnerability of children in adverse situations to their development. It proposes that the vulnerability of children is analyzed by means of the following dimensions: individual , which is related to ongoing nurturing relationships, physical protection and security; social , which concerns the social insertion of family and access to rights of social protection and promotion; and programmatic , which involves the political-programmatic scenario and the guidelines and political-programmatic implementation. The practical application of this matrix allows apprehending the health-disease process beyond the individual dimension, enabling the articulation of public policies and actions of professionals to achieve effectiveness in meeting the needs of children. The use of this conceptual matrix can provide to health teams a specific understanding of the adverse situations to child development as well as subsidizing intervention plans based on the analytical dimensions of vulnerability. PMID- 24626368 TI - [Marxism as a theoretical and methodological framework in collective health: implications for systematic review and synthesis of evidence]. AB - In this study, we discuss the integration in systematic reviews of research developed from a Marxist perspective of knowledge production and their results as evidence in healthcare. The study objectives are to review the assumptions of dialectical and historical materialism (DHM) and discuss the implications of dialectics for a literature review and the synthesis of evidence. DHM is a powerful framework for knowledge generation and transformation of policies and practices in healthcare. It assumes that social contradictions underlie the health-disease process, the fundamental theoretical construction in the field of collective health. Currently, we observe a considerable influence of the critical paradigm, of Marxist origin, in the construction of knowledge in health. Studies based on this critical paradigm incorporate complex methods, which are inherent to the guidelines of dialect, to identify the object and arrive at results that constitute evidence in healthcare. Systematic reviews should address the methodological difficulties associated with entirely integrating these results to healthcare. PMID- 24626370 TI - [Nursing governance: an integrative review of the literature]. AB - The objective of this study was to identify and characterize types of nursing governance, with emphasis on its impact on nursing practice and health care. This integrative review covered reports published from 2007 to 2011 and indexed in MEDLINE, CINAHL, LILACS, and the Scientific Electronic Library Online (SciELO). Keywords used were governance and nursing , which retrieved 25 manuscripts. Most studies were from the United States and the United Kingdom. We identified three models of governance: shared governance, clinical governance, and public governance. The effects of the models identified included quality care improvement, more autonomy for nursing professionals, improved connections among health services, and greater satisfaction among nursing professionals. Additional studies on nursing governance in Latin America are needed to evaluate its applicability in different contexts. PMID- 24626369 TI - [Effectiveness of cleaning or disinfecting the urinary meatus before urinary catheterization: a systematic review]. AB - The urinary tract infections associated with catheterization are very common in hospital and home care contexts. Currently there are several recommendations for its prevention, however, when approaching the kind of solute used in the urinary meatus prior to catheterization doubts continue to persist. Thus this study aimed at determining the effectiveness of cleaning the urinary meatus with water or saline comparing to its sterilization through a systematic review and meta analysis. In order to do so, the principles proposed by the Cochrane Handbook were followed, a critical analysis was conducted by two researchers and the statistical analysis was performed with the use of STATA 11.1. We concluded that the cleaning or disinfection of the urinary canal prior to bladder catheterization is not statistically significant (OR=1.07, CI 95%=0.68-1.68, p=0.779) and that there is some evidence that the use of water/saline reduces rates of UTI (urinary tract infection). PMID- 24626371 TI - [Clinical Nurse Specialist: a model of advanced nursing practice in pediatric oncology in Brazil]. AB - The objective of this paper is to report the experience of implementing a model of advanced nursing practice that integrates a clinical nurse specialist into the nursing staff. The authors describe the concept of this model and the process of its implementation in a pediatric oncology reference institution in the city of Sao Paulo, Brazil. The main result achieved in evaluating the clinical nurse specialist was strengthening of the role of the nurse as a reference professional for the articulation of the various demands of care in assisting the child, adolescent or young adult with cancer and his/her family. The satisfaction of these users due to the closer relationship between the patient, family and clinical nurse in all stages of the caring process also stands out. PMID- 24626372 TI - [Working Education Program in Health: transforming experience of nursing teaching and practice]. AB - This is an experience report of tutors from nursing Working Education Program in Health ( PET- Saude ) from the Federal University of Alagoas, from May 2009 to April 2010. The objective of the nursing PET-Saude was to develop health education actions aimed at the needs of the communities attended by the Family Health Units in Maceio, Alagoas. We conducted a health planning guided by the problem-based methodology. The activities resulted in changes in student learning and in the practice of nurses PET-Saude , indicating the importance of this program for teaching and practice of nursing. PMID- 24626373 TI - [Vaginal discharge in pregnant women: comparison between syndromic approach and examination of clinical nursing practice]. AB - This is a study for assessment of a quantitative approach in pregnant women (N=104), in which findings of vaginal infection were compared. The findings were obtained by two means, flowchart of vaginal discharge, and typical examinations in the clinical nursing practice. Data were collected from January to July 2011 through interviews and gynecological examinations. The flowchart showed no efficacy to identify candidiasis and trichomoniasis. Furthermore, it showed low sensitivity (0.0%; 50%) and positive predictive value (0.0%; 3.6%) for both infections, and low specificity for trichomoniasis (46%). The flowchart was shown to be satisfactory for bacterial vaginosis, with high sensitivity (100%), negative predictive value (100%), and accuracy (74%). We conclude that use of the flowchart should be reassessed, as it was not able to identify important infections in pregnant women. A continuous effort must be directed for development of effective tests in order to prevent the spread of infection and reduce the number of unnecessary treatments. PMID- 24626374 TI - [Handling of preterm infants in a neonatal intensive care unit]. AB - While hospitalized in neonatal units, preterm infants undergo various manipulations and procedures that have negative health consequences. The aim of this study was to describe the manipulations that preterm infants are subjected to over a 24-hour period in a neonatal intensive care unit (NICU). An observational, descriptive, exploratory study was conducted with 20 preterm infants who were filmed continuously in a NICU over a 24-hour period from September 2008 to March 2009. Preterm infants were subjected to an average of 768 manipulations and 1341 procedures. The average duration of the manipulations over the 24-hour period was 2 hours and 26 minutes. Each manipulation included an average of 2.2 procedures, most occurring during the morning shift. Individual manipulations accounted for 65.6% of all manipulations, and most manipulations lasted less than a minute. The results of this study show that preterm infants in the NICU underwent an excessive number of manipulations over the 24-hour period evaluated. PMID- 24626375 TI - [The practice of intensive care nursing: alliance among technique, technology and humanization]. AB - A qualitative, field research study whose aim was to characterize the specific practice of intensive care nursing. Observation and interviews were conducted with 21 nurses in an intensive care unit. The results evidenced eight characteristics of this care, which included subjectivity and objectivity, translated into: interaction, dialogue, humanistic principles, vigilance, knowledge, and mastery of machinery. Because of this practice, subjectivity is not always expressed in a clear way, and objectivity requires training of nurses to perform intensive care. It is concluded that the practice of intensive care nursing combines technique, technology and humanization, which underlie the nursing care performed at the unit. PMID- 24626376 TI - C-Cl bond activation and catalytic hydrodechlorination of hexachlorobenzene by cobalt and nickel complexes with sodium formate as a reducing agent. AB - A benzyne cobalt complex, Co(eta(2)-C6Cl4)(PMe3)3 (2), was generated from the reaction of hexachlorobenzene with 2 equiv. of Co(PMe3)4 through selective activation of two C-Cl bonds of hexachlorobenzene. Meanwhile, the byproduct CoCl2(PMe3)3 was also confirmed by IR spectra. The cobalt(II) complex, CoCl(C6Cl5)(PMe3)3 (1), as an intermediate in the formation of aryne complex 2, was also isolated by the reaction of hexachlorobenzene with the stoichiometric amount of Co(PMe3)4. Complex 2 could be obtained by the reaction of 1 with Co(PMe3)4. Under similar reaction conditions, the reaction of Ni(PMe3)4 with hexachlorobenzene afforded only a mono-(C-Cl) bond activation nickel(II) complex, NiCl(C6H5)(PMe3)2 (5). The expected benzyne nickel complex was not formed. The structures of complexes 2 and 5 were determined by X-ray single crystal diffraction. Successful selective hydrodechlorinations of hexachlorobenzene were studied and in the presence of Co(PMe3)4 or Ni(PMe3)4 as catalysts and sodium formate as a reducing agent pentachlorobenzene and 1,2,4,5-tetrachlorobenzene were obtained. The catalytic hydrodechlorination mechanism is proposed and discussed. PMID- 24626377 TI - Enzymatic biosensors based on inga-cipo peroxidase immobilised on sepiolite for TBHQ quantification. AB - Sepiolite clay mineral was used as a support for the immobilisation of the peroxidase enzyme from inga-cipo (Inga edulis Mart.) and was used with graphite powder, multi-walled carbon nanotubes (CNTs), mineral oil, and nafion 0.5% (v/v) in the development of a new biosensor for the determination of the antioxidant tert-butylhydroquinone (TBHQ) by square-wave voltammetry (SWV). For the optimisation and application of the biosensor, several parameters were investigated to determine the optimum experimental conditions using SWV. The best performance was obtained using a 0.1 mol L(-1) phosphate buffer solution (pH 7.0), 4.0 * 10(-4) mol L(-1) hydrogen peroxide, a frequency of 50 Hz, a pulse amplitude of 60 mV, and a scan increment of 6 mV. The biosensor showed good repeatability and reproducibility and remained stable for a period of 20 weeks. The analytical curve revealed a linear response range of 1.65 to 9.82 mg L(-1) (r = 0.994) with detection and quantification limits of 0.41 and 1.25 mg L(-1). A recovery study of TBHQ in salad dressing samples yielded values from 99.6-104.8%. The proposed biosensor was successfully used for the determination of TBHQ in commercial salad dressing samples, giving a relative error of 5.4% in relation to the comparative method (chromatographic). PMID- 24626378 TI - Racial/Ethnic Disparities in Preventive Care Practice Among U.S. Nursing Home Residents. AB - OBJECTIVE: To assess racial/ethnic disparities in preventive care practices among U.S. nursing home residents. METHOD: To implement the Institute of Medicine definition of health care disparity, we used the rank-and-replace adjustment method to assess the disparity in receipt of eight preventive care services among residents and evaluate trends in disparities. The sampling design (stratification and clustering) was accounted for using Stata 11. RESULTS: The 2004 National Nursing Home Surveys data show White residents were more likely to have pain management, scheduled toilet plan/bladder retraining, influenza vaccination, and pneumococcal vaccination than Black residents. White residents were also more likely to have scheduled toilet plan/bladder retraining than residents of Other race/ethnicity. Significant Black-White disparities in receipt of influenza vaccination and pneumococcal vaccination were found. Time trend analysis showed that disparities were neither exacerbated nor reduced. CONCLUSION: Persistent racial/ethnic disparities in preventive care among nursing home residents exist. We urge the development and implementation of targeted interventions to improve the quality of preventive care in nursing homes. PMID- 24626379 TI - De novo synthesis of a narrow size distribution low-molecular-weight heparin. AB - Heparin, a commonly used anticoagulant drug, is a mixture of highly sulfated polysaccharides with various molecular weights (MWs). The unique sulfation pattern dictates the anticoagulant activity of heparin. Commercial heparins are categorized into three forms according to their average MW: unfractionated heparin (UFH, MWavg 14,000), low-MW heparin (LMWH, MWavg 3500-6500) and the synthetic pentasaccharide (fondaparinux, MW 1508.3). UFH is isolated from porcine intestine while LMWH is derived from UFH by various methods of depolymerization, which generate a wide range of oligosaccharide chain lengths. Different degradation methods result in structurally distinct LMWH products, displaying different pharmacological and pharmacokinetic properties. In this report, we utilized a chemoenzymatic method to synthesize LMWH with the emphasis on controlling the size distribution of the oligosaccharides. A tetrasaccharide primer and a controlled enzyme-based polymerization were employed to build a narrow size oligosaccharide backbone. The oligosaccharide backbones were further modified by a series of sulfation and epimerization steps in order to obtain a full anticoagulation activity. Determination of the anticoagulation activity in vitro and ex vivo indicated that the synthetic LMWH has higher potency than enoxaparin, a commercial LMWH drug in clinical usage. PMID- 24626381 TI - Missed canal...call from radix entomolaris. AB - A comprehensive understanding of root and root canal morphology of primary teeth is valuable for successful endodontic therapy. A supernumerary root is a developmental anomaly which can affect any tooth. An extra root placed lingually (radix entomolaris) or buccally (radix paramolaris) can be seen in mandibular molars nonetheless; bilateral association of an additional root in deciduous mandibular molars is rare. This report aimed to describe the diagnosis, significance and management of an extra root in deciduous mandibular molars bilaterally in perspective of modern clinical paediatric endodontics. PMID- 24626380 TI - A rare association of extragonadal seminoma with synchronous papillary carcinoma of the thyroid. AB - A 45-year-old man presented with a large para-aortic retroperitoneal tumour, a smaller second mediastinal tumour and elevated lactate dehydrogenase (LDH). Biopsy established a diagnosis of extragonadal seminoma. Treatment with cisplatin and etoposide resulted in complete resolution of the mediastinal mass, reduction of the size of the retroperitoneal mass and normalisation of LDH. Postchemotherapy positron emission tomography (PET) scan showed a small residual focus of uptake in the retroperitoneal mass and an unexpected focus in the left side of the neck. This was initially thought to represent residual active disease, but an ultrasound (US) scan and US-guided core biopsy of a cervical lymph node demonstrated metastatic papillary thyroid cancer rather than seminoma. A small (1 cm) primary papillary tumour in the thyroid was identified subsequently. The patient received consolidation radiotherapy to the retroperitoneum and underwent total thyroidectomy and neck dissection followed by radio-iodine treatment. He is currently in complete remission from both cancers. PMID- 24626382 TI - Successful gefitinib treatment administration via gastrostomy tube in a patient with non-small cell lung cancer with dysphagia. AB - A 72-year-old woman with dysphagia was diagnosed with lung adenocarcinoma and metastatic meningeal tumour that impaired the medulla. Owing to a bulky tumour beside the medulla, radiosurgical control of the meningeal tumour was achieved before systemic therapy. Genomic examination of the tumour revealed an existing epidermal growth factor receptor (EGFR) exon 19 deletion, for which an EGFR tyrosine kinase inhibitor such as gefitinib was the standard therapy. However, because of dysphagia, the patient was unable to orally ingest gefitinib. Gefitinib was delivered via gastrostomy tube as a suspension after spontaneous dissolution in hot water. One month later, the patient's symptoms, including dysphagia, were drastically improved and she had recovered sufficiently to orally ingest gefitinib. Gefitinib-associated toxicity comprises only mild liver dysfunction and skin rash. CT scanning and MRI detected drastic shrinkage of the primary lung and meningeal tumours. The patient continued to take gefitinib and has remained symptom-free for 9 months. PMID- 24626383 TI - Chest pain caused by pulmonary vein thrombi could be curable by dabigatran. AB - Chest pain is a common clinical event that overwhelms many patients and is often a sign of coronary ischaemia. The comprehensive influence of pulmonary vein thrombosis (PVT) on coronary artery ischaemia is underappreciated. A 64-slice multidetector CT (64-MDCT) scan can detect pulmonary vein thrombi. A 68-year-old man was referred for the assessment of recent chest pain. A 64-MDCT scan was performed to assess his coronary artery. Although the scan did not show a coronary artery plaque, it did show a thrombus in the right lower pulmonary vein. After 3 months of dabigatran therapy, some parts of the thrombus had dissolved, and the image of the thrombus was more vague. The darkness of the thrombus was lost, indicating that the thrombus had loosened in structure and that the contrast enhancements were able to penetrate into the thrombus. PVT was identified as the likely aetiology for the cause of the chest pain. PMID- 24626384 TI - Semilobar holoprosencephaly with 21q22 deletion: an autopsy report. AB - Holoprosencephaly (HPE) is the most common forebrain developmental anomaly with a prevalence of 1:16 000 live-births. Possible aetiological agents include environmental factors and genetic defects such as trisomies (13, 18) and deletions (18p, 7q, 2p and 21q). This complex malformation is due to incomplete division of the cerebral hemisphere. The phenotypes of HPE include alobar, semilobar, lobar and midline interhemispheric fusion variants. Craniofacial anomalies occur in 80% of cases. Severely affected babies die in the neonatal period. Here we report an autopsied case of semilobar HPE with pituitary and adrenal agenesis with 21q22 deletion. Additional findings are noted that would help expand the spectrum of 21q22 deletion. PMID- 24626385 TI - Neisseria meningitidis as a cause of facial cellulitis. AB - A 68-year-old man presented with facial cellulitis and found to have Neisseria meningitidis bacteraemia with no evidence of infection outside of the facial soft tissue. He was treated with a course of intravenous ceftriaxone and transitioned to oral amoxicillin on discharge with significant improvement of his symptoms. N meningitidis is best recognised as a causal agent of bacterial meningitis. To our knowledge N meningitidis cellulitis has only been described in 12 other cases. In this case series we describe and summarise our case, along with the 12 cases already reported in the literature. We report this case series to highlight the importance of recognising N meningitidis in the differential in patients presenting with acute skin and soft tissue infections especially involving the periorbital, head and neck regions. PMID- 24626386 TI - Mycoplasma pneumonia-associated mucositis. AB - We present a case of a young man with severe mucositis following an upper respiratory tract infection limited to the ophthalmic and oral mucosa while sparing the rest of the skin, genitalia and perianal regions. Investigations revealed that the mucositis was a rare extrapulmonary manifestation of Mycoplasma pneumoniae infection. He had progressive vision-threatening symptoms despite antibiotics and best supportive care and thus was treated with intravenous corticosteroids, immunoglobulins, temporary ocular amniotic membrane grafts and tarsorrhaphy. The patient made an almost complete recovery over 6 weeks. PMID- 24626387 TI - Small bowel obstruction and perforation secondary to primary enterolithiasis in a patient with jejunal diverticulosis. AB - We describe a rare case of small bowel obstruction and perforation secondary to a primary enterolith in an 84-year-old female patient with jejunal diverticulosis. She underwent an emergency laparotomy, small bowel resection and primary anastomosis. Multiple jejunal diverticula and a large stone were identified at the time of operation. Analysis of the stone demonstrated mainly faecal material consistent with a true primary enterolith. A literature search of Medline and PubMed revealed three cases similar to the one described. The pathogenesis and management of enterolithiasis in jejunal diverticular disease is considered. PMID- 24626388 TI - Holy Saturday asthma. AB - A 61-year-old man complained of cough and dyspnoea after exposure to colophony containing solder fumes at work. A histamine challenge test confirmed airway hyper-responsiveness, and colophony-challenge demonstrated a 16.7% drop in peak expiratory flow rate (PEFR), supporting a diagnosis of colophony-induced occupational asthma. At review, the patient presented with cough, dyspnoea and wheeze that occurred acutely when exposed to the fumes from burning incense during Easter Saturday services, necessitating his departure from the church. Inhalation challenge tests using two blends of incense used at his church (Greek and Vatican) led to identical symptoms and a significant reduction in forced expiratory volume in 1 s 15 min after exposure and PEFRs up to 48 h after exposure, indicating an early and late phase asthmatic reaction. This is the first report of coexistent colophony and incense-induced asthma. The similarities in chemical structures between abietic acid in colophony and boswellic acid in incense suggest a common mechanism. PMID- 24626389 TI - Unprecedented catalytic performance in disordered nickel niobate through photo synergistic promotion. AB - A novel catalyst was successfully prepared, which shows superior catalytic activity and stability toward reduction of 4-nitrophenol due to a unique photo synergistic catalytic mechanism that relies on a synergy between thermal active sites and photogenerated electrons in NiNb2O6 nanoparticles. PMID- 24626391 TI - Assessment of surgical results in patients with empty nose syndrome using the 25 item Sino-Nasal Outcome Test Evaluation. AB - IMPORTANCE Empty nose syndrome (ENS) is an iatrogenic disorder, which severely affects the normal nasal breathing function. People affected by ENS may experience decreased productivity and lifestyle disruption. The 20-Item Sino Nasal Outcome Test (SNOT-20) is a validated quality-of-life measurement and can be used to compare before and after intervention outcomes. OBJECTIVES To evaluate the effectiveness of the Medpor implant (Porex Surgical Inc) to improve the disease-specific quality of life in patients with ENS and to validate the 25-Item SNOT (SNOT-25) as an assessment tool in patients with ENS. DESIGN, SETTING, AND PARTICIPANTS We prospectively enrolled 24 patients from our hospital who received inferior turbinate reconstruction surgery after drug therapy failed to improve their symptoms. INTERVENTIONS All the patients underwent submucosal Medpor implant surgery to reconstruct their inferior turbinate. MAIN OUTCOMES AND MEASURES Patient assessments were based on the SNOT-25 questionnaire prior to surgery and at 3, 6, and 12 months after surgery. RESULTS The total scores of the SNOT-25 declined postoperatively, showing a significant difference at 3, 6, and 12 months after surgery compared with their initial visit (P = .045, P < .001, and P < .001, respectively). The 5 items most frequently reported by patients as important at their initial visit were "fatigue," "reduced concentration," "sadness," "dryness," and "nose is too open." The mean overall scores for these 5 important items also declined, showing statistically significant decreases compared with their initial visit (P < .05) and indicating that the items patients believed were important had improved. CONCLUSIONS AND RELEVANCE Medpor implant surgery in patients with ENS is associated with statistically significant improvements in disease-specific quality of life measures. The modified version of SNOT-20 Health Survey Scales, the SNOT-25,may be a useful measurement tool in patients with ENS. PMID- 24626392 TI - Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. AB - HIV-1 infection is associated with a progressive loss of T cell functional capacity and reduced responsiveness to antigenic stimuli. The mechanisms underlying T cell dysfunction in HIV-1/AIDS are not completely understood. Multiple studies have shown that binding of program death ligand 1 (PD-L1) on the surface of monocytes and dendritic cells to PD-1 on T cells negatively regulates T cell function. Here we show that neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1. PD-L1 is induced by HIV-1 virions, TLR 7/8 ligand, bacterial lipopolysaccharide (LPS), and IFNalpha. Neutrophil PD-L1 levels correlate with the expression of PD-1 and CD57 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils (LDNs) expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). Collectively, the accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function. PMID- 24626393 TI - A bidirectional brain-machine interface algorithm that approximates arbitrary force-fields. AB - We examine bidirectional brain-machine interfaces that control external devices in a closed loop by decoding motor cortical activity to command the device and by encoding the state of the device by delivering electrical stimuli to sensory areas. Although it is possible to design this artificial sensory-motor interaction while maintaining two independent channels of communication, here we propose a rule that closes the loop between flows of sensory and motor information in a way that approximates a desired dynamical policy expressed as a field of forces acting upon the controlled external device. We previously developed a first implementation of this approach based on linear decoding of neural activity recorded from the motor cortex into a set of forces (a force field) applied to a point mass, and on encoding of position of the point mass into patterns of electrical stimuli delivered to somatosensory areas. However, this previous algorithm had the limitation that it only worked in situations when the position-to-force map to be implemented is invertible. Here we overcome this limitation by developing a new non-linear form of the bidirectional interface that can approximate a virtually unlimited family of continuous fields. The new algorithm bases both the encoding of position information and the decoding of motor cortical activity on an explicit map between spike trains and the state space of the device computed with Multi-Dimensional-Scaling. We present a detailed computational analysis of the performance of the interface and a validation of its robustness by using synthetic neural responses in a simulated sensory-motor loop. PMID- 24626394 TI - Prognostic value of circulating microRNA-210 levels in patients with moderate to severe aortic stenosis. AB - BACKGROUND: Circulating micro-RNAs have been proposed as a novel class of cardiovascular (CV) biomarkers, but whether they meet analytical requirements and provide additional information to establish risk indices have not been established. miR-210 levels are increased in subjects with low VO2 max, which is a recognized risk factor in patients with aortic stenosis (AS), and we hypothesized that circulating miR-210 levels may be increased in patients with AS and associated with a poor prognosis. METHODS: We measured circulating miR-210 levels by real-time PCR in 57 patients with moderate to severe AS and in 10 age- and gender-matched healthy controls. The merit of miR-210 as a biomarker was assessed according to established criteria, including by comparing miR-210 levels with NT-proBNP and miR-22 levels, which is another miRNA biomarker candidate. RESULTS: All patients and control subjects had miR-210 levels within the range of detection (Cq<35) and the analytical variability was low. Circulating miR-210 levels were 2.0+/-0.2 [mean+/-SEM] fold increased in AS patients compared to controls (p = 0.002), whereas miR-22 levels were not differently expressed in the AS patients (0.12+/-0.06 fold increase, p = 0.45). The increase in miR-210 levels in AS patients was comparable to the increment in NT-proBNP levels: [AUC] 0.82 (95% CI 0.70-0.90) vs. 0.85 (0.75-0.93), respectively, p = 0.71. During a median follow-up of 1287 days, 15 patients (26%) died. There was a significant association between higher circulating levels of miR-210 and increased mortality during follow-up: hazard ratio [supra- vs. inframedian levels] 3.3 (95% CI 1.1 10.5), p = 0.039. Adjusting for other risk indices in multivariate analysis did not attenuate the prognostic merit of circulating miR-210 levels. CONCLUSION: Circulating miR-210 levels are increased in patients with AS and provide independent prognostic information to established risk indices. Analytical characteristics were also excellent supporting the potential of micro-RNAs as novel CV biomarkers. PMID- 24626395 TI - Intraspecific variation in physiological condition of reef-building corals associated with differential levels of chronic disturbance. AB - Even in the absence of major disturbances (e.g., cyclones, bleaching), corals are subject to high levels of partial or whole-colony mortality, often caused by chronic and small-scale disturbances. Depending on levels of background mortality, these chronic disturbances may undermine individual fitness and have significant consequences on the ability of colonies to withstand subsequent acute disturbances or environmental change. This study quantified intraspecific variations in physiological condition (measured based on total lipid content and zooxanthellae density) through time in adult colonies of two common and widespread coral species (Acropora spathulata and Pocillopora damicornis), subject to different levels of biological and physical disturbances along the most disturbed reef habitat, the crest. Marked intraspecific variation in the physiological condition of A. spathulata was clearly linked to differences in local disturbance regimes and habitat. Specifically, zooxanthellae density decreased (r2 = 26, df = 5,42, p<0.02, B = -121255, p = 0.03) and total lipid content increased (r2 = 14, df = 5,42, p = 0.01, B = 0.9, p = 0.01) with increasing distance from exposed crests. Moreover, zooxanthellae density was strongly and negatively correlated with the individual level of partial mortality (r2 = 26, df = 5,42, p<0.02, B = -7386077, p = 0.01). Conversely, P. damicornis exhibited very limited intraspecific variation in physiological condition, despite marked differences in levels of partial mortality. This is the first study to relate intraspecific variation in the condition of corals to localized differences in chronic disturbance regimes. The next step is to ascertain whether these differences have further ramifications for susceptibility to periodic acute disturbances, such as climate-induced coral bleaching. PMID- 24626396 TI - Capillary electrophoresis-based assessment of nanobody affinity and purity. AB - Drug purity and affinity are essential attributes during development and production of therapeutic proteins. In this work, capillary electrophoresis (CE) was used to determine both the affinity and composition of the biotechnologically produced "nanobody" EGa1, the binding fragment of a heavy-chain-only antibody. EGa1 is an antagonist of the epidermal growth factor receptor (EGFR), which is overexpressed on the surface of tumor cells. Using a background electrolyte (BGE) of 50mM sodium phosphate (pH 8.0) in combination with a polybrene poly(vinylsulfonic acid) capillary coating, CE analysis of EGa1 showed the presence of at least three components. Affinity of the EGa1 components towards the extracellular domain of EGFR was assessed by adding different concentrations (0-12 nM) of the receptor to the BGE while measuring the effective electrophoretic mobility of the respective EGa1 components. Binding curves obtained by plotting electrophoretic mobility shifts as a function of receptor concentration, yielded dissociation constants (Kd) of 1.65, 1.67, and 1.75 nM for the three components, respectively; these values were comparable to the Kd of 2.1 nM obtained for the bulk EGa1 product using a cellular assay. CE with mass spectrometry (MS) detection using a BGE of 25 mM ammonium acetate (pH 8.0) revealed that the EGa1 sample comprised of significant amounts of deamidated, bisdeamidated and N-terminal pyroglutamic acid products. CE-MS using a BGE of 100mM acetic acid (pH 2.8) in combination with a polybrene-dextran sulfate polybrene capillary coating demonstrated the additional presence of minor products related to incomplete removal of the signal peptide from the produced nanobody. Combining the results obtained from affinity CE and CE-MS, it is concluded that the EGa1 nanobody product is heterogeneous, comprising highly related proteins that exhibit very similar affinity towards EGFR. PMID- 24626398 TI - Enhanced response of microbial fuel cell using sulfonated poly ether ether ketone membrane as a biochemical oxygen demand sensor. AB - The present study is focused on the development of single chamber microbial fuel cell (SCMFC) using sulfonated poly ether ether ketone (SPEEK) membrane to determine the biochemical oxygen demand (BOD) matter present in artificial wastewater (AW). The biosensor produces a good linear relationship with the BOD concentration up to 650 ppm when using artificial wastewater. This sensing range was 62.5% higher than that of Nafion((r)). The most serious problem in using MFC as a BOD sensor is the oxygen diffusion into the anode compartment, which consumes electrons in the anode compartment, thereby reducing the coulomb yield and reducing the electrical signal from the MFC. SPEEK exhibited one order lesser oxygen permeability than Nafion((r)), resulting in low internal resistance and substrate loss, thus improving the sensing range of BOD. The system was further improved by making a double membrane electrode assembly (MEA) with an increased electrode surface area which provide high surface area for electrically active bacteria. PMID- 24626397 TI - A new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms. AB - During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution. Actually, most authors assess homogeneity using parameters of the histogram of intensities (e.g. mean, skewness and kurtosis). However, this approach does not take into account spatial information and loses the main advantage of imaging. To overcome this limitation, we propose a new criterion: Distributional Homogeneity Index (DHI). DHI has been tested on simulated maps and formulation development samples. The distribution maps of the samples were obtained without validated calibration model since different formulations were under investigation. The results obtained showed a linear relationship between content uniformity values and DHI values of distribution maps. Therefore, DHI methodology appears to be a suitable tool for the analysis of homogeneity of distribution maps even without calibration during formulation development. PMID- 24626399 TI - Speciation analysis of arsenic in prenatal and children's dietary supplements using microwave-enhanced extraction and ion chromatography-inductively coupled plasma mass spectrometry. AB - A study was conducted to develop a microwave-enhanced extraction method for the determination of arsenic species in prenatal and children's dietary supplements prepared from plant materials. The method was optimized by evaluating the efficiency of various solutions previously used to extract arsenic from the types of plant materials used in the dietary supplement formulations. A multivitamin standard reference material (NIST SRM 3280) and a prenatal supplement sample were analyzed in the method optimization. The identified optimum conditions were 0.25 g of sample, 5 mL of 0.3 mol L(-1) orthophosphoric acid (H3PO4) and microwave heating at 90 degrees C for 30 min. The extracted arsenic was speciated by cation exchange ion chromatography-inductively coupled plasma mass spectrometry (IC-ICP-MS). The method detection limit (MDL) for the arsenic species was in the range 2-8 ng g(-1). Ten widely consumed prenatal and children's dietary supplements were analyzed using the optimized protocol. The supplements were found to have total arsenic in the concentration range 59-531 ng g(-1). The extraction procedure recovered 61-92% of the arsenic from the supplements. All the supplementary products were found to contain arsenite (As(3+)) and dimethylarsinic acid (DMA). Arsenate (As(5+)) was found in two of the supplements, and an unknown specie of arsenic was detected in one product. The results of the analysis were validated using mass balance by comparing the sum of the extracted and non-extracted arsenic with the total concentration of the element in the corresponding samples. PMID- 24626400 TI - In situ assessment of atorvastatin impurity using MALDI mass spectrometry imaging (MALDI-MSI). AB - The analysis of impurities and degradation products in pharmaceutical preparations are usually performed by chromatographic techniques such as high performance liquid chromatography (HPLC). This approach demands extensive analysis time, mostly due to extraction and separation phases. These steps must be carried out in samples in order to adapt them to the requirements of the analytical method of choice. In the present contribution, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was employed to quantify an important degradation product in atorvastatin calcium 80 mg tablets: the atorvastatin lactone. Through the standard of the impurity, it was possible to perform quantitative analysis directly on the drug tablet, using a quick and novel approach, suitable for quality control processes in the pharmaceutical industry. PMID- 24626401 TI - Analysis of ochratoxin A in grapes, musts and wines by LC-MS/MS: first comparison of stable isotope dilution assay and diastereomeric dilution assay methods. AB - Ochratoxin A (OTA) exhibits potent nephrotoxic, carcinogenic and teratogenic effects and its maximum level in wines has been set to 2 MUg L(-1) by regulation. Consequently, the analytical procedures for OTA determination in wines have to be both very sensitive and reliable. In this paper, we compared two quantification methods: the stable isotope dilution assay (SIDA) and the diastereomeric dilution assay (DIDA). For this purpose, non-natural analogues of OTA were synthesized: the labeled OTA (OTA-d4) as a diastereomeric mixture for the SIDA and one non natural OTA's diastereomer (OTA-dia) for the DIDA. To quantify OTA in red grapes, musts or wines, the sample preparation was optimized using immunoaffinity column extraction and the analysis was performed by LC-MS/MS in Multiple Reaction Monitoring mode. A validation procedure in agreement with the International Organization of Vine and Wine recommendations was conducted. It appeared that SIDA quantification exhibited excellent sensitivity (LOD<1 ng L(-1)), accuracy (recovery=98%), repeatability (RSD<3%) and intermediate reproducibility (RSD<4%) compared to quantification by DIDA. Indeed, DIDA method did not provide satisfactory results demonstrating that immunoaffinity extraction is exclusively selective for the natural OTA and not for its diastereomer, which therefore cannot be considered as a good internal standard for this particular method. PMID- 24626402 TI - Application of ZnO quantum dots dotted carbon nanotube for sensitive electrochemiluminescence immunoassay based on simply electrochemical reduced Pt/Au alloy and a disposable device. AB - We report on a disposable microdevice suitable for sandwich-type electrochemiluminescence (ECL) detection of prostate specific antigen (PSA). The method is making use of ZnO quantum dots dotted carbon nanotube (ZnO@CNT) and simply electrochemical reduced Pt/Au alloy. The latter was selected as immunosensing probe to modify screen-printed carbon electrode, due to its excellent electrical property. For further ultrasensitive, low-potential and stable ECL detection, ZnO@CNT composite was first synthesized using a facile solvothermal method, and employed as signal amplification label. In this work, two working electrodes in one device were used for one determination to obtain more exact results based on screen-print technique. Taking advantage of dual amplification effects of the Pt/Au and ZnO@CNT, this immunosensor could detect the PSA quantitatively, in the range of 0.001-500 ng mL(-1), with a low detection limit of 0.61 pg mL(-1). The resulting versatile immunosensor possesses high sensitivity, satisfactory reproducibility and regeneration. This simple and specific strategy has vast potential to be used in other biological assays. PMID- 24626403 TI - A novel aptamer functionalized CuInS2 quantum dots probe for daunorubicin sensing and near infrared imaging of prostate cancer cells. AB - In this paper, a novel daunorubicin (DNR)-loaded MUC1 aptamer-near infrared (NIR) CuInS2 quantum dot (DNR-MUC1-QDs) conjugates were developed, which can be used as a targeted cancer imaging and sensing system. After the NIR CuInS2 QDs conjugated with the MUC1 aptamer-(CGA)7, DNR can intercalate into the double-stranded CG sequence of the MUC1-QDs. The incorporation of multiple CG sequences within the stem of the aptamers may further increase the loading efficiency of DNR on these conjugates. DNR-MUC1-QDs can be used to target prostate cancer cells. We evaluated the capacity of MUC1-CuInS2 QDs for delivering DNR to cancer cells in vitro, and its binding affinity to MUC1-positive and MUC1-negative cells. This novel aptamer functionalized QDs bio-nano-system can not only deliver DNR to the targeted prostate cancer cells, but also can sense DNR by the change of photoluminescence intensity of CuInS2 QDs, which concurrently images the cancer cells. The quenched fluorescence intensity of MUC1-QDs was proportional to the concentration of DNR in the concentration ranges of 33-88 nmol L(-1). The detection limit (LOD) for DNR was 19 nmol L(-1). We demonstrate the specificity and sensitivity of this DNR-MUC1-QDs probe as a cancer cell imaging, therapy and sensing system in vitro. PMID- 24626404 TI - Bovine serum albumin as a molecular sensor for the discrimination of complex metabolite samples. AB - The potential for using serum albumin (SA) as a broadly applicable molecular sensor was explored in an effort to develop a method for rapid analysis of complex metabolite samples. SA is a protein present at high concentration in blood, which transports a diverse set of compounds including fatty acids, hormones, and drugs. The effectiveness of the bovine ortholog (BSA) as a molecular sensor was tested by analyzing the pool of small molecules bound to the protein after a brief incubation with complex fluids of biological origin. As an initial test, three varietals of red wine were readily distinguished. Further analysis using four varietals of white wine also showed clear separation. In a second analysis using urine, animals in hemorrhagic shock were separated from a group of comparably treated controls. A time course analysis showed that recovery from injury could also be followed using the assay. This finding is significant as there currently is no method or biomarker for predicting the onset of shock. Comparison of samples was based on liquid chromatography mass spectrometry (LCMS) analysis of compounds selectively bound by BSA. Analysis of the samples after protein selection revealed a significant reduction in complexity and clear separation of groups by Principle Component Analysis (PCA). These results show the potential for using cargo-carrying proteins as molecular sensors for screening complex samples without the need for prior knowledge of sample composition or concentration and may streamline elucidation of biomarkers. PMID- 24626405 TI - Suberoylanilide hydroxamic acid-induced HeLa cell death is closely correlated with oxidative stress and thioredoxin 1 levels. AB - Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor which has anticancer effects. We evaluated the growth inhibitory effects of SAHA on HeLa cervical cancer cells in relation to reactive oxygen species (ROS) levels. SAHA inhibited the growth of HeLa cells with an IC(50) of approximately 10 uM at 24 h, and induced apoptosis which was accompanied by the cleavage of PARP, caspase-3 activation and loss of mitochondrial membrane potential (MMP; ?psi(m)). All the tested caspase inhibitors prevented HeLa cell death induced by SAHA whereas TNF-alpha intensified apoptotic cell death in SAHA-treated HeLa cells. With respect to ROS and glutathione (GSH) levels, SAHA increased ROS levels, especially mitochondrial O(2)*- in HeLa cells and also induced GSH depletion. Caspase inhibitors reduced the levels of ROS and GSH depletion in SAHA treated HeLa cells whereas TNF-alpha enhanced the levels in these cells. The well known antioxidant N-acetyl cysteine (NAC) attenuated cell death and an increase in ROS levels was caused by SAHA. Moreover, SAHA decreased the levels of thioredoxin 1 (Trx1) in HeLa cells. While the downregulation of Trx1 enhanced cell death and ROS levels in SAHA-treated HeLa cells, the overexpression of Trx1 attenuated the levels in these cells. In conclusion, SAHA inhibited the growth of HeLa cell via caspase-dependent apoptosis, which was influenced by the mitochondrial O(2)*- and Trx1 levels. PMID- 24626406 TI - Exacerbation of pemphigus foliaceus after electron-beam radiation. PMID- 24626407 TI - Organization and intramolecular charge-transfer enhancement in tripodal tris[(pyridine-4-yl)phenyl]amine push-pull molecules by intercalation into layered materials bearing acidic functionalities. AB - Two new intercalates of tris[4-(pyridin-4-yl)phenyl]amine (TPPA) with zirconium hydrogen phosphate and zirconium 4-sulfophenylphosphonate having formulae Zr(HPO4)2.0.21(C33H24N4).2.5H2O and Zr(HO3SC6H4PO3)(1.3)(C6H5PO3)(0.7).0.35(C33H24N4).2.5H2O were prepared and characterized by thermogravimetry, IR spectroscopy, and powder X-ray diffraction. The TPPA molecule has been selected as a model tripodal push-pull system with three peripheral basic centers that may undergo protonation. Their protonation/quaternization afforded HTPPA/MeTPPA molecules with enhanced intramolecular charge-transfer (ICT), which has been documented by electrochemical measurements, UV-Vis spectra and calculated properties such as the HOMO/LUMO levels and the first and second hyperpolarizabilities. Intercalation of TPPA into layered zirconium hydrogen phosphate and zirconium 4 sulfophenylphosphonate led to its significant organization and protonation as shown by the IR spectra. From the powder X-ray data we can deduce that the TPPA molecules are placed in the interlayer space of both hosts by anchoring two peripheral nitrogen atoms to one host layer and the opposite pyridine-4-yl terminus to the other neighboring host layer. In zirconium 4 sulfophenylphosphonate, the TPPA molecules are oriented perpendicularly, while in zirconium phosphate these molecules are slanted with respect to the layers of the host. On dehydration by heating, the interlayer distance of the intercalate decreases, which indicates a further slanting of the TPPA molecules. It follows from the UV-Vis spectra that TPPA is present in both intercalates in an equilibrium of protonated and non-protonated forms. The described materials represent the first case when a tripodal push-pull system was incorporated into a system with restricted geometry with the aim to influence its optical properties. PMID- 24626408 TI - Multiplex SYBR(r) green-real time PCR (qPCR) assay for the detection and differentiation of Bartonella henselae and Bartonella clarridgeiae in cats. AB - A novel SYBR(r) green-real time polymerase chain reaction (qPCR) was developed to detect two Bartonella species, B. henselae and B. clarridgeiae, directly from blood samples. The test was used in blood samples obtained from cats living in animal shelters in Southern Brazil. Results were compared with those obtained by conventional PCR targeting Bartonella spp. Among the 47 samples analyzed, eight were positive using the conventional PCR and 12 were positive using qPCR. Importantly, the new qPCR detected the presence of both B. henselae and B. clarridgeiae in two samples. The results show that the qPCR described here may be a reliable tool for the screening and differentiation of two important Bartonella species. PMID- 24626409 TI - Comparison between automated system and PCR-based method for identification and antimicrobial susceptibility profile of clinical Enterococcus spp. AB - Enterococci are increasingly responsible for nosocomial infections worldwide. This study was undertaken to compare the identification and susceptibility profile using an automated MicrosScan system, PCR-based assay and disk diffusion assay of Enterococcus spp. We evaluated 30 clinical isolates of Enterococcus spp. Isolates were identified by MicrosScan system and PCR-based assay. The detection of antibiotic resistance genes (vancomycin, gentamicin, tetracycline and erythromycin) was also determined by PCR. Antimicrobial susceptibilities to vancomycin (30 ug), gentamicin (120 ug), tetracycline (30 ug) and erythromycin (15 ug) were tested by the automated system and disk diffusion method, and were interpreted according to the criteria recommended in CLSI guidelines. Concerning Enterococcus identification the general agreement between data obtained by the PCR method and by the automatic system was 90.0% (27/30). For all isolates of E. faecium and E. faecalis we observed 100% agreement. Resistance frequencies were higher in E. faecium than E. faecalis. The resistance rates obtained were higher for erythromycin (86.7%), vancomycin (80.0%), tetracycline (43.35) and gentamicin (33.3%). The correlation between disk diffusion and automation revealed an agreement for the majority of the antibiotics with category agreement rates of > 80%. The PCR-based assay, the van(A) gene was detected in 100% of vancomycin resistant enterococci. This assay is simple to conduct and reliable in the identification of clinically relevant enterococci. The data obtained reinforced the need for an improvement of the automated system to identify some enterococci. PMID- 24626410 TI - Effect of Bifidobacterium animalis on mice infected with Strongyloides venezuelensis. AB - The administration of viable Bifidobacterium animalis was tested to induce resistance against Strongyloides venezuelensis infection in mice. Effects on parasite burden, worm length, egg output, and intestinal mucosal histology were evaluated. The oral administration of B. animalis, strain 04450B, starting 14 days before the inoculation of nematode larvae significantly decreased the worm burden and egg output. In probiotic treated animals, the percent reduction of adult worms in the intestine was of 33% and the reduction of egg production was of 21%, compared with those of the control group. The duodenum villous height and villous/crypt ratio were significantly higher in probiotic-treated mice, indicating that this group could be experiencing less intestinal damage. The present findings revealed that the administration of B. animalis for the amelioration of host response to nematode infections is biologically plausible and could have some potential for impacting public health. Meanwhile, further study is needed to delineate the nature and identity of the factor(s) involved in these beneficial effects. PMID- 24626411 TI - Prevalence of intestinal parasites among food handlers in Western Iran. AB - Parasitic infection is one of the problems that affect human health, especially in developing countries. In this study, all of the fast food shops, restaurants, and roast meat outlets of Khorramabad (Western Iran) and all the staff employed by them, some 210 people, were selected through a census and their stools were examined for the presence of parasites. The parasitological tests of direct wet mount, Lugol's iodine staining, formaldehyde-ether sedimentation and Trichrome staining techniques were performed on the samples. The data was analyzed with a chi-square test and logistic regression was selected as the analytical model. The results showed 19 (9%) stool specimens were positive for different intestinal parasites. These intestinal parasites included Giardia lamblia 2.9%, Entamoeba coli 4.3%, Blastocystis sp. 1.4%, and Hymenolepis nana 0.5%. There was a significant difference between the presence of a valid health card, awareness of transmission of intestinal parasites, participation in training courses in environmental health with intestinal parasites (p < 0.05). No statistically significant difference was found between the rate of literacy and gender among patients infected with intestinal parasites (p > 0.05). To control parasitic infection in food handlers, several strategies are recommended such as stool examinations every three months, public education, application of health regulations, controlling the validity of health cards and training on parasitic infection transmission. In this regard, the findings of the present study can be used as a basis to develop preventive programs targeting food handlers because the spread of disease via them is a common problem worldwide. PMID- 24626412 TI - Prehistorical Pediculus humanus capitis infestation: quantitative data and low vacuum scanning microscopy. AB - A pre-Columbian Peruvian scalp was examined decades ago by a researcher from the Oswaldo Cruz Foundation. Professor Olympio da Fonseca Filho described nits and adult lice attached to hair shafts and commented about the origin of head lice infestations on mankind. This same scalp was sent to our laboratory and is the subject of the present paper. Analysis showed a massive infestation with nine eggs/cm2 and an impressive number of very well preserved adult lice. The infestation age was roughly estimated as nine months before death based on the distance of nits from the hair root and the medium rate of hair growth. A small traditional textile was associated with the scalp, possibly part of the funerary belongings. Other morphological aspects visualized by low-vacuum scanning electron microscopy are also presented here for adults and nits. PMID- 24626413 TI - Decreasing prevalence of the acute/subacute clinical form of paracoccidioidomycosis in Mato Grosso do Sul State, Brazil. AB - With the objective to evaluate the behavior of paracoccidioidomycosis in the last three decades, clinical and epidemiological data of 595 patients admitted to clinical services of the Federal University of Mato Grosso do Sul from 1980 to 2009 were investigated. Gender, age distribution, clinical form, comorbidity with tuberculosis or AIDS, and mortality were compared by decades of clinical admission. It was shown that during the three decades there was a decrease in women percentage, and the same manner occurred a reduction in participants in the age group of 20 to 39 years. Moreover, the acute/subacute forms have been diminished in the period. These fluctuations are closely related and can be simultaneously analyzed. Increased AIDS co-infection prevalence from the first to the second decade was also revealed, coinciding with the appearance of the retroviral epidemic and stabilizing during the third decade. No change in the tuberculosis co-infection rate was observed (overall = 6.9%). It reinforces the importance of this co-morbidity. The overall mortality rate remained steady at 6.7%, not varying significantly from one decade to another. The persistent mortality rate calls attention to the importance of this neglected disease. PMID- 24626415 TI - Risk factors of HIV-1 vertical transmission (VT) and the influence of antiretroviral therapy (ART) in pregnancy outcome. AB - In the absence of intervention, the rate of vertical transmission of HIV can range from 15-45%. With the inclusion of antiretroviral drugs during pregnancy and the choice of delivery route this amounts to less than 2%. However ARV use during pregnancy has generated several questions regarding the adverse effects of the gestational and neonatal outcome. This study aims to analyze the risk factors for vertical transmission of HIV-1 seropositive pregnant women living in Rio Grande and the influence of the use of ARVs in pregnancy outcome. Among the 262 pregnant women studied the rate of vertical transmission of HIV was found to be 3.8%. Regarding the VT, there was a lower risk of transmission when antiretroviral drugs were used and prenatal care was conducted at the referral service. However, the use of ART did not influence the outcome of pregnancy. However, initiation of prenatal care after the first trimester had an influence on low birth weight, as well as performance of less than six visits increased the risk of prematurity. Therefore, the risk factors analyzed in this study appear to be related to the realization of inadequate pre-natal and maternal behavior. PMID- 24626414 TI - Association between smoking, crack cocaine abuse and the discontinuation of combination antiretroviral therapy in Recife, Pernambuco, Brazil. AB - Despite the effectiveness of combination antiretroviral therapy in the treatment of people living with HIV/AIDS (PLWHA), nonadherence to medication has become a major threat to its effectiveness. This study aimed to estimate the prevalence of self-reported irregular use of antiretroviral therapy and the factors associated with such an irregularity in PLWHA. A cross-sectional study of PLWHA who attended two referral centers in the city of Recife, in Northeastern Brazil, between June 2007 and October 2009 was carried out. The study analyzed socioeconomic factors, social service support and personal habits associated with nonadherence to antiretroviral therapy, adjusted by multivariable logistic regression analysis. The prevalence of PLWHA who reported irregular use of combination antiretroviral therapy (cART) was 25.7%. In the final multivariate model, the irregular use of cART was associated with the following variables: being aged less than 40 years (OR = 1.66, 95%-CI: 1.29-2.13), current smokers (OR = 1.76, 95%-CI: 1.31-2.37) or former smokers (OR = 1.43, 95%-CI: 1.05-1.95), and crack cocaine users (OR = 2.79, 95%-CI: 1.24-6.32). Special measures should be directed towards each of the following groups: individuals aged less than 40 years, smokers, former smokers and crack cocaine users. Measures for giving up smoking and crack cocaine should be incorporated into HIV-control programs in order to promote greater adherence to antiretroviral drugs and thus improve the quality of life and prolong life expectancy. PMID- 24626416 TI - Quantitative real-time PCR (q-PCR) for sputum smear diagnosis of pulmonary tuberculosis among people with HIV/AIDS. AB - OBJECTIVE: To assess quantitative real-time polymerase chain reaction (q-PCR) for the sputum smear diagnosis of pulmonary tuberculosis (PTB) in patients living with HIV/AIDS with a clinical suspicion of PTB. METHOD: This is a prospective study to assess the accuracy of a diagnostic test, conducted on 140 sputum specimens from 140 patients living with HIV/AIDS with a clinical suspicion of PTB, attended at two referral hospitals for people living with HIV/AIDS in the city of Recife, Pernambuco, Brazil. A Lowenstein-Jensen medium culture and 7H9 broth were used as gold standard. RESULTS: Of the 140 sputum samples, 47 (33.6%) were positive with the gold standard. q-PCR was positive in 42 (30%) of the 140 patients. Only one (0.71%) did not correspond to the culture. The sensitivity, specificity and accuracy of the q-PCR were 87.2%, 98.9% and 95% respectively. In 39 (93%) of the 42 q-PCR positive cases, the CT (threshold cycle) was equal to or less than 37. CONCLUSION: q-PCR performed on sputum smears from patients living with HIV/AIDS demonstrated satisfactory sensitivity, specificity and accuracy, and may therefore be recommended as a method for diagnosing PTB. PMID- 24626417 TI - Aspects of the ecology of phlebotomines (Diptera: Psychodidae: Phlebotominae) in an area of cutaneous leishmaniasis occurrence, municipality of Angra dos Reis, coast of Rio de Janeiro State, Brazil. AB - Over a complete two-year period, phlebotomine specimens were caught in an area of cutaneous leishmaniasis occurrence in the municipality of Angra dos Reis. A manual suction tube was used to catch phlebotomines on house walls, and also light traps in domestic and peridomestic settings and in the forest. This yielded 14,170 specimens of 13 species: two in the genus Brumptomyia and eleven in the genus Lutzomyia. L. intermedia predominantly in domestic and peridomestic settings, with little presence in the forest, with the same trend being found in relation to L. migonei, thus proving that these species have adapted to the human environment. L. fischeri appeared to be eclectic regarding location, but was seen to be proportionally more endophilic. L. intermedia and L. migonei were more numerous in peridomestic settings, throughout the year, while L. fischeri was more numerous in domestic settings except in March, April, May and September. From the prevalence of L. intermedia, its proven anthropophily and findings of this species naturally infected with Leishmania (Viannia) braziliensis, it can be incriminated as the main vector for this agent of cutaneous leishmaniasis in the study area, especially in the peridomestic environment. L. fischeri may be a coadjuvant in carrying the parasite. PMID- 24626418 TI - Temporal trends in the detection rates of hepatitis B in the Santa Catarina State, Brazil. AB - Hepatitis B is a serious public health problem. The state of Santa Catarina presents areas of high endemicity. The aim of this study was to describe temporal trends in detection rates of hepatitis B in the period from 2002 to 2009 in Santa Catarina and in its regions. A time series study was carried out. Crude rates were calculated and standardized by age using the direct method. Annual variation percentages were estimated by Joinpoint regression. There were two distinct and significant trends in Santa Catarina. From 2002 to 2006 a significant increase of 5.9% per year was observed. From 2006, there was a significant decrease of 6.4% per year. In this same period the southern and far-western regions had significant increases of 15.9% and 4.6% and significant decreases of 7.5% and 4.8%, respectively. Greater Florianopolis and Northeast also showed significant increases until 2006, of 15.4% and 17.4%, respectively. In the following period, non-significant decreases of 5.8% and 9.8% respectively were observed. Foz do Rio Itajai and Planalto Serrano showed non-significant increases up to half of the studied period of 21.1% and 12.0%, respectively and after, significant decreases of 21.5% and 18.0%, respectively. Vale do Itajai showed a significant decrease of 9.7%; Planalto Norte showed a non-significant decrease of 0.6% and Midwest a non significant increase of 2.7% per year, in the period from 2002 to 2009. PMID- 24626419 TI - Occupational exposures to body fluids and behaviors regarding their prevention and post-exposure among medical and nursing students at a Brazilian public university. AB - A cross-sectional study was conducted to assess the frequencies and characteristics of occupational exposures among medical and nursing students at a Brazilian public university, in addition to their prevention and post-exposure behavior. During the second semester of 2010, a self-administered semi-structured questionnaire was completed by 253/320 (79.1%) medical students of the clinical course and 149/200 (74.5%) nursing students who were already performing practical activities. Among medical students, 53 (20.9%) suffered 73 injuries, which mainly occurred while performing extra-curricular activities (32.9%), with cutting and piercing objects (56.2%), in the emergency room (39.7%), and as a result of lack of technical preparation or distraction (54.8%). Among nursing students, 27 (18.1%) suffered 37 injuries, which mainly occurred with hollow needles (67.6%) in the operating room or wards (72.2%), and as a result of lack of technical preparation or distraction (62.1%). Among medical and nursing students, respectively, 96.4% and 48% were dissatisfied with the instructions on previously received exposure prevention; 48% and 18% did not always use personal protective equipment; 67.6% and 16.8% recapped used needles; 49.3% and 35.1% did not bother to find out the source patient's serological results post-exposure; and 1.4% and 18.9% officially reported injuries. In conclusion, this study found high frequencies of exposures among the assessed students, inadequate practices in prevention and post-exposure, and, consequently, the need for training in "standard precautions" to prevent such exposures. PMID- 24626420 TI - Vertical transmission of dengue virus in Aedes aegypti collected in Puerto Iguazu, Misiones, Argentina. AB - A finding of vertical transmission of the DEN 3 virus in male specimens of Aedes aegypti, collected in the 2009 fall-winter period, in Puerto Iguazu city, Misiones, Argentina, using the RT-PCR technique in a 15-specimen pool is reported. This result is analyzed within the context of the epidemiological situation of Argentina's northeast border. PMID- 24626421 TI - Seroprevalence of T. cruzi infection in blood donors and Chagas cardiomyopathy in patients from the coal mining region of Coahuila, Mexico. AB - CONTEXT AND OBJECTIVE: Chagas disease is considered a worldwide emerging disease; it is endemic in Mexico and the state of Coahuila and is considered of little relevance. The objective of this study was to determine the seroprevalence of T. cruzi infection in blood donors and Chagas cardiomyopathy in patients from the coal mining region of Coahuila, Mexico. DESIGN AND SETTING: Epidemiological, exploratory and prospective study in a general hospital during the period January to June 2011. METHODS: We performed laboratory tests ELISA and indirect hemagglutination in three groups of individuals: 1) asymptomatic voluntary blood donors, 2) patients hospitalized in the cardiology department and 3) patients with dilated cardiomyopathy. RESULTS: There were three levels of seroprevalence: 0.31% in asymptomatic individuals, 1.25% in cardiac patients and in patients with dilated cardiomyopathy in 21.14%. CONCLUSIONS: In spite of having detected autochthonous cases of Chagas disease, its importance to local public health remains to be established as well as the details of the dynamics of transmission so that the study is still in progress. PMID- 24626422 TI - Two new records of Isomyia paurogonita Fang and Fan, 1986 and Sumatria latifrons Malloch, 1926 (Diptera: Calliphoridae) from northern Thailand, with revised key to the species of Isomyia. AB - During the annual fly survey at Doi Nang Kaew in Doi Saket District, Chiang Mai Province of Thailand in 2011, Isomyia paurogonita Fang & Fan, 1986 (Diptera: Calliphoridae) and Sumatria latifrons Malloch, 1926 (Diptera: Calliphoridae) were collected for the first time in Thailand. They are the rare species of the subfamily Rhiniinae (tribe Cosminini). Prior to this finding, fifteen species of Isomyia and two species of Sumatria were recorded from Thailand. Therefore, 96 blow fly species have been found in this country. These new locality records of both flies are very important for further research on their biology and ecology in Thailand. PMID- 24626423 TI - Species composition of carrion blow flies in northern Thailand: altitude appraisal. AB - Distribution and occurrence of blow flies of forensic importance was performed during 2007 and 2008 in Chiang Mai and Lampang Provinces, northern Thailand. Surveys were conducted in forested areas for 30 minutes using a sweep net to collected flies attracted to a bait. A total of 2,115 blow flies belonging to six genera and 14 species were collected; Chrysomya megacephala (Fabricius) (44.7%), C. pinguis (Walker) (15.1%), C. chani Kurahashi (9.3%), C. thanomthini Kurahashi & Tumrasvin (0.3%); Achoetandrus rufifacies (Macquart) (10.5%), A. villeneuvi (Patton) (2.2%); Lucilia papuensis Macquart (2.2%), L. porphyrina (Walker) (12.4%), L. sinensis Aubertin (0.7%); Hemipyrellia ligurriens (Wiedemann) (1.3%), H. pulchra (Wiedemann) (0.1%); Hypopygiopsis infumata (Bigot) (0.6%), Hy. tumrasvini Kurahashi (0.2%) and Ceylonomyia nigripes Aubertin (0.4%). Among them, C. megacephala was the predominant species collected, particularly in the summer. The species likely to prevail in highland areas are C. pinguis, C. thanomthini, Hy. tumrasvini, L. papuensis and L. porphyrina. PMID- 24626424 TI - Clinical manifestations seemed more severe among patients with antibody 4-fold or a greater increase in titer both against pH1N1 and against seasonal influenza than those whose antibody 4-fold or greater increase in titer was only against one type of seasonal influenza. PMID- 24626425 TI - Copper-catalyzed benzylic C(sp(3))-H alkoxylation of heterocyclic compounds. AB - We achieved intra- and intermolecular C(sp(3))-H alkoxylation of benzylic positions of heteroaromatic compounds using CuBrn (n = 1, 2)/5,6 dimethylphenanthroline (or 4,7-dimethoxyphenanthroline) and ((t)BuO)2 as a catalyst and an oxidant, respectively. The reaction proceeded at both terminal and internal benzylic positions of the alkyl groups. The intramolecular alkoxylation was performed on a gram scale. PMID- 24626426 TI - Clinical and pathologic features of Bipolaris endophthalmitis after intravitreal triamcinolone. AB - IMPORTANCE: This is a notice to ophthalmologists performing intravitreal injections of triamcinolone or other medications of the risk for endophthalmitis caused by Bipolaris hawaiiensis-contaminated medications. OBSERVATIONS: Histopathologic review of 5 eyes from a series of 17 treated with intravitreal triamcinolone for retinal vascular disease and diabetes mellitus over 1 year from 1 lot prepared by a compounding pharmacy. Endophthalmitis occurred in 14 of 17 eyes, the first presenting a mild vitritis 5 days following injection. The onset of signs and symptoms of endophthalmitis (eg, decreased vision, anterior chamber, or vitreous cells) in the 5 cases presented here varied from 5 to 174 days. CONCLUSIONS AND RELEVANCE: Vitreous biopsy with cytospin and periodic acid-Schiff stain for hyphae was the most sensitive method for proving that fungus was present (positive in 3 of 5 of our cases). Five of 5 sample results from the whole series of 14 clinical cases were confirmed as positive for Bipolaris hawaiiensis by genotyping at the Centers for Disease Control and Prevention. Three of the removed eyes received fresh were culture negative; however, all 5 demonstrated organisms with fungal stains. Symptoms of fungal endophthalmitis can be minimal and delayed long beyond the 5 to 7 days expected for acute bacterial endophthalmitis. Also, apparently viable organisms persist in ocular tissues despite prolonged exposure to antifungal agents. This series reminds us that cytological or histological examination of tissue specimens may be necessary to exclude fungal infections that fail to grow in culture. PMID- 24626427 TI - Changes in the gene expression levels of microRNAs in the rat hippocampus by sevoflurane and propofol anesthesia. AB - General anesthesia is commonly used in the surgical arena, but little is known regarding its influence at the genomic and molecular levels. MicroRNAs (miRNAs) belong to a new class of non-coding RNA molecules which influence cell biology. In the present study, it was hypothesized that miRNAs alter gene expression levels under general anesthesia. The aim was to compare the miRNA expression profiles in the rat hippocampus in response to anesthesia with representative volatile (sevoflurane) and intravenous (propofol) anesthetics. Wistar Rats were randomly assigned to either a 2.4% sevoflurane, 600 ug/kg/min propofol or control (without anesthetics) group. Total RNA from hippocampal samples which contained miRNA was subjected to quantitative reverse transcription-polymerase chain reaction and Taqman Low-Density Arrays (TLDA). A total of 373 miRNAs are associated with rats and the TLDA analysis revealed that 279 expressed miRNAs (74.8%) were expressed in all three groups. Significant differences in the levels of 33 of the 279 expressed miRNAs (11.8%) were observed among the three groups in response to the anesthetic agents, and when compared with the control group, significant differences were found in 26 of the 279 expressed miRNAs (9.3%). Following sevoflurane anesthesia, the levels of four miRNAs were significantly increased and those of 12 were significantly reduced. By contrast, following propofol anesthesia, the levels of 11 miRNAs were significantly reduced but no miRNAs exhibited significantly elevated levels. One miRNA was common between the two anesthesia groups, whereas 14 miRNAs were significantly differentially expressed. In conclusion, sevoflurane and propofol exerted different effects on miRNA expression in the rat hippocampus. PMID- 24626428 TI - Sonication assisted preparation of graphene oxide/graphitic-C3N4 nanosheet hybrid with reinforced photocurrent for photocatalyst applications. AB - Graphitic C3N4 (g-C3N4), as an advanced metal free photocatalyst, is known to be poorly exfoliated and dispersed in water from its powder form which has a layered structure, the intrinsic plane structure is not destroyed, and this has largely limited its application. In this work, we report our progress on successful sonication exfoliation of g-C3N4 nanosheets in graphene oxide (GO) aqueous solution. By making use of the substrate character of GO, g-C3N4 nanosheets of unvaried intrinsic structure were exfoliated and anchored on the GO surface, resulting in a GO/g-C3N4 hybrid. Moreover, the photocurrent of the hybrid was largely reinforced at the optimal weight fraction of GO. As a result, the corresponding photocatalytic performance of the hybrid with optimized photocurrent character was largely improved. PMID- 24626429 TI - Modulation of phagosomal pH by Candida albicans promotes hyphal morphogenesis and requires Stp2p, a regulator of amino acid transport. AB - Candida albicans, the most important fungal pathogen of humans, has a unique interaction with macrophages in which phagocytosis induces a switch from the yeast to hyphal form, allowing it to escape by rupturing the immune cell. While a variety of factors induce this switch in vitro, including neutral pH, it is not clear what triggers morphogenesis within the macrophage where the acidic environment should inhibit this transition. In vitro, C. albicans grown in similar conditions in which amino acids are the primary carbon source generate large quantities of ammonia to raise the extracellular pH and induce the hyphal switch. We show here that C. albicans cells neutralize the macrophage phagosome and that neutral pH is a key inducer of germination in phagocytosed cells by using a mutant lacking STP2, a transcription factor that regulates the expression of multiple amino acid permeases, that is completely deficient in alkalinization in vitro. Phagocytosed stp2Delta mutant cells showed significant reduction in hypha formation and escaped from macrophages less readily compared to wild type cells; as a result stp2Delta mutant cells were killed at a higher rate and caused less damage to RAW264.7 macrophages. Stp2p-regulated import leads to alkalinization of the phagosome, since the majority of the wild type cells fail to co-localize with acidophilic dyes, whereas the stp2Delta mutant cells were located in acidic phagosomes. Furthermore, stp2Delta mutant cells were able to form hyphae and escape from neutral phagosomes, indicating that the survival defect in these cells was pH dependent. Finally, these defects are reflected in an attenuation of virulence in a mouse model of disseminated candidiasis. Altogether our results suggest that C. albicans utilizes amino acids to promote neutralization of the phagosomal pH, hyphal morphogenesis, and escape from macrophages. PMID- 24626430 TI - Propagating the nephrology research workforce: a Kidney Research National Dialogue training commentary. AB - The National Institute of Diabetes and Digestive and Kidney Diseases conducted the Kidney Research National Dialogue as an interactive means to formulate and prioritize research goals necessary to address the needs of patients with renal disease. This commentary summarizes the discussion and priorities arising from the training domain of the dialogue and posits three overall strategies to broaden the nephrology research workforce pipeline. The community needs to recruit and provide support for mentors in nephrology, target medical and graduate students earlier in their education for exposure to renal research, and expand the research workforce to include basic scientists from many disciplines as well as under-represented minorities. PMID- 24626431 TI - Should rituximab be used to prevent relapse in patients with ANCA-associated vasculitis? PMID- 24626432 TI - Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. AB - BACKGROUND AND OBJECTIVES: Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined. RESULTS: In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase-ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS] = 0) was achieved in all patients. Major relapse (BVAS >= 3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population. CONCLUSION: This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted. PMID- 24626434 TI - The association between peritoneal dialysis modality and peritonitis. AB - BACKGROUND AND OBJECTIVES: There is conflicting evidence comparing peritonitis rates among patients treated with continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). This study aims to clarify the relationship between peritoneal dialysis (PD) modality (APD versus CAPD) and the risk of developing PD-associated peritonitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the association between PD modality (APD versus CAPD) and the risks, microbiology, and clinical outcomes of PD-associated peritonitis in 6959 incident Australian PD patients between October 1, 2003, and December 31, 2011, using data from the Australia and New Zealand Dialysis and Transplant Registry. Median follow-up time was 1.9 years. RESULTS: Patients receiving APD were younger (60 versus 64 years) and had fewer comorbidities. There was no association between PD modality and time to first peritonitis episode (adjusted hazard ratio [HR] for APD versus CAPD, 0.98; 95% confidence interval [95% CI], 0.91 to 1.07; P=0.71). However, there was a lower hazard of developing Gram-positive peritonitis with APD than CAPD, which reached borderline significance (HR, 0.90; 95% CI, 0.80 to 1.00; P=0.05). No statistically significant difference was found in the risk of hospitalizations (odds ratio, 1.12; 95% CI, 0.93 to 1.35; P=0.22), but there was a nonsignificant higher likelihood of 30-day mortality (odds ratio, 1.33; 95% CI, 0.93 to 1.88; P=0.11) at the time of the first episode of peritonitis for patients receiving APD. For all peritonitis episodes (including subsequent episodes of peritonitis), APD was associated with lower rates of culture-negative peritonitis (incidence rate ratio [IRR], 0.81; 95% CI, 0.69 to 0.94; P=0.002) and higher rates of gram-negative peritonitis (IRR, 1.28; 95% CI, 1.13 to 1.46; P=0.01). CONCLUSIONS: PD modality was not associated with a higher likelihood of developing peritonitis. However, APD was associated with a borderline reduction in the likelihood of a first episode of Gram-positive peritonitis compared with CAPD, and with lower rates of culture-negative peritonitis and higher rates of Gram-negative peritonitis. Peritonitis outcomes were comparable between both modalities. PMID- 24626433 TI - The effect of lowering LDL cholesterol on vascular access patency: post hoc analysis of the Study of Heart and Renal Protection. AB - BACKGROUND AND OBJECTIVES: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering LDL-C on vascular access patency is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo. This study aimed to explore the effects of treatment on vascular access occlusive events, defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis access. RESULTS: Among 2353 SHARP participants who had functioning vascular access at randomization, allocation to simvastatin plus ezetimibe resulted in a 13% proportional reduction in vascular access occlusive events (355 [29.7%] for simvastatin/ezetimibe versus 388 [33.5%] for placebo; risk ratio [RR], 0.87; 95% confidence interval [95% CI], 0.75 to 1.00; P=0.05). There was no evidence that the effects of treatment differed for any of the separate components of this outcome. To test the hypothesis raised by SHARP, comparable analyses were performed using the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort. AURORA did not provide independent confirmation (vascular access occlusive events: 352 [28.9%] for rosuvastatin versus 337 [27.6%] for placebo; RR, 1.06, 95% CI, 0.91 to 1.23; P=0.44). After combining the two trials, the overall effect of reducing LDL-C with a statin-based regimen on vascular access occlusive events was not statistically significant (707 [29.3%] with any LDL-C-lowering therapy versus 725 [30.5%] with placebo; RR, 0.95, 95% CI, 0.85 to 1.05; P=0.29). CONCLUSIONS: Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy may improve vascular access patency, but there was no evidence of benefit in AURORA. Taken together, the available evidence suggests that any benefits of lowering LDL-C on vascular access patency are likely to be modest. PMID- 24626435 TI - Carbon dioxide insufflation improves the intubation depth and total enteroscopy rate in single-balloon enteroscopy: a randomised, controlled, double-blind trial. AB - OBJECTIVE: The total enteroscopy rate of single-balloon enteroscopy (SBE) using air insufflation is not satisfactory, and whether carbon dioxide (CO2) insufflation increases the total enteroscopy rate of SBE is unknown. This randomised controlled trial aimed to determine whether CO2 insufflation facilitates the intubation depth and total enteroscopy rate of SBE. DESIGN: A total of 214 eligible patients referred for SBE were randomised to receive either air or CO2 insufflation, and included in the intention-to-test (ITT) analysis. In addition, 199 patients in whom enteroscopy was completed were included in the per protocol (PP) analysis. Both the patients and endoscopists were blinded, and the intubation depth and total enteroscopy rate were defined as the primary outcomes. RESULTS: The CO2 group showed a superiority of intubation in the ITT analysis (oral route: 323.8+/-64.2 vs 238.3+/-68.6 cm; anal route: 261.6+/-74.2 vs 174.7+/ 62.1 cm, both p<0.001), and the total enteroscopy rate (34.9% vs 17.6%, p=0.006). Similar results were obtained in a PP analysis for both outcomes. In addition, in the PP analysis, the addition of circumference after the procedure was less in the CO2 group (0.8+/-0.6 vs 3.3+/-1.8 cm, p=0.005) for the oral route. No serious complications were reported. The overall percentage of procedures with significant pathological findings was 52.8%; the rates were 58.5% and 47.2% (p=0.100, ITT analysis) in the CO2 and air groups, respectively. CONCLUSIONS: CO2 insufflation improves the intubation depth and total enteroscopy rate in SBE with a good safety profile and acceptability compared with that of air, and thus is recommended for clinical utilisation. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov identifier: NCT01758900. PMID- 24626436 TI - Full toxicity assessment of Genkwa Flos and the underlying mechanism in nematode Caenorhabditis elegans. AB - Genkwa Flos (GF), the dried flower bud from Daphne genkwa Sieb. et Zucc. (Thymelaeaceae), is a well-known and widely used traditional Chinese medicine. However, we know little about the in vivo mechanism of GF toxicity. Nematode Caenorhabditis elegans has been considered as a useful toxicity assay system by offering a system best suited for asking the in vivo questions. In the present study, we employed the prolonged exposure assay system of C. elegans to perform the full in vivo toxicity assessment of raw-processed GF. Our data show that GF exposure could induce the toxicity on lifespan, development, reproduction, and locomotion behavior. GF exposure not only decreased body length but also induced the formation of abnormal vulva. The decrease in brood size in GF exposed nematodes appeared mainly at day-1 during the development of adult nematodes. The decrease of locomotion behavior in GF exposed nematodes might be due to the damage on development of D-type GABAergic motor neurons. Moreover, we observed the induction of intestinal reactive oxygen species (ROS) production and alteration of expression patterns of genes required for development of apical domain, microvilli, and apical junction of intestine in GF exposed nematodes, implying the possible dysfunction of the primary targeted organ. In addition, GF exposure induced increase in defecation cycle length and deficits in development of AVL and DVB neurons controlling the defecation behavior. Therefore, our study implies the usefulness of C. elegans assay system for toxicity assessment from a certain Chinese medicine or plant extract. The observed toxicity of GF might be the combinational effects of oxidative stress, dysfunction of intestine, and altered defecation behavior in nematodes. PMID- 24626438 TI - Plasma-parathyroid hormone is associated with subclinical and clinical atherosclerotic disease in 2 community-based cohorts. AB - OBJECTIVE: Cardiovascular risk factors have different impact on different arterial territories. Diseases with elevated circulating parathyroid hormone (PTH) such as primary hyperparathyroidism and chronic renal failure have been shown to be associated with an increased risk of cardiovascular disease, predominantly heart or cerebrovascular diseases. However, data on the associations between circulating PTH and peripheral atherosclerosis are limited. APPROACH AND RESULTS: Two prospective, community-based studies were used. In 306 men and women, who were 70 years old, from the Prospective investigation of the vasculature in Uppsala seniors (PIVUS) study, cross-sectional relations between PTH and atherosclerotic burden assessed by whole-body magnetic resonance angiography were investigated. In 998 men, who were 71 years old, from the Uppsala longitudinal study of adult men (ULSAM) study, the association between PTH concentration and risk of subsequent nonfatal atherosclerotic disease (excluding coronary or cerebrovascular disease) was investigated. Adjusting for established vascular risk factors, PTH was associated with burden of atherosclerosis (increase in total atherosclerotic score per SD PTH increase: 0.04, 0.003-0.08; P=0.03) in the PIVUS study. During follow-up in the ULSAM study (median 16.7 years), 89 men were diagnosed with nonfatal atherosclerotic disease. In Cox-regression analyses adjusting for established vascular risk factors and mineral metabolism, higher PTH was associated with an increased risk of nonfatal atherosclerotic disease (hazard ratio for 1 SD increase of PTH: 1.55, 1.33-1.88; P<0.0001). Results were similar when including fatal atherosclerotic disease in the outcome. CONCLUSIONS: In 2 independent community-based cohorts, PTH was associated to the degree of atherosclerosis and risk of clinically overt atherosclerotic disease, respectively. Our data confirm and extend previous studies supporting a role for PTH in the development of atherosclerotic disease. PMID- 24626437 TI - Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. AB - OBJECTIVE: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) are secreted proteins that inhibit lipoprotein lipase in vitro. Genetic variants at the ANGPTL3 and ANGPTL4 gene loci are significantly associated with plasma lipid traits. The aim of this study was to evaluate the association of plasma ANGPTL3 and ANGPTL4 concentrations with lipid and metabolic traits in a large community based sample. APPROACH AND RESULTS: Plasma ANGPTL3 and ANGPTL4 levels were measured in 1770 subjects using a validated ELISA assay. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, sex, and race were performed. ANGPTL3 levels were significantly positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels (both P<2*10(-5)) but not triglycerides. In contrast, ANGPTL4 levels were significantly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (both P<2*10(-5)) and positively associated with triglycerides (P=0.003). In addition, ANGPTL4, but not ANGPTL3, levels were significantly positively associated with fasting blood glucose and metabolic syndrome. CONCLUSIONS: Despite having similar biochemical effects in vitro, plasma ANGPTL3 and ANGPTL4 concentrations have nearly opposite relationships with plasma lipids. ANGPTL4 is strongly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and positively with multiple features of the metabolic syndrome including triglycerides, whereas ANGPTL3 is positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and not with metabolic syndrome traits including triglycerides. Although ANGPTL3 and ANGPTL4 both inhibit lipoprotein lipase in vitro and influence lipoprotein metabolism in vivo, the physiology of these related proteins and their effects on lipoproteins is clearly divergent and complex. PMID- 24626439 TI - High birth weight is associated with obesity and increased carotid wall thickness in young adults: the cardiovascular risk in young Finns study. AB - OBJECTIVE: There is some evidence that people born with high birth weight may be at increased risk of cardiovascular disease in adulthood. Details of the underlying mechanisms remain unknown. We sought to determine whether people born large for gestational age have poor arterial health, increased adiposity, and a poor cardiovascular risk factor profile. APPROACH AND RESULTS: Carotid intima media thickness, brachial flow-mediated dilatation, and cardiovascular risk factors were compared between young adults (24-45 years) born at term who were large for gestational age (birth weight >90th percentile; n=171), and a control group with normal birth weight (50-75th percentile; n=525), in the Cardiovascular Risk in Young Finns Study. Those born large for gestational age had higher body mass index throughout childhood, adolescence, and as young adults (26.4 kg/m(2) [SD 4.9], versus normal birth weight 25.1 kg/m(2) [SD 4.6]; P=0.002), and 2-fold greater risk of obesity. Other cardiovascular risk factors and arterial function did not differ; however, carotid intima-media thickness was increased in people born large for gestational age (0.60 mm [SD 0.09], versus normal birth weight 0.57 mm [SD 0.09]; P=0.003), independent of cardiovascular risk factors (P=0.001 after adjustment). Both obesity and high birth weight were independently associated with carotid intima-media thickness in a graded and additive fashion. CONCLUSIONS: Young adults born large for gestational age are more likely to be obese, yet have an otherwise healthy cardiovascular risk profile. Nonetheless, they have increased carotid intima-media thickness, a marker of subclinical atherosclerosis, consistent with an increased risk of cardiovascular disease. PMID- 24626440 TI - Trends in patterns of intermediate uveitis in a tertiary institution in Singapore. AB - PURPOSE: The study aims to describe the characteristics and etiologic causes of intermediate uveitis (IU) patients seen by a tertiary eye center in Singapore over 8 years. METHODS: This was a retrospective analysis of the clinical records of consecutive new cases of IU that presented to the uveitis subspecialty clinic from 2004-2011 at Tan Tock Seng Hospital. Data collected included demographics, clinical and laboratory findings. Diagnoses were based on standardized clinical history, ophthalmological examination and investigations. RESULTS: There were 66 new cases of IU, comprising 5.7% of 1168 new uveitis patients. The median age of diagnosis was 40 years (mean 39.4+/-15.9), with largest subgroup of the patients in the age group of 41-60 years (36.4%). The majority was Chinese (57.6%), followed by Asian Indians (18.2%) and Malays (16.7%). The ethnicity distribution was dissimilar to our ethnic distribution in Singapore (p<0.001) with an increased incidence of IU in the Asian Indian population. Most were idiopathic (59.1%) in etiology, followed by tuberculosis (TB) (15.2%). Ocular complications developed in 21 patients (31.8%), with cystoid macular edema (CME) being the commonest (28.8%). Severe vitritis occurred in 9.1% of patients, and was significantly associated with TB-associated IU (p<0.001). There was a downward trend for the incidence of the proportion of IU patients over the total uveitis patients (p = 0.021), with Spearman's rho of -0.786. CONCLUSIONS: Despite the downward trend, TB-associated IU was still of higher prevalence compared to less endemic areas, emphasizing the need for increased TB surveillance. A high index of suspicion for TB-associated IU is required in patients with severe vitritis. Comparisons with other countries revealed disparities in the IU etiologies, indicating possible geographical differences. Prevalence of known immune-mediated etiologies of IU is less compared to the western population. Our study also suggests a probable predisposition of the Singapore local Indian population for IU. PMID- 24626441 TI - [Health expenditures, income inequality, and the marginalization index in Mexico's health system]. AB - OBJECTIVE: Evaluate the effect of the relationship among public health expenditures, income inequality, and the marginalization index on maternal and child mortality in Mexico, to determine the effect of these factors on health system performance from a technical efficiency perspective. METHODS: An ecological study of 32 Mexican states. Correlations were estimated between maternal and infant mortality and public health expenditures in total per capita, federal per capita, and state per capita for the years 2000, 2005, and 2010 (Gini coefficient and marginalization index). Linear regressions were used to explore the association of these variables with health indicators in the state systems. RESULTS: Negative correlations were observed for the marginalization index and Gini coefficient with regard to life expectancy at birth (-0.62 and -0.28 respectively). Furthermore, there was a positive correlation of 0.59 between the marginalization index and infant mortality (P <0.05). Multiple linear regression models revealed a negative effect of the marginalization index and Gini coefficient on health out-comes. Federal funding had a positive effect on system performance in terms of health indicators. CONCLUSIONS: Health system reform in Mexico has had a positive impact on the country's health indicators; federal financial investment seems to be effective in this regard. Social determinants have an important effect on health system performance, and analysis using multisectoral and multidisciplinary approaches are needed in addressing them. PMID- 24626442 TI - Functioning outcomes for abused immigrant women and their children 4 months after initiating intervention. AB - OBJECTIVE: To measure the impact of shelter intervention and protection orders on the mental health functioning, resiliency, and further abuse of documented and undocumented immigrant women and their children in Houston, Texas, United States. METHODS: A prospective cohort study initiated in 2011 examined a subsample of 106 immigrant mothers, primarily from Mexico and Central America, and evaluated their functioning with a battery of 13 well-established instruments as they accessed either shelter or justice services; followed-up was conducted 4 months later to measure improvement. Data were analyzed with a series of repeated measures 2 x 2 x 2 factorial analysis of variance tests. RESULTS: Large effect size improvements were observed in abused immigrant women's mental health, resiliency, and safety, regardless of whether the intervention accessed was safe shelter or justice services, and regardless of duration of shelter stay and whether or not a protection order was issued. Similarly, large effect size improvements were observed in child functioning, independent of which type of intervention, the duration of shelter stay, or the issuance of a protection order. CONCLUSIONS: Accessing protective services has the potential to improve the health of immigrant women and their children, regardless of documentation status. Global policy for improved access and acceptability of shelter and justice services is essential to promote immigrant women's safety and to maximize functioning of women and children. PMID- 24626443 TI - [Characteristics of hospital care and its relationship to severe maternal morbidity in Medellin, Colombia]. AB - OBJECTIVE: The objective of this study was to determine whether there is an association between severe maternal mortality (SMM) and the characteristics of access to and use of obstetric services by the participating women. METHODS: A study of cases and controls was conducted in a group of 600 women who were attended during pregnancy or the puerperium between 2011 and 2012 by obstetric services located in Medellin, Colombia. The study considered cases (n = 150) in obstetric patients who met the criteria for SMM established by the surveillance system being used in Medellin at the time of their admission. The controls (n = 450) were randomly selected in the same institutions where the patients were being treated. The information was obtained through an in-person interview, review of the patient's clinical history, and rating of the medical care provided by surveillance program personnel. The analysis was based on the model Road Map for Preventing Maternal Death developed jointly by Pan American Health Organization/World Health Organization, Centers for Disease Control, United Nations Population Fund for Latin America and the Caribbean, and Mothercare UK. RESULTS: The proportion of unplanned pregnancies in the women studied was 57.6%, while the proportion of delay in the decision to seek care was 32.0%. Two variables were found to be associated with SMM: ethnicity (OR = 1.79) and delays due to deficiencies in the quality of care provided (OR = 8.54). CONCLUSIONS: The findings suggest that improving the effectiveness and quality of family planning, prenatal check-up, and hospital obstetric care programs could help to reduce avoidable cases of SMM. PMID- 24626444 TI - [Prevalence of root caries among adults and the elderly in southeast Brazil]. AB - OBJECTIVE: To assess the prevalence and factors associated with root caries (RC) among adults and the elderly in the Southeast of Brazil. METHODS: This study used secondary data from the Health Ministry's 2010 National Oral Health Survey. In the Southeast, a household probability sample of 1 586 adults and 1 277 elderly was evaluated in four capitals and 30 municipalities. The RC outcome was evaluated according to World Health Organization criteria for oral health surveys, based on the root caries index (RCI) and root, decayed, filled (RDF) surface index. Participants answered a sociodemographic questionnaire. The chi square test was used to determine the association between prevalence of RC and gender, income, educational attainment, and place of residence (capitals or noncapital municipality). RESULTS: The mean RDF index in adults was 0.36, and the RCI was 6.1%. In 15.2% of adults, the RDF index was > 0. The mean RDF index was 0.17 in the elderly and 0.37 in dentate individuals. Prevalence of RDF > 0 was 12.4% and 27.2%, respectively, and the RCI was 10% among the elderly. In both groups, untreated RC was the most prevalent. RC in adults was associated with income, educational attainment, and residence location. In the elderly, it was associated only with gender. CONCLUSIONS: Prevalence of RC indicates that further attention should be paid to this oral condition, especially as RC was untreated in most subjects. We suggest that future studies evaluate new strategies for the care and prevention of RC. PMID- 24626445 TI - Cohort study of smoke-free homes in economically disadvantaged communities in the Dominican Republic. AB - OBJECTIVE: To analyze household smoking-ban prevalence over time and predictors among communities in the Dominican Republic, historically a significant tobacco growing country with few tobacco control regulations. METHODS: Baseline (2004) and follow-up surveillance surveys (2006, 2007) (each n > 1 000 randomly selected households) conducted in six economically disadvantaged communities (three tobacco-growing and two each urban, peri-urban, and rural) assessed household members' demographics, health status, and household characteristics, including smoking restrictions. RESULTS: Between 2004 and 2007, household smoking-ban prevalence increased in all communities, with overall rates increasing from 23.9% (2004) to 45.3% (2007). Households with smokers adopted smoking bans at lower rates (6%-17%) versus those without smokers (which had an adoption rate of 35% 58%). Logistic regression models demonstrated that the associations between allowing smoking in households with no members who smoked and being located in a tobacco-growing community, being a Catholic household, and having a member with a cardiovascular problem were statistically significant. The association between having a child under age 5 or a member with a respiratory condition and prohibiting smoking in the home was not statistically significant. CONCLUSIONS: Prevalence of households banning smoking increased in all communities but remained well below rates in industrialized countries. For low- and middle-income countries or those in early stages of tobacco control, basic awareness-raising measures (including surveillance activities) may lead to statistically significant increases in household smoking-ban adoption, particularly among households with no smokers. An increase in household smoking-ban prevalence may result in changes in community norms that can lead to a further increase in the adoption of smoking bans. Having household members who smoke and being in a tobacco-growing community may mitigate the establishment of household bans. Increasing individuals' knowledge about the far-reaching health effects of secondhand smoke exposure on children and nonsmoking adults (healthy or unhealthy) may help overcome these obstacles. PMID- 24626446 TI - [Contribution of extended school hours to the nutritional and physical activity profile of schoolchildren]. AB - OBJECTIVE: To evaluate the influence of the amount of time spent in school on food intake, nutritional status, and physical activity profile. METHODS: In this cross-sectional study, student data from two programs were compared in a city school in Belo Horizonte: integrated school (EI), in which students spend longer hours in school, and traditional school (ET), where students stay in school one shift only. First to 6th year students were studied in the first half of 2010. Demographic, socioeconomic, and physical data, as well as anthropometric activity and food intake were assessed. RESULTS: Two hundred and ninety-four students participated in the study, 53.0% from the EI program. Overweight was observed in 14.5% and 17.6% of EI and ET students, respectively (P = 0.781). A higher median frequency of physical activity was identified in EI (4.5 [2.0-7.0] hours/week vs. 2.0 [2.0-5.2] in ET; P = 0.004). EI students also had more adequate intake of carbohydrates (82.9% vs. 76.1% in ET; P = 0.01) and fruit (81.8% vs. 18.2% in ET; P = 0.004), and more adequate number of daily meals (67.6% vs. 32.4% in ET; P = 0.002). CONCLUSIONS: Longer hours school provided better dietary parameters and favored physical activity among students. Such findings may be useful to foster change in anthropometric parameters to be investigated in the long term. PMID- 24626447 TI - [Health-related quality of life in Latin American adolescents]. AB - OBJECTIVE: The objective of the present study was to find out if there are differences in terms of sex, age, or country of origin for the components of health-related quality of life (HRQL) in samples of adolescents from three cities in Argentina, Brazil, and Chile, respectively-using data collected through an internationally recognized and validated survey questionnaire, KIDSCREEN-52. METHODS: The KIDSCREEN-52 questionnaire was administered to 1 357 adolescents between 12 and 17 years of age (48.6% of them male) in selected samples in the three countries. Univariate analysis of variation (ANCOVA) was used. Not only sex and age differences, but also differences for each component of HRQL, were found between the three country groups. RESULTS: The data showed significant differences between the three countries for each of the specific components of HRQL. Males scored significantly higher than females in the following components: Physical Well-being (P < 0.001), Psychological Well-being (P = 0.019), Moods and Emotions (P < 0.001), Self-perception (P = 0.001), Autonomy (P < 0.001), and Parent Relations and Home Life (P = 0.008). Furthermore, the average scores for Physical Well-being (P = 0.001), Psychological Well-being (P = 0.001), Self Perception (P = 0.038), Autonomy (P = 0.001), Parent Relations and Home Life (P = 0.001), School Environment (P = 0.001), and Financial Resources (P = 0.022) showed a significantly declining trend with each advancing year, while average scores for the component Social Acceptance (Bullying) increased significantly with age (P < 0.001). CONCLUSIONS: The evidence suggests that interventions in disease prevention and health promotion should be developed for specific target groups, using appropriate actions depending on the sex and age of the adolescents. PMID- 24626448 TI - Factors associated with hepatitis C seropositivity in people living with HIV. AB - OBJECTIVE: To identify risk factors associated with hepatitis C virus (HCV) seropositivity in human immunodeficiency virus (HIV)-infected patients. METHODS: A paired case-control study adjusted by age and gender was conducted. It included adults coinfected with HIV and HCV (cases) and HIV mono-infected subjects (controls) using non-probability sampling. Data were collected through interviews and review of medical records. The chi-square test was used for comparing categorical variables and the Student's t-test or Wilcoxon (Mann-Whitney U) test for continuous variables. Confidence intervals (95%) were estimated along with crude and adjusted odds ratios using conditional logistic regression. RESULTS: A total of 165 patients were surveyed, including 55 cases and 110 controls. The mean age was 43.6 +/- 8.4 years, ranging from 19 to 64 years; 70.9% were male. Independent risk factors for HIV/HCV coinfection were education (up to eight years of schooling); age at first intercourse < 15 years; having undergone tattooing; blood transfusion; and use of injecting drugs. CONCLUSIONS: Low level of education, early age at first sexual intercourse, tattooing, blood transfusions, and sharing needles and other drug injection equipment were factors that increased the risk of HIV/HCV coinfection. The results from this research can be compared with similar data from other regions to help direct preventive and educational efforts targeting people living with HIV. PMID- 24626449 TI - Structural social determinants and catastrophic illnesses in municipalities in the Colombian department of Valle del Cauca. AB - OBJECTIVE: To explore possible associations between self-reported prevalence of catastrophic illnesses such as chronic renal failure, HIV/AIDS and cancer and a set of structural social determinants. METHODS: Ecological study using data from the 2005 Population Census conducted by the National Administrative Department of Statistics (DANE), focusing on municipalities in the Colombian department of Valle del Cauca that experienced the highest prevalence rates for catastrophic illnesses during 2000-2005. Associations were measured with Pearson's chi-squared statistic and Fisher's Exact Test. Prevalence ratios were calculated, with 95% confidence intervals. RESULTS: Statistically significant associations were observed between catastrophic illnesses and social structural determinants in the form of illiteracy, deficient sanitary infrastructure, quality of housing units and access to health services. CONCLUSIONS: A role was observed for social determination of catastrophic illnesses in this context. However, additional analyses are required that recognize the complexity of health-determining processes and that explore the interrelationships among social, structural, behavioral and psychosocial determinants in depth. PMID- 24626450 TI - [Factors associated with dental caries and periodontal diseases in Latin American indigenous peoples: a systematic review]. AB - OBJECTIVE: To identify the factors associated with dental caries and periodontal diseases in indigenous populations in Latin America. METHODS: The search was conducted between January and February 2012 in the following databases: MEDLINE/PubMed, SCOPUS, SciELO, and LILACS. The references of the identified articles were also searched. The initial search retrieved 74 articles, 33 of which were selected according to inclusion and exclusion criteria. The methodological quality of the studies was evaluated according to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) recommendations. RESULTS: Most of the populations studied were Brazilian, with the highest percentage of studies focusing on the Xingu and Xavante communities (31.6%). Most studies were cross-sectional. One of the studies showed a positive association between tooth loss and increasing age among the Guarani population in Brazil, with the largest proportion of gingival bleeding among adolescent males and females showing a higher number of sextants excluded for tooth loss. Two Brazilian longitudinal studies with Xavante communities showed significant differences in the incidence of caries for age and sex. CONCLUSIONS: Increasing age and differences between sexes are possible factors associated with an increase in dental caries and periodontal diseases in the Guarani and Xavante people in Brazil. The lack of studies with an appropriate methodology renders Latin American indigenous peoples epidemiologically invisible, hindering the production of knowledge on oral health status and on the development of strategies for oral disease prevention and health promotion in these populations. PMID- 24626451 TI - [About socioeconomic inequalities in dental care in Chile]. PMID- 24626452 TI - [Reply to the letter of Cornejo-Ovalle. About socioeconomic inequalities in dental care in Chile]. PMID- 24626453 TI - Left maxillary artery pseudoaneurysm: a rare and late postoperative complication after head and neck cancer treatment. AB - We report a case of a 50-year-old man presented with pulsatile swelling in the left side of the face since 2 months and a continuous sinus discharge since 3 days. Three years earlier, he was operated for squamous cell carcinoma (SCC) of the left lower alveolus and underwent surgical excision with myocutaneous flap reconstruction, followed by chemoradiotherapy. CT angiogram of the expansile swelling revealed pseudoaneurysm of third part of the left maxillary artery and treated by surgical intervention. PMID- 24626454 TI - Three-dimensional transoesophageal echocardiography for the diagnosis of prosthetic valve endocarditis. PMID- 24626456 TI - Institution-Specific Victimization Surveys: Addressing Legal and Practical Disincentives to Gender-Based Violence Reporting on College Campuses. AB - This review brings together both the legal literature and original empirical research regarding the advisability of amending the Jeanne Clery Disclosure of Campus Security Policy and Campus Crime Statistics Act or creating new Department of Education regulations to mandate that all higher education institutions survey their students approximately every 5 years about students' experiences with sexual violence. Legal research conducted regarding the three relevant federal legal regimes show inconsistent incentives for schools to encourage victim reporting and proactively address sexual violence on campus. Moreover, the original research carried out for this article shows that the experience of institutions that have voluntarily conducted such surveys suggests many benefits not only for students, prospective students, parents, and the general public but also for schools themselves. These experiences confirm the practical viability of a mandated survey by the Department of Education. PMID- 24626457 TI - Psychological Treatment of Sexual Offenders Against Children: A Meta-Analytic Review of Treatment Outcome Studies. AB - Numerous meta-analyses and reviews have been conducted on the effectiveness of psychological treatment of sexual offenders in reducing recidivism, but no meta analysis has been done on sexual offenders against children (SOAC) specifically. A moderate treatment effect has been shown in several evaluations of general sexual offenders, while many scholars maintain that the question remains unanswered until an adequate number of effectiveness studies with a strong research design have been carried out. In this meta-analysis, we evaluated 14 studies selected and coded according to Collaborative Outcome Data Committee (CODC) criteria. They included 1,421 adult offenders in psychotherapy and 1,509 nontreated controls, with a minimum average follow-up period of 3 years, published in peer-reviewed journals in 1980 or later. Recidivism was defined as rearrest or reconviction. Study quality was classified into strong, good, weak or rejected. The analysis revealed a treatment effect size of r = .03 for nine studies evaluated as Good or Weak, while all studies yielded an effect size of r = .08, including five studies classified as Rejected. The results show that the available research cannot establish any effect of treatment on SOAC. Despite a large amount of research, only a tiny fraction of studies meet a minimum of scientific standards, and even fewer provide sensible and useful data from which it is possible to draw conclusions. PMID- 24626458 TI - Traumatogenic Processes and Pathways to Mental Health Outcomes for Sexual Minorities Exposed to Bias Crime Information. AB - Vicarious traumatization of nonvictim members of communities targeted by bias crimes has been suggested by previous qualitative studies and often dominates public discussion following bias events, but proximal and distal responses of community members have yet to be comprehensively modeled, and quantitative research on vicarious responses is scarce. This comprehensive review integrates theoretical and empirical literatures in social, clinical, and physiological psychology in the development of a model of affective, cognitive, and physiological responses of lesbian, gay, and bisexual individuals upon exposure to information about bias crimes. Extant qualitative research in vicarious response to bias crimes is reviewed in light of theoretical implications and methodological limitations. Potential pathways to mental health outcomes are outlined, including accumulative effects of anticipatory defensive responding, multiplicative effects of minority stress, and putative traumatogenic physiological and cognitive processes of threat. Methodological considerations, future research directions, and clinical implications are also discussed. PMID- 24626459 TI - Intimate Partner Violence in Pakistan: A Systematic Review. AB - Intimate partner violence (IPV) is a major social and public health problem affecting people in various cultures and societies. Though the issue of IPV in Pakistan has been researched since the 1990 s, no attempt has been made systematically to review the available evidence on IPV in Pakistan. This article presents findings of a systematic review of available empirical literature related to IPV in Pakistan. Using various key words, MEDLINE, CINAHL, and PsycINFO were searched to identify relevant studies. This resulted in the identification of 55 potential studies for inclusion. After application of exclusion criteria 23 studies were identified, 20 of which used quantitative research designs, two used qualitative designs and one adopted a mixed method case study approach. All studies reported men as the perpetrators of IPV and women as its victims. Findings are presented and discussed for IPV for its forms, predictors, effects and victims' responses. Pakistani peoples' perceived reasons for and their attitudes towards IPV are also presented and discussed. PMID- 24626460 TI - Significance, Nature, and Direction of the Association Between Child Sexual Abuse and Conduct Disorder: A Systematic Review. AB - To elucidate the significance, nature, and direction of the potential relationship between child sexual abuse and conduct disorder, all the pertinent studies were reviewed. Ten databases were searched. Blind assessments of study eligibility and quality were performed by two independent researchers. Thirty-six studies including 185,358 participants and meeting minimum quality criteria that were enough to ensure objectivity and to not invalidate results were analyzed. Across the majority of studies, conduct disorder was significantly and directly related to child sexual abuse, especially repeated sexual molestation and abuse involving penetration, even after controlling for various sociodemographic, family, and clinical variables. The association between child sexual abuse and conduct disorder was not confounded by other risk factors, such as gender, socioeconomic status, school achievement, substance problems, physical abuse, parental antisocial behavior or substance problems, parent-child relationships, and family disruption, conflict, or violence. Evidence for a significant interactive effect between child sexual abuse and monoamine oxidase A gene on conduct disorder was scant. Early sexual abuse might predispose to the subsequent onset of conduct disorder which, in turn, may lead to further sexual victimization through association with sexually abusive peers or involvement in dangerous situations or sexual survival strategies. PMID- 24626461 TI - Hepatitis C virus core protein induces hypoxia-inducible factor 1alpha-mediated vascular endothelial growth factor expression in Huh7.5.1 cells. AB - Hepatitis C virus (HCV) infection is one of the major causes of hepatocellular carcinoma (HCC). It has been demonstrated that the overexpression of angiogenic factors are associated with the maintenance of liver neoplasia. Hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) are important regulators of angiogenesis and are important in wound healing, the regeneration of new vessels and reproductive functions. The present study investigated the role of the HCV core protein in the induction of HIF-1alpha and VEGF expression. The HCV core gene and HIF-1alpha siRNA were transfected into Huh7.5.1 cells. The results demonstrated that the induction of HCV core gene expression in Huh7.5.1 cells leads to the overexpression and stabilization of HIF 1alpha, and the activation of HIF-1alpha leads, in turn, to the stimulation of VEGF, which is one of the most important angiogenic factors. These results provide new information to facilitate the understanding of HCC oncogenesis. PMID- 24626462 TI - Unexpected behavior of some nitric oxide modulators under cadmium excess in plant tissue. AB - Various nitric oxide modulators (NO donors--SNP, GSNO, DEA NONOate and scavengers -PTIO, cPTIO) were tested to highlight the role of NO under Cd excess in various ontogenetic stages of chamomile (Matricaria chamomilla). Surprisingly, compared to Cd alone, SNP and PTIO elevated Cd uptake (confirmed also by PhenGreen staining) but depleted glutathione (partially ascorbic acid) and phytochelatins PC2 and PC3 in both older plants (cultured hydroponically) and seedlings (cultured in deionised water). Despite these anomalous impacts, fluorescence staining of NO and ROS confirmed predictable assumptions and revealed reciprocal changes (decrease in NO but increase in ROS after PTIO addition and the opposite after SNP application). Subsequent tests using alternative modulators and seedlings confirmed changes to NO and ROS after application of GSNO and DEA NONOate as mentioned above for SNP while cPTIO altered only NO level (depletion). On the contrary to SNP and PTIO, GSNO, DEA NONOate and cPTIO did not elevate Cd content and phytochelatins (PC2, PC3) were rather elevated. These data provide evidence that various NO modulators are useful in terms of NO and ROS manipulation but interactions with intact plants affect metal uptake and must therefore be used with caution. In this view, cPTIO and DEA NONOate revealed the less pronounced side impacts and are recommended as suitable NO scavenger/donor in plant physiological studies under Cd excess. PMID- 24626463 TI - Reduction of an Fe(I) mesityl complex induced by pi-acid ligands. AB - Treatment of the Fe(I) mesityl complex [Fe(Mes)(BPEP-Ph)] (BPEP-Ph = 2,6-bis[1 phenyl-2-(2,4,6-tri-tert-butylphenyl)-2-phosphaethenyl]pyridine) with pi-acid ligands (L = CO, RNC) leads to one-electron reduction via Mes group migration from Fe to P, followed by homolytic elimination of the 2,4,6-tBu3C6H2 group, to afford Fe(0) complexes of the formula [Fe(L)2(BPEP-Ph*)] (BPEP-Ph* = 2-[1-phenyl 2-mesityl-2-phosphaethenyl]-6-[1-phenyl-2-(2,4,6-tri-tert-butylphenyl)-2 phosphaethenyl]pyridine). This reduction process is supported by radical trapping experiments and theoretical studies. The 2,4,6-tBu3C6H2 radical is captured by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) in high yield. DFT calculations reveal the mechanism of Mes group migration with a reasonable energy profile. PMID- 24626464 TI - Hyperammonaemia in four cats with renal azotaemia. AB - Hyperammonaemia is well reported in animals with advanced hepatic disease and portosystemic shunts, but is unreported in cats with renal disease. This case series describes four cats with severe renal azotaemia in which elevated ammonia levels were detected during the course of treatment. In two cases hyperammonaemia was detected at a time when neurological signs consistent with encephalopathy had developed. This raises the possibility that hyperammonaemia may play a role in the development of encephalopathy in cats with renal azotaemia. PMID- 24626465 TI - Trained vs untrained evaluator assessment of body condition score as a predictor of percent body fat in adult cats. AB - Body condition scoring (BCS) provides a readily available technique that can be used by both veterinary professionals and owners to assess the body condition of cats, and diagnose overweight or underweight conditions. The objective of this study was to evaluate a five-point BCS system with half-point delineations using dual-energy x-ray absorptiometry (DXA). Four evaluators (a veterinarian, veterinary technician, trained scorer and untrained scorer) assessed 133 neutered adult cats. For all scorers, BCS score was more strongly correlated with percent body fat than with body weight. Percent body fat increased by approximately 7% within each step increase in BCS. The veterinarian had the strongest correlation coefficient between BCS and percent fat (r = 0.80). Mean body fat in cats classified as being in ideal body condition was 12 and 19%, for 3.0 and 3.5 BCS, respectively. Within BCS category, male cats were significantly heavier in body weight than females within the same assigned BCS category. However, DXA-measured percent body fat did not differ significantly between male and female cats within BCS category, as assigned by the veterinarian (P >0.13). Conversely, when assessed by others, mean percent body fat within BCS category was lower in males than females for cats classified as being overweight (BCS >4.0). The results of this study show that using a BCS system that has been validated within a range of normal weight to moderately overweight cats can help to differentiate between lean cats and cats that may not be excessively overweight, but that still carry a higher proportion of body fat. PMID- 24626466 TI - MiR-132 suppresses the migration and invasion of lung cancer cells via targeting the EMT regulator ZEB2. AB - MicroRNAs (miRNAs) are small, non-coding RNAs which can function as oncogenes or tumor suppressor genes in human cancers. Emerging evidence reveals that deregulation of miRNAs contributes to the human non-small cell lung cancer (NSCLC). In the present study, we demonstrated that the expression levels of miR 132 were dramatically decreased in examined NSCLC cell lines and clinical NSCLC tissue samples. Then, we found that introduction of miR-132 significantly suppressed the migration and invasion of lung cancer cells in vitro, suggesting that miR-132 may be a novel tumor suppressor. Further studies indicated that the EMT-related transcription factor ZEB2 was one direct target genes of miR-132, evidenced by the direct binding of miR-132 with the 3' untranslated region (3' UTR) of ZEB2. Further, miR-132 could decrease the expression of ZEB2 at the levels of mRNA and protein. Notably, the EMT marker E-cadherin or vimentin, a downstream of ZEB2, was also down-regulated or up-regulated upon miR-132 treatment. Additionally, over-expressing or silencing ZEB2 was able to elevate or inhibit the migration and invasion of lung cancer cells, parallel to the effect of miR-132 on the lung cancer cells. Meanwhile, knockdown of ZEB2 reversed the enhanced migration and invasion mediated by anti-miR-132. These results indicate that miR-132 suppresses the migration and invasion of NSCLC cells through targeting ZEB2 involving the EMT process. Thus, our finding provides new insight into the mechanism of NSCLC progression. Therapeutically, miR-132 may serve as a potential target in the treatment of human lung cancer. PMID- 24626467 TI - Oral mycobiome analysis of HIV-infected patients: identification of Pichia as an antagonist of opportunistic fungi. AB - Oral microbiota contribute to health and disease, and their disruption may influence the course of oral diseases. Here, we used pyrosequencing to characterize the oral bacteriome and mycobiome of 12 HIV-infected patients and matched 12 uninfected controls. The number of bacterial and fungal genera in individuals ranged between 8-14 and 1-9, among uninfected and HIV-infected participants, respectively. The core oral bacteriome (COB) comprised 14 genera, of which 13 were common between the two groups. In contrast, the core oral mycobiome (COM) differed between HIV-infected and uninfected individuals, with Candida being the predominant fungus in both groups. Among Candida species, C. albicans was the most common (58% in uninfected and 83% in HIV-infected participants). Furthermore, 15 and 12 bacteria-fungi pairs were correlated significantly within uninfected and HIV-infected groups, respectively. Increase in Candida colonization was associated with a concomitant decrease in the abundance of Pichia, suggesting antagonism. We found that Pichia spent medium (PSM) inhibited growth of Candida, Aspergillus and Fusarium. Moreover, Pichia cells and PSM inhibited Candida biofilms (P = .002 and .02, respectively, compared to untreated controls). The mechanism by which Pichia inhibited Candida involved nutrient limitation, and modulation of growth and virulence factors. Finally, in an experimental murine model of oral candidiasis, we demonstrated that mice treated with PSM exhibited significantly lower infection score (P = .011) and fungal burden (P = .04) compared to untreated mice. Moreover, tongues of PSM-treated mice had few hyphae and intact epithelium, while vehicle- and nystatin-treated mice exhibited extensive fungal invasion of tissue with epithelial disruption. These results showed that PSM was efficacious against oral candidiasis in vitro and in vivo. The inhibitory activity of PSM was associated with secretory protein/s. Our findings provide the first evidence of interaction among members of the oral mycobiota, and identifies a potential novel antifungal. PMID- 24626468 TI - Vitamin D signaling regulates oral keratinocyte proliferation in vitro and in vivo. AB - The secosteroidal hormone 1,25-dihyroxyvitamin D [1,25(OH)(2)D(3)] and its receptor, the vitamin D receptor (VDR), are crucial regulators of epidermal proliferation and differentiation. However, the effects of 1,25(OH)(2)D(3) directed signaling on oral keratinocyte pathophysiology have not been well studied. We examined the role of 1,25(OH)(2)D(3) in regulating proliferation and differentiation in cultured oral keratinocytes and on the oral epithelium in vivo. Using lentiviral-mediated shRNA to silence VDR, we generated an oral keratinocyte cell line with stable knockdown of VDR expression. VDR knockdown significantly enhanced proliferation and disrupted calcium- and 1,25(OH)(2)D(3) induced oral keratinocyte differentiation, emphasizing the anti-proliferative and pro-differentiation effects of 1,25(OH)(2)D(3) in oral keratinocytes. Using vitamin D(3)-deficient diets, we induced chronic vitamin D deficiency in mice as evidenced by decreased serum 25-hydroxyvitamin D (25OHD) concentrations. The vitamin D-deficient mice manifested increased proliferation of the tongue epithelium, but did not develop any morphological or histological abnormalities in the oral epithelium, suggesting that vitamin D deficiency alone is insufficient to alter oral epithelial homeostasis and provoke carcinogenesis. Immunohistochemical analyses of human and murine oral squamous cell carcinomas showed increased VDR expression. Overall, our results provide strong support for a crucial role for vitamin D signaling in oral keratinocyte pathophysiology. PMID- 24626469 TI - Retinoblastoma: the Zimmerman family story. PMID- 24626470 TI - Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise. AB - BACKGROUND: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. METHODS: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. RESULTS: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8 1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. CONCLUSIONS: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter. PMID- 24626471 TI - Analysis of isotopic labeling in peptide fragments by tandem mass spectrometry. AB - Phenotype in multicellular organisms is the consequence of dynamic metabolic events that occur in a spatially dependent fashion. This spatial and temporal complexity presents challenges for investigating metabolism; creating a need for improved methods that effectively probe biochemical events such as amino acid biosynthesis. Isotopic labeling can provide a temporal-spatial recording of metabolic events through, for example, the description of enriched amino acids in the protein pool. Proteins are therefore an important readout of metabolism and can be assessed with modern mass spectrometers. We compared the measurement of isotopic labeling in MS2 spectra obtained from tandem mass spectrometry under either higher energy collision dissociation (HCD) or collision induced dissociation (CID) at varied energy levels. Developing soybean embryos cultured with or without 13C-labeled substrates, and Escherichia coli MG1655 enriched by feeding 7% uniformly labeled glucose served as a source of biological material for protein evaluation. CID with low energies resulted in a disproportionate amount of heavier isotopologues remaining in the precursor isotopic distribution. HCD resulted in fewer quantifiable products; however deviation from predicted distributions were small relative to the CID-based comparisons. Fragment ions have the potential to provide information on the labeling of amino acids in peptides, but our results indicate that without further development the use of this readout in quantitative methods such as metabolic flux analysis is limited. PMID- 24626472 TI - Health and economic benefits of improved injury prevention and trauma care worldwide. AB - OBJECTIVES: Injury is a significant source of morbidity and mortality worldwide, and often disproportionately affects younger, more productive members of society. While many have made the case for improved injury prevention and trauma care, health system development in low- and middle-income countries is often limited by resources. This study aims to determine the economic benefit of improved injury prevention and trauma care in low- and middle-income countries. METHODS: This study uses existing data on injury mortality worldwide from the 2010 Global Burden of Disease Study to estimate the number of lives that could be saved if injury mortality rates in low- and middle-income countries could be reduced to rates in high-income countries. Using economic modeling--through the human capital approach and the value of a statistical life approach--the study then demonstrates the associated economic benefit of these lives saved. RESULTS: 88 percent of injury-related deaths occur in low- and middle-income countries. If injury mortality rates in low- and middle-income countries were reduced to rates in high-income countries, 2,117,500 lives could be saved per year. This would result in between 49 million and 52 million disability adjusted life years averted per year, with discounting and age weighting. Using the human capital approach, the associated economic benefit of reducing mortality rates ranges from $245 to $261 billion with discounting and age weighting. Using the value of a statistical life approach, the benefit is between 758 and 786 billion dollars per year. CONCLUSIONS: Reducing injury mortality in low- and middle-income countries could save over 2 million lives per year and provide significant economic benefit globally. Further investments in trauma care and injury prevention are needed. PMID- 24626473 TI - Functional gene group analysis indicates no role for heterotrimeric G proteins in cognitive ability. AB - Previous functional gene group analyses implicated common single nucleotide polymorphisms (SNPs) in heterotrimeric G protein coding genes as being associated with differences in human intelligence. Here, we sought to replicate this finding using five independent cohorts of older adults including current IQ and childhood IQ, and using both gene- and SNP-based analytic strategies. No significant associations were found between variation in heterotrimeric G protein genes and intelligence in any cohort at either of the two time points. These results indicate that, whereas G protein systems are important in cognition, common genetic variation in these genes is unlikely to be a substantial influence on human intelligence differences. PMID- 24626474 TI - Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control. AB - Receptors of the signalling lymphocyte-activation molecules (SLAM) family are involved in the functional regulation of a variety of immune cells upon engagement through homotypic or heterotypic interactions amongst them. Here we show that murine cytomegalovirus (MCMV) dampens the surface expression of several SLAM receptors during the course of the infection of macrophages. By screening a panel of MCMV deletion mutants, we identified m154 as an immunoevasin that effectively reduces the cell-surface expression of the SLAM family member CD48, a high-affinity ligand for natural killer (NK) and cytotoxic T cell receptor CD244. m154 is a mucin-like protein, expressed with early kinetics, which can be found at the cell surface of the infected cell. During infection, m154 leads to proteolytic degradation of CD48. This viral protein interferes with the NK cell cytotoxicity triggered by MCMV-infected macrophages. In addition, we demonstrate that an MCMV mutant virus lacking m154 expression results in an attenuated phenotype in vivo, which can be substantially restored after NK cell depletion in mice. This is the first description of a viral gene capable of downregulating CD48. Our novel findings define m154 as an important player in MCMV innate immune regulation. PMID- 24626475 TI - Transcriptional and epigenetic regulation of KIF14 overexpression in ovarian cancer. AB - KIF14 (kinesin family member 14) is a mitotic kinesin and an important oncogene in several cancers. Tumor KIF14 expression levels are independently predictive of poor outcome, and in cancer cells KIF14 can modulate metastatic behavior by maintaining appropriate levels of cell adhesion and migration proteins at the cell membrane. Thus KIF14 is an exciting potential therapeutic target. Understanding KIF14's regulation in cancer cells is crucial to the development of effective and selective therapies to block its tumorigenic function(s). We previously determined that close to 30% of serous ovarian cancers (OvCa tumors) exhibit low-level genomic gain, indicating one mechanism of KIF14 overexpression in tumors. We now report on transcriptional and epigenetic regulation of KIF14. Through promoter deletion analyses, we identified one cis-regulatory region containing binding sites for Sp1, HSF1 and YY1. siRNA-mediated knockdown of these transcription factors demonstrated endogenous regulation of KIF14 overexpression by Sp1 and YY1, but not HSF1. ChIP experiments confirmed an enrichment of both Sp1 and YY1 binding to the endogenous KIF14 promoter in OvCa cell lines with high KIF14 expression. A strong correlation was seen in primary serous OvCa tumors between Sp1, YY1 and KIF14 expression, further evidence that these transcription factors are important players in KIF14 overexpression. Hypomethylation patterns were observed in primary serous OvCa tumors, suggesting a minor role for promoter methylation in the control of KIF14 gene expression. miRNA expression analysis determined that miR-93, miR-144 and miR-382 had significantly lower levels of expression in primary serous OvCa tumors than normal tissues; treatment of an OvCa cell line with miRNA mimics and inhibitors specifically modulated KIF14 mRNA levels, pointing to potential novel mechanisms of KIF14 overexpression in primary tumors. Our findings reveal multiple mechanisms of KIF14 upregulation in cancer cells, offering new targets for therapeutic interventions to reduce KIF14 in tumors, aiming at improved prognosis. PMID- 24626476 TI - Upland cotton gene GhFPF1 confers promotion of flowering time and shade-avoidance responses in Arabidopsis thaliana. AB - Extensive studies on floral transition in model species have revealed a network of regulatory interactions between proteins that transduce and integrate developmental and environmental signals to promote or inhibit the transition to flowering. Previous studies indicated FLOWERING PROMOTING FACTOR 1 (FPF1) gene was involved in the promotion of flowering, but the molecular mechanism was still unclear. Here, FPF1 homologous sequences were screened from diploid Gossypium raimondii L. (D-genome, n = 13) and Gossypium arboreum L. genome (A-genome, n = 13) databases. Orthologous genes from the two species were compared, suggesting that distinctions at nucleic acid and amino acid levels were not equivalent because of codon degeneracy. Six FPF1 homologous genes were identified from the cultivated allotetraploid Gossypium hirsutum L. (AD-genome, n = 26). Analysis of relative transcripts of the six genes in different tissues revealed that this gene family displayed strong tissue-specific expression. GhFPF1, encoding a 12.0 kDa protein (Accession No: KC832319) exerted more transcripts in floral apices of short-season cotton, hinting that it could be involved in floral regulation. Significantly activated APETALA 1 and suppressed FLOWERING LOCUS C expression were induced by over-expression of GhFPF1 in the Arabidopsis Columbia-0 ecotype. In addition, transgenic Arabidopsis displayed a constitutive shade-avoiding phenotype that is characterized by long hypocotyls and petioles, reduced chlorophyll content, and early flowering. We propose that GhFPF1 may be involved in flowering time control and shade-avoidance responses. PMID- 24626477 TI - Interaction of Cm(III) and Am(III) with human serum transferrin studied by time resolved laser fluorescence and EXAFS spectroscopy. AB - The complexation of Cm(III) with human serum transferrin was investigated in a pH range from 3.5 to 11.0 using time-resolved laser fluorescence spectroscopy (TRLFS). At pH >= 7.4 Cm(III) is incorporated at the Fe(III) binding site of transferrin whereas at lower pH a partially bound Cm(III) transferrin species is formed. At physiological temperature (310 K) at pH 7.4, about 70% of the partially bound and 30% of the incorporated Cm(III) transferrin species are present in solution. The Cm(III) results obtained by TRLFS are in very good agreement with Am(III) EXAFS results, confirming the incorporation of Am(III) at the Fe(III) binding site at pH 8.5. PMID- 24626478 TI - Progressive outer retinal necrosis (PORN): a catchy acronym but is the anatomy correct? The salient observation of Lorenz E. Zimmerman, MD. PMID- 24626479 TI - Genetic exchange of fimbrial alleles exemplifies the adaptive virulence strategy of Porphyromonas gingivalis. AB - Porphyromonas gingivalis is a gram-negative anaerobic bacterium, a member of the human oral microbiome, and a proposed "keystone" pathogen in the development of chronic periodontitis, an inflammatory disease of the gingiva. P. gingivalis is a genetically diverse species, and is able to exchange chromosomal DNA between strains by natural competence and conjugation. In this study, we investigate the role of horizontal DNA transfer as an adaptive process to modify behavior, using the major fimbriae as our model system, due to their critical role in mediating interactions with the host environment. We show that P. gingivalis is able to exchange fimbrial allele types I and IV into four distinct strain backgrounds via natural competence. In all recombinants, we detected a complete exchange of the entire fimA allele, and the rate of exchange varies between the different strain backgrounds. In addition, gene exchange within other regions of the fimbrial genetic locus was identified. To measure the biological implications of these allele swaps we compared three genotypes of fimA in an isogenic background, strain ATCC 33277. We demonstrate that exchange of fimbrial allele type results in profound phenotypic changes, including the quantity of fimbriae elaborated, membrane blebbing, auto-aggregation and other virulence-associated phenotypes. Replacement of the type I allele with either the type III or IV allele resulted in increased invasion of gingival fibroblast cells relative to the isogenic parent strain. While genetic variability is known to impact host-microbiome interactions, this is the first study to quantitatively assess the adaptive effect of exchanging genes within the pan genome cloud. This is significant as it presents a potential mechanism by which opportunistic pathogens may acquire the traits necessary to modify host-microbial interactions. PMID- 24626480 TI - Foodborne transmission of nipah virus in Syrian hamsters. AB - Since 2001, outbreaks of Nipah virus have occurred almost every year in Bangladesh with high case-fatality rates. Epidemiological data suggest that in Bangladesh, Nipah virus is transmitted from the natural reservoir, fruit bats, to humans via consumption of date palm sap contaminated by bats, with subsequent human-to-human transmission. To experimentally investigate this epidemiological association between drinking of date palm sap and human cases of Nipah virus infection, we determined the viability of Nipah virus (strain Bangladesh/200401066) in artificial palm sap. At 22 degrees C virus titers remained stable for at least 7 days, thus potentially allowing food-borne transmission. Next, we modeled food-borne Nipah virus infection by supplying Syrian hamsters with artificial palm sap containing Nipah virus. Drinking of 5*108 TCID50 of Nipah virus resulted in neurological disease in 5 out of 8 hamsters, indicating that food-borne transmission of Nipah virus can indeed occur. In comparison, intranasal (i.n.) inoculation with the same dose of Nipah virus resulted in lethal respiratory disease in all animals. In animals infected with Nipah virus via drinking, virus was detected in respiratory tissues rather than in the intestinal tract. Using fluorescently labeled Nipah virus particles, we showed that during drinking, a substantial amount of virus is deposited in the lungs, explaining the replication of Nipah virus in the respiratory tract of these hamsters. Besides the ability of Nipah virus to infect hamsters via the drinking route, Syrian hamsters infected via that route transmitted the virus through direct contact with naive hamsters in 2 out of 24 transmission pairs. Although these findings do not directly prove that date palm sap contaminated with Nipah virus by bats is the origin of Nipah virus outbreaks in Bangladesh, they provide the first experimental support for this hypothesis. Understanding the Nipah virus transmission cycle is essential for preventing and mitigating future outbreaks. PMID- 24626481 TI - Development of a convenient in vivo hepatotoxin assay using a transgenic zebrafish line with liver-specific DsRed expression. AB - Previously we have developed a transgenic zebrafish line (LiPan) with liver specific red fluorescent protein (DsRed) expression under the fabp10a promoter. Since red fluorescence in the liver greatly facilitates the observation of liver in live LiPan fry, we envision that the LiPan zebrafish may provide a useful tool in analyses of hepatotoxicity based on changes of liver red fluorescence intensity and size. In this study, we first tested four well-established hepatotoxins (acetaminophen, aspirin, isoniazid and phenylbutazone) in LiPan fry and demonstrated that these hepatotoxins could significantly reduce both liver red fluorescence and liver size in a dosage-dependent manner, thus the two measurable parameters could be used as indicators of hepatotoxicity. We then tested the LiPan fry with nine other chemicals including environmental toxicants and human drugs. Three (mefenamic acid, lindane, and arsenate) behave like hepatotoxins in reduction of liver red fluorescence, while three others (17beta estradiol, TCDD [2,3,7,8-tetrachlorodibenzo-p-dioxin] and NDMA [N nitrosodimethylamine]) caused increase of liver red fluorescence and the liver size. Ethanol and two other chemicals, amoxicillin (antibiotics) and chlorphenamine (pain killer) did not resulted in significant changes of liver red fluorescence and liver size. By quantitative RT-PCR analysis, we found that the changes of red fluorescence intensity caused by different chemicals correlated to the changes of endogenous fabp10a RNA expression, indicating that the measured hepatotoxicity was related to fatty acid transportation and metabolism. Finally we tested a mixture of four hepatotoxins and observed a significant reduction of red fluorescence in the liver at concentrations below the lowest effective concentrations of individual hepatotoxins, suggesting that the transgenic zebrafish assay is capable of reporting compound hepatotoxicity effect from chemical mixtures. Thus, the LiPan transgenic fry provide a rapid and convenient in vivo hepatotoxicity assay that should be applicable to high-throughput hepatotoxicity test in drug screening as well as in biomonitoring environmental toxicants. PMID- 24626483 TI - A homoleptic eta2 hydroxylaminato Ce(IV) complex with S4 symmetry. AB - An electron rich, air-stable hydroxylamine ligand and a strongly stabilized cerium(IV) hydroxylaminato complex are described. The synthesis of Ce[eta(2) ON((t)Bu)(2-OMe-5-(t)Bu-C6H3)]4 (1) proceeded through a one pot protonolysis and oxidation procedure. Complex 1 crystallized with the molecule in exact S4 symmetry. The hydroxylaminato ligands were bound in an eta(2) mode that is of interest for potential application in the separations chemistry of rare earth metals. PMID- 24626484 TI - Monoamine oxidase inhibitors: promising therapeutic agents for Alzheimer's disease (Review). AB - Activated monoamine oxidase (MAO) has a critical role in the pathogenesis of Alzheimer's disease (AD), including the formation of amyloid plaques from amyloid beta peptide (Abeta) production and accumulation, formation of neurofibrillary tangles, and cognitive impairment via the destruction of cholinergic neurons and disorder of the cholinergic system. Several studies have indicated that MAO inhibitors improve cognitive deficits and reverse Abeta pathology by modulating proteolytic cleavage of amyloid precursor protein and decreasing Abeta protein fragments. Thus, MAO inhibitors may be considered as promising therapeutic agents for AD. PMID- 24626482 TI - DNA and protein co-immunization improves the magnitude and longevity of humoral immune responses in macaques. AB - We tested the concept of combining DNA with protein to improve anti-HIV Env systemic and mucosal humoral immune responses. Rhesus macaques were vaccinated with DNA, DNA&protein co-immunization or DNA prime followed by protein boost, and the magnitude and mucosal dissemination of the antibody responses were monitored in both plasma and mucosal secretions. We achieved induction of robust humoral responses by optimized DNA vaccination delivered by in vivo electroporation. These responses were greatly increased upon administration of a protein boost. Importantly, a co-immunization regimen of DNA&protein injected in the same muscle at the same time induced the highest systemic binding and neutralizing antibodies to homologous or heterologous Env as well as the highest Env-specific IgG in saliva. Inclusion of protein in the vaccine resulted in more immunized animals with Env-specific IgG in rectal fluids. Inclusion of DNA in the vaccine significantly increased the longevity of systemic humoral immune responses, whereas protein immunization, either as the only vaccine component or as boost after DNA prime, was followed by a great decline of humoral immune responses overtime. We conclude that DNA&protein co-delivery in a simple vaccine regimen combines the strength of each vaccine component, resulting in improved magnitude, extended longevity and increased mucosal dissemination of the induced antibodies in immunized rhesus macaques. PMID- 24626486 TI - Identification of isoafricanol and its terpene cyclase in Streptomyces violaceusniger using CLSA-NMR. AB - The recently developed CLSA-NMR technique that is based on feeding experiments with (13)C-labelled precursors was applied in the identification of isoafricanol as the main volatile terpene emitted by Streptomyces violaceusniger. The isoafricanol synthase of this organism is presented, together with a recent phylogenetic analysis of bacterial terpene cyclases. PMID- 24626487 TI - [Institutionalization of Public Health Care in Sao Paulo between 1930 and 1940]. AB - The aim of the study was to interpret and understand the institutionalization of public health care in the state of Sao Paulo over the years 1930-1940, based on the history of medical specialties. The methodology involved analysis of new sources of documents, which were compared with the existing literature, thereby leading to identification of new indices relating to the issue of eugenics and the presence of physicians' religious beliefs as a social movement. As physicians became public health experts, they proposed a project to elevate the Brazilian race, by merging the hygienist discourse with sanitary actions. Sao Paulo sought primacy in this project, believing that this was a State already constituted by a race of "historically healthy men". Religious beliefs influenced the debate and the decisions of that time with regard to the established order within public health. In this manner, it could be shown that, historically, public health discourse was constituted by merging technical-scientific issues with political ideological and cultural issues, producing a mixture of different interests and corporative perspectives of the profession. PMID- 24626488 TI - [Perinatal mortality in the municipality of Salvador, Northeastern Brazil: evolution from 2000 to 2009]. AB - OBJECTIVE: To describe and analyze the evolution of perinatal mortality with regards the scale and extent of the problem. METHODS: A descriptive time trend study with 10,994 perinatal deaths to mothers living in Salvador, Bahia, Northeastern Brazil, with a gestational age of >= 22 weeks, newborn age of up to six days and birth weight of 500 grams or more, recorded from 2000 to 2009. Data from the Information Systems on Live Births and Mortality of DATASUS/Ministry of Health available on the website were used. Rates of perinatal and fetal mortality per 1,000 births and early neonatal mortality per 1,000 live births were calculated. The Pearson's Qui-square test for differences in proportions, sequence (runs) test, the calculation of moving averages and linear coefficient of determination (R2) were used for trend analysis. The Wigglesworth classification of causes of death was used. RESULTS: The rates of perinatal mortality showed a decreasing trend, of -42.0% in the period (from 33.1 (2000) to 19.2 (2009)), with a greater share of rates of neonatal mortality (-56.3%). Fetal mortality accounted for a large proportion (61.9%) of rates of perinatal mortality in 2009. The classification of deaths showed the following most frequent causes of perinatal deaths: intrapartum asphyxia (8.8/1,000), immaturity (7.1/1,000) and congenital malformations (1.3/1,000). CONCLUSIONS : Perinatal mortality remains high despite the downward trend, and the predominance of fetal mortality indicates recent changes in the profile of causes of death and impact on prevention activities. The quality of prenatal care with risk control and improving care during the delivery may reduce the occurrence of preventable causes of death. PMID- 24626489 TI - [Social inequalities and tuberculosis: an analysis by race/color in Mato Grosso do Sul, Brazil]. AB - OBJECTIVE: To describe the sociodemographic and clinical-epidemiological characteristics of tuberculosis cases and identify associated factors with abandoning treatment and death whilst undergoing treatment. METHODS: Epidemiological study based on cases of tuberculosis recorded in indigenous and non-indigenous individuals according to race/color in Mato Grosso do Sul, Midwestern Brazil, between 2001 and 2009. Descriptive analysis of the cases was carried out according to the variables of sex, age group, residence, type of test used in the diagnosis, clinical form, supervised treatment and final status, according to race/color. Univariate/multivariate logistic regression analyses were used to identify predictors of abandoning treatment and death, using odds ratio as a measure of association. A time series of incidence according to race/color was constructed. RESULTS: In the period, 6,962 new cases of tuberculosis were registered, 15.6% being among indigenous. The illness was predominantly found in men and adults (20-44 years old) in all groups. Most of the indigenous patients lived in rural areas (79.8%) and 13.5% of the records in indigenous occurred in children aged < 10 years. The average incidence in the state was 34.5/100,000 inhabitants, being 209.0, 73.1, 52.7, 23.0 and 22.4 in indigenous, and those with yellow, black, white and brown skin, respectively. Patients aged 20 to 44 years (OR = 13.3, 95%CI 1.9;96.8), male (OR = 1.6, 95%CI 1.1;2.3) and of black race/color (OR = 2.5, 95%CI 1.0;6.3) were associated with abandoning treatment, while patients aged > 45 years (OR = 3.0, 95%CI 1.2;7.8) and with the mixed form (OR = 2.3, 95%CI 1.1;5.0) showed association with death. Although they only account for 3.0% of the population, the indigenous were responsible for 15.6% of cases recorded during the period. CONCLUSIONS: Major inequalities in the tuberculosis illness process were found between the categories studied. Incidence in the indigenous population was consistently higher than recorded in any other group, reaching more than six times the national average. It was among those with black and brown skin that the worst treatment results were observed, as they were twice as likely to abandon treatment as the indigenous. Poor program performance was strongly associated with abandoning treatment and death. It is thought that as long as there is no reduction in poverty inequalities in health indicators will remain. PMID- 24626490 TI - Direct treatment costs of HIV/AIDS in Portugal. AB - OBJECTIVE: To analyze the direct medical costs of HIV/AIDS in Portugal from the perspective of the National Health Service. METHODS: A retrospective analysis of medical records was conducted for 150 patients from five specialized centers in Portugal in 2008. Data on utilization of medical resources during 12 months and patients' characteristics were collected. A unit cost was applied to each care component using official sources and accounting data from National Health Service hospitals. RESULTS: The average cost of treatment was 14,277 ?/patient/year. The main cost-driver was antiretroviral treatment (? 9,598), followed by hospitalization costs (? 1,323). Treatment costs increased with the severity of disease from ? 11,901 (> 500 CD4 cells/ul) to ? 23,351 (CD4 count <= 50 cells/ ul). Cost progression was mainly due to the increase in hospitalization costs, while antiretroviral treatment costs remained stable over disease stages. CONCLUSIONS: The high burden related to antiretroviral treatment is counterbalanced by relatively low hospitalization costs, which, however, increase with severity of disease. The relatively modest progression of total costs highlights that alternative public health strategies that do not affect transmission of disease may only have a limited impact on expenditure, since treatment costs are largely dominated by constant antiretroviral treatment costs. PMID- 24626491 TI - The AIDS epidemic in the Amazon region: a spatial case-control study in Rondonia, Brazil. AB - OBJECTIVE: To analyze spatial changes in the risk of AIDS and the relationship between AIDS incidence and socioeconomic variables in the state of Rondonia, Amazon region. METHODS: A spatial, population case-control study in Rondonia, Brazil, based on 1,780 cases reported to the Epidemiological Surveillance System and controls based on demographic data from 1987 to 2006. The cases were grouped into five consecutive four-year periods. A generalized additive model was adjusted to the data; the dependent variable was the status of the individuals (case or control), and the independent variables were a bi-dimensional spline of the geographic coordinates and some municipality-level socioeconomic variables. The observed values of the Moran's I test were compared to a reference distribution of values generated under conditions of spatial randomness. RESULTS: AIDS risk shows a marked spatial and temporal pattern. The disease incidence is related to socioeconomic variables at the municipal level in Rondonia, such as urbanization and human capital. The highest incidence rates of AIDS are in municipalities along the BR-364 highway and calculations of the Moran's I test show positive spatial correlation associated with proximity of the municipality to the highway in the third and fourth periods (p = 0.05). CONCLUSIONS: Incidence of the disease is higher in municipalities of greater economic wealth and urbanization, and in those municipalities bisected by Rondonia's main roads. The rapid development associated with the opening up of once remote regions may be accompanied by an increase in these risks to health. PMID- 24626493 TI - Seroprevalence of Toxoplasma gondii IgG antibody in HIV/AIDS-infected individuals in Maputo, Mozambique. AB - OBJECTIVE: To analyze the prevalence of IgG antibodies to Toxoplasma gondii in patients infected with HIV/AIDS and the association of demographic and social variables. METHODS: Descriptive cross-sectional study that included the analysis of sociodemographic data and laboratory findings of 200 patients infected with HIV/AIDS treated in a laboratory unit in Maputo, Mozambique, in 2010. Individual data for all participants were collected with a self-administered questionnaire. Plasma samples were tested for IgG testing of anti- T. gondii using hemagglutination for the analysis of antibodies. RESULTS: The seroprevalence of IgG anti- T. gondii was 46.0% (95%CI 39.2;52.9), 39.3% (95%CI 29.5;50.0) in men and 50.9% (95%CI 41.9;59.8) in women, with no difference between sex (OR 1.30; 95%CI 0.95;1.77; p = 0.12). Ages ranged from 10 to 60 years, with a higher prevalence of infection in older age groups, but with no significant difference between them. Regularly consuming cattle meat (OR 1.74; 95%CI 1.04;2.89, p = 0.05), breeding cats/dogs (OR 6.18; 95%CI 3.60;10.62, p < 0.000) and having regular contact with soil (OR 3.38; 95%CI 2.19;5.21; p < 0.000) were significantly associated with risk of latent infection. CONCLUSIONS: Toxoplasmosis is an infection with high prevalence in Mozambique. Cultural and behavioral aspects increase the risk. Toxoplasmosis can be responsible in our environment by the great burden of morbidity and mortality associated with meningoencephalic injuries in patients with HIV/AIDS. PMID- 24626492 TI - [Yellow fever: reemerging in the state of Sao Paulo, Brazil, 2009]. AB - OBJECTIVE: To describe the investigation of a sylvatic yellow fever outbreak in the state of Sao Paulo and the main control measures undertaken. METHODS: This is a descriptive study of a sylvatic yellow fever outbreak in the Southwestern region of the state from February to April 2009. Suspected and confirmed cases in humans and in non-human primates were evaluated. Entomological investigation in sylvatic environment involved capture at ground level and in the tree canopy to identify species and detect natural infections. Control measures were performed in urban areas to control Aedes aegypti . Vaccination was directed at residents living in areas with confirmed viral circulation and also at nearby cities according to national recommendation. RESULTS: Twenty-eight human cases were confirmed (39.3% case fatality rate) in rural areas of Sarutaia, Piraju, Tejupa, Avare and Buri. The deaths of 56 non-human primates were also reported, 91.4% were Allouatta sp. Epizootics was confirmed in two non-human primates in the cities of Itapetininga and Buri. A total of 1,782 mosquitoes were collected, including Haemagogus leucocelaenus , Hg. janthinomys/capricornii , and Sabethes chloropterus, Sa. purpureus and Sa. undosus . Yellow fever virus was isolated from a group of Hg. Leucocelaenus from Buri. Vaccination was carried out in 49 cities, with a total of 1,018,705 doses. Nine serious post-vaccination adverse events were reported. CONCLUSIONS: The cases occurred between February and April 2009 in areas with no recorded yellow fever virus circulation in over 60 years. The outbreak region occurred outside the original recommended vaccination area with a high percentage of susceptible population. The fast adoption of control measures interrupted the human transmission within a month and the confirmation of viral circulation in humans, monkeys and mosquitoes. The results allowed the identification of new areas of viral circulation but further studies are required to clarify the dynamics of the spread of this disease. PMID- 24626494 TI - [Smoking and occupational stressors in firefighters, 2011]. AB - OBJECTIVE: To analyze the prevalence of smoking in firefighters and associated factors. METHODS: Cross sectional study of 711 firefighters in Belo Horizonte, MG, Southeastern Brazil, in 2011. The data were obtained using a self-applied structured questionnaire, which included sociodemographic characteristics, occupational stressors, health status and adverse life events. Smoking was analyzed as a dichotomous variable (multiple logistic regression). RESULTS: The prevalence of smoking among firefighters was 7.6%. Currently smoking status was associated with low levels of schooling, a monthly income in the middle band, the existence of psychiatric problems in the past, high exposure to traumatic events in life, social discrimination, occupational stressors and low demand at work. CONCLUSIONS: The low prevalence of smoking indicates the relevance of employment conditions in explaining harmful habits and health. Organizational and operational stressors contribute independently to explaining current smoking status in the population studied. PMID- 24626495 TI - [Medication use by the quilombola population: a survey in Southwestern Bahia, Brazil]. AB - OBJECTIVE: To characterize the medication use by the quilombola population. METHODS: A population-based cross-sectional study was conducted with 797 adult quilombola in Vitoria da Conquista, BA, Northeastern Brazil, in 2011. Analysis of variance was used to compare means of drugs by subject, according to demographic, socioeconomic and health-related behavior variables. Prevalence, prevalence ratios and their 95% confidence intervals were estimated. Multivariate analysis was carried out using Poisson regression with robust variance. RESULTS: The most widely consumed drugs by the population were those for the cardiovascular and nervous systems. Prevalence of medication use was 41.9%, significantly higher among women (50.3%) than men (31.9%). After adjusted analysis, medication use was associated with being female gender, being aged 60 or older, higher economic level, worse self-rated health, greater number of self-reported diseases and number of medical appointments. CONCLUSIONS: Strategies to improve rational drug use should preferentially focus on women and older adults. Thus, special attention should be given to promote rational prescription in everyday health services. PMID- 24626496 TI - [Association of chronic pain with the use of health care services by older adults in Sao Paulo]. AB - OBJECTIVE: Evaluate the association between use of health care services by older adults with chronic pain and sociodemographic and health variables. METHODS: Cross-sectional study whose population sample of 1,271 older adults with chronic pain and with no cognitive deficit was obtained through home surveys in Sao Paulo, SP, Southeastern Brazil,, in 2006. The study considered pain lasting for six or more months as chronic. The criterion for health care service use was more than four doctor appointments or having been admitted to a hospital during the past year. For those in chronic pain for at least one year, the existence of an association between the use of health care services and independent variables (pain and socio-demographical characteristics and self-reported morbidities) was tested using univariate (RaoScott test of association) and multivariate analysis (Cox Multiple Regression with robust variance). Stata 11.0 was used for the statistical analysis, and the significance level adopted was p < 0.05. RESULTS: The prevalence of health care service use among older people with pain was 48,0% (95%CI 35.1;52.8) and did not differ from older adults without chronic pain (50.5%, 95%CI 45.1;55.9). The multivariate analysis showed that the chance of using health care services was 33,0% lower for older adults with pain for more than two years than those with pain between one and two years (p = 0.002). The chance was 55,0% higher for those with intense pain (p = 0.003) and 45,0% higher for those with moderate pain interference in the work (p = 0.015). CONCLUSIONS: Chronic pain was found to be common and was associated with negative effects on independence and mobility. More intense and recent chronic pain that affected work resulted in greater use of health care services. PMID- 24626497 TI - [Cognitive performance and frailty in older adults clients of a private health care plan]. AB - OBJECTIVE: To investigate the association between frailty syndrome and cognitive performance in the older adults and the effect of schooling and age on this association. METHODS: Data on frailty in older adults from Phase 1 of the FIBRA RJ Study were analyzed, relating to 737 customers of a private health care provider, aged 65 and over, living in Rio de Janeiro, Southeastern Brazil, between January 2009 and January 2010. Data on socioeconomic and demographic characteristics, medical conditions and functional capacity were collected. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Individuals who exhibited three or more of the following features were considered to be frail: unintentional weight loss (>= 4.5 kg in the last year); feeling self-reported exhaustion, low grip strength, low physical activity level and slowness. The association between frailty and cognitive performance was evaluated using multivariate logistic regression, with adjustment for medical conditions, activities of daily living and socioeconomic variables. We evaluated the age and schooling as possible effect modifiers in this association. RESULTS: The frail subjects had a higher prevalence of low cognitive performance, compared to not frail or pre-frail, in the three age groups studied (65-74; 75-84; >= 85 years), p < 0.001. After adjustment, the association between frailty and cognitive performance was found among older adults individuals aged 75 and older, with an OR(adj)= 2.78 (95%CI 1.23;6.27) for those aged 75 to 84 and OR(adj)= 15.62 (95%CI 2.20;110.99) for 85 and older. The age variable was an effect modifier in the association between frailty and cognitive performance, chi2(5) = 806.97, p < 0.0001; the same was not the case with schooling. CONCLUSIONS: Frailty syndrome is associated with cognitive performance in the aging. Age proved to be an effect modifier in this association. The oldest patients showed a more significant association between the two phenomena. PMID- 24626498 TI - [Motorcycle accident mortality time trends in Brazil, 1996-2009]. AB - OBJECTIVE: To analyze motorcycle accidents mortality trends in Brazil. METHODS: A descriptive time series study of mortality from motorcycle accidents in Brazil between 1996 and 2009 according to state and age group. The data on mortality were obtained from the National Mortality Information System of Ministry of Health and the population data from the Brazilian Institute of Geography and Statistics. Standardized mortality rates were calculated for the entire period for the country as a whole and for each state. Annual variability in mortality rates was estimated using Prais-Winsten generalized linear correlation. RESULTS: Between 1996 and 2009 the mortality rate increased from 0.5 to 4.5 per 100.000 habitants (an increase of 800.0% in mortality rates during the period studied and an average annual increase of 19.0%). High mortality rates in 2009 were observed in the states of Piaui, Sergipe and Mato Grosso. The largest increases were observed in states in the North, Northeast and Midwest of Brazil. CONCLUSIONS: There was a significant increase in motorcycle accident mortality rates for the country as a whole during the studied period, mainly in states in the Northeast. PMID- 24626499 TI - [Social mobility, lifestyle and body mass index in adolescents]. AB - OBJECTIVE: To analyze the association between social mobility, lifestyle and body mass index in adolescents. METHODS: A cohort study of 1,716 adolescents aged 10 to 17 years of both sexes. The adolescents were participants in a cohort study and were born between 1994 and 1999. The adolescents, from public and private schools, were assessed between 2009 and 2011. Lifestyle was assessed by interview and anthropometry was used to calculatebody mass index. For the economic classification, both at pre-school age and in adolescence, the criteria recommended by the Brazilian Association of Research Companies were used. Upward social mobility was categorized as an increase by at least one class in economic status within a 10-year-period. Poisson regression was used to estimate the association between upward social mobility and the outcomes assessed. RESULTS: Among all respondents (71.4% follow-up of the cohort), 60.6% had upward social mobility. Among these, 93.6% belonged to socioeconomic class D and 99.9% to economy class E. Higher prevalence of social mobility was observed for students with black skin (71.4%) and mulatto students (61.9%) enrolled in public schools (64.3%) whose mothers had less schooling in the first evaluation (67.2%) and revaluation (68.7%). After adjustment for confounding variables, upward social mobility was associated only with sedentary behavior (p = 0.02). The socioeconomic class in childhood was more associated with the outcomes assessed than was upward mobility. CONCLUSIONS: Upward social mobility was not associated with most of the outcomes evaluated, possibly as it is discreet and because the period considered in the study may not have been sufficient to reflect substantial changes in lifestyle and body mass index in adolescents. PMID- 24626500 TI - [Evaluation of the safety of different doses of folic acid supplements in women in Brazil]. AB - OBJECTIVE: To evaluate the distribution of folic acid intake and the safety of different doses of supplements in women of childbearing age. METHODS: Data were used from two non-consecutive days of food records of 6,837 women of childbearing age (19-40 years old) participants of the National Food Survey, a module of the Household Budget Survey 2008-2009. Means and percentiles of usual consumption of natural folate and folic acid were estimated using the National Cancer Institute method. Five scenarios were simulated by adding different daily doses of fortification (400 mcg, 500 mcg, 600 mcg, 700 mcg and 800 mcg) to folic acid derived from food consumed by the women. To define a safe dose of the supplement, the total folate (dietary + supplement) was compared with the tolerable upper intake level (UL = 1,000 mcg). RESULTS: Women with usual intake of folic acid above the tolerable upper intake levels were observed only for doses of supplement of 800 mcg (7.0% of women). Below this value, any dose of the supplement was safe. CONCLUSIONS: The use of supplements of up to 700 mcg of folic acid was shown to be safe. PMID- 24626501 TI - [Physical activity in pregnant women receiving care in primary health care units]. AB - OBJECTIVE: To describe physical-activity patterns of low-risk pregnant women and investigate associated factors. METHODS: This is a cross-sectional study based on a sample (n = 256) of adult pregnant women in their 2nd trimester. The participants were randomly selected among those attending primary health care units in Botucatu in Sao Paulo State in 2010. Physical activities were investigated by using the pregnancy physical activity questionnaire and by analyzing the time and intensity of the following activities: occupational, commuting, household and leisure, expressed in metabolic equivalents/day. The pregnant women were classified according to their level of physical activity and to achieving 150 minutes/week of leisure physical activities, which were the dependent variables in the study. The association between such variables and socioeconomic variables, maternal characteristics, behavioral factors and the care model in the health care unit was evaluated by Poisson regression models with robust variance and by adopting the hierarchical model. RESULTS: Most pregnant women were insufficiently active (77.7%); 12.5% were moderately active and 9.8% were vigorously active. The highest daily energy expenditure was in carrying out household activities, followed by commuting activities. Only 10.2% of them followed the recommendation, successfully achieving 150 minutes of leisure physical activities per week. Having a job outside of the home reduced the chance of achieving such recommendation (OR = 0.39, 95%CI 0.16;0.93). Having at least one previous delivery (OR = 0.87, 95%CI 0.77;0.99) and being overweight pre-pregnancy (OR = 0.85, 95%CI 0.731;0.99) reduced the chance of being insufficiently active whereas consuming healthy foods less frequently slightly increased it: OR = 1.18, 95%CI 1.02;1.36. CONCLUSIONS: Pregnant women who were cared for in primary health care units were insufficiently active. Having at least one previous delivery and being overweight pre-pregnancy were identified as protective factors against such condition. Less frequent intake of healthy foods was found to be a risk factor, therefore suggesting a cluster of health risk factors. PMID- 24626502 TI - [Study of the work and of working in Family Health Care Support Center]. AB - OBJECTIVE: To understand the organization of and the working conditions in family health care support centers, as well as subjective experiences related to work in two of these centers. METHODS: This was a case study carried out during 2011 and 2012 in two family health care support centers in Sao Paulo, Southeastern Brazil. Data were collected and analyzed using two theoretical-methodological references from ergonomics and work psychodynamics influenced, respectively, by ergonomic work analysis, developed based on open observations of a variety of tasks and on interviews and in practice in work psychodynamics, carried out using think tanks about the work. RESULTS: The work of the Family Health Care Support Centers in question is constituted on the bases of complex, diversified actions to be shared among the various professionals and teams involved. Innovative technological tools, which are not often adopted by primary health care professionals, are used and the parameters and productivity measures do not encompass the specificity and the complexity of the work performed. These situations require constant organizational rearrangement, especially between the Family Health Care Support Centers and the Family Health Care Teams, causing difficulties in carrying out the work as well as in constituting the identity of the professionals studied. CONCLUSIONS: The study attempts to lend greater visibility to the work processes at the Family Health Care Support Centers in order to contribute to advances in public policy on primary healthcare. It is important to stress that introducing changes at work, which affect both its organization and work conditions, is above all a commitment, which to be effective, must be permanent and must involve the different levels of hierarchy. PMID- 24626503 TI - [Budget impact of using the Kangaroo Method in neonatal care]. AB - OBJECTIVE: To estimate the budget impact of using the Kangaroo Method in a municipal health care network. METHODS: An analytical decision model was developed to simulate the costs of the Kangaroo Method and Neonatal Intermediate Care Unit in Rio de Janeiro, RJ, in 2011. The reference population was clinically stable newborns, who may receive either of the two types of care. The budget impact for a hypothetical cohort of 1,000 eligible newborns was estimated for one year. The proportion of eligible infants receiving the two type of care was obtained through data collection in hospitals included in the study. The probabilities of events and resource consumption of health care in the period were incorporated into the model. A scenario analysis was developed to reflect the adoption of the Kangaroo Method on a greater or smaller scale. RESULTS: The use of the second and third stage of Kangaroo Method means a cost reduction of R$ 1,085,379.64 (16.0%) in a year if all eligible infants were assisted in Kangaroo Method. CONCLUSIONS: The Kangaroo Method options costs less than the Neonatal Intermediate Care Unit. The analysis of the budget impact of this method on the public health care system showed significant savings in the year long period analyzed. PMID- 24626504 TI - Modern epidemiology and its discontents. AB - The goal of this article is to present a snapshot of an ongoing debate within epidemiology, pitching opposing sides in the struggle to define the path it should follow in the years to come. The debate among epidemiologists in the mid 90s pitted those who defended the idea that epidemiology should necessarily deal with a wide context against those who believed that science and public health are better served by focusing on the individual level. Ian Hacking's concept of styles of reasoning was used as a theoretical tool. The literature was reviewed using a core set of articles as an entry point, seeking articles that cited them, and then back-tracking the citations of the resulting set in the Scopus database. The main arguments are presented according to levels (ontological, epistemological, axiological and pragmatic), in order to show an even deeper disagreement, in the very conception of science and its relation to social issues and public policy. PMID- 24626505 TI - [Prevalence of preterm birth according to birth weight group: a systematic review]. AB - OBJECTIVE: To estimate the prevalence of preterm birth by categories of birth weight, and to obtain an equation to correct the estimates. METHODS: Systematic review of the Brazilian literature published from 1990 to 2012, to identify studies with primary collection of data on birth weight and gestational age. Twelve studies were selected and contributed for tabulations of preterm prevalence according to 100 g birth weight categories. These results were combined using sex-specific fractional polynomial equations and the resulting curves were compared with results from the Live Birth Information System for the years 2000, 2005, 2010 and 2011. RESULTS: For all birth weight categories, preterm prevalence estimates based on primary studies had a higher prevalence than those of the the Live Birth Information System. The prevalence reported by the Live Birth Information System was of 7.2% in 2010, about 38.0% lower than the estimated prevalence of 11.7% obtained with the correctional equation. CONCLUSIONS: Information reported by the Live Birth Information System on preterm prevalence does not reflect the true magnitude of the problem in Brazil, and should not be used without the correction factors proposed in the present analyses. PMID- 24626506 TI - Attention performance among Brazilian truck drivers and its association with amphetamine use: pilot study. AB - The aim of this article was to describe the attention functioning of twenty-two truck drivers and its relationship with amphetamine use. Those drivers who reported using amphetamines in the twelve months previous to the interview had the best performance in a test evaluating sustained attention functioning. Although amphetamine use may initially seem advantageous to the drivers, it may actually impair safe driving. The findings suggest the importance of monitoring the laws regarding amphetamine use in this country. PMID- 24626507 TI - Advertising of ultra-processed foods and beverages: children as a vulnerable population. AB - The rapid nutrition transition occurring in Latin America has resulted in a sharp increase of childhood overweight and obesity. Recent evidence has shown that food and beverage advertising has a great influence on children's eating behavior. This population has become a key target market for the ultra-processed foods and beverages industry, which is marketing products in an aggressive way. Evidence shows that Latin American countries have poor regulation of ultra-processed foods and beverages advertising, where the discourse of self-regulation still prevails over statutory regulations. The following commentary explores how advertising might play an important role in developing unhealthy dietary patterns and obesity in Latin American children, as well as the urgent need for government action and the involvement of civil society to tackle this public health issue. PMID- 24626508 TI - [Discussion of public health and decriminalization of doping]. AB - These reflections aim to increase awareness of the contradictions inherent in the definition of sport and its relation to health and education. Taking the doping issue as a point of departure, we seek to open a general debate regarding the impact of the sports performance industry on public health. Illegal doping practices lead to the health insecurity of many professional and aspiring athletes, and, moreover, to the ethical disorientation of sports amateurs and educators. We therefore consider the necessity of discussing a possible decriminalization of doping in professional sports. PMID- 24626509 TI - [Anti-doping control and public health: limits to the exposure of human health to risk in the name of sporting glory]. AB - Given the current regulatory environment surrounding doping in the world, and in view of the recurring scandals linking leading athletes in a variety of sports with doping, this paper aims to provide some thoughts on the relationship between doping and public health, taking as base reference the risks doping poses to health and considering the regulatory options that have been adopted by the international community and the sports federations to control and supervise this unsporting and risky practice. The text seeks to reflect on the necessary balance between sport and health, as well as on the role of the state in preserving this balance. PMID- 24626510 TI - Adaptive gene amplification as an intermediate step in the expansion of virus host range. AB - The majority of recently emerging infectious diseases in humans is due to cross species pathogen transmissions from animals. To establish a productive infection in new host species, viruses must overcome barriers to replication mediated by diverse and rapidly evolving host restriction factors such as protein kinase R (PKR). Many viral antagonists of these restriction factors are species specific. For example, the rhesus cytomegalovirus PKR antagonist, RhTRS1, inhibits PKR in some African green monkey (AGM) cells, but does not inhibit human or rhesus macaque PKR. To model the evolutionary changes necessary for cross-species transmission, we generated a recombinant vaccinia virus that expresses RhTRS1 in a strain that lacks PKR inhibitors E3L and K3L (VVDeltaEDeltaK+RhTRS1). Serially passaging VVDeltaEDeltaK+RhTRS1 in minimally-permissive AGM cells increased viral replication 10- to 100-fold. Notably, adaptation in these AGM cells also improved virus replication 1000- to 10,000-fold in human and rhesus cells. Genetic analyses including deep sequencing revealed amplification of the rhtrs1 locus in the adapted viruses. Supplying additional rhtrs1 in trans confirmed that amplification alone was sufficient to improve VVDeltaEDeltaK+RhTRS1 replication. Viruses with amplified rhtrs1 completely blocked AGM PKR, but only partially blocked human PKR, consistent with the replication properties of these viruses in AGM and human cells. Finally, in contrast to AGM-adapted viruses, which could be serially propagated in human cells, VVDeltaEDeltaK+RhTRS1 yielded no progeny virus after only three passages in human cells. Thus, rhtrs1 amplification in a minimally permissive intermediate host was a necessary step, enabling expansion of the virus range to previously nonpermissive hosts. These data support the hypothesis that amplification of a weak viral antagonist may be a general evolutionary mechanism to permit replication in otherwise resistant host species, providing a molecular foothold that could enable further adaptations necessary for efficient replication in the new host. PMID- 24626511 TI - How molecular motors work in the crowded environment of living cells: coexistence and efficiency of normal and anomalous transport. AB - Recent experiments reveal both passive subdiffusion of various nanoparticles and anomalous active transport of such particles by molecular motors in the molecularly crowded environment of living biological cells. Passive and active microrheology reveals that the origin of this anomalous dynamics is due to the viscoelasticity of the intracellular fluid. How do molecular motors perform in such a highly viscous, dissipative environment? Can we explain the observed co existence of the anomalous transport of relatively large particles of 100 to 500 nm in size by kinesin motors with the normal transport of smaller particles by the same molecular motors? What is the efficiency of molecular motors in the anomalous transport regime? Here we answer these seemingly conflicting questions and consistently explain experimental findings in a generalization of the well known continuous diffusion model for molecular motors with two conformational states in which viscoelastic effects are included. PMID- 24626512 TI - From the economics of TAVI and the pathophysiology of heart and vessel disease to metabolic disease in Africa and the developing world. PMID- 24626513 TI - Vascular calcification is not associated with increased ambulatory central aortic systolic pressure in prevalent dialysis patients. AB - INTRODUCTION: Central aortic systolic pressure (CASP) strongly predicts cardiovascular outcomes. We undertook to measure ambulatory CASP in 74 prevalent dialysis patients using the BPro (HealthStats, Singapore) device. We also determined whether coronary or abdominal aortic calcification was associated with changes in CASP and whether interdialytic CASP predicted ambulatory measurement. METHODS: All patients underwent computed tomography for coronary calcium score, lateral abdominal radiography for aortic calcium score, echocardiography for left ventricular mass index and ambulatory blood pressure measurement using BPro calibrated to brachial blood pressure. HealthStats was able to convert standard BPro SOFT((r)) data into ambulatory CASP. RESULTS: Ambulatory CASP was not different in those without and with coronary (137.6 vs 141.8 mmHg, respectively, p = 0.6) or aortic (136.6 vs 145.6 mmHg, respectively, p = 0.2) calcification. Furthermore, when expressed as a percentage of brachial systolic blood pressure to control for peripheral blood pressure, any difference in CASP was abolished: CASP: brachial systolic blood pressure ratio = 0.9 across all categories regardless of the presence of coronary or aortic calcification (p = 0.2 and 0.4, respectively). Supporting this finding, left ventricular mass index was also not different in those with or without vascular calcification (p = 0.7 and 0.8 for coronary and aortic calcification). Inter-dialytic office blood pressure and CASP correlated excellently with ambulatory measurements (r = 0.9 for both). CONCLUSION: Vascular calcification was not associated with changes in ambulatory central aortic systolic pressure in this cohort of prevalent dialysis patients. Inter-dialytic blood pressure and CASP correlated very well with ambulatory measurement. PMID- 24626514 TI - Non-compaction is not a simple genetic disorder. PMID- 24626515 TI - Atrial electromechanical coupling intervals in pregnant subjects. AB - OBJECTIVE: The aim of this study was to evaluate atrial conduction abnormalities obtained by tissue Doppler imaging (TDI) and electrocardiogram analysis in pregnant subjects. METHODS: A total of 30 pregnant subjects (28 +/- 4 years) and 30 controls (28 +/- 3 years) were included. Systolic and diastolic left ventricular (LV) function was measured using conventional echocardiography and TDI. Inter-atrial, intraatrial and intra-left atrial electromechanical coupling (PA) intervals were measured with TDI. P-wave dispersion (PD) was calculated from a 12-lead electrocardiogram. RESULTS: Atrial electromechanical coupling at the septal and left lateral mitral annulus (PA septal, PA lateral) was significantly prolonged in pregnant subjects (62.1 +/- 2.7 vs 55.3 +/-3.2 ms, p < 0.001; 45.7 +/- 2.5 vs 43.1 +/- 2.7 ms, p < 0.001, respectively). Inter-atrial (PA lateral - PA tricuspid), intra-atrial (PA septum - PA tricuspid) and intra-left atrial (PA lateral - PA septum) electromechanical coupling intervals, maximum P-wave (Pmax) duration and PD were significantly longer in the pregnant subjects (26.4 +/- 4.0 vs 20.2 +/- 3.6 ms, p < 0.001; 10.0 +/- 2.0 vs 8.0 +/- 2.6 ms, p = 0.002; 16.4 +/ 3.3 vs 12.2 +/- 3.0 ms, p < 0.001; 103.1 +/- 5.4 vs 96.8 +/- 7.4 ms, p +/- 0.001; 50.7 +/- 6.8 vs 41.6 +/- 5.5 ms, p < 0.001, respectively). We found a significant positive correlation between inter-atrial and intraleft atrial electromechanical coupling intervals and Pmax (r = 0.282, p = 0.029, r = 0.378, p = 0.003, respectively). CONCLUSION: This study showed that atrial electromechanical coupling intervals and PD, which are predictors of AF, were longer in pregnant subjects and this may cause an increased risk of AF in pregnancy. PMID- 24626516 TI - An analysis of real-world cost-effectiveness of TAVI in South Africa. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) has become the standard of care for inoperable patients with severe aortic stenosis and is an alternative to conventional surgery for high-risk aortic valve replacement (AVR) patients. There is a positive correlation between severity of pre-operative patients and hospital costs. The aim of this study was to compare empirically derived costs of the two therapies in South Africa. METHODS: The cost-comparison analysis was performed with a MediClinic database including 239 conventional isolated AVR (cAVR) and 75 TAVI cases. All costs are given in 2011 ZAR. The subset of cAVR patients were derived from the relevant and available information in the database and their costs were compared with TAVI costs. RESULTS: From the 75 available subjects, mean TAVI costs were ZAR 335.5k +/- 47.9k, (median ZAR 326.5k) with a mean (median) ICU and hospital length of stay (LoS) of 2.7 (2.0) and 7.6 (6.5) days, respectively. The mean cAVR cost was lower at ZAR 213.9 +/- 87.5k (median ZAR 193.6k) but this included the entire population costs (i.e. low to high surgical risk). When estimating cAVR costs, defined by LoS of more than six and 13 days in the ICU and hospital, respectively, and being over 75 years of age, the estimate increased to ZAR 337.9k, which was above the TAVI mean costs. In hospital mortality was 5.3 and 7.9% for TAVI and the entire cAVR group, respectively. When considering the subset of cAVR patients most likely to be high risk, it increased to 21.4%. CONCLUSION: Within the context of limited clinical data we performed the first attempt at cost-effective analysis of TAVI vs cAVR in South Africa. Treatment of aortic stenosis with cAVR in a post hoc defined high risk patient segment was more expensive than TAVI in South African centres. Despite common perceptions on costs, adoption of TAVI as an alternative, less invasive therapy that has been clinically proven and recommended by an FDA advisory panel (Partner A) to be at least as effective as cAVR, has a viable economic argument in appropriate patients. PMID- 24626517 TI - Prevalence of the metabolic syndrome and determination of optimal cut-off values of waist circumference in university employees from Angola. AB - BACKGROUND: Estimates of the prevalence of the metabolic syndrome in Africans may be inconsistent due to lack of African-specific cut-off values of waist circumference (WC). This study determined the prevalence of the metabolic syndrome and defined optimal values of WC in Africans. METHODS: This cross sectional study collected demographic, anthropometric and clinical data of 615 Universitary employees, in Luanda, Angola. The metabolic syndrome was defined using the third report of the National Cholesterol Education Program Adult Treatment Panel (ATPIII) and the Joint Interim Statement (JIS) criteria. Receiver operating characteristics curves were constructed to assess cut-off values of WC. RESULTS: The crude prevalence of the metabolic syndrome was higher with the JIS definition (27.8%, age-standardised 14.1%) than with the ATP III definition (17.6%, age-standardised 8.7%). Optimal cut-off values of WC were 87.5 and 80.5 cm in men and women, respectively. CONCLUSION: There was a high prevalence of the metabolic syndrome among our African subjects. Our data suggest different WC cut off values for Africans in relation to other populations. PMID- 24626518 TI - B-type natriuretic peptide for the prediction of left ventricular remodelling. PMID- 24626520 TI - AstraZeneca Pharmaceuticals enables scientific innovation. PMID- 24626519 TI - Echocardiographic estimation of left ventricular filling pressures in patients with mitral valve stenosis. AB - BACKGROUND: Estimation of left ventricular end-diastolic pressure (LVEDP) among patients with mitral valve disease may help to explain their symptoms. However, conventional Doppler measurements have limitations in predicting LVEDP in this group of patients. The aim of this study was to construct a Doppler-derived LVEDP prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves. METHODS: Thirty-three patients with moderate to severe mitral stenosis (MS) who had indications for left heart catheterisation enrolled. Two-dimensional, M-mode, colour Doppler and tissue Doppler imaging indices, such as annular early diastolic velocity (Ea), isovolumic relaxation time (IVRT), pulmonary vein systolic and diastolic flow velocities, velocity propagation, left atrium area (LAA), interval between the onset of mitral E and annular Ea (TE-Ea), and Tei index were obtained. LVEDP was measured in all patients during left cardiac catheterisation. Linear correlation and multiple linear regressions were used for analysis. RESULTS: The mean of LVEDP was 9.9 +/- 5.3 mmHg. In univariate analysis, the only significant relationship was noted with LAA (p = 0.05, R(2) = 0.11). However, in multivariate regression, LAA, Tei index and Ea remained in the model to predict LVEDP (p = 0.02, R(2) = 0.26). For prediction of LVEDP >= 15 mmHg, the best model consisted of LAA, IVRT and Ea, and had a sensitivity of 85% and specificity of 85%. CONCLUSIONS: Our results provided evidence that, in patients with moderate to severe MS, LVEDP can be estimated by combining Doppler echocardiographic variables of mitral flow. However, more studies are required to confirm these results. PMID- 24626521 TI - Usefulness of a red chromagen in the diagnosis of melanocytic lesions of the conjunctiva. AB - IMPORTANCE: Immunohistochemical analyses may assist in the diagnosis of precancerous and cancerous conjunctival lesions. OBJECTIVE: To use Vector Red (VR) to identify an immunologic marker that is sensitive for all melanocytes and another that is sensitive and specific for activated and/or atypical conjunctival melanocytic lesions (MLs). DESIGN, SETTING, AND PARTICIPANTS: Eight specimens each of control lesions (normal conjunctiva and normal uvea as well as choroidal melanoma) and 8 from the diagnostic categories (conjunctival nevus, primary acquired melanosis with mild or no atypia, primary acquired melanosis with moderate to severe atypia, and conjunctival melanoma) that provided sufficient quantity and quality of tissue were available for processing. The specimens were obtained from the Ophthalmic Pathology Laboratory, The Ottawa Hospital, from 2005 to 2013. The specimens were immunolabeled with human melanoma black 45 (HMB45), melanoma antigen recognized by T cells 1 (Melan-A), S100, and Ki67 using VR and a double panmelanoma cocktail (dPANMEL) using 3,3'-diaminobenzidine (DAB) and VR. The HMB45-immunolabeled specimens were additionally developed with DAB, with and without overnight bleaching with hydrogen peroxide, 4%. Data were collected by 2 pathologists who were masked to sample grouping. MAIN OUTCOMES AND MEASURES: Differentiation between benign and malignant MLs based on immunomarker profile. RESULTS: Immunoreactivity was best visualized in specimens with VR. Melan-A labeled all melanocytes (100% sensitivity; panmelanocyte marker) without discriminating between benign and malignant lesions (0% specificity). Atypical melanocytes were most specifically labeled with HMB45 (96% specificity, 97% sensitivity; atypia marker). In primary acquired melanosis specimens, we found that the percentage of HMB45 (P < .001), S100 (P < .001), and Ki67 (P <= .02) positivity increased significantly with worsening atypia. CONCLUSIONS AND RELEVANCE: We recommend VR, which rarely requires specimen bleaching, as the standard substrate for immunohistochemical analysis of conjunctival MLs. We found Melan-A and HMB45 to best characterize MLs. In conjunctival MLs, the use of VR with Melan-A and HMB45 provides substantial sensitivity for all melanocytes and for atypical melanocytes, respectively, and reduces specimen-processing time for laboratories performing immunohistochemistry on MLs. PMID- 24626522 TI - Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. AB - Apigenin (4',5,7-trihydroxyflavone) is a natural flavonoid, shown to have chemopreventive and/or anticancer properties in a variety of human cancer cells. The involvement of autophagy in apigenin-induced apoptotic cell death of HCT116 human colon cancer cells was investigated. Apigenin induced suppression of cell growth in a concentration-dependent manner in HCT116 cells. Flow cytometric analyses indicated that apigenin resulted in G2/M phase arrest. This flavone also suppressed the expression of both cyclin B1 and its activating partners, Cdc2 and Cdc25c, whereas the expression of cell cycle inhibitors, such as p53 and p53 dependent p21(CIP1/WAF1), was increased after apigenin treatment. Apigenin induced poly (ADP-ribose) polymerase (PARP) cleavage and decreased the levels of procaspase-8, -9 and -3. In addition, the apigenin-treated cells exhibited autophagy, as characterized by the appearance of autophagosomes under fluorescence microscopy and the accumulation of acidic vesicular organelles by flow cytometry. Furthermore, the results of the western blot analysis revealed that the levels of LC3-II, the processed form of LC3-I, was increased by apigenin. Treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly enhanced the apoptosis induced by apigenin, which was accompanied by an increase in the levels of PARP cleavage. These results indicate that apigenin has apoptosis- and autophagy-inducing effects in HCT116 colon cancer cells. Autophagy plays a cytoprotective role in apigenin-induced apoptosis, and the combination of apigenin and an autophagy inhibitor may be a promising strategy for colon cancer control. PMID- 24626523 TI - CO2 fixation by dicopper(II) complexes in hypodentate framework of N8O2. AB - A new ligand with N8O2 donors containing three potential metal-binding sites (H2L) and its tricopper(II) complex 1 are synthesized. The tricopper species is found to be formed from a hypodentate dicopper(II) complex 2 in basic solutions. Complex 2 may be isolated from the reaction of H2L with a copper source under acidic conditions. Complex 2 can undergo CO2-abstraction to yield an octacopper(II) complex 3. The single crystal structures of complexes 2 and 3 are characterized by X-ray crystallography. PMID- 24626524 TI - Breastfeeding Knowledge, Attitudes, and Intention in a Sample of Undergraduate Students in Mainland China. AB - BACKGROUND: Despite the high breastfeeding initiation rate in China (> 90%), the low exclusivity rate is of concern. Some traditional behaviors, combined with increasing popularity of infant formula, may negatively affect future breastfeeding rates. As suggested by the theory of planned behavior, understanding breastfeeding beliefs of young adults may help identify and address misperceptions of future parents, supporting maintenance of the current initiation rate while increasing rates of exclusivity and duration. No research has evaluated these factors among young adults in Mainland China. OBJECTIVE: The objective was to explore any relationships between breastfeeding knowledge, attitudes, previous experiences, and future intention among undergraduate students in Mainland China. METHODS: This was a cross-sectional, quantitative study conducted from May to June 2012. A convenience sample of 395 students from a major public university in southwest China participated in the survey. RESULTS: Breastfeeding knowledge was moderate (76.7% of total score), and breastfeeding was considered to be painful (34.2%), to make breasts sag (43.1%), and to restrict the freedom of mothers (52.5%). In addition, 58.2% of students reported that they would feel embarrassed if they or their partners were to breastfeed in public, and acceptability of breastfeeding in public was low (34.7%). Three fourths of the students (75.1%) expressed future breastfeeding intent, though males were more likely to report this intention (ie, to support a partner in breastfeeding) than were females (81.3% vs 71.7%, P = .04). CONCLUSION: To create a more breastfeeding-friendly culture, future research is warranted to explore these negative beliefs about breastfeeding and to counter misunderstandings among future parents in Mainland China. PMID- 24626525 TI - Cholera toxin, a typical protein kinase A activator, induces G1 phase growth arrest in human bladder transitional cell carcinoma cells via inhibiting the c Raf/MEK/ERK signaling pathway. AB - The biotoxin cholera toxin has been demonstrated to have anti-tumor activity in numerous types of cancer, including glioma. However, the role of cholera toxin in the tumorigenesis of transitional cell carcinoma (TCC), the most common malignant tumor of the bladder, remains to be elucidated. To address this, in the present study, two TCC cell lines, T24 and UM-UC-3, were treated with cholera toxin [protein kinase A (PKA) activator] and KT5720 (PKA inhibitor). Cell survival and proliferation, cell cycle alterations and apoptosis were analyzed using Hoechst staining, the MTT assay, fluorescence microscopy and flow cytometry. Western blot analysis was used to detect the expression of proteins involved in cell cycle regulation. The results revealed that cholera toxin significantly induced G1 arrest and downregulated the expression of cyclin D1 and cyclin-dependent kinase 4/6 in the TCC cell lines, and this was rescued by KT5720. Furthermore, it was demonstrated that cholera toxin downregulated the activation of the c-Raf/Mek/Erk cascade, an important mediator of tumor cell proliferation, via the PKA-dependent c-Raf phosphorylation at Ser-43. Furthermore, inhibition of Mek activity with UO126 mimicked the effects of cholera toxin. In conclusion, these results confirmed that cholera toxin specifically inhibited proliferation and induced G1 phase arrest in human bladder TCC cells. This effect was due to PKA-dependent inactivation of the c-Raf/Mek/Erk pathway. This suggested that cholera toxin may be a viable therapeutic treatment against tumorigenesis and proliferation in bladder cancer. PMID- 24626526 TI - Decreased PPAR-gamma expression in the conjunctiva and increased expression of TNF-alpha and IL-1beta in the conjunctiva and tear fluid of dry eye mice. AB - The aim of this study was to investigate the expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma), tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta in the conjunctiva and the association between inflammatory cytokines and PPAR-gamma in dry eye mice. Dry eye was induced in 6 week-old female C57 mice. mRNA expression of PPAR-gamma, TNF-alpha and IL-1beta were measured. PPAR-gamma protein expression in the conjunctiva, and the contents of TNF-alpha and IL-1beta in the conjunctiva and tear-wash fluid were determined. A PPAR-gamma agonist, pioglitazone (PIO), was used to treat dry eye mice. Dry eye mice presented with similar manifestations as in humans. The PPAR-gamma expression in the conjunctiva of dry eye mice was downregulated, accompanied by increased contents of TNF-alpha and IL-1beta. PIO treatment markedly reduced the contents of TNF-alpha and IL-1beta in tear fluid of dry eye mice. Following PIO treatment, the PPAR-gamma expression increased markedly. PIO may activate PPAR gamma to inhibit the expression of the inflammatory cytokines TNF-alpha and IL 1beta in dry eye mice. This suppresses the inflammatory progression, increases the tear fluid production, elevates the tear film stability and reduces the damage to the ocular surface, exerting a therapeutic effect on dry eye. PMID- 24626528 TI - Advances in network-based metabolic pathway analysis and gene expression data integration. AB - With the emergence of metabolic networks, novel mathematical pathway concepts were introduced in the past decade, aiming to go beyond canonical maps. However, the use of network-based pathways to interpret 'omics' data has been limited owing to the fact that their computation has, until very recently, been infeasible in large (genome-scale) metabolic networks. In this review article, we describe the progress made in the past few years in the field of network-based metabolic pathway analysis. In particular, we review in detail novel optimization techniques to compute elementary flux modes, an important pathway concept in this field. In addition, we summarize approaches for the integration of metabolic pathways with gene expression data, discussing recent advances using network based pathway concepts. PMID- 24626527 TI - Atheroprotective pulsatile flow induces ubiquitin-proteasome-mediated degradation of programmed cell death 4 in endothelial cells. AB - OBJECTIVES: We recently found low level of tumor suppressor programmed cell death 4 (PDCD4) associated with reduced atherosclerotic plaque area (unpublished). We investigated whether atheroprotective unidirectional pulsatile shear stress affects the expression of PDCD4 in endothelial cells. METHODS AND RESULTS: En face co-immunostaining of the mouse aortic arch revealed a low level of PDCD4 in endothelial cells undergoing pulsatile shear stress. Application of unidirectional pulsatile shear stress to human umbilical vein endothelial cells (HUVECs) decreased PDCD4 protein but not mRNA level. Immunoprecipitation revealed that pulsatile shear stress induced the coupling of ubiquitin with PDCD4 expression. The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway was involved in this ubiquitin-proteasome-mediated degradation of PDCD4. Gain of function and loss of function experiments showed that PDCD4 induced turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level was associated with reduced proliferation but not apoptosis or phosphorylation of endothelial nitric oxide synthase caused by pulsatile shear stress to help maintain the homeostasis of endothelial cells. CONCLUSIONS: Pulsatile shear stress induces ubiquitin proteasome-mediated degradation of PDCD4 via a PI3K/Akt pathway in HUVECs. PDCD4 induces turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level is associated with reduced proliferation for maintenance of HUVEC homeostasis under pulsatile shear stress. PMID- 24626529 TI - Rich annotation of DNA sequencing variants by leveraging the Ensembl Variant Effect Predictor with plugins. AB - High-throughput DNA sequencing has become a mainstay for the discovery of genomic variants that may cause disease or affect phenotype. A next-generation sequencing pipeline typically identifies thousands of variants in each sample. A particular challenge is the annotation of each variant in a way that is useful to downstream consumers of the data, such as clinical sequencing centers or researchers. These users may require that all data storage and analysis remain on secure local servers to protect patient confidentiality or intellectual property, may have unique and changing needs to draw on a variety of annotation data sets and may prefer not to rely on closed-source applications beyond their control. Here we describe scalable methods for using the plugin capability of the Ensembl Variant Effect Predictor to enrich its basic set of variant annotations with additional data on genes, function, conservation, expression, diseases, pathways and protein structure, and describe an extensible framework for easily adding additional custom data sets. PMID- 24626530 TI - Glomerular function time trends in long-term survivors of childhood cancer: a longitudinal study--letter. PMID- 24626532 TI - Changing pertussis epidemiology: everything old is new again. AB - Before vaccination, pertussis was a universal disease of early childhood. Although apparent control of the disease in the United States and other countries was achieved through vaccination, pertussis is resurgent. Though acellular vaccines have been in use for 20 years, new data are emerging on their effectiveness and durability of protection and the contribution of these characteristics to the resurgence of pertussis. PMID- 24626533 TI - Pertussis pathogenesis--what we know and what we don't know. AB - Pertussis is a worldwide public health threat. Bordetella pertussis produces multiple virulence factors that have been studied individually, and many have recently been found to have additional biological activities. Nevertheless, how they interact to cause the disease pertussis remains unknown. New animal models, particularly the infection of infant baboons with B. pertussis, are enabling longstanding questions about pertussis pathogenesis to be answered and new ones to be asked. Enhancing our understanding of pathogenesis will enable new approaches to the prevention and control of pertussis. PMID- 24626540 TI - [Adherence to the food guide for the Brazilian population]. AB - OBJECTIVE: To analyze adherence to the Food Guide for the Brazilian Population. METHODS: Sample composed of participants in the Health Survey for Sao Paulo (n = 1,661) who completed two non-consecutive 24-hour recalls. A bivariate mixed model was created for the ratio of energy from a food group and total energy intake. The estimated ratio was used to calculate the percentage of individuals with intake above or below the recommendation. RESULTS: At least 80.0% of the individuals consume below the recommendation for milk and dairy; fruit and fresh juice; and cereals, tubers and roots; about 60.0% for vegetables; 30.0% for beans; and 8.0% for meat and eggs. Adolescents had the greatest inadequacy for vegetables (90.0%), and the highest income group had the lowest inadequacy for oils, fat and seeds (57.0%). CONCLUSIONS: The intake of food groups related to increased risk of chronic diseases were found to be inadequate. PMID- 24626541 TI - [Chewing impairment and associated factors among adults]. AB - OBJECTIVE: The aim of this study was to estimate the prevalence of chewing impairment according to sex, and its associated factors in adults. METHODS: A cross-sectional population-based study was carried out with 2,016 subjects aged between 20 and 59 years in Florianopolis, SC, Southern Brazil, in 2009. The sampling was undertaken in two stages, census tracts and households. The outcome 'chewing impairment' was obtained from the question "How often do you have chewing impairment due to teeth or denture problems?". Analyses were carried out with demographics and socioeconomic factors, dental services utilization, and self-related oral health using multivariable logistic regression and stratified by sex. RESULTS: The response rate was 85.3% (1,720 adults). The prevalence of chewing impairment was 13,0% (95%CI 10.3;15.8) and 18,0% (95%CI 14.6;21.3) among men and women, respectively. Women and men fifty years old and over, who had ten or fewer natural teeth and those who reported toothache were more likely to have chewing impairment. The combination of tooth loss and toothache on chewing impairment was almost four times higher among women. CONCLUSIONS: The magnitude of the associations among socioeconomic, demographics and self-related oral health factors was different according to sex, in general higher for women, with emphasis on toothache. The findings suggest that the impact of oral conditions varies by sex. PMID- 24626542 TI - [Inequalities in oral health: are schoolchildren receiving the Bolsa Familia more vulnerable?]. AB - OBJECTIVE: To evaluate the association between being a recipient of the Bolsa Familia program and oral health conditions in Brazilian schoolchildren. METHODS: A cross-sectional study was conducted with 1,107 schoolchildren aged between eight and 12 years from 20 public and private schools in Pelotas, RS, Southern Brazil. A list of all children receiving the Bolsa Familia program was provided by the participant schools. Demographic, socioeconomic and oral hygiene information were assessed using a questionnaire completed by the schoolchildren and their parents. Dental exams were performed to assess the presence of dental plaque and prevalence of dental caries. Data were analyzed by Chi-square test, Chi-square test for linear trend and multivariate Poisson Regression (prevalence ratio; 95% confidence interval). RESULTS: Schoolchildren from non-nuclear families, with a DMFT >= 1 and who had never visited a dentist were associated with receiving the Bolsa Familia. Final model showed that caries prevalence was twice as high (PR 2.00; 95%CI 1.47;2.69) in schoolchildren benefiting from the Bolsa Familia . It was also showed that schoolchildren benefiting from the program presented greater severity of dental caries compared to school children from private schools (RR 1.53; 95%CI 1.18;2.00). After final adjustments, the prevalence of schoolchildren who have never visited a dentist was six times higher in children who received the government benefit (PR 6.18; 95%CI 3.07;12.45) compared to those from private schools. CONCLUSIONS: Schoolchildren benefiting from the Bolsa Familia program experienced more caries lesions and have less frequently accessed dental care services, which suggest the need to include oral health in the program. PMID- 24626543 TI - [Correcting vital information: estimating infant mortality, Brazil, 2000-2009]. AB - OBJECTIVE: To propose a simplified method of correcting vital information and estimating the coefficient of infant mortality in Brazil. METHODS: Vital data in the information systems on mortality and live births were corrected using correction factors, estimated based on events not reported to the Brazilian Ministry of Health and obtained by active search. This simplified method for correcting vital information for the period 2000-2009 for Brazil and its federal units establishes the level of adequacy of information on deaths and live births by calculating the overall coefficient of mortality standardized by age and the ratio between reported and expected live births, respectively, in each Brazilian municipality. By applying correction factors to the number of deaths and live births reported in each county, the vital statistics were corrected, making it possible to estimate the coefficient of infant mortality. RESULTS: The highest correction factors were related to infant deaths, reaching values higher than 7 for municipalities with very precarious mortality information. For deaths and live births, the correction factors exhibit a decreasing gradient as indicators of adequacy of the vital information improve. For the year 2008, the vital information corrected by the simplified method per state were similar to those obtained in the research of active search. Both the birth rate and the infant mortality rate decreased in the period in all Brazilian regions. In the Northeast, the annual rate of decline was 6.0%, the highest in Brazil (4.7%). CONCLUSIONS: The active search of deaths and births allowed correction factors to be calculated by level of adequacy of mortality information and live births. The simplified method proposed here allowed vital information to be corrected per state for the period 2000-2009 and the progress of the coefficient of infant mortality in Brazil, its regions and states to be assessed. PMID- 24626544 TI - [Exploratory study of air quality in elementary schools, Coimbra, Portugal]. AB - OBJECTIVE: To analyze the air quality in elementary schools and their structural and functional conditions. METHODS: Air quality in 51 elementary schools (81 classrooms) in the city of Coimbra, Portugal, both inside and outside of the rooms was evaluated during the four seasons, from 2010 to 2011. Temperature (T degrees ), relative humidity (Hr), concentrations of carbon monoxide (CO), carbon dioxide (CO2), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), compounds were evaluated, as were volatile organics (VOC), formaldehyde and particulate matter (PM10), from November 2010 to February 2011 (autumn/winter) and March 2011 to June 2011 (spring/summer). A grid characterizing the structural and functional conditions of the schools was created. The statistical Student t test for paired samples and the Wilcoxon t test were applied. RESULTS: In 47 schools, the average CO2 concentrations were above the maximum reference concentration (984 ppm) mentioned in Portuguese legislation. The maximum concentration values found inside the rooms were critical, especially in the fall/winter (5,320 ppm). In some schools the average concentrations of VOC and PM10 within the maximum concentration exceeded the reference legislated. The values (risk) of CO, formaldehyde, NO2, SO2 and O3 detected were not relevant. CONCLUSIONS: There was a higher concentration of pollutants inside the rooms compared with outside. Inadequate ventilation is associated with high CO2 concentration in the classroom. PMID- 24626545 TI - Access to medicines for acute illness in middle income countries in Central America. AB - OBJECTIVE: To analyze the main predictors of access to medicines for persons who experienced acute health conditions. METHODS: This was a cross-sectional analytic study, based on data from household surveys. We examined the predictors of: (1) seeking care for acute illness in the formal health care system and (2) obtaining all medicines sought for the acute condition. RESULTS: The significant predictors of seeking health care for acute illnesses were urban geographic location, head of household with secondary school education or above, age under 15, severity of illness perceived by the respondent, and having health insurance. The most important predictor of obtaining full access to medicines was seeking care in the formal health care system. People who sought care in the formal system were three times more likely to receive all the medicines sought (OR 3.0, 95%CI 2.3;4.0). For those who sought care in the formal health system, the strongest predictors of full access to medicines were seeking care in the private sector, having secondary school education or above, and positive perceptions of quality of health care and medicines in public sector health facilities. For patients who did not seek care in the formal health system, full access to medicines was more likely in Honduras or Nicaragua than in Guatemala. Urban geographic location, higher economic status, and male gender were also significant predictors. CONCLUSIONS: A substantial part of the population in these three countries sought and obtained medicines outside of the formal health care system, which may compromise quality of care and pose a risk to patients. Determinants of full access to medicines inside and outside the formal health care system differ, and thus may require different strategies to improve access to medicines. PMID- 24626547 TI - [Factors associated with low adherence to medication in older adults]. AB - OBJECTIVE: To assess factors associated with low adherence to pharmacotherapy in older adults. METHODS: Cross-sectional population-based study, with a representative sample of 1,593 individuals aged 60 or older, living in the urban area of Bage, RS, Southern Brazil, in 2008. A multiple stage sampling model was used. The data were collected through individual household interviews. The analyses of the association between low adherence regarding pharmacotherapy, measured using the Brief Medication Questionnaire (BMQ), and demographic, socioeconomic, behavioral, health, assistance and prescription factors were carried out applying Poisson regression model to assess crude and adjusted prevalence ratios, their respective 95% confidence intervals and p-value (Wald test). RESULTS: Around 78.0% of individuals reported have taken at least one medication in the seven days prior to the interview. Of these, approximately one third (28.7%) were considered to have low adherence to the treatment. The factors significantly associated to low adherence to treatment were: age (65 to 74 years old), not having health insurance, having to purchase (totally or partially) their own medicines, having three or more morbidities, having functional disabilities and using three or more medicines. CONCLUSIONS: The increased use of medicines by older adults, because of the high prevalence of non-communicable diseases in this group, and the access to the treatment need to be considered by health care professionals regarding fostering adherence to treatment, which increases therapeutic solutions and quality of life among older people. PMID- 24626546 TI - [Seroprevalence of rubella in Colombia: a birth-year cohort analysis]. AB - OBJECTIVE: To estimate the seroprevalence of rubella and associated factors. METHODS: Population-based seroprevalence study in a random sample of 2,124 individuals, aged six to 64 years, representative by age, sex and area in Medellin, Colombia, 2009. Biological and socioeconomic variables were analyzed for their association with serum protection against rubella, according to birth year cohort; those born before (1954-1990) and after (1991-2003) the introduction of universal immunization. Titer of IgG antibodies against the rubella virus was detected using a high sensitivity (AxSYM(r) Rubella IgG--Abbott Laboratories) and a high specificity test (VIDAS RUB IgG II(r)--BioMerieux Laboratories). Proportions and weighted averages derived from a complex sample, including a correction factor for differences in gender participation, were estimated. Association with protection for groups of biological and social variables according to birth cohort was analyzed using a logistic regression model. RESULTS: Titers of IgG antibodies were higher in those born before (mean 110 UI/ml, 95%CI 100.5;120.2) compared to those born after (mean 64 UI/ml; 95%CI 54.4;72.8; p = 0.000) the introduction of mass immunization. The proportion of protection increased from 88.9% in those born 1990-1994, to 89.2% in those born 1995-1999 and to 92.1% in those born between 2000 and 2003, possibly due to boosters being administered from 1998 onwards. In those born before the introduction of the immunization, seroprotection was associated with previous contact with cases (OR 2.6; 95%CI 1.1;5.9), self-perceived health status (OR 2.5; 95%CI 1.05;6.0), educational level (OR 0.2; 95%CI 0.08;0.8) and years of residence in the neighborhood (RD 0,96; 95%CI 0.98;1.0) after adjusting for all variables. In those born after, serum protection was associated with effective sleep time (OR 1,4; 95%CI 1.09;1.8) and self-perceived health status (OR 5.5; 95%CI 1.2;23.8). CONCLUSIONS: The seroprevalence profile changed with the mass immunization plan, with higher titers of IgG antibodies in those born before the start of the immunization. It is recommended that the level of long-term protection be monitored and concerted action taken to improve potentially associated socioeconomic conditions. PMID- 24626548 TI - [Adverse drug events in hospital: pilot study with trigger tool]. AB - OBJECTIVE: To estimate the frequency of and to characterize the adverse drug events at a terciary care hospital. METHODS: A retrospective review was carried out of 128 medical records from a hospital in Rio de Janeiro in 2007, representing 2,092 patients. The instrument used was a list of triggers, such as antidotes, abnormal laboratory analysis results and sudden suspension of treatment, among others. A simple random sample of patients aged 15 and over was extracted. Oncologic and obstetric patients were excluded as were those hospitalized for less than 48 hours or in the emergency room. Social and demographic characteristics and those of the disease of patients who underwent adverse events were compared with those of patients who did not in order to test for differences between the groups. RESULTS: Around 70.0% of the medical records assessed showed at least one trigger. Adverse drug events triggers had an overall positive predictive value of 14.4%. The incidence of adverse drug events was 26.6 per 100 patients and 15.6% patients suffered one or more event. The median length of stay for patients suffering an adverse drug event was 35.2 days as against 10.7 days for those who did not (p < 0.01). The pharmacological classes most commonly associated with an adverse drug event were related to the cardiovascular system, nervous system and alimentary tract and metabolism. The most common active substances associated with an adverse drug event were tramadol, dypirone, glibenclamide and furosemide. Over 80.0% of events provoked or contributed to temporary harm to the patient and required intervention and 6.0% may have contributed to the death of the patient. It was estimated that in the hospital, 131 events involving drowsiness or fainting 33 involving falls, and 33 episodes of hemorrhage related to adverse drug effects occur annually. CONCLUSIONS: Almost one-sixth of in-patients (16.0%) suffered an adverse drug event. The instrument used may prove useful as a technique for monitoring and evaluating patient care results. Psycothropic therapy should be critically appraised given the frequency of associated events, such as excessive sedation, lethargy, and hypotension. PMID- 24626549 TI - [Physical activity in the older adults related to commuting and leisure, Maceio, Brazil]. AB - OBJECTIVE: To evaluate the level of physical activity of older adults by commuting and leisure time and associated factors. METHODS: This was a cross sectional study carried out with a population-based sample of 319 older individuals in Maceio, AL, Northeastern Brazil, in 2009. The level of physical activity in leisure and commuting was measured by applying the International Physical Activity Questionnaire, long version. The variables analyzed were: age, schooling, sex, per capita income and perceived health. We used descriptive analysis, Fisher's exact test and multiple regression analysis of prevalence rates. RESULTS: We classified 87.5% as insufficiently active in commuting, being significantly higher among those individuals with older ages, with more education and who feel dissatisfied with their physical health. The prevalence of older people who are insufficiently active in leisure time activity was 76.2%, being more frequent in women, in men with advanced age; older adults with lower per capita income, and dissatisfaction with comparative physical health and self perceived mental health. CONCLUSIONS: The prevalence of insufficiently active was high in commuting and leisure time activities. Factors such as age, gender and income should be considered, especially with regards leisure, in order to ensure fairness in the development of policies to promote health and physical activity in this population. PMID- 24626550 TI - Pictorial health warnings on cigarette packs and the impact on women. AB - OBJECTIVE: To analyze the association between the pictorial graphic health warnings on cigarette packs and their impact on intention to quit smoking among women. METHODS: Population-based cross-sectional study among 265 women daily smokers in the State of Parana in 2010. The sample size was calculated using cluster sampling. Participants were asked whether they had seen any pictorial graphic health warnings in the past 30 days, whether these warnings made them think about quitting, and intensity of these thoughts. The data was analyzed using logistic regression and the independent variables included age, educational attainment, whether they had children, whether they had attempted to quit smoking in the past 12 months, age of smoking initiation, number of cigarettes smoked per day, their town of residence, and how soon after waking do they smoke their first cigarette. RESULTS: Participants (91.7%) reported seeing the pictorial graphic health warnings in the past 30 days. Women with elementary education or below and women with some/complete high school education were more likely to think about quitting smoking after seeing the pictorial graphic health warnings than women with higher education (OR = 4.85; p = 0.0028 and OR = 2.91; p = 0.05), respectively). Women who attempted to quit smoking in the past 12 months were more likely to think about quitting than women who had not (OR = 2.49; p = 0.001). Quit attempts within the last 12 months were associated with intensity of these thoughts (OR = 2.2; p = 0.03). CONCLUSIONS: Results show an association between pictorial graphic health warnings and intent to quit smoking among women with warnings having a greater impact among women with less education and who had attempted to quit smoking within the past year. Tobacco control strategies should be implemented across all groups of women regardless of their educational attainment. PMID- 24626551 TI - [Breastfeeding-Friendly Primary Care Unit Initiative and the relationship with exclusive breastfeeding]. AB - OBJECTIVE: To analyze the prevalence of exclusive breastfeeding and the association with the Breastfeeding-Friendly Primary Care Unit Initiative. METHODS: Cross-sectional study, whose data source were research on feeding behaviors in the first year of life conducted in the vaccination campaigns of 2003 and 2006, at the municipality of Barra Mansa, RJ, Southeastern Brazil. For the purposes of this study, infants under six months old, accounting for a total of 589 children in 2003 and 707 children in 2006, were selected. To verify the relationship between being followed-up by Breastfeeding-Friendly Primary Care Unit Initiative units and exclusive breastfeeding practice, only data from the 2006 inquiry was used. Variables that in the bivariate analysis were associated (p-value <= 0.20) with the outcome (exclusive breastfeeding practice) were selected for multivariate analysis. Prevalence ratios (PR) of exclusive breastfeeding were obtained by Poisson Regression with robust variance through a hierarchical model. The final model included the variables that reached p-value <= 0.05. RESULTS: The prevalence of exclusive breastfeeding increased from 30.2% in 2003 to 46.7% in 2006. Multivariate analysis showed that mother's low education level reduced exclusive breastfeeding practice by 20.0% (PR = 0.798; 95%CI 0.684;0.931), cesarean delivery by 16.0% (PR = 0.838; 95%CI 0.719;0.976), and pacifier use by 41.0% (PR = 0.589; 95%CI 0.495;0.701). In the multiple analysis, each day of the infant's life reduced exclusive breastfeeding prevalence by 1.0% (PR = 0.992; 95%CI 0.991;0.994). Being followed-up by Breastfeeding-Friendly Primary Care Initiative units increased exclusive breastfeeding by 19.0% (PR = 1.193; 95%CI 1.020;1.395). CONCLUSIONS: Breastfeeding-Friendly Primary Care Unit Initiative contributed to the practice of exclusive breastfeeding and to the advice for pregnant women and nursing mothers when implemented in the primary health care network. PMID- 24626552 TI - [Implementation of the Brazilian Breastfeeding Network and prevalence of exclusive breastfeeding]. AB - OBJECTIVE: To evaluate the association between the level of implementation of the Brazilian Breastfeeding Network and the prevalence of exclusive breastfeeding. METHODS: Cross-sectional study of a representative sample of 916 infants < 6 months, in Ribeirao Preto, SP, Southeastern Brazil, in 2011. Data on breastfeeding, place of outpatient care and other characteristics were collected during the National Vaccination Campaign. The factor studied is where outpatient care took place: Private; Non-Network Public; Public with Network Workshop; and Public certified by Network. The individualized effect of the factor studied on the outcome was analyzed using Poisson regression with robust variance. RESULTS: The comparison between private (reference category) and other outpatient care showed significant dose-response relationship with a progressive increase in the prevalence of exclusive breastfeeding in public non-Network, public with Network Workshop and public accredited by Network outpatient care (p = 0.047). As regards the Basic Health Units accredited by Network category, the Prevalence Ratio of exclusive breastfeeding was equal to 1.47 (95%CI 1.00;2.17), after adjustment for confounding variables. CONCLUSIONS: The prevalence of exclusive breastfeeding for infants < 6 months was higher in places accredited by the Brazilian Breastfeeding Network, which evinces the importance of investing in accreditation of Basic Units of Health by this strategy. PMID- 24626553 TI - [Tuberculosis diagnosis: primary health care or emergency medical services?]. AB - OBJECTIVE: To assess primary health care and emergency medical services performance for tuberculosis diagnosis. METHODS: Cross-sectional study were conducted with 90 health professionals from primary health care and 68 from emergency medical services, in Ribeirao Preto, SP, Southeastern Brazil, in 2009. A structured questionnaire based on an instrument of tuberculosis care assessment was used. The association between health service and the variables of structure and process for tuberculosis diagnosis was assessed by Chi-square test, Fisher's exact test (both with 5% of statistical significance) and multiple correspondence analysis. RESULTS: Primary health care was associated with the adequate provision of inputs and human resources, as well as with the sputum test request. Emergencial medical services were associated with the availability of X-ray equipment, work overload, human resources turnover, insufficient availability of health professionals, unavailability of sputum collection pots and do not request sputum test. In both services, tuberculosis diagnosis remained as a physician's responsibility. CONCLUSIONS: Emergencial medical services presented weaknesses in its structure to identify tuberculosis suspects. Gaps on the process were identified in both primary health care and emergencial medical services. This situation highlights the need for qualification of health services that are the main gateway to health system to meet sector reforms that prioritize the timely diagnosis of tuberculosis and its control. PMID- 24626554 TI - [Cash transfer in Brazil and nutritional outcomes: a systematic review]. AB - OBJECTIVE: To analyze the influence of conditional cash transfer programs on diet and nutrition outcomes among beneficiary families in Brazil. METHODS: A systematic review of literature was carried out with original evaluation studies conducted in Brazil, including all types of clinical trials and observational studies. The search was conducted in PubMed, Scopus, Web of Science and LILACS databases for papers published since 1990. The studies were analyzed according to the program evaluated, participants, study design, location, principal conclusions, confounding factors and methodological limitations. They were classified according to outcomes (nutritional status, dietary intake and food security) and level of evidence for the association with conditional cash transfer programs (adequacy or plausibility). RESULTS: We found 1,412 non duplicated papers. Fifteen met the eligibility criteria and twelve evaluated the Bolsa Familia program. Five plausibility studies and two adequacy analyses indicated a positive influence of conditional cash transfer programs on nutritional status of the beneficiary children. The conditional cash transfer programs influence on dietary intake was analyzed in one population-based adequacy study and three cross-sectionals plausibility researches in different municipalities. All of them indicated that beneficiaries had higher food intake than non-beneficiaries. The three cross-sectional plausibility analyses suggest a positive influence of conditional cash transfer programs on the food security of the beneficiaries. The main methodological limitations found were using cross sectional analysis and difficulties in data collection, small sample sizes and limitations of the instruments used. CONCLUSIONS: The few studies found indicated a positive association between Brazilian conditional cash transfer programs and improvements in the recipients' diet and nutrition. Greater efforts to widen and qualify evaluations are needed in order to assess more comprehensively the impact of conditional cash transfer programs in Brazil. PMID- 24626556 TI - [Humanization policy in primary health care: a systematic review]. AB - OBJECTIVE: To analyze humanization practices in primary health care in the Brazilian Unified Health System according to the principles of the National Humanization Policy. METHODS: A systematic review of the literature was carried out, followed by a meta-synthesis, using the following databases: BDENF (nursing database), BDTD (Brazilian digital library of theses and dissertations), CINAHL (Cumulative Index to nursing and allied health literature), LILACS (Latin American and Caribbean health care sciences literature), MedLine (International health care sciences literature), PAHO (Pan-American Health Care Organization Library) and SciELO (Scientific Electronic Library Online). The following descriptors were used: Humanization; Humanizing Health Care; Reception: Humanized care: Humanization in health care; Bonding; Family Health Care Program; Primary Care; Public Health and Sistema Unico de Saude (the Brazilian public health care system). Research articles, case studies, reports of experiences, dissertations, theses and chapters of books written in Portuguese, English or Spanish, published between 2003 and 2011, were included in the analysis. RESULTS: Among the 4,127 publications found on the topic, 40 studies were evaluated and included in the analysis, producing three main categories: the first referring to the infrastructure and organization of the primary care service, made clear the dissatisfaction with the physical structure and equipment of the services and with the flow of attendance, which can facilitate or make difficult the access. The second, referring to the health work process, showed issues about the insufficient number of professionals, fragmentation of the work processes, the professional profile and responsibility. The third category, referring to the relational technologies, indicated the reception, bonding, listening, respect and dialog with the service users. CONCLUSIONS: Although many practices were cited as humanizing they do not produce changes in the health services because of the lack of more profound analysis of the work processes and ongoing education in the health care services. PMID- 24626557 TI - [Race and stroke mortality in Brazil]. AB - As stroke mortality rates according to race were not known in Brazil, data on mortality for the year 2010 was collected from the Mortality Information System of the Brazilian Ministry of Health. Cerebrovascular mortality rates adjusted for age (per 100,000) were calculated with a confidence interval of 95% (95%CI) by sex and race/skin color. The differences between races were significant for men with rates of 44.4 (43.5;45.3), 48.2 (47.1;49.3) and 63.3 (60.6;66.6) for white, brown and black, respectively; and for women, with rates of 29.0 (28.3;29.7), 33.7 (32.8;34.6) and 51.0 (48.6;53.4) for white, brown and black, respectively. The burden of stroke mortality is higher among blacks compared to brown and white. PMID- 24626555 TI - Infection and childhood leukemia: review of evidence. AB - OBJECTIVE: To analyze studies that evaluated the role of infections as well as indirect measures of exposure to infection in the risk of childhood leukemia, particularly acute lymphoblastic leukemia. METHODS: A search in Medline, Lilacs, and SciELO scientific publication databases initially using the descriptors "childhood leukemia" and "infection" and later searching for the words "childhood leukemia" and "maternal infection or disease" or "breastfeeding" or "daycare attendance" or "vaccination" resulted in 62 publications that met the following inclusion criteria: subject aged <= 15 years; specific analysis of cases diagnosed with acute lymphoblastic leukemia or total leukemia; exposure assessment of mothers' or infants' to infections (or proxy of infection), and risk of leukemia. RESULTS: Overall, 23 studies that assessed infections in children support the hypothesis that occurrence of infection during early childhood reduces the risk of leukemia, but there are disagreements within and between studies. The evaluation of exposure to infection by indirect measures showed evidence of reduced risk of leukemia associated mainly with daycare attendance. More than 50.0% of the 16 studies that assessed maternal exposure to infection observed increased risk of leukemia associated with episodes of influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus, and Helicobacter pylori . CONCLUSIONS: Although no specific infectious agent has been identified, scientific evidence suggests that exposure to infections has some effect on childhood leukemia etiology. PMID- 24626558 TI - [Secular trends in breastfeeding in Brazil]. AB - The objective of this study was to document the secular trend in breastfeeding in Brazil. Data bases from seven national surveys conducted from 1975 to 2008 were reanalyzed. To obtain compatible data from the different surveys, children in the same age group and the same indicators were analyzed, using the same statistical techniques. The median duration of breastfeeding increased from 2.5 to 11.3 months, and the prevalence of exclusive breastfeeding in infants under six months of age increased from 3.1% to 41.0% in the period. The results indicate important challenges in accelerating the rhythm at which this practice in Brazil moves towards meeting international recommendations. PMID- 24626559 TI - [Association between exposure to particulate matter and hospital admissions for respiratory disease in children]. AB - The aim of this study was to estimate the association between exposure to particulate matter less than 2.5 microns in diameter and hospitalization for respiratory disease. It was an ecological time series study with daily indicators of hospitalization for respiratory diseases in children up to 10 years old, living in Piracicaba, SP, Southeastern Brazil, between August 1, 2011 and July 31, 2012. A generalized additive Poisson regression model was used. The relative risks were RR = 1.008; 95%CI 1.001;1.016 for lag 1 and RR = 1.009; 95%CI 1.001;1.017 for lag 3. The increment of 10 MUg/m3 in particulate matter less than 2.5 microns in diameter implies increase in relative risk of between 7.9 and 8.6 percentage points. In conclusion, exposure to particulate matter less than 2.5 microns in diameter was associated with hospitalization for respiratory disease in children. PMID- 24626560 TI - [Measles outbreak in the metropolitan region of Campinas, Sao Paulo State, Brazil]. AB - Brazil has not had endemic circulation of the measles virus since 2000. Between May and June 2011, the Metropolitan Region of Campinas, State of Sao Paulo, Southeastern Brazil, reported three cases of measles. This report presents a descriptive study of the cases, control measures, and the search for a possible source and secondary cases. The genotypic characterization of the virus identified genotype D4, circulating in Europe. Secondary cases or index case were not found. The control measures and adequate vaccination coverage in Metropolitan Region of Campinas contributed to the interruption of disease transmission. PMID- 24626561 TI - IL-1beta-stimulated urokinase plasminogen activator expression through NF-kappaB in gastric cancer after HGF treatment. AB - The potential of hepatocyte growth factor (HGF) to regulate the expression of urokinase plasminogen activator (uPA) in a gastric cancer cell is not widely acknowledged. To identify the genes associated with the plasminogen activator proteolytic axis by HGF, we used cDNA microarray technology and selected genes upregulated or downregulated in two gastric cell lines (NUGC-3 and MKN-28). First, IL-1beta RNA and protein were confirmed to be upregulated. Then, we investigated the effect of IL-1beta induced by HGF on the uPA system, facilitating the migration and invasion of cancer cells in the metastatic process. The role for IL-1beta in HGF-induced upregulation of uPA was determined by knockdown of IL-1beta with IL-1beta shRNA and a chromatin immune precipitation assay. The levels of IL-1beta and uPA were upregulated in cells treated with HGF in a dose-dependent manner. HGF-induced upregulation of uPA was suppressed by IL 1beta knockdown. HGF enhanced the binding activity of NF-kappaB to the uPA promoter in control cells, but not in the IL-1beta shRNA cells. We confirmed the functional role of HGF inactivation of the uPA promoter by a reporter gene assay. Downregulation of IL-1beta using IL-1beta shRNA also decreased cell proliferation and in vitro cell invasion. IL-1beta stimulated uPA expression through ERK and NF kappaB in gastric cancer, which may therefore be promising targets for gastric cancer therapy. PMID- 24626562 TI - A new multifunctional Schiff base as a fluorescence sensor for Al3+ and a colorimetric sensor for CN- in aqueous media: an application to bioimaging. AB - A multifunctional fluorescent and colorimetric receptor 1 ((E)-N'-((8-hydroxy 1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)methylene)benzohydrazide) for the detection of both Al(3+) and CN(-) in aqueous solution has been developed. Receptor 1 exhibited an excellent selective fluorescence response toward Al(3+). The sensitivity of the fluorescent based assay (0.193 MUM) for Al(3+) is far below the limit in the World Health Organization (WHO) guidelines for drinking water (7.41 MUM). In addition, receptor 1 showed an excellent detection ability in a wide pH range of 4-10 and also in living cells. Moreover, receptor 1 showed a highly selective colorimetric response to CN(-) by changing its color from colorless to yellow immediately without any interference from other anions. PMID- 24626563 TI - MnO(x)-modified ZnAl-LDOs as high-performance adsorbent for the removal of methyl orange. AB - MnO(x) modified ZnAl layered double oxides (M-LDO) nanocomposites were prepared through an intercalation/reduction/calcination process. The morphology and crystal structure of M-LDO were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), Thermogravimetric analysis (TGA) and Fourier transform infrared spectroscopy (FT-IR) analysis methods. The results confirmed that the manganese oxide nanoparticles were well distributed on the LDO support. Methyl orange (MO) was chosen as a common water-soluble azo dye probe to evaluate the adsorption performance of M-LDO. The effects of MO initial concentration, agitation time, and temperature on MO adsorption were investigated. It was found that adsorption equilibrium data were best represented by the Langmuir and Redlich-Peterson isotherms and the maximum adsorption capacity was 617.28 mg g(-1) obtained from the Langmuir isotherm, which was much larger than some reported adsorbents. Besides, the adsorption process was spontaneous and endothermic in nature and followed a pseudo-second-order kinetic model. The mechanism of the adsorption process was elaborated by an intraparticle diffusion model. Moreover, the regeneration test of M-LDO was carried out and it showed that the used M-LDO was feasible for at least five times. In principle, this adsorbent with a high adsorption capacity and great reutilization performance could be a very promising adsorbent for wastewater treatment. PMID- 24626564 TI - Double Ring Array Catheter for In Vivo Real-Time 3D Ultrasound. AB - We developed new forward-viewing matrix transducers consisting of double ring arrays of 118 total PZT elements integrated into catheters used to deploy medical interventional devices. Our goal is 3D ultrasound guidance of medical device implantation to reduce x-ray fluoroscopy exposure. The double ring arrays were fabricated on inner and outer custom polyimide flexible circuits with inter element spacing of 0.20 mm and then wrapped around an 11 French (Fr) catheter to produce a 15 Fr catheter (outer diameter [O.D.]). We used a braided cabling technology to connect the elements to the Volumetrics Medical Imaging (VMI) real time 3D ultrasound scanner. Transducer performance yielded an average -6 dB fractional bandwidth of 49% +/- 11% centered at 4.4 MHz for 118 elements. Real time 3D cardiac scans of the in vivo pig model yielded good image quality including en face views of the tricuspid valve and real-time 3D guidance of an endo-myocardial biopsy catheter introduced into the left ventricle. PMID- 24626565 TI - Power MOSFET-diode-based limiter for high-frequency ultrasound systems. AB - The purpose of the limiter circuits used in the ultrasound imaging systems is to pass low-voltage echo signals generated by ultrasonic transducers while preventing high-voltage short pulses transmitted by pulsers from damaging front end circuits. Resistor-diode-based limiters (a 50 Omega resistor with a single cross-coupled diode pair) have been widely used in pulse-echo measurement and imaging system applications due to their low cost and simple architecture. However, resistor-diode-based limiters may not be suited for high-frequency ultrasound transducer applications since they produce large signal conduction losses at higher frequencies. Therefore, we propose a new limiter architecture utilizing power MOSFETs, which we call a power MOSFET-diode-based limiter. The performance of a power MOSFET-diode-based limiter was evaluated with respect to insertion loss (IL), total harmonic distortion (THD), and response time (RT). We compared these results with those of three other conventional limiter designs and showed that the power MOSFET-diode-based limiter offers the lowest IL (-1.33 dB) and fastest RT (0.10 us) with the lowest suppressed output voltage (3.47 Vp-p) among all the limiters at 70 MHz. A pulse-echo test was performed to determine how the new limiter affected the sensitivity and bandwidth of the transducer. We found that the sensitivity and bandwidth of the transducer were 130% and 129% greater, respectively, when combined with the new power MOSFET-diode-based limiter versus the resistor-diode-based limiter. Therefore, these results demonstrate that the power MOSFET-diode-based limiter is capable of producing lower signal attenuation than the three conventional limiter designs at higher frequency operation. PMID- 24626566 TI - Tissue-mimicking gel phantoms for thermal therapy studies. AB - Tissue-mimicking phantoms that are currently available for routine biomedical applications may not be suitable for high-temperature experiments or calibration of thermal modalities. Therefore, design and fabrication of customized thermal phantoms with tailored properties are necessary for thermal therapy studies. A multitude of thermal phantoms have been developed in liquid, solid, and gel forms to simulate biological tissues in thermal therapy experiments. This article is an attempt to outline the various materials and techniques used to prepare thermal phantoms in the gel state. The relevant thermal, electrical, acoustic, and optical properties of these phantoms are presented in detail and the benefits and shortcomings of each type are discussed. This review could assist the researchers in the selection of appropriate phantom recipes for their in vitro study of thermal modalities and highlight the limitations of current phantom recipes that remain to be addressed in further studies. PMID- 24626567 TI - Artifact reduction of ultrasound Nakagami imaging by combining multifocus image reconstruction and the noise-assisted correlation algorithm. AB - Several studies have investigated Nakagami imaging to complement the B-scan in tissue characterization. The noise-induced artifact and the parameter ambiguity effect can affect performance of Nakagami imaging in the detection of variations in scatterer concentration. This study combined multifocus image reconstruction and the noise-assisted correlation algorithm (NCA) into the algorithm of Nakagami imaging to suppress the artifacts. A single-element imaging system equipped with a 5 MHz transducer was used to perform the brightness/depth (B/D) scanning of agar phantoms with scatterer concentrations ranging from 2 to 32 scatterers/mm(3). Experiments were also carried out on a mass with some strong point reflectors in a breast phantom using a commercial scanner with a 7.5 MHz linear array transducer operated at multifocus mode. The multifocus radiofrequency (RF) signals after the NCA process were used for Nakagami imaging. In the experiments on agar phantoms, an increasing scatterer concentration from 2 to 32 scatterers/mm(3) led to backscattered statistics ranging from pre-Rayleigh to Rayleigh distributions, corresponding to the increase in the Nakagami parameter measured in the focal zone from 0.1 to 0.8. However, the artifacts in the far field resulted in the Nakagami parameters of various scatterer concentrations to be close to 1 (Rayleigh distribution), making Nakagami imaging difficult to characterize scatterers. In the same scatterer concentration range, multifocus Nakagami imaging with the NCA simultaneously suppressed two types of artifacts, making the Nakagami parameter increase from 0.1 to 0.8 in the focal zone and from 0.18 to 0.7 in the far field, respectively. In the breast phantom experiments, the backscattered statistics of the mass corresponded to a high degree of pre-Rayleigh distribution. The Nakagami parameter of the mass before and after artifact reduction was 0.7 and 0.37, respectively. The results demonstrated that the proposed method for artifact reduction allows a sensitive and effective scatterer characterization by Nakagami imaging. PMID- 24626569 TI - Chronic dissecting aneurysm of the ascending aorta developed in a patient who had rejected surgical treatment for type II acute ascending aortic dissection three years earlier. AB - A 66-year-old male patient was admitted to our clinic because of shortness of breath and chest pain. A grade 4/6 diastolic murmur was heard on auscultation. Physical examination revealed signs of congestive heart failure and poor peripheral perfusion. There was a diagnosis of type II ascending aortic dissection in the history of the patient. He had refused emergency surgical intervention three years earlier. Computed tomography revealed that the ascending aorta was dilated to about 10 cm in diameter, and there was a chronic aortic type II dissection. The patient had second- to third-degree aortic insufficiency and he had a calcified bicuspid aortic valve on echocardiography. Two-vessel disease and a 90-mmHg aortic gradient were detected on angiography. Graft replacement of the ascending aorta, serape aortic valve replacement with a mechanical valve, and coronary arterial bypass grafting were performed successfully under cardiopulmonary bypass with an open aortic technique. The patient was discharged on the 10th postoperative day with no problems. PMID- 24626568 TI - Nr4a3, a possibile oncogenic factor for neuroblastoma associated with CpGi methylation within the third exon. AB - Aberrant methylation of Nr4a3 exon 3 CpG island (CpGi) was initially identified during multistep mouse skin carcinogenesis. Nr4a3 is also known as a critical gene for neuronal development. Thus, we examined the Nr4a3 exon 3 CpGi methylation in mouse brain tissues from 15-day embryos, newborns and 12-week-old adults and found significant increase of its methylation and Nr4a3 expression during mouse brain development after birth. In addition, homologous region in human genome was frequently and aberrantly methylated in neuroblastoma specimens. A quantitative analysis of DNA methylation revealed that hypomethylation of CpG islands on Nr4a3 exon 3, but not on exon 1 was identified in three neuroblastomas compared with matched adrenal glands. Additional analysis for 20 neuroblastoma patients was performed and 8 of 20 showed hypomethylation of the CpGi on Nr4a3 exon 3. The survival rate of those 8 patients was significantly lower compared with those in patients with hypermethylation. Immunohistochemical Nr4a3 expression was generally faint in neuroblastoma tissues compared with normal tissues. Moreover, the MYCN amplified NB9 cell line showed hypomethylation and low expression of Nr4a3, while the non-MYCN amplified NB69 cell line showed hypermethylation and high expression. These results indicate that DNA hypomethylation of the CpGi at Nr4a3 exon 3 is associated with low Nr4a3 expression, and correlates with poor prognosis of neuroblastoma. Since Nr4a3 upregulation associated with the hypermethylation and neuronal differentiation in mice, poor prognosis of neuroblastoma associated with Nr4a3 low expression may be partly explained by dysregulation of its differentiation. PMID- 24626570 TI - Successful primary percutaneous coronary intervention in a centenarian patient with acute myocardial infarction. AB - A 104-year-old male patient was admitted to the emergency department with chest pain. An electrocardiogram showed ST-segment elevation in the anterior leads. He was immediately taken to the catheterisation laboratory for emergency angiography, which showed thrombotic stenosis at the proximal portion of the left anterior descending (LAD) artery. After intervention on the LAD lesion, successful balloon angioplasty with stenting was performed. Here, we report a case of successful primary percutaneous coronary intervention (PCI) in a centenarian patient with acute myocardial infarction. There are few clinical data on centenarian patients with acute myocardial infarction undergoing primary PCI. To the best of best our knowledge, this case is the first reported in the literature where primary PCI was performed on a centenarian patient. PMID- 24626571 TI - Intracellular Theileria annulata promote invasive cell motility through kinase regulation of the host actin cytoskeleton. AB - The intracellular, protozoan Theileria species parasites are the only eukaryotes known to transform another eukaryotic cell. One consequence of this parasite dependent transformation is the acquisition of motile and invasive properties of parasitized cells in vitro and their metastatic dissemination in the animal, which causes East Coast Fever (T. parva) or Tropical Theileriosis (T. annulata). These motile and invasive properties of infected host cells are enabled by parasite-dependent, poorly understood F-actin dynamics that control host cell membrane protrusions. Herein, we dissected functional and structural alterations that cause acquired motility and invasiveness of T. annulata-infected cells, to understand the molecular basis driving cell dissemination in Tropical Theileriosis. We found that chronic induction of TNFalpha by the parasite contributes to motility and invasiveness of parasitized host cells. We show that TNFalpha does so by specifically targeting expression and function of the host proto-oncogenic ser/thr kinase MAP4K4. Blocking either TNFalpha secretion or MAP4K4 expression dampens the formation of polar, F-actin-rich invasion structures and impairs cell motility in 3D. We identified the F-actin binding ERM family proteins as MAP4K4 downstream effectors in this process because TNFalpha induced ERM activation and cell invasiveness are sensitive to MAP4K4 depletion. MAP4K4 expression in infected cells is induced by TNFalpha-JNK signalling and maintained by the inhibition of translational repression, whereby both effects are parasite dependent. Thus, parasite-induced TNFalpha promotes invasive motility of infected cells through the activation of MAP4K4, an evolutionary conserved kinase that controls cytoskeleton dynamics and cell motility. Hence, MAP4K4 couples inflammatory signaling to morphodynamic processes and cell motility, a process exploited by the intracellular Theileria parasite to increase its host cell's dissemination capabilities. PMID- 24626572 TI - Telbivudine decreases proportion of peripheral blood CD4+CD25+CD127low T cells in parallel with inhibiting hepatitis B virus DNA. AB - Regulatory T cells (Treg) have significant roles in the immunopathology of patients with chronic hepatitis B (CHB) and exhibit an evident correlation with antiviral immunity when antiviral therapy is applied. In order to investigate how circulating Tregs are affected by telbivudine treatment and its significance in patients with CHB, peripheral blood mononuclear cells (PBMCs) were isolated and the proportions of circulating cluster of differentiation (CD)4+CD25+CD127low and CD8+CD25+ T cells of CHB patients prior to and during the three or six months of treatment were assessed and detected by flow cytometric analysis. The levels of forkhead/winged helix transcription factor (Foxp3) mRNA were also quantified using quantitative polymerase chain reaction. A significantly higher percentage of CD4+CD25+CD127low and CD8+CD25+ T cells in the PBMCs of patients with CHB were identified compared with that of healthy individuals. Patients with CHB also demonstrated significantly higher levels of Foxp3 mRNA compared with that of healthy individuals. Following six months of telbivudine treatment, the proportion of circulating CD4+CD25+CD127low and CD8+CD25+ T cells and the relative levels of Foxp3 mRNA in patients with CHB was comparable to the proportion in healthy individuals. The proportions of circulating peripheral blood CD4+CD25+CD127low T cells were paralleled with its HBV DNA inhibition. The results of the present study indicate that telbivudine treatment reduces HBV DNA levels rapidly and indirectly affects the immune system by downregulating the proportion of circulating Treg markedly, which may be beneficial to restore the antiviral immune response. PMID- 24626573 TI - Ultrafast exciton dynamics in dinaphtho[2,3-b:2'3'-f]thieno[3,2-b]-thiophene thin films. AB - Ultrafast dynamics of excitons in organic semiconductors is essential for a deep understanding of the working mechanism of plastic opto-electronic devices. In this work, excited state dynamics in dinaphtho[2,3-b:2'3'-f]thieno[3,2-b] thiophene thin films has been studied with femtosecond transient absorption and time-resolved photoluminescence spectroscopy. Upon the excitation with a femtosecond pulse at 400 nm, a broad positive absorption band at 1.5-2.4 eV is observed that contains two components: one decays with a time constant of a few ps and the other with 67 +/- 7 ps. Because the decay curve of the latter coincides with that of photoluminescence, the slow decay component is ascribed to the lowest singlet exciton. The former fast decay component is ascribed to mixed states between charge transfer (CT) and Frenkel excitons, because it is accompanied by a feature due to the Stark effect caused by transient charged species: a combination of bleach and positive absorption at hnuprobe > 2.4 eV which looks like derivative modulations of the ground state absorption spectrum. A pronounced polarization dependence is observed for the derivative-like features; this is due to anisotropic distributions of the dipole moments formed by the CT excitons. The derivative-like feature changes its shape after the decay of the mixed Frenkel-CT exciton and grows with a pump-probe delay time of up to 1 ns due to a thermal effect. The decay rate of the mixed Frenkel-CT exciton strongly depends on its density because of exciton-exciton annihilation at high density. PMID- 24626575 TI - [The Brazilian Oral Health Survey (SBBrasil Project. Editorial]. PMID- 24626574 TI - Autophagy promotes the survival and development of tumors by participating in the formation of vasculogenic mimicry. AB - Autophagy, type II nonapoptotic cell death, is characterized by the formation of double-membrane cytosolic vesicles, the recycling of damaged cytoplasmic content and the maintenance of genetic stability and cellular homeostasis, under conditions of nutrient starvation, hypoxia or other therapeutic stress. In the present study, we comprehensively discuss its indispensable role in the formation of vasculogenic mimicry (VM), capillary-like tubes consisting of cells from the tumor itself instead of vascular endothelial cells. A short hairpin RNA (shRNA) to silence beclin1, an autophagy-specific gene, was designed, synthesized and subcloned into a vector to establish an autophagy-inhibited group, while negative control and blank groups were also established using human gastric cancer SGC7901 cells. We then investigated the VM formation ability of these three groups and detected changes in gene expression, survival and invasion correspondingly. The results showed that, following the formation of VM, the expression of pluripotent genes (c-myc, oct3/4, sox-2) and autophagy-specific genes (beclin1, ATG5, ATG7) were increased, which was consistent with the negative control cell group. However, the autophagy inhibited cell group did not form VM, and the expression of pluripotent genes was decreased. Moreover, the inhibition of autophagy reduced the survival and invasive ability of cancer cells under stress. We suggest that during the formation of VM, the stable expression of genes and the maintenance of survival and invasion are indispensable. Under a stress environment, autophagy is activated to maintain the stability of gene expression, maintain survival and invasive ability and facilitate VM formation, which can provide nutrients, oxygen and invasive channels to tumors, facilitating survival and development under stress. PMID- 24626576 TI - [Sampling plan, weighting process and design effects of the Brazilian Oral Health Survey]. AB - OBJECTIVE: To present aspects of the sampling plan of the Brazilian Oral Health Survey (SBBrasil Project). with theoretical and operational issues that should be taken into account in the primary data analyses. METHODS: The studied population was composed of five demographic groups from urban areas of Brazil in 2010. Two and three stage cluster sampling was used. adopting different primary units. Sample weighting and design effects (deff) were used to evaluate sample consistency. RESULTS: In total. 37,519 individuals were reached. Although the majority of deff estimates were acceptable. some domains showed distortions. The majority (90%) of the samples showed results in concordance with the precision proposed in the sampling plan. The measures to prevent losses and the effects the cluster sampling process in the minimum sample sizes proved to be effective for the deff. which did not exceeded 2. even for results derived from weighting. CONCLUSIONS: The samples achieved in the SBBrasil 2010 survey were close to the main proposals for accuracy of the design. Some probabilities proved to be unequal among the primary units of the same domain. Users of this database should bear this in mind, introducing sample weighting in calculations of point estimates, standard errors, confidence intervals and design effects. PMID- 24626577 TI - [Ethical responsibility in the SBBrasil 2010 from the perspective of the managers of the population survey]. AB - OBJECTIVE: To analyze the ethical problems involved in the Brazilian Oral Health Survey - SBBrasil 2010. METHODS: We carried out a descriptive qualitative case study from the perspective of the ethics of responsibility. Key informants (n = 14) involved in the planning and implementation of a population survey in the Federal District and 11 States were individually interviewed using a semi structured questionnaire. The participants of this research belonged either to the Management Group or the Technical Advisory Committee of the Ministry of Health, responsible for the planning and implementation of SBBrasil 2010. Two coordinators, one municipal the other state were also involved. The results are expressed as collective subject discourse. Complementary information about the content of the interviews was obtained from the participants in order to clarify terms and to understand facts and contexts. RESULTS: The following core ideas were identified: the teams need to feel responsible for SBBrasil 2010; fabrication of data compromised the DMFT (decayed, missing, filled tooth) in some places; non-adherence to field work protocol as moral problem. Data exam showed that in one capital the caries index at 12 years was well above the average expected for that place. A breakdown of the database led to the detection of solid evidence of registration error on the part of two examiners, which would indicate that there was either a failure in the training and calibration stage, or fabrication of data, or both. CONCLUSIONS: The anomalous behavior of these examiners was detected in time and the fieldwork was redone. However, from the perspective of the ethics of responsibility, there was a transgression in the sphere of individual responsibility, the effects of which affected all the researchers involved and jeopardized the credibility of the research. PMID- 24626578 TI - [Sociodemographic and clinical aspects of quality of life related to oral health in adolescents]. AB - OBJECTIVE: To estimate the prevalence and to identify sociodemographic and oral health factors associated with the negative impact of oral health conditions on the quality of life in adolescents. METHODS: Data from 5,445 adolescents aged 15 19, who took part in the Brazilian Oral Health Survey (SBBrasil 2010) were analyzed, using a multistage sampling design. The outcome was quality of life related to oral health, which was assessed using the Oral Impacts on Daily Performance questionnaire and analyzed as a discrete variable. The independent variables were sex, skin color, schooling, household income, age, untreated dental caries, malocclusion.,gingival bleeding, dental calculus, and periodontal pocket. Poisson regression analysis was carried out and mean ratios (MR) with their respective 95% confidence intervals (95%CI) were presented. RESULTS: Of the total, 39.4% reported at least one negative impact on their quality of life. After adjustment, the mean negative impact was 1.52 (95%CI 1.16;2.00) times higher in females and 1.42 (95%CI 1.01;1.99), 2.66 (95%CI 1.40;5.07) and 3.32 (95%CI 1.68;6.56) higher in those with brown, yellow, and indigenous skin color, respectively, when compared to those with white skin. The lower the level of schooling, the greater the negative impact (MR 2.11, 95%CI 1.30;3.41), likewise for individuals with household income below R$ 500.00 (MR 1.84, 95%CI 1.06;3.17) compared with those with higher incomes. The greatest impact on quality of life was found among adolescents with four or more teeth with untreated dental caries (MR 1.53, 95%CI 1.12;2.10), one or more missing teeth (MR 1.44. 95%CI 1.16;1.80). those with dental pain (RM 3.62, 95%CI 2.93;4.46) and with severe (MR 1.52, 95%CI 1.04;2.23) and very severe malocclusion (MR 1.32, 95%CI 1.01;1.72). CONCLUSIONS: Brazilian adolescents reported a high negative impact of oral health on their quality of life. Inequalities in distribution should be taken into account when planning preventive, monitoring and treatment strategies for oral health problems in groups with the highest impact on their quality of life. PMID- 24626579 TI - [Social inequalities and periodontal disease: multilevel approach in SBBrasil 2010 survey]. AB - OBJECTIVE: To estimate the prevalence and geographical distribution of periodontal disease in the Brazilian adult population and its associations with contextual and individual social inequalities. METHODS: Data from adults aged 35 to 44 who participated in the 2010 Brazilian Brazilian Oral Health Survey (SBBrasil 2010) (n = 9,564) were used. The Community Periodontal Index (CPI) and clinical attachment loss (CAL) were used to define "moderate to severe" periodontal disease (CPI > 2 and CAL > 0) and "severe" periodontal disease (CPI > 2 and CAL > 1). Contextual social inequalities assessed were Human Development Index and income inequalitiy (Gini Index). Other contextual variables were integration of oral health teams in the Family Health Programme and the percentage of adult smokers. Multilevel logistic regression models for participants with complete data (n = 4,594) were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) between social inequalities and periodontal disease. RESULTS: The prevalence of "moderate to severe" and "severe" periodontal disease in Brazilian adults was 15.3% and 5.8%, respectively, with considerable variation across municipalities. Of the contextual variables, income inequality was independently associated with "severe" periodontal disease (OR = 3.0, 95%CI 1.5;5.9). Lower oral health teams coverage was associated with both definitions of periodontal disease whereas the percentage of smokers remained associated with "moderate to severe" periodontal disease. Older adults, brown skin color, males and those with lower family income and less schooling were more likely to both periodontal conditions. CONCLUSIONS: In Brazil, the prevalence of periodontal disease varied across the municipalities and according to definition of periodontal disease. Income inequality played a significant role in the occurrence of "severe" periodontal disease. Individual characteristics of social position were associated with both forms of periodontal disease. PMID- 24626580 TI - [Individual and contextual determinants of dental caries in Brazilian 12-year olds in 2010]. AB - OBJECTIVE: To estimate the prevalence and severity of dental caries in Brazilian children and the association with individual and contextual factors. METHODS: Data were taken from the Brazilian Oral Health Survey (SBBrasil 2010) a sample of 7,247 12-year-olds. The data were collected using clinical examinations and interviews. The dependent variables were the prevalence of dental caries (decayed, missing and filled teeth [DMFT] >= 1 and DMFT >= 4). Bivariate (Rao Scott test) and multivariate (Poisson regression) analyses were carried out. The individual variables were sociodemographic variables, periodontal health and reporting discomfort while brushing. Contextual factors were the presence of water fluoridation, the percentage of residences connected to the water supply and median income of the municipality. RESULTS: The prevalence of DMFT >= 1 was 56.0%. Mean DMFT was 2.04 (95%CI 1.76;2.31) and 22.2% of children had DMFT >= 4. Caries experience was significantly more common in children with black, brown or yellow skin; in low-income families; in children with dental calculus or bleeding gums and in those who reported discomfort while brushing. Living in towns with fluoridated tap water, with low coverage of water supply and with low median income were contextual factors associated with the disease. CONCLUSIONS: The prevalence of dental caries in Brazilian 12-year-olds was low, according to World Health Organization criteria. There were significant geographical and socioeconomic inequalities in levels of the disease. PMID- 24626581 TI - [Dental caries and treatment needs in adolescents from the state of Sao Paulo, Brazil]. AB - OBJECTIVE: To estimate the prevalence of dental caries and treatment needs in 12 year-olds and adolescents. METHODS: Cross-sectional study based on results from the epidemiological surveys: Oral Health Conditions in the State of Sao Paulo, 2002 and the Brazilian Oral Health Survey (SBBrasil) 2010. Secondary data for 5,782 (2002) and 369 (2010) 12-year-olds and 880 (2002) and 300 (2010) 15- to 19 year-olds were analyzed. Dental caries attack was evaluated using the DMFT (decayed, missing or filled teeth) index and the need for treatment verified using the criteria proposed by the World Health Organization. The Significant Caries Index was used to measure the severity of the decay in the tercile of the group with the highest prevalence of the disease. In order to analyze the results, the Chi-squared and Mann-Whitney tests were used, with a 5% significance. RESULTS: There was a decrease of 39.3 percentage points in the DMFT index for 12-year-olds (p < 0.001) and of 41.1 percentage points for the adolescents (p < 0.001) between 2002 and 2010, and an increase of around 161.0 and 303.0 percentage in the group which was free from dental caries respectively. The percentage of restored teeth decreased in both age groups, although the prevalence of dental caries did not change in the group more affected by dental caries. In the group with few dental caries, there was a decrease in the component 'tooth loss' for adolescents and increase in the component 'decayed teeth' for the 12-years-old and the adolescents. There was an increase in the need for dental treatment in the group as a whole and in the group of 12-year olds more affected by dental caries; and among the adolescents, the need for restoration on two or more surface decreased in the group as a whole and also in the group which suffered least from dental caries. CONCLUSIONS: The decreasing need for non-complex treatment in adolescents suggests that promotion and prevention activities are having a positive effect on this group. Moreover, the two epidemiological surveys in the state of Sao Paulo show improvements in oral health conditions in both age groups studied and calls for monitoring aimed also at the group least affected by dental caries. PMID- 24626582 TI - [Root caries prevalence and severity in Brazilian adults and older people]. AB - OBJECTIVE: To estimate the prevalence of root caries in Brazilian adults and elderly. METHODS: We assessed data from the Brazilian Oral Health Survey (SBBrasil 2010). Dental examinations were performed on 9,564 adults and 7,509 elderly individuals in households in the 26 state capitals, the Federal District and 150 provincial towns. Diagnostic criteria and data assessment tools were those standardized by the World Health Organization. The outcome was measured by using root caries index and the index of decayed and filled dental roots. RESULTS: The prevalence of root caries was 16.7% in adults and 13.6% in the elderly. The index of decayed and filled dental roots was 0.42 and 0.32 for adults and the elderly respectively, with most of the index represented by untreated caries. The prevalence of root caries differed significantly among states capitals and provincial towns, with higher values being reported in the state capitals in the North and Northeastern Brazilian regions. In adults, the root caries index ranged from 1.4% in Aracaju to 15.1% in Salvador (both in the Northeast). Among the elderly, this index ranged from 3.5% in Porto Velho to 29.9% in Palmas (both North). Root caries was more prevalent in men than in women in both age groups. CONCLUSIONS: There is a wide variation in root caries indices in adults and in the elderly, and between and within Brazilian regions. Most root caries is untreated. We recommend the incorporation of this disease into the oral health surveillance system. PMID- 24626583 TI - [Dental health in Brazilian adults between 1986 and 2010]. AB - OBJECTIVE: To identify trends in the pattern of dental caries in Brazilian adults. METHODS: Data from epidemiological surveys carried out by the Brazilian Ministry of Health in 1986, 2003 and 2010 were used. Dental caries experience, using the DMFT index (decayed, missing and filled teeth) and dental health, expressed by the FS-T index (filled and sound teeth) related to functional teeth, were compared using random samples of 35 to 44 year old residents of each region of Brazil. The differences in dental health between the years were estimated using the ratio of the index values, by Poisson regression analysis adjusted for age. RESULTS: Reduction in the DMFT index and increase in the FS-T index in all regions in the period between 1986 and 2010. The North, where the worst standards were found in 1986, showed the greatest improvements in terms of functional teeth. CONCLUSIONS: The dental health of Brazilian adults changed for the better. It is plausible that this oral health transition is related to the addition of fluoride to water and to toothpaste as well as increased incorporation of restorative services and improvements in human development due to public policies. PMID- 24626584 TI - [Tooth loss in Brazil: analysis of the 2010 Brazilian Oral Health Survey]. AB - OBJECTIVE: To estimate the mean number of missing teeth, lack of functional dentition and total tooth loss (edentulism) among adolescents, adults and the elderly in Brazil, comparing the results with those of 2003. METHODS: Data from 5,445 adolescents aged 15-19, 9,779 adults aged 35-44 and 7,619 elderly individuals aged 65-74, participants in the Brazilian Oral Health Survey (SBBrasil) 2010, were analyzed. The mean missing teeth, proportion of lack of functional dentition (< 21 natural teeth) and proportion of edentulism (total tooth loss) were estimated for each age group, each state Capital and each macro region. Multivariable logistic regression (tooth loss) and Poisson (absence of functional dentition and edentulism) analyses were performed in order to identify socioeconomic factors and demographic characteristics associated with each outcome. RESULTS: The prevalence of tooth loss among adolescents was 17.4% (38.9% in 2002-03) ranging from 8.1% among those earning higher income to almost 30% among those with less schooling. Among adolescents, females, those with black or brown skin and those with the lowest levels of income and schooling had a higher prevalence of tooth loss. Lack of functional dentition affected nearly 1/4 of adults, it was higher among women, among those with black and brown skin and among those with the lowest levels of income and schooling. Mean missing teeth in adults decreased from 13.5 in 2002-03 to 7.4 in 2010. More than half of elderly is edentulous (similar to the 2002-03 findings); higher prevalence of edentulism was found among women and those with the lowest levels of income and schooling. Among adolescents the mean missing teeth ranged from 0.1 (in Curitiba, South Brazil and Vitoria, Southeast Brazil) to 1.2 (in the North countryside). Among adults the lowest mean missing teeth was found in Vitoria (4.2) and the highest in Rio Branco, North Brazil (13.6). CONCLUSIONS: A remarkable reduction in tooth loss among adolescents and adults was identified between 2010 and 2003. Among the elderly, tooth loss figure remained the same. In spite of important achievements in tooth loss figures, social and regional inequalities persist. PMID- 24626585 TI - [Factors associated with the use of dental services by elderly Brazilians]. AB - OBJECTIVE: To assess the association between recent use of dental services, socioeconomic factors and oral health measures among elderly Brazilians. METHODS: The sample consisted of elderly individuals aged 65 to 74, who participated in the Brazilian Oral Health Survey in 2010 (Brazil SB-2010). The dependent variable was "recent use of dental services" (last dental visit <= 2 years). The independent variables were: 1) sociodemographic factors, clinical oral health measures, and subjective measure of oral health. Statistical analysis included descriptive analyses of frequency, bivariate and multiple analyses using Poisson regression. RESULTS: About 46.5% of the elderly individuals had had a dental appointment in the last two years. In the multiple Poisson regression model, education, income and region were independently associated with the outcome. Individuals with 0-20 teeth and need for prosthesis had a lower prevalence of recent dental visit. A higher prevalence of recent dental visit was observed among individuals in need of dental treatment and among those with dental prosthesis. CONCLUSIONS: Recent use of dental services was associated with socioeconomic factors (education, income, and region) and clinical oral health measures (number of teeth, use and need for dental prosthesis and need for dental treatment). PMID- 24626586 TI - [Self-perceived oral health among adults in Northeastern Brazil]. AB - OBJECTIVE: To identify self-perceived oral health in adults and associated variables. METHODS: The study involved primary data from the Brazilian Oral Health Survey (SBBrasil) 2010 with 2,456 adults aged 35 to 44 in the Northeastern Brazil. The dependent variable was self-perceived oral health and the independent variables were grouped into four blocks: demographic, predisposing/facilitation, oral health status and those related to self-perceived need for treatment. The Rao and Scott test was used to test the association between these variables. To test the effect of the independent variables on the outcome, a multinomial logistic regression model was used according to the hierarchical model, resulting in an analysis divided into two stages: simple analysis and hierarchical multiple regression analysis. RESULTS: Positive self-perception of oral health was observed in 37% of the participants. In the final model, the features directly associated with this perception were being white, having a household income exceeding R$ 500.00, owning goods number above the median, having more sound teeth, not experiencing bleeding, not requiring prosthesis, Oral Imparcts on Daily Performances = 0, not requiring treatment, having gone to the dentist less than 3 years ago. CONCLUSIONS: The results show that self-perceived oral health in adults living in the Northeast is directly associated with a multidimensional structure of factors. The poor economic conditions associated with poor clinical conditions impact heavily on this population's self-perception of oral health. PMID- 24626587 TI - [Epidemiological pattern of severe malocclusions in Brazilian adolescents]. AB - OBJECTIVE: To describe the distribution of malocclusion and its associated factors in Brazilian adolescents. METHODS: Data from 7,328 subjects aged 12 years and 5,445 adolescents aged 15-19 years were analyzed. The adolescents took part in the Brazilian Oral Health Survey (SBBrasil 2010). The outcome was severe malocclusion according to the dental aesthetic index. The independent variables were sex, skin color, monthly household income, possessions, number of individuals in the household, untreated dental caries, missing teeth and dental appointments or lack thereof, frequency, and reason. Logistical regression analysis was carried out, considering the complex sampling cluster design, based on a hierarchical model. RESULTS: The prevalence of severe malocclusion was 6.5% and 9.1% in the 12-year-olds and the 15-19-year-olds, respectively. After adjustment, those with lighter- skinned black or black skin were 1.59 (95%CI 1.08;2.34) times more likely to present the outcome compared with those with white skin. The loss of one or more first molars increased 2.66 (95%CI 1.26;5.63) the chance to present severe malocclusion by the age of 12. Adolescents aged 15 19 whose household income was below R$ 1,500.00 (OR 2.69 [95%CI 1.62; 4.47]) and those who had seen a dentist for treatment (OR 2.59 [95%CI 2.55;4.34]) had the greatest chance of having severe malocclusion compared with those with higher incomes and those who visited the dentist for prevention. PMID- 24626588 TI - [Individual and contextual factors associated with malocclusion in Brazilian children]. AB - OBJECTIVE: To assess the association between the prevalence of malocclusion in Brazilian 12 years-olds with individual and contextual variables. METHODS: A cross-sectional, analytical study was conducted with data from the Brazilian Oral Health Survey - SBBrazil 2010. The outcome studied was malocclusion, categorized as absent, set, severe and very severe. The independent variables were classified as individual and contextual. Data were analyzed using a multilevel model with a 5% significance level. RESULTS: It was found that the prevalence of severe and very severe malocclusion in 12-year-olds did not differ between the Brazilian regions, although variation between the cities was significant (p < 0.001). Male children (p = 0.033), those on lower income (p = 0.051), those who had visited a dentist (p = 0.009), with lower levels of satisfaction with mouth and teeth (p < 0.001) and embarrassed to smile (p < 0.001) had more severe malocclusion. The characteristics of the cities also affected the severity of malocclusion; cities with more families on social benefits per 1,000 inhabitants, with lower scores on the health care system performance index and lower gross domestic product per capita were significantly associated with malocclusion. CONCLUSION: Significant associations between the presence and severity of malocclusion were observed at the individual and contextual level. PMID- 24626589 TI - [Inequalities in untreated dental caries prevalence in preschool children in Brazil]. AB - OBJECTIVE: To evaluate the influence of social inequalities of individual and contextual nature on untreated dental caries in Brazilian children. METHODS: The data on the prevalence of dental caries were obtained from the Brazilian Oral Health Survey (SBBrasil 2010) Project, an epidemiological survey of oral health with a representative sample for the country and each of the geographical micro regions. Children aged five (n = 7,217) in 177 municipalities were examined and their parents/guardians completed a questionnaire. Contextual characteristics referring to the municipalities in 2010 (mean income, fluorodized water and proportion of residences with water supply) were supplied by the Fundacao Instituto Brasileiro de Geografia e Estatistica (Brazilian Institute of Geography and Statistics). Multilevel Poisson regression analysis models were used to assess associations. RESULTS: The prevalence of non-treated dental caries was 48.2%; more than half of the sample had at least one deciduous tooth affected by dental caries. The index of dental caries in deciduous teeth was 2.41, with higher figures in the North and Northeast. Black and brown children and those from lower income families had a higher prevalence of untreated dental caries. With regards context, the mean income in the municipality and the addition of fluoride to the water supply were inversely associated with the prevalence of the outcome. CONCLUSIONS: Inequalities in the prevalence of untreated dental caries remain, affecting deciduous teeth of children in Brazil. Planning public policies to promote oral health should consider the effect of contextual factors as a determinant of individual risk. PMID- 24626590 TI - [Methodological discussion about prevalence of the dental fluorosis on dental health surveys]. AB - OBJECTIVE: To analyze the limitations of studying dental fluorosis in cross sectional studies. METHODS: Data from the Oral Health of the Brazilian Population (SBBrasil 2003) and the Brazilian Oral Health Survey (SBBrasil 2010) were used. Epidemiological trends for fluorosis in 12-year-old Brazilians, aspects of the reliability of the data as well as the accuracy of the estimates are assessed for these two studies. The distribution of prevalence of fluorosis was carried out according to the domains of the study (state capitals and regions) and the year in which the study took place. The confidence intervals (95%CI) were also shown for simple prevalence (without taking into account level of severity). RESULTS: The prevalence of dental fluorosis showed considerable variation, between 0% and 61% in 2003 and 0% and 59% in 2010. Inconsistencies were observed in the data in individual terms (for year and for domain) and in the behavior of the trend. Considering the expected prevalence and the data available in the two studies, the minimum sample size should be 1,500 individuals in order to obtain 3.4% and 6.6% confidence intervals, considering the minimum coefficient of variation to be 15%. Given the subjectivity in its classification, examinations for dental fluorosis may show more variation than those for other oral health conditions. The power to establish differences between the domains of the study with the sample of the SBBrasil 2010 is quite limited. CONCLUSIONS: Based on the 2003 and 2010 studies, it was not possible to analyze patterns of dental fluorosis in Brazil; these data are merely exploratory indicators of the prevalence of dental fluorosis. It was impossible to make comparisons due to different analysis models being used in the two surveys. Investigating dental fluorosis in population-based surveys is not even an economically viable technique, using localized epidemiological studies with a sampling plan would be more suitable [corrected]. PMID- 24626591 TI - [Dental fluorosis in children from Sao Paulo, Southeastern Brazil, 1998-2010]. AB - OBJECTIVE: To assess the trend of dental fluorosis prevalence in 12-year-old children, in the context of exposure to multiple sources of fluoride. METHODS: An analysis was carried out of the trends in prevalence of dental fluorosis in the city of Sao Paulo, Southeastern Brazil, between 1998 and 2010. The rates of prevalence were calculated for different years (1998, 2002, 2008 and 2010) using secondary data obtained from epidemiological surveys of representative samples of 12-year-old children. Occurrence of fluorosis was assessed in natural light using the Dean index, recommended by the World Health Organization and categorized into normal, questionable, very mild, mild, moderate and severe. In 1998, 125 children were examined, 249 in 2002, 4,085 in 2008 and 231 in 2010. RESULTS: In 1998 the prevalence of fluorosis was 43.8% (95%CI 35.6;52.8) in 2002 it was 33.7% (95%CI 28.2;39.8), it was 40.3% (95%CI 38.8;41.8) in 2008 and 38.1% (95%CI 32.1;44.5) in 2010.The categories very mild + mild totaled 38.4% (95%CI 30.3;47.6) in 1998, 32.1% (95%CI 26.6;38.2) in 2002, 38.0% (95%CI 36.5;39.5) in 2008 and 36.4% (95%CI 30.4;42.7) in 2010. Severe fluorosis was not observed, with statistical significance, in the analyzed period. CONCLUSIONS: The prevalence of dental fluorosis in children from Sao Paulo can be classified as stationary between 1998 and 2010, both when considering all categories, and when considering only the categories very mild + mild. PMID- 24626592 TI - [Population surveys as management tools and health care models]. AB - The article briefly systematizes health care models, emphasizes the role of population surveys as a management tool and analyzes the specific case of the Brazilian Oral Health Survey (SBBrasil 2010) and its contribution to the consolidation process of health care models consistent with the principles of the Sistema Unico de Saude (SUS, Public Health Care System). While in legal terms SUS corresponds to a health care model, in actual practice the public policy planning and health action, the system gives rise to a care model which is not the result of legal texts or theoretical formulations, but rather the praxis of the personnel involved. Bearing in mind that the management of day-to-day health affairs is a privileged space for the production and consolidation of health care models, it is necessary to stimulate and support the development of technical and operational skills which are different from those required for the management of care related to individual demands. PMID- 24626593 TI - [Progresses and challenges to the Oral Health Surveillance Policy in Brazil]. AB - This comprehensive critical review, carried out in a descriptive-discursive style, presents the oral health surveillance policy currently in force in Brazil. Based on an appraisal of the national and international literature on the subject of health surveillance, it examines the formulation of a scientific and political agenda for oral health surveillance, which is anchored in the institutions of the Brazilian Public Health System. The accomplishment of this agenda is exemplified by the presentation of the most recent Brazilian Oral Health survey (SBBrasil 2010). A conclusive summary is presented on the search for a theoretical and methodological convergence of both the identification of the obstacles and weaknesses still detectable in this policy, and the recognition of its virtues already confirmed by important advances and achievements. PMID- 24626594 TI - Mid-point for open-ended income category and the effect of equivalence scales on the income-health relationship. AB - To estimate the mid-point of an open-ended income category and to assess the impact of two equivalence scales on income-health associations. Data were obtained from the 2010 Brazilian Oral Health Survey (Pesquisa Nacional de Saude Bucal--SBBrasil 2010). Income was converted from categorical to two continuous variables (per capita and equivalized) for each mid-point. The median mid-point was R$ 14,523.50 and the mean, R$ 24,507.10. When per capita income was applied, 53% of the population were below the poverty line, compared with 15% with equivalized income. The magnitude of income-health associations was similar for continuous income, but categorized equivalized income tended to decrease the strength of association. PMID- 24626595 TI - Effect of hypoxic stress on migration and characteristics of monocytes in uveal melanoma. AB - IMPORTANCE: Among the characteristics of uveal melanoma that are associated with a poor prognosis are a large tumor size and the presence of increased numbers of lymphocytes and macrophages. In rapidly growing tumors, reduction in oxygen tension may occur with increased distance from blood vessels, which we hypothesize may lead to an inflammatory microenvironment, further stimulating tumor growth. OBJECTIVES: To analyze whether hypoxia induces uveal melanoma cells to express proinflammatory cytokines and whether tumor supernatant (TSN) affects monocyte migration and differentiation. DESIGN AND SETTING: The expression of proinflammatory genes in freshly cultured uveal melanoma samples was studied in an in vitro 24-hour hypoxic culture system using quantitative polymerase chain reaction. In addition, cell lines cultured under normoxic and hypoxic conditions were used. The effect of TSN on monocyte chemotaxis was tested using a transwell migration system and by analyzing monocyte differentiation. The levels of the cytokines CCL2, IL6, and PGE2 in TSN were determined by enzyme-linked immunosorbent assay. PARTICIPANTS: Five cell lines (OCM8, 92.1, Mel270,Mel290 and OMM2.5) and 11 primary short-term cultures. RESULTS: Exposure of freshly cultured uveal melanoma cells to hypoxia led to an increased expression of the proinflammatory cytokines PLGF (OMIM 601121), TGFbeta (OMIM 190180), END1 (OMIM +131240), and ICAM1 (OMIM 147840) and a lower expression of AIMP1 (OMIM 603605) (EMAP2), CCL2 (MCP-1) (OMIM +158105), and IL1b (OMIM *147720). The TSN from cultured melanoma cell lines induced chemotaxis of monocytes, but this was independent of the normoxic or hypoxic state. The TSN of 1 cell line and 2 primary uveal melanoma cultures inhibited the dendritic cell maturation and did not induce M2 macrophage polarization in vitro. CONCLUSIONS AND RELEVANCE: Our results indicate that under hypoxic conditions, immune response genes are differentially expressed in cultured primary uveal melanoma cells. The TSN from uveal melanoma cell lines is capable of affecting the chemotactic response and maturation of monocytes in vitro, but this is irrespective of hypoxia. PMID- 24626596 TI - Arsenate stabilized Cu2O nanoparticle catalyst for one-electron transfer reversible reaction. AB - The befitting capping capabilities of AsO4(3-) provide a stable Cu2O nanocatalyst from a galvanic reaction between a Cu(II) precursor salt and As(0) nanoparticles. This stable Cu2O hydrosol appears to be a suitable catalyst for the one-electron transfer reversible redox reaction between Eosin Y and NaBH4. The progress of the reaction relates to three different kinetic stages. In the presence of the new catalyst the reversible redox reaction of Eosin Y in air shows a periodic color change providing a new crowd-pleasing demonstration, i.e. a "clock reaction". PMID- 24626597 TI - Is the physician's behavior in dyslipidemia diagnosis in accordance with guidelines? Cross-sectional ESCARVAL study. AB - BACKGROUND: Clinical inertia has been defined as mistakes by the physician in starting or intensifying treatment when indicated. Inertia, therefore, can affect other stages in the healthcare process, like diagnosis. The diagnosis of dyslipidemia requires >=2 high lipid values, but inappropriate behavior in the diagnosis of dyslipidemia has only previously been analyzed using just total cholesterol (TC). OBJECTIVES: To determine clinical inertia in the dyslipidemia diagnosis using both TC and high-density lipoprotein cholesterol (HDL-c) and its associated factors. DESIGN: Cross-sectional. SETTING: All health center visits in the second half of 2010 in the Valencian Community (Spain). PATIENTS: 11,386 nondyslipidemic individuals aged >=20 years with >=2 lipid determinations. MEASUREMENT VARIABLES: Gender, atrial fibrillation, hypertension, diabetes, cardiovascular disease, age, and ESCARVAL training course. Lipid groups: normal (TC<5.17 mmol/L and normal HDL-c [>=1.03 mmol/L in men and >=1.29 mmol/L in women], TC inertia (TC>=5.17 mmol/L and normal HDL-c), HDL-c inertia (TC<5.17 mmol/L and low HDL-c), and combined inertia (TC>=5.17 mmol/L and low HDL-c). RESULTS: TC inertia: 38.0% (95% CI: 37.2-38.9%); HDL-c inertia: 17.7% (95% CI: 17.0-18.4%); and combined inertia: 9.6% (95% CI: 9.1-10.2%). The profile associated with TC inertia was: female, no cardiovascular risk factors, no cardiovascular disease, middle or advanced age; for HDL-c inertia: female, cardiovascular risk factors and cardiovascular disease; and for combined inertia: female, hypertension and middle age. LIMITATIONS: Cross-sectional study, under reporting, no analysis of some cardiovascular risk factors or other lipid parameters. CONCLUSIONS: A more proactive attitude should be adopted, focusing on the full diagnosis of dyslipidemia in clinical practice. Special emphasis should be placed on patients with low HDL-c levels and an increased cardiovascular risk. PMID- 24626600 TI - A hybrid vanadium fluoride with structurally isolated S = 1 kagome layers. AB - A new organically-templated vanadium(III) fluoride, (NH4)2(C2H8N)[V3F12], has been prepared using an ionothermal approach. This compound has a unique layered structure featuring distorted S = 1 kagome planes separated by the cationic species. The compound exhibits magnetic frustration, with a canted antiferromagnetic ground state. On further cooling in the ground state a pronounced change in magnetisation kinetics is observed. PMID- 24626601 TI - An integrative review of paternal depression. AB - The aim of this project was to review current research regarding postnatal depression in fathers and to present potential screening and referral options. The search was limited to scholarly (peer reviewed) journals and all articles were retrieved with date limits. Initial search parameters were the following: antenatal depression OR pregnancy depression OR postnatal depression OR perinatal depression AND father* OR men OR paternal. The search yielded 311 abstracts returned. With reference to the inclusion criteria and primary and secondary outcomes intended for the focus of this review, N=63 articles were retrieved and read in full by the researchers. These articles were included in the final integrative review. Depression in fathers following the birth of their child was associated with a personal history of depression and with the existence of depression in their partner during pregnancy and soon after delivery. Based on the review the authors suggest routine screening and assessment of both parents should occur across the pregnancy and postnatal period. The use of the Edinburgh Postnatal Depression Scale for screening of depression in men needs to be linked to referral guidelines for those individuals who require further investigation and care. PMID- 24626598 TI - Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. AB - In this in vitro study, we determined whether masitinib could reverse multidrug resistance (MDR) in cells overexpressing the ATP binding cassette subfamily G member 2 (ABCG2) transporter. Masitinib (1.25 and 2.5 uM) significantly decreases the resistance to mitoxantrone (MX), SN38 and doxorubicin in HEK293 and H460 cells overexpressing the ABCG2 transporter. In addition, masitinib (2.5 uM) significantly increased the intracellular accumulation of [(3)H]-MX, a substrate for ABCG2, by inhibiting the function of ABCG2 and significantly decreased the efflux of [(3)H]-MX. However, masitinib (2.5 uM) did not significantly alter the expression of the ABCG2 protein. In addition, a docking model suggested that masitinib binds within the transmembrane region of a homology-modeled human ABCG2 transporter. Overall, our in vitro findings suggest that masitinib reverses MDR to various anti-neoplastic drugs in HEK293 and H460 cells overexpressing ABCG2 by inhibiting their transport activity as opposed to altering their levels of expression. PMID- 24626602 TI - Metabolic syndrome and military policemen's quality of life: an interdisciplinary comprehensive approach. AB - Men generally have a lower life expectancy and higher mortality than women in nearly all age groups. Military police, whose main activity in Brazil is the maintenance of public order and the prevention of crimes and transgressions of the laws, is mostly composed of men; it is also a risky and stressful profession generally related to poor quality of life. Considering that risk factors for disease and death from cardiovascular causes--including the multiple risk factor metabolic syndrome-are mostly related to lifestyle and associated with impaired quality of life, this study aims to provide a theoretical basis for other studies about the prevalence of metabolic syndrome among police officers. In a theoretical study, the authors present an interdisciplinary review based on studies on the health and quality of life of men in general and policemen in their specificity; published studies were selected according to the key words: men, health, quality of life, police, metabolic syndrome; they should also have been published in the past 15 years and available in the Scientific Electronic Library Online--SciELO--and in the Public Medline--PubMed. In conclusion, military policemen have a risky profession, whose conditions may contribute to low quality of life, illness, and mortality from cardiovascular causes; these conditions indicate a need for the characterization of metabolic syndrome in this population as an important element for promotion of health. Studying these conditions may contribute to the adoption of comprehensive and continuing care for military policemen's integral health. PMID- 24626603 TI - Impaired hematopoiesis and delayed thrombopoietic recovery following sublethal irradiation in SRC-3 knockout mice. AB - The objective of the present study was to investigate the role of the steroid receptor coactivator-3 (SRC-3) in hematopoiesis of mouse bone marrow (BM) following total body irradiation (TBI). SRC-3-/- mice and wild-type (WT) mice were exposed to 4.5 Gy gamma rays. Immunoblotting analysis revealed that the SRC 3 protein (p160) levels in normal BM-nucleated cells in WT were higher than in SRC-3-/- mice. Furthermore, peripheral blood cell counts, BM cellularity and colony-forming unit (CFU) assays were performed following irradiation. The results showed that peripheral blood cells were significantly lower in number and recovered less rapidly in irradiated SRC-3-/- mice as compared with control animals. BM-nucleated cell and CFU counts were significantly decreased in SRC-3-/ mice on the 7th and 14th day. Of note, the recovery of platelet (PLT) and megakaryocytic lineage were more depressed than the granulocytic and erythroid lineage in SRC-3-/- mice. In conclusion, the present study demonstrated that the hematopoietic ability in SRC-3 knockout mice is severely impaired following a sublethal dose of irradiation. PMID- 24626604 TI - Type III collagen regulates osteoblastogenesis and the quantity of trabecular bone. AB - Type III collagen (Col3), a fibril-forming collagen, is a major extracellular matrix component in a variety of internal organs and skin. It is also expressed at high levels during embryonic skeletal development and is expressed by osteoblasts in mature bone. Loss of function mutations in the gene encoding Col3 (Col3a1) are associated with vascular Ehlers-Danlos syndrome (EDS). Although the most significant clinical consequences of this syndrome are associated with catastrophic failure and impaired healing of soft tissues, several studies have documented skeletal abnormalities in vascular EDS patients. However, there are no reports of the role of Col3 deficiency on the murine skeleton. We compared craniofacial and skeletal phenotypes in young (6-8 weeks) and middle-aged (>1 year) control (Col3(+/+)) and haploinsufficient (Col3(+/-)) mice, as well as young null (Col3(-/-)) mice by microcomputed tomography (MUCT). Although Col3(+/ ) mice did not have significant craniofacial abnormalities based upon cranial morphometrics, MUCT analysis of distal femur trabecular bone demonstrated significant reductions in bone volume (BV), bone volume fraction (BV/TV), connectivity density, structure model index and trabecular thickness in young adult female Col3(+/-) mice relative to wild-type littermates. The reduction in BV/TV persisted in female mice at 1 year of age. Next, we evaluated the role of Col3 in vitro. Osteogenesis assays revealed that cultures of mesenchymal progenitors collected from Col3(-/-) embryos display decreased alkaline phosphatase activity and reduced capacity to undergo mineralization. Consistent with this data, a reduction in expression of osteogenic markers (type I collagen, osteocalcin and bone sialoprotein) correlates with reduced bone Col3 expression in Col3(+/-) mice and with age in vivo. A small but significant reduction in osteoclast numbers was found in Col3(+/-) compared to Col3(+/+) bones. Taken together, these findings indicate that Col3 plays a role in development of trabecular bone through its effects on osteoblast differentiation. PMID- 24626605 TI - Effect of aquatic exercise on ankylosing spondylitis: a randomized controlled trial. AB - Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease that affects mainly the axial skeleton and causes significant pain and disability. Aquatic (water-based) exercise may have a beneficial effect in various musculoskeletal conditions. The aim of this study was to compare the effectiveness of aquatic exercise interventions with land-based exercises (home based exercise) in the treatment of AS. Patients with AS were randomly assigned to receive either home-based exercise or aquatic exercise treatment protocol. Home-based exercise program was demonstrated by a physiotherapist on one occasion and then, exercise manual booklet was given to all patients in this group. Aquatic exercise program consisted of 20 sessions, 5* per week for 4 weeks in a swimming pool at 32-33 degrees C. All the patients in both groups were assessed for pain, spinal mobility, disease activity, disability, and quality of life. Evaluations were performed before treatment (week 0) and after treatment (week 4 and week 12). The baseline and mean values of the percentage changes calculated for both groups were compared using independent sample t test. Paired t test was used for comparison of pre- and posttreatment values within groups. A total of 69 patients with AS were included in this study. We observed significant improvements for all parameters [pain score (VAS) visual analog scale, lumbar flexion/extension, modified Schober test, chest expansion, bath AS functional index, bath AS metrology index, bath AS disease activity index, and short form-36 (SF-36)] in both groups after treatment at week 4 and week 12 (p < 0.05). Comparison of the percentage changes of parameters both at week 4 and week 12 relative to pretreatment values showed that improvement in VAS (p < 0.001) and bodily pain (p < 0.001), general health (p < 0.001), vitality (p < 0.001), social functioning (p < 0.001), role limitations due to emotional problems (p < 0.001), and general mental health (p < 0.001) subparts of SF-36 were better in aquatic exercise group. It is concluded that a water-based exercises produced better improvement in pain score and quality of life of the patients with AS compared with home-based exercise. PMID- 24626609 TI - Electrodeposited ZnO nanowires as photoelectrodes in solid-state organic dye sensitized solar cells. AB - A new approach for developing solid-state dye-sensitised solar cells (DSSCs) on glass/ITO and plastic substrates (PEN/ITO) is presented in this manuscript. A two step electrodeposition technique has been employed to realize the ZnO photoelectrodes. First a ZnO thin film is deposited on the ITO substrate and subsequently on this buffer layer 650 nm long ZnO nanowires are grown. The different nanostructured electrodes are crystallized and show a transparency close to 80% in the visible spectral range. The electrodes are then sensitized with a new purely organic dye, whose synthesis is presented here, which reveals a wide absorption spectrum and a high molar extinction coefficient. Finally, the sensitized electrodes were employed for the fabrication of liquid and solid-state DSSCs, using, respectively, a liquid iodine/iodide electrolyte and the spiro OMeTAD hole transporter. These devices represent the first solid-state DSSCs fabricated using electrodeposited zinc oxide nanowires. Their power conversion efficiency is still limited, respectively, 0.18% and 0.03% under standard AM 1.5G sunlight (100 mW cm(-2)), nevertheless, these results prove the interest in this low-temperature deposition method for the realization of nanostructured electrodes on rigid and flexible substrates, and open up new perspectives for the development of solid state DSSCs on plastic substrates. PMID- 24626607 TI - Rac-GTPases Regulate Microtubule Stability and Axon Growth of Cortical GABAergic Interneurons. AB - Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics. PMID- 24626608 TI - Enhancing Hebbian Learning to Control Brain Oscillatory Activity. AB - Sensorimotor rhythms (SMR, 8-15 Hz) are brain oscillations associated with successful motor performance, imagery, and imitation. Voluntary modulation of SMR can be used to control brain-machine interfaces (BMI) in the absence of any physical movements. The mechanisms underlying acquisition of such skill are unknown. Here, we provide evidence for a causal link between function of the primary motor cortex (M1), active during motor skill learning and retention, and successful acquisition of abstract skills such as control over SMR. Thirty healthy participants were trained on 5 consecutive days to control SMR oscillations. Each participant was randomly assigned to one of 3 groups that received either 20 min of anodal, cathodal, or sham transcranial direct current stimulation (tDCS) over M1. Learning SMR control across training days was superior in the anodal tDCS group relative to the other 2. Cathodal tDCS blocked the beneficial effects of training, as evidenced with sham tDCS. One month later, the newly acquired skill remained superior in the anodal tDCS group. Thus, application of weak electric currents of opposite polarities over M1 differentially modulates learning SMR control, pointing to this primary cortical region as a common substrate for acquisition of physical motor skills and learning to control brain oscillatory activity. PMID- 24626610 TI - Age, survival predictors, and metastatic death in patients with choroidal melanoma: tentative evidence of a therapeutic effect on survival. AB - OBJECTIVE: To determine whether treatment of choroidal melanoma influences survival by correlating age at death, cause of death, age at treatment, and survival predictors. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study performed at the Liverpool Ocular Oncology Centre, a supraregional, tertiary referral service in England. We included 3072 patients treated for choroidal melanoma from January 15, 1993, through November 23, 2012, and who reside in the mainland United Kingdom. EXPOSURES: A diagnosis of choroidal melanoma (ie, any uveal melanoma involving the choroid). MAIN OUTCOMES AND MEASURES: Largest basal tumor diameter, tumor thickness, TNM stage, ciliary body involvement, extraocular spread, melanoma cytomorphological findings, closed connective tissue loops, mitotic count, chromosome 3 loss, chromosome 6p gain, chromosome 8q gain, age at treatment, age at death, and cause of death. RESULTS: The largest basal tumor diameter correlated with all survival predictors except for chromosome 6p gain. Older age at treatment correlated with ciliary body involvement, extraocular spread, largest basal tumor diameter, tumor thickness, TNM stage, epithelioid cells, chromosome 3 loss, and chromosome 8q gain. A total of 1005 patients had died by the close of the study. The cause of death was metastatic disease due to uveal melanoma in 561 patients. Among the 561 patients, survival time after treatment correlated with sex, basal tumor diameter, ciliary body involvement, extraocular spread, TNM stage, closed loops, and mitotic count. In this group of patients, none of the survival predictors correlated with age at death except for mitotic count, which showed a weak correlation. All survival predictors correlated with an increased likelihood of metastatic melanoma as the cause of death. CONCLUSIONS AND RELEVANCE: Patients who are younger at the time of treatment tend to have a smaller, less extensive tumor with a lower degree of malignancy. A tentative explanation for these findings is that ocular treatment prevents tumor growth, dedifferentiation, and metastatic disease in some patients, especially those with a smaller tumor. PMID- 24626612 TI - Long range charge transfer in trimetallic mixed-valence iron complexes mediated by redox non-innocent cyanoacetylide ligands. AB - The reaction of Fe(C=CC=N)(dppe)Cp (1) with one-half equivalent of [trans Fe(N=CMe)2(dppx)2][BF4]2 (dppx = dppe ([2][BF4]2) or dppm ([3][BF4]2)) affords trimetallic [trans-Fe{N=CC=CFe(dppe)Cp}2(dppx)2][BF4]2 (dppx = dppe [4][BF4]2; dppx = dppm [5][BF4]2). Both [4][BF4]2 and [5][BF4]2 undergo three, one-electron oxidation processes, arising from sequential oxidation of the two terminal Fe(C=CR)(dppe)Cp moieties and finally the central Fe(N=CR)2(dppx)2 fragment. The redox products [4](n+) and [5](n+) (n = 3, 4) have been characterised by UV-vis NIR and IR spectroelectrochemistry. The shifts in the characteristic nu(C=CC=N) bands upon oxidation demonstrate not only the localised electronic structure of the trications, but also the redox non-innocence of the cyanoacetylide ligands. The trimetallic [formally Fe(II/II/III) mixed-valence] complexes [4](3+) and [5](3+) feature two distinct IVCT transitions, one associated with charge transfer from the central 18-electron {Fe(N=CR)2(dppx)2}(2+) to terminal {Fe(C=CR)(dppe)Cp}(+) moiety, and a lower energy transition involving charge transfer between the terminal Fe fragments which are separated by the redox active 9-atom, 10-bond -C=C-C=N{Fe(dppx)2}N=C-C=C- bridge. The tetracationic complexes [4](4+) and [5](4+) generated by a further stepwise oxidation exhibit a single {Fe(N=CR)2(dppx)2}(2+)->{Fe(C=CR)(dppe)Cp}(+) IVCT transition. PMID- 24626611 TI - Evaluation of premature senescence and senescence biomarkers in carcinoma cells and xenograft mice exposed to single or fractionated irradiation. AB - The purpose of the present study was to elucidate whether premature senescence contributes to the outcome of radiotherapy (RT) and to validate senescence biomarkers in vitro and in vivo. Cultured human cancer cell lines and xenografted mice were exposed to single (SR; 2, 6 or 12 Gy) or fractionated radiation (FR; 3 x 2 Gy or 6 x 2 Gy), and premature senescence was assessed using senescence associated beta-galactosidase (SA-beta-Gal) activity, hypophosphorylation of pRb and p21 accumulation. A variety of senescence-associated biomarkers including cathepsin D (CD), the eukaryotic translation elongation factors eEF1A1, eEF1B2, decoy receptor 2 and Dec1 were further validated in vivo or in vitro. We demonstrated the beneficial tumor suppressive role of ionizing radiation (IR) induced premature senescence in vitro and in vivo. FR inhibited tumor growth via induction of premature senescence as effectively as an equivalent SR dose (>=6 Gy). In addition, CD and eEF1 were valuable biomarkers of cellular senescence in either SR- or RF-exposed carcinoma cells or xenograft mice. Our results suggest that 2 Gy of a conventional RT regime could achieve a better clinical outcome if premature senescence could be increased through an improved understanding of its molecular action mechanism. PMID- 24626613 TI - Coexpression of ANXA2, SOD2 and HOXA13 predicts poor prognosis of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is the main type of esophageal cancer, and is the sixth leading cause of cancer-related mortality among all types of cancers. Previously, we found that the homeobox A13 gene (HOXA13) plays a crucial role in the carcinogenesis of ESCC and both Annexin A2 (ANXA2) and superoxide dismutase 2 (SOD2) were its potential targets. Samples from 258 patients from two independent cohorts were collected. RT-qPCR and immunohistochemistry (IHC) were used to detect the expression levels of HOXA13, ANXA2 and SOD2. Kaplan-Meier survival curve analysis and Cox proportional hazards regression model were employed to determine their prognostic significance. Results showed that ESCC tissues had higher ANXA2 and SOD2 mRNA and protein levels than the non-cancerous tissues. ANXA2 and SOD2 were found to be positively correlated with HOXA13 expression not only at the mRNA level but also at the protein level. In both the study cohort and the validation cohort, the median overall survival time of patients with high expression of HOXA13, ANXA2 and SOD2 was shorter than the survival time of the patients with low expression. The Cox proportional hazards model revealed that both TNM stage and coexpression of HOXA13/ANXA2/SOD2 are independent predictors of overall survival of ESCC patients. In conclusion, the present study demonstrated that ANXA2 and SOD2 are potential target genes of HOXA13 and their coexpression predicts the poor prognosis of ESCC patients. PMID- 24626614 TI - A rhomboid-shaped organic host molecule with small binding space. Unsymmetrical and symmetrical inclusion of halonium ions. AB - A shape persistent rhomboid-shaped organic host molecule having two pyridyl units was synthesized which induces size selective halonium inclusion. Cl(+) and Br(+) are included to form unsymmetric and symmetric complexes, while I(+) does not form a stable complex. The difference among the haloniums was ascribed to the matching (or mismatching) of the shape of the cavity and the guest ions. The complexation of the host molecule with other cations, such as Ag(+), Pd(2+), Zn(2+) and H(+), is also mentioned. PMID- 24626615 TI - Improving comprehension and accuracy of health questionnaires using pictorial descriptions. PMID- 24626616 TI - Hemoglobin A1c: a reliable and accurate test for diabetes care? A prospective study in Mexico. AB - OBJECTIVE: To compare the concordance correlation coefficient for HbA1c results in an in-field experience. MATERIALS AND METHODS: A prospective study in Monterrey, Mexico from April to August 2012 was conducted to evaluate the day-to day clinical situation when measuring HbA1c. Blood samples from 38 consecutive patients were sent to seven local laboratories and one international reference laboratory. RESULTS: Poor concordance was found in 4 out of 7 laboratories, moderate in 2 out of 7, and significant in just one. HbA1c values from three laboratories fluctuated more than 1% above or below the reference laboratory in more than 30% of cases, and more than 2% in 10%-20% of subjects. CONCLUSIONS: Standardized HbA1c measurement has not occurred worldwide. Physicians should be aware of this issue and be cautious of HbA1c guidelines on diabetes diagnosis or management until proper standardization programs are implemented. PMID- 24626617 TI - [In situ and invasive carcinoma identified through an opportunistic screening mammography in asymptomatic women in Mexico City]. AB - OBJECTIVE: To describe the mammographic findings and carcinoma detection rate in asymptomatic women of Mexico City, that participated in an opportunistic screening program. MATERIALS AND METHODS: 39 491 participants were included, with mammograms performed and interpreted in the National Cancer Institute, from 2008 to 2011. The mammographic findings, type of lesion and true positives (TP), are described by age groups. We calculated the crude effect of age on the classification BIRADS (Breast Imaging Reporting and Data System) 0 and the type of lesion. RESULTS: The median age was 50 (45-57) years. 80.5% were classified as BIRADS 2, 11.4%(0), 4.1%(1), 3.5%(3), 0.5%(4) y 0.1%(5). Malignant lesions were detected in 1.3 and 3.3 per 1000 and the proportion of true positives (TP) was 8.2% and 20.6%, in women of 41-50 and 51-70 years, respectively. CONCLUSIONS: Although some cases are detected in women 40 to 50 years, in women over 50 years the screening by mammography is more efficient, with a higher proportion of cases detected and fewer false positives. PMID- 24626618 TI - Low prevalence of iron deficiency anemia between 1981 and 2010 in Chilean women of childbearing age. AB - OBJECTIVE: To determine the prevalence of anemia and iron status among Chilean women of childbearing age between 1981 and 2010. MATERIALS AND METHODS: Calculation of the prevalence of anemia and iron status was based on multiple cross-sectional iron absorption studies performed in 888 women during this period of time. All studies included measurements of hemoglobin, mean corpuscular volume, zinc protoporphyrin, percentage of transferrin saturation and serum ferritin. Data were grouped by decade (1981-1990, 1991-2000, and 2001-2010). RESULTS: Prevalence of anemia for these decades was 9, 6 and 10%, respectively (p=NS). Iron deficiency anemia was the main cause of anemia in all periods (55, 85 and 75%, respectively; p=NS). A high prevalence of women with normal iron status was observed for all periods (64, 69, and 67, respectively; p=NS). Prevalence of iron deficiency without anemia in 1981-1990, 1991-2000 and 2001 2010 was 7, 20 and 12%, respectively (p<0.05). Finally, prevalence of iron depleted stores was 20, 6 and 10%, respectively (p<0.05). CONCLUSIONS: Prevalence of iron deficiency anemia in Chilean women of childbearing age was mild between 1981 and 2010. More than 60% of childbearing age women presented normal iron status in all periods. However, prevalence of iron depleted stores was moderate during 1981-1990, and was mild during 1991-2000 and 2001-2010. PMID- 24626619 TI - Screen time in Mexican children: findings from the 2012 National Health and Nutrition Survey (ENSANUT 2012). AB - OBJECTIVE: To provide descriptive information on the screen time levels of Mexican children. MATERIALS AND METHODS: 5 660 children aged 10-18 years from the 2012 National Health and Nutrition Survey (ENSANUT 2012) were studied. Screen time (watching television, movies, playing video games and using a computer) was self-reported. RESULTS: On average, children engaged in 3 hours/day of screen time, irrespective of gender and age. Screen time was higher in obese children, children from the northern and Federal District regions of the country, children living in urban areas, and children in the highest socioeconomic status and education categories. Approximately 33% of 10-14 year olds and 36% of 15-18 year olds met the screen time guideline of <= 2 hours/day. CONCLUSIONS: 10-18 year old Mexican children accumulate an average of 3 hours/day of screen time. Two thirds of Mexican children exceed the recommended maximal level of time for this activity. PMID- 24626620 TI - Association between leisure-time physical activity and hypertension status in Korean adults. AB - OBJECTIVE: To examine whether leisure-time physical activity (PA) is associated with hypertension status in Korean adults (men, 586; women, 1135) who visited a public health promotion center for a medical checkup in Seoul from 2010 to 2011. MATERIALS AND METHODS: Multivariate logistic regression analysis adjusted for age, body mass index, sleep duration, mental stress, education level, economic status, and drinking and smoking frequencies was performed. RESULTS: Odds ratios and 95% confidence intervals for having hypertension and performing PA compared to having hypertension and not performing PA were not significant for both sexes regardless of the PA frequency and intensity, except for moderate PA 3 times per week in women. CONCLUSION: We conclude that PA has no or little association with hypertension status in Korean adults. PMID- 24626622 TI - [Design and evaluation of a ovitrap for monitoring and control of Aedes aegypti, dengue fever vector]. AB - OBJECTIVE: To design and evaluate in field conditions an ovitrap with chemical attractants and a population regulator for the monitoring and control of dengue vectors. MATERIALS AND METHODS: CRISPP ovitrap (OC) effectiveness was evaluated in comparison with a standard ovitrap (OE). A septum containing two chemical attractants and a mesh tricot on the surface of the water was collocated in the OC. The number of eggs in both ovitraps and the mortality of the emerged adults were counted. Also the residual effect was determined. RESULTS: There were a total of 7168 eggs, 4659 (65%) were layed in the OC and 2509 (35%) in the OE and the emergence of adults in the OC was 0% compared with 93% in the OE. The residual effect was four days. CONCLUSIONS: The OC contained more eggs and caused minor emergency dengue vector adults in comparison with the OE. PMID- 24626621 TI - [Dexamethasone and diclofenac by LC-MS-MS as herbal product adulterants]. AB - OBJECTIVE: To confirm the presence of dexamethasone and diclofenac as adulterants of an herbal product. MATERIALS AND METHODS: For identificaction and confirmation of drugs a method of instrumental analysis by liquid chromatography coupled with high pressure tandem mass spectrometry was used. RESULTS: The presence of dexamethasone and diclofenac was confirmed in samples of 11 bottles of Reumofan Plus obtained from patients and/or physicians. The methodology used, allowed separation of stereoisomers dexamethasone and betamethasone, the relative abundances of product ions 237.2 and 279.2 m / z spectrally differentiate the compounds. CONCLUSIONS: The presence of dexamethasone and diclofenac was confirmed in samples of a product marketed as "100% natural" obtained from patients and / or physicians in a period from January to December, 2011. PMID- 24626623 TI - [Sociocultural epidemiology: an essential aproach]. AB - The necessity of an inclusive epidemiological approach, capable to attend the diverse dimensions involved in health damage as a reflective phenomenon of society is analyzed. The range of perspectives involved requires an inclusive methodological scope and applicative channels, in order to deal with sanitary realities systematically related to culture and social organization. Some constitutive elements of sociocultural epidemiology are underlined, shaping an operative proposal that can enhance the relationship between disciplines and sectors regarding specific outstanding public health problems. PMID- 24626624 TI - [Social service in medicine in Mexico: an urgent and possible reform]. AB - One third of the primary care units in the public system keeps being covered exclusively by interns. It is shown that with the resources available in the System for Social Protection in Health it is possible to hire graduate health personnel for all Ministry of Health rural units. It is necessary to modify the current legislation to impede an intern to be located in units without supervision of a graduate doctor. There is an urgent need for a reform of social service in medicine that responds both to the institutional modernization and to the increased capacity of the newly insured to demand high-quality services. PMID- 24626625 TI - [Academic modernization of Mexican School of Public Health: 1983-1995]. AB - In this paper we discuss the recent efforts to modernize the School of Public Health of Mexico (ESPM). In the first part we analyze the conditions in which the ESPM operated at the beginning of the 1980s. In part two we describe the changes introduced in the ESPM between 1983 and 1986, up until its incorporation into the National Institute of Public Health (INSP). In part three we discuss the conceptual renovation which built the platform for the new academic programs introduced by the School between 1987 and 1995. In the fourth part we discuss the construction of the new facilities of INSP and the process of moving to the city of Cuernavaca. The main message of this paper is that the transformations witnessed by the ESPM in the final decades of the past century turned it into a true academic institution which uses research as the motor for training of human resources in public health. PMID- 24626626 TI - [The World Health Report 2013: a path for research on universal health coverage]. PMID- 24626628 TI - Oncogenic effects of WNT5A in Epstein-Barr virus-associated nasopharyngeal carcinoma. AB - The molecular events that drive the progression of Epstein-Barr virus (EBV) associated nasopharyngeal carcinoma (NPC) are still to be elucidated. Here, we report for the first time the pathogenic significance of an NPC-associated gene, wingless-type MMTV integration site family, member 5A (WNT5A) and the contribution of EBV to its expression. WNT5A is a representative Wnt protein that activates non-canonical Wnt signalling. With regard to its role in carcinogenesis, there is conflicting evidence as to whether WNT5A has a tumour promoting or tumour-suppressive role. We show that WNT5A is upregulated in primary NPC tissue samples. We also demonstrate that WNT5A expression was dramatically increased in NPC cell lines expressing the EBV-encoded LMP2A gene, suggesting that this EBV-encoded latent gene is responsible for upregulating WNT5A in NPC. In addition, in vitro WNT5A overexpression promotes the proliferation, migration and invasion of NPC cells. Our results not only reveal pro-tumorigenic effects of WNT5A in NPC but also suggest that WNT5A could be an important therapeutic target in patients with EBV-associated disease. PMID- 24626629 TI - Co-stimulation with stem cell factor and erythropoietin enhances migration of c Kit expressing cervical cancer cells through the sustained activation of ERK1/2. AB - The cytokines erythropoietin (Epo) and stem cell factor (SCF), coupled with the cooperation between their receptors (EpoR and c-Kit), are essential components of normal physiological erythropoiesis. In earlier studies, we demonstrated the expression of c-Kit and EpoR in cervical cancer cells. It was identified that SCF is a survival factor, whereas Epo promotes cell proliferation. Cooperation between EpoR and SCF in cervical cancer has rarely been studied, despite the fact that cell migration and anchorage independent growth are considered initial steps in metastasis. Thus, the aim of this study was to analyse the effect of SCF and Epo alone, or in combination, on the migration and anchorage independent growth of two cervical cancer-derived cell lines. First, we demonstrated the expression of EpoR and c-Kit in the cell lines. Next, we evaluated anchorage independent growth, and identified that Epo and SCF produced a modest number of colonies, whereas the combination Epo/SCF induced a significantly higher number of colonies. Migration was then evaluated in Boyden chambers. Co-stimulation with Epo/SCF induced a significantly higher number of migrating cells than either cytokine alone. SCF-, Epo- and Epo/SCF-induced migration was inhibited by blocking phosphorylation of Janus kinase 2 (JAK2). Accordingly, western blot analysis demonstrated that the JAK2/signal transducer and activator of transcription-5 (STAT5) axis was activated in all cases. By contrast, inhibition of extracellular signal-related kinase (ERK) 1/2 abrogated migration induced by SCF and Epo/SCF only. Concurrently, Epo induced a modest, transient activation of ERK1/2, whereas SCF and Epo/SCF prompted a strong, sustained phosphorylation of ERK1/2. The results from this study have revealed that co-stimulation with Epo/SCF promotes migration and anchorage independent cell growth, and that co signalling from EpoR and c-Kit converge on JAK2/STAT5 activation. Furthermore, SCF- and Epo/SCF-induced migration depends on the sustained activation of ERK1/2. These results indicate that co-signalling from different cytokine receptors induces migration, and this suggests that migratory behaviour may be regulated by the cooperative activity of Epo and SCF in cells expressing their cognate receptors. PMID- 24626631 TI - Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability. AB - We describe the characterization of a gene for mild nonsyndromic autosomal recessive intellectual disability (ID) in two unrelated families, one from Austria, the other from Pakistan. Genome-wide single nucleotide polymorphism microarray analysis enabled us to define a region of homozygosity by descent on chromosome 17q25. Whole-exome sequencing and analysis of this region in an affected individual from the Austrian family identified a 5 bp frameshifting deletion in the METTL23 gene. By means of Sanger sequencing of METTL23, a nonsense mutation was detected in a consanguineous ID family from Pakistan for which homozygosity-by-descent mapping had identified a region on 17q25. Both changes lead to truncation of the putative METTL23 protein, which disrupts the predicted catalytic domain and alters the cellular localization. 3D-modelling of the protein indicates that METTL23 is strongly predicted to function as an S adenosyl-methionine (SAM)-dependent methyltransferase. Expression analysis of METTL23 indicated a strong association with heat shock proteins, which suggests that these may act as a putative substrate for methylation by METTL23. A number of methyltransferases have been described recently in association with ID. Disruption of METTL23 presented here supports the importance of methylation processes for intact neuronal function and brain development. PMID- 24626632 TI - Eccentric muscle challenge shows osteopontin polymorphism modulation of muscle damage. AB - A promoter polymorphism of the osteopontin (OPN) gene (rs28357094) has been associated with multiple inflammatory states, severity of Duchenne muscular dystrophy (DMD) and muscle size in healthy young adults. We sought to define the mechanism of action of the polymorphism, using allele-specific in vitro reporter assays in muscle cells, and a genotype-stratified intervention in healthy controls. In vitro reporter constructs showed the G allele to respond to estrogen treatment, whereas the T allele showed no transcriptional response. Young adult volunteers (n = 187) were enrolled into a baseline study, and subjects with specific rs28357094 genotypes enrolled into an eccentric muscle challenge intervention [n = 3 TT; n = 3 GG/GT (dominant inheritance model)]. Female volunteers carrying the G allele showed significantly greater inflammation and increased muscle volume change as determined by magnetic resonance imaging T1- and T2-weighted images after eccentric challenge, as well as greater decrement in biceps muscle force. Our data suggest a model where the G allele enables enhanced activities of upstream enhancer elements due to loss of Sp1 binding at the polymorphic site. This results in significantly greater expression of the pro inflammatory OPN cytokine during tissue remodeling in response to challenge in G allele carriers, promoting muscle hypertrophy in normal females, but increased damage in DMD patients. PMID- 24626634 TI - Identification of hypo- and hypermethylated genes related to atherosclerosis by a genome-wide analysis of DNA methylation. AB - Epigenetic modification, particularly changes in DNA methylation at gene promoters, is implicated in the pathogenesis of atherosclerosis. However, the analysis of DNA methylation in atherosclerosis has been limited to a few selected candidate genes. In this study, we therefore performed a genome-wide analysis of DNA methylation in the atherosclerotic human aorta. A total of 48 post-mortem human aortic intima specimens were examined. To avoid the effects of interindividual variation, we performed intraindividual paired comparisons between atheromatous plaque lesions and corresponding plaque-free tissue for 24 subjects. Bisulfite-modified genomic DNA was analyzed for DNA methylation with a specific microarray (Illumina HumanMethylation450 BeadChip). We compensated for multiple comparisons by applying Bonferroni's correction for statistical significance of association. DNA methylation was significantly (P<1.03x10-7) reduced at 15 CpG sites in 14 genes and increased at 30 CpG sites in 22 genes in atheromatous plaque compared with plaque-free intima. Three of the hypomethylated genes [Drosophila headcase (HECA), early B-cell factor 1 (EBF1) and nucleotide binding oligomerization domain containing 2 (NOD2)] and three of the hypermethylated genes [human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), zinc finger E-box binding homeobox 1 (ZEB1) and FYN] were previously been implicated in atherosclerosis. The overexpression of HECA, EBF1 or NOD2 or the suppression of MAP4K4, ZEB1 or FYN expression in cultured HEK293 cells resulted in significant (P<4.80x10-7) changes in the expression of atherosclerosis-related genes, as determined with an expression microarray (Illumina HumanHT-12 v4 Expression BeadChip). Our findings suggested that HECA, EBF1 and NOD2 were significantly hypomethylated, whereas MAP4K4, ZEB1 and FYN were hypermethylated, in atheromatous plaque lesions compared with plaque-free intima. Epigenetic mechanisms may thus contribute to the pathogenesis of atherosclerosis. PMID- 24626633 TI - Genetic suppression of beta2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. AB - Accumulation of the microtubule-binding protein tau is a key event in several neurodegenerative disorders referred to as tauopathies, which include Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Thus, understanding the molecular pathways leading to tau accumulation will have a major impact across multiple neurodegenerative disorders. To elucidate the pathways involved in tau pathology, we removed the gene encoding the beta-2 adrenergic receptors (beta2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of beta2ARs is increased in brains of AD patients and epidemiological studies show that the use of beta-blockers decreases the incidence of AD. The mechanisms underlying these observations, however, are not clear. We show that the tau transgenic mice lacking the beta2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the beta2ARs from the tau transgenic mice also significantly improved motor deficits. Neuropathologically, the improvement in lifespan and motor function was associated with a reduction in brain tau immunoreactivity and phosphorylation. Mechanistically, we provide compelling evidence that the beta2AR-mediated changes in tau were linked to a reduction in the activity of GSK3beta and CDK5, two of the major tau kinases. These studies provide a mechanistic link between beta2ARs and tau and suggest the molecular basis linking the use of beta-blockers to a reduced incidence of AD. Furthermore, these data suggest that a detailed pharmacological modulation of beta2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies. PMID- 24626635 TI - Single-molecule magnet engineering: building-block approaches. AB - Tailoring the specific magnetic properties of any material relies on the topological control of the constituent metal ion building blocks. Although this general approach does not seem to be easily applied to traditional inorganic bulk magnets, coordination chemistry offers a unique tool to delicately tune, for instance, the properties of molecules that behave as "magnets", the so-called single-molecule magnets (SMMs). Although many interesting SMMs have been prepared by a more or less serendipitous approach, the assembly of predesigned, isolatable molecular entities into higher nuclearity complexes constitutes an elegant and fascinating strategy. This Feature article focuses on the use of building blocks or modules (both terms being used indiscriminately) to direct the structure, and therefore also the magnetic properties, of metal ion complexes exhibiting SMM behaviour. PMID- 24626636 TI - An atomistic insight into the corrosion of the oxide film in liquid lead-bismuth eutectic. AB - When used as a protective scale, the Fe3O4 layer covering the stainless steel surface in accelerator driven subcritical systems (ADS) is corroded by liquid lead-bismuth eutectics (LBE). By performing theoretical calculations, we reveal that both Pb and Bi at the interface between the LBE and the Fe3O4 scale, favorably adsorb onto the Fe3O4 surfaces, weakening the strength of Fe-O bonds nearby significantly. This facilitates the movement of iron atoms toward the deposited Pb(Bi) and away from the Fe3O4 surface, thus causing corrosion. Such corrosion behavior becomes severe if oxygen vacancies exist in the surface region. PMID- 24626637 TI - Tungsten doped titanium dioxide nanowires for high efficiency dye-sensitized solar cells. AB - Metal oxide semiconductors offering simultaneously high specific surface area and high electron mobility are actively sought for fabricating high performance nanoelectronic devices. The present study deals with synthesis of tungsten doped TiO2 (W:TiO2) nanowires (diameter ~50 nm) by electrospinning and evaluation of their performance in dye-sensitized solar cells (DSCs). Similarity in the ionic radii between W(6+) and Ti(4+) and availability of two free electrons per dopant are the rationale for the present study. Materials were characterized by X-ray diffraction, scanning and transmission electron microscopy, X-ray fluorescence measurements, and absorption spectroscopy. Nanowires containing 2 at% W:TiO2 gave 90% higher short circuit current density (JSC) (~15.39 mA cm(-2)) in DSCs with a nominal increase in the open circuit voltage compared with that of the undoped analogue (JSC ~8.1 mA cm(-2)). The results are validated by multiple techniques employing absorption spectroscopy, electrochemical impedance spectroscopy and open circuit voltage decay. The above studies show that the observed increments resulted from increased dye-loading, electron density, and electron lifetime in tungsten doped samples. PMID- 24626638 TI - Altered brain activation during action imitation and observation in schizophrenia: a translational approach to investigating social dysfunction in schizophrenia. AB - OBJECTIVE: Social impairments are a key feature of schizophrenia, but their underlying mechanisms are poorly understood. Imitation, a process through which we understand the minds of others, involves the so-called mirror neuron system, a network comprising the inferior parietal lobe, inferior frontal gyrus, and posterior superior temporal sulcus. The authors examined mirror neuron system function in schizophrenia. METHOD: Sixteen medicated schizophrenia patients and 16 healthy comparison subjects performed an action imitation/observation task during functional MRI. Participants saw a video of a moving hand or spatial cue and were instructed to either execute finger movements associated with the stimulus or simply observe. Activation in the mirror neuron system was measured during imitative versus nonimitative actions and observation of a moving hand versus a moving spatial cue. These contrasts were compared across groups. RESULTS: Activation in the mirror neuron system was less specific for imitation in schizophrenia. Relative to healthy subjects, patients had reduced activity in the posterior superior temporal sulcus during imitation and greater activity in the posterior superior temporal sulcus and inferior parietal lobe during nonimitative action. Patients also showed reduced activity in these regions during action observation. Mirror neuron system activation was related to symptom severity and social functioning in patients and to schizotypal syndrome in comparison subjects. CONCLUSIONS: Given the role of the inferior parietal lobe and posterior superior temporal sulcus in imitation and social cognition, impaired imitative ability in schizophrenia may stem from faulty perception of biological motion and transformations from perception to action. These findings extend our understanding of social dysfunction in schizophrenia. PMID- 24626639 TI - Nilotinib combined with interleukin-2 mediates antitumor and immunological effects in a B16 melanoma model. AB - The immune system contributes to tumor cell killing which can be enhanced by cancer chemotherapeutics and immune modulatory pharmaceuticals such as tyrosine kinase inhibitors (TKIs). Recently, the beneficial effect of natural killer (NK) cells was demonstrated when combining interleukin-2 (IL-2) with the TKI imatinib. The aim of the present study was to address the antitumor and immunological effects of recently approved TKIs. Therefore, we focused on the comparison of the efficacy between imatinib and nilotinib in combination with IL-2 in a murine B16F10 melanoma model. Both TKIs possessed antitumor activity in vivo. However, the combination of nilotinib and IL-2 showed a superior outcome. Importantly, both the use of immunodeficient Rag2gammac-/- mice, which lack T-lymphocytes, B lymphocytes and NK cells, as well as NK cell-depletion in C57Bl/6 mice reduced the therapeutic effect of nilotinib. Flow cytometry revealed a significant increase in the IFN-gamma-producing CD27+ NK cell subpopulation following treatment with nilotinib and IL-2. Furthermore, the therapeutic antitumor effect of nilotinib/IL-2 was completely lost in IFN-gamma-/- mice. In summary, we suggest that nilotinib combined with IL-2 confers high antitumor activity involving the subset of IFN-gamma-producing CD27+ NK cells. These new insights are of high importance for the understanding and development of immunotherapeutic protocols using TKIs. PMID- 24626640 TI - Controlling uniformity of photopolymerized microscopic hydrogels. AB - This paper studies hydrogels created by photopolymerization with a uniform beam of light. Under some conditions the density profiles of the resulting hydrogels were uniform cylinders, mirroring the illumination profiles. However, under other conditions, gels with hollow cylindrical shapes were formed. We studied the photopolymerization of poly-N-isopropylacrylamide (pNIPAAM), a hydrogel that has been widely used in tissue engineering and microfluidic applications, and examined how the size and uniformity of pNIPAAM microscopic gels can be controlled by varying parameters such as exposure time, exposure area, exposure intensity, monomer concentration, photoinitiator concentration and terminator concentration. A simplified reaction-diffusion model of the polymerization process was developed and was found to describe the experiment for a wide range of parameters. This general framework will guide attempts to establish optimal conditions for the construction of microscopic hydrogels using photolithography, which is a method that has found applications in fields such as microfluidics, drug delivery, cell and tissue culturing, and high resolution 3D printing. PMID- 24626641 TI - Mitofusin 1 degradation is induced by a disruptor of mitochondrial calcium homeostasis, CGP37157: a role in apoptosis in prostate cancer cells. AB - Mitochondria constantly divide (mitochondrial fission) and fuse (mitochondrial fusion) in a normal cell. Disturbances in the balance between these two physiological processes may lead to cell dysfunction or to cell death. Induction of cell death is the prime goal of prostate cancer chemotherapy. Our previous study demonstrated that androgens increase the expression of a mitochondrial protein involved in fission and facilitate an apoptotic response to CGP37157 (CGP), an inhibitor of mitochondrial calcium efflux, in prostate cancer cells. However, the regulation and role of mitochondrial fusion proteins in the death of these cells have not been examined. Therefore, our objective was to investigate the effect of CGP on a key mitochondrial fusion protein, mitofusin 1 (Mfn1), and the role of Mfn1 in prostate cancer cell apoptosis. We used various prostate cancer cell lines and western blot analysis, qRT-PCR, siRNA, M30 apoptosis assay and immunoprecipitation techniques to determine mechanisms regulating Mfn1. Treatment of prostate cancer cells with CGP resulted in selective degradation of Mfn1. Mfn1 ubiquitination was detected following immunoprecipitation of overexpressed Myc-tagged Mfn1 protein from CGP-treated cells, and treatment with the proteasomal inhibitor lactacystin, as well as siRNA-mediated knockdown of the E3 ubiquitin ligase March5, protected Mfn1 from CGP-induced degradation. These data indicate the involvement of the ubiquitin-proteasome pathway in CGP-induced degradation of Mfn1. We also demonstrated that downregulation of Mfn1 by siRNA enhanced the apoptotic response of LNCaP cells to CGP, suggesting a likely pro survival role for Mfn1 in these cells. Our results suggest that manipulation of mitofusins may provide a novel therapeutic advantage in treating prostate cancer. PMID- 24626642 TI - SOCS3 and SOCS6 are required for the risperidone-mediated inhibition of insulin and leptin signaling in neuroblastoma cells. AB - Antipsychotic drugs are regularly used for the treatment of many types of psychiatric disorders. The administration of second-generation antipsychotics is often associated with weight gain and the development of diabetes mellitus; however, the molecular mechanisms underlying the effects of these drugs remain poorly understood. Leptin and insulin play key roles in the regulation of energy balance and glucose homeostasis, and resistance to the actions of these hormones can occur with obesity and inflammation, resulting in the pathogenesis of obesity and type 2 diabetes. In this study, the effects of risperidone on the insulin induced protein kinase B (PKB) phosphorylation and leptin-stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation were investigated in the human SH-SY5Y neuroblastoma cell line. The treatment of these cells with risperidone induced the activation of extracellular signal-related kinase (ERK) by cellular cyclic adenosine 3-monophosphate (cAMP)-dependent protein kinase (also known as protein kinase A; PKA) and the mechanisms involved include the induction of suppressor of cytokine signaling 3 (SOCS3) and suppressor of cytokine signaling 6 (SOCS6) expression. The risperidone-induced ERK activation induced an upregulation of SOCS3 and SOCS6 mRNA expression levels. Taken together, these results suggest that risperidone modulates SOCS3 and SOCS6 expression through adenylate cyclase-mediated ERK activation, which, in turn, leads to an inhibition of insulin-induced PKB phosphorylation and leptin stimulated STAT3 phosphorylation. Eventually, these effects result in excessive body weight gain due to the inhibition of both the leptin and insulin signaling pathways. PMID- 24626644 TI - Acquired hyperpigmentations. AB - Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis. PMID- 24626647 TI - Chilblains in Turkey: a case-control study. AB - BACKGROUND: Chilblains are rather common in winter months in our country. OBJECTIVES: Determination of demographical and clinical characteristics of patients presenting with chilblains in Diyarbakir, Turkey. Evaluation of body mass index (BMI) as risk factor for development of chilblains. METHODS: Sixty nine patients who were diagnosed as chilblains at our outpatient clinics were included in this study. No exclusion criteria were sought. Demographical data including height and weight and answers to questions related to personal history were recorded. A control group consisting of 108 controls were chosen from among patients presenting with complaints of hair loss. Statistical analyses were conducted using SPSS 17.0. RESULTS: Of the 69 patients with chilblains, 45 (65.2%) were females and 24 (34.8%) were males. Mean age (+/- SD) of the patients was 21 +/- 9. 71.2% of the patients complained of itching, 51.6% of pain, 31.3% of burning in the lesions. 61.3% of the patients reported recurrence of the lesions every winter season. Mean BMI of the patients was 20.5 +/- 2.9. Mean BMI of the controls was 22.4 +/- 3.7 and the difference was statistically significant (p=0.01). CONCLUSIONS: Low BMI may be a risk factor contributing to development of chilblains in persons exposed to cold weather conditions. Apart from external factors, there seems to be a personal tendency to develop lesions, as many patients report recurrences every year. Diagnosis of chilblains requires wariness, as history of cold exposure may not be evident. PMID- 24626646 TI - Utility of dermoscopy for demarcation of surgical margins in Mohs micrographic surgery. AB - BACKGROUND: Skin cancer is the most common malignancy and can be treated in various ways. One treatment modality is Mohs micrographic surgery. Due to the increasing incidence of skin cancer in the last decades, there is a need for improvement of the Mohs technique to optimize its effectiveness. OBJECTIVE: The aim of this study was to evaluate the use of dermoscopy to guide demarcation of Mohs micrographic surgery margins and ascertain whether this method can reduce operative time and, therefore, reduce surgical morbidity and cost. METHODS AND MATERIALS: The sample comprised 44 patients who underwent Mohs micrographic surgery, allocated into two groups: the control group and the intervention group. In the latter, surgical margins were guided by dermoscopy. RESULTS: There were no statistically significant differences between the two groups by chi-square analysis (p = 0.399). CONCLUSION: Although outcomes were similar in the two groups, demonstrating that dermoscopy does not help in the demarcation of surgical margins for Mohs micrographic surgery, the study provides a practical proposal for improvement of the Mohs technique. PMID- 24626645 TI - Incontinentia pigmenti. AB - Incontinentia pigmenti is a rare genodermatosis in which the skin involvement occurs in all patients. Additionally, other ectodermal tissues may be affected, such as the central nervous system, eyes, hair, nails and teeth. The disease has a X-linked dominant inheritance pattern and is usually lethal to male fetuses. The dermatological findings occur in four successive phases, following the lines of Blaschko: First phase - vesicles on an erythematous base; second phase - verrucous hyperkeratotic lesions; third phase - hyperchromic spots and fourth phase - hypochromic atrophic lesions. PMID- 24626648 TI - American tegumentary leishmaniasis: correlations among immunological, histopathological and clinical parameters. AB - BACKGROUND: American tegumentary leishmaniasis has an annual incidence of 1 to 1.5 million cases. In some cases, the patient's immune response can eliminate the parasite, and the lesion spontaneously resolves. However, when this does not occur, patients develop the disseminated form of the disease. OBJECTIVE: To investigate the association between clinical, laboratory and pathological findings in cases of American tegumentary leishmaniasis. METHODS: A retrospective study of the medical records of 47 patients with American cutaneous leishmaniasis. Clinical, laboratory and epidemiological data were collected, and semi-quantitative histopathological analyses were performed using the Spearman correlation coefficient (p <0.05). RESULTS: Mean patient age was 40.5 years. A total of 29.7% individuals were female and 70.2% were male, and 40.4% of the patients were farmers. The ulcerative form was found in 53.2% of patients, of whom 59.6% had lesions in the limbs. The average time to diagnosis was 22.3 months. The following positive correlations were significant: age and duration of the disease, Montenegro reaction, degree of granulomatous transformation and epithelioid cell count; duration of disease, Montenegro reaction and number of lymphocytes; epithelial hyperplasia and edema, hemorrhaging, and epithelial aggression; number of plasmocytes and number of parasites. The main negative correlations found were as follows: age and serology; time and parasite load; epithelial hyperplasia and degree of granulomatous transformation. CONCLUSION: The long duration of the disease could be explained by the fact that lesions were relatively asymptomatic, and therefore ignored by patients with low literacy levels. Individuals may have simply waited for spontaneous healing, which proved to be dependent on the activation of hypersensitivity mechanisms. PMID- 24626649 TI - Adult mastocytosis: a review of the Santo Antonio Hospital 's experience and an evaluation of World Health Organization criteria for the diagnosis of systemic disease. AB - BACKGROUND: Mastocytosis is a clonal disorder characterized by the accumulation of abnormal mast cells in the skin and/or in extracutaneous organs. OBJECTIVES: To present all cases of mastocytosis seen in the Porto Hospital Center and evaluate the performance of World Health Organization diagnostic criteria for systemic disease. METHODS: The cases of twenty-four adult patients with mastocytosis were reviewed. Their clinical and laboratorial characteristics were assessed, and the properties of the criteria used to diagnose systemic mastocytosis were evaluated. RESULTS: The age of disease onset ranged from 2 to 75 years. Twenty-three patients had cutaneous involvement and 75% were referred by dermatologists. Urticaria pigmentosa was the most common manifestation of the disease. One patient with severe systemic mast cell mediator-related symptoms showed the activating V560G KIT mutation. The bone marrow was examined in 79% of patients, and mast cell immunophenotyping was performed in 67% of the participants. Systemic disease was detected in 84% of cases, and 81% of the sample had elevated serum tryptase levels. All the diagnostic criteria for systemic mastocytosis had high specificity and positive predictive value. Bone marrow biopsy had the lowest sensitivity, negative predictive value and efficiency, while the highest such values were observed for mast cell immunophenotyping. Patients were treated with regimens including antihistamines, sodium cromoglycate, alpha-interferon, hydroxyurea and phototherapy. CONCLUSIONS: Cutaneous involvement is often seen in adult mastocytosis patients, with most individuals presenting with indolent systemic disease. Although serum tryptase levels are a good indicator of mast cell burden, bone marrow biopsy should also be performed in patients with normal serum tryptase, with flow cytometry being the most adequate method to diagnose systemic disease. PMID- 24626650 TI - Superficial mycoses at the Hospital do Servidor Publico Municipal de Sao Paulo between 2005 and 2011. AB - BACKGROUND: Superficial mycoses are fungal infections limited to the outermost layers of the skin. Dermatophytic filamentous fungi and yeasts are the major causative agents of these mycoses. Dermatophytosis is one of the clinical conditions caused by fungal infections most commonly found in dermatological practice. Thus, knowledge of the ecology of dermatophytes provides a better understanding of the natural history of dermatophytosis. OBJECTIVE: This study aimed to investigate epidemiological and mycological features of superficial mycoses diagnosed from 2005 to 2011 in the Dermatology Clinic of the Hospital do Servidor Publico Municipal de Sao Paulo, Brazil. METHOD: This retrospective study was conducted in the Laboratory of Medical Mycology at the Dermatology Clinic of the Hospital do Servidor Publico Municipal de Sao Paulo. Mycological examinations of 9042 patients with clinical suspicion of superficial mycoses performed between 2005 and 2011 were reviewed. RESULTS: Of 9042 direct microscopic examinations, 2626 (29%) were positive for dermatophytes, 205 (2.3%) were positive for Malassezia, 191 (2.1%) were positive for other types of yeast, 48 (0.5%) were positive for bacteria, and 5972 (66%) were negative. Mean age of patients was 48 years, 6920 (77%) patients were female and 2112 (23%) were male. CONCLUSION: The biota consisted of six dermatophyte species: T. rubrum, T. mentagrophytes, M. gypseum, T. tonsurans, E. floccosum, and M. canis. The most common site of involvement was the nail and foot in adults and scalp in children, with a female predominance. Both Candida and Malassezia were more prevalent in adult women, the former most commonly affecting the interdigital region and nails and the latter the chest and neck. PMID- 24626651 TI - Quality of life profile and correlated factors in chronic leg ulcer patients in the mid-west of Sao Paulo State, Brazil. AB - BACKGROUND: Chronic leg ulcer may have an impact on patients' quality of life. OBJECTIVES: This study aimed to identify the impact of leg ulcers on patient's quality of life using the Dermatology Life Quality Index and to define the main factors correlated with this perception. METHOD: Cross-sectional, non probabilistic sampling study. We included patients with chronic leg ulcers being treated for at least 3 months. A sociodemographic and clinical survey was conducted to assess the profile of the ulcers. We administered a screening for depressive symptoms and the Dermatology Life Quality Index. We performed a descriptive statistical analysis, chi-square test and Mann-Whitney test for categorical data, Pearson for numeric variables, and multiple regression for categorical data. RESULTS: Forty-one patients were assessed. Their mean age was 61.78 years. Venous ulcers (48.8%) were the most prevalent. Seventy-three percent of the sample perceived no impact/low impact on quality of life in the past week, and 26.8% perceived moderate/high impact. A multiple regression analysis identified the causes of lesion, pain related to the ulcers, time of onset, and severity of the depressive symptoms as the variables that had an influence on quality of life. CONCLUSIONS: The majority of the sample perceived low or no impact of the condition on the quality of the life. The variables etiology of the lesion (p<0.001), pain related to the ulcers (p=0.001), time of onset (p=0.006), and severity of the depressive symptoms (p<0.001) had an influence on the quality of life, suggesting the need for further studies with more robust designs to confirm the causal relationship between these characteristics and quality of life. PMID- 24626652 TI - Acne-specific quality of life questionnaire (Acne-QoL): translation, cultural adaptation and validation into Brazilian-Portuguese language. AB - BACKGROUND: many studies about the psychosocial impact of acne have been reported in international medical literature describing quality of life as a relevant clinical outcome. It is well known that the patient's perception about the disease may be different from the physician's evaluation. Therefore, it is important to use validated instruments that turn the patient's subjective opinion into objective information. OBJECTIVES: to translate into Brazilian-Portuguese language and to culturally adapt a quality of life questionnaire, the Acne Specific Quality of Life Questionnaire (Acne-QoL), as well as to evaluate its reliability and validity. METHODS: measurement properties were assessed: 1) validity: comparison between severity and Acne-QoL domain scores, correlations between acne duration and Acne-QoL domain scores, and correlation between Acne QoL domain scores and SF-36 components; 2) internal consistency: Cronbach's alpha coefficient; 3) test-retest reproducibility: intraclass correlation coefficient and Wilcoxon test. RESULTS: Eighty subjects with a mean age of 20.5 +/- 4.8 years presenting mild (33.8%), moderate (36.2%) and severe (30%) facial acne were enrolled. Acne-QoL domain scores were similar among the different acne severity groups except for role-social domain. Subjects with shorter acne duration presented significant higher scores. Acne-QoL domains showed significant correlations, both between themselves and with SF-36 role-social and mental health components. Internal consistency (0.925-0.952) and test-retest reproducibility were considered acceptable (0.768-0.836). CONCLUSIONS: the Brazilian-Portuguese version of the Acne-QoL is a reliable and valid satisfactory outcome measure to be used in facial acne studies. PMID- 24626653 TI - Keratosis pilaris and prevalence of acne vulgaris: a cross-sectional study. AB - BACKGROUND: Acne vulgaris has an important genetic predisposition, as well as keratosis pilaris. Clinical observations suggest that patients with keratosis pilaris have less frequent or less severe acne breakouts; however, we found no studies on this regard OBJECTIVE: To determine if the presence of keratosis pilaris is associated with lower prevalence and severity of acne. METHODS: A cross-sectional study was conducted with dermatology outpatients aged between 14 and 35 years. We evaluated history and clinical grade of acne, demographic variables, history of atopy, smoking, and use of hormonal contraceptives. Two groups were defined by the presence or absence of moderate to severe keratosis pilaris on the arms and were compared by bivariate analysis and by conditional multiple logistic regression. RESULTS: We included 158 patients (66% women), with a median age of 23 +/- 11 years. Twenty-six percent of them had keratosis pilaris, which was associated with a history of atopy (odds ratio [OR]=2.80 [1.36 to 5.75]; p<0.01). Acne was present in 66% of subjects, and was related to family history of acne (OR=5.75 [2.47 to 13.37]; p<0.01). In bivariate and multivariate analysis, the group with keratosis pilaris had a less frequent history of acne (OR=0.32 [0.14 to 0.70]; p<0.01). CONCLUSION: The presence of moderate to severe keratosis pilaris on the arms was associated with lower prevalence of acne vulgaris and lower severity of facial lesions in adolescents and young adults. PMID- 24626655 TI - Epidemiological situation of leprosy in Salvador from 2001 to 2009. AB - Mycobacterium leprae was first described as the bacillus that causes leprosy, a chronic granulomatous infectious disease, in 1873 by Amauer Hansen. Leprosy is part of a group of 10 neglected diseases and Bahia has endemic levels of this illness, varying between high and very high. The detection of 52 new cases of leprosy in children under 15 years old in Salvador in 2006 is alarming, and suggests an early contact with the disease. The aim of this review is to analyze the epidemiological situation, the detection rate and evaluate the clinical and epidemiological profile of leprosy in Salvador, in the period 2001-2009. A retrospective cross-sectional study was performed using secondary data collected at Notifiable Diseases Information System Database (SINAN) through the notification of patients with leprosy. Over these nine years 3,226 patients were reported, with a predominance of: females (51.5%), and clinical multibacillary forms in the general population (51.7%), but when we analyze those under 15 years old, paucibacillary forms (tuberculoid + indeterminate) prevailed. The tuberculoid form was the most diagnosed type of presentation. The annual detection rate in Salvador remained at a very high level of endemicity during the studied period and for those under 15 years old it ranged between high and very high. Grade 2 disabilities both at the time of diagnosis and at discharge after cure, varied between low and medium. Based on these data we conclude that the high levels of leprosy detection rates in the general population, plus the variation between high and very high levels in those under 15 years old, associated with the medium level of grade 2 disabilities at the time of diagnosis and discharge, demonstrate the need for improvement on the existing services, investment in active case finding and training of the healthcare professionals in Salvador. PMID- 24626654 TI - Non-classical forms of pemphigus: pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus. AB - The pemphigus group comprises the autoimmune intraepidermal blistering diseases classically divided into two major types: pemphigus vulgaris and pemphigus foliaceous. Pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus are rarer forms that present some clinical, histological and immunopathological characteristics that are different from the classical types. These are reviewed in this article. Future research may help definitively to locate the position of these forms in the pemphigus group, especially with regard to pemphigus herpetiformis and the IgG/ IgA pemphigus. PMID- 24626656 TI - Lupus erythematosus: considerations about clinical, cutaneous and therapeutic aspects. AB - Systemic Lupus Erythematosus is a chronic inflammatory disease with multifactorial etiology. Although clinical manifestations are varied, the skin is an important target-organ, which contributes to the inclusion of skin lesions in 4 out of the 17 new criteria for the diagnosis of the disease, according to the Systemic Lupus International Collaborating Clinics. The cutaneous manifestations of lupus are pleomorphic. Depending on their clinical characteristics, they can be classified into Acute Cutaneous Lupus Erythematosus, Subacute Cutaneous Lupus Erythematosus, Chronic Cutaneous Lupus Erythematosus and Intermittent Cutaneous Lupus Erythematosus. Treatment is based on preventive measures, reversal of inflammation, prevention of damage to target organs and relief of adverse events due to pharmacological therapy. The most commonly used treatment options are topical, systemic and surgical treatment, as well as phototherapy. The correct handling of the cases depends on a careful evaluation of the morphology of the lesions and the patient's general status, always taking into consideration not only the benefits but also the side effects of each therapeutic proposal. PMID- 24626658 TI - Genital warts: comparing clinical findings to dermatoscopic aspects, in vivo reflectance confocal features and histopathologic exam. AB - Genital warts can be diagnosed through physical examination and confirmed by histopathology. Noninvasive methods are useful for ruling out other diagnoses with no harm to the patient. In this study the clinical findings were compared to dermoscopy, reflectance confocal microscopy (RCM), and to histopathology findings, in order to determine possible patterns that can aid diagnosis of the lesion. It was possible to identify structural changes on reflectance confocal microscopy that are already known by dermoscopy, in addition to cellular changes previously seen only by histopathological examination. This study shows the use of reflectance confocal microscopy in cases of genital warts, providing important information that can be used in further studies. PMID- 24626657 TI - Nanotechnology in dermatology. AB - The scientific community and general public have been exposed to a series of achievements attributed to a new area of knowledge: Nanotechnology. Both abroad and in Brazil, funding agencies have launched programs aimed at encouraging this type of research. Indeed, for many who come into contact with this subject it will be clear the key role that chemical knowledge will play in the evolution of this subject. And even more, will see that it is a science in which the basic structure is formed by distilling different areas of inter-and multidisciplinary knowledge along the lines of new paradigms. In this article, we attempt to clarify the foundations of nanotechnology, and demonstrate their contribution to new advances in dermatology as well as medicine in general. Nanotechnology is clearly the future. PMID- 24626660 TI - Acquired epidermodysplasia verruciformis in a renal transplant recipient--case report. AB - A 24-year-old male patient, who underwent kidney transplant six years ago due to Lupus nephritis, for the last two years presented asymptomatic erythematous scaly plaques on the abdomen and areas exposed to light. Post-transplantation immunosuppressive medications included prednisone, mycophenolate sodium and sirolimus. The histopathologic features were typical for epidermodysplasia verruciformis. Epidermodysplasia verruciformis is a rare autosomal recessive genodermatosis with increased susceptibility to specific strains of cutaneous human papilloma virus. The term ''acquired epidermodysplasia verruciformis'' was recently introduced to the literature and describes epidermodysplasia verruciformis occurring in patients with impaired cell-mediated immunity. We report an additional case associated to immunosuppression after kidney transplantation. PMID- 24626659 TI - Fabry disease: clinical and genotypic aspects of three cases in first degree relatives. AB - Fabry disease is an X-linked, lysosomal storage disease caused by the inherited deficiency of the enzyme alpha-galactosidase A. The diagnosis is usually late, with renal, cardiovascular and/or cerebral complications that reduce life expectancy. Angiokeratomas are asymptomatic lesions present as the initial manifestation and usually less appreciated. Their detection is important for early diagnosis and institution of treatment with enzyme replacement therapy, which prevents late complications reducing morbidity and mortality. We report a case of a male teenager with acroparestesias and angiokeratomas. Family medical research discovered that his mother and brother had similar signs and symptoms and that the three patients had the same mutation in the gene encoding the enzyme, confirming the diagnosis. PMID- 24626662 TI - Extra-pulmonary manifestations of paracoccidioidomycosis associated with acquired immunodeficiency syndrome: a case report. AB - We present a patient with Paracoccidioidomycosis/HIV coinfection which has been investigated because of chronic monoarthritis and mucocutaneous lesions. A biopsy of the synovial membrane and skin revealed structures consistent with Paracoccidioides brasiliensis. At diagnosis, the count of CD4 + T cells was 44 cells/mm3. We emphasize the importance of clinical suspicion of Paracoccidioidomycosis in patients with HIV/AIDS who live in or are from risk areas. PMID- 24626661 TI - Superficial Acral Fibromyxoma involving the nail's apparatus. Case report and literature review. AB - Superficial Acral Fibromyxoma is a rare tumor of soft tissues. It is a relatively new entity described in 2001 by Fetsch et al. It probably represents a fibrohistiocytic tumor with less than 170 described cases. We bring a new case of SAF on the 5th toe of the right foot, in a 43-year-old woman. After surgical excision with safety margins which included the nail apparatus, it has not recurred (22 months of follow up). We carried out a review of the location of all SAF published up to the present day. PMID- 24626663 TI - Segmental vitiligo after infliximab use for rheumatoid arthritis--a case report. AB - The tumor necrosis factor alpha is a cytokine related to immune and inflammatory processes by acting on different parts of the body. It is secreted by several cell types including macrophages, lymphocytes, monocytes, neutrophils, dendritic cells, among others. Infliximab is a chimeric monoclonal antibody that specifically binds to soluble and transmembrane tumor necrosis factor alpha form blocking its action. In rheumatoid arthritis it is used because the cytokines that cause inflammation in this disease are regulated by tumor necrosis factor alpha and IL-1. We report the case of a 46-year-old patient with rheumatoid arthritis who developed segmental vitiligo after two months using infliximab. The event aims to alert to the existence of this adverse effect that can be induced with the use of this medication. PMID- 24626664 TI - Melanoma developed during pregnancy--a case report. AB - We describe a case of plantar interdigital cutaneous melanoma in a 22-year-old woman who reported changes in a pigmented lesion during pregnancy. Diagnosis was late and evolution unfavourable. The purpose of this report is to draw the attention of dermatologists to the need for careful regular examination of melanocytic lesions in pregnant women, not ignoring possible changes as always physiological. PMID- 24626665 TI - Dysplastic nevus associated with seborrheic keratosis. AB - Seborrheic keratosis is a common skin lesion which may coincidentally be associated melanocytic nevi. The authors describe a case of dysplastic nevus associated with seborrheic keratosis and discuss the clinical, dermoscopic, and histological findings of this association. They also discuss the association between seborrheic keratosis and other benign and malignant tumours. PMID- 24626666 TI - Dermoscopy as an auxiliary method in the diagnosis of social wasp (Hymenoptera, Vespidae) stings. AB - We describe the case of a 32-year-old male patient that sought medical treatment complaining of severe pain in his second and third right-hand fingers. The symptoms had started two hours before. The hypotheses of spider bite, scorpion or insect sting and injury caused by a foreign body were considered in the differential diagnoses. On dermoscopy, two foreign bodies were identified on his skin. After extraction, we concluded that they were wasp stingers. PMID- 24626667 TI - A case of Tinea nigra associated to a bite from a European rabbit (Oryctolagus cuniculus, Leporidae): the role of dermoscopy in diagnosis. AB - We report a case of Tinea nigra in an adolescent living in Itapema, Santa Catarina, Brazil, who presented a hyperchromic macule on the palm of the left hand, close to another erythematous macule caused by a rabbit bite. The patient received guidance on accidents and animal bites and evolved well treated with topical butenafine for the dermatomycosis. The authors also highlight the efficacy of the dermoscopic exam in diagnosing Tinea nigra with animal bite lesions and other traumas. PMID- 24626668 TI - Case for diagnosis. Pemphigoid gestationis. AB - Pemphigoid gestationis is a rare, autoimmune blistering dermatosis of pregnancy. No increase in fetal or maternal mortality has been demonstrated, but a greater prevalence of premature and small-for-gestational age babies has been reported. Topical and systemic corticosteroids and antihistamines are the manstay of treatment. The authors report a case of a 27-year-old woman at 28-weeks gestation with sudden onset of pruriginous vesicles and blisters in the abdomen and limbs. Systemic corticosteroids were introduced and maintained throughout gestation to prevent flares and tapered after the birth of a healthy child. PMID- 24626669 TI - Case for diagnosis. Subcutaneous phaeohyphomycosis. AB - Subcutaneous phaeohyphomycosis is an infection caused by dematiaceous fungi which mainly affects immunosuppressed patients. We report a case of subcutaneous phaeohyphomycosis on the back of the left hand in a kidney transplant patient who had been taking prednisone, tacrolimus, and azathioprine daily for 3 years. PMID- 24626670 TI - Case for diagnosis. Cutaneous Rosai-Dorfman disease. AB - Cutaneous Rosai-Dorfman disease is a rare, lymphoproliferative disease. It is benign and self-limited, only involves skin and subcutaneous tissue and typically occurs as histiocyte-rich inflammatory infiltrates, manifesting as erythematous to brown papules, plaques, or nodules, without predilection for site. The authors describe a case of cutaneous Rosai-Dorfman disease in a 72-year-old man who presented erythematous and scaled plaque on the right neck for three months without systemic symptoms. Owing to local involvement, the patient received a surgery to exsect the lesion completely and remained asymptomatic with no signs of recurrence at the 9-month follow up. PMID- 24626671 TI - Case for diagnosis. Cutaneous involvement associated to multiple myeloma. AB - Cutaneous involvement associated to multiple myeloma varies from 5 to 10% of cases and is infrequently recognized. Cutaneous metastatic plasmacitomas are rare. We present the case of a 72-year-old man with multiple myeloma in complete remission since 2 years ago with cutaneous tumors on the trunk and face. A cutaneous biopsy was consistent with plasmacytoma. The patient was treated with melphalan, prednisolone and radiotherapy. Despite optimal therapeutic response of the lesions, the disease progressed, with the appearance of new extra-cutaneous plasmocytomas. The cutaneous metastatic plasmocytomas were the first sign of progression of the disease. PMID- 24626672 TI - Syndrome in question. Brooke-Spiegler syndrome. AB - Brooke-Spiegler syndrome is an autosomal dominant disorder with variable penetrance and expression. It is characterized by a genetic predisposition to develop multiple adnexal neoplasias: cylindromas, trichoepitheliomas, and trichoblastomas. We describe a 54-year-old male patient with cylindromas, trichoepitheliomas, and trichoblastoma. PMID- 24626673 TI - Syndrome in question. MAGIC syndrome. AB - The authors present a male 40-year-old patient with established diagnosis of Behcet's disease which had evolved to recurrent bilateral auricular polychondritis crises. MAGIC syndrome (mouth and genital ulcers with inflamed cartilage) is rare and groups together patients with this clinical picture without necessarily fulfilling the clinical criteria for Behcet's disease or relapsing polychondritis, demonstrating an independent disorder. PMID- 24626674 TI - Dermatoscopic aspects of the microphthalmia with linear skin defects (MLS) syndrome. AB - The association of microphthalmia and linear skin defects was named microphthalmia with linear skin defects syndrome (MLS) or MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea), an X-chromosomal disorder manifesting mainly in females. We examined a female newborn with facial linear skin defects following the Blaschko lines. Computer tomography and ophthalmological examination confirmed bilateral microphthalmia. An interstitial microdeletion at Xp22.2, encompassing the entire HCCS gene, was identified. Dermatoscopic examination showed erythematous linear areas with telangectasias and absence of sebaceous glands, which appear as brilliant white dots. Vellus hairs were also absent in the red areas. Dermatoscopy could help to establish the diagnosis of MLS/MIDAS syndrome by confirming the aplastic nature of the lesions. PMID- 24626675 TI - Women in medicine and dermatology: history and advances. AB - The history of women in medicine has been marked by many challenges and achievements. Although the role of women in the "art of healing" can be traced back many centuries, only males are traditionally highlighted in history. Across antiquity, access to medical education was denied to females. Dermatology is a medical specialty in which women displayed particular skill and proficiency. Gradually, determination and competence allowed women to lay claim in an essentially male-dominated world. This article presents a brief review of the performance, progress and achievements of women in the history of medicine and dermatology. PMID- 24626676 TI - Distal and lateral toenail onychomycosis caused by Trichophyton rubrum: treatment with photodynamic therapy based on methylene blue dye. AB - The study showed the effectiveness of photodynamic therapy based on methylene blue to treat severe distal and lateral subungual toenail onychomycosis. 22 patients were divided into two groups: group A consisting of 11 patients with severe toenail onychomycosis and group B consisting of 11 patients with mild-to moderate toenail onychomycosis. All patients had onychomycosis caused by Trichophyton rubrum. The patients were treated with sessions of 2% methylene blue aqueous solution irradiated with light emission diode device with 630 nm and 36 J/cm2 biweekly for six months. The clinical response was significantly better in patients with mild-to-moderate (100%) onychomycosis compared with patients with severe onychomycosis (63.6%). PMID- 24626677 TI - Z-Plasty: useful uses in dermatologic surgery. AB - Z-Plasty is a procedure involving the transposition of two interdigitating triangular flaps. This technique is useful in a number of dermatological procedures. It can be used to correct defects resulting from surgical complications. This paper highlights several examples where Z-Plasty is of benefit in dermatosurgery, including the correction of: ectropion, lip misalignment and bifid earlobe. A valuable technique that every dermatologist should be able to perform. PMID- 24626678 TI - Clear cell acanthoma of the nipple: another report from Italy. PMID- 24626680 TI - MicroRNA expression profiles in human breast cancer cells after multifraction and single-dose radiation treatment. AB - MicroRNAs (miRNAs) are small non-coding RNAs that contribute to modulating signaling pathways after radiation exposure and have emerged as a potential therapeutic target or biomarker in the radiation response of cancer. Exposing breast cancer cells to single-dose (SD) or multifractionated (MF) radiation may affect the cells differently. However, the roles of miRNAs in breast cancer cells after the response to SD or MF is not thoroughly understood. Therefore, the purpose of the present study was to comprehensively investigate the response of miRNAs in MDA-MB-361 by using various radiation exposing protocols. Our results revealed that only a small fraction of miRNAs exhibiting differential expressions (>1.5-fold) was identified after MDA-MB-361 cells were exposed to SD (10 Gy) or MF radiation (2 Gy x 5 MF). In addition, we observed that several miRNAs in the MDA-MB-361 cells frequently exhibited differential responses to various types of radiation treatment. Among these miRNAs, the expression levels of an oncogenic miR-17-92 cluster increased following SD radiation treatment. Conversely, miR-19a 3p, miR-20a-5p, and miR-19b-3p expressions were inhibited by >1.5-fold in the following MF treatment. Further analysis of the miR-17-92 cluster expression levels revealed that miR-17, miR-18a, miR-19a/b and miR-20a were significantly overexpressed and miR-92a was downregulated in breast cancer. Functional annotation demonstrated that target genes of the miR-17-92 cluster were predominantly involved in the regulation of radiation-associated signal pathways such as mitogen-activated protein kinase (MAPK), ErbB, p53, Wnt, transforming growth factor-beta (TGF-beta), mTOR signaling pathways and cell cycles with an FDR <0.05. Overall, the results of the present study revealed distinct differences in the response of miRNAs to SD and MF radiation exposure, and these radiation-associated miRNAs may contribute to radiosensitivity and can be used as biomarkers for radiotherapy. PMID- 24626681 TI - Analysis of mutational characteristics of the drug-resistant gene katG in multi drug resistant Mycobacterium tuberculosis L-form among patients with pneumoconiosis complicated with tuberculosis. AB - The aim of the present study was to investigate the mutational characteristics of drug-resistant genetic mutations in the katG gene to isoniazid (INH) in multi drug resistant Mycobacterium tuberculosis (MTB) L-form among patients with pneumoconiosis complicated with tuberculosis (TB), in order to reduce the occurrence of drug resistance in patients, and gain further insight into the mechanisms underlying drug resistance in MDR-TB L-form. A total of 114 clinically isolated strains of MTB L-forms were collected. The MDR-TB L-forms were identified using a conventional antimicrobial susceptibility test (AST). The DNA genomes were extracted, the target genes were amplified by polymerase chain reaction technology and the hotspot mutational regions in the katG gene were analyzed by direct sequencing. The results of AST analysis demonstrated that there were 31 strains of MDR-TB L-forms in 114 clinical isolates. The mutation rate of katG was 61.29% (19/31) in INH-resistant isolates, mainly concentrated in codon 315 (Ser315Thr, 48.39% and Ser315Asn, 9.68%) and 431 (Ala431Val, 3.23%). Base substitutions were identified, however, no multisite mutations were found. No mutations in katG were identified in 10 INH-sensitive strains that were randomly selected. INH-resistance was more severe in MDR-TB L-form isolates among patients with pneumoconiosis complicated with TB. The substitution of highly conserved amino acids encoded by the katG gene resulted in the molecular mechanisms responsible for INH resistance in MDR-TB L-form isolates. It was also verified that the katG gene was in diversiform. The katG Ser315Thr mutation is one of the main causes of resistance to INH in MDR-TB L-form isolates. PMID- 24626682 TI - A new turn in codon-anticodon selection through halogen bonds. AB - The halogen bond is relatively a less characterized intermolecular interaction compared to the hydrogen bond and the structure, stability and electronic structures of halogenated base pairs, particularly at the wobble junction have been investigated using DFT. Three halogens, namely Cl, Br and I, have been tested for their role in such situations with uracil as the anticodon base. Computed results reveal that when halogen atoms replace protons in the hydrogen bonding positions they induce lot of geometric changes that flip some of the observed base pairs into unobserved base pairs and vice versa. NCI, NBO and AIM analyses explain these changes at the electronic level. The new codons will have lot of impact in future applications, particularly in self assembly of biomaterials and t-RNA synthetic strategies. PMID- 24626683 TI - The use of climatologies and Bayesian models to link observations to outcomes; an example from the Torres Strait. AB - After widespread coral bleaching in the Torres Strait in 2009-2010 a monitoring program was established under the National Environmental Research Program and run by the Torres Strait Regional Authority to identify ocean conditions that may lead to future bleaching. One component of this program was a real time ocean monitoring station located between Thursday and Horn Islands in the south-western part of the Torres Strait. A key outcome of the project was to make the scientific data and knowledge available to the local communities in a form that they could engage with and with which they could act to instigate outcomes relevant to their needs. The project developed climatologies to give context to the temperature data allowing for historical limits to define the significance of the real time data as related to the longer term mean. This allowed the identification of 'normal', 'significant' and 'extreme' temperature events which could be linked into appropriate responses. Bayesian models were used to encapsulate the current scientific knowledge about the drivers and responses involved in coral bleaching. These models were used to convert the environmental parameters to an output index reflecting the current and future likelihood of coral bleaching occurring. Two web sites were used to integrate the real time data, climatology data and the bleaching indices generated from the Bayesian models. The first was a more technical site developed for the local environmental managers within the Torres Strait Regional Authority, the second was targeted at the general public with a display located within the local radio station and broadcast on a daily basis. Engagement with the project has been high to the point where additional monitoring stations and data display kiosks are to be installed in the near future. The combination of climatologies to give context and conceptual models to embody system knowledge has allowed the project to go from delivering simple measurements to being able to deliver knowledge about the system in a format that engages the local community and that can be used to facilitate environmental management outcomes. PMID- 24626684 TI - [Users' perception about of quality ambulatory healthcare services in Mexico]. AB - OBJECTIVE: To identify users' perception about ambulatory healthcare services quality and associated factors in Mexico. MATERIALS AND METHODS: Analysis of the 2006 and 2012 National Surveys of Health and Nutrition that included users' perception of healthcare services and improvement in health status. A multivariate regression analysis allowed identifying the associated factors with the perception of improved health status. RESULTS: Between 2006 and 2012, users' positive perception of healthcare services increased from 82 to 85%, and user report of improvement in health status increased from 79 to 81%. Health status improvement, explanations about the disease and treatment, being attended without appointment, freedom to choose the provider and short waiting time were associated with a perception of better quality of care. CONCLUSIONS: Users' perception about the quality of care in ambulatory healthcare settings has improved, yet it is still neccessary to strengthen organizational strategies to provide healthcare when needed and to improve fulfillment of users' expectations. PMID- 24626685 TI - [Gaps in effective coverage by socioeconomic status and poverty condition]. AB - OBJECTIVE: To analyze, in the context of increased health protection in Mexico, the gaps by socioeconomic status and poverty condition on effective coverage of selected preventive interventions. MATERIALS AND METHODS: Data from the National Health & Nutrition Survey 2012 and 2006, using previously defined indicators of effective coverage and stratifying them by socioeconomic (SE) status and multidimensional poverty condition. RESULTS: For vaccination interventions, immunological equity has been maintained in Mexico. For indicators related to preventive interventions provided at the clinical setting, effective coverage is lower among those in the lowest SE quintile and among people living in multidimensional poverty. Comparing 2006 and 2012, there is no evidence on gap reduction. CONCLUSION: While health protection has significantly increased in Mexico, thus reducing SE gaps, those gaps are still important in magnitude for effective coverage of preventive interventions. PMID- 24626686 TI - [Factor associated with medicines utilization and expenditure in Mexico]. AB - OBJECTIVE: To analyze medicine utilization and expenditure and associated factors in Mexico, as well as to discuss their implications for pharmaceutical policy. MATERIALS AND METHODS: Analysis of a sample of 193,228 individuals from the Mexican National Health and Nutrition Survey 2012. Probability and amount of expenditure were estimated using logit, probit and quantile regression models, evaluating three dimensions of access to medicines: (1) likelihood of utilization of medicines in the event of a health problem, (2) probability of incurring expenses and (3) amount spent on medicines. RESULTS: Individuals affiliated to IMSS were more likely to use medicines (OR=1.2, p<0.05). Being affiliated to the IMSS, ISSSTE or SP reduced the likelihood of spending compared to those without health insurance (about RM 0.7, p<0.01). Median expenditures varied between 195.3 and 274.2 pesos. CONCLUSIONS: Factors associated with the use and expenditure on medicines indicate that inequities in the access to medicines persist. PMID- 24626688 TI - [Diabetes mellitus in Mexico. Status of the epidemic]. AB - OBJECTIVE: To estimate the magnitude of diabetes in Mexico, as well as discuss alternative policies to face it appropriately. MATERIALS AND METHODS: Descriptive analysis of the National Health and Nutrition Survey 2012, using reported information on previous diagnosis of diabetes from adults and adolescents. RESULTS: From all adults 20 years and older in Mexico, 9.17% has been diagnosed with diabetes, presenting an important geographical heterogeneity, ranging from 5.6% in the southern state of Chiapas, to 12.3% in Mexico City. Of all people with diabetes, 46.95% also have been diagnosed with hypertension, 4.47% has had a stroke, and 54.46%, reported family background of diabetes. Regarding adolescents, 0.68% has been already diagnosed with diabetes. CONCLUSIONS: The burden of diabetes in Mexico and the fact that is a preventable condition, calls to strengthen the health sector strategies to face it. The negative effect it has on the quality of life makes diabetes a priority for the health sector. PMID- 24626687 TI - [Persisting health and health access inequalities in Mexican indigenous population, 2006-2012]. AB - OBJECTIVE: To analyze socioeconomic, health conditions and access to health services of Mexican indigenous population between 2006 and 2012. MATERIALS AND METHODS: A comparative analysis was done between indigenous and non indigenous population, using the information from th National Health and Nutrition Survey (2006 and 2012). RESULTS: 60% of the indigenous population was allocated at the poorest socioeconomic level in 2012 despite the implementation of social programs. The Seguro Popular increased its coverage from 14 to 61.9% in indigenous population. The increase observed in coverage in no indigenous population was from 10 to 35.7%. Nevertheless, no increase was observed in the utilization of healthcare services between indigenous and non indigenous population. The access to hospital services for childbirth delivery increased from 63.8 to 76.4% in indigenous population. However there is an important difference with non indigenous population (93.9%). CONCLUSIONS: The increase in the coverage of the Seguro Popular in Mexico has had heterogeneous results in the utilization of health care services. Other social programs such a Oportunidades have not had an impact to alleviate poverty in indigenous groups. PMID- 24626689 TI - [Type 2 diabetes and frecuency of prevention and control measures]. AB - OBJECTIVE: To determine the frequency of application of prevention and control measures for type 2 diabetes in Mexican population. MATERIALS AND METHODS: ENSANUT 2012 is a nationally and by-state representative survey. Sample design was probabilistic, multistage, stratified and clustered. The information of 46 277 adults>=20 was used for this analysis. A weighted analysis was performed using Stata 12. RESULTS: Prevalence of diabetes by previous diagnosis was 9.2% (6.4 millions) in ENSANUT 2012, 7.3% (3.7 millions) in 2006 and 4.6% (2.1 millions) in 2000. In 2012, the mean of medical examinations in the previous year related to diabetes control was 7.3. However, the percentage of cases in which preventive actions for chronic complications were performed (such as foot care [14.6%], ophthalmology [8.6%] and determination of HbA1c [9.6%]) was low. CONCLUSIONS: Patients with diabetes have frequent access to medical services. However, preventive actions are applied insufficiently both in quality and quantity. PMID- 24626690 TI - [Hypertension: prevalence, early diagnosis, control and trends in Mexican adults]. AB - OBJECTIVE: The present study aims to describe the prevalence, distribution and trends of hypertension (HT) in Mexican adults >=20 years, and to describe the prevalence of early diagnosis and treatment of HT. MATERIALS AND METHODS: A total of 10 898 adults were considered. The measurement of blood pressure was performed following the procedures recommended by the American Heart Association. An adult was considered, hypertensive when he met the diagnostic criteria of JNC-7. RESULTS: The prevalence of HT was 31.5%, of which 47.3% were unaware of their condition. Pharmacological treatment was not associated with a higher percentage of subjects under control. CONCLUSION: Prevalences from 2000, 2006 and 2012 suggest that there is a stabilization. A health problem of this magnitude requires better diagnosis, care and training of the medical sector so that appropriate treatments are prescribed and HT control can be enhanced. PMID- 24626691 TI - [Prevalence of obesity in Mexican adults 2000-2012]. AB - OBJECTIVE: To describe the prevalence of overweight and obesity in Mexican adults >=20 y of age, as well as to describe its trends in the last three Mexican health surveys. MATERIALS AND METHODS: A sample of 38 208 adults with anthropometric's. The classification to categorize body mass index (BMI) was the World health Organization's (WHO). To define abdominal obesity classification was used the International Diabetes Federation (IDF) data. RESULTS: The prevalence of overweight and obesity was 71.3% (overweight 38.8% and obesity 32.4%). The prevalence of abdominal adiposity was 74.0%, being higher in women (82.8%) than in men (64.5%). Over the past 12 years the mean annualized BMI percent increase was 1.3%. This increase was higher in the 2000-2006 (1%) than in the 2006-2012 (0.3%) period. CONCLUSION: In spite of the deacceleration of the increasing prevalence, there is no evidence to infer that prevalences will decrease in the next years. Thus, public policies for obestiy prevention and control should be strengthened and improved. PMID- 24626692 TI - [Stunting in Mexico in the last quarter century: analysis of four national surveys]. AB - OBJECTIVE: To describe the magnitude, distribution, and trends of undernutrition and overweight from 1988 to 2006, and provide recommendations for their erradication. MATERIALS AND METHODS: Antrhopometric indicators of nutritional status in children <5 y from four surveys were analyzed. RESULTS: Despite its significant reduction in the study period, stunting remains as a public health problem, with the highest prevalences in indigenous population, the rural south and the lowest living conditions quintile. CONCLUSIONS: Several policies and programs have demonstrated effectiveness, but implementation challenges persist among the poorest population, particularly in indigenous households. Measures for improving the effectiveness of the nutrition policies and programs, particularly among the indigenous and poorest population, are provided, which include adjusting current programs according to the results of evaluations, and the implementation of policies that address the social determinants of undernutrition. PMID- 24626693 TI - [Infant feeding practices and deterioration of breastfeeding in Mexico]. AB - OBJECTIVE: To present data on infant and young child feeding practices (IYCFP) in Mexico from the 2012 National Health and Nutrition Survey (ENSANUT 2012) to support the development of public policy. MATERIALS AND METHODS: POPULATION: Women 12-49y and children <2y. Indicators of IYCFP suggested by WHO were analyzed by geographic, socioeconomic, participation in food programs and health insurance variables. RESULTS: Median duration of breast-feeding: 10.2mo and 14.4% with exclusive breastfeeding (EBF) <6m. Breastfeeding deteriorated in most vulnerable groups. Decline in EBF<6m 2006-2012 was explained by increases in consumption of formula and other milks (4%) and water (4%). Three-quarters (74%) of 6-11mo infants had minimum food diversity, and it was lower in the most vulnerable. CONCLUSIONS: Complementary feeding improved but breastfeeding declined in Mexico. Promotion actions must be integral, coordinated, financed and evaluated, with Federal government leadership and should include the participation of various stakeholders. PMID- 24626694 TI - [Prevalence of anemia in Mexican children and adolescents: Results from three national surveys]. AB - OBJECTIVE: To describe the prevalence of anemia in Mexican children and adolescents from ENSANUT 2012. MATERIALS AND METHODS: Data had the power to make distinctions at the national, regional and rural/urban dwelling. Hemoglobin was measured by Hemocue. Descriptions were made by adjusted frequencies and 95%CI. Confounders were tested in a logistic regression models. RESULTS: The prevalence of anemia in 2012 was: in children 1-4 y, 23.3%; 5-11y, 10.1%, and 12-19 y, 5.6%. The prevalence in female adolescents was 7.7% and 3.6% in males. Reductions in the prevalence of anemia from 1999 was 8.3pp in <5y, 5.1pp in children 5-11y and 3.6pp from 2006 in adolescents. CONCLUSIONS: Despite the decrease in the prevalence of anemia in children 1-4 y in the last 13 years, it still is of great concern. There is a need of awareness among social and medical communities about this, to extend the distribution of micronutrient supplements in children <3y, and to promote nutritional education to incentive mothers to provide foods rich in iron. PMID- 24626695 TI - [Prevalence of anemia in reproductive-age Mexican women]. AB - OBJECTIVE: To update the prevalence of anemia and its trend in Mexican women of childbearing age over the past 13 years using information from the National Health and Nutrition Survey 2012 and 2006 (ENSANUT 2012 and ENSANUT 2006, respectively) and from the National Nutrition Survey 1999 (ENN 99). MATERIALS AND METHODS: Data came from three national probabilistic surveys, representative at regional and rural / urban level. Hemoglobin (Hb) in women was measured using a HemoCue photometer and classified as anemia according to the WHO criteria. Frequencies and CI95% were estimated for each survey (ENSANUT 2012, ENSANUT 2006 and ENN 99) as well as percentage changes in anemia prevalence among pregnant and non-pregnant women in this survey sequence. RESULTS: The national prevalence of anemia in 2012 in non-pregnant women was 11.6% and in pregnant women was 17.9%. Between 1999 and 2012, a 10 percentage point (pp) decreasing in anemia prevalence was observed in the first ones and a 13.5 pp in the second ones. CONCLUSIONS: Although it has declined in the past 13 years, anemia in women of childbearing age remains as a serious public health problem. It is considered necessary to design strategies to prevent iron deficiency and for the early detection of anemia in women. PMID- 24626696 TI - [Food assistance programs in Mexico, coverage and targeting]. AB - OBJECTIVE: To describe the distribution of social food assistance programs in Mexico. MATERIALS AND METHODS: Information about 36 150 households from the National Health and Nutrition Survey (ENSANUT 2012) was included. The distribution of the social assistance food programs by characteristics as rural/urban locality, country region, ethnicity, socioeconomic level and nutritional status was observed. RESULTS: At the national level, food assistance programs with the greater coverage are Oportunidades (reaching 18.8% of the population), Liconsa (milk distribution, 9.7%) and School Breakfasts (12.2%). The program that assists in the best way the target population is Oportunidades, where 75% of its beneficiaries belong to the "low" and "lower" socioeconomic levels, in contrast to Liconsa and School Breakfasts programs, where only 42% and 55% of the beneficiaries are in such levels, respectively. CONCLUSION: Current focus and application of the food assistance programs must be adjusted under the perspective of wellness, health and nutrition of the children population. PMID- 24626697 TI - [Epidemiology of food insecurity in Mexico]. AB - OBJECTIVE: To estimate the proportion of Mexican households in food insecurity (FI) and their distribution in relation to nutrition and socioeconomic conditions. MATERIALS AND METHODS: We evaluated information from 40 809 households. FI was measured using a harmonized version for Mexico of the Latin American and Caribbean food Security Scale. Households were classified according to the level of food insecurity as follows: Food security, mild, moderate and severe FI. We describe the distribution of FI according to some household socioeconomic variables. RESULTS: Nationally, 28.2% of households had moderate or severe FI. Rural, indigenous ethnicity and household deprivation were risk factors moderate to severe FI (35.4, 42.2 and 45.9%, respectively). Severe FI was also associated with lower children height and weight. CONCLUSIONS: Multi sectorial actions are needed to address the basic needs of households with moderate and severe FI. PMID- 24626698 TI - [Coverage for birth care in Mexico and its interpretation within the context of maternal mortality]. AB - OBJECTIVE: To evaluate health coverage for birth care in Mexico within the frame of maternal mortality reduction. MATERIALS AND METHODS: Two information sources were used: 1) The comparison between the results yield by the Mexican National Health and Nutrition Surveys 2006 and 2012 (ENSANUT 2006 and 2012), and 2) the databases monitoring maternal deaths during 2012 (up to December 26), and live births (LB) in Mexico as estimated by the Mexican National Population Council (Conapo). RESULTS: The national coverage for birth care by medical units is nearly 94.4% at the national level, but in some federal entities such as Chiapas (60.5%), Nayarit (87.8%), Guerrero (91.2%), Durango (92.5%), Oaxaca (92.6%), and Puebla (93.4%), coverage remains below the national average. In women belonging to any social security system (eg. IMSS, IMSS Oportunidades, ISSSTE), coverage is almost 99%, whereas in those affiliated to the Mexican Popular Health Insurance (which depends directly from the Federal Ministry of Health), coverage reached 92.9%. In terms of Maternal Mortality Ratio (MMR), there are still large disparities among federal states in Mexico, with a national average of 47.0 per 100 000 LB (preliminary data for 2012, up to December 26). The MMR estimation has been updated using the most recent population projections. CONCLUSION: There is no correlation between the level of institutional birth care and the MMR in Mexico. It is thus necessary not only to guarantee universal birth care by health professionals, but also to provide obstetric care by qualified personnel in functional health services networks, to strengthen the quality of obstetric care, family planning programs, and to promote the implementation of new and innovative health policies that include intersectoral actions and human rights-based approaches targeted to reduce the enormous social inequity still prevailing in Mexico. PMID- 24626699 TI - [Sociodemographic and reproductive characteristics associated with the increase of cesarean section practice in Mexico]. AB - OBJECTIVE: To describe the trend of cesarean section practice in Mexico, and its association with women's sociodemographic and reproductive characteristics. MATERIALS AND METHODS: Based on the 2000, 2006 and 2012 National Health Surveys, information on c-section was analyzed. A multivariate logistic regression model was used in 2012. RESULTS: A 50.3% increase in the use of c-section was observed nationally from 2000 to 2012. Women more likely to undergo a c-section include those whose delivery care takes place in the private sector (OR=2.84, 95%CI:2.15 3.74). When associating women's age and parity, the greatest risks are observed among primiparous women between 12 and 19 years of age, and those aged 35 years and more (OR=6.02, 95%CI:1.24-29.26 and OR=5.20, 95%CI:2.41-11.21, respectively). CONCLUSIONS: Some recommendations to revert the increase of this clinical practice, especially when there is no full justification for its realization, are proposed. PMID- 24626700 TI - [Use of contraception and family planning in adolescent and adult women in Mexico]. AB - OBJECTIVE: To offer current evidence about age at sexual initiation and contraceptive use among adolescent and adult women of different age groups, places of residence, and marital status in Mexico. MATERIALS AND METHODS: Data were analyzed from ENSANUT 2006 and 2012 surveys on knowledge and use of contraceptives. RESULTS: In 2012 31.2% of 15-19 year old adolescent women had undergone sexual debut. Condom use increased from 31.8% in 2006 to 47.8% in 2012. Women in rural areas reported lower levels of contraceptive use at last sexual intercourse; 47.9% of 30-34 year-old and 53.2% of 35-49 year-old women reported not using any contraception at last sexual intercourse. A high percentage of women did not adopt contraception after the most recent obstetric event: 52% (15 19 years), 44.2% (20-29 years), 42.5% (30-34 years) and 39% (>=35 years)]. CONCLUSIONS: Equitable policies to promote contraception, particularly after a post-obstetric event, are needed. PMID- 24626701 TI - [Utilization patterns of prevention and early diagnosis for cancer in women]. AB - OBJECTIVE: To estimate the utilization patterns of cancer prevention programs in women during the period 2000-2012 in Mexican women who participated in three national surveys. MATERIALS AND METHODS: We analyzed data from the ENSA 2000, ENSANUT 2006 and ENSANUT 2012 that are representative of the Mexican population. Prevalences were obtained, trend tests and Poisson regression were used to determine the possibility of having more coverage. RESULTS: The coverage of Papanicolaou use in the last 12 months in 2012 was 45.5%, HPV testing in the last four years was 11.9% and mammography use in the past two years was 29.4% and 17.2% in women aged 50-69 years and 40-49 years, respectively. CONCLUSIONS: Although there was an increase in the coverage of screening programs, there should be a boost in the service quality and universal coverage. PMID- 24626702 TI - [Interpersonal violence in Mexican young people and prevention opportunities]. AB - OBJECTIVE: To estimate the prevalence of health damage due to interpersonal violence in teenagers and young adults. MATERIALS AND METHODS: The consequences of violence in Mexico are presented in this analysis, with data from the National Health and Nutrition Survey 2012 conducted between October 2011 and May 2012. Statistical analysis consisted in calculating general and specific prevalences and intervals obtained at 95% confidence for the group of adolescents and young people. RESULTS: Four of each hundred youngsters have presented health damage due to interpersonal violence. The prevalence of interpersonal violence is higher among men (5.0% men, 3.3% women), the most vulnerable age group is that of men 20 to 29 years old; one of four women reported domestic violence (24.5%). CONCLUSIONS: It is necessary to implement comprehensive measures for young people, designed to prevent this problem from growing in frequency as well as in its variety of forms and spaces. PMID- 24626703 TI - [Child wellbeing and development indicators in Mexico]. AB - OBJECTIVE: To provide evidence and input for monitoring child welfare and wellbeing in Mexico. MATERIALS AND METHODS: Adjusting for sampling design, information from ENSANUT 2012 for children <10 years was compared with national and international parameters and goals. RESULTS: While 8.37% of infants were born with low birth weight (<2,500 g), neonatal screening was not performed on 9.4% of newborns. Of children <5 years, 78.03% were breastfed until at least four months. Among mothers of newborns, 69.5% received training in early stimulation. At the national level, 28% of children (23% in rural areas) received five medical consultations to monitor their early development. 29% of children either had a disability or were at risk of developing one. CONCLUSIONS: Progress has been made in Mexico in terms of services promoting early child development and wellbeing but important challenges persist. National standards and a system for monitoring, screening, referring and providing care for child development and wellbeing are necessary. PMID- 24626704 TI - [Tobacco consumption, mortality and fiscal policy in Mexico]. AB - OBJECTIVE: To analyze tobacco consumption in the last 12 years, its impact on chronic diseases mortality and the potential benefits of fiscal policy in Mexico. MATERIALS AND METHODS: Through the analysis of national health surveys (ENSA, ENSANUT), records of mortality and economic surveys between 2000 and 2012, smoking prevalence, chronic diseases mortality and consumption were estimated. RESULTS: In 2012, 9.2% and 19% of Mexican youths and adults were current smokers. Between 2000 and 2012, smoking prevalence did not change. However, the average consumption among adolescents and adults declined whilst the special tobacco tax has being increased. Mortality attributable to tobacco consumption for four diseases was estimated in 60 000 in 2010. CONCLUSIONS: Tobacco consumption remains the leading cause of preventable death. Increasing taxes on tobacco products could deter the tobacco epidemic and consequently chronic diseases mortality in Mexico. PMID- 24626705 TI - [Gaps in the continuum of care during pregnancy and delivery in Mexico]. AB - OBJECTIVE: To develop a composite index for coverage of antenatal and delivery continuum of care, and use it to measure the gaps among different populations of pregnant women in Mexico. MATERIALS AND METHODS: Based in the information of 5 766 women from the National Health and Nutrition Survey 2012, a composite index of coverage of continuum of care (Cobac in spanish) was developed, integrating five interventions for antenatal, delivery, and puerperium periods. RESULTS: Women living in metropolitan areas who were affiliated to social security had the best Cobac (0.879; IC95%:0.867-0.891); the worst were found in women living in rural areas, with the lower socio-economic level (NSE-I), (0.722; IC95%: 0.700 0.745), women without health insurance (0.735; IC95%: 0.700-0.770), and indigenous women (0.759; IC95%: 0.740-0.779). CONCLUSIONS: The Cobac during pregnancy and childbirth has important differences within the country, which allows for the identification of areas where we must focus efforts to move towards universal health coverage. PMID- 24626706 TI - [Impact of harmful consumption of alcohol in accident-related mortality and chronic diseases in Mexico]. AB - OBJECTIVE: To analyze alcohol consumption, and its impact on road traffic-related mortality and chronic diseases. MATERIALS AND METHODS: Through the analysis of national health surveys, registry of traffic collisions, mortality records and economic surveys, we estimated prevalence, mortality and consumption indicators. RESULTS: Between 2000 and 2012, alcohol consumption in adolescents remained stable, with a significant increase among adults. Traffic collision rates related with alcohol were 0.36 and 0.58 among adolescents and adults, respectively; 8.4% of the population who suffered traffic injuries was under alcohol effects when the accident occurred. The trend in mortality from two alcohol-attributable diseases has been constant, with an average of 18 000 deaths per year. CONCLUSION: Alcohol abuse causes serious health damages. Tax raises to alcohol, along with other policies, could reduce harmful alcohol consumption and its associated mortality. PMID- 24626707 TI - [Vaccination coverage in children and adolescents in Mexico: vaccinated, under vaccinated and non vaccinated]. AB - OBJECTIVE: To assess vaccination coverage of children and adolescents. MATERIALS AND METHODS: Study based on National Health and Nutrition Survey 2012. RESULTS: Coverage in <1 year infants olds infants was <70% for 3 vaccines and <50% for 5. In 15-23 months-olds infants coverage was 59.8% for four vaccines and 51% for six. In 6-year-olds coverage was 93.2% for 1 dose of MMR, and was below 50% for three vaccines in adolescents. Proportion of non-vaccinated individuals was 4.7% in <1-year-olds, 0.2% in 15-23-month-olds, 6.8% in 6-year-olds and 37% in adolescents. Coverage for BCG, HB, and Pneumococcal vaccines in <1-year-olds, and MMR in 15-23-month-olds was >80%. No health insurance and maternal or adolescent illiteracy were explanatory variables for incomplete schema. CONCLUSIONS: Results suggest it is necessary to strengthen information systems, health promotion, training, and daily vaccination without restrictive schedules, ensuring timely and adequate supply of vaccines. PMID- 24626708 TI - [Vaccination coverage in young, middle age and elderly adults in Mexico]. AB - OBJECTIVE: To estimate vaccination coverage in adults 20 years of age and older. MATERIALS AND METHODS: Analysis of data obtained from the National Health and Nutrition Survey 2012. RESULTS: Among adults 20-59 years old coverage with complete scheme, measles and rubella (MR) and tetanus toxoid and diphtheria toxoid (Td) was 44.7,49. and 67.3%, respectively. Coverage and percentage of vaccination were significantly higher among women than men. Among women 20-49 years coverages with complete scheme, MR and Td were 48.3, 53.2 and 69.8%, respectively. Among adults 60-64 years old, coverage with complete scheme, Td and influenza vaccine were 46.5, 66.2 and 56.0%, respectively. Among adults >65 years coverages for complete scheme, Td, influenza vaccine and pneumococcal vaccine were 44.0, 69.0, 63.3 and 62.0%, respectively. CONCLUSION: Vaccination coverage among adult population as obtained from vaccination card or self-report is below optimal values although data may be underestimated. Recommendations for improvements are proposed. PMID- 24626709 TI - [Acute respiratory infections among children and identification of alarm signs by parents and caregivers in Mexico]. AB - OBJECTIVE: To estimate the prevalence of acute respiratory infection (ARI) during the two weeks previous to the interview among children <5 years of age and to describe the frequency of identification of alarm signs by parents or caregivers (PC). MATERIALS AND METHODS: Analysis of data from the National Health and Nutrition Surveys 2012 and 2006 and of National Health Survey 2000. RESULTS: ARI prevalence decreased from 2006 to 2012 (47.0-44.8%), particularly in the lower socioeconomic strata and children <1 year of age. 2012 Survey revealed highest prevalence for <1 year children. Fever was the main pneumonia-associated alarm sign (28.6%) in contrast to "breathes rapidly" (10.2%) or "unable to breathe" (20.9%). CONCLUSIONS: Results show that the magnitude of the problem has decreased in recent years, mainly among the more vulnerable groups, such as smaller children and those belonging to the lowest socioeconomic strata. However, training is required, particularly at the community level. PMID- 24626710 TI - [Acute diarrheal diseases and feeding practices among children under five years in Mexico]. AB - OBJECTIVE: To estimate the prevalence of acute diarrheal diseases (ADD) during the two weeks previous to the interview among children <5 years of age and to describe alarm signs and feeding practices of parents and caregivers (PCG) during children's ADD. MATERIALS AND METHODS: Analysis of data from the National Health and Nutrition Surveys 2012 and 2006 and the National Health Survey 2000. RESULTS: ADD prevalence decreased significantly from 2006 (13.1%) to 2012 (11.0%), particularly in the lower socioeconomic status. "Frequent bowel movements" were the main warning sign identified by PCG (66.0%) in contrast to "crying without tears" (4.3%) and "blood in faeces" (0.5%); only 42% PCG reported administering oral rehydration therapy. Factors associated with ADD were child's age <1 year and mother's age <20 years. CONCLUSIONS: It is necessary to reinforce appropriate ADD preventive and treatment practices among PCG of children <5 years of age. PMID- 24626711 TI - [Health conditions and functional status of older adults in Mexico]. AB - OBJECTIVE: To describe the health conditions and functional status of Mexicans older adults. MATERIALS AND METHODS: Descriptive study with a sample of 8,874 adults aged 60 and over, based on a nationally representative study. We analyzed major indicators associated with health conditions and functional status, obtaining prevalence and statistical tests of differences in proportions. RESULTS: The main conditions of this population are: hypertension (40%), diabetes (24%) and hypercholesterolemia (20%). For mental health indicators, 17.6% had depressive symptoms, 7.3% cognitive decline, and 7.9% dementia. For functional status, 26.9% reported difficulty in daily activities and 24.6% in instrumental activities. CONCLUSIONS: It is required the implementation of a new model of care to address the increasing prevalence of chronic degenerative diseases in old age, as well as the increased disability and consequent dependence resulting from them. PMID- 24626712 TI - [National Health and Nutrition Survey 2012: design and coverage]. AB - OBJECTIVE: To describe the design and population coverage of the National Health and Nutrition Survey 2012 (NHNS 2012). MATERIALS AND METHODS: The design of the NHNS 2012 is reported, as a probabilistic population based survey with a multi stage and stratified sampling, as well as the sample inferential properties, the logistical procedures, and the obtained coverage. RESULTS: Household response rate for the NHNS 2012 was 87%, completing data from 50,528 households, where 96 031 individual interviews selected by age and 14,104 of ambulatory health services users were also obtained. CONCLUSION: The probabilistic design of the NHNS 2012 as well as its coverage allowed to generate inferences about health and nutrition conditions, health programs coverage, and access to health services. Because of their complex designs, all estimations from the NHNS 2012 must use the survey design: weights, primary sampling units, and stratus variables. PMID- 24626713 TI - [Household socioeconomic classification in the National Health and Nutrition Survey 2012]. AB - OBJECTIVE: To describe the socioeconomic (SE) indicator developed for the analysis of the National Health and Nutrition Survey 2012 (NHNS 2012) and its validation. MATERIALS AND METHODS: The SE indicator was generated imputing deciles of income level to the households on the NHNS 2012, using demographic and socioeconomic characteristics, and based on the National Income and Expenditure Survey 2010. As a validation, distribution of different household characteristics related to SE status was described by predicted decile. RESULTS: The resulting SE indicator adequately describes heterogeneity on standard socioeconomic variables, as schooling years of the head of household, income, access to services, and household assets. CONCLUSION: The socioeconomic heterogeneity captured by the proposed SE indicator allows identifying variability and gaps on health outcomes and programs coverage related to socioeconomic level. PMID- 24626714 TI - [Non communicable chronic diseases, the main health problem in Mexico]. PMID- 24626715 TI - [Health care coverage and quality according to the National Health and Nutrition Survey, 2012]. PMID- 24626716 TI - [The analysis of ENSANUT 2012 as a contribution for public policy]. PMID- 24626717 TI - [ENSANUT 2012: Analysis of its main results]. PMID- 24626718 TI - [Health protection coverage in Mexico, and profile of unprotected population 2000 2012]. AB - OBJECTIVE: To analyze the coverage of health protection in Mexico, as well as its trends from 2000 to 2012. MATERIALS AND METHODS: Descriptive analysis using household informant report about health protection in the national health surveys 2000, 2006 & 2012, profiling unprotected population in 2012, and demographic differences by scheme of health protection. RESULTS: From 2000 to 2012, Mexican population that reported to be without health protection decreased from 57.6 to 21.4%. This reduction is mainly due to the increase in coverage of Seguro Popular, which by 2012 is the main insurer in Mexico, covering 38.5 of the population. Unprotected population is concentrated between 15 and 30 years of age. CONCLUSION: These results present a huge increase in health protection in Mexico in the past 12 years. Nevertheless, they also highlight the complexity of reaching universal health protection in a fragmented health system. PMID- 24626719 TI - [Effect of Seguro Popular on health expenditure in Mexican households ten years after its implementation]. AB - OBJECTIVE: To estimate the effect of Seguro Popular Program (SP) on the probability of health spending (HE), the excessive expenditure on health (EEH) and the amount of health spending. Materials and methods. Cross-sectional analysis was carried out using data from the ENSANUT 2012. Propensity score matching was used to estimate the effect of SP (n=12.250). We estimated the average effect on SP homes (treated) and differences in median spending. RESULTS: SP reduces the likelihood of HE in 3.6 and 7.1% in households with patients diagnosed with DM and/or hypertension, respectively. The reduction in EEH was 36% at national level. This reduction was 46.5 and 41.7% among households with hospitalized patients and those reporting a sick member. CONCLUSIONS: SP has a positive effect, protecting households from having either HE or EEH among those with greater health needs. However, there are still some challenges for the SP, which include improving access to services for low-income population. PMID- 24626720 TI - Light-extraction enhancement of a GaN-based LED covered with ZnO nanorod arrays. AB - We investigate the mechanism of light extraction enhancement of a GaN-based light emitting diode (LED) grown on patterned sapphire substrate (PSS), that has ZnO nanorod arrays (NRAs) fabricated on top of the device using the hydrothermal method. We found that the light output power of the LED with ZnO NRAs increases by approximately 30% compared to the conventional LED without damaging the electrical properties of the device. We argue that the gradual decrease of the effective refractive index, which is caused by the fabrication of ZnO NRAs, is the mechanism of the observed improvement. Our argument is confirmed by cross sectional confocal scanning electroluminescence microscopy (CSEM) and the theoretical simulations, where we observed a distinct increase of the transmission at the interface between LED and air at the operation wavelength of the LED. In addition, the plane-view CSEM results indicate that ZnO NRAs, which were grown on the bare p-type GaN layer as an electrical safety margin area, also contribute to the enhanced light output power of the LED, which indicate further enhancement is manifested even in the optically ineffective sacrificial area. PMID- 24626721 TI - "Occult" post-contrast signal enhancement in pediatric diffuse intrinsic pontine glioma is the MRI marker of angiogenesis? AB - INTRODUCTION: In diffuse intrinsic pontine gliomas (DIPG), subtracting pre contrast from post-contrast T1-weighted images (T1WI) occasionally reveals subtle, "occult" enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors. METHODS: We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion MRI studies of 61 patients. To determine the incidence of occult enhancement, cerebral blood volume (CBV) values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM). RESULTS: Tumors of 10 patients (16.4 %) had occult enhancement; those of 6 patients (9.8 %) had no enhancement at all. The average CBV in areas of occult enhancement was significantly higher than that in non enhancing areas of the same tumor (P = .03), within DCWM in the same patient (P = .03), and when compared to anatomically paired/similar regions of interest (ROI) in patients with non-enhancing tumors (P = .005). CONCLUSION: Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy. PMID- 24626722 TI - The role of autophagy induced by pemetrexed in lung adenocarcinoma cells. AB - Autophagy is known as an important regulatory mediator for cell survival or death and its important role in cancer. Pemetrexed (PTX) has been used in chemotherapy for lung cancer. However, the underlying molecular mechanisms have not been fully clarified. To investigate the role of autophagy induced by PTX in A549 cells, we performed MTT assay, acridine orange staining, western blotting, Annexin V/PI by using the 3-MA autophagy inhibitor. PTX induced autophagy after 48 h treatment in A549 cells. Furthermore, PTX showed acidic vesicular organelles (AVOs) and expressed LC3-II in A549 cells. The induction of autophagy by PTX was inhibited by 3-MA which was confirmed by reduced AVOs. When the autophagy was inhibited, Annexin V was increased. In addition, PARP cleavage was increased as shown by western blotting. Taken together, PTX induced autophagy in A549 cells and these cellular events possibly cause the apoptotic and/or necrotic cell death of A549 cells. PMID- 24626723 TI - Dynamics of metal uptake by charged soft biointerphases: impacts of depletion, internalisation, adsorption and excretion. AB - A comprehensive theory is elaborated for the dynamics of metal ion uptake by charged spherical microorganisms. The formalism integrates the interplay over time between bulk metal depletion, metal adsorption, metal excretion (efflux) and transport of metals by conductive diffusion toward the metal-consuming biomembrane. The model further involves the basic physicochemical features of the microbial interphase in terms of size, distribution of electrostatic charges and thickness of peripheral soft surface appendage. A generalization of the Best equation is proposed and leads to the expression of the time-dependent concentration of metal ions at the active membrane surface as a function of bulk metal concentration. Combination of this equation with the metal conservation condition over the sample volume allows a full evaluation of bulk metal depletion kinetics and the accompanying time-dependent uptake and excretion fluxes as a function of metal-microorganism electrostatic interaction, microbe concentration and relevant biophysicochemical features of the interphase. Practically tractable expressions are derived in the limit where the Biotic Ligand Model (BLM) is obeyed and in situations where conductive diffusion transport of metals significantly determines the rate of biouptake. In particular, the plateau value reached at sufficiently long times by bulk metal concentration is rigorously expressed in terms of the key parameters pertaining to the adsorption process and to the kinetics of metal uptake and excretion. The theory extends and unifies previous approximate models where the impacts of extracellular metal transport and/or metal efflux on the overall rate of uptake were ignored. PMID- 24626724 TI - [Lipid therapy for patients with coronary heart disease and diabetes. Current state and perspectives]. AB - For patients with diabetes mellitus and coronary heart disease high-dose statin therapy is recommended independent of basal low density lipoprotein (LDL) cholesterol levels and with a target value <70 mg/dl (1.8 mmol/l). Drug combinations which lower LDL, e.g. cholesterol absorption inhibitors, are an option. Fibrates have not been proven to have a cardiovascular advantage but these drugs could be of value in diabetic microangiopathy. A low level of high density lipoprotein (HDL) cholesterol is the most common phenomenon in diabetes. Clinical endpoint studies for the combination with nicotinic acid were negative but therapeutic alternatives are lacking. Therefore, statin therapy is the primary lipid lowering therapy also for diabetic dyslipidemia. PMID- 24626725 TI - Influence of Annona muricata (soursop) on biodistribution of radiopharmaceuticals in rats. AB - PURPOSE: To evaluate the effect of hydroalcoholic extract of A. muricata on biodistribution of two radiopharmaceuticals: sodium phytate and dimercaptosuccinic acid (DMSA), both labeled with 99mtechnetium. METHODS: Twenty four Wistar rats were divided into two treated groups and two controls groups. The controls received water and the treated received 25mg/kg/day of A. muricata by gavage for ten days. One hour after the last dose, the first treated group received 99mTc-DMSA and the second sodium 99mTc-phytate (0.66MBq each group), both via orbital plexus. Controls followed the same protocol. Forty min later, all groups were sacrificed and the blood, kidney and bladder were isolated from the first treated group and the blood, spleen and liver isolated from the second treated group. The percentage of radioactivity per gram of tissue (%ATI/g) was calculated using a gamma counter. RESULTS: The statistical analysis showed that there was a statistically significant decrease (p<0.05) in the uptake of %ATI/g in bladder (0.11+/-0.01and1.60+/-0.08), kidney (3.52+/-0.51and11.84+/-1.57) and blood (0.15+/-0.01and 0.54+/-0.05) between the treated group and control group, respectively. CONCLUSION: The A. muricata hydroalcoholic extract negatively influenced the uptake of 99mTc-DMSA in bladder, kidney and blood of rats. PMID- 24626726 TI - Behavioural and cognitive effects of simvastatin dose used in stimulation of bone regeneration in rats. AB - PURPOSE: To analyze the effects of simvastatin (SVT) in the locomotion, anxiety and memory of rats, as a reflection of the administration of a minimum dose capable of stimulating bone regeneration in defects in the calvariae. METHODS: Surgical procedures were performed in 15 female Wistar rats, 2-month old, to insert the grafting material regenerator (Bone-ceramic(r)) and/or SVT, followed by behavioural and cognitive assessments in the 7th, 30th and 60th days post surgery. RESULTS: The SVT locally applied with the goal of bone regeneration in defects created in rat calvariae does not interfere with locomotion, anxiety levels and/or memories of rats, except for the first week following surgery, when an anxiolytic effect was observed, as a result of a possible central action. CONCLUSION: Failure to provoke any response within 30 and 60 days post surgical procedures suggests that SVT may constitute a good choice in stimulating bone regeneration without affecting the long term neural functions. PMID- 24626727 TI - Validation of the gastroschisis experimental model and the influence of the mother's diet enriched with glutamine in the fetal morphology. AB - PURPOSE: To validate the gastroschisis experimental model in female rats and the effects on the glutamine fetal morphology during pregnancy. METHODS: Twelve pregnant rats Wistar were separated in two groups: Group I (n = 6 rats, 71 fetuses) took glutamine and Group II (n = 6 rats, 75 fetuses) took isocaloric supplementation. At the 18th day of pregnancy, female rats were taken to hysterotomy and the fetuses which were selected for the act of gastroschisis were partially removed from the womb and by the laparotomy technique, the exclusion of the intestine was done. After that, fetuses were put in the womb cavity again and the rats' abdomen sutured. At the 21st day of pregnancy, date before delivery, by C-section ordinary animals and the ones with gastroschisis were removed and studied separately. The morphometrical parameters studied were the body weight (PC); the intestine weight (PI); the intestine length (CI) and its relations (PI/PC, PI/CI e PC-PI). RESULTS: The intestine weight (PI) and the intestine length (CI) were different in fetuses with gastroschisis (p<0.05), however no difference between the groups regarding supplementation with glutamine. CONCLUSIONS: The gastroschisis experimental model is valid and reproducible. The nutritional therapy with glutamine did not change the morphometrical parameters. PMID- 24626728 TI - Description of a new experimental model skin flap for studying skin viability in rats. AB - PURPOSE: To describe a new experimental flap for studying skin viability in rats. METHODS: Twenty male Wistar rats weighing between 250-300g were divided into two groups: group A - McFarlane technique, a 4 x 10cm flap was used (McFarlane); and in group B modified McFarlane technique, a 3 x 10cm flap was used. Seven days later, the animals were sacrificed and the area of necrosis was evaluated in both groups. RESULTS: Group A presented necrosis in 3% of the total area of the flap (CI: 0.01-0.05), Group B presented necrosis in 37% of the total area of the flap (CI: 0.29-0.46), (p<0.001). CONCLUSION: The modified McFarlane flap presented a larger area of necrosis and could be an adequate experimental model of skin flap viability. PMID- 24626729 TI - Comparative efficacy of Belzer or Euro-Collins solutions for pancreatic preservation during cold ischemic storage in rats. AB - PURPOSE: To compare the efficacy of different types of solutions (Belzer or Euro Collins) for the preservation of rat pancreas during cold ischemia. METHODS: Thirty Wistar rats were divided into three groups according to the perfusion or storage solution: Group E (perfusion and storage in Euro-Collins solution); Group B (perfusion and storage in Belzer solution) and Group BE (Perfusion in Belzer solution and storage in Euro-Collins solution). After perfusion, the pancreas was excised and stored at 4C for 18 hours. Amylase was measured at 6, 12 and 18h, and histological analysis of the pancreas was performed after 18h of cold storage. RESULTS: Amylase was elevated and comparable in Groups E and BE after 12 and 18 hours of ischemia (p<0.05). In the exocrine pancreas, histological differences in the amount of necrosis (p=0.049), lymphocytic infiltrate (p<0.001) and neutrophilic infiltrate (p=0.004) were observed, with more favorable features present in Group B. In the endocrine pancreas, Group B showed less edema (p<0.001), but other parameters were similar among all groups. CONCLUSION: The Euro-Collins solution is inferior to the Belzer solution for the preservation of rat pancreas during cold ischemia. PMID- 24626730 TI - Oxidative stress and fatty acid profile in Wistar rats subjected to acute food restriction and refeeding with high-fat diets. AB - PURPOSE: To assess oxidative stress and the profile of fatty acids incorporated into the hepatic tissue of animals refed with high-fat (HF) diets after acute food restriction. METHODS: Fifty male Wistar rats were divided into five groups and fasting for 48 hours. One group was sacrificed without refeeding (NR), a control group (C) was refed with the standard AIN-93 diet and the remaining groups with HF diets respectively consisting of hydrogenated vegetable oil (PHVO), trans-free (TF) margarine and trans-free margarine enriched with omega-3 and omega-6 (O). After this period the animals were sacrificed for malondialdehyde (MDA), catalase and hepatic fatty acid determination. RESULTS: The groups refed with HF diets showed elevation of MDA levels compared to the C group (p<0.001 for GVH and p<0.01 for TF and O). Hepatic catalase activity was higher in the TF and O groups compared to group C (p<0.05 for both). The amount of saturated fatty acids was lower in the PHVO and O groups compared to the remaining ones (p<0.001). CONCLUSION: The consumption of high-fat diets after prolonged fasting favors oxidative imbalance in hepatic tissue. PMID- 24626731 TI - Gene expression profile of oxidative stress in the lung of inbred mice after intestinal ischemia/reperfusion injury. AB - PURPOSE: To determine the gene expression profile associated with oxidative stress and antioxidant defense in the lung tissue of mice subjected to intestinal ischemia and reperfusion. METHODS: Twelve male, inbred mice (C57BL/6) were randomly assigned to one of two groups. The control group (CG) underwent anesthesia and laparotomy and was observed for 120 minutes; the ischemia/reperfusion group (IRG) was subjected to anesthesia, laparotomy, and ischemia of the small intestine for 60 minutes and to 60 minutes of reperfusion. A pool of six mice from each group was subjected to a reverse transcription quantitative polymerase chain reaction (RT-qPCR) to analyze the oxidative stress and antioxidant defense genes. All genes that were up-regulated or down-regulated greater than three-fold, based on the algorithm [2^(DeltaDeltaCt)], were considered to be biologically meaningful. RESULTS: Out of a total of 84 genes in the lung that are related to oxidative stress, 67 (79.7%) were up-regulated and 17 (20.2%) were down-regulated. Only two genes (2.3%), Lpo (lactoperoxidase) (+3.51) and Gpx4 (glutathione peroxidase) (+4.10), were expressed above the three fold threshold, while none of the down-regulated genes were expressed outside of this threshold. CONCLUSION: The intestinal ischemia/reperfusion injury promoted a gene expression profile consisting of the positive expression of oxidative genes in a remote organ. This suggests that activate signaling pathways are implicated in both cell survival and the maintenance of genome integrity in the lung. PMID- 24626732 TI - Torsional force applied to the tibia of living lambs in an attempt to change the bone rotational axis. AB - PURPOSE: To evaluate the effects of torsional force on the rotational axis of living lamb tibias. METHODS: An external fixator device was designed to apply rotation to the tibias of lambs. Once a week, the bone distal extremity was rotated 2o. After achieving ~20o of internal rotation, the turning was discontinued and the device was maintained in situ for one month and euthanasia occurred in group A (n=10) after this. In group B (n=9) euthanasia occurred three months after removing the device. Computed tomography scans evaluated the rotational angle; dual-energy X-ray absorptiometry assessed the bone mineral density, and conventional and polarized light microscopy studied the bone microstructure. RESULTS: In group A, the mean angle of the external rotation in the control tibias was 24o and 8o in the twisted tibias (p<0.0001); in group B, the angle was 23o (control) and 7o (twisted, p<0.0001), with no differences between groups A and B (p=0.9567). The BMD increased in the twisted tibias in group A (p<0.0001) and in group B (p=0.0023), with no between-group differences (p>0.05). Microscopically, the twisted tibias showed asymmetrical subperiosteal bone deposition on the lateral cortex surface. CONCLUSION: Gradual torsion applied to the immature tibia significantly modified its rotational axis. PMID- 24626733 TI - Epidural anesthesia with ropivacaine with or without clonidine and postoperative pain in hemorrhoidectomies. AB - PURPOSE: To determine the safety, pain intensity correlated with age and body mass index (BMI), epidural anesthesia with ropivacaine and clonidine in hemorrhoidectomy. METHODS: Eighty patients, both genders, 20-70 years old, ASA I or II, for hemorrhoidectomy were randomly divided into two groups: Control (n=38), epidural anesthesia with 14 mL of ropivacaine 0.75 % plus 0.0266 mL/kg of 0.9% saline solution; Experimental (n=42) epidural anesthesia with 14 mL of 0.75% ropivacaine plus 4.0 mcg/kg of clonidine. In preoperative and postoperative period were evaluated: systolic blood pressure (SBP), diastolic blood pressure (DBP ), heart rate (HR ), pulse oximetry (SpO2), electrocardiography (ECG), pain intensity (VAS ) in four, eight and, 12 hours and analgesic consumption. RESULTS: The VAS values differed between four, eight and 12 hours in the Experimental Group, where correlation of VAS 12h with age (p<0.05) occurred and not with BMI and more patients (p<0.05) did not receive analgesics. SBP, DBP, HR changed similarly in both groups at 15, 30 and 45 min. The ECG and SpO2 remained unchanged. CONCLUSIONS: Clonidine (4mcg/kg) in epidural anesthesia with ropivacaine 0.75% in hemorrhoidectomy showed safety and greater analgesia within four hours. The pain at 12 hours showed correlation with age and not with body mass index. PMID- 24626734 TI - Antibiotic prophylaxis in obese patients submitted to bariatric surgery. A systematic review. AB - PURPOSE: To review the use of cefazolin in prophylaxis of surgical wound infection (SSI) in bariatric surgery (BS). METHODS: A systematic review was performed from October to November, 2013 using the following databases: The Cochrane Library, Medline, LILACS, and EMBASE. The inclusion criteria were randomized clinical trials and observational studies that were evaluated by two independent reviewers. RESULTS: Nine hundred and sixty one titles were recovered after preliminary analysis (title and abstract), seven studies remained for final analysis. There were three clinical trials (one with SSI, and two with antibiotic levels as the outcome), and four were observational studies (three cohorts and one case-control, all had SSI as the outcome). After administration of 1g or 2 g, levels of cefazolin in serum and tissue were suboptimal according to two studies. Results from observational studies indicated that different antibiotics were used for prophylaxis of SSI in BS and that use of other drugs may be associated with higher rates of SSI. CONCLUSION: The use of cefazolin for surgical wound infection prophylaxis in bariatric surgery is recommended, however further studies are needed in order to refine parameters as initial dose, redose, moment of administration and lasting of prophylaxis. PMID- 24626735 TI - Significant Publications About the Medication Use Process in 2012. AB - PURPOSE: This article identifies, prioritizes, and summarizes the published literature on the medication use process (MUP) from calendar year 2012 that can impact health-system pharmacists' daily practice. SUMMARY: The MUP is the foundational system that provides the framework for safe patient care within the health care environment. The MUP is defined in this article as having the following components: prescribing/transcribing, dispensing, administration, and monitoring. A PubMed search was conducted in January 2013 for calendar year 2012 using targeted Medical Subject Headings (MeSH) keywords, providing a total of 944 articles. A thorough review identified 46 potentially significant articles: 14 for prescribing/transcribing, 12 for dispensing, 10 for administration, and 10 for monitoring. Peer review led to the selection of key articles from each category. These articles are briefly summarized, with a mention of why this article is important within health-system pharmacy. The other articles are listed for further review and evaluation. CONCLUSION: It is important to routinely review the published literature and to incorporate significant findings into daily practice. Health-system pharmacists have an active role in improving the MUP in their institution and awareness of the significant published studies can assist in changing practice at the institutional level. PMID- 24626737 TI - A diet formula of Puerariae radix, Lycium barbarum, Crataegus pinnatifida, and Polygonati rhizoma alleviates insulin resistance and hepatic steatosis in CD-1 mice and HepG2 cells. AB - According to the principles of traditional Chinese medicine, medicinal and edible herbs exhibit holistic effects through their actions on multiple target organs. Four herbs, Puerariae radix, Lycium barbarum, Crataegus pinnatifida, and Polygonati rhizoma, were selected and combined to create a new herbal formula (PLCP). The protective effects of both the aqueous extract (AE) and ethanol extract (EE) of PLCP against insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) were evaluated in both high fat and high fructose diet-fed mice. Active fractions and constituents were screened in HepG2 cells with IR or an over-accumulation of triglycerides, and were further identified by high performance liquid chromatography/electrospray ionization/mass spectrometry. The results indicate that the AE did not improve (p > 0.05) glucose tolerance after three weeks, whereas EE showed a promising effect throughout the experiment. Medium and high doses of EE were found to reduce fasting blood glucose at week 9 by 21.1% and 24.4%, respectively. In addition, their efficacies for alleviating IR were comparable with that of metformin. Compared with AE, EE effectively improved hyperlipidemia, antioxidant status, and NAFLD. In contrast, metformin did not alleviate hyperlipidemia (p > 0.05) or NAFLD in the mice model. Results from the cell-based study indicate that the protective effects of EE were possibly due to the actions from puerarin, 3'-methoxypuerarin, daidzin, daidzein, and ononin. PMID- 24626736 TI - Metalloproteinase dependent reduction of cell surface cluster determinants upon the induction of apoptosis. AB - LN18 glioblastoma cells were used as a model to examine changes in surface cluster determinants (CDs) as the cells undergo apoptosis. LN18 cells proceeding through apoptosis manifested a decrease in cell adhesion molecules, growth factor receptors and other surface proteins. Apoptosis was induced by MK886, a known FLAP and PPAR-alpha inhibitor, or staurosporine, a known inhibitor of protein kinases including protein kinase C (PKC). The detection and decrease of surface CDs were observed by flow cytometry using CD-specific primary antibodies followed by secondary antibodies conjugated to phycoerythrin. It was determined that there was an apoptotic induced decrease of alpha and beta integrin determinants and the growth factor receptors EGFR and IGF1R. The MHC-1 cell surface marker HLA-ABC was also reduced in the apoptotic cells. The level of EGFR, IGF1R and detected alpha and beta integrin determinants dropped dramatically. The degradation takes place in mid to late apoptosis. It was determined by real-time RT-PCR that the decrease in integrins, EGFR, IGF1R and MHC-1 determinants were not due to a reduction in transcription. Inhibitors of metallo-proteinases blocked the apoptotic decrease in cell surface determinants indicating that metalloproteinases mediated the reduction in these CDs in a manner that can reduce growth and survival signals while stimulating the NK surveillance system. Overall, the data indicate that the final stages of the pharmacological induction of apoptosis, while proceeding to a full commitment to non-necrotic cell death, involves the degradation of integrin, insulin and epidermal growth factor receptors caused by a programmed dysregulation of the cell's metalloproteinases. PMID- 24626738 TI - Early prevention of antisocial personality: long-term follow-up of two randomized controlled trials comparing indicated and selective approaches. AB - OBJECTIVE: Antisocial personality is a common adult problem that imposes a major public health burden, but for which there is no effective treatment. Affected individuals exhibit persistent antisocial behavior and pervasive antisocial character traits, such as irritability, manipulativeness, and lack of remorse. Prevention of antisocial personality in childhood has been advocated, but evidence for effective interventions is lacking. METHOD: The authors conducted two follow-up studies of randomized trials of group parent training. One involved 120 clinic-referred 3- to 7-year-olds with severe antisocial behavior for whom treatment was indicated, 93 of whom were reassessed between ages 10 and 17. The other involved 109 high-risk 4- to 6-year-olds with elevated antisocial behavior who were selectively screened from the community, 90 of whom were reassessed between ages 9 and 13. The primary psychiatric outcome measures were the two elements of antisocial personality, namely, antisocial behavior (assessed by a diagnostic interview) and antisocial character traits (assessed by a questionnaire). Also assessed were reading achievement (an important domain of youth functioning at work) and parent-adolescent relationship quality. RESULTS: In the indicated sample, both elements of antisocial personality were improved in the early intervention group at long-term follow-up compared with the control group (antisocial behavior: odds ratio of oppositional defiant disorder=0.20, 95% CI=0.06, 0.69; antisocial character traits: B=-4.41, 95% CI=-1.12, -8.64). Additionally, reading ability improved (B=9.18, 95% CI=0.58, 18.0). Parental expressed emotion was warmer (B=0.86, 95% CI=0.20, 1.41) and supervision was closer (B=-0.43, 95% CI=-0.11, -0.75), but direct observation of parenting showed no differences. Teacher-rated and self-rated antisocial behavior were unchanged. In contrast, in the selective high-risk sample, early intervention was not associated with improved long-term outcomes. CONCLUSIONS: Early intervention with severely antisocial children for whom treatment is indicated may prevent the development of antisocial personality in adolescence and may improve academic performance. In contrast, early intervention with selective high-risk samples may be ineffective. PMID- 24626739 TI - Phosphorylated signal transducer and activator of transcription 1 is a potential predictor of interferon response in patients with advanced renal cell carcinoma. AB - The present study aimed to evaluate the expression status of Janus kinase (JAK) Signal Transducer and Activator of Transcription (STAT) in renal cell carcinoma and benign renal tissue, and identify a potential biomarker for interferon (IFN) response prediction. A total of 32 specimens of human renal cell carcinoma and 10 specimens of benign renal tissue were harvested from surgically removed kidneys. The expression levels of JAK-STAT were determined by immunohistochemical staining and quantitative polymerase chain reaction. Furthermore, the expression levels of JAK-STAT in renal cell carcinoma tissues that were stimulated with IFN-alpha were quantified by western blot analysis. The positive expression rates of JAK1, STAT1 and phosphorylated (P)-STAT1 in the renal cell carcinomas were significantly lower than that in the benign renal tissues (25.0, 31.2, and 12.5% vs. 70.0, 50.0, and 70.0%, respectively; P<0.05). The relative expression levels of JAK1 (0.696 +/- 0.102) and STAT1 mRNA (0.341 +/- 0.068) in the tumor tissue were lower than those in the benign tissue (0.957 +/- 0.103 and 0.547 +/- 0.082, respectively; P<0.05). IFN stimulation enhanced the expression levels of P-STAT1 in the renal cell carcinoma tissues, and enhancement of the P-STAT1 expression levels was associated with tumor relapse and metastasis. In conclusion, P-STAT1 is a potential predictor of IFN response in patients with advanced renal cell carcinoma. PMID- 24626740 TI - Palladium-phosphorus/sulfur nanoparticles (NPs) decorated on graphene oxide: synthesis using the same precursor for NPs and catalytic applications in Suzuki Miyaura coupling. AB - PdP2 and Pd4S nanoparticles (NPs) (size: ~2-6 and 9-15 nm respectively) have been prepared for the first time from a single source precursor complex [Pd(L)Cl2] (1) by its one pot thermolysis at 200 degrees C in TOP and OA/ODE (1 : 1) respectively. These NPs were stirred with graphene oxide (GO) at room temperature to prepare NP composites, GO-PdP2 and GO-Pd4S. The GO-PdP2 NPs have been synthesized for the first time. The thioether ligand L prepared by reaction of 1,3-dibromo-2-propanol with the in situ generated PhSNa reacts with [PdCl2(CH3CN)2] in CH3CN at 70 degrees C resulting in 1. The L and 1 have been characterized by (1)H and (13)C{(1)H} NMR and HR-MS. The single crystal structure of 1 determined by X-ray diffraction reveals nearly square planar geometry around the Pd metal centre. The catalytic activities of two palladium nano-phases having phosphorus and sulphur respectively as a co-constituent for Suzuki-Miyaura coupling have been found to be exceptionally different, as PdP2 nanoparticles (NPs) grafted on graphene oxide (GO-PdP2) are significantly more efficient than Pd4S NPs grafted on GO. Without grafting PdP2 and Pd4S both have low efficiency. This is the first report comparing the influence of P and S on the catalytic activity of Pd NPs. TEM, SEM-EDX and powder-XRD have been used to authenticate all NPs. The GO-PdP2 NPs have been found to be efficient catalysts for Suzuki Miyaura coupling reactions (yield up to 96% in 30 min) at room temperature to 80 degrees C. Their recyclability has been found up to 6 cycles. In contrast, GO Pd4S NPs are little active in comparison with GO-PdP2 NPs. The size of NPs and their distribution on GO appear to be key factors affecting the catalytic efficiency of the composite NPs. Leaching of Pd from GO-PdP2 NPs contributes significantly to the catalysis as evidenced by the three phase test, hot filtration and recycling experiments. The catalysis is almost homogeneous. PMID- 24626741 TI - Metabonomic analysis of the joint toxic action of long-term low-level exposure to a mixture of four organophosphate pesticides in rat plasma. AB - In previously published articles, we evaluated the toxicity of four organophosphate (OP) pesticides (dichlorvos, dimethoate, acephate, and phorate) in rats using metabonomic technology at their corresponding no observed adverse effect levels (NOAELs). The results show that a single pesticide did not elicit a toxic response. The joint toxic action of four pesticides (at their corresponding NOAELs) was evaluated by metabolomic analysis of rat plasma under experimental conditions similar to those of the four single OP pesticides. The pesticides were administered daily to rats through drinking water for 24 weeks. The mixture of four pesticides showed a joint toxic action at the NOAELs of each pesticide. The 19 metabolites were statistically significantly changed in all the treated groups compared with those in the control group (p < 0.05 or p < 0.01). Exposure to OP pesticides resulted in increased lysoPC (15 : 0/0 : 0), lysoPC (16 : 0/0 : 0), lysoPC (O-18 : 0/0 : 0), lysoPC (P-19 : 1(12Z)/0 : 0), lysoPC (18 : 1(9Z)/0 : 0), lysoPC (18 : 0/0 : 0), lysoPC (20 : 4(5Z, 8Z, 11Z, 14Z)/0 : 0), lysoPE (16 : 0/0 : 0), lysoPC (17 : 0/0 : 0), 4-pyridoxic acid, glutamic acid, glycocholic acid, and arachidonic acid, as well as decreased C16 sphinganine, C17 sphinganine, phytosphingosine, indoleacrylic acid, tryptophan, and iodotyrosine in rat plasma. The results indicate that the mixture of OP pesticides induced oxidative stress, liver and renal dysfunction, disturbed the metabolism of lipids and amino acids, and interfered with the function of the thyroid gland. The present plasma results provided complementarities with our previous metabolomic analysis of the rat urine profile exposed to a mixture of four OP pesticides, and also contributed to the understanding of the mechanism of joint toxic action. PMID- 24626742 TI - Local interactions influence the fibrillation kinetics, structure and dynamics of Abeta(1-40) but leave the general fibril structure unchanged. AB - A series of peptide mutants was studied to understand the influence of local physical interactions on the fibril formation mechanism of amyloid beta (Abeta)(1 40). In the peptide variants, the well-known hydrophobic contact between residues phenylalanine 19 and leucine 34 was rationally modified. In single site mutations, residue phenylalanine 19 was replaced by amino acids that introduce higher structural flexibility by a glycine mutation or restrict the backbone flexibility by introduction of proline. Next, the aromatic phenylalanine was replaced by tyrosine or tryptophan, respectively, to probe the influence of additional hydrogen bond forming capacity in the fibril interior. Furthermore, negatively charged glutamate or positively charged lysine was introduced to probe the influence of electrostatics. In double mutants, the hydrophobic contact was replaced by a putative salt bridge (glutamate and lysine) or two electrostatically repelling lysine residues. The influence of these mutations on the fibrillation kinetics and morphology, cross-beta structure as well as the local structure and dynamics was probed using fluorescence, transmission electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. While the fibrillation kinetics and the local structure and dynamics of the peptide variants were influenced by the introduction of these local fields, the overall morphology and cross-beta structure of the fibrils remained very robust against all the probed interactions. Overall, 7 out of the 8 mutated peptides formed fibrils of very similar morphology compared to the wildtype. However, characteristic local structural and dynamical changes indicate that amyloid fibrils show an astonishing ability to respond to local perturbations but overall show a very homogenous mesoscopic organization. PMID- 24626743 TI - Ruthenium-catalyzed alkenylation of azoxybenzenes with alkenes through ortho selective C-H activation. AB - A highly selective alkenylation of azoxybenzenes catalyzed by the Ru(III)-complex was developed. It provides a direct access to a series of olefinated azoxy compounds in good yields. PMID- 24626744 TI - Analytical tools for single-molecule fluorescence imaging in cellulo. AB - Recent technological advances in cutting-edge ultrasensitive fluorescence microscopy have allowed single-molecule imaging experiments in living cells across all three domains of life to become commonplace. Single-molecule live-cell data is typically obtained in a low signal-to-noise ratio (SNR) regime sometimes only marginally in excess of 1, in which a combination of detector shot noise, sub-optimal probe photophysics, native cell autofluorescence and intrinsically underlying stochasticity of molecules result in highly noisy datasets for which underlying true molecular behaviour is non-trivial to discern. The ability to elucidate real molecular phenomena is essential in relating experimental single molecule observations to both the biological system under study as well as offering insight into the fine details of the physical and chemical environments of the living cell. To confront this problem of faithful signal extraction and analysis in a noise-dominated regime, the 'needle in a haystack' challenge, such experiments benefit enormously from a suite of objective, automated, high throughput analysis tools that can home in on the underlying 'molecular signature' and generate meaningful statistics across a large population of individual cells and molecules. Here, I discuss the development and application of several analytical methods applied to real case studies, including objective methods of segmenting cellular images from light microscopy data, tools to robustly localize and track single fluorescently-labelled molecules, algorithms to objectively interpret molecular mobility, analysis protocols to reliably estimate molecular stoichiometry and turnover, and methods to objectively render distributions of molecular parameters. PMID- 24626745 TI - Assessment of portal hypertension and high-risk oesophageal varices with liver and spleen three-dimensional multifrequency MR elastography in liver cirrhosis. AB - OBJECTIVE: To assess the value of the liver and spleen viscoelastic parameters at multifrequency MR elastography to determine the degree of portal hypertension and presence of high-risk oesophageal varices in patients with cirrhosis. METHODS: From January to September 2012, 36 consecutive patients with cirrhosis evaluated for transplantation were prospectively included. All patients underwent hepatic venous pressure gradient (HVPG) measurements and endoscopy to assess oesophageal varices. Multifrequency MR elastography was performed within the liver and spleen. The shear, storage and loss moduli were calculated and compared to the HVPG with Spearman coefficients and multiple regressions. Patients with and without severe portal hypertension and high-risk varices were compared with Mann Whitney tests, logistic regression and ROC analysis. RESULTS: The liver storage and loss moduli and the spleen shear, storage and loss moduli correlated with the HVPG. At multiple regression, only the liver and the spleen loss modulus correlated with the HVPG (r = 0.44, p = 0.017, and r = 0.57, p = 0.002, respectively). The spleen loss modulus was the best parameter for identifying patients with severe portal hypertension (p = 0.019, AUROC = 0.81) or high-risk varices (p = 0.042, AUROC = 0.93). CONCLUSIONS: The spleen loss modulus appears to be the best parameter for identifying patients with severe portal hypertension or high-risk varices. KEY POINTS: 1. Noninvasive HVPG assessment can be performed with liver and spleen MR elastography 2. The spleen loss modulus enables the detection of high-risk oesophageal varices 3. The spleen loss modulus enables the detection of severe portal hypertension. PMID- 24626746 TI - Fluid flow modulates the expression of genes involved in the Wnt signaling pathway in osteoblasts in 3D culture conditions. AB - The balance between osteoclastic bone resorption and osteoblastic bone formation maintains bone mass, while mechanical loads stimulate bone formation and suppress resorption. The molecular mechanisms responsible for this process have not yet been fully elucidated. In the present study, we assessed whether mechanical stimulation by pulsating fluid flow (PFF) leads to functional Wnt production and affects the function of osteoblasts. ROS17/2.8 osteoblasts were submitted to 1-4 h PFF (0.8 Pa) by three-dimensional (3D) cell culture system with fluid flow. PFF upregulated the gene expression levels of adenomatous polyposis coli, alkaline phosphatase, low density lipoprotein receptor-related protein 5 (LRP5), Wnt3a and beta-catenin [catenin beta 1 (CTNNB1)] in all the groups of osteoblasts. Our results suggest that mechanical stimulation by PFF induces the differentiation of osteoblasts and the activation of the Wnt/beta-catenin signaling pathway in a 3D cell culture system. Furthermore, mechanical stress plays an important role in the Wnt/beta-catenin signaling pathway and is involved in bone formation. PMID- 24626747 TI - Dietary patterns as predictors of successful ageing. AB - OBJECTIVES: To examine associations between dietary patterns identified by factor analysis, and successful ageing. DESIGN: Prospective cohort study with diet measured in 1990-4, and successful ageing in 2003-7. Ordered logistic regression with outcome determined as dead/usual ageing/successful ageing was used to examine associations with quintile groups of dietary factor scores. PARTICIPANTS: Men and women (n=6308), without history of major illness at baseline, and aged >70 years at follow-up, or who had died before follow-up but would have been aged >70 at the commencement of follow-up, from the Melbourne Collaborative Cohort Study. MEASUREMENTS: Frequencies of intake of 121 foods at baseline were collected in a food frequency questionnaire. Anthropometry and other health and lifestyle data were collected. At follow-up, questionnaire data relating to mental health, physical function and medical history were used to define successful ageing. RESULTS: Four dietary factors were identified, characterized by higher loadings for (1) vegetables; (2) fruit, (3) feta, legumes, salad, olive oil, and inverse loadings for tea, margarine, cake, sweet biscuits and puddings; (4) meat, white bread, savoury pastry dishes and fried foods. In models excluding body size, the second factor 'Fruit' was positively associated with successful ageing (OR in top 20% vs lowest 20% of score 1.31, 95%CI (1.05-1.63), p trend across quintile groups 0.001); while the fourth factor 'Meat/fatty foods' was inversely associated (OR in top 20% vs lowest 20% of score 0.69, 95%CI (0.55 0.86), p trend across quintile groups 0.001). Factors 1 and 3 did not show significant associations with successful ageing. The association for 'Fruit' was little altered after adjustment for body size, while for 'Meat/fatty foods' the association was somewhat attenuated. CONCLUSION: A dietary pattern including plenty of fruit while limiting meat and fried foods may improve the likelihood of ageing successfully. PMID- 24626748 TI - Sexually dimorphic patterns of nutritional intake and eating behaviors in community-dwelling older adults with normal and slow gait speed. AB - OBJECTIVES: Assess sex-specific nutritional intake and dietary habits of independently living older adults with normal and slow gait speeds. DESIGN: New Mexico Aging Process Study, cross-sectional, secondary data analysis. SETTING: Albuquerque, New Mexico USA. PARTICIPANTS: Three-hundred fifteen adults 60 years and older (194 women and 121 men). MEASUREMENTS: Gait speed test, 3-day diet records, Mini-Mental State Examination, and body mass index. RESULTS: Slow gait speed was associated with lower total calories (-154 kcal/day) and zinc (1 mg/day) (.05 < p < .1). Slower men consumed less protein (-4.1 g/day), calcium ( 140 mg), fiber (-2.8 g/day) and iron (-2.5 mg/day) (p<=.05). Slower women consumed less, protein (-5.5 g/day), carbohydrate (-19.1 g/day), fiber (-2.7 gm/day), vitamin C (-18.4 mg/day) and higher fat intake (p=0.03). Slower women snacked less, had trouble chewing/biting, and lived alone (p= .04). Slower men were less likely to snack. CONCLUSIONS: We found sex-specific nutritional differences associated with gait speed. Those presenting with slow gait speed may need encouragement to increase meat and whole grain breads/cereal. Those with trouble eating should be advised on adapting diet to maintain adequate nutrition and encouraged on regular snacking to achieve higher nutrient intake. Prospective and randomized controlled studies are needed to confirm these findings and provide further evidence for putting these suggestions into practice. PMID- 24626749 TI - Eating and aging: trends in dietary intake among older Americans from 1977-2010. AB - OBJECTIVE: We examined trends from 1977-2010 in calorie, macronutrient, and food group intake among US adults 55 and older. DESIGN: Cross-sectional time series. SETTING: A nationally representative sample of the US non-institutionalized population. PARTICIPANTS: Older Americans aged >=55 years (n=18,603) from four surveys of dietary intake in 1977-1978, 1989-1991, 1994-1996, and 2005-2010. MEASUREMENTS: Dietary intake was assessed using one 24-hour recall. Multivariable linear regression models were used to determine adjusted per capita mean energy and macronutrient intake for each survey year. Interactions were used to examine differences by race/ethnicity, gender, and generation. The top five food group contributors to total calorie intake were identified for each year. RESULTS: Mean total calorie intake increased significantly among older Americans from 1977 2010. Increases in carbohydrate intake (43% to 49% of total calories) were coupled with decreases in total fat intake (from 40% to 34%) while saturated fat (11%) remained constant. Corresponding shifts in food group intake were observed, as red meat intake greatly declined while bread and grain desserts became dominant calorie sources. Calorie intake was significantly higher for whites compared to blacks from 1994-2010. Cohort analysis indicated a shift from decreasing caloric intake with age to relatively stable calorie intake despite increasing age in more recent cohorts. CONCLUSION: Increases in total calorie intake from 1977-2010, coupled with the finding that more recent generations did not show the expected age-related decrease in caloric consumption, raise concerns about obesity risk among older Americans. Additionally, despite declines across time in total fat intake, saturated fat intake continues to exceed recommendations, and shifts toward increased consumption of grain-based desserts suggest that high discretionary calorie intake by older Americans might make it difficult to meet nutrient requirements while staying within energy needs. PMID- 24626750 TI - Diet quality in elderly Portuguese households. AB - OBJECTIVE: To identify diet quality time trends in Portuguese elderly households and the association of diet quality with sociodemographic characteristics. DESIGN: Set of four cross-sectional studies. SETTING: Portuguese population. SUBJECTS: Nationally representative samples from Household Budget Surveys (1989 1990, 1994-1995, 2000-2001 and 2005-2006 versions). Households with members aged >= 65 years were categorized as solitary elderly female, solitary elderly male, or elderly couple (composed of one elderly female and one elderly male) and compared with adult households with the same composition. METHODS: Diet quality was assessed through a revised version of the Healthy Diet Indicator (HDIr). Univariate and multiple backward linear regression models were used to study the association with sociodemographic characteristics. RESULTS: Mean values of dietary index were low and the proportion of elderly households with low diet quality (HDIr<=4) was high (between 47.4% and 68.4%). However, the frequency of HDIr inadequacy for adult household was even higher (P<0.05). In general, adjusted coefficients for survey year, educational level of the household head, and eating out expenses were inversely associated with HDIr; whilst semi-urban and rural location of the households predicted higher HDIr values. Exceptions were found in elderly male households where the educational level of the household head was positively associated with HDIr values. CONCLUSIONS: Overall, diet quality was low and decreased over time but lonely elderly female and elderly couple households had higher values of HDIr. Adherence to a healthier diet was associated with lower educational level of the household head and location of the household in less urbanized areas. PMID- 24626751 TI - Association between diet quality with concurrent vision and hearing impairment in older adults. AB - OBJECTIVES: Published literature shows that individual nutrients could influence the risk of developing vision and hearing loss. There is, however, a lack of population-based data on the relationship between overall patterns of food intake and the presence of concurrent vision and hearing impairment. We aimed to assess the associations between diet quality with the prevalence and 5-year incidence of dual sensory impairment (DSI). DESIGN: Cross-sectional and 5-year longitudinal analyses. SETTING: Blue Mountains, Sydney, Australia. PARTICIPANTS: 2443 participants aged >=50 from baseline were examined and followed over 5 years. MEASUREMENTS: Dietary data were collected using a semi-quantitative food frequency questionnaire. A modified version of the Healthy Eating Index for Australians was developed to determine total diet score (TDS). Visual impairment was defined as visual acuity less than 20/40 (better eye), and hearing impairment as average pure-tone air conduction threshold greater than 25 dB HL (500-4000 Hz, better ear). RESULTS: After adjusting for age, sex, education, noise exposure, current smoking, and type 2 diabetes, participants in the lowest compared to the highest quintile of TDS had a 2-fold increased likelihood of having prevalent DSI, odds ratio, OR, 2.62 (95% confidence intervals, CI, 1.08-6.36), P trend=0.04. Significant associations were not observed between TDS and the prevalence of having a single sensory impairment (vision or hearing loss). Baseline TDS was not significantly associated with the 5-year incidence of DSI. Adherence to dietary guidelines was associated with a reduced likelihood of having DSI in cross-sectional, but not in longitudinal analyses. CONCLUSIONS: Further studies with adequate power are warranted to assess the prospective relationship between diet quality and DSI. PMID- 24626752 TI - Nutritional status according to Mini Nutritional Assessment is related to functional status in geriatric patients--independent of health status. AB - OBJECTIVES: The aim of this study was to investigate the relationship between nutritional and functional status in acute geriatric patients including mobility and considering health status. DESIGN: Cross-sectional study. SETTING: Hospital. PARTICIPANTS: 205 geriatric patients (median age 82.0 (IQR: 80-86) years, 69.3% women). MEASUREMENTS: Nutritional status was determined by Mini Nutritional Assessment (MNA) and patients were categorized as well-nourished (>= 24 points), at risk of malnutrition (17-23.5 points) or as malnourished (< 17 points). Functional status was determined by Barthel Index (BI) and Timed 'Up and Go' Test (TUG) and related to MNA categories. Using binary multiple logistic regression the impact of nutritional status on functional status was examined, adjusted for health status. RESULTS: 60.3% of the patients were at risk of malnutrition and 29.8% were malnourished. Ability to perform basic activities of daily living (ADL) decreased with declining nutritional status. The proportion of patients unable to perform the TUG increased with worsening of nutritional status (45.0% vs. 50.4% vs. 77.0%, p<0.01). After adjusting for age, gender, number of diagnoses, disease severity and cognitive function, a higher MNA score significantly lowered the risk of being dependent in ADL (OR 0.85, 95 % CI 0.77 0.94) and inability to perform the TUG (OR 0.90, 95 % CI 0.82-0.99). CONCLUSION: Nutritional status according to MNA was related to ADL as well as to mobility in acute geriatric patients. This association remained after adjusting for health status. PMID- 24626753 TI - Association between nutritional status (MNA(r)-SF) and frailty (SHARE-FI) in acute hospitalised elderly patients. AB - OBJECTIVE: This study aimed to explore the association between the impaired nutritional status and frailty in acute hospitalised elderly patients by using two tools, the MNA(r)-SF (Mini Nutritional Assessment(r) short-form) and the SHARE-FI (Frailty Instrument for Primary Care of the Survey of Health, Ageing and Retirement in Europe). DESIGN: Cross-sectional study. SETTING: Acute hospitalised, community-dwelling elderly patients were recruited at internal medicine wards in Vienna, Austria. PARTICIPANTS: 133 men (39%) and women (61%) aged 74 (65-97) years. MEASUREMENTS: MNA(r)-SF was used to investigate malnutrition (<7 points) and patients at risk of malnutrition (8 to 11 points). By using the SHARE-FI, subjects were classified as frail, pre-frail or robust. A factor analysis was applied to identify overlaps between the MNA(r)-SF and SHARE FI items. Internal consistency of different dimensions was assessed by using Cronbach's Alpha. RESULTS: Malnutrition or risk of malnutrition was found in 76.7% of the total sample and in 46.8% of robust, in 69.0% of pre-frail, and in 93.0% of frail participants. Frailty or prefrailty was found in 75.9% of the total sample and in 45.1% of the subjects with no risk of malnutrition, in 80.9% of subjects at risk of malnutrition, and in 94.1% of malnourished patients. The two used tools show overlaps in three dimensions: (1) nutrition problems, (2) mobility problems and (3) anthropometric items with a moderate to strong internal consistency (Cronbach's Alpha of 0.670, 0.834 and 0.946, respectively). 64.7% of the total sample (79.5% of frail and 87.9% of malnourished subjects) would participate in a home-based muscle training and nutritional intervention program. CONCLUSIONS: This study underlines the association and the overlap between frailty and impaired nutritional status. There is a high readiness to participate in a program to tackle the problems associated with malnutrition and frailty, especially in those, who would benefit most from it. PMID- 24626754 TI - Nutritional risk, nutritional status and incident disability in older adults. The FRADEA study. AB - OBJECTIVES: To analyze if body mass index (BMI) and waist circumference (WC) as measures of nutritional status, and the Mini Nutritional Assessment Short Form (MNA-SF) as a nutritional risk measure are associated with increased risk of incident disability in basic activities of daily living (BADL) in a population based cohort of Spanish older adults. DESIGN: Concurrent cohort study. SETTING: Albacete City, Spain. PARTICIPANTS: 678 subjects over age 70 from the FRADEA Study (Frailty and Dependence in Albacete). MEASUREMENTS: BMI, WC and MNA-SF were recorded at the basal visit of the FRADEA Study. Incident disability in BADL was defined as loss of the ability to perform bathing, grooming, dressing, toilet use, or feeding from basal to follow-up visit, using the Barthel index. The association between nutritional status and nutritional risk with incident BADL disability was determined by Kaplan-Meier analysis and logistic regression adjusted for age, sex, basal function, comorbidity, cognitive decline, depression risk and frailty status. RESULTS: Each point less of MNA-SF (OR 1.17, 95%CI 1.04 1.31) and MNA-SF<14 (OR 2.33, 95%CI 1.39-3.89), but not MNA-SF<12 (OR 1.47, 95%CI 0.89-2.42) had a greater adjusted risk of incident disability in BADL. Neither BMI (OR 1.02, 95%CI 0.97-1.06) nor WC (OR 1.01, 95%CI 0.99-1.03) were associated. Weight loss (OR 1.75, 95%CI 1.08-2.83) and mobility impairment (OR 3.35, 95%CI 1.67-6.73) remained as adjusted predictors of incident BADL disability, while anorexia almost reached the significance (OR 1.65, 95%CI 0.94-2.87). CONCLUSION: Nutritional risk measured with the MNA-SF is associated with incident disability in BADL in older adults, while nutritional status measured with BMI or WC is not. PMID- 24626755 TI - A pilot study of the SARC-F scale on screening sarcopenia and physical disability in the Chinese older people. AB - INTRODUCTION: The SARC-F scale is a newly developed tool to diagnose sarcopenia and obviate the need for measurement of muscle mass. SARC-F >= 4 is defined as sarcopenia. The questions of SARC-F cover physical functions targeting sarcopenia or initial presentation for sarcopenia. The aim of the study is to explore the application of SARC-F in the Chinese people. METHODS: Two hundred thirty Chinese people over 65 years old were assessed by the SARC-F scale, PSMS, Lawton IADL and the shortened version of the falls efficacy scale-international(the short FES-I). Hospitalization was investigated. Physical performance and strength were measured. The association of SARC-F with other scales or tests was analyzed. RESULTS: Poor physical performance and grip strength were associated with SARC-F >= 4 independently (P<0.005). The kappa value for agreement of SARC-F >= 4 and cutoff points of tests were 0.391 to 0.635. The short FES-I were correlated to SARC-F scores (Spearman's coefficient 0.692). Poor PSMS and Lawton IADL scores were associated with SARC-F >= 4(P=0.000) and SARC-F >= 4 was associated with hospitalization in the past 2 years (P=0.000). CONCLUSION: The SARC-F scale can identify old Chinese people with impaired physical function who may suffered from sarcopenia. SARC-F judgment reflects fear of falling, indicates the hospitalization events and is associated with ability of daily life. Thus, SARC-F may be a simple and useful tool for screening individuals with impaired physical function. Further studies on SARC-F in Chinese people would be worthy. PMID- 24626756 TI - Prevalence and associated factors of sarcopenia among elderly in Brazil: findings from the SABE study. AB - OBJECTIVES: The aim of the present study was to examine the prevalence and factors associated with sarcopenia in older residents in Sao Paulo, Brazil. DESIGN: Cross-sectional study. SETTING: Sao Paulo, Brazil. PARTICIPANTS: 1,149 older individuals from the second wave of the Saude, Bem-Estar e Envelhecimento (SABE) study from 2006. MEASUREMENTS: The definition of sarcopenia was based on the consensus of the European Working Group on Sarcopenia in Older People (EWGSOP), which include three components: low muscle mass, assessed by a skeletal muscle mass index of <=8.90 kg/m2 for men and <=6.37 kg/m2 for women; low muscle strength, assessed by handgrip strength <30 kg for men and <20 kg for women; and low physical performance, assessed by gait speed <0.8 m/s. Diagnosis of sarcopenia required presence of low muscle mass plus low muscle strength or low physical performance. Socio-demographic and behavioral characteristics, medical conditions and nutritional status were considered as independent variables to determine the associated factors using a logistic regression model. RESULTS: The prevalence of sarcopenia was 16.1% in women and 14.4% in men. Advanced age with a dose response effect, cognitive impairment, lower income, smoking, undernutrition and risk for undernutrition (p<0.05) were factors associated with sarcopenia. CONCLUSIONS: The EWGSOP algorithm is useful to define sarcopenia. The prevalence of sarcopenia in the Brazilian elderly population is high and several associated factors show that this syndrome is affected by multiple domains. No differences were observed by gender in any age groups. PMID- 24626758 TI - Body mass index is related to autonomic nervous system activity as measured by heart rate variability--a replication using short term measurements. AB - OBJECTIVES: The present analysis is a replication of previous findings presenting first evidence of an association between body mass index (BMI) and autonomic nervous system (ANS) activity as measured by heart rate variability (HRV), in healthy non-obese adults. DESIGN: A total of fifty-nine apparently healthy male (M) and female (F) individuals (M/F = 15/44) were included in the trial. HRV data for analysis was derived from 5 minutes of baseline recordings, while the subject was sitting on a comfortable chair. Subjects' body measures (weight and height) were taken and BMI was obtained according to common calculation (kg/m2). RESULTS: BMI was inversely related to pNN50 and RMSSD components of HRV. Statistically significant differences between stratified groups (BMI<20, BMI 20-25, BMI >25) only occurred for analysis of pNN50 components. The pNN50 components and RMSSD are strongly associated with cardiac vagal influence, and thus represents parasympathetic activity. CONCLUSIONS: The present data supports previous findings, that sympatho-vagal balance is related to BMI in non-obese, healthy individuals, providing evidence for a prominent role of the vagus nerve in the modulation of the energy expenditure of the human organism. Furthermore, this relation can be observed in short term recordings of HRV of 5 minutes in length. PMID- 24626757 TI - Souvenaid(r): a new approach to management of early Alzheimer's disease. AB - Synaptic loss correlates closely with cognitive deficits in Alzheimer's disease and represents a new target for intervention. Souvenaid(r) is the first medical nutrition product to be designed to support synapse formation and function in early Alzheimer's disease, and has undergone an extensive, 12-year development programme. The relatively large amount of clinical data available for Souvenaid(r) is unusual for a medical nutrition product. Souvenaid(r) contains omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid), uridine (as uridine monophosphate) and choline which are nutritional precursors required for synaptic membrane phospholipid synthesis, together with phospholipids and other cofactors. Souvenaid(r) has demonstrated cognitive benefits in patients with mild Alzheimer's disease but not in patients with mild to-moderate Alzheimer's disease. Two randomised, double-blind, controlled trials (duration 12 and 24 weeks) in patients with mild Alzheimer's disease untreated with acetylcholinesterase inhibitors and/or memantine have demonstrated that Souvenaid(r) is well tolerated and improves episodic memory performance. The daily intake of Souvenaid(r) has not been associated with any harmful effects or interactions with medications and none are anticipated. The ongoing, 24-month, European Union-funded LipiDiDiet trial in subjects with prodromal Alzheimer's disease is evaluating the potential benefits of Souvenaid(r) on memory and in slowing progression to Alzheimer's dementia. If Souvenaid(r) induces synaptogenesis and improved synaptic function, it may provide benefits in other clinical conditions characterised by neurodegeneration. A number of trials are ongoing and planned to evaluate the potential wider benefits of Souvenaid(r). PMID- 24626759 TI - Anxiety after a fall in elderly subjects and subsequent risk of developing post traumatic stress disorder at two months. A pilot study. AB - BACKGROUND: The psychological burden suffered by elderly subjects after a fall adds to rehabilitation difficulties. We hypothesised that Post Traumatic Stress Disorder (PTSD) may be at the root of these psychological post-fall problems. The immediate psychological state was examined after 2 months post-fall in order to determine the prevalence of anxiety and PTSD and their possible correlates. METHOD: A single centre prospective survey including elderly subjects referred to an emergency department (ED) after a fall with a 2-month follow-up. RESULTS: 30.5% of patients showed a significant level of anxiety after their fall and (26%) showed evidence supporting the presence of PTSD at 2-months. Immediate anxiety, ability to re-establish upright posture and a history of repeated falls were significant predictors of PTSD at 2-months. CONCLUSION: persistent psychological problems post fall may be related to PTSD which is significantly correlated to immediate anxiety. This study can be seen as a first step in patient characterisation, and predicts who may benefit from which of the various approaches of rehabilitation. PMID- 24626760 TI - Spatial variability during gait initiation while dual tasking is increased in individuals with mild cognitive impairment. AB - BACKGROUND: Gait initiation (GI) is a complex transition phase of gait that can induce postural instability. Gait impairment has been well documented in people with Alzheimer's disease, but it is still inconclusive in individuals with Mild Cognitive Impairment (MCI). Previous studies have usually investigated gait performance of cognitive impaired persons under steady state walking. OBJECTIVE: This study aimed to examine spatiotemporal variability during GI under single- and dual-task conditions in people with and without MCI. METHODS: Spatiotemporal stepping characteristics and variability under single- and dual-task conditions (counting backwards by 3s) were assessed in 30 older adults with MCI and 30 cognitively intact controls. Mean and coefficients of variation (COV) of swing time, step time, step length and step width were compared between the two groups. RESULTS: Mixed-model repeated measures ANOVA revealed a significant Group x Walking condition interaction for COV of step length and step width (P<0.05). Post-hoc analysis revealed that variability for these measures were significantly larger in the MCI group compared with the control group under the dual-task condition (P<0.05). CONCLUSIONS: Step length and step width variability is increased in people with MCI during GI, particularly in a condition involving a secondary cognitive task. These findings suggest that individuals with MCI have reduced balance control when undertaking a challenging walking task such as gait initiation, and this is exacerbated with an added cognitive task. Future studies should prospectively investigate the relationship between GI variability and fall risk in this population. PMID- 24626761 TI - Lifestyle habits and mortality from all and specific causes of death: 40-year follow-up in the Italian Rural Areas of the Seven Countries Study. AB - OBJECTIVES: Three lifestyle factors were investigated in a population study to explore their relationships with a long-term mortality. MATERIAL AND METHODS: In a cohort of 1564 men aged 45-64 and examined in 1965 within the Italian Rural Areas of the Seven Countries Study, smoking habits, physical activity at work and eating habits (as derived from factor analysis) were determined. During the follow-up 693 men died in 20 years and 1441 in 40 years. RESULTS: In Cox proportional hazards models men smoking cigarettes (versus never smokers), those having a sedentary activity (versus the very active) and those following the Diet Score 1, indexing an unhealthy Diet (versus men with a Diet close to the healthy Mediterranean style) had highly significant hazards ratios (HR) in relations with 20- and 40-year mortality from all causes, coronary heart disease (CHD), cardiovascular disease (CVD) and cancer. HR for all causes in 40 years were 1.44 (95% confidence intervals, CI, 1.27 and 1.64) for smokers, 1.43 (CI 1.23 and 1.67) for sedentary people, and 1.31 (CI 1.15 and 1.50) for men with unhealthy diet. Larger HR were found for CHD, CVD and cancers deaths. Combination of 3 unhealthy risk factors versus their absence was associated with 4.8-year life loss in the 20-year follow-up and 10.7-year in the 40-year follow-up. CONCLUSIONS: Lifestyle behavior linked to physical activity and smoking and eating habits is strongly associated with mortality and survival in middle aged men during long-term follow-up. PMID- 24626762 TI - Association of calcium concentration with pulse pressure in older women: data from a large population-based multicentric study. AB - OBJECTIVE: High arterial pulse pressure is a predictor of cardiovascular morbimortality. Mineral metabolism has been associated with blood pressure regulation. Our objective was to determine which variable among serum calcium, parathyroid hormone and 25-hydroxyvitamin D concentrations, was associated with pulse pressure among older adults. DESIGN: Cross-sectional study corresponding to the baseline assessment of the EPIDOS study. SETTING: Five French cities including Amiens, Lyon, Montpellier, Paris and Toulouse. PARTICIPANTS: Randomized sample of 610 community-dwelling older women (mean age 80.2+/-3.5years) using no antihypertensive drugs. MEASUREMENTS: Serum calcium, parathyroid hormone and 25 hydroxyvitamin D concentrations; supine pulse pressure after 15 minutes of rest (hypertension defined as pulse pressure >50mmHg). Age, body mass index, the number of morbidities and of drugs daily taken, diabetes mellitus, dysthyroidy, the use of estrogenic drugs, smoking, alcohol consumption, practice of a regular physical activity, creatinine clearance, and the effects of season and study centers were used as potential confounders. RESULTS: Hypertensive participants (n=539) had higher calcium concentrations than normotensive ones (94.33+/ 4.12mg/L versus 93.28+/-3.36mg/L respectively, P=0.040). There were no between group differences for serum parathyroid hormone and 25-hydroxyvitamin D concentrations. The multiple logistic regressions examining the serum calcium, parathyroid hormone and 25-hydroxyvitamin D concentrations as predictors of hypertension found an association only with calcium (adjusted odds ratio=1.19, P=0.015), but not with parathyroid hormone (adjusted OR=1.01, P=0.349) or 25 hydroxyvitamin D concentration (adjusted OR=0.99, P=0.971). CONCLUSION: Increased serum calcium concentration was independently and positively associated with high pulse pressure in our study, possibly due to increased arterial stiffness. Interventions aimed at normalizing calcaemia may be attractive to prevent hypertension and cardiovascular risk in older adults. PMID- 24626763 TI - Do not resuscitate orders and aging: impact of multimorbidity on the decision making process. AB - BACKGROUND: The "Do Not Resuscitate" orders (DNR) are defined as advance medical directives to withhold cardiopulmonary resuscitation during cardiac arrest. Age related multimorbidity may influence the DNR decision-making process. Our objective was to perform a systematic review and meta-analysis of published data examining the relationship between DNR orders and multimorbidity in older patients. METHODS: A systematic Medline and Cochrane literature search limited to human studies published in English and French was conducted on August 2012, with no date limits, using the following Medical Subject Heading terms: "resuscitation orders" OR "do-not-resuscitate" combined with "aged, 80 and over" combined with "comorbidities" OR "chronic diseases". RESULTS: Of the 65 selected studies, 22 met the selection criteria for inclusion in the qualitative analysis. DNR orders were positively associated with multimorbidity in 21 studies (95%). The meta analysis included 7 studies with a total of 27,707 participants and 5065 DNR orders. It confirmed that multimorbidity were associated with DNR orders (summary OR = 1.25 [95% CI: 1.19-1.33]). The relationship between DNR orders and multimorbidity differed according to the nature of morbidities; the summary OR for DNR orders was 1.15 (95% CI: 1.07-1.23) for cognitive impairment, OR=2.58 (95% CI: 2.08-3.20) for cancer, OR=1.07 (95% CI: 0.92-1.24) for heart diseases (i.e., coronary heart disease or congestive heart failure), and OR=1.97 (95% CI: 1.61-2.40) for stroke. CONCLUSIONS: This systematic review and meta-analysis showed that DNR orders are positively associated with multimorbidity, and especially with three morbidities, which are cognitive impairment, cancer and stroke. PMID- 24626764 TI - The association of hemoglobin concentration with disability and decreased mobility among older Brazilians. AB - OBJECTIVE: To examine the association between hemoglobin concentration and disability and mobility difficulty among older adults living in Sao Paulo, Brazil. DESIGN: Cross-sectional study. SETTING: Population-based study conducted in Sao Paulo, Brazil. PARTICIPANTS: Adults age 60 and over (n=1,256) from the third data collection wave of the SABE Study (Health, Well-being, and Aging) conducted in 2010. MEASUREMENTS: Two outcome measures were included in the analyses: 1) a difficulty to perform at least one of the instrumental activities of daily living (IADL) and 2) mobility difficulty, which was assessed using the Short Physical Performance Battery (SPPB). Logistic regression models assessed the association between hemoglobin and each of the outcome measures. All analyses were adjusted for sociodemographic and health characteristics. RESULTS: The prevalence of IADL disability was 26.8% and 10.7% of participants had mobility difficulty. The mean hemoglobin concentration was significantly lower in older adults who already presented disability (13.7g/dL versus 14.4g/dL among independent elderly) or decreased mobility (13.4g/dL versus 14.3g/dL among elderly with preserved mobility). Higher values of hemoglobin concentration were associated with lower the risk of IADL disability (OR=0.88; p=0.04) and mobility difficulty (OR=0.81; p=0.02). Hemoglobin concentrations showed a dose-response effect in the probability of each outcome. CONCLUSIONS: Lower hemoglobin concentration was associated with a higher probability of IADL disability and mobility difficulty, showing a clear dose-response effect. PMID- 24626766 TI - Does self-defense training prevent sexual violence against women? AB - Self-defense classes are offered across the nation as a strategy for reducing women's vulnerability to sexual assault. Yet there has been little systematic research assessing the effectiveness of these classes. In this article, I use data from a mixed methods study of a 10-week, university-based, feminist self defense class to examine the effectiveness of self-defense training over a 1-year follow-up period. My analyses indicate that women who participate in self-defense training are less likely to experience sexual assault and are more confident in their ability to effectively resist assault than similar women who have not taken such a class. PMID- 24626767 TI - The group dynamics of women's self-defense training. AB - The current study examines the role of group interaction in a women's self defense class. Study methods included individual interviews with women who had completed a college-based women-only self-defense course as well as supplemental observation of group behavior during a mock "attack" simulation class. The unique relationship that develops among women's self-defense classmates seems to improve overall learning and performance due to the group collaboration and vicarious experiences. Results demonstrated that women's self-defense courses offer participants a beneficial and supportive group atmosphere. PMID- 24626768 TI - Reflections on researching rape resistance. AB - This article provides a retrospective account of my experience embarking on research about women's resistance to rape, including reflections on personal and professional experiences related to studying this topic. I discuss factors inspiring my interest, including pioneering feminist rape researchers, my experience as a woman living with the reality and fear of rape, and influential mentors who facilitated my career development as a scholar in graduate school and beyond. I weave this narrative together with my thoughts about how the study of resistance relates to other important issues in the field of sexual assault including alcohol, recovery, and prevention. PMID- 24626769 TI - Image-based mechanical analysis of stent deformation: concept and exemplary implementation for aortic valve stents. AB - An approach for extracting the radial force load on an implanted stent from medical images is proposed. To exemplify the approach, a system is presented which computes a radial force estimation from computer tomography images acquired from patients who underwent transcatheter aortic valve implantation (TAVI). The deformed shape of the implanted valve prosthesis' Nitinol frame is extracted from the images. A set of displacement vectors is computed that parameterizes the observed deformation. An iterative relaxation algorithm is employed to adapt the information extracted from the images to a finite-element model of the stent, and the radial components of the interaction forces between the stent and the tissue are extracted. For the evaluation of the method, tests were run using the clinical data from 21 patients. Stent modeling and extraction of the radial forces were successful in 18 cases. Synthetic test cases were generated, in addition, for assessing the sensitivity to the measurement errors. In a sensitivity analysis, the geometric error of the stent reconstruction was below 0.3 mm, which is below the image resolution. The distribution of the radial forces was qualitatively and quantitatively reasonable. An uncertainty remains in the quantitative evaluation of the radial forces due to the uncertainty in defining a radial direction on the deformed stent. With our approach, the mechanical situation of TAVI stents after the implantation can be studied in vivo, which may help to understand the mechanisms that lead to the complications and improve stent design. PMID- 24626770 TI - Application of molecular docking and ONIOM methods for the description of interactions between anti-quorum sensing active (AHL) analogues and the Pseudomonas aeruginosa LasR binding site. AB - Molecular docking methods were applied to simulate the coupling of a set of nineteen acyl homoserine lactone analogs into the binding site of the transcriptional receptor LasR. The best pose of each ligand was explored and a qualitative analysis of the possible interactions present in the complex was performed. From the results of the protein-ligand complex analysis, it was found that residues Tyr-64 and Tyr-47 are involved in important interactions, which mainly determine the antagonistic activity of the AHL analogues considered for this study. The effect of different substituents on the aromatic ring, the common structure to all ligands, was also evaluated focusing on how the interaction with the two previously mentioned tyrosine residues was affected. Electrostatic potential map calculations based on the electron density and the van der Waals radii were performed on all ligands to graphically aid in the explanation of the variation of charge density on their structures when the substituent on the aromatic ring is changed through the elements of the halogen group series. A quantitative approach was also considered and for that purpose the ONIOM method was performed to estimate the energy change in the different ligand-receptor complex regions. Those energy values were tested for their relationship with the corresponding IC50 in order to establish if there is any correlation between energy changes in the selected regions and the biological activity. The results obtained using the two approaches may contribute to the field of quorum sensing active molecules; the docking analysis revealed the role of some binding site residues involved in the formation of a halogen bridge with ligands. These interactions have been demonstrated to be responsible for the interruption of the signal propagation needed for the quorum sensing circuit. Using the other approach, the structure-activity relationship (SAR) analysis, it was possible to establish which structural characteristics and chemical requirements are necessary to classify a compound as a possible agonist or antagonist against the LasR binding site. PMID- 24626771 TI - N-myc downstream regulated gene 1 acts as a tumor suppressor in ovarian cancer. AB - Although implicated in a number of tumor types, the role of N-myc downstream regulated gene 1 (NDRG1) in ovarian cancer (OC) is unclear. In the present study, we used short hairpin RNA (shRNA) to silence NDRG1 in the OC cell line OVCAR3 and assessed the effect of its knockdown on cell morphology, proliferation, colony formation, migration and invasion. To complement these knockdown studies, we overexpressed NDRG1 in the same cell line. We found that NDRG1 knockdown significantly enhanced OVCAR3 proliferation, migration and invasion; however, there were no apparent changes in cell morphology. We also examined the effect in vivo and found that NDRG1 depletion promoted OVCAR3 xenograft growth in nude mice. In accordance with these data, we found that NDRG1 overexpression decreased proliferation, adhesion and apoptosis, and induced G0/G1 cell cycle arrest in OVCAR3 cells; expression of p21 and p53 was also increased. In conclusion, we demonstrated that NDRG1 acts as a tumor suppressor in ovarian carcinogenesis and may be a potential therapeutic target in this disease. PMID- 24626772 TI - Effects of canine myoblasts expressing human cartilage-derived morphogenetic protein-2 on the repair of meniscal fibrocartilage injury. AB - The aim of the present study was to explore the effects of human cartilage derived morphogenetic protein-2 (hCDMP-2)-expressing canine myoblasts on the repair of meniscal fibrocartilage injury. Purified canine myoblasts were infected with lentiviruses carrying an empty vector or the hCDMP-2 gene. The following four experimental groups were established to study the in vivo meniscal repair in a canine model of meniscal injury: Group A, suture only; group B, suture with the addition of the recombinant hCDMP-2 on a polylactic acid/polyglycolic acid (PLA/PGA) scaffold; group C, a PLA/PGA scaffold with canine myoblasts carrying the empty vector; and group D, a PLA/PGA scaffold with canine myoblasts expressing hCDMP-2. Samples of the regenerated tissue were extracted at weeks 3, 8 and 12 post-repair and analyzed by morphological observation, immunohistochemistry (IHC) and quantitative analysis. At week 12 post-repair, the scaffold material had completely dissolved in the control groups and no changes were observed at the injured area, while regenerated tissue was observed in group D only. Hematoxylin and eosin and Safranin-O staining techniques further revealed cartilage lacunae and fibers present at the red-red zone of the repaired tissue, while cartilage lacunae without fibers were observed at the white-white zone in group D. In addition, IHC studies demonstrated that collagen I and II, and the S 100 protein were expressed at the red-red and the white-white zones of the repaired tissue in group D. It was concluded that purified canine myoblasts expressing the hCDMP-2 gene were able to promote meniscal fibrocartilage healing by regenerating fibrocartilage-like tissue. The tissue in the red-red zone was regenerated more rapidly than that in the white-white zone. Further studies are required to identify the best way to combine hCDMP-2 growth factor with myoblasts for use in the clinic due to the limitations regarding the clinical use of lentiviral infections. PMID- 24626774 TI - Development of loop-mediated isothermal amplification method for detection of Kudoa septempunctata (Myxozoa: Multivalvulida) in olive flounder (Paralichthys olivaceus). AB - A loop-mediated isothermal amplification (LAMP) assay was developed and validated for early, rapid, and sensitive detection of Kudoa septempunctata, a myxosporean parasite found in olive flounder (Paralichthys olivaceus). Recently, several outbreaks associated with ingestion of raw olive flounder muscles harboring mature K. septempunctata spores have been reported, and it is becoming obvious that fresh K. septempunctata spores can cause problems in humans when ingested. Thus, it is necessary to develop reliable detection method of K. septempunctata, to prevent outbreaks and ensure food safety. The LAMP assay has advantages over other molecular detection methods for detecting K. septempunctata in olive flounder muscle, in terms of simplicity, rapidity, and sensitivity. The reaction condition was optimized as 63 degrees C, 45 min, with three sets of specific primers. The results can be simply confirmed with the naked eye after adding SYBR Green I or by conventional electrophoresis followed by ethidium bromide staining. This LAMP assay did not show any cross-reaction with other kudoid myxosporeans (Kudoa lateolabracis, Kudoa thyrsites) can be found in olive flounder muscles and was validated by testing Kudoa septempunctata spore-spiked samples and field samples. The results showed that the LAMP assay is ten times more sensitive than the conventional polymerase chain reaction in this study and can be applied for early detection for monitoring and epidemiological studies of K. septempunctata in olive flounder aquaculture farms. PMID- 24626776 TI - Valuing telecare using willingness to pay from the perspective of carers for people with dementia: a pilot study from the West Midlands. AB - We carried out a cost-benefit analysis of the STAY telecare service (Sandwell Telecare Assisting You) for unpaid carers of people with dementia in the West Midlands. This was done from the perspective of the carers. We employed the willingness to pay (WTP) approach, an established economic method to quantify the benefits of healthcare. A questionnaire was given to 87 unpaid carers of people with dementia, and 34 completed questionnaires were returned (39%). Two WTP question designs were used (open-ended and bounded style). The annual mean WTP for telecare was L242-310 per person. Carers offered higher values if the cared for person was suffering from moderate dementia. Carers offered WTP values that were similar to the resource costs of providing telecare services. The pilot study suggests that the provision of telecare for unpaid carers of people with dementia is beneficial to society. PMID- 24626773 TI - A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research. AB - OBJECTIVE: In this critical review, the authors appraise neuroimaging findings in bipolar disorder in emotion-processing, emotion-regulation, and reward-processing neural circuitry in order to synthesize the current knowledge of the neural underpinnings of bipolar disorder and provide a neuroimaging research road map for future studies. METHOD: The authors examined findings from all major studies in bipolar disorder that used functional MRI, volumetric analysis, diffusion imaging, and resting-state techniques, integrating findings to provide a better understanding of larger-scale neural circuitry abnormalities in bipolar disorder. RESULTS: Bipolar disorder can be conceptualized, in neural circuitry terms, as parallel dysfunction in prefrontal cortical (especially ventrolateral prefrontal cortical)-hippocampal-amygdala emotion-processing and emotion-regulation circuits bilaterally, together with an "overactive" left-sided ventral striatal ventrolateral and orbitofrontal cortical reward-processing circuitry, resulting in characteristic behavioral abnormalities associated with bipolar disorder: emotional lability, emotional dysregulation, and heightened reward sensitivity. A potential structural basis for these functional abnormalities is gray matter volume decreases in the prefrontal and temporal cortices, the amygdala, and the hippocampus and fractional anisotropy decreases in white matter tracts connecting prefrontal and subcortical regions. CONCLUSIONS: Neuroimaging studies of bipolar disorder clearly demonstrate abnormalities in neural circuits supporting emotion processing, emotion regulation, and reward processing, although there are several limitations to these studies. Future neuroimaging research in bipolar disorder should include studies adopting dimensional approaches; larger studies examining neurodevelopmental trajectories in youths with bipolar disorder or at risk for bipolar disorder; multimodal neuroimaging studies using integrated systems approaches; and studies using pattern recognition approaches to provide clinically useful individual-level data. Such studies will help identify clinically relevant biomarkers to guide diagnosis and treatment decision making for individuals with bipolar disorder. PMID- 24626777 TI - Prostate cancer: prognostic significance of the association of heterogeneous nuclear ribonucleoprotein K and androgen receptor expression. AB - The management of prostate cancer (PCa) remains challenging because to date, there has been no way to distinguish between indolent and aggressive tumors. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is implicated in the network of mechanisms that control androgen receptor (AR) expression. We studied the expression of the two proteins in PCa to evaluate their prognostic potential and elucidate the hnRNP K function in PCa progression. HnRNP K and AR expression were analyzed immunohistochemically in 105 patients who had undergone radical prostatectomy. The association between the expression of hnRNP K and/or AR and PSA progression or death was evaluated by univariate and multivariate analyses. The expression of hnRNP K was also investigated in vitro using the BPH-1 cell line and two different LNCaP populations that recapitulate the progression of PCa towards a more aggressive disease. AR and hnRNP K were differentially expressed between cancer and normal prostate tissues. A strong association with a good prognosis was evident in PCa exhibiting high percentage of AR-positive cells (>75%) (p<=0.005) and more interestingly, the combination of high AR and low cytoplasmic hnRNP K expression emerged as the most significant independent prognostic marker for PSA failure-free survival, in a multivariate analysis (p<=0.001). In vitro, a higher expression of hnRNP K and pERK was associated with higher PSA levels, suggesting a relationship between hnRNP K phosphorylation and AR-regulated genes. These results indicate that the interaction between the AR and hnRNP K has an important role in the progression of PCa. Changes of the expression of the two proteins are strongly associated with the clinical outcome and may be a potential prognostic marker. PMID- 24626778 TI - Outcome prediction in patients after cardiac arrest: a simplified method for determination of gray-white matter ratio in cranial computed tomography. AB - PURPOSE: Out-of-hospital cardiac arrest is a frequent cause of death in Europe. Hypoxic ischemic encephalopathy (HIE) often develops in initial survivors, and the question of treatment limitation arises in severely affected patients. To establish a poor prognosis with a high level of certainty, the use of a combination of prognostic parameters such as neurological examination, somatosensory evoked potentials, and neuron-specific enolase is common practice. A few recent studies suggest that gray-white matter ratio (GWR) determined from cranial computed tomography (CT) scans is an additional reliable predictor of poor prognosis. The standard GWR determination method involves measurements of 16 different regions of interest (ROIs). We tested whether a simplified method to obtain GWR has equivalent reliability for poor outcome prediction. MATERIALS AND METHODS: We retrospectively analyzed 98 patients after cardiac arrest who had been treated with hypothermia. CT scans were obtained within the first 7 days after cardiac arrest. Neurological outcome was determined at intensive care unit discharge. Four different methods to obtain GWR were compared in a receiver operating characteristic curve analysis with respect to their prognostic value for poor outcome prediction. RESULTS: The simplest method using only four ROIs (putamen and internal capsule bilaterally) had the same prognostic value compared with the standard method using 16 ROIs. The simplified GWR predicted poor outcome with a sensitivity of 44 % at 100 % specificity. CONCLUSION: Our results indicate that for poor outcome prediction in survivors of cardiac arrest, a simplified GWR determination is feasible and has the same reliability as the complex standard procedure. PMID- 24626779 TI - Cu2-xSe@mSiO2-PEG core-shell nanoparticles: a low-toxic and efficient difunctional nanoplatform for chemo-photothermal therapy under near infrared light radiation with a safe power density. AB - A low-toxic difunctional nanoplatform integrating both photothermal therapy and chemotherapy for killing cancer cells using Cu2-xSe@mSiO2-PEG core-shell nanoparticles is reported. Silica coating and further PEG modification improve the hydrophilicity and biocompatibility of copper selenide nanoparticles. As prepared Cu2-xSe@mSiO2-PEG nanoparticles not only display strong near infrared (NIR) region absorption and good photothermal effect, but also exhibit excellent biocompatibility. The mesoporous silica shell is provided as the carrier for loading the anticancer drug, doxorubicin (DOX). Moreover, the release of DOX from Cu2-xSe@mSiO2-PEG core-shell nanoparticles can be triggered by pH and NIR light, resulting in a synergistic effect for killing cancer cells. Importantly, the combination of photothermal therapy and chemotherapy driven by NIR radiation with safe power density significantly improves the therapeutic efficacy, and demonstrates better therapeutic effects for cancer treatment than individual therapy. PMID- 24626780 TI - Direct observation of the dual-switching behaviors corresponding to the state transition in a DNA nanoframe. AB - To create a nanoscale dual switch, two responsive DNA motifs, azobenzene-modified DNAs and G-telomeric repeat sequences, were introduced together into the nanoframe system. The dual-switching behaviors controlled by photoirradiation and K(+) were successfully visualized in real time by high-speed atomic force microscopy. PMID- 24626781 TI - A highly efficient fullerene acceptor for polymer solar cells. AB - C70-based acceptors show great potential in polymer solar cells (PSCs). Two high LUMO C70 acceptors, the 66pi OQMF70 and the 64pi bis-OQMF70, based on methano[70]fullerene (C70CH2) were developed. An outstanding power conversion efficiency (PCE) of 6.88% was obtained from OQMF70:P3HT solar cells. PMID- 24626782 TI - Vitamin B6 activates p53 and elevates p21 gene expression in cancer cells and the mouse colon. AB - Increasing evidence indicates vitamin B6 acts as a protective factor against colon cancer. However, the mechanisms of the effect of vitamin B6 are poorly understood. The present preliminary study using DNA microarray and real-time PCR indicates p21 mRNA is upregulated in human colon carcinoma (HT29) cells exposed to pyridoxal (PL, 500 uM). A similar effect was observed in human epithelial colorectal adenocarcinoma (Caco2) cells, human colon adenocarcinoma (LoVo) cells, human embryonic kidney (HEK293T) cells, and human hepatoma (HepG2) cells. Adding other B6-vitamers such as pyridoxal 5'-phosphate (PLP), pyridoxine (PN), and pyridoxamine (PM) caused no such effect. In order to understand the mechanism of higher mRNA expression of p21 by PL, effect of PL on the p53 activation was examined (the upstream factor for p21 mRNA transcription) in HT29 cells, LoVo cells, and HepG2 cells. PL increased the phosphorylated p53 protein levels (active form) in whole-cell lysates and the nuclei of the cells. Noteworthy, the consumption of a vitamin B6-deficient diet for 5 weeks significantly reduced p21 mRNA levels and tended to reduce phosphorylated p53 protein levels (P=0.053) in the colons of mice compared to a diet with adequate vitamin B6. Thus, these results suggest vitamin B6 plays a role in increasing p21 gene expression via p53 activation in several cancer cells and the mouse colon. PMID- 24626783 TI - Prediction of outer membrane proteins by combining the position- and composition based features of sequence profiles. AB - Locating the transmembrane regions of outer membrane proteins (OMPs) is highly important for deciphering their biological functions at both molecular and cellular levels. Here, we propose a novel method to predict the transmembrane regions of OMPs by employing the position- and composition-based features of sequence profiles. Furthermore, a simple probability-based prediction model, which is estimated by the secondary structures of structurally known OMPs, is also developed. Considering that these two methods are both effective and well complementary, we integrate them into a method called TransOMP, which is also capable of identifying OMPs. Furthermore, we develop an OMP identification measure I_CScore by considering transmembrane regions by TransOMP and secondary structural topology by SSEA-OMP. Our methods were benchmarked against state-of the-art methods and assessed in the genome of Escherichia coli. Benchmark results confirmed that our methods were reliable and useful. Meanwhile, we constructed an OMP prediction web server, which can be used for OMP identification, transmembrane region location, and 3D model building. PMID- 24626784 TI - Identification of suitable reference genes for quantitative RT-PCR during 3T3-L1 adipocyte differentiation. AB - Quantitative reverse transcription PCR (qRT-PCR) is becoming increasingly important in the effort to gain insight into the molecular mechanisms underlying adipogenesis. However, the expression profile of a target gene may be misinterpreted due to the unstable expression of the reference genes under different experimental conditions. Therefore, in this study, we investigated the expression stability of 10 commonly used reference genes during 3T3-L1 adipocyte differentiation. The mRNA expression levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and transferrin receptor (TFRC) significantly increased during the course of 3T3-L1 adipocyte differentiation, which was decreased by berberine, an inhibitor of adipogenesis. Three popular algorithms, GeNorm, NormFinder and BestKeeper, identified 18 ribosomal RNA and hydroxymethylbilane synthase (HMBS) as the most stable reference genes, while GAPDH and TFRC were the least stable ones. Peptidylprolyl isomerase A [PIPA (cyclophilin A)], ribosomal protein, large, P0 (36-B4), beta-2-microglobulin (B2M), alpha1-tubulin, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta-actin showed relatively stable expression levels. The choice of reference genes with various expression stabilities exerted a profound influence on the expression profiles of 2 target genes, peroxisome proliferator-activated receptor (PPAR)gamma2 and C/EBPalpha. In addition, western blot analysis revealed that the increased protein expression of GAPDH was markedly inhibited by berberine during adipocyte differentiation. This study highlights the importance of selecting suitable reference genes for qRT-PCR studies of gene expression during the process of adipogenesis. PMID- 24626785 TI - Selenoprotein P is the essential selenium transporter for bones. AB - Selenium (Se) plays an important role in bone physiology as best reflected by Kashin-Beck disease, an endemic Se-dependent osteoarthritis. Bone development is delayed in children with mutations in SECIS binding protein 2 (SBP2), a central factor for selenoprotein biosynthesis. Circulating selenoprotein P (SePP) is positively associated with bone turnover in humans, yet its function for bone homeostasis is not known. We have analysed murine models of altered Se metabolism. Most of the known selenoprotein genes and factors needed for selenoprotein biosynthesis are expressed in bones. Bone Se is not associated with the mineral but exclusively with the organic matrix. Genetic ablation of Sepp expression causes a drastic decline in serum (25-fold) but only a mild reduction in bone (2.5-fold) Se concentrations. Cell-specific expression of a SePP transgene in hepatocytes efficiently restores bone Se levels in Sepp-knockout mice. Of the two known SePP receptors, Lrp8 was detected in bones while Lrp2 was absent. Interestingly, Lrp8 mRNA concentrations were strongly increased in bones of Sepp-knockout mice likely in order to counteract the developing Se deficiency. Our data highlight SePP as the essential Se transporter to bones, and suggest a novel feedback mechanism for preferential uptake of Se in Se-deprived bones, thereby contributing to our understanding of hepatic osteodystrophy and the consistent bone phenotype observed in subjects with inherited selenoprotein biosynthesis mutations. PMID- 24626786 TI - Ion-dependent gate dielectric characteristics of ion-conducting SiO(2) solid electrolytes in oxide field-effect transistors. AB - The effect of ions on the gate dielectric behavior of oxide field-effect transistors (FETs) was studied using lithium ion-incorporated porous SiO2. The frequency dependence of the impedance was observed to vary with the ion concentrations in the ion-conducting SiO2 solid-electrolyte. The microstructure of the porous SiO2 was tailored by changing the depositions and porous SiO2 with an ordered columnar microstructure was realized, which provides an unobstructed pathway for the transportation of electrolyte ions. An enhanced electric-double layer (EDL) capacitance of 11.9 MUF cm(-2) and an improved EDL formation upper limit-frequency of ~10(5) Hz were obtained. Due to the enhanced EDL capacitance, oxide FETs gated by these solid-electrolytes showed a very low operating voltage of 0.6 V. A current on/off ratio of ~10(6), a subthreshold swing of ~82 mV per decade, a near-zero threshold voltage of ~-0.01 V, and an electron field-effect mobility of ~27.1 cm(2) V(-1) s(-1) were obtained. These ultra low-voltage FETs have potential applications in portable devices and biochemical sensors. PMID- 24626788 TI - ADAM17 silencing suppresses the migration and invasion of non-small cell lung cancer. AB - A disintegrin and metalloprotease (ADAM) 17 has been implicated in the tumor progression of various types of solid tumor; however, little is known about its role in non-small cell lung carcinoma (NSCLC). The present study evaluated whether the downregulation of ADAM17 affects cell proliferation, the cell cycle, cell migration and cell invasion in NSCLC. A recombinant lentiviral small hairpin RNA (shRNA) expression vector carrying ADAM17 was constructed and then infected into A549 cells, a human NSCLC cell line. Cell proliferation, cell cycle progression, cell migration and cell invasion were determined following the downregulation of ADAM17 by siRNA. It was revealed that downregulation of ADAM17 expression using an RNA silencing approach in A549 tumor cells significantly suppressed cell proliferation and invasion in vitro, and tumor growth in vivo. These data suggested that ADAM17 is an important regulator of the tumorigenic properties of human NSCLC and may be used as a potential anticancer therapeutic target in NSCLC. PMID- 24626787 TI - Limb-girdle muscular dystrophies: where next after six decades from the first proposal (Review). AB - Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders, which has led to certain investigators disputing its rationality. The mutual feature of LGMD is limb-girdle affection. Magnetic resonance imaging (MRI), perioral skin biopsies, blood-based assays, reverse-protein arrays, proteomic analyses, gene chips and next generation sequencing are the leading diagnostic techniques for LGMD and gene, cell and pharmaceutical treatments are the mainstay therapies for these genetic disorders. Recently, more highlights have been shed on disease biomarkers to follow up disease progression and to monitor therapeutic responsiveness in future trials. In this study, we review LGMD from a variety of aspects, paying specific attention to newly evolving research, with the purpose of bringing this information into the clinical setting to aid the development of novel therapeutic strategies for this hereditary disease. In conclusion, substantial progress in our ability to diagnose and treat LGMD has been made in recent decades, however enhancing our understanding of the detailed pathophysiology of LGMD may enhance our ability to improve disease outcome in subsequent years. PMID- 24626791 TI - Effect of pulmonary arterial hypertension-specific therapies on health-related quality of life: a systematic review. AB - BACKGROUND: Health-related quality of life (HRQoL) is severely impaired in pulmonary arterial hypertension (PAH). We aimed to assess the effect of PAH specific therapies on HRQoL. METHODS: A literature search was performed in MEDLINE and Embase databases (January 1990 to September 2013) to retrieve prospective placebo-controlled randomized trials of at least 6 weeks duration reporting the effect of PAH-specific therapies on HRQoL in adult patients with PAH. The articles were independently reviewed, and the validity of the trials was assessed using the Cochrane's Risk of Bias Tool. RESULTS: The literature search identified 1,172 titles. Seventeen articles reporting on 14 trials were retrieved, all of which were associated with a low risk of bias. The median study duration of the different trials was 12 weeks. Most patients had idiopathic PAH or PAH associated with connective tissue disease. A variety of HRQoL questionnaires were used in these trials, and most were generic. HRQoL results were most commonly minimally detailed, and some pivotal trials did not even assess HRQoL. Nevertheless, these trials consistently demonstrated statistically significant improvements in HRQoL with PAH-specific therapies, especially for the physical domains. In most cases, however, these improvements were smaller than the minimal important difference in HRQoL previously reported in PAH. CONCLUSION: This review shows that PAH-specific therapies improve HRQoL in PAH. However, it remains difficult to draw any firm conclusion about the clinical significance of these improvements. Further work is mandatory to validate PAH-specific questionnaires that are responsive to clinical changes as well as to establish their interpretability. PMID- 24626789 TI - Pharmacotherapy and family-focused treatment for adolescents with bipolar I and II disorders: a 2-year randomized trial. AB - OBJECTIVE: Previous studies have found that family-focused treatment is an effective adjunct to pharmacotherapy in stabilizing symptoms in adult bipolar disorder. The authors examined whether pharmacotherapy and family-focused treatment for adolescents with bipolar disorder was more effective than pharmacotherapy and brief psychoeducation (enhanced care) in decreasing time to recovery from a mood episode, increasing time to recurrence, and reducing symptom severity over 2 years. METHOD: A total of 145 adolescents (mean age, 15.6 years) with bipolar I or II disorder and a DSM-IV-TR manic, hypomanic, depressive, or mixed episode in the previous 3 months were randomly assigned, with family members, either to pharmacotherapy and family-focused treatment, consisting of psychoeducation (i.e., recognition and early intervention with prodromal symptoms), communication enhancement training, and problem-solving skills training, delivered in 21 sessions over 9 months; or to pharmacotherapy and three weekly sessions of enhanced care (family psychoeducation). Independent evaluators assessed participants at baseline, every 3 months during year 1, and every 6 months during year 2, using weekly ratings of mood. RESULTS: Twenty-two participants (15.2%) withdrew shortly after randomization. Time to recovery or recurrence and proportion of weeks ill did not differ between the two treatment groups. Secondary analyses revealed that participants in family-focused treatment had less severe manic symptoms during year 2 than did those in enhanced care. CONCLUSIONS: After an illness episode, intensive psychotherapy combined with best practice pharmacotherapy does not appear to confer advantages over brief psychotherapy and pharmacotherapy in hastening recovery or delaying recurrence among adolescents with bipolar disorder. PMID- 24626792 TI - Surface water characterization of three rivers in the lead/zinc mining region of northeastern Macedonia. AB - Mine waste is recognized as being one of the most serious threats for freshwater ecosystems, and it still represents one of the greatest environmental concerns in Macedonia. The aim of our investigation was to obtain an in-depth understanding of mining influence on freshwater systems from water contamination to effects on aquatic organisms. In this study, we assessed the impact of active lead (Pb)/zinc (Zn) mines Zletovo and Toranica on the water quality of three rivers in northeastern Macedonia (Bregalnica, Zletovska, and Kriva rivers) based on data collected in spring and autumn of 2012. The Bregalnica River, near Shtip, was characterized mainly by weak contamination with arsenic, barium, iron, molybdenum, titanium, uranium, vanadium, nitrate, and phosphate, as well as critical faecal pollution, which alltogether could be connected to agricultural activities; however, an impact of the mines was not observed. Contrary, both the Zletovska and Kriva rivers showed a clear impact of Pb/Zn mines on water quality. In the Zletovska River, increased concentrations of cadmium (Cd), cobalt, cesium, copper, lithium, manganese (Mn), nickel, rubidium, tin, strontium, thallium, Zn, sulphates, and chlorides were found, especially in autumn (e.g., Cd 2.0 MUg L( 1); Mn 2.5 mg L(-1); Zn 1.5 mg L(-1)). In the Kriva River, increased Cd (0.270 MUg L(-1)) and Pb (1.85 MUg L(-1)) concentrations were found only in spring, possibly due to sediment resuspension during greater water discharge. The selected sampling sites on the Bregalnica, Zletovska, and Kriva rivers were confirmed as being appropriate locations for further studies of mining waste's impact on freshwater ecosystems, the first one as a nonimpacted site and the other two as possible areas of increased exposure of aquatic organisms to metals. PMID- 24626793 TI - Pyrroles versus cyclic nitrones: catalyst-controlled divergent cyclization of N (2-perfluoroalkyl-3-alkynyl) hydroxylamines. AB - The IPrAuNTf2/HNTf2 co-catalyzed cyclization of N-(2-perfluoroalkyl-3-alkynyl) hydroxylamines produces pyrroles in moderate to excellent yield, whereas the AgOTf-catalyzed reaction affords cyclic nitrones in high yields. PMID- 24626794 TI - GIS-based multicriteria municipal solid waste landfill suitability analysis: a review of the methodologies performed and criteria implemented. AB - Multicriteria spatial decision support systems (MC-SDSS) have emerged as an integration of the geographical information systems (GIS) and multiple criteria decision analysis (MCDA) methods. GIS-based MCDA allows the incorporation of conflicting objectives and decision maker (DM) preferences into spatial decision models. During recent decades, a variety of research articles have been published regarding the implementation of methods and/or tools in a variety of real-world case studies. The article discusses, in detail, the criteria and methods that are implemented in GIS-based landfill siting suitability analysis and especially the exclusionary and non-exclusionary criteria that can be considered when selecting sites for municipal solid waste (MSW) landfills. This paper reviews 36 seminal articles in which the evaluation of candidate landfill sites is conducted using MCDA methods. After a brief description of the main components of a MC-SDSS and the applied decision rules, the review focuses on the criteria incorporated into the decision models. The review provides a comprehensive guide to the landfill siting analysis criteria, providing details regarding the utilization methods, their decision or exclusionary nature and their monotonicity. PMID- 24626795 TI - An inelastic neutron scattering study of dietary phenolic acids. AB - The conformational preferences and hydrogen-bonding motifs of several potential chemopreventive hydroxycinnamic derivatives were determined by inelastic neutron scattering spectroscopy. The aim is to understand their recognized beneficial activity and establish reliable structure-activity relationships for these types of dietary phytochemicals. A series of phenolic acids with different hydroxyl/methoxyl ring substitution patterns were studied: trans-cinnamic, p coumaric, m-coumaric, trans-caffeic and ferulic acids. Their INS spectra were completely assigned by theoretical calculations performed at the Density Functional Theory level, for the isolated molecule, dimeric centrosymmetric species and the solid (using plane-wave expansion approaches). Access to the low energy vibrational region of the spectra enabled the identification of particular modes associated with intermolecular hydrogen-bonding interactions, which are the determinants of the main conformational preferences and antioxidant capacity of these systems. PMID- 24626800 TI - Growth of rutile TiO2 on the convex surface of nanocylinders: from nanoneedles to nanorods and their electrochemical properties. AB - In this work, bundles of rutile TiO2 nanoneedles/nanorods are hydrothermally grown on carbon nanofibers (CNFs), forming free-standing mats consisting of three dimensional hierarchical nanostructures (TiO2-on-CNFs). Morphologies and structures of the TiO2-on-CNFs are studied using a field-emission scanning electron microscope (FESEM), transmission electron microscope (TEM), X-ray diffractometer (XRD) and thermogravimetric analyzer (TGA). Their electrochemical properties as electrodes in lithium ion batteries (LIBs) are investigated and correlated with the morphologies and structures. It is shown that the lateral size of the TiO2 nanoneedles/nanorods ranges from a few nanometers to tens of nanometers, and increases with the hydrothermal temperature. Small interspaces are observed between individual nanoneedles/nanorods, which are due to the diverging arrangement of nanoneedles/nanorods induced by growing on the convex surface of nanocylinders. It is found that the growth process can be divided into two stages: initial growth on the CNF surface and further growth upon re nucleation on the TiO2 bundles formed in the initial growth stage. In order to achieve good electrochemical performance in LIBs, the size of the TiO2 nanostructures needs to be small enough to ensure complete alloying and fast charge transport, while the further growth stage has to be avoided to realize direct attachment of TiO2 nanostructures on the CNFs, facilitating electron transport. The sample obtained after hydrothermal treatment at 130 degrees C for 2 h (TiO2-130-2) shows the above features and hence exhibits the best cyclability and rate capacity among all samples; the cyclability and rate capacity of TiO2 130-2 are also superior to those of other rutile TiO2-based LIB electrodes. PMID- 24626801 TI - Mangiferin increases Nrf2 protein stability by inhibiting its ubiquitination and degradation in human HL60 myeloid leukemia cells. AB - The nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling pathway is a key target for cancer chemoprevention. Recent studies have that Nrf2 activation may be the result of an increase in Nrf2 protein stability. Mangiferin (MA), a compound monomer extracted from the mango plant, has antioxidant and cytoprotective activities. Our previous study demonstrated that MA increased Nrf2 expression and activated Nrf2 signaling in hematopoietic cells. Thus, in the present study, we aimed to investigate the mechanisms by which MA increases Nrf2 expression in human HL60 myeloid leukemia cells in vitro. Our western blot analysis results revealed that MA markedly increased Nrf2 expression in dose- and time-dependent manner. However treatment with MA did not affect the Nrf2 mRNA level. The results of cycloheximide (CHX)-chase analysis demonstrated that the Nrf2 protein half-life was prolonged to 58 min when the HL60 cells were pre-incubated with 50 uM MA for 4 h, whereas its half-life was only 20 min in the non-MA treated control cells. Further experiments revealed that MA mainly enhanced non-ubiquitinated Nrf2 protein levels when increasing Nrf2 protein stability; these effects differed from those induced by the proteasome inhibitor, MG132. Subsequent immunoprecipitation experiments confirmed that MA inhibited Nrf2 ubiquitination in HL60 cells. These results provide evidence that MA increases Nrf2 protein stability by inhibiting its ubiquitination and degradation in hematopoietic cells. This may be one of the mechanisms through which MA activates the Nrf2-mediated antioxidant response and exerts cytoprotective effects. PMID- 24626802 TI - Socio-demographic and fertility-related characteristics and motivations of oocyte donors in eleven European countries. AB - STUDY QUESTION: Do the socio-demographic and fertility-related characteristics and motivations of oocyte donors differ in European countries? SUMMARY ANSWER: The socio-demographic and fertility-related characteristics and motivations of oocyte donors differ considerably across countries. WHAT IS KNOWN ALREADY: There have been no other international studies comparing the characteristics of oocyte donors. Regarding their motivations, most studies indicate mixed motives. STUDY DESIGN, SIZE, DURATION: The proposed study was a transversal epidemiological study. Data were collected from 63 voluntarily participating assisted reproduction technology centres practising oocyte donation in 11 European countries (Belgium, Czech Republic, Finland, France, Greece, Poland, Portugal, Russia, Spain, UK and Ukraine). The survey was conducted between September 2011 and June 2012 and ran for 1-6 calendar months depending on the number of cycles of oocyte donation performed at the centre. The sample size was computed in order to allow an estimate of the percentage of a relatively rare characteristic (~2%) with a precision (95% confidence interval) of 1%. The calculation gave 1118 donors. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1423 forms were obtained from oocyte donors. All consecutive donors in these centres filled out an anonymous questionnaire when they started their hormonal stimulation, asking for their socio-demographic and fertility-related characteristics, their motivations and compensation. Population characteristics were described and compared by country of donation. Motives for donation and mean amount of money were compared between countries and according to the donors characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The socio-demographic and fertility-related characteristics and motivations of oocyte donors varied enormously across European countries. The number of received forms corresponded with a participation rate of 61.9% of the cycles performed by the participating centres. Mean age was 27.4 years. About 49% of donors were fully employed, 16% unemployed and 15% student. The motivation in the total group of donors was 47.8% pure altruism, 33.9% altruism and financial, 10.8% pure financial, 5.9% altruism and own treatment and finally 2% own treatment only. About 15% of the donors were egg sharers (patient donors), mainly from the UK and Poland. Women were donating for the first time in 55.4% of cases, for the second time in 20.3% and for the third time in 12.8%. The motivation to donate was significantly related to being of foreign origin (P < 0.01), age (P < 0.001), living in couple or not (P < 0.01), level of education (P < 0.001) and number of donations (P < 0.001). The amount of compensation differed considerably between centres and/or countries. The general donor profile in this study was a well-educated, 27-year-old woman living with her partner and child who mainly donated to help others. LIMITATIONS, REASONS FOR CAUTION: The selection of clinics in some countries and the limited participation rate may have led to a bias in donor characteristics. A possible effect of social desirability in the answers by the donors should be taken into account. WIDER IMPLICATIONS OF THE FINDINGS: The diversity of the donor population reflects the differences in European legislation (for example, on anonymity and payment) and economic circumstances. The differences in systems of reimbursement/payment demonstrate the need to have a thorough discussion on the specific meaning of these terms. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the European Society for Human Reproduction and Embryology. The authors declare no conflicting interests. PMID- 24626803 TI - Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age dependent manner. AB - STUDY QUESTION: Does triiodothyronine (T3) regulate the secretion of angiogenic growth factors and cytokines by human decidual cells isolated from early pregnancy? SUMMARY ANSWER: T3 modulates the secretion of specific angiogenic growth factors and cytokines, with different regulatory patterns observed amongst various isolated subpopulations of human decidual cells and with a distinct change between the first and second trimesters of pregnancy. WHAT IS KNOWN ALREADY: Maternal thyroid dysfunction during early pregnancy is associated with complications of malplacentation including miscarriage and pre-eclampsia. T3 regulates the proliferation and apoptosis of fetal-derived trophoblasts, as well as promotes the invasive capability of extravillous trophoblasts (EVT). We hypothesize that T3 may also have a direct impact on human maternal-derived decidual cells, which are known to exert paracrine regulation upon trophoblast behaviour and vascular development at the uteroplacental interface. STUDY DESIGN, SIZE, DURATION: This laboratory-based study used human decidua from first (8-11 weeks; n = 18) and second (12-16 weeks; n = 12) trimester surgical terminations of apparently uncomplicated pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Primary cultures of total decidual cells, and immunomagnetic bead isolated populations of stromal-enriched (CD10+) and stromal-depleted (CD10-) cells, uterine natural killer cells (uNK cells; CD56+) and macrophages (CD14+) were assessed for thyroid hormone receptors and transporters by immunocytochemistry. Each cell population was treated with T3 (0, 1, 10, 100 nM) and assessments were made of cell viability (MTT assay) and angiogenic growth factor and cytokine secretion (immunomediated assay). The effect of decidual cell conditioned media on EVT invasion through Matrigel((r)) was evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Immunocytochemistry showed the expression of thyroid hormone transporters (MCT8, MCT10) and receptors (TRalpha1, TRbeta1) required for thyroid hormone-responsiveness in uNK cells and macrophages from the first trimester. The viability of total decidual cells and the different cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P < 0.05) and increased angiopoietin-2 secretion by stromal depleted cells (P < 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P < 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P < 0.05), and reduced granulocyte macrophage colony stimulating factor (P < 0.01), IL-8 (P < 0.05), IL 10 (P < 0.01), IL-1beta (P < 0.05) and monocyte chemotactic protein -1 (P < 0.001) secretion by macrophages, but increased tumour necrosis factor-alpha secretion by stromal-depleted cells (P < 0.05) and increased IL-6 by uNK cells (P < 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P < 0.01) but did not affect cytokine secretion by uNK cells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro. LIMITATIONS, REASONS FOR CAUTION: Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory 'switch' in T3 responsiveness between the first and second trimesters, and support the notion that the timely and early correction of maternal thyroid dysfunction is critical in influencing pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study is funded by Wellbeing of Women (RG/1082/09 to S.Y.C., M.D.K., J.A.F., L.S.L., G.E.L.) and Action Medical Research - Henry Smith Charity (SP4335 to M.D.K., S.Y.C., L.S.L., J.A.F.). The authors have no conflicts of interest to disclose. PMID- 24626804 TI - IL-10 gene promoter and intron polymorphisms and changes in IL-10 secretion in women with idiopathic recurrent miscarriage. AB - STUDY QUESTION: Is recurrent pregnancy loss (RPL) associated with polymorphisms in the promoter and intron regions of the interleukin-10 (IL-10) gene? SUMMARY ANSWER: IL-10 rs1518111 was found to be associated with RPL but the commonly studied promoter variants rs1800872, rs1800871 and 1800896 were not. WHAT IS KNOWN ALREADY: Reduced expression of IL-10 is implicated in RPL, due to defective maternal immune tolerance (causing early miscarriages) or placental vascular insufficiency (causing late losses). IL-10 production is in part inherited, and IL-10 gene variants associated with reduced IL-10 expression have been analyzed for their association with RPL, often with inconclusive results. STUDY DESIGN, SIZE, DURATION: A retrospective case-control study was performed between January 2011 and April 2012. The subjects comprised 296 RPL cases and 305 control women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Genotyping of the IL-10 intron (rs1878672, rs3024492, rs1554286, rs1518111, rs3024491, rs3024490) and promoter (rs1800872, rs1800871, rs1800896) variants was done by real-time PCR, with defined clusters. MAIN RESULTS AND THE ROLE OF CHANCE: A higher minor allele frequency (MAF) of rs1518111 (P = 0.03) was in seen RPL cases; but the MAFs of the remaining SNPs were comparable between cases and controls. Setting the homozygous major allele genotype (1/1) as the reference, significantly higher frequencies of heterozygous rs1554286 and rs1800872, and homozygous rs1800896 genotype carriers, and a reduced frequency of homozygous rs1518111 genotype carriers, were seen in RPL cases, while the distribution of the remaining genotypes were comparable between cases and controls. Serum IL-10 levels were significantly reduced in RPL cases compared with control women (P = 0.002), and this correlated with rs1518111 and rs1800871 genotypes in both groups, and with the rs1800872 genotype among control women. A nine-locus (rs1878672, rs3024492, rs1554286, rs1518111, rs3024491, rs3024490, rs1800872, rs1800871 and rs1800896) haploview analysis demonstrated an increased frequency of haplotype 112112121 in RPL cases, thus conferring a disease susceptibility nature to this haplotype. LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study was that it was limited to Bahraini Arabs, thereby necessitating parallel studies of other ethnic groups. Another limitation is the study design, which prompts speculation on whether it is a cause-effect relationship. WIDER IMPLICATIONS OF THE FINDINGS: While the lack of association of the various IL-10 promoter variants with RPL was in agreement with reports from varied ethnic groups, this is the first study to confirm the association between IL-10 rs151811 intronic variant and RPL. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by grants from the Arabian Gulf University Research Fund. None of the authors report any competing interests. PMID- 24626805 TI - Pre-mixing serum samples with assay buffer is a prerequisite for reproducible anti-Mullerian hormone measurement using the Beckman Coulter Gen II assay. AB - STUDY QUESTION: Does pre-mixing stored serum samples with assay buffer improve the reproducibility of the Beckman Gen II assay for anti-Mullerian hormone (AMH)? SUMMARY ANSWER: Pre-mixing serum samples with assay buffer is a prerequisite for reproducible measurement of AMH in serum using the Beckman Coulter Gen II assay. WHAT IS KNOWN ALREADY: Discrepancies in the results obtained from AMH assays have raised doubts concerning the clinical utility of measuring AMH. Sample storage conditions may be responsible for the lack of reproducibility of results obtained from the Gen II kit. STUDY DESIGN, SIZE, DURATION: This was a prospective study in which serum samples were stored at three different temperatures and assayed for AMH at times 0, 4, 8, 12, 24, 48 h and 1 or 2 weeks after collection. Volunteers (n = 28) were healthy non-pregnant and early pregnant women aged 22-41 years. Anonymized long-term stored samples (n = 42, stored at -20 degrees for 2 weeks) from fertility clinic attendees were also included. For determining the reference range, 179 samples from healthy pregnant women presenting for first trimester screening were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty separate assays were performed by two operators using four different Gen II kit lots with both kit and in-house quality controls (QCs) included in each assay. In addition to the standard protocol, a modified protocol (pre-mixing samples with assay buffer) was used for selected sample groups. MAIN RESULTS AND THE ROLE OF CHANCE: In non-pregnant women, AMH concentrations remained unchanged in serum stored for up to 8 h at room temperature, -20 and -80 degrees C. At room temperature, levels started to rise by 24 h, increasing by up to 29% of the time 0 h value by 48 h and 26% after 1 week. Significant changes versus baseline (time 0 h) in measured AMH concentration were also observed after storage at -20 and 80 degrees C (only at the 12 h time point). In the pregnant group, there was a 50% increase above baseline in samples stored for 48 h at room temperature. When samples were pre-mixed with assay buffer, AMH concentrations showed a consistent increase versus the standard assay in both non-pregnant (29%) and pregnant (280%) groups, regardless of storage conditions and duration, but concentrations remained constant during long-term storage (2 weeks). Stored fertility clinic patient samples also exhibited stability of AMH values after a consistent 2-fold increase following pre-mixing. Kit QCs were consistent over 30 weeks using either standard or modified protocols while the in-house pooled serum QC rose over time unless using the modified protocol. Overall, there was a 2-fold increase in medians in the pre-mixed reference range, with the biggest increase observed in the oldest age bracket (41-45 years, 3.4-fold). LIMITATIONS, REASONS FOR CAUTION: The cause of the observed instability of AMH in stored serum samples requires further investigation, which is outside the scope of this publication. A larger and wider population study is necessary for a more reliable and clinically relevant reference range. WIDER IMPLICATIONS OF THE FINDINGS: Our study has confirmed previous findings of lack of consistency in AMH concentrations when measured with the Gen II assay. Pre-mixing serum samples with assay buffer gave higher but also the most consistent results regardless of storage conditions; therefore, we propose that all serum samples for AMH assay should be pre-mixed with assay buffer. Furthermore, clinical laboratories that offer AMH measurement as part of the assessment of endocrinopathies, such as polycystic ovary syndrome or premature ovarian failure, or for management of ovulation induction as part of assisted reproduction, must re-establish their own normal ranges using the modified method. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained for this study. There are no conflicts of interest to declare. PMID- 24626807 TI - Prostaglandin E2 receptor EP2 mediates Snail expression in hepatocellular carcinoma cells. AB - Prostaglandin E2 (PGE2) has been shown to influence cell invasion and metastasis in several types of cancer, including hepatocellular carcinoma (HCC). however, the molecular mechanisms underlying it remain to be further elucidated. Snail, as one of key inducers of epithelial-mesenchymal transition (EMT), plays pivotal roles in HCC invasion and metastasis. The present study was designed to evaluate the possible signaling pathways through which PGE2 regulates Snail protein expression in HCC cell lines. PGE2 markedly enhanced Huh-7 cell invasion and migration ability by upregulating the expression level of Snail protein, and EP2 receptor played an important role in this process. Src, EGFR, Akt and mTOR were all activated and involved in the regulation of snail protein expression. Our findings suggest that PGE2 could upregulate the expression level of Snail protein through the EP2/Src/EGFR/Akt/mTOR pathway in Huh-7 cells, which promotes HCC cell invasion and migration. PMID- 24626808 TI - Cell growth and protein expression of Shewanella oneidensis in biofilms and hydrogel-entrapped cultures. AB - The performance of biofilm-based bioprocesses is difficult to predict and control because of the intrinsic heterogeneous and dynamic properties of microbial biofilms. Biofilm mimics, such as microbial cells entrapped in polymeric scaffolds that are permeable for nutrients, have been proposed to replace real biofilms to achieve long-term robust performance in engineering applications. However, the physiological differences between cells that are physically entrapped in a synthetic polymeric matrix and biofilm cells that are encased in a self-produced polymeric matrix remain unknown. In this study, using Shewanella oneidensis as a model organism and alginate hydrogel as a model synthetic matrix, we compared the cell growth and protein expression in entrapped cultures and biofilms. The hydrogel-entrapped cultures were found to exhibit a growth rate comparable with biofilms. There was no substantial difference in cell viability, surface charge, as well as hydrophobicity between the cells grown in alginate hydrogel and those grown in biofilms. However, the gel-entrapped cultures were found to be physiologically different from biofilms. The gel-entrapped cultures had a higher demand for metabolic energy. The siderophore-mediated iron uptake was repressed in the gel-entrapped cells. The presence of the hydrogel matrix decreased the expression of proteins involved in biofilm formation, while inducing the production of extracellular DNA (eDNA) in the gel-entrapped cultures. These results advance the fundamental understanding of the physiology of hydrogel-entrapped cells, which can lead to more efficient biofilm mimic-based applications. PMID- 24626806 TI - Seminal plasma induces global transcriptomic changes associated with cell migration, proliferation and viability in endometrial epithelial cells and stromal fibroblasts. AB - STUDY QUESTION: How does seminal plasma (SP) affect the transcriptome of human primary endometrial epithelial cells (eEC) and stromal fibroblasts (eSF)? SUMMARY ANSWER: Exposure of eEC and eSF to SP in vitro increases expression of genes and secreted proteins associated with cellular migration, proliferation, viability and inhibition of cell death. WHAT IS KNOWN ALREADY: Studies in both humans and animals suggest that SP can access and induce physiological changes in the upper female reproductive tract (FRT), which may participate in promoting reproductive success. STUDY DESIGN, SIZE, DURATION: This is a cross sectional study involving control samples versus treatment. SP (pooled from twenty donors) was first tested for dose- and time-dependent cytotoxic effects on eEC and eSF (n = 4). As exposure of eEC or eSF to 1% SP for 6 h proved to be non-toxic, a second set of eEC/eSF samples (n = 4) was treated under these conditions for transcriptome, protein and functional analysis. With a third set of samples (n = 3), we further compared the transcriptional response of the cells to SP versus fresh semen. PARTICIPANTS/MATERIALS, SETTING, METHODS: eEC and eSF were isolated from endometrial biopsies from women of reproductive age undergoing benign gynecologic procedures and maintained in vitro. RNA was isolated and processed for microarray studies to analyze global transcriptomic changes. Secreted factors in conditioned media from SP-treated cells were analyzed by Luminex and for the ability to stimulate migration of CD14+ monocytes and CD4+ T cells. MAIN RESULTS AND THE ROLE OF CHANCE: Pathway identifications were determined using the Z-scoring system in Ingenuity Pathways Analysis (Z scores >=|1.5|). SP induced transcriptomic changes (P < 0.05) associated with promoting leukocyte and endothelial cell recruitment, and proliferation of eEC and eSF. Cell viability pathways were induced, while those associated with cell death were suppressed (P < 0.05). SP and fresh semen induced similar sets of pathways, suggesting that SP can model the signaling effects of semen in the endometrium. SP also induced secretion of pro-inflammatory and pro-chemotactic cytokines, as well as pro angiogenic and proliferative growth factors (P < 0.05) in both eEC and eSF. Finally, functional assays revealed that conditioned media from SP-treated eEC and eSF significantly increased (P < 0.05) chemotaxis of CD14+ monocytes and CD4+ T cells. LIMITATIONS, REASONS FOR CAUTION: This study is limited to in vitro analyses of the effects of SP on endometrial cells. In addition, the measured response to SP was conducted in the absence of the ovarian hormones estradiol and progesterone, as well as epithelial-stromal paracrine signaling. While this study focused on establishing the baseline cellular response of endometrial cells to SP, future work should assess how hormone signaling in the presence of appropriate paracrine interactions affects SP-induced genes in these cells. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study support previous findings that SP and semen contain bioactive factors capable of eliciting chemotactic responses in the uterus, which can lead to recruitment of leukocytes to the endometrium. Future directions will explore if similar changes in gene expression do indeed occur after coitus in vivo, and how the signaling cascades initiated by SP in the endometrium can affect reproductive success, female reproductive health and susceptibility to sexually transmitted diseases. The gene list provided by the transcriptome analysis reported here should prove a valuable resource for understanding the response of the upper FRT to SP exposure. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by NIH AI083050-04 (W.C.G./L.C.G.); NIH U54HD 055764 (L.C.G.); NIH 1F32HD074423-02 (J.C.C.); DOD W81XWH-11-1-0562 (W.C.G.); NIH 5K12-DK083021-04, NIH 1K99AI104262-01A1, The UCSF Hellman Award (N.R.R.). The authors have nothing to disclose. PMID- 24626809 TI - Werner syndrome protein positively regulates XRCC4-like factor transcription. AB - XRCC4-like factor (XLF) is involved in non-homologous end joining-mediated repair of DNA double-strand breaks (DSBs). Mutations in the WRN gene results in the development of Werner syndrome (WS), a rare autosomal recessive disorder characterized by premature ageing and genome instability. In the present study, it was identified that XLF protein levels were lower in WRN-deficient fibroblasts, compared with normal fibroblasts. Depletion of WRN in HeLa cells led to a decrease of XLF mRNA and its promoter activity. Chromatin immunoprecipitation assays demonstrated that WRN was associated with the XLF promoter. Depletion of XLF in normal human fibroblasts increased the percentage of beta-galactosidase (beta-gal) staining-positive cells, indicating acceleration in cellular senescence. Taken together, the results suggest that XLF is a transcriptional target of WRN and may be involved in the regulation of cellular senescence. PMID- 24626810 TI - Translocation of protein kinase C delta contributes to the moderately high glucose-, but not hypoxia-induced proliferation in primary cultured human retinal endothelial cells. AB - Diabetic retinopathy is one of the most common complications in patients with diabetes and affects ~75% of them within 15 years of the onset of the disease. Activation of protein kinase C (PKC) is a key feature of diabetes mellitus and may be involved in the pathogenesis of diabetic retinopathy. The present study aimed to examine the translocation of protein kinase C (PKC) isoforms, which are triggered by high an moderately high glucose levels as well as hypoxic conditions. The underlying cell mechanisms of PKC translocation in primary cultured human retinal endothelial cells (HRECs) were also investigated. The expression levels of PKC isoforms were assessed using western blot analysis. Cell proliferation was determined using the MTT assay and DNA synthesis was assessed by bromodeoxyuridine incorporation. Translocation of PKC isoforms was examined by western blot analysis and immunofluorescence. The expression of PKC alpha, betaI, betaII, delta and epsilon was detected, while PKC zeta was not detected in HRECs. The results of the present study were consistent with the findings of a previous study by our group, reporting that moderately high glucose levels and hypoxia, but not high glucose levels, significantly increased cell proliferation. It was demonstrated that the PKC delta isoform was translocated from the cytosol to the membrane only under moderately high glucose conditions, while PKC alpha and epsilon isoforms were translocated from the cytosol to the membrane at high glucose conditions. In addition, PKC betaI was translocated under all three conditions. Translocation of PKC betaII was comparable among all groups. Furthermore, rottlerin, an inhibitor of PKC delta, blocked cell proliferation, which was induced by moderately high glucose levels, but not by hypoxia. Ro32 0432, an inhibitor of PKC alpha, betaI and epsilon, did not significantly affect proliferation of HRECs in all treatment groups. In conclusion, the present study suggested that PKC alpha, betaI, betaII, delta and epsilon were expressed in primary cultured HRECs, whereas PKC zeta was not. Cell proliferation induced by moderately high glucose concentrations was associated with translocation of the PKC delta isoform; however, hypoxic conditions did not induce translocation. PMID- 24626811 TI - Impact of extracellular RNA on endothelial barrier function. AB - Different types of high and low molecular weight extracellular RNA (eRNA) are liberated from cells upon conditions of tissue damage or vascular diseases and have been demonstrated in vivo and in vitro to influence the integrity and barrier function of the vascular endothelium. Among the types of self eRNA studied in this respect, ribosomal RNA appears to engage cytokines to promote hyperpermeability, while counteracting RNase1 serves as a potent vessel protective factor. Different microRNAs may change the expression program of endothelial cells with consequences for cellular contacts and stability. Non-self viral RNAs are recognized by Toll-like receptors that transmit intracellular inflammation signals to disturb the vascular barrier function, largely in connection with infectious diseases. Although derived from the same nucleotide building blocks, the various forms of eRNA exhibit a multitude of molecular interactions with the endothelium that may drastically change its phenotypical characteristics. The impact of eRNA on vascular integrity in health and disease is summarized in this concise review. PMID- 24626812 TI - trans-1,2-Disiloxybenzocyclobutene, an adequate partner for the auto-oxidation: EPR/spin trapping and theoretical studies. AB - The auto-oxidation of trans-1,2-disiloxybenzocyclobutene was found to be very efficient, giving endo-peroxide in quantitative yield. Each step of the mechanism of spin-forbidden addition of triplet oxygen O2((3)Sigmag) was studied by both EPR/spin trapping and theoretical studies. PMID- 24626813 TI - Level of urinary liver-type fatty acid-binding protein is associated with cardiac markers and electrocardiographic abnormalities in type-2 diabetes with chronic kidney disease stage G1 and G2. AB - Urinary liver-type fatty acid-binding protein (L-FABP) reflects the degree of stress in proximal tubules of the kidney. We examined the level of L-FABP in type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD) stage G1 and G2, and its relationship with cardiac markers and electrocardiographic (ECG) abnormalities. T2DM patients whose estimated glomerular filtration rate (eGFR) was >=60 mL/min/1.73 m(2) were recruited [n = 276 (165 males), mean age 64 years]. The median level of urinary L-FABP was 6.6 MUg/gCr. Urinary L-FABP showed significant correlation with urinary albumin-to-creatinine ratio (ACR) (r = 0.51, p < 0.0001). Median (25th-75th percentile) eGFR was 82 (72-95) mL/min/1.73 m2. We divided patients into four subgroups (group 1, L-FABP <=8.4 MUg/gCr and ACR <=30 mg/gCr; group 2, L-FABP <=8.4 MUg/gCr and ACR >30 mg/gCr; group 3, L-FABP >8.4 MUg/gCr and ACR <=30 mg/gCr; group 4, L-FABP >8.4 MUg/gCr and ACR >30 mg/gCr). Compared with group 1, group 4 was significantly higher in systolic blood pressure, and eGFR using standardized serum cystatin C, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Group 4 had significantly higher level of NT-proBNP than group 3. Groups 2, 3 and 4 showed more ECG abnormalities than group 1. These findings suggest that simultaneous measurement of urinary L-FABP and ACR should be useful to assess cardiovascular damage reflecting on the elevation of cardiac markers and ECG abnormalities in T2DM with CKD G1 and G2. PMID- 24626814 TI - Angiographic result of T-stenting with small protrusion using drug-eluting stents in the management of ischemic side branch: the ARTEMIS study. AB - The aim of this study was to examine the mid-term angiographic result of T stenting with small protrusion (TAP) as the bailout strategy for treating coronary bifurcation lesions. From 2009 to 2012, symptomatic patients who had severe coronary bifurcation stenoses were treated with one-stent strategy using drug-eluting stents, with kissing balloon inflation performed whenever side branch (SB) impingement occurred. TAP was performed if residual diameter stenosis of SB was >=75%, presence of >=type B dissection or flow impairment was observed in the SB. Seventy-one patients (83% male, mean age of 61 +/- 12 years) were recruited into the study. MEDINA classification 1,1,1 lesions were observed in over 60% of patients. The mean stent size and length in the main vessel (MV) and SB were 2.86 +/- 0.43 and 30 +/- 12, and 2.45 +/- 0.26 and 16 +/- 6 mm, respectively. Restudy angiography was performed on 64 (90 %) patients at 9.2 +/- 3.9 months. Angiographic restenosis was observed in 8 (12.5%) patients with late lumen loss in the MV and SB being 0.22 +/- 0.19 and 0.34 +/- 0.37 mm, respectively. The use of TAP as the bailout technique for treating coronary bifurcation lesions is associated with good angiographic outcomes, in terms of late lumen loss and restenosis, at 9 months. PMID- 24626815 TI - Characterization of secreted vesicles from vascular smooth muscle cells. AB - The artery medial layer is mainly composed of vascular smooth muscle cells (VSMCs). These cells contribute to the formation of neointima and atherosclerotic plaques by switching from the quiescent-contractile to migratory-activated state. Apoptotic blebs, microvesicles and exosomes are secreted vesicles, with differences in composition and size, involved in cellular communication at multiple levels. In this article, an untargeted, proteomics approach was exploited to characterise VSMC released vesicles and a preliminary protein profile for microvesicles and exosomes of different cell phenotypes was obtained. Enriched samples of vesicles from serum-free and serum-activated VSMCs were analysed by a LC-MS/MS strategy leading to the identification of 349 proteins. In microvesicles, the most abundant classes of identified proteins were cytoplasmic or organelle associated, house keeping and metabolic factors. Otherwise, exosomes from different phenotypes revealed a sharper peculiarity thus, as suggested by the high percentage of ECM and ECM related proteins and cell adhesion molecules, they seem to play an important role in outward or cell-to-cell signalling. Comparison between exosomes or microvesicles from quiescent and activated VSMCs evidenced 29 differentially expressed proteins. Among these, in microvesicles there are several proteins that are involved in vesicle trafficking while in exosomes focal adhesion and ECM related factors are the most interesting. These data, although preliminary, are promising for a possible identification of potential circulating markers of a cell state. PMID- 24626816 TI - Necrotizing enterocolitis in infants with congenital heart disease: the role of red blood cell transfusions. AB - Necrotizing enterocolitis (NEC) is a rare but catastrophic complication that may occur in newborns with congenital heart disease (CHD). In the preterm population, transfusion of red blood cells (RBCs) and use of RBCs with longer storage time have been independently associated with the development of NEC. To date, it is not known whether similar associations exist for the term newborn with CHD. This retrospective study identified the incidence of NEC among 1,551 newborns admitted to the authors' cardiac intensive care unit between 7 January 2002 and 7 January 2010. The study was limited to term newborns (>36 weeks gestation). To understand the impact of RBC transfusions on the development of NEC, a nested 2:1 matched case-control analysis was undertaken to compare RBC transfusion patterns between an age-matched group and a cardiac lesion-matched control group. In the study population, NEC developed in 45 term infants during the postoperative period. Of these 45 infants, 30 (66.7%) had single-ventricle heart defects, whereas 22 (48.8%) required surgery for aortic arch obstruction. The median patient age at NEC diagnosis was 21 days. The RBC transfusion rate was higher among the patients who experienced NEC (0.21/day) than among the control subjects (0.10/day) (p = 0.048). A multivariate analysis indicated that onset of NEC was associated with a greater number of RBC transfusions (odds ratio [OR] 1.83; 95% confidence interval [CI] 1.07-7.47; p = 0.045). The duration of RBC storage was not significantly longer in the NEC group (9 days) than in the control cohort (7 days) (p = 0.16). Increased exposure to RBC transfusions is associated with the development of NEC in term infants with CHD. Longer storage of RBCs does not appear to increase this risk. Although causality cannot be confirmed, these data prompt a careful review of RBC transfusion practices with this population. PMID- 24626817 TI - MicroRNA-100 regulates SW620 colorectal cancer cell proliferation and invasion by targeting RAP1B. AB - MicroRNAs (miRNAs) have been demonstrated to play important roles in tumorigenesis of human cancer. Fewer studies have explored the roles of miR-100 on human colorectal cancer cell proliferation and invasion. In this study, we utilized real-time PCR to verify whether miR-100 was downregulated in human colorectal cancer tissues compared with matched adjacent normal tissues. Functional studies demonstrated that ectopic expression of miR-100 inhabits cell growth and invasion and induce apoptosis, whereas knockdown of miR-100 yielded the reverse phenotype. Mechanistic studies reveal that miR-100 repressed the activity of a reporter gene fused to the 3'-untranslated region (3'-UTR) of RAP1B, whereas miR-100 silencing upregulated the expression of the reporter gene. Furthermore, we also detected that RAP1B mRNA was inversely expressed with miR 100 in colorectal cancer tissues. These data indicate that the miR-100 plays a tumor suppressor role by regulating colorectal cancer cell growth and invasion phenotype, and could serve as a potential maker for colorectal cancer therapy. PMID- 24626818 TI - Understanding the growth and photoelectrochemical properties of mesocrystals and single crystals: a case of anatase TiO(2). AB - Anatase TiO2 mesocrystals and single crystals with dominant {101} facets were successfully synthesized without any additives using titanate nanowires as precursors under solvothermal and hydrothermal conditions, respectively. It is proposed that the oriented self-assembly process for the formation of TiO2 mesocrystals was controlled by the same thermodynamic principle as that of single crystals in this simple reaction system. Furthermore, the TiO2 mesocrystals were applied in photoelectrochemical (PEC) water splitting and demonstrated much enhanced photocurrent, almost 191% and 274% compared with that of TiO2 single crystals and commercial P25, respectively. Electrochemical impedance measurements under illumination revealed that the photocurrent increase was largely ascribed to the effective charge separation of electron-hole pairs and fast interfacial charge transfer. This could be attributed to the intrinsic characteristics of the mesostructured TiO2 composed of highly oriented nanocrystal subunits offering few grain boundaries, nanoporous nature and a short transport distance. PMID- 24626822 TI - Foveal injury from a red laser pointer. PMID- 24626819 TI - Omega-3 fatty acid supplementation during pregnancy and respiratory symptoms in children. AB - BACKGROUND: Prenatal consumption of omega-3 fatty acids can act as an adjuvant in the development of the immune system and affect the inflammatory response of neonates. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in Cuernavaca, Mexico. We randomly assigned 1,094 pregnant women (18-35 years of age) to receive 400 mg/d of algal docosahexaenoic acid (DHA) or placebo from 18 to 22 weeks of gestation through delivery. Birth outcomes and respiratory symptoms information until 18 months were available for 869 mother-child pairs. Questionnaires were administered, and maternal blood samples were obtained at baseline. Maternal atopy was based on specific IgE levels. During follow-up, information on infants' respiratory symptoms was collected through questionnaires administered at 1, 3, 6, 9, 12, and 18 months of age. Negative binomial regression models were used to evaluate the effect of supplementation on respiratory symptoms in infants. RESULTS: Among infants of atopic mothers, a statistically significant protective effect of DHA treatment was observed on phlegm with nasal discharge or nasal congestion (0.78; 95% CI, 0.60-1.02) and fever with phlegm and nasal discharge or nasal congestion (0.53; 95% CI, 0.29 0.99), adjusting for potential confounders. CONCLUSIONS: Our results support the hypothesis that DHA supplementation during pregnancy may decrease the incidence of respiratory symptoms in children with a history of maternal atopy. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00646360; URL: www.clinicaltrials.gov. PMID- 24626823 TI - Retinal hemangioblastoma. PMID- 24626824 TI - Geographic atrophy: a histopathological assessment. AB - IMPORTANCE: Geographic atrophy (GA) is the major cause of blind registration in Western communities, although, with few exceptions, it is less common than choroidal neovascular disease. The variation of phenotype implies that age related macular degeneration (AMD) does not follow the same course from one case to another and that phenotyping may be important before initiating a therapeutic trial. OBJECTIVE: To document photoreceptor and retinal pigment epithelium (RPE) cell loss and other changes at the RPE-choroid interface in donated human eyes in which visual loss was deemed to be due to GA. DESIGN, SETTING, AND PARTICIPANTS: Histological study of a consecutive series of eyes donated by individuals previously diagnosed clinically as having GA. Donors were chosen on the basis of available clinical records (from MidAmerica Transplant Services, St Louis, Missouri; the Iowa Lions Eye Bank, Iowa City; and the Utah Lions Eye Bank, Salt Lake City) and selected were those considered to have GA due to AMD. Tissues in the regions of atrophy were examined with light, electron, and autofluorescence microscopy. RESULTS: In most of the 37 donors examined, there was marked loss of photoreceptor cells for variable distances distal from the edge of the GA. Rod loss was greater than cone loss. An inverse relationship existed between the quantity of autofluorescent inclusions in the RPE and the thickness of sub-RPE basal laminar deposit. Integrity of the choroid varied from one eye to another and was not related strictly to photoreceptor survival. In some eyes, photoreceptor loss existed in the absence of obvious morphological changes in the Bruch membrane or RPE. CONCLUSIONS AND RELEVANCE: The findings support the view that photoreceptor loss occurs early in AMD in a proportion of cases and imply that photoreceptor-cell loss may contribute to the functional loss recorded in early stages of AMD at least in part. The variation of changes from one eye to another implies that patients selected for a specific prophylactic therapy for early AMD should be chosen on the basis of the characteristics of their disease. PMID- 24626825 TI - Adolph Barkan (1845-1935), European ophthalmologist in San Francisco. AB - Adolph Barkan, a mid-19th century Central European-born and -trained ophthalmologist, spent almost half his nearly 91 years in a very successful career on the West Coast of the United States. His activities included intimate involvement in the development of a private medical school and with this school's acquisition by Stanford University as its medical school. In retirement, he founded, financed, and stocked a large medical history library at that university. In the 1890s, Siegfried Czapski, the developer of the Carl Zeiss corneal biomicroscope, the direct precursor of today's slitlamp, incorporated Barkan's suggestion that Czapski replace the planned monoscopic binocular microscope with a stereoscopic binocular one, an essential modification of the device. This Zeiss invention lacked only the slit illumination of today's instrument. Comments he wrote in a memoir-diary during World War I explain how he came to the decision to stray and to stay so far from his roots. PMID- 24626826 TI - Pigmented ocular fundus lesions in a 6-year-old girl. PMID- 24626827 TI - Successful management of secondary iris cysts with viscoelastic-assisted endophotocoagulation. PMID- 24626828 TI - Spontaneous improvement in visual acuity in age-related geographic atrophy of the macula. PMID- 24626829 TI - Systemic inflammatory pseudotumor and myasthenia gravis. PMID- 24626830 TI - Reperfusion of large ischemic areas associated with central retinal vein occlusion: a potential novel treatment with activated protein C. PMID- 24626831 TI - Statins and cataract. PMID- 24626832 TI - Statin use and cataract. PMID- 24626833 TI - Statins and cataract--reply. PMID- 24626834 TI - Statin use and cataract--reply. PMID- 24626835 TI - Cataracts and statin use: cause and effect not confirmed. PMID- 24626836 TI - Cataracts and statin use--reply. PMID- 24626837 TI - Statin use and cataracts. PMID- 24626838 TI - Regarding stereotactic radiosurgery for uveal melanoma. PMID- 24626839 TI - Regarding stereotactic radiosurgery for uveal melanoma--reply. PMID- 24626840 TI - The effect of zipper-interacting protein kinase on high glucose-stimulated human aortic smooth muscle cells. AB - Biologic abnormalities in vascular smooth muscle cells (VSMC) may perform a crucial role in the pathogenesis of diabetic vascular disease. The principal aim of this study was to determine the effects of zipper-interacting protein kinase (ZIPK) on human aortic smooth muscle cells (HASMCs) stimulated by high glucose (HG). To elucidate the role of ZIPK in HG-treated HASMCs, we overexpressed ZIPK by lentivirus infection and knocked down ZIPK by gene deletion using ZIPK shRNA. Flow cytometry and Cell Counting kit-8 (CCK-8) were separately used to analyze cell apoptosis and proliferation. Migratory activity was examined using transwell migration chamber assays. The results showed that ZIPK overexpression inhibited cell growth and migration, enhanced cell apoptosis, and reversed cell cycle disturbance by regulating the related proteins of cellular physiological process, such as human cell division cycle 14A phosphatase (Hcdc14A) and intercellular adhesion molecule 1 (ICAM-1). In conclusion, the results suggested that ZIPK plays a role in HG-treated HASMCs, indicating ZIPK is a potential therapeutic target for the treatment of diabetic vascular complications. PMID- 24626842 TI - Role of Nogo-A in the regulation of hepatocellular carcinoma SMMC-7721 cell apoptosis. AB - Nogo-A has been identified as an inhibitor of neurite outgrowth specific to the central nervous system. However, little is known about the role of Nogo-A in hepatocellular carcinoma (HCC), the most common primary malignant tumor with a high mortality rate. This study aimed to investigate the role of endogenous Nogo A in human liver cancer cells. Reverse transcription polymerase chain reaction was used to detect the expression of Nogo-A in four liver cancer cell lines. A lentivirus vector was then constructed to mediate RNA interference (RNAi) targeting of Nogo-A (LV-Nogo-A-siRNA) and was confirmed to successfully suppress the expression of the Nogo-A gene in SMMC-7721 cells. Furthermore, Nogo-A was observed to be highly expressed in liver cancer cell lines. RNAi of Nogo-A using the LV-Nogo-A-siRNA construct significantly decreased Nogo-A protein expression and specifically inhibited the growth of SMMC-7721 cells. This growth inhibitory effect may be attributed to an increase in G2/M phase arrest and apoptosis in SMMC-7721 cells containing Nogo-A-siRNA. The results of this study demonstrate that Nogo-A may represent a novel therapeutic target for the treatment of liver cancer, in addition to its potent roles in neural systems. PMID- 24626843 TI - Cell biology at the host-microbe interface. PMID- 24626844 TI - Cells: Shaping tissues and organs. PMID- 24626845 TI - Cell-cell and cell-matrix interactions. PMID- 24626846 TI - Regulation of vesicle trafficking: GTPases and friends. PMID- 24626847 TI - Organelle and proteome quality control mechanisms: how cells are able to keep calm and carry on. PMID- 24626848 TI - Organization, stability, and expression of the genome. PMID- 24626849 TI - Stem cells and their niche in homeostasis/regeneration and disease. PMID- 24626850 TI - Intrinsic activity in cells and the brain. AB - Motile cells such as bacteria, amoebae, and fibroblasts display a continual level of energy-consuming reactions involving the cytoskeleton and signal pathways, regardless of whether or not they are actually migrating. I draw parallels between these "silent signals" and the intrinsic activity of the human brain, especially that associated with the brain stem. In both cases, it can be argued that the organism continually rehearses possible future actions, so it can act quickly and accurately when suitable cues are received from the environment. PMID- 24626852 TI - Abstracts of the SICB 2014 Annual Meeting, January 3-7, 2014, Austin, TX. PMID- 24626853 TI - Specific anion effects on the pressure dependence of the protein-protein interaction potential. AB - We present a study on ion specific effects on the intermolecular interaction potential V(r) of dense protein solutions under high hydrostatic pressure conditions. Small-angle X-ray scattering in combination with a liquid-state theoretical approach was used to determine the effect of structure breaking/making salt anions (Cl(-), SO4(2-), PO4(3-)) on the intermolecular interaction of lysozyme molecules. It was found that besides the Debye-Huckel charge screening effect, reducing the repulsiveness of the interaction potential V(r) at low salt concentrations, a specific ion effect is observed at high salt concentrations for the multivalent kosmotropic anions, which modulates also the pressure dependence of the protein-protein interaction potential. Whereas sulfate and phosphate strongly influence the pressure dependence of V(r), chloride anions do not. The strong structure-making effect of the multivalent anions, dominating for the triply charged PO4(3-), renders the solution structure less bulk-water like at high salt concentrations, which leads to an altered behavior of the pressure dependence of V(r). Hence, the particular structural properties of the salt solutions are able to influence the spatial organization and the intermolecular interactions of the proteins, in particular upon compression. These results are of interest for exploring the combined effects of ionic strength, temperature and pressure on the phase behavior of protein solutions, but may also be of relevance for understanding pressure effects on the hydration behavior of biological matter under extreme environmental conditions. PMID- 24626851 TI - Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies. AB - BACKGROUND: Efficacy of available therapies for patients with HCV who have previously failed treatment is limited. Two Phase III, open-label trials in Japan investigated efficacy and safety of simeprevir and peginterferon-alpha 2a/ribavirin (PR) combination therapy in treatment-experienced patients with genotype 1 HCV infection. METHODS: In CONCERTO-2, prior non-responders to IFN based therapy (N = 106) received simeprevir (TMC435) 100 mg QD with PR for 12 (SMV12, n = 53) or 24 weeks (SMV24, n = 53) followed by response-guided therapy (RGT) with PR for 12/36 (SMV12) or 0/24 (SMV24) weeks. In CONCERTO-3, relapsers after IFN-based therapy (N = 49) received simeprevir 100 mg QD with PR for 12 weeks followed by RGT with PR for 12/36 weeks. Primary endpoints were the rates of sustained virologic response 12 weeks after treatment end (SVR12). RESULTS: SVR12 rates were 52.8% (SMV12) and 35.8% (SMV24) for prior non-responders, and 95.9% for prior relapsers (SMV12; p <= 0.0001 vs null hypothesis, respectively). Most prior non-responders (SMV12: 81.1%; SMV24: 73.6%) and prior relapsers (95.9%) met RGT criteria and completed PR to Week 24. Of these, 60.5%, 48.7%, and 95.7%, respectively, achieved SVR12. Viral breakthrough occurred in 13.2 % (SMV12) and 11.3% (SMV24) of prior non-responders; no viral breakthrough occurred in prior relapsers. Viral relapse occurred in 38.6% (SMV12) and 51.1% (SMV24) of prior non-responders and 8.2% of prior relapsers. Simeprevir with PR was generally well tolerated in both studies. CONCLUSION: Re-treatment with 12 weeks of simeprevir QD with PR provided high SVR in treatment-experienced patients with chronic HCV genotype 1 infection, and allowed most patients to complete treatment in 24 weeks. PMID- 24626854 TI - Lacking alignments? The next-generation sequencing mapper segemehl revisited. AB - MOTIVATION: Next-generation sequencing has become an important tool in molecular biology. Various protocols to investigate genomic, transcriptomic and epigenomic features across virtually all species and tissues have been devised. For most of these experiments, one of the first crucial steps of bioinformatic analysis is the mapping of reads to reference genomes. RESULTS: Here, we present thorough benchmarks of our read aligner segemehl in comparison with other state-of-the-art methods. Furthermore, we introduce the tool lack to rescue unmapped RNA-seq reads which works in conjunction with segemehl and many other frequently used split read aligners. AVAILABILITY: lack is distributed together with segemehl and freely available at www.bioinf.uni-leipzig.de/Software/segemehl/. PMID- 24626855 TI - Spatial expression of claudin family members in various organs of mice. AB - Claudins (CLDNs) are tetraspan transmembrane proteins, which are components of tight junctions. The CLDN family is composed of 27 members that are responsible for paracellular transport and certain CLDNs form charge-selective ion channels. CLDNs have two extracellular loops, and the charge of the first extracellular loop determines the ion selectivity of each CLDN. Although the expression and function of each CLDN have been previously investigated, the distribution of CLDNs in various target organs remains to be determined. In the present study, the tissue-specific mRNA distribution of CLDNs (1-5, 7-8, 10a and b, 11-12, 14-17 and 19) in the duodenum, ileum, colon, kidney, liver and lung were defined. Among the tested CLDNs, CLDN1, 2, 12 and 16 were selected for further investiagtion. It was observed that CLDN1, CLDN2 and CLDN12 transcripts and proteins were particularly abundant in the investigated organs. Notably, immune-reactive CLDN16 was detected in a tissue-specific manner and shown in the renal tubules and portal vein. The tested CLDNs were localized to intercellular apical junctions in the epithelium of the intestine, renal tubule and bronchus. Based on this novel information, the presence of several types of CLDNs is of interest as CLDNs may promote or dampen the paracellular diffusion of specific ions. PMID- 24626856 TI - [A simple method for reduction of chylothorax after minimally invasive esophagectomy]. PMID- 24626857 TI - Expression of the monocyte chemotactic protein-1-induced protein 1 decreases human neuroblastoma cell survival. AB - The importance of monocyte chemotactic protein-1-induced protein 1 (MCPIP1) in the negative regulation of inflammatory reactions has already been extensively studied. However, its role in cancer is not yet established. We studied MCPIP1 gene expression in primary human neuroblastomas and several neuroblastoma cell lines. Our results showed a lack of MCPIP1 expression in primary neuroblastoma tumors. Moreover, it was found that the low expression of the protein measured in human neuroblastoma cell lines might be important for neuroblastoma survival, since enforced MCPIP1 gene expression in human neuroblastoma BE(2)-C cells caused a significant decrease in neuroblastoma cell viability and proliferation. PMID- 24626858 TI - Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. AB - BACKGROUND: Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). METHODS: We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization. RESULTS: The frequency of overexpression was 11.8% for HER2, 23.5% for EGFR, 24.9 % for MET and 31.1% for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7% of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9% of the GACs, respectively. CONCLUSIONS: Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy. PMID- 24626859 TI - Circulating miR-18a in plasma contributes to cancer detection and monitoring in patients with gastric cancer. AB - BACKGROUND: Recently, circulating microRNAs have been reported to be stably detectable in plasma/serum and to function as potent non-invasive biomarkers in various cancers. We hypothesized that miR-18a could contribute to a novel plasma biomarker in patients with gastric cancer (GC). METHODS: We focused on miR-18a, which is a component of miR-17-92 cluster and has been reported as highly expressed in GC tissues. The study involved three steps: (1) confirmation of the higher miR-18a expression in primary GC tissues and GC cell lines than in normal gastric tissues and a fibroblast cell line; (2) evaluation of the plasma miR-18a assay using quantitative RT-PCR by comparing 104 GC patients and 65 healthy volunteers; (3) evaluation of monitoring tumor dynamics by the plasma miR-18a assay. RESULTS: (1) The miR-18a expressions were significantly higher in GC tissues than in normal gastric tissues (P = 0.0286) and higher in all examined GC cell lines than in the fibroblast cell line. (2) The plasma miR-18a concentrations were significantly higher in GC patients than in healthy controls (P < 0.0001). The value of the area under the receiver-operating characteristic curve was 0.8059. (3) The plasma miR-18a levels were significantly reduced in postoperative samples compared to in preoperative samples (P = 0.0002). In an miR 18a overexpressing cell line, the miR-18a concentration of cultured medium increased in both cell number and time-course dependent manners, suggesting microRNA might be released from cancer cells into the surrounding environment. CONCLUSIONS: Circulating miR-18a could be a useful biomarker for screening GC and monitoring tumor dynamics. PMID- 24626861 TI - Retraction note: Overestimated accuracy of circular dichroism in determining protein secondary structure. Eur Biophys J (2013) 42:455-61. PMID- 24626860 TI - Quantitative phosphoproteomic profiling of PINK1-deficient cells identifies phosphorylation changes in nuclear proteins. AB - The Parkinson's disease (PD) associated gene PINK1 encodes a protein kinase that mediates the phosphorylation of multiple proteins involved in mitochondrial homeostasis. The broader downstream signaling events mediated by PINK1 kinase activity have not been well documented. We combine quantitative phosphoproteomic strategies with siRNA mediated PINK1 knock down in mammalian cells to identify alterations of phosphorylation events downstream of PINK1. Although down regulation of PINK1 has no major effect on the proteome expression in these cells, phosphorylation of over one hundred proteins was reduced reflecting basal levels of phosphorylation signaling events downstream of PINK1. Motif analysis of the residues flanking the phosphorylation sites indicates proline-directed kinase specificity. Surprisingly, we found that the downstream signaling nodes included many transcription factors, as well as nuclear proteins involved in DNA and RNA metabolism. Thus, PINK1 dependent phosphorylation signaling may regulate nuclear activities. PMID- 24626865 TI - Can we conquer coqueluche? PMID- 24626866 TI - Mouse and pig models for studies of natural and vaccine-induced immunity to Bordetella pertussis. AB - The increasing incidence of whooping cough in many developed countries has been linked with waning immunity induced after immunization with acellular pertussis (aP) vaccines. The rational design of an improved aP vaccine requires a full understanding of the mechanism of protective immunity and preclinical studies in animal models. Infection of mice and pigs with Bordetella pertussis has many features of the infection seen in humans and has already provided valuable information on the roles of innate and adaptive immune responses in protection. Recent findings in these models have already indicated that it may be possible to develop an improved aP vaccine based on a formulation that includes a Toll-like receptor agonist as an adjuvant. PMID- 24626867 TI - Nonhuman primate and human challenge models of pertussis. AB - Despite pertussis vaccination rates in excess of 95%, pertussis rates in the United States have been rising over the last 30 years, with increasingly larger outbreaks in 2004, 2010, and 2012. The reasons for this resurgence of pertussis are not clearly understood. The recent development of a baboon model of pertussis, along with the future development of a human challenge model of pertussis, has the potential to provide a path forward for answering critical questions about pertussis pathogenesis and host responses and will likely aid in the development of next-generation pertussis vaccines. PMID- 24626868 TI - Possible options for new pertussis vaccines. AB - Increasing evidence that the currently available acellular pertussis vaccines are not providing optimal control of pertussis in the United States and many other countries has stimulated interest in improvements of the current vaccines and in the development of new vaccines. A better understanding of the limitations of the current vaccines and the basis for the pertussis resurgence is needed to design improved vaccines. This article outlines several alternate approaches and summarizes the challenges related to the development of new or modified vaccines. PMID- 24626869 TI - Clinical evaluation of pertussis vaccines: US Food and Drug Administration regulatory considerations. AB - The resurgence of pertussis in the United States has stimulated considerable public health interest in developing new vaccination strategies to improve control of pertussis. The purpose of this article is to review the US Food and Drug Administration's regulatory framework for the prelicensure clinical evaluation of preventive vaccines and the clinical approaches that have been used to demonstrate effectiveness of US-licensed vaccines containing an acellular pertussis component. PMID- 24626870 TI - Pertussis resurgence: perspectives from the Working Group Meeting on pertussis on the causes, possible paths forward, and gaps in our knowledge. PMID- 24626871 TI - Pertussis vaccine trials in the 1990s. AB - The significant burden of disease due to pertussis, which predominantly affects newborns during their first few months of life, was substantially decreased following the introduction of inactivated whole-bacterial-cell vaccines in the middle of the 20th century. Although these vaccines were effective in reducing the incidence of pertussis in the countries that implemented their widespread use, increasing concerns about pertussis vaccine-associated adverse events led the development of acellular pertussis vaccines containing 1 or more purified Bordetella pertussis proteins. During the 1990s, collaborative international clinical trials were conducted to evaluate the safety, immunogenicity, and/or efficacy of different acellular vaccines. PMID- 24626872 TI - A preliminary quality of life questionnaire-bronchiectasis: a patient-reported outcome measure for bronchiectasis. AB - BACKGROUND: The Quality of Life Questionnaire-Bronchiectasis (QOL-B) is the first disease-specific, patient-reported outcome measure for patients with bronchiectasis. Content validity, cognitive testing, responsivity to open-label treatment, and psychometric analyses are presented. METHODS: Reviews of literature, existing measures, and physician input were used to generate the initial QOL-B. Modifications following preliminary cognitive testing (N = 35 patients with bronchiectasis) generated version (V) 1.0. An open-ended patient interview study (N = 28) provided additional information and was content analyzed to derive saturation matrices, which summarized all disease-related topics mentioned by each participant. This resulted in QOL-B V2.0. Psychometric analyses were carried out using results from an open-label phase 2 trial, in which 89 patients were enrolled and treated with aztreonam for inhalation solution. Responsivity to open-label treatment was observed. Additional analyses generated QOL-B V3.0, with 37 items on eight scales: respiratory symptoms; physical, role, emotional, and social functioning; vitality; health perceptions; and treatment burden. For each scale, scores are standardized on a 0-to-100-point scale; higher scores indicate better health-related quality of life. No total score is calculated. A final cognitive testing study (N = 40) resulted in a minor change to one social functioning scale item (QOL-B V3.1). RESULTS: Content validity, cognitive testing, responsivity to open-label treatment, and initial psychometric analyses supported QOL-B items and structure. CONCLUSIONS: This interim QOL-B is a promising tool for evaluating the efficacy of new therapies for patients with bronchiectasis and for measuring symptoms, functioning, and quality of life in these patients on a routine basis. A final psychometric validation study is needed and is forthcoming. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00805025; URL: www.clinicaltrials.gov. PMID- 24626873 TI - The relationship of coping style with depression, burden, and life dissatisfaction in caregivers of patients with subarachnoid haemorrhage. AB - OBJECTIVE: To assess the relationship of coping style with depression, burden and life satisfaction in caregivers of patients with subarachnoid haemorrhage. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-one primary caregivers of patients with subarachnoid haemorrhage. METHODS: Caregivers completed several questionnaires within the first year after subarachnoid haemorrhage. Coping style was assessed using the Utrecht Coping List, depression with the Goldberg Depression Scale (GDS), burden with the Sense of Competence Questionnaire, and life satisfaction with the Life Satisfaction Questionnaire. RESULTS: Caregivers had a mean burden score of 37.8 (standard deviation (SD) = 7.4) and a life satisfaction score of 5.0 (SD = 0.6). Nine caregivers (23%) had depressive symptoms (GDS >= 2). A palliative coping style was positively associated with the presence of depressive symptoms (odds ratio (OR) = 1.45, p = 0.016). A passive coping style was positively related to burden (beta = 1.61, p = 0.024), adjusted for morbidity of the caregiver (beta = 11.90, p = 0.013), and inversely related to life satisfaction (beta = -0.10, p = 0.025). CONCLUSION: In caregivers of patients with subarachnoid haemorrhage palliative or passive coping styles are related to depressive symptoms, higher burden and life dissatisfaction. This implies that rehabilitation programmes for patients with subarachnoid haemorrhage should also include caregiver support programmes that focus on coping style. PMID- 24626874 TI - Guanidines: from classical approaches to efficient catalytic syntheses. AB - From organosuperbases capable of base-catalyzing organic reactions, through versatile 'ligand-sets' for use in coordination chemistry, to fundamental entities in medicinal chemistry, guanidines are amongst the most interesting, attractive, valuable, and versatile organic molecules. Since the discovery of these compounds, synthetic chemists have developed new methodologies that are mainly based on multi-step and stoichiometric reactions. Despite the fact that these methodologies are still being used by the interested scientific and industrial communities, drawbacks such as the poor availability of precursors, low yields, and use and production of undesirable substances highlight the need for safe, simple and efficient syntheses of these entities. This review focuses on the metal-mediated catalytic addition of amines to carbodiimides as an atom economical alternative to the classical synthesis. PMID- 24626876 TI - The sonochemical approach improves the CuO-ZnO/TiO(2) catalyst for WGS reaction. AB - The CuO-ZnO composite was deposited onto two kinds of titania supports, which are synthetic mesoporous TiO2 and commercial TiO2 P25 (Degussa), via the ultrasound assisted precipitation and incipient wetness impregnation (IWI) methods, respectively. The catalysts were tested for WGS reaction in the temperature range of 200-400 degrees C, and the best catalytic performance was achieved for the sonochemically prepared catalysts supported on the commercial TiO2 P25, which contains well crystallized anatase and rutile phases. Although the synthetic mesoporous TiO2 has a higher surface area, its textural structure is not stable under the reaction conditions, leading to gradual deactivation of the CuO ZnO/TiO2 catalyst. It is found that the sonochemical preparation offers at least two advantages: (1) generation of mesopores on the catalyst surface and (2) doping of ZnO into the CuO phase. The doping of ZnO, particularly in the case of commercial TiO2 P25, provides high activity and extra stability to the active phase of Cu(0). These new findings provide new insights into the design and development of better heterogeneous catalysts for WGS reaction. PMID- 24626875 TI - Recombinant growth factor mixtures induce cell cycle progression and the upregulation of type I collagen in human skin fibroblasts, resulting in the acceleration of wound healing processes. AB - Application of growth factor mixtures has been used for wound healing and anti wrinkles agents. The aim of this study was to evaluate the effect of recombinant growth factor mixtures (RGFM) on the expression of cell cycle regulatory proteins, type I collagen, and wound healing processes of acute animal wound models. The results showed that RGFM induced increased rates of cell proliferation and cell migration of human skin fibroblasts (HSF). In addition, expression of cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)4, and Cdk2 proteins was markedly increased with a growth factor mixtures treatment in fibroblasts. Expression of type I collagen was also increased in growth factor mixtures-treated HSF. Moreover, growth factor mixtures-induced the upregulation of type I collagen was associated with the activation of Smad2/3. In the animal model, RGFM-treated mice showed accelerated wound closure, with the closure rate increasing as early as on day 7, as well as re-epithelization and reduced inflammatory cell infiltration than phosphate-buffered saline (PBS)-treated mice. In conclusion, the results indicated that RGFM has the potential to accelerate wound healing through the upregulation of type I collagen, which is partly mediated by activation of Smad2/3-dependent signaling pathway as well as cell cycle progression in HSF. The topical application of growth factor mixtures to acute and chronic skin wound may accelerate the epithelization process through these molecular mechanisms. PMID- 24626877 TI - The ins and outs of pyloromyotomy: what we have learned in 35 years. AB - PURPOSE/BACKGROUND: The aim of the study is to evaluate a large series of infantile hypertrophic pyloric stenosis (IHPS) patients treated by one pediatric surgeon focusing on their diagnostic difficulties and complications. METHODS: From July 1969 to December 2003 (inclusive), the charts of 791 infants with IHPS were retrospectively reviewed. RESULTS: There were 647 (82%) males and 144 (18%) females; mean age was 38 days, median 51 (range 7 days-10 months). When ultrasonography (US) was routinely used (1990), the age at diagnosis decreased to <40 days. The mean weight before and after routine US was 3.2 kg, median 3 (range 1.5-6). Twenty-five (3.1%) were premature at diagnosis, mean age 49 days, median 56, (range 1-3 months) and mean weight 2.5 kg, median 2.3 (range 1.5-3.2). Eighty one (10%) had a positive family history. Forty-four (5%) were non-Caucasians. Seventy-five (9 %) had other medical conditions, anomalies and/or associated findings. Sixty (7%) patients had abnormal preoperative electrolytes. Ten (1.2%) pylorics occurred after newborn operations. Of the entire total (791) who were treated, there were 13 (1.7%) not operated on. All operations were done open initially through one of two right upper quadrant incisions, and then through an upper midline incision under general endotracheal anesthesia; 14 (1.7 %) had concomitant procedures. Prophylactic antibiotics (from 1982) decreased the wound infection rate to 3.9%. There were a total of 87 (10%) complications which included 9 (1.1%) intraoperative, (including mistaken diagnoses) 78 (9%) postoperative: 59 (2%) early (<1 month) and 19 (2.4%) late (>1 month). The 13 (1.6%) postoperative transfers (12 from non-pediatric surgeons) had 16 (18%) complications (including 1 death); five (33%) requiring reoperation (4 incomplete, 1 perforation). There were two deaths. CONCLUSIONS: IHPS should be considered in any vomiting infant. US allows earlier diagnosis. Serious complications are uncommon and avoidable, but recognizable and easily corrected. Higher surgeon volume of pyloromyotomies (>14 per year) is associated with fewer complications. PMID- 24626879 TI - Autologous buccal mucosa graft for repair of recurrent rectovaginal fistula. AB - Post-operative pediatric rectovaginal fistulas are rare, can be challenging to repair, and often recur. The versatility, ease of accessibility, vascularization, and likeness to native vaginal tissues make autologous buccal mucosal grafts a novel tissue substitute for the repair of a recurrent rectovaginal fistula after the surgical repair of anorectal malformations. PMID- 24626878 TI - Safety and efficacy of selective sac extraction method of inguinal hernia repair in children: results of a prospective study. AB - PURPOSE: A prospective study was conducted to confirm the safety and efficacy of the selective sac extraction method (SSEM) of inguinal hernia repairs in children. METHODS: Primary endpoints of the study were the incidence of any complication related to the SSEM, or hernia recurrence. Secondary endpoints included the success rate of the SSEM, length of incision at the end of operation, and duration of operation. The incidence of contralateral manifestation of hernia was also examined. RESULTS: Between October 2009 and December 2011, a total of 317 repairs, 145 male repairs and 172 female repairs, were performed by applying the SSEM. There were three operative conversions, and the success rate of the SSEM was 99% in both male and female patients. The length of incision ranged from 4.0 to 12.5 mm (median 6.0 mm) and was <=7.0 mm in 93% repairs. The incisional length for male repairs ranged from 4.0 to 12.5 mm (median 6.0 mm) and was <=7.0 mm in 86% repairs, while it ranged from 4.0 to 9.0 mm (median 5.5 mm) in female repairs and was <=6.5 mm in 96% repairs. The duration of the operation for unilateral repair ranged from 9 to 66 min (median 21 min). Eighty percent of repairs were examined 6-44 months (median 12 months) after the operation. There was one (0.4%) recurrence among 250 repairs and two (1.7%) cases of testicular dislocation among 115 male repairs. Contralateral hernia presented in 19 (9.5%) of 199 patients with unilateral hernia who underwent the follow-up. CONCLUSIONS: The feasibility of the SSEM was reconfirmed, and it was revealed that the complication and recurrence rates were low and acceptable. The SSEM is safe and effective, and should be a standard method for repairing inguinal hernia in children. PMID- 24626880 TI - Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGFR but not with the KRAS/BRAF mutational status in colorectal cancer. AB - Cetuximab, an IgG1 monoclonal antibody against the epidermal growth factor receptor (EGFR), is widely used for the treatment of metastatic colorectal cancer (mCRC). One of the mechanisms of action is considered to be antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by Fcgamma-R on natural killer cells. However, whether ADCC is associated with EGFR expression and/or the mutational status of EGF downstream effectors (KRAS and BRAF) in colorectal cancer (CRC) remains unclear. The aim of the present study was to verify whether ADCC activities are associated with the cell surface expression levels of EGFR and/or the mutational status of KRAS and BRAF. Five human CRC cell lines with different cell surface expression levels of EGFR and different KRAS and BRAF mutational statuses were selected to evaluate ADCC activity using peripheral blood mononuclear cells (PBMCs) from healthy human donors. Furthermore, tumor cells from resected specimens of CRC patients were used to evaluate the cell surface expression level of EGFR using immunohistochemistry and the KRAS and BRAF mutational statuses using direct sequencing, while the ADCC activity was examined using PBMCs from the same CRC patients. A strong correlation was observed between the expression levels of EGFR and the ADCC activities in the cell lines (correlation coefficient: 0.949; P=0.003). Of the 13 resected specimens, a high ADCC activity level was significantly observed in tumor cells with high expression levels of cell surface EGFR, when compared with that in the tumor cells with low expression levels (P=0.027). In both CRC cell lines and tumor cells from CRC patients, the ADCC activities were significantly associated with the cell surface expression levels of EGFR [standard partial regression coefficients: 0.911 (P=0.017) and 0.660 (P=0.018), respectively], but not with the mutational status of KRAS and BRAF [standard partial regression coefficient: 0.101 (P=0.631) and 0.160 (P=0.510), respectively]. Cetuximab-mediated ADCC activity may be correlated with the cell surface expression level of EGFR, regardless of the mutational statuses of KRAS and BRAF, in CRC. PMID- 24626881 TI - IL-33 attenuates cardiac remodeling following myocardial infarction via inhibition of the p38 MAPK and NF-kappaB pathways. AB - The inflammatory response has adverse effects on left ventricular (LV) function and remodeling post-myocardial infarction (MI). Interleukin (IL)-33 is considered to have anti-inflammatory properties. The present study examined whether the suppression of inflammation with IL-33 was able to attenuate LV dysfunction and remodeling post-MI. The MI model was induced and the mice were treated with either saline or recombinant IL-33. Inflammatory mediators, LV functional changes and structural remodeling were evaluated. IL-33 significantly suppressed macrophage infiltration and the production of inflammatory cytokines in the myocardium. IL-33 treatment significantly improved LV function, reduced infarct size and infarct wall thinning. MI-induced activation of the p38 mitogen activated protein kinase (p38 MAPK) and nuclear factor-kappaB (NF-kappaB) pathways was also suppressed. Our data demonstrated that IL-33 suppresses inflammatory responses and improved LV function and remodeling by inhibiting the p38 MAPK and NF-kappaB pathways. IL-33 may be a potential therapeutic target for heart dysfunction post-MI. PMID- 24626884 TI - "Epidemics" of tinnitus in the 21st century: preparing our children and grandchildren. PMID- 24626885 TI - Influence of obesity on the correlation between laryngopharyngeal reflux and obstructive sleep apnea. AB - INTRODUCTION: The obstructive sleep apnea (OSA) is caused by recurrent episodes of partial or total obstruction of the upper airway lasting more than 10 seconds during sleep. Laryngopharyngeal reflux (LPR) is a variant of the disease Gastroesophageal Reflux that affects the larynx and pharynx. OBJECTIVES: Evaluate the influence of obesity on the relationship between RFL and OSAS in patients with OSA. MATERIALS AND METHODS: An observational retrospective cross. We reviewed care protocol for patients with OSA that includes validated questionnaires for RFL as Sympton Reflux Index (RSI) and Reflux Finding Score (RSI), and polysomnography nasolaringofibroscopia. RESULTS: 105 patients were divided into obese group (39 patients) and non-obese patients (66 patients). In the evaluation of the mean RSI group of non-obese was similar between patients with mild OSA (11.96) and moderate (11.43). In the obese group the mean RSI was 6.7 in patients with mild OSA and 11.53 in patients with moderate to severe OSA (p < 0.05). DISCUSSION: The subgroup of patients with OSA and RFL have several factors that promote inflammation of the upper airway. Patients with OSA should be screened and treated as the RFL increasing the quality of life. CONCLUSION: The RFL are positively correlated and OSAS in obese patients. PMID- 24626886 TI - Olfaction disorders: retrospective study. AB - INTRODUCTION: The smell, subjective phenomenon of great importance, is poorly understood and studied in humans. Physicians with more knowledge about smell disorders tend to consider the phenomenon important and to better manage the diagnosis and its treatment. AIMS: First to describe a sample of patients presenting with main complaint of disturbances of smell. And second, to show our experience on management and treatment of this disease. DESIGN: Retrospective cross-sectional cohort study. MATERIALS AND METHODS: Sample description and assessment of treatment response in patients with main complaint of hyposmia or anosmia from January 2005 to October 2011. RESULTS: From 38 patients presented with main complaint of an olfactory disorder, 68.4% of the patients were presented with hyposmia and 31,5% with anosmia, with a mean duration of 30.8 months. The main etiologic diagnoses were idiopathic (31.5%), rhinitis (28.9%) and CRS with polyps (10.5%). Responses to treatment with topical steroids and alpha-lipoic acid were variable, as well as in the literature. CONCLUSION: Greater importance should be given to disorders of smell in practice of otolaryngologists, since its large differential diagnosis and the fact that could increase morbidity to patients, impacting on their quality of life. PMID- 24626887 TI - Influence of estradiol administration on estrogen receptors of nasal mucosa: an experimental study on guinea pigs. AB - INTRODUCTION: Some clinical trials revealed a correlation between increased serum estrogen and nasal symptoms or inflammatory changes in nasal mucosa. Estrogen receptors tend to be controlled by a negative feedback, to avoid a deleterious stimulus over several body functions while in hyperestrogenic periods. This study proposes a hypothesis where mechanisms regulating expression of estradiol receptors in nasal mucosa are absent in some patients, and their concentration remains steady even in periods of high serum hormonal concentration, potentially leading to local estrogenic symptoms in nasal mucosa. STUDY DESIGN: This was an experimental prospective study. AIM: To determine whether estrogen levels induce the reduction of the number of estrogen receptors in the nasal mucosa. METHODS: In the present study, 30 adult male guinea pigs were subjected to a biopsy of the middle nasal turbinate and received 0.5 mL of estradiol cypionate intraperitoneally for 30 consecutive days. Afterwards, samples from contralateral middle turbinate were obtained. Immunohistochemical analysis of estrogen receptors were performed pre- and post-treatment. RESULTS: The post-treatment group showed reduction of receptor expression when compared to the pre-treatment group. (p = 5.2726-5). CONCLUSION: A reduction in the expression of the nasal estrogen receptor was observed after 30 days of estradiol administration. PMID- 24626888 TI - Study of the relationship between the degree of tinnitus annoyance and the presence of hyperacusis. AB - INTRODUCTION: Hyperacusis can be defined as a manifestation of an increased of central auditory pathways gain and can be considered a pre-tinnitus state. In some cases tinnitus can be caused by such increased gain. AIM: To evaluate the prevalence of hyperacusis in patients with tinnitus and its relation to the annoyance of tinnitus. MATERIALS AND METHODS: Retrospective study with patients from the neurotology service complaining of tinnitus in the first consultation were submitted to clinical evaluation, a questionnaire and audiological evaluation of tinnitus and hyperacusis. The degree of annoyance of tinnitus and hyperacusis was measured using a visual analog scale. RESULTS: We analyzed medical records of 309 patients, 169 (54.7%) females and 140 (45.3%) males. The mean age was 53 years. The median degree of tinnitus annoyance was 7. Hyperacusis was present in 57 (18.4%) patients, with a median degree of 5. The degree of annoyance due to tinnitus patients with hyperacusis was similar to that of patients without hyperacusis. CONCLUSION: Hyperacusis was present in 18.4% of patients with tinnitus. The degree of annoyance due to tinnitus had no correlation with the presence of hyperacusis. PMID- 24626889 TI - Localization of ectopic and supernumerary parathyroid glands in patients with secondary and tertiary hyperparathyroidism: surgical description and correlation with preoperative ultrasonography and Tc99m-Sestamibi scintigraphy. AB - INTRODUCTION: Hyperparathyroidism is an expected metabolic consequence of chronic kidney disease (CKD). Ectopic and/or supernumerary parathyroid glands (PT) may be the cause of surgical failure in patients undergoing total parathyroidectomy (PTX). AIM: To define the locations of ectopic and supernumerary PT in patients with renal hyperparathyroidism and to correlate intraoperative findings with preoperative tests. MATERIALS AND METHODS: A retrospective study was conducted with 166 patients submitted to PTX. The location of PT during surgery was recorded and classified as eutopic or ectopic. The preoperative localizations of PT found by ultrasonography (USG) and Tc99m-Sestamibi scintigraphy (MIBI) were subsequently compared with intraoperative findings. RESULTS: In the 166 patients studied, 664 PT were found. Five-hundred-seventy-seven (86.4%) glands were classified as eutopic and 91(13.6%) as ectopic. Eight supernumerary PT were found. The most common sites of ectopic PT were in the retroesophageal and thymic regions. Taken together, USG and MIBI did not identify 56 (61.5%) ectopic glands. MIBI was positive for 69,7% of all ectopic glands located in the mediastinal and thymic regions. CONCLUSION: The presence of ectopic and supernumerary PT in patients with renal hyperparathyroidism is significant. Although preoperative imaging tests did not locate most of ectopic glands, MIBI may be important for identifying ectopic PT in the mediastinal and thymic regions. PMID- 24626890 TI - Comparative study between pure tone audiometry and auditory steady-state responses in normal hearing subjects. AB - INTRODUCTION: Auditory steady-state responses (ASSR) are an important tool to detect objectively frequency-specific hearing thresholds. Pure-tone audiometry is the gold-standard for hearing evaluation, although sometimes it may be inconclusive, especially in children and uncooperative adults. AIM: Compare pure tone thresholds (PT) with ASSR thresholds in normal hearing subjects. MATERIALS AND METHODS: In this prospective cross-sectional study we included 26 adults (n = 52 ears) of both genders, without any hearing complaints or otologic diseases and normal puretone thresholds. All subjects had clinical history, otomicroscopy, audiometry and immitance measurements. This evaluation was followed by the ASSR test. The mean pure-tone and ASSR thresholds for each frequency were calculated. RESULTS: The mean difference between PTand ASSR thresholdswas 7,12 for 500 Hz, 7,6 for 1000 Hz, 8,27 for 2000 Hz and 9,71 dB for 4000 Hz. There were no difference between PT and ASSR means at either frequency. CONCLUSION: ASSR thresholds were comparable to pure-tone thresholds in normal hearing adults. Nevertheless it should not be used as the only method of hearing evaluation. PMID- 24626891 TI - Sound pressure level generated by individual portable sound equipment. AB - INTRODUCTION: The use of Personal Digital Audio Players can cause hearing injuries, as the sound is generated directly in the ear canal. It is believed that different types of headphones can cause different amplifications, since they cause changes in the volume and resonance of the ear canal according to their depth. OBJECTIVE: This study aimed to determine the sound pressure to which young individuals are exposed when using Personal Digital Audio Players with two types of headphones: insertion earphones and anatomical insertion earphones. MATERIALS AND METHODS: This was an experimental study. The probe microphone measurements were made with different headphones in 54 ears (27 young individuals). The resonance peaks were also recorded. RESULTS: A statistically significant difference was observed between the evaluated headphones, showing that anatomical insertion earphones had higher levels of sound pressure than insertion earphones for all frequencies measured. There was no correlation between the resonance peak of the closed canal and the frequency where the highest sound pressure level was obtained. There was a significant difference between ears at some frequencies with the different headphones. CONCLUSION: It was concluded that anatomical insertion earphones generate a higher sound pressure level than insertion earphones. PMID- 24626892 TI - Vestibular evoked myogenic potential (VEMP) with galvanic stimulation in normal subjects. AB - INTRODUCTION: The vestibular evoked myogenic potential (VEMP) generated by galvanic vestibular stimulation (GVS) is related to the vestibulo-spinal pathway. The response recorded from soleus muscle is biphasic with onset of short latency (SL) component around 60 ms and medium latency (ML) component around 100 ms. The first component reflects otolith function (sacule and utricle) and the last deals with semicircular canals. AIM: To describe VEMP generated by GVS. METHODS: In this cross-sectional clinical study, VEMP was generated by 2 mA/400 ms binaural GVS, frequency of 5-6 ms that was recorded from soleus muscles of 13 healthy adults, mean age 56 years. The subjects remained standing, head turned contralateral to the GVS applied to the mastoid. Thirty GVS were applied to the mastoid in the position cathode right anode left, followed by 30 in inverted position. SL and ML were measured. RESULTS: SL and ML components were recorded from both legs of all participants and were similar. The average of SL component was 54 ms and of ML was 112 ms. CONCLUSION: The components SL and ML of the VEMP response in soleus were reproducible and are useful measures of vestibular-spinal function. PMID- 24626894 TI - Influence of smoking isolated and associated to multifactorial aspects in vocal acoustic parameters. AB - INTRODUCTION: Smoking affect voice quality in a long period of time, but other factors may compromise it, such as professional using of voice, habits, alcohol dependence and GERD. The aim was associate the influence of these factors on vocal parameters. STUDY DESIGN: Contemporary cohort study with cross-sectional. MATERIALS AND METHODS: Eighty adults of 35 to 60 years old had participated in this study, they had been divided into two groups, smokers (GF) and control (GC). There was application of questionnaire and voices were recorded. Praat software has been used for voice assessment and Man-Whitney, chi-square and logistic regression has been used for statistical analysis. RESULTS: The GF had a higher incidence of alcohol dependence, coughing, throat clearing and professional voice using. Respecting to the acoustic parameters: noise-to-harmonic ratio (NHR), jitter and shimmer, the GF presented higher values. Relating these data to the questionnaire, it's noticed that female gender have influence over all acoustic parameters, GERD have influence over jitter and smoking can affect fundamental frequency, jitter, shimmer and NHR. CONCLUSION: Smoking interferes in acoustics parameters isolated and associated with alcohol dependence, GERD, cough, throat clearing, gender and professional using of voice. PMID- 24626893 TI - Could the type of treatment for chronic kidney disease affect the auditory system? AB - INTRODUCTION: Chronic kidney disease (CKD) is defined as the presence of renal injury that leads to the slow and progressive loss of kidney function. AIM: To compare audiological tests between patients with CKD receiving different types of treatment. MATERIAL AND METHOD: This was a clinical and experimental study. Groups were divided according to treatment: hemodialysis (n = 35), peritoneal dialysis (n = 15), and conservative (n = 51), and were compared to 27 healthy controls. Patients older than 60 years; those with congenital hearing loss, genetic syndromes, and middle-ear infections; and those who had been submitted to a kidney transplant were excluded. Audiologic evaluation included pure-tone audiometry, transient evoked otoacoustic emissions, and auditory brainstem response (ABR). The variables considered were gender, age, diagnosis of arterial hypertension, time since the diagnosis of diabetes and hypertension, CKD stage, duration of CKD, and duration of treatment. RESULTS: The variables age, presence of arterial hypertension, and time of CKD were statistically significant and controlled. The auditory thresholds measured by pure-tone threshold audiometry were worse for the conservative treatment group, and the III-V interval of the ABR of the conservative treatment group was significantly greater than that of the hemodialysis groups. CONCLUSION: The conservative treatment group presented worse audiological tests, regardless of hypertension and diabetes, reinforcing that patients need to undergo a complete hearing assessment for better understanding of the disease and its effects on the auditory system. PMID- 24626895 TI - The importance of electrically evoked stapedial reflex in cochlear implant. AB - INTRODUCTION: The most important stage in fitting a cochlear implant is the identification of its dynamic range. The use of objective measures, in particular the electrically elicited stapedius reflex, may provide suitable assistence for initial fitting of cochlear implant, especially in children or adult with multiple disorders, because they provide specific values that serve as the basis of early cochlear implant programming. OBJECTIVE: Verify through a review the use of the electrically elicited stapedius reflex threshold during the activation and mapping process of cochlear implant. METHODS: Bibliographical search on the Pubmed and Bireme plataforms, and also on Medline, LILACS and SciELO databases, with standard searches until September 2012, using specific keywords. For the selection and evaluation of scientific studies found in the search, criterias have been established, considering the following aspects: author, year/location, grade of recommendation/level of evidence, purpose, sample, age, mean age in years, evaluative testing, results and conclusion. RESULTS: Among 7,304 articles found, 7,080 were excluded from the title, 152 from the abstract, 17 from the article reading, 43 were repeated and 12 were selected for the study. CONCLUSION: The electrically elicited stapedius reflex may support when programming the cochlear implant, especially in patients with inconsistent responses. PMID- 24626896 TI - Oral manifestations resulting from chemotherapy in children with acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphocytic leukemia is a type of cancer most common in children and it is characterized by excessive and disordered immature leukocytes in the bone marrow. AIM: Identify most frequent oral manifestations in children with acute lymphocytic leukemia under chemotherapy treatment. METHODOLOGY: The research was conducted on the electronic database PubMed/Medline, Science Direct, Scielo and Scopus. It has been sought papers with full presentation, wrote in Portuguese, English and Spanish, published between January 1992 and April 2013. RESULTS: From studies primarily selected, only eight met the criteria of inclusion. All studies performed intraoral examinations to diagnose oral lesions. According to results, the most frequent lesions were mucositis, candidiasis, periodontitis and gingivitis. The oral health condition from acute lymphocytic leukemia carriers varied according oral hygiene of the patient. CONCLUSION: The results of studies identified such a great part of patients with ALL presented some lesion in oral cavity during or after chemotherapy treatment. The dentist surgeon needs to recognize oral manifestations and intervene in the oral health of patients with ALL, contributing and helping with treatment. PMID- 24626897 TI - Primary chromohifomycosis of the nasal septum. PMID- 24626898 TI - Simultaneous occurrence of dentigerous cyst and residual cyst in the maxilla. PMID- 24626899 TI - Multiple symmetrical lipomatosis (Madelung's disease). PMID- 24626900 TI - Tuberculous otomastoiditis in patient with lupus. PMID- 24626901 TI - Time for new schizophrenia Rx. PMID- 24626906 TI - Eastern Europe. Ukraine's science reformers seize the moment. PMID- 24626907 TI - U.S. science funding. The future is flat in White House's 2015 spending request. PMID- 24626908 TI - HIV/AIDS. Cancer genes help HIV persist, complicating cure efforts. PMID- 24626909 TI - Paleoclimate. How Earth can cool without plunging into a deep freeze. PMID- 24626910 TI - Talking back to madness. PMID- 24626911 TI - Water's tough skin. PMID- 24626912 TI - Conserving carnivores: more than numbers. PMID- 24626913 TI - Conserving carnivores: politics in play. PMID- 24626914 TI - Obscuring gender bias with "choice". PMID- 24626915 TI - Obscuring gender bias with "choice"--response. PMID- 24626916 TI - Big data. The parable of Google Flu: traps in big data analysis. PMID- 24626917 TI - Climate change. Simplicity amid complexity. PMID- 24626918 TI - Molecular biology. Internal mRNA methylation finally finds functions. PMID- 24626919 TI - Genetics. Stirring the simmering "designer baby" pot. PMID- 24626920 TI - Materials science. Where do batteries end and supercapacitors begin? PMID- 24626921 TI - Virology. Getting rid of a persistent troublemaker to cure hepatitis. PMID- 24626922 TI - Ecology. Society, where none intrudes. PMID- 24626923 TI - Ligand-controlled C(sp3)-H arylation and olefination in synthesis of unnatural chiral alpha-amino acids. AB - The use of ligands to tune the reactivity and selectivity of transition metal catalysts for C(sp(3))-H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst controlled C(sp(3))-H arylation using pyridine and quinoline derivatives: The former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of beta-Ar-beta-Ar'-alpha amino acids with excellent levels of diastereoselectivity (diastereomeric ratio > 20:1). Both configurations of the beta-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp(3))-H olefination of a protected alanine. PMID- 24626924 TI - Free-standing single-atom-thick iron membranes suspended in graphene pores. AB - The excess of surface dangling bonds makes the formation of free-standing two dimensional (2D) metals unstable and hence difficult to achieve. To date, only a few reports have demonstrated 2D metal formation over substrates. Here, we show a free-standing crystalline single-atom-thick layer of iron (Fe) using in situ low voltage aberration-corrected transmission electron microscopy and supporting image simulations. First-principles calculations confirm enhanced magnetic properties for single-atom-thick 2D Fe membranes. This work could pave the way for new 2D structures to be formed in graphene membranes. PMID- 24626925 TI - Main-group compounds selectively oxidize mixtures of methane, ethane, and propane to alcohol esters. AB - Much of the recent research on homogeneous alkane oxidation has focused on the use of transition metal catalysts. Here, we report that the electrophilic main group cations thallium(III) and lead(IV) stoichiometrically oxidize methane, ethane, and propane, separately or as a one-pot mixture, to corresponding alcohol esters in trifluoroacetic acid solvent. Esters of methanol, ethanol, ethylene glycol, isopropanol, and propylene glycol are obtained with greater than 95% selectivity in concentrations up to 1.48 molar within 3 hours at 180 degrees C. Experiment and theory support a mechanism involving electrophilic carbon-hydrogen bond activation to generate metal alkyl intermediates. We posit that the comparatively high reactivity of these d(10) main-group cations relative to transition metals stems from facile alkane coordination at vacant sites, enabled by the overall lability of the ligand sphere and the absence of ligand field stabilization energies in systems with filled d-orbitals. PMID- 24626927 TI - Selective methylation of histone H3 variant H3.1 regulates heterochromatin replication. AB - Histone variants have been proposed to act as determinants for posttranslational modifications with widespread regulatory functions. We identify a histone modifying enzyme that selectively methylates the replication-dependent histone H3 variant H3.1. The crystal structure of the SET domain of the histone H3 lysine-27 (H3K27) methyltransferase ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) in complex with a H3.1 peptide shows that ATXR5 contains a bipartite catalytic domain that specifically "reads" alanine-31 of H3.1. Variation at position 31 between H3.1 and replication-independent H3.3 is conserved in plants and animals, and threonine-31 in H3.3 is responsible for inhibiting the activity of ATXR5 and its paralog, ATXR6. Our results suggest a simple model for the mitotic inheritance of the heterochromatic mark H3K27me1 and the protection of H3.3 enriched genes against heterochromatization during DNA replication. PMID- 24626928 TI - Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition. AB - Vertebrate limbs first emerge as small buds at specific locations along the trunk. Although a fair amount is known about the molecular regulation of limb initiation and outgrowth, the cellular events underlying these processes have remained less clear. We show that the mesenchymal limb progenitors arise through localized epithelial-to-mesenchymal transition (EMT) of the coelomic epithelium specifically within the presumptive limb fields. This EMT is regulated at least in part by Tbx5 and Fgf10, two genes known to control limb initiation. This work shows that limb buds initiate earlier than previously thought, as a result of localized EMT rather than differential proliferation rates. PMID- 24626929 TI - The stum gene is essential for mechanical sensing in proprioceptive neurons. AB - Animal locomotion depends on proprioceptive feedback, which is generated by mechanosensory neurons. We performed a genetic screen for impaired walking in Drosophila and isolated a gene, stumble (stum). The Stum protein has orthologs in animals ranging from nematodes to mammals and is predicted to contain two transmembrane domains. Expression of the mouse orthologs of stum in mutant flies rescued their phenotype, which demonstrates functional conservation. Dendrites of stum-expressing neurons in legs were stretched by both flexion and extension of corresponding joints. Joint angles that induced dendritic stretching also elicited elevation of cellular Ca(2+) levels-not seen in stum mutants. Thus, we have identified an evolutionarily conserved gene, stum, which is required for transduction of mechanical stimuli in a specific subpopulation of Drosophila proprioceptive neurons that sense joint angles. PMID- 24626930 TI - Complement is activated by IgG hexamers assembled at the cell surface. AB - Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy. PMID- 24626931 TI - Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution. AB - Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass types ranging from "slow" to "fast," whose biophysical properties govern the timing, gradation, and amplitude of muscle force. Here we identify the noncanonical Notch ligand Delta-like homolog 1 (Dlk1) as a determinant of motor neuron functional diversification. Dlk1, expressed by ~30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in the mouse and chick. Dlk1 suppresses Notch signaling and activates expression of the K(+) channel subunit Kcng4 to modulate delayed-rectifier currents. Dlk1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Our findings provide insights into the development of motor neuron functional diversity and its contribution to the execution of movements. PMID- 24626926 TI - Lethal interactions between parasites and prey increase niche diversity in a tropical community. AB - Ecological specialization should minimize niche overlap, yet herbivorous neotropical flies (Blepharoneura) and their lethal parasitic wasps (parasitoids) exhibit both extreme specialization and apparent niche overlap in host plants. From just two plant species at one site in Peru, we collected 3636 flowers yielding 1478 fly pupae representing 14 Blepharoneura fly species, 18 parasitoid species (14 Bellopius species), and parasitoid-host associations, all discovered through analysis of molecular data. Multiple sympatric species specialize on the same sex flowers of the same fly host-plant species-which suggests extreme niche overlap; however, niche partitioning was exposed by interactions between wasps and flies. Most Bellopius species emerged as adults from only one fly species, yet evidence from pupae (preadult emergence samples) show that most Bellopius also attacked additional fly species but never emerged as adults from those flies. PMID- 24626932 TI - Transcriptional assessment by microarray analysis and large-scale meta-analysis of the metabolic capacity of cardiac and skeletal muscle tissues to cope with reduced nutrient availability in Gilthead Sea Bream (Sparus aurata L.). AB - The effects of nutrient availability on the transcriptome of cardiac and skeletal muscle tissues were assessed in juvenile gilthead sea bream fed with a standard diet at two feeding levels: (1) full ration size and (2) 70 % satiation followed by a finishing phase at the maintenance ration. Microarray analysis evidenced a characteristic transcriptomic profile for each muscle tissue following changes in oxidative capacity (heart > red skeletal muscle > white skeletal muscle). The transcriptome of heart and secondly that of red skeletal muscle were highly responsive to nutritional changes, whereas that of glycolytic white skeletal muscle showed less ability to respond. The highly expressed and nutritionally regulated genes of heart were mainly related to signal transduction and transcriptional regulation. In contrast, those of white muscle were enriched in gene ontology (GO) terms related to proteolysis and protein ubiquitination. Microarray meta-analysis using the bioinformatic tool Fish and Chips ( http://fishandchips.genouest.org/index.php ) showed the close association of a representative cluster of white skeletal muscle with some of cardiac and red skeletal muscle, and many GO terms related to mitochondrial function appeared to be common links between them. A second round of cluster comparisons revealed that mitochondria-related GOs also linked differentially expressed genes of heart with those of liver from cortisol-treated gilthead sea bream. These results show that mitochondria are among the first responders to environmental and nutritional stress stimuli in gilthead sea bream, and functional phenotyping of this cellular organelle is highly promising to obtain reliable markers of growth performance and well-being in this fish species. PMID- 24626933 TI - Dobutamine stress echocardiography for the assessment of pressure-flow relationships of the pulmonary circulation. AB - BACKGROUND: Stress testing of the pulmonary circulation (via increasing pulmonary blood flow) can reveal abnormal mean pulmonary artery pressure-cardiac output (mPpa-Q) responses, which may facilitate early diagnosis of pulmonary vascular disease. We investigated the application of dobutamine stress echocardiography (DSE) for the noninvasive assessment of mPpa-Q relationships. METHODS: DSE using an incremental dose protocol (<= 20 MUg/kg/min) was performed in 38 subjects (16 patients with pulmonary arterial hypertension [PAH] and 22 healthy control subjects). An additional 22 healthy control subjects underwent exercise stress echocardiography as a comparator group. Multipoint mPpa-Q plots were analyzed, and the pulmonary vascular distensibility coefficient alpha was calculated. RESULTS: DSE was feasible and informative in 93% of subjects. The average dobutamine-induced mPpa-Q slope was 1.1 +/- 0.7 mm Hg/L/min in healthy control subjects and 5.1 +/- 2.5 mm Hg/L/min in patients with PAH (P < .001). The dobutamine-induced alpha was markedly reduced in patients with PAH (0.003 +/- 0.001 mm Hg vs 0.02 +/- 0.01 mm Hg in control subjects, P < .001). When exercise and dobutamine stress were compared in healthy control subjects, the exercise induced mPpa-Q slope was modestly higher (1.6 +/- 0.7 mm Hg/L/min, P = .03 vs dobutamine). In patients with PAH, lower functional class status was associated with lower dobutamine-induced mPpa-Q slopes (P = .014), but not with resting total pulmonary vascular resistance. CONCLUSIONS: Noninvasive assessment of mPpa Q relationships is feasible with dobutamine stress. DSE may potentially be a useful noninvasive technique for stress testing of the pulmonary vasculature. PMID- 24626934 TI - Genetics of canine anal furunculosis in the German shepherd dog. AB - Canine anal furunculosis (AF) is characterised by ulceration and fistulation of perianal tissue and is a disease that particularly affects German shepherd dogs (GSDs). There are some similarities between AF and perianal Crohn's disease (CD) in man. An immune-mediated aetiopathogenesis for AF has been suggested due to tissue pathology, a major histocompatibility complex (MHC) association and clinical response to ciclosporin. Genome-wide association studies (GWAS) can be conducted in dogs with fewer markers and individuals than would be required in a human study. A discovery GWAS was performed on 21 affected and 25 control GSDs from the UK. No SNPs reached genome-wide significance levels at this stage. However, 127 nominally associated SNPs were genotyped in further 76 cases and 191 controls from the UK and Finland. Sequencing of these regions was undertaken to discover novel genetic variation. Association testing of these variants in the UK and Finnish cohorts revealed nine significantly associated SNPs, six of which cause non-synonymous changes in protein sequence. The ADAMTS16 and CTNND2 gene regions were most significantly associated with disease. Members of the butyrophilin protein family, important in intestinal inflammatory regulation, were also associated with disease, but their independence from the MHC region remains to be established. The CTNND2 gene region is also interesting as this locus was implicated in human ulcerative colitis and CD, albeit at a different candidate gene: DAP. We suggest that this represents a common association between inflammatory bowel disease-related conditions in both species and believe that future studies will strengthen this link. PMID- 24626936 TI - Off-pump coronary artery bypass prevents visceral organ damage. AB - OBJECTIVES: Visceral malperfusion after coronary artery bypass grafting (CABG) results in high morbidity and mortality. This study was designed to evaluate the effect of CABG performed by surgical techniques on visceral perfusion and function. METHODS: Pigs (n = 28) were studied in four groups: I. Sham; II. Off pump coronary artery bypass grafting (OPCAB): 1 h stabilizer with 40 min intracoronary shunt; III. Extracorporeal circulation (ECC): 1 h ECC with 40 min aortic cross-clamping and cardioplegic arrest; IV. Impella: 1 h left ventricular blood-pump support and stabilizer with 40 min intracoronary shunt. A left internal mammary to left anterior descending coronary artery bypass was performed in Groups II-IV. All animals were observed for a further 240 min. During the experiment haemodynamics, creatinine clearance, intestinal fatty acid binding protein (iFABP), pancreatic (lipase and amylase) and liver enzymes (alpha glutathione s-transferase, glutamate-oxaloacetate transaminase (GOT), gamma glutamyl transferase (GGT), glutamate dehydrogenase and glutamate-pyruvate transaminase (GPT)) were measured. Visceral perfusion (VP) was assessed in both kidneys, intestine, pancreas, liver and spleen with 15 um fluorescent microspheres. RESULTS: During OPCAB surgery, VP decreased slightly. Renal functional parameters, iFABP, pancreatic and liver enzymes remained unchanged. ECC and Impella led to significantly reduced renal, pancreatic and intestinal blood flow (P < 0.05). Creatinine clearance, pancreatic and liver (GPT, GGT) enzymes were significantly decreased only after ECC (P < 0.05). ECC and Impella resulted in a significantly increased iFABP level (P < 0.05). GOT was elevated significantly after surgery in Groups II, III and IV (P < 0.05). CONCLUSIONS: CABG with ECC or Impella leads to impaired visceral blood flow and function. OPCAB minimizes these procedure associated alterations. PMID- 24626935 TI - Characteristics of endogenous gamma-aminobutyric acid (GABA) in human platelets: functional studies of a novel collagen glycoprotein VI inhibitor. AB - gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, and it also appears in peripheral tissues. Platelets are anuclear blood cells that play a central role in hemostatic processes. Although platelets possess a GABA uptake system, the functional activity of GABA in platelets has remained unclear. We determined that GABA is abundantly distributed in the platelets at a concentration of approximately 1.03 ng/10(6) cells. GABA (0.5 MUM) specifically inhibited collagen-induced platelet activation accompanied by [Ca(2+)]i mobilization, phospholipase Cgamma2, protein kinase C, Akt phosphorylation, and hydroxyl radical formation. In addition, GABA interfered with fluorescein isothiocyanate-collagen binding to platelet membranes and produced a concentration-dependent shift in the collagen concentration-response curve and a Schild plot slope of -0.96 +/- 0.11, indicating competitive inhibition. Platelet activation induced by convulxin, a glycoprotein VI agonist, was inhibited by GABA, whereas activation induced by the integrin alpha(2)beta(1) agonist, aggretin, was not. Immunoprecipitation and surface plasmon resonance revealed that GABA binds directly to glycoprotein VI in human platelets with equilibrium dissociation (binding) constant (K(D)) of 41.4 nM. The closure time of whole blood and the occlusion time of platelet plug formation were significantly prolonged by GABA in vivo. In this study, GABA is a specific inhibitor of collagen glycoprotein VI and may be involved in an endogenous negative feedback mechanism for platelet activation. Thus, GABA may represent a potential target for the development of novel interventions for the treatment of cardiovascular diseases associated with platelet activation, such as stroke and myocardial infarction. KEY MESSAGES: GABA is abundantly distributed in the platelets. GABA inhibited platelet activation stimulated by convulxin. GABA directly associated with glycoprotein VI in platelet membrane. GABA prolonged the closure time of whole blood and the occlusion time of platelet plug formation in vivo. PMID- 24626937 TI - Human heat shock protein 27 exacerbates ischemia reperfusion injury in rats by reducing the number of T regulatory cells. AB - Ischemia reperfusion injury (IRI) occurs in almost every liver surgery and is associated with the reduction of the liver blood flow. Ischemia impairs liver function and can even cause liver failure following surgery. The present study aimed to identify a new molecular target allowing the reduction of IRI and explore the related cellular mechanism. Adenovirus (~2.5x10(12) viral particles) bearing the human heat shock protein 27 (HSP27) gene was injected into rat liver through the ileocecal vein. Five days following the injection, ischemia was induced by clamping the median and left portal veins, hepatic arteries and bile ducts. The levels of alanine transaminase (ALT), aspartate aminotransferase (AST), glutathione (GSH) and superoxide dismutase (SOD) were measured. The infiltration of inflammatory cells and the expression of pro-inflammatory factors were investigated. The number of regulatory T cells (Tregs) was measured by flow cytometry. At 2 h following reperfusion, the group injected with HSP27 had the highest level of ALT and AST, followed by the group injected with HSP27 and treated with gadolinium trichloride (GdCl3), the empty vector-injected and the vector+GdCl3 groups. The HSP27 group also had the lowest levels of the oxidative stress-protective factors SOD and GSH, and the highest levels of pro-inflammatory factors. The number of Tregs was reduced in the groups injected with HSP27. In conclusion, the human HSP27 protein can effectively accelerate liver damage at the early stages of IRI in rats. Tregs might play a critical role in HSP27 induced liver injury. PMID- 24626938 TI - Writing scientific articles like a native English speaker: top ten tips for Portuguese speakers. PMID- 24626939 TI - Sjogren's syndrome: An underdiagnosed condition in mixed connective tissue disease. AB - OBJECTIVE: To determine the prevalence of sicca symptoms, dry eye, and secondary Sjogren's syndrome and to evaluate the severity of dry eye in patients with mixed connective tissue disease. METHODS: In total, 44 consecutive patients with mixed connective tissue disease (Kasukawa's criteria) and 41 healthy controls underwent Schirmer's test, a tear film breakup time test, and ocular surface staining to investigate dry eye. In addition, the dry eye severity was graded. Ocular and oral symptoms were assessed using a structured questionnaire. Salivary gland scintigraphy was performed in all patients. Classification of secondary Sjogren's syndrome was assessed according to the American-European Consensus Group criteria. RESULTS: The patients and controls had comparable ages (44.7+/-12.4 vs. 47.2+/-12.2 years) and frequencies of female gender (93 vs. 95%) and Caucasian ethnicity (71.4 vs. 85%). Ocular symptoms (47.7 vs. 24.4%) and oral symptoms (52.3 vs. 9.7%) were significantly more frequent in patients than in controls. Fourteen (31.8%) patients fulfilled Sjogren's syndrome criteria, seven of whom (50%) did not have this diagnosis prior to study inclusion. A further comparison of patients with mixed connective tissue disease with or without Sjogren's syndrome revealed that the former presented significantly lower frequencies of polyarthritis and cutaneous involvement than did the patients without Sjogren's syndrome. Moderate to severe dry eye was found in 13 of 14 patients with mixed connective tissue disease and Sjogren's syndrome (92.8%). CONCLUSIONS: Sjogren's syndrome, particularly with moderate to severe dry eye, is frequent in patients with mixed connective tissue disease. These findings alert the physician regarding the importance of the appropriate diagnosis of this syndrome in such patients. PMID- 24626940 TI - Possible adverse drug events leading to hospital admission in a Brazilian teaching hospital. AB - OBJECTIVES: Drug safety problems can lead to hospital admission. In Brazil, the prevalence of hospitalization due to adverse drug events is unknown. This study aims to estimate the prevalence of hospitalization due to adverse drug events and to identify the drugs, the adverse drug events, and the risk factors associated with hospital admissions. METHOD: A cross-sectional study was performed in the internal medicine ward of a teaching hospital in Sao Paulo State, Brazil, from August to December 2008. All patients aged >=18 years with a length of stay >=24 hours were interviewed about the drugs used prior to hospital admission and their symptoms/complaints/causes of hospitalization. RESULTS: In total, 248 patients were considered eligible. The prevalence of hospitalization due to potential adverse drug events in the ward was 46.4%. Overprescribed drugs and those indicated for prophylactic treatments were frequently associated with possible adverse drug events. Frequently reported symptoms were breathlessness (15.2%), fatigue (12.3%), and chest pain (9.0%). Polypharmacy was a risk factor for the occurrence of possible adverse drug events. CONCLUSION: Possible adverse drug events led to hospitalization in a high-complexity hospital, mainly in polymedicated patients. The clinical outcomes of adverse drug events are nonspecific, which delays treatment, hinders causality analysis, and contributes to the underreporting of cases. PMID- 24626941 TI - Evaluation of conjunctival bacterial flora in patients with Stevens-Johnson Syndrome. AB - OBJECTIVE: To determine the conjunctival bacterial flora present in patients with Stevens-Johnson syndrome. METHODS: A prospective study of the conjunctival bacterial flora was performed in 41 eyes of 22 patients with Stevens-Johnson syndrome. The information gathered included the patient's sex and age, the duration of disease, the cause of Stevens-Johnson syndrome, and treatments. Scrapings of the inferior conjunctival fornix were performed in both eyes. Fourteen days before scraping, the patients were asked to interrupt all topical medication and start using 0.5% nonpreserved methylcellulose. The microbiological evaluation included microorganism identification and determination of antibiotic sensitivity. RESULTS: Of 22 patients (41 eyes), 14 (64%) were females, and eight (36%) were males. The mean age was 33.2 years, and the mean duration of disease was 15.6 years. Visual acuity ranged from light perception to 20/25 (1.57 logMar). The treatment received by most patients consisted of tear substitutes, topical antibiotics, and contact lenses. Bacterial identification was positive in 39 eyes (95%) and negative in two eyes (5%). Gram-positive cocci accounted for 55.5% of the microorganisms, whereas gram-positive bacilli and gram-negative bacilli accounted for 19% and 25.5%, respectively. Half of the patients (54%) had multiple bacterial species in their flora, and only one bacterial species was identified in the other half. Resistant bacteria were isolated from four eyes. The antibiotic sensitivity results for the Streptococcus group showed the lowest sensitivity and the highest microbial resistance identified. CONCLUSION: Patients with Stevens-Johnson syndrome have a diverse conjunctival flora that includes many pathogenic species. PMID- 24626942 TI - Severe hypoxemia during veno-venous extracorporeal membrane oxygenation: exploring the limits of extracorporeal respiratory support. AB - OBJECTIVE: Veno-venous extracorporeal oxygenation for respiratory support has emerged as a rescue alternative for patients with hypoxemia. However, in some patients with more severe lung injury, extracorporeal support fails to restore arterial oxygenation. Based on four clinical vignettes, the aims of this article were to describe the pathophysiology of this concerning problem and to discuss possibilities for hypoxemia resolution. METHODS: Considering the main reasons and rationale for hypoxemia during veno-venous extracorporeal membrane oxygenation, some possible bedside solutions must be considered: 1) optimization of extracorporeal membrane oxygenation blood flow; 2) identification of recirculation and cannula repositioning if necessary; 3) optimization of residual lung function and consideration of blood transfusion; 4) diagnosis of oxygenator dysfunction and consideration of its replacement; and finally 5) optimization of the ratio of extracorporeal membrane oxygenation blood flow to cardiac output, based on the reduction of cardiac output. CONCLUSION: Therefore, based on the pathophysiology of hypoxemia during veno-venous extracorporeal oxygenation support, we propose a stepwise approach to help guide specific interventions. PMID- 24626943 TI - Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in polycystic ovary syndrome. AB - OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment. PMID- 24626944 TI - Predictive factors for pelvic magnetic resonance in response to arterial embolization of a uterine leiomyoma. AB - OBJECTIVE: Minimally invasive methods are used as alternatives to treat leiomyomas and include uterine artery embolization, which has emerged as a safe, effective method. This study aims to evaluate the magnetic resonance imaging predictors for a reduction in leiomyoma volume in patients undergoing uterine artery embolization. METHODS: This prospective longitudinal study was performed at a university hospital. We followed 50 symptomatic premenopausal women with uterine leiomyomas who underwent uterine artery embolization. We examined 179 leiomyomas among these patients. Magnetic resonance imaging was performed one month before and six months after uterine artery embolization. Two radiologists who specialized in abdominal imaging independently interpreted the images. MAIN OUTCOME MEASURES: The magnetic resonance imaging parameters were the uterus and leiomyomas volumes, their localizations, contrast perfusion pattern and node-to muscle ratio. RESULTS: Six months after treatment, the average uterine volume reduction was 38.91%, and the leiomyomas were reduced by 55.23%. When the leiomyomas were submucosal and/or had a higher node-to-muscle ratio in the T2 images, the volume reduction was even greater (greater than 50%). Other parameters showed no association. CONCLUSIONS: We conclude that symptomatic uterine leiomyomas in patients undergoing uterine artery embolization exhibit volume reductions greater than 50% by magnetic resonance imaging when the leiomyomas are submucosal and/or had a high node-to-muscle ratio in the T2 images. PMID- 24626945 TI - Neutrophil-to-lymphocyte ratio and in-hospital mortality in patients with acute heart failure. AB - OBJECTIVES: Previous studies have demonstrated the role of inflammation in acute heart failure. The neutrophil-to-lymphocyte ratio was found to be a useful inflammatory marker for predicting adverse outcomes. We hypothesized that an elevated neutrophil-to-lymphocyte ratio would be associated with increased mortality in acute heart failure patients. METHODS: The study cohort consisted of 167 acute heart failure patients with an ejection fraction <50%. The primary endpoint was in-hospital mortality, and the patients were divided into two groups according to in-hospital mortality. RESULTS: In a multivariate regression analysis, including baseline demographic, clinical, and biochemical covariates, the neutrophil to lymphocyte ratio remained an independent predictor of mortality (OR 1.156, 95% CI 1.001 - 1.334, p = 0.048). CONCLUSION: In conclusion, an elevated neutrophil-to-lymphocyte ratio seems to be a predictor of short-term mortality in patients with acute heart failure and a reduced left ventricular ejection fraction. PMID- 24626946 TI - Subjective memory complaints in the elderly: a sign of cognitive impairment? AB - OBJECTIVES: Cognitive impairment in the elderly is frequently overlooked by general practitioners. The use of subjective memory complaints as a sign of cognitive impairment by the general practice is controversial. METHODS: Elderly individuals (N = 248) were asked whether they had memory complaints and underwent a cognitive impairment screening. Subjects classified as exhibiting "probable cognitive impairment" underwent a complete cognitive evaluation, and the final diagnoses were established by expert consensus. RESULTS: A total of 147 patients presented with subjective memory complaints, and 43 were further classified as demented or "cognitively impaired not demented". Subjective memory complaints presented a sensitivity of 100% and a negative predictive value of 100%. CONCLUSION: Subjective memory complaints are an indicator for cognitive impairment screening. PMID- 24626947 TI - Depression in hemodialysis patients: the role of dialysis shift. AB - OBJECTIVE: Depression is the most important neuropsychiatric complication in chronic kidney disease because it reduces quality of life and increases mortality. Evidence demonstrating the association between dialysis shift and depression is lacking; thus, obtaining such evidence was the main objective of this study. METHOD: This cross-sectional study included patients attending a hemodialysis program. Depression was diagnosed using Beck's Depression Inventory. Excessive daytime sleepiness was evaluated using the Epworth Sleepiness Scale. RESULTS: A total of 96 patients were enrolled (55 males, age 48+/-14 years). Depression and excessive daytime sleepiness were observed in 42.7% and 49% of the patients, respectively. When comparing variables among the three dialysis shifts, there were no differences in age, dialysis vintage, employment status, excessive daytime sleepiness, hemoglobin, phosphorus levels, or albumin levels. Patients in the morning shift were more likely to live in rural areas (p<0.0001), although patients in rural areas did not have a higher prevalence of depression (p = 0.30). Patients with depression were more likely to be dialyzed during the morning shift (p = 0.008). Independent risk factors for depression were age (p<0.03), lower levels of hemoglobin (p<0.01) and phosphorus (p<0.01), and dialysis during the morning shift (p = 0.0009). The hospitalization risk of depressive patients was 4.5 times higher than that of nondepressive patients (p<0.008). CONCLUSION: These data suggest that depression is associated with dialysis shift, higher levels of phosphorus, and lower levels of hemoglobin. The results highlight the need for randomized trials to determine whether this association occurs by chance or whether circadian rhythm disorders may play a role. PMID- 24626948 TI - Runners in their forties dominate ultra-marathons from 50 to 3,100 miles. AB - OBJECTIVES: This study investigated performance trends and the age of peak running speed in ultra-marathons from 50 to 3,100 miles. METHODS: The running speed and age of the fastest competitors in 50-, 100-, 200-, 1,000- and 3,100 mile events held worldwide from 1971 to 2012 were analyzed using single- and multi-level regression analyses. RESULTS: The number of events and competitors increased exponentially in 50- and 100-mile events. For the annual fastest runners, women improved in 50-mile events, but not men. In 100-mile events, both women and men improved their performance. In 1,000-mile events, men became slower. For the annual top ten runners, women improved in 50- and 100-mile events, whereas the performance of men remained unchanged in 50- and 3,100-mile events but improved in 100-mile events. The age of the annual fastest runners was approximately 35 years for both women and men in 50-mile events and approximately 35 years for women in 100-mile events. For men, the age of the annual fastest runners in 100-mile events was higher at 38 years. For the annual fastest runners of 1,000-mile events, the women were approximately 43 years of age, whereas for men, the age increased to 48 years of age. For the annual fastest runners of 3,100-mile events, the age in women decreased to 35 years and was approximately 39 years in men. CONCLUSION: The running speed of the fastest competitors increased for both women and men in 100-mile events but only for women in 50-mile events. The age of peak running speed increased in men with increasing race distance to approximately 45 years in 1,000-mile events, whereas it decreased to approximately 39 years in 3,100-mile events. In women, the upper age of peak running speed increased to approximately 51 years in 3,100-mile events. PMID- 24626949 TI - Auditory evoked potentials: predicting speech therapy outcomes in children with phonological disorders. AB - OBJECTIVES: This study investigated whether neurophysiologic responses (auditory evoked potentials) differ between typically developed children and children with phonological disorders and whether these responses are modified in children with phonological disorders after speech therapy. METHODS: The participants included 24 typically developing children (Control Group, mean age: eight years and ten months) and 23 children clinically diagnosed with phonological disorders (Study Group, mean age: eight years and eleven months). Additionally, 12 study group children were enrolled in speech therapy (Study Group 1), and 11 were not enrolled in speech therapy (Study Group 2). The subjects were submitted to the following procedures: conventional audiological, auditory brainstem response, auditory middle-latency response, and P300 assessments. All participants presented with normal hearing thresholds. The study group 1 subjects were reassessed after 12 speech therapy sessions, and the study group 2 subjects were reassessed 3 months after the initial assessment. Electrophysiological results were compared between the groups. RESULTS: Latency differences were observed between the groups (the control and study groups) regarding the auditory brainstem response and the P300 tests. Additionally, the P300 responses improved in the study group 1 children after speech therapy. CONCLUSION: The findings suggest that children with phonological disorders have impaired auditory brainstem and cortical region pathways that may benefit from speech therapy. PMID- 24626950 TI - Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via nuclear factor-kappaB activation in a hypoxia-inducible factor 1-alpha dependent manner. AB - Recently, mutations of the isocitrate dehydrogenase (IDH) 1 gene, which specifically occur in the majority of low-grade and secondary high-grade gliomas, have drawn particular attention of neuro-oncologists. Mutations of the IDH1 gene have been proposed to have significant roles in the tumorigenesis, progression and prognosis of gliomas. However, the molecular mechanism of the role of IDH1 mutants in gliomagenesis remains to be elucidated. The present study, showed that forced expression of an IDH1 mutant, of which the 132th amino acid residue arginine is substituted by histidine (IDH1R132H), promoted cell proliferation in cultured cells, while wild-type IDH1 overexpression had no effect on cell proliferation. Consistent with previous studies, it was also observed that expression of hypoxia-inducible factor 1-alpha (HIF1-alpha) was upregulated in IDH1R132H expressing cells with the induction of vascular endothelial growth factor (VEGF) expression. However, knockdown of VEGF via small RNA interference had no significant influence on the cell proliferation induced by overexpression of IDH1R132H, implying that another signaling pathway may be involved. Next, forced expression of IDH1R132H was found to activate nuclear factor-kappaB (NF kappaB), since the inhibitory IkappaB protein (IkappaBalpha) was highly phosphorylated and the NF-kappaB p65 subunit was translocated into the nucleus. Notably, knockdown of HIF1-alpha significantly blocked NF-kappaB activation, which was induced by the overexpression of IDH1 mutants. In addition, expression of IDH1 mutants markedly induced the NF-kappaB target gene expression, including cyclin D1 and E and c-myc, which were involved in the regulation of cell proliferation. In conclusion, it was demonstrated that the IDH1 mutant activated NF-kappaB in a HIF1-alpha-dependent manner and was involved in the regulation of cell proliferation. PMID- 24626951 TI - Origination and assessment of metal pollution in Qarechay River bed sediments. AB - In the present investigation, bulk and chemical partitioning of elements (Cu, Mn, Ni, Zn, Fe, Ca) together with organic matter as a loss in ignition in the Qarechay River bed sediments have been studied. The concentration of metals in Qarechay River bed sediments is governed by the geological units of the study area. The study of anthropogenic portion shows that a small proportion of elemental concentration belongs to this phase. However, Mn has a large portion of anthropogenic sources (43 %). Also, Mn has a share of 13.6 % in sulfide fractions. This result indicates that Mn is a highly mobile element and can easily enter the water column. The presence of Mn in sulfide fraction might be indicative of initial stages of conversion of oxidation state into reduction in Qarechay River. Share of metals in anthropogenic portion is in the following order: Mn (43 %) > Cu (19 %) > Zn (10 %) > Ni (3 %) > Fe (0 %). Organic metallic bonds are not significantly present in the study area. Geochemical index (I geo), pollution index (I poll), enrichment factor (EF), and pollution load index (PLI) values are indicative of a clean environment throughout the river course. These values are in well agreement with results of chemical partitioning data. Eventually, based on the results of chemical partitioning, regional standard of elements for Qarechay River bed sediments has been established. PMID- 24626952 TI - Advances in genome studies in plants and animals. AB - The area of plant and animal genomics covers the entire suite of issues in biology because it aims to determine the structure and function of genetic material. Although specific issues define research advances at an organism level, it is evident that many of the fundamental features of genome structure and the translation of encoded information to function share common ground. The Plant and Animal Genome (PAG) conference held in San Diego (California), in January each year provides an overview across all organisms at the genome level, and often it is evident that investments in the human area provide leadership, applications, and discoveries for researchers studying other organisms. This mini-review utilizes the plenary lectures as a basis for summarizing the trends in the genome level studies of organisms, and the lectures include presentations by Ewan Birney (EBI, UK), Eric Green (NIH, USA), John Butler (NIST, USA), Elaine Mardis (Washington, USA), Caroline Dean (John Innes Centre, UK), Trudy Mackay (NC State University, USA), Sue Wessler (UC Riverside, USA), and Patrick Wincker (Genoscope, France). The work reviewed is based on published papers. Where unpublished information is cited, permission to include the information in this manuscript was obtained from the presenters. PMID- 24626953 TI - Copy number and haplotype variation at the VRN-A1 and central FR-A2 loci are associated with frost tolerance in hexaploid wheat. AB - KEY MESSAGE: The interaction between VRN - A1 and FR - A2 largely affect the frost tolerance of hexaploid wheat. Frost tolerance is critical for wheat survival during cold winters. Natural variation for this trait is mainly associated with allelic differences at the VERNALIZATION 1 (VRN1) and FROST RESISTANCE 2 (FR2) loci. VRN1 regulates the transition between vegetative and reproductive stages and FR2, a locus including several tandemly duplicated C REPEAT BINDING FACTOR (CBF) transcription factors, regulates the expression of Cold-regulated genes. We identified sequence and copy number variation at these two loci among winter and spring wheat varieties and characterized their association with frost tolerance. We identified two FR-A2 haplotypes-'FR-A2-S' and 'FR-A2-T'-distinguished by two insertion/deletions and ten single nucleotide polymorphisms within the CBF-A12 and CBF-A15 genes. Increased copy number of CBF A14 was frequently associated with the FR-A2-T haplotype and with higher CBF14 transcript levels in response to cold. Factorial ANOVAs revealed significant interactions between VRN1 and FR-A2 for frost tolerance in both winter and spring panels suggesting a crosstalk between vernalization and cold acclimation pathways. The model including these two loci and their interaction explained 32.0 and 20.7 % of the variation in frost tolerance in the winter and spring panels, respectively. The interaction was validated in a winter wheat F 4:5 population segregating for both genes. Increased VRN-A1 copy number was associated with improved frost tolerance among varieties carrying the FR-A2-T allele but not among those carrying the FR-A2-S allele. These results suggest that selection of varieties carrying the FR-A2-T allele and three copies of the recessive vrn-A1 allele would be a good strategy to improve frost tolerance in wheat. PMID- 24626954 TI - Association mapping of resistance to Puccinia hordei in Australian barley breeding germplasm. AB - KEY MESSAGE: "To find stable resistance using association mapping tools, QTL with major and minor effects on leaf rust reactions were identified in barley breeding lines by assessing seedlings and adult plants." Three hundred and sixty (360) elite barley (Hordeum vulgare L.) breeding lines from the Northern Region Barley Breeding Program in Australia were genotyped with 3,244 polymorphic diversity arrays technology markers and the results used to map quantitative trait loci (QTL) conferring a reaction to leaf rust (Puccinia hordei Otth). The F3:5 (Stage 2) lines were derived or sourced from different geographic origins or hubs of international barley breeding ventures representing two breeding cycles (2009 and 2011 trials) and were evaluated across eight environments for infection type at both seedling and adult plant stages. Association mapping was performed using mean scores for disease reaction, accounting for family effects using the eigenvalues from a matrix of genotype correlations. In this study, 15 QTL were detected; 5 QTL co-located with catalogued leaf rust resistance genes (Rph1, Rph3/19, Rph8/14/15, Rph20, Rph21), 6 QTL aligned with previously reported genomic regions and 4 QTL (3 on chromosome 1H and 1 on 7H) were novel. The adult plant resistance gene Rph20 was identified across the majority of environments and pathotypes. The QTL detected in this study offer opportunities for breeding for more durable resistance to leaf rust through pyramiding multiple genomic regions via marker-assisted selection. PMID- 24626955 TI - Overexpression of microRNA-143 inhibits growth and induces apoptosis in human leukemia cells. AB - Microrna-143 (miR-143) has been suggested to be a tumor suppressor, yet its role in hematological tumors has not been determined. Thus, we aimed to explore the expression and function of miR-143 in leukemia cells. miR-143 expression was assessed in bone marrow samples from 63 leukemia patients and 15 healthy controls using q-PCR, and its correlation with DNMT3A expression was determined. In addition, after lentiviral-mediated miR-143 overexpression, K562 cell proliferation was evaluated using CCK-8 analysis; cell cycle progression and apoptosis were determined using flow cytometry. The expression of Bcl-2 and pro caspase-3 and -9 was assessed by q-PCR and western blot analysis, respectively. Leukemia patients had significantly lower relative miR-143 expression than healthy controls (P=0.004), and the expression levels of miR143 and DNMTA3A were negatively correlated (r=-0.663, P=0.001). Overexpression of miR-143 decreased DNMT3A mRNA and protein expression, and significantly reduced K562 cell proliferation at 72 and 96 h (both P <= 0.018). In addition, reduced colony formation and cell cycle progression were observed upon miR-143 overexpression. Flow cytometric analysis revealed that the early apoptosis rate was higher in the miR-143 group than the rate in the NC group. Bcl-2 mRNA expression and pro caspase-3 and -9 protein expression were reduced in the miR-143-expressing cells. These findings suggest that miR-143 plays an important role in leukemia cell proliferation and apoptosis, possibly through silencing of DNMT3A. Further studies are necessary to determine the prognostic value and therapeutic potential of targeting miR-143. PMID- 24626956 TI - Detection of hTERC and c-MYC genes in cervical epithelial exfoliated cells for cervical cancer screening. AB - Cervical cancer is the principal cause of mortality due to cancer in women worldwide. New predictive markers may increase survival rates by improving the treatment of patients at a high risk for cancer. This study was carried out to investigate the amplification of human telomerase RNA component (hTERC) or/and c MYC in cervical epithelial exfoliated cells for cervical carcinoma screening. We collected 171 specimens. including speciments from normal cervix, benign lesions, cervical intraepithelial neoplasia (CIN)1, CIN2 and CIN3, or carcinoma in situ, as well as invasive cervical squamous cell carcinoma. Fluorescence in situ hybridization (FISH) was performed to detect alterations in hTERC and c-MYC expression. We analyzed the area under the receiver operating characteristic (ROC) curve (AUC), as well as the sensitivity and specificity of single screening and conjoined screening. There was a trend toward an increasing amplification of 2 genes with the increasing severity of cervical lesions. ROC curve analysis demonstrated that the AUC values of the hTERC gene for the screening of different cervical lesions were >0.8. Compared with the hTERC gene, the AUC of the c-MYC gene for the screening of >=CIN3 was >0.8 and the AUC for the screening of other cervical lesions was >0.7. For the screening of cervical lesions above the grade of benign lesions, cytological diagnosis was superior to the gene detection with significant differences. For the screening of cervical lesions >CIN1, there were no statistically significant differences (P>0.05) between the hTERC gene and cytological diagnosis, whereas the screening results of c-MYC detection and cytological diagnosis differed significantly (P<0.05). For the screening of cervical lesions >CIN2 or >CIN3, the detection of hTERC and c-MYC genes and cytological diagnosis had similar screening results with no statistically significant differences (P>0.05). In conclusion, using FISH to detect the amplification of hTERC or/and c-MYC on cervical epithelial exfoliated cells may be a useful and specific screening method for precancerous lesions. PMID- 24626959 TI - The chemical origin and catalytic activity of coinage metals: from oxidation to dehydrogenation. AB - The high oxidation activity of coinage metals (Cu, Ag and Au) has been widely applied in various important reactions, such as oxidation of carbon monoxide, alkenes or alcohols. The catalytic behavior of those inert metals has mostly been attributable to their size effect, the physical effect. In the present study, the chemical effects on their high oxidation activity have been investigated. We mechanistically examine the direct and oxidative dehydrogenation (partial oxidation) reactions of ethanol to acetaldehyde on a series of transition metals (groups 9, 10 and 11) with identical physical characteristics and varied chemical origins using density functional theory (DFT) calculations and electronic structure analyses at the GGA-PW91 level. The energetic results show that coinage metals have much lower activation energies and higher exothermicities for the oxidative dehydrogenation steps although they have higher energy for the direct dehydrogenation reaction. In the electronic structure analyses, coinage metals with saturated d bands can efficiently donate electrons to O* and OH*, or other electronegative adspecies, and better promote their p bands to higher energy levels. The negatively charged O* and OH* with high-lying p bands are responsible for lowering the energies in oxidative steps. The mechanistic understanding well explains the better oxidation activity of coinage metals and provides valuable information on their utilization in other useful applications, for example, the dehydrogenation process. PMID- 24626957 TI - Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions. AB - On a molecular level, cells sense changes in oxygen availability through the PHDs, which regulate the protein stability of the alpha-subunit of the transcription factor HIF. Especially, PHD3 has been additionally associated with apoptotic cell death. We hypothesized that PHD3 plays a role in cell-fate decisions in macrophages. Therefore, myeloid-specific PHD3(-/-) mice were created and analyzed. PHD3(-/-) BMDM showed no altered HIF-1alpha or HIF-2alpha stabilization or increased HIF target gene expression in normoxia or hypoxia. Macrophage M1 and M2 polarization was unchanged likewise. Compared with macrophages from WT littermates, PHD3(-/-) BMDM exhibited a significant reduction in TUNEL-positive cells after serum withdrawal or treatment with stauro and SNAP. Under the same conditions, PHD3(-/-) BMDM also showed less Annexin V staining, which is representative for membrane disruption, and indicated a reduced early apoptosis. In an unbiased transcriptome screen, we found that Angptl2 expression was reduced in PHD3(-/-) BMDM under stress conditions. Addition of rAngptl2 rescued the antiapoptotic phenotype, demonstrating that it is involved in the PHD3-mediated response toward apoptotic stimuli in macrophages. PMID- 24626958 TI - Pathobiology of cervical spondylotic myelopathy. AB - In this narrative review, we aim to outline what is currently known about the pathophysiology of cervical spondylotic myelopathy (CSM), the most common cause of spinal cord dysfunction. In particular, we note the unique factors that distinguish it from acute spinal cord injury. Despite its common occurrence, the reasons why some patients develop severe symptomatology while others have few or no symptoms despite radiographic evidence confirming similar degrees of compression is poorly understood. Neither is there a clear understanding of why certain patients have a stable clinical myelopathy and others present with only mild myelopathy. Moreover, the precise molecular mechanisms which contribute to the pathogenesis of the disease are incompletely understood. The current treatment method is decompression of the spinal cord but a lack of clinically relevant models of CSM have hindered the understanding of the full pathophysiology which would aid the development of new therapeutic avenues of investigation. Further elucidation of the role of ischemia, currently a source of debate, as well as the complex cascade of biomolecular events as a result of the unique pathophysiology in this disease will pave the way for further neuroprotective strategies to be developed to attenuate the physiological consequences of surgical decompression and augment its benefits. PMID- 24626960 TI - Nutritional requirements and media development for Lactococcus lactis IL1403. AB - Lactic acid bacteria are extensively used in food technology and for the production of various compounds, but they are fastidious in nutrient requirements. In order to elucidate the role of each component precisely, defined multicomponent media are required. This study focuses on determining nutrient auxotrophies and minimizing media components (amino acids, vitamins, metal ions, buffers and additional compounds) for the cultivation of Lactococcus lactis subsp. lactis IL1403, using microtitre plates and test tubes. It was shown that glutamine and asparagine were the most important media components for achieving higher biomass yields while the branched-chain amino acids were necessary to increase specific growth rate. The amino acid and glucose ratio was reduced to achieve minimal residual concentration of amino acids in the medium after the growth of cells, whereas the specific growth rate and biomass yield of cells were not considerably affected. As the percentage of each consumed amino acid compared to initial amount is larger than measurement error, these optimized media are important for achieving more precise data about amino acid utilization and metabolism. PMID- 24626961 TI - Rethinking guidelines for VTE risk among nursing home residents: a population based study merging medical record detail with standardized nursing home assessments. AB - BACKGROUND: Nursing home (NH) residents are at increased risk for both VTE and bleeding from pharmacologic prophylaxis. Construction of prophylaxis guidelines is hampered by NH-specific limitations with VTE case identification and characterization of risk. We addressed these limitations by merging detailed provider-linked Rochester Epidemiology Project (REP) medical records with Centers for Medicare and Medicaid Services Minimum Data Set (MDS) NH assessments. METHODS: This population-based nested case-control study identified all Olmsted County, Minnesota, residents with first-lifetime VTE October 1, 1998, through December 31, 2005, while a resident of an NH (N = 91) and one to two age-, sex-, and calendar year-matched NH non-VTE control subjects. For each NH case without hospitalization 3 months before VTE (n = 23), we additionally identified three to four nonhospitalized NH control subjects. REP and MDS records were reviewed before index date (VTE date for cases; respective REP encounter date for control subjects) for numerous characteristics previously associated with VTE in non-NH populations. Data were modeled using conditional logistic regression. RESULTS: The multivariate model consisting of all cases and control subjects identified only three characteristics independently associated with VTE: respiratory infection vs no infection (OR, 5.9; 95% CI, 2.6-13.1), extensive or total assistance with walking in room (5.6, 2.5-12.6), and general surgery (3.3, 1.0 10.8). In analyses limited to nonhospitalized cases and control subjects, only nonrespiratory infection vs no infection was independently associated with VTE (8.8, 2.7-29.2). CONCLUSIONS: Contrary to previous assumptions, most VTE risk factors identified in non-NH populations do not apply to the NH population. NH residents with infection, substantial mobility limitations, or recent general surgery should be considered potential candidates for VTE prophylaxis. PMID- 24626962 TI - Predicting the probability of mortality of gastric cancer patients using decision tree. AB - BACKGROUND: Gastric cancer is the fourth most common cancer worldwide. This reason motivated us to investigate and introduce gastric cancer risk factors utilizing statistical methods. AIM: The aim of this study was to identify the most important factors influencing the mortality of patients who suffer from gastric cancer disease and to introduce a classification approach according to decision tree model for predicting the probability of mortality from this disease. METHODS: Data on 216 patients with gastric cancer, who were registered in Taleghani hospital in Tehran,Iran, were analyzed. At first, patients were divided into two groups: the dead and alive. Then, to fit decision tree model to our data, we randomly selected 20% of dataset to the test sample and remaining dataset considered as the training sample. Finally, the validity of the model examined with sensitivity, specificity, diagnosis accuracy and the area under the receiver operating characteristic curve. The CART version 6.0 and SPSS version 19.0 softwares were used for the analysis of the data. RESULTS: Diabetes, ethnicity, tobacco, tumor size, surgery, pathologic stage, age at diagnosis, exposure to chemical weapons and alcohol consumption were determined as effective factors on mortality of gastric cancer. The sensitivity, specificity and accuracy of decision tree were 0.72, 0.75 and 0.74 respectively. CONCLUSIONS: The indices of sensitivity, specificity and accuracy represented that the decision tree model has acceptable accuracy to prediction the probability of mortality in gastric cancer patients. So a simple decision tree consisted of factors affecting on mortality of gastric cancer may help clinicians as a reliable and practical tool to predict the probability of mortality in these patients. PMID- 24626963 TI - CYP1A1 Ile462Val polymorphism as a risk factor in cervical cancer development in the Polish population. AB - BACKGROUND AND OBJECTIVE: There are inconsistent data of the cytochrome P450 1A1 (CYP1A1) Ile462Val (rs1048943) single nuclear polymorphism (SNP) as a genetic susceptibility factor for cervical cancer in various populations. Moreover, little is known about the interaction of this SNP with other risk factors, including contraceptive use, postmenopausal status, parity, and tobacco smoking. METHODS: Polymerase chain reaction-restriction fragment length polymorphism was used to study the prevalence of the CYP1A1 Ile462Val SNP in women with cervical cancer (n = 456) and controls (n = 495). RESULTS: Logistic regression analysis adjusting for age, parity, oral contraceptive use, tobacco smoking, and menopausal status demonstrated that that the CYP1A1 Ile/Val polymorphism was not associated with an increased risk of cervical cancer in all patients. The adjusted odds ratio (OR) for patients with the Ile/Val genotype vs. Ile/Ile genotype was 1.539 (95 % confidence interval [CI] 0.932-2.541, p = 0.091). However, an increase in cervical cancer risk was seen among patients with a positive history of tobacco smoking and parity. The adjusted OR for positive history of tobacco smoking with the Ile/Val vs. Ile/Ile genotypes was 2.978 (95 % CI 1.382-6.418, p = 0.0052). The adjusted OR for parity with the Ile/Val vs. Ile/Ile genotype was 1.739 (95 % CI 1.006-3.009, p = 0.0472). CONCLUSION: Our genetic study suggests that the CYP1A1 Ile462Val SNP may be a risk factor for cervical cancer among patients with a positive history of tobacco smoking and parity. PMID- 24626964 TI - The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis. AB - Stromal cell-derived factor-1 (SDF-1) and its receptor, CXC chemokine receptor-4 (CXCR4), are important regulators in the migration of bone marrow mesenchymal stem cells (BMSCs). However, the mechanisms underlying this effect in acute pancreatitis (AP) have not been investigated. In this study, BMSCs were identified by specific cell surface markers and differentiation potentials, and labeled with chloromethylbenzamido-1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate (CM-Dil) for in vivo cell tracking. AP was induced by retrograde infusion of sodium taurocholate into the common bile duct in rats. The expression of SDF-1 in the injured pancreas was determined by immunohistochemistry and western blot analysis. BMSCs were incubated with or without anti-CXCR4 antibody and the contribution of SDF-1 to the migration of BMSCs was investigated. Our results demonstrated that the expression of SDF-1 was significantly increased in the injured pancreas, and that these levels peaked on days 5-7 and began to decrease on day 10. SDF-1 induced a dose-dependent migration of BMSCs in an in vitro transwell migration assay, which was almost completely blocked by AMD3100 (CXCR4-specific antagonist) or anti-CXCR4 antibody. In addition, by encouraging the migration of CM-Dil-labeled BMSCs, the SDF 1/CXCR4 axis facilitated the repair of the injured pancreas. This effect was inhibited by the anti-CXCR4 antibody. Taken together, these results indicate that the interaction of locally produced SDF-1 with CXCR4 on BMSCs, has an important regulatory role in the migration of BMSCs towards the injured pancreas in AP. PMID- 24626965 TI - Anti-inflammatory and anti-proliferative effect of herbal medicines (APR) in RAW264.7 cells. AB - The objective of the present study was to analyze the effect of a mixture of medicinal plants [Angelica gigas Nakai, Panax ginseng and Rhus verniciflua Stokes (APR)] on lipopolysaccharide (LPS)-induced inflammatory responses in the murine macrophage cell line RAW264.7. Cells were treated with APR and LPS at various concentrations and indicated times. WST assay, trypan blue assay and quantification of activated cells demonstrated that APR suppressed cell proliferation in a dose-dependent manner. APR induced G1 cell cycle arrest and inhibited the LPS-induced phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (p38) and necrosis factor kappaB (NF-kappaB). APR also suppressed nitric oxide synthase isoform (iNOS) and prostaglandin endoperoxide synthase 2 (Cox-2) messenger ribonucleic acid (mRNA) expression induced by LPS. Furthermore, APR decreased LPS-induced intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential, as well as induced PARP and caspase-3 cleavage, suggesting that APR causes apoptosis. In conclusion, the present study indicated that APR may be advantageous in treating inflammatory disease. PMID- 24626966 TI - Aquimarina pacifica sp. nov., isolated from seawater. AB - A Gram-stain-negative, rod-shaped, non-flagellated, strictly aerobic bacterium with gliding motility, designated strain SW150(T), was isolated from surface seawater of the South Pacific Gyre (39 degrees 19' S 139 degrees 48' W) during the Integrated Ocean Drilling Program Expedition 329. Optimal growth occurred in the presence of 2-4% (w/v) NaCl, at pH 7-8 and at 28-30 degrees C. The dominant fatty acids were iso-C(15 : 0), iso-C(17 : 0) 3-OH, iso-C(15 : 1) G, C(16 : 1)omega6c and/or C(16 : 1)omega7c and 10-methyl C(16 : 0) and/or iso-C(17 : 1)omega9c. The polar lipids of strain SW150(T) comprised phosphatidylethanolamine, three unknown polar lipids and one unknown aminolipid. The major respiratory quinone was MK-6. The DNA G+C content of strain SW150(T) was 33.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel strain was related most closely to Aquimarina macrocephali JAMB N27(T) and Aquimarina muelleri KMM 6020(T) with 97.8 and 96.8% sequence similarities, respectively. The estimated DNA-DNA hybridization values were 21.00+/-2.33% between strain SW150(T) and A. macrocephali JAMB N27(T) and 20.60+/-2.32% between strain SW150(T) and Aquimarina megaterium XH134(T). On the basis of polyphasic analyses, strain SW150(T) represents a novel species of the genus Aquimarina, for which the name Aquimarina pacifica sp. nov. is proposed. The type strain is SW150(T) ( = JCM 18214(T) = CGMCC 1.12180(T)). PMID- 24626967 TI - Angio-Seal closure of an iatrogenic right ventricular perforation. PMID- 24626968 TI - Retrospective examination of selected outcomes of Medicines Use Review (MUR) services in New Zealand. AB - BACKGROUND: Poor adherence to medication can lead to suboptimal outcomes, and is reported to occur frequently. Pharmacists in some countries are funded to support the appropriate use of medications in patients and enhance medication adherence, by providing services such as Medicines Use Review (MUR). OBJECTIVE: To describe and investigate factors that may influence patients' knowledge and perceptions of and adherence to medications as determined during MUR. SETTING: Community pharmacies in a locality in New Zealand. Method Following consent from five MUR service providers, records of patients' MUR consultations conducted between November 2007 and December 2011 were retrospectively reviewed for information on patients, services, and outcomes. Using multilevel mixed-effects logistic regression, factors that predicted the providers' score of the patients' medication knowledge, and the patients' score of their adherence to and perceptions of medications, were investigated. Main outcome measure patients' knowledge, perceptions and adherence scores. RESULTS: A total of 353 MUR patients' records were evaluated. The median (IQR) age of patients was 73 (63-81) years. About 41.1 % of patients were Maori. A total of 204 (57.8 %) patients had two MUR consultations and only 53 (15 %) had four. The mean score of patients' knowledge, perceptions of, and adherence to medications were found to increase in each visit which suggests that adherence support by pharmacists might improve patients' outcomes. Females had higher medication knowledge scores than males (OR 3.09, 95 % CI 1.29-7.44). There was some evidence to suggest Maori had lower scores for knowledge of medications than non-Maori (OR 0.092, 95 % CI 0.02-0.36). In addition, longer duration in the program predicted better scores for medication knowledge, adherence and perceptions of medications. CONCLUSIONS: MUR was found to have the potential to improve the scores of patients' knowledge and perceptions of and adherence to medicines, and factors such as gender, ethnicity and longer duration in the services were found to predict these outcomes. PMID- 24626969 TI - Hearing loss in children with HIV/AIDS. AB - PURPOSE: To investigate the occurrence of hearing loss in children with HIV and its association with viral load, opportunistic diseases, and antiretroviral treatment. METHODS: A cross-sectional study was carried out with 23 HIV-positive children under care at two specialized centers in Joao Pessoa, Paraiba, Brazil. Their parents or legal guardians responded to a questionnaire, containing data on the clinical situation and the hearing health of the children, who were then submitted to audiological assessment. We complied with the guidelines for human research contained in the CNE (National Education Council) Resolution number 196/1996. The findings were analyzed through descriptive statistics. RESULTS: We observed that lamivudine (3TC) was the antiretroviral drug most used in 17 (94.4%) patients, followed by Kaletra (KAL), administered in 14 (77.8%) patients, d4T in 11 (61.1%) patients, and zidovudine (AZT) in 7 (38.9%) participants. Otitis was the most frequent opportunistic disease, with 11 (61.1%) cases. In the audiometric examination, we observed 39 (84.8%) ears with hearing loss and 7 (15.2%) normal ears. After the immitance testing, we found five (10.9%) normal ears, characterized by type A tympanometric curves. The other 41 (89.1%) ears were revealed as altered, with predominance of type B curves in 67.4% of the cases. CONCLUSION: There were hearing alterations in children with HIV/AIDS analyzed in this study. Discreet hearing losses were the most occurring. We verified statistically significant associations with the use of antiretroviral therapy and otitis. Therefore, we point out the importance of auditory monitoring and intervention as soon as possible, thus favoring adequate development in language and decreasing possible difficulties in learning and social inclusion. PMID- 24626970 TI - A new proposal for evaluation of the pharyngoesophageal segment and its relation with the narrow-band spectrogram in tracheoesophageal speakers. AB - PURPOSE: The primary purpose of this study was to assess the relationship between pharyngoesophageal segment (PES) configuration and narrow-band spectrogram of tracheoesophageal voices. METHODS: This study included 30 total laryngectomees tracheoesophageal speakers. Patients were assessed by videofluoroscopy (VF), during deglutition and voicing, and the vowel /a/ was recorded for spectrographic analysis. The evaluation of VF recording consisted of visual perceptual rating of degree of contact between the prominence of PES and its anterior wall, defined as absent/mild (hypo contact), moderate (normo contact) and intense (hyper contact); and quantitative measures of PES: anteroposterior distance (APD) and length of the PES (lenPES); PES surface area in swallowing (areaSw), and phonation (areaPh), and the area of the air reservoir (areaAir). Visual inspection of a narrow-band spectrogram was made and four different acoustic signal typing were defined as Type I, II, III or IV. RESULTS: Type I-II is correlated with moderate contact; Type III, with intense and Type IV, with absent/mild contact. Type I-II has bigger APD and PES with lower length than Type IV. There is a correlation between bigger APD and shorter PES. CONCLUSION: The group with I-II signal typing has PES with normo contact; Type III with hyper contact and Type IV has PES with hypo contact. The best tracheoesophageal voices are achieved by PES with moderate contact of the prominence and with shorter and larger anteroposterior PES distances. What differentiates the PES with hyper contact from PES with normal one is only the degree of contact between the prominence of the PES and its anterior wall. PMID- 24626971 TI - Long latency auditory evoked potentials in children with cochlear implants: systematic review. AB - The aim of this study was to analyze the findings on Cortical Auditory Evoked Potentials in children with cochlear implant through a systematic literature review. After formulation of research question and search of studies in four data bases with the following descriptors: electrophysiology (eletrofisiologia), cochlear implantation (implante coclear), child (crianca), neuronal plasticity (plasticidade neuronal) and audiology (audiologia), were selected articles (original and complete) published between 2002 and 2013 in Brazilian Portuguese or English. A total of 208 studies were found; however, only 13 contemplated the established criteria and were further analyzed; was made data extraction for analysis of methodology and content of the studies. The results described suggest rapid changes in P1 component of Cortical Auditory Evoked Potentials in children with cochlear implants. Although there are few studies on the theme, cochlear implant has been shown to produce effective changes in central auditory path ways especially in children implanted before 3 years and 6 months of age. PMID- 24626972 TI - Cross-cultural adaptation of the Brazilian version of the Eating Assessment Tool EAT-10. AB - The Eating Assessment Tool (EAT-10) was conceptually developed in the United States from data collected from 482 patients, for use as a self-administered survey regarding risk identification of dysphagia and symptoms related to clinical response to treatment. The purpose of this study is to present the cultural equivalence of the Brazilian version of the EAT-10. The process followed the Scientific Advisory Committee of Medical Outcome Trust (SACMOT). The questionnaire was translated by two Brazilian bilingual speech-language pathologists, aware of the purpose of this study. A back translation was performed by a third Brazilian speech-language pathologist, bilingual and English teacher that had not participated in the previous stage. After comparing both translations, a final version of the questionnaire was produced and called Instrumento de Autoavaliacao da Alimentacao (EAT-10). It was administered to 107 adult inpatients of the Hospital Sao Paulo, cwith request for bedside clinical evaluation of swallow. During the process of translation and cultural adaptation, no item was modified and/or suppressed. The EAT-10 maintained the same structure as the original American English version with ten questions, of which three of functional domain, three of emotional domain and four of physical symptoms domain. The cultural equivalence of the Brazilian version of the EAT-10 was demonstrated, being a score of three points or above it the cutoff for dysphagia risk, also for the Brazilian population. PMID- 24626973 TI - The impact of speech disorders quality of life: a questionnaire proposal. AB - PURPOSE: To develop a questionnaire to analyze the impact of speech disorders on quality of life and verify its reliability. METHODS: A literature review on instruments that assess the quality-of-life was performed, particularly those concerning communication disorders. The questionnaire was designed with 18 closed questions: one related to speech impairments, another about quality-of-life, and 16 questions covering the physical, emotional, and social domains. The questionnaire was applied to a population of 24 individuals of both sexes, aged between 12 and 50 years; 12 patients (case group) had phonetic speech disorders, and 12 (control group) had no impairment in oral communication. They were paired according to age and sex. To analyze the reliability of the instrument, the internal consistency of the items was assessed through Cronbach's Alpha coefficient. RESULTS: The internal consistency of the 16 questions concerning the domains was alpha=0.93; for the physical domain, alpha=0.71; for the emotional domain, alpha=0.77; and for the social domain, alpha=0.85. CONCLUSION: The questionnaire showed good reliability in identifying the impact of speech disorders on the individuals' quality of life. PMID- 24626974 TI - The social appreciation of research. PMID- 24626975 TI - P300 auditory cognitive evoked potential as an indicator of therapeutical evolution in students with developmental dyslexia. AB - PURPOSE: To verify the effectiveness of the Cognitive Auditory Evoked Potential P300 (CAEP-P300) for monitoring the therapeutical evolution of students with developmental dyslexia. METHODS: Twenty students diagnosed with developmental dyslexia, of both genders, aged between 8 and 14 years, divided into two randomized groups, one of them submitted to a phonological remediation program associated with reading and writing (GI), and the other one representing the control group (GII), participated in the study. The groups were paired up, and the individuals were submitted to two evaluations of the CAEP-P300 and the same interval was kept for both. Paired Student's t-test, ANOVA test, and Pearson's correlation coefficient were used, adopting 5% significance level. RESULTS: The statistical comparison of the pre and post evaluations of each group demonstrated difference in the Phonological Awareness Test (p=0.000) and in the P300 latency (p=0.005) only for GI. CONCLUSION: CAEP-P300 use for monitoring the therapeutical evolution of children with developmental dyslexia is possible and represents a viable option for intervention programs. PMID- 24626976 TI - Bilingualism and auditory processing abilities: performance of adults in dichotic listening tests. AB - PURPOSE: To evaluate and compare the dichotic listening abilities in non-hearing impaired adults monolingual speakers of the Brazilian Portuguese language (CG) and simultaneous Brazilian Portuguese-German (GG) bilingual speakers or successive Brazilian Portuguese-Italian bilingual speakers (IG). METHODS: This is about an observational, descriptive, transverse and quantitative research. The sample consisted of 87 subjects aged between 18 and 55 years, divided into: Control Group (CG), of 30 monolingual speakers of Brazilian Portuguese; Study Group A (SGA), of 31 simultaneous Brazilian Portuguese-German bilingual speakers; and Study Group I (SGI), of 26 successive Brazilian Portuguese-Italian speakers. The individuals were submitted to the Dichotic digits test (DDT) and to Staggered Spondaic Words (SSW). RESULTS: The DTT results showed difference in right ear and total scores when comparing SGA to CG. Comparing the CG and the SGI, it was observed difference in right and left ears and total scores. Comparing the SGA and the SGI, no difference was observed between the groups. Results of SSW showed that both bilingual groups were significantly better in the right and left ears scores and even in total one when compared to CG. Comparing the SGA and the SGI, the SGI showed better significant scores in the right ear and total. CONCLUSION: Bilingual experiences seem to influence positively the ability of high predictability dichotic listening, evaluated by DDT, and the low predictability dichotic listening, evaluated by SSW test. The SSW results also showed statistically significantly better results for successive Brazilian Portuguese Italian bilingual speakers when compared to simultaneous Brazilian Portuguese German speakers. PMID- 24626977 TI - Development of P1 cortical auditory evoked potential in children presented with sensorineural hearing loss following cochlear implantation: a longitudinal study. AB - PURPOSE: To assess the characteristics of P1 component in children presented with pre-lingual hearing loss, users of cochlear implants, and correlate them with speech perception performance. METHODS: Ten children presented with pre-lingual sensory neural hearing loss using cochlear implants participated in this research. The cortical auditory evoked potential research was carried out with the /da/ speech stimulus, presented in free field, in three moments: at cochlear implant activation, with three and six months following activation. The Infant Toddler Meaningful Auditory Integration Scale was used to verify the speech perception. RESULTS: The correlation of the three moments of the test with the latency and the amplitude of P1 component through analysis of variance were observed. The comparison of latency and amplitude of P1 in each assessment moment was performed with Tukey's test. Wilcoxon and t-test showed that the score on the Infant-Toddler Meaningful Auditory Integration Scale increased significantly with the time of cochlear implant use, nevertheless with no correlation with the latency and amplitude of P1 component in the moments assessed, as demonstrated by Spearman's and Pearson's correlations. CONCLUSION: The latency and amplitude of P1 component diminish as the time of cochlear implant use increases. However, there was no correlation between its development and speech perception performance. PMID- 24626978 TI - Study of evoked otoacoustic emissions and suppression effect on workers exposed to pesticides and noise. AB - PURPOSE: To analyze the findings for Evoked Otoacoustic Emissions (EOEA) and suppression effect in workers with normal hearing exposed to pesticides and noise . METHODS: The sample consisted of 55 participants with normal hearing, with ages ranging from 18 to 35 years, divided into two groups: one group exposed to noise and pesticides (GRA) and a control group (CG). The GRA was composed of 25 participants exposed to a representative average level of daily occupational noise exposure of 86 dBA and organophosphate-type pesticides, whereas the GC was composed of 30 participants who were not exposed to noise or pesticides. All participants underwent Transient Evoked Otoacoustic Emissions (TEOAE) and Distortion Product Otoacoustic Emissions (DPOAE) examinations and research of the suppression effect. RESULTS: The findings revealed differences between the results of TEOAE and DPOAE exams between GRA and GC groups. GRA participants showed worse results in EOAE findings. Regarding the suppression effect, lesser effects were observed in the GRA. CONCLUSION: The results suggest that the study of EOAE and suppression effect can be used in early identification of hearing damage to workers simultaneously exposed to pesticides and noise. PMID- 24626979 TI - Auditory perceptual performance of children in the identification of contrasts between stressed vowels. AB - PURPOSE: To assess the auditory perceptual performance of children in a task of identification of vowel contrasts, to classify which phonemes and vowel contrasts provide higher or lower degrees of difficulty, and to verify the influence of age in this performance. METHODS: Data recordings of auditory perceptual performance of 66 children in a task of identification using the software Perception Evaluation Auditive & Visuelle (PERCEVAL) were selected from a database. The task consisted of presenting sound stimuli through headphones to children, who would then choose, from two pictures arranged on the computer screen, the one corresponding to the word they heard. The time between auditory inputs and the child's reaction was automatically computed in the software. RESULTS: The perceptual accuracy was 88% and we found a positive correlation with the variable age. The time of response was significantly longer for incorrect answers as opposed to correct answers (p=0.00). Different degrees of similarity in auditory perception were observed, where front vowels were similar more often than back vowels. The tendency for errors was prevalent in the range of non-peripheral to peripheral vowels, which suggests that the latter may serve as a reference or perceptual anchor. CONCLUSION: The auditory perceptual ability concerning the identification of vowel contrasts is not yet established in the age group studied. The auditory perception of vowel contrasts occurs gradually and asymmetrically, as the order of acquisition in terms of production and perception was not always the same. PMID- 24626980 TI - Short-term speech-language intervention for children with disorders of the autism spectrum. AB - PURPOSE: To assess any changes in the Functional Communicative Profile (FCP) and in the Social Cognitive Performance (SCP) of children with Autism Spectrum Disorders, based on two short periods of intervention. METHODS: The study was conducted with 21 children with Autism Spectrum Disorder diagnoses, randomly allocated into two groups, who received the same short-term intervention types (6 weeks with the mother and 6 weeks with the support of an educational software program). The intervention process was conducted by speech-language pathologists who were part of a graduate program in this area. RESULTS: Samples of 15-minute interaction sessions between the child and speech-language pathologist were used to assess the changes in the FCP and the SCP. The statistic analysis pointed out differences only in Group 1 for the variables "percentage of communicative space used" and "use of the mediating object". CONCLUSION: With the intervention sessions structured over 12 weeks, it was possible to observe a few changes in the children's FCP and in the SCP. Therefore, we point out the need for new research studies of longer duration. PMID- 24626981 TI - Relation between voice disorders and work in a group of Community Health Workers. AB - PURPOSE: To analyze the relationship between voice disorders and work in a group of Community Health Agents (CHA). METHODS: The subjects of this study were 65 CHA working in the city of Sao Paulo. Thefiinstrument used for data collection was an adaptation of the questionnaire named Conditions of Vocal Production - Teachers (CPV-P). The results were keyed in twice and submitted to statistical analysis, in order to verify: the self-reported frequency of voice disorder frequency of present vocal symptoms, the association among the three most frequently reported present symptoms, and environmental and organizational aspects of work. RESULTS: Of the 65 (100%) CHA in the study, 37 (56.9%) self-reported having present or past vocal disorders. The most frequently reported present symptoms were: dry throat, tiredness when speaking, and burning sensation in the throat. There was significant association between: taking work to home, having personal items stolen, police intervention, violence against employees and vocal symptom dry throat, not having enough time to complete all tasks, difficulty in leaving work, inadequate furniture, intense physical strain, objects stolen from the health unit, racism and vocal symptom tiredness when speaking, dust, job dissatisfaction, work stress, building destruction, drug issues, and vocal symptom burning in throat. CONCLUSION: Based on the obtained results, the initial hypothesis of association between the development of vocal disorders among the subjects and the adversities present in their work environment and organization was confirmed. PMID- 24626982 TI - Factors associated with voice disorders among teachers: a case-control study. AB - PURPOSE: We aimed at verifying an association between voice disorders/stress and loss of work ability among female teachers who work in Sao Paulo's public school system. METHODS: This is a paired case- control study. The case group was composed offiteachers with alterations in speech and larynges assessments, and the control group was formed by teachers without alterations in these evaluations who work in the same schools. Both groups answered the following questionnaires: Conditions of Vocal Production-Teachers, Job Stress Scale, and Work Ability Index. The analysis was performed using the chi-square association test and logistic regression models with the purpose of estimating the association between independent variables and voice disorders. RESULTS: We found differences between the groups in relation to stress in the workplace under high demand, a situation that poses greater risks of adverse reactions to the workers' physical and mental health. Regarding the ability to work, the categories poor and moderate ability for work are associated with voice disorders, regardless of job stress factors, age, and the unsatisfactory acoustic properties of the classrooms. CONCLUSION: This study confirmed the association between voice disorders and job stress, as well as between voice disorders and loss of work ability. PMID- 24626983 TI - Parameters acoustic and high-speed kymography identified effects of voiced vibration and vocal fry exercises. AB - PURPOSE: To identify the immediate effects of voiced vibration and vocal fry exercises on healthy subjects by means of acoustic parameters and high-speed kymography. METHODS: Thirty healthy subjects (18 women and 12 men, aged from 19 to 45 years old) participated in this study. The voices were recorded at the range of 44.100 samples/second, before and after of the vocal exercises. We developed a computational routine to extract jitter and shimmer. High-speed kymography was generated from laryngeal images for the analysis of the phase times: closed (CPh), open (OPh), of closing (cPh) and of opening (oPh) and used the paired t-Student test and the Mann-Whitney test, with a significance level of 0.05. RESULTS: After voiced vibrations, acoustic parameters showed reduced jitter for both genders (p=0.018 for men and p<0.01 for women) and reduced shimmer for female voices (p<0.01). There was a decrease in CPh (p=0.046) and cPh (p=0.026) and an increase in OPh (p=0.05) in female vocal folds. After vocal fry, we identified decreased jitter (p<0.01) in female voices and cPh (p=0.026) in male vocal folds. CONCLUSION: We observed more positive immediate effects of the voiced vibrations, mainly in voice quality and vocal folds among females. Nevertheless, studies with larger male sample and investigation of the appropriate time of vocal fry are necessary to confirm the results of this search. PMID- 24626984 TI - Questionnaires on satisfaction of amplification in children: a systematic review. AB - PURPOSE: To perform a systematic review of the literature on questionnaires to assess the benefits of using hearing aids in children. METHODS: A literature search was conducted in the data-bases Web of Science and Virtual Health Library (BIREME). The selection criteria included: title consistent with the purpose of this review; participants necessarily being children using hearing aids; and questionnaires to assess the benefits and satisfaction. RESULTS: More evidence was found in studies that used the scale Parent's Evaluation of Aural/Oral Performance of Children (PEACH), making it possibly the most consistent scale on the subjective evaluation of the use of amplification in children. CONCLUSION: There is a paucity of studies with this approach; however, the results showed the importance of researches in this area, which turns the subject into an important field of research. PMID- 24626985 TI - Child language interventions in public health: a systematic literature review. AB - PURPOSE: Systematically review the literature on interventions in children's language in primary health care. METHODS: One searched the electronic databases (January 1980 to March 2013) MEDLINE (accessed by PubMed), Scopus, Lilacs and Scielo. The search terms used were "child language", "primary health care", "randomized controlled trial" and "intervention studies" (in English, Portuguese and Spanish). There were included any randomized controlled trials that addressed the issues child language and primary health care. The analysis was based on the type of language intervention conducted in primary health care. RESULTS: Seven studies were included and used intervention strategies such as interactive video, guidance for parents and group therapy. Individuals of both genders were included in the seven studies. The age of the children participant in the samples of the articles included in this review ranged from zero to 11 years. These seven studies used approaches that included only parents, parents and children or just children. CONCLUSION: The mainly intervention in language on primary health care, used in randomized controlled trials, involved the use of interactional video. Several professionals, beyond speech and language therapist, been inserted in the language interventions on primary health care, demonstrating the importance of interdisciplinary work. None of the articles mentioned aspects related to hearing. There was scarcity of randomized controlled trials that address on language and public health, either in Brazil or internationally. PMID- 24626986 TI - Functional Communication Profile and speech-language diagnosis in children of the autism spectrum: checklist use. AB - PURPOSE: The use of a different protocol to assess the same aspects of the Functional Communication Profile (FCP) may contribute to a faster and less expensive determination of individual profiles of abilities and inabilities. The purpose of this study was to verify the applicability of a checklist to replace the aforementioned complete protocol as a way to facilitate clinical and therapeutic follow-up processes. METHODS: The participants in this study were 50 children aged from 3 to 12 years, with diagnoses within the autism spectrum who were receiving specialized speech-language therapy for at least six months. The participants were filmed while interacting with the speech-language pathologist, and the data were transcribed to the FCP protocol. After the recording and prior to the transcription, the speech-language pathologists were asked to answer the checklist of Communicative Functions. RESULTS: All answers on the checklist and on the FCP were compared. The results indicated that there were statistical differences in nine of the 20 communicative functions, and in nine of the 50 children. These results suggest that the checklist is efficient to describe a group of children but not to characterize them individually. Therefore, it is possible to identify differences in the communicative profile but not to specify the frequency with which each function occurs. CONCLUSION: The checklist can be used as a tool in the therapeutic follow-up processes of children with autism spectrum disorders, but it does not replace the complete FCP protocol. PMID- 24626987 TI - Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis. AB - Usher syndrome (USH), the leading cause of hereditary combined hearing and vision loss, is characterized by sensorineural deafness and progressive retinal degeneration. Mutations in several different genes produce USH, but the proximal cause of sensory cell death remains mysterious. We adapted a proximity ligation assay to analyze associations among three of the USH proteins, Cdh23, Harmonin and Myo7aa, and the microtubule-based transporter Ift88 in zebrafish inner ear mechanosensory hair cells. We found that the proteins are in close enough proximity to form complexes and that these complexes preassemble at the endoplasmic reticulum (ER). Defects in any one of the three USH proteins disrupt formation and trafficking of the complex and result in diminished levels of the other proteins, generalized trafficking defects and ER stress that triggers apoptosis. ER stress, thus, contributes to sensory hair cell loss and provides a new target to explore for protective therapies for USH. PMID- 24626988 TI - Axon degeneration and PGC-1alpha-mediated protection in a zebrafish model of alpha-synuclein toxicity. AB - alpha-synuclein (aSyn) expression is implicated in neurodegenerative processes, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In animal models of these diseases, axon pathology often precedes cell death, raising the question of whether aSyn has compartment-specific toxic effects that could require early and/or independent therapeutic intervention. The relevance of axonal pathology to degeneration can only be addressed through longitudinal, in vivo monitoring of different neuronal compartments. With current imaging methods, dopaminergic neurons do not readily lend themselves to such a task in any vertebrate system. We therefore expressed human wild-type aSyn in zebrafish peripheral sensory neurons, which project elaborate superficial axons that can be continuously imaged in vivo. Axonal outgrowth was normal in these neurons but, by 2 days post-fertilization (dpf), many aSyn-expressing axons became dystrophic, with focal varicosities or diffuse beading. Approximately 20% of aSyn-expressing cells died by 3 dpf. Time-lapse imaging revealed that focal axonal swelling, but not overt fragmentation, usually preceded cell death. Co-expressing aSyn with a mitochondrial reporter revealed deficits in mitochondrial transport and morphology even when axons appeared overtly normal. The axon-protective protein Wallerian degeneration slow (WldS) delayed axon degeneration but not cell death caused by aSyn. By contrast, the transcriptional coactivator PGC-1alpha, which has roles in the regulation of mitochondrial biogenesis and reactive-oxygen species detoxification, abrogated aSyn toxicity in both the axon and the cell body. The rapid onset of axonal pathology in this system, and the relatively moderate degree of cell death, provide a new model for the study of aSyn toxicity and protection. Moreover, the accessibility of peripheral sensory axons will allow effects of aSyn to be studied in different neuronal compartments and might have utility in screening for novel disease-modifying compounds. PMID- 24626989 TI - An atrial-fibrillation-linked connexin40 mutant is retained in the endoplasmic reticulum and impairs the function of atrial gap-junction channels. AB - Connexin40 (Cx40)-containing gap-junction channels are expressed in the atrial myocardium and provide a low-resistance passage for rapid impulse propagation. A germline mutation in the GJA5 gene, which encodes Cx40, resulting in a truncated Cx40 (Q49X) was identified in a large Chinese family with lone (idiopathic) atrial fibrillation (AF). This mutation co-segregated with seven AF probands in an autosomal-dominant way over generations. To test the hypothesis that this Cx40 mutant affects the distribution and function of atrial gap junctions, we studied the Q49X mutant in gap-junction-deficient HeLa and N2A cells. The Q49X mutant, unlike wild-type Cx40, was typically localized in the cytoplasm and failed to form gap-junction plaques at cell-cell interfaces. When the Q49X mutant was co expressed with Cx40 or Cx43, the mutant substantially reduced the gap-junction plaque formation of Cx40 and Cx43. Electrophysiological studies revealed no electrical coupling of cell pairs expressing the mutant alone and a significant decrease in the coupling conductance when the mutant was co-expressed with Cx40 or Cx43. Further colocalization experiments with the organelle residential proteins indicate that Q49X was retained in the endoplasmic reticulum. These findings provide evidence that the Q49X mutant is capable of impairing gap junction distribution and function of key atrial connexins, which might play a role in the predisposition to and onset of AF. PMID- 24626990 TI - Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. AB - A major medical challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening, which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. We evaluated the skeletal phenotypes of mice with disrupted telomere maintenance mechanisms as models for human bone aging, including mutants in Werner helicase (Wrn(-/-)), telomerase (Terc(-/-)) and Wrn(-/-)Terc(-/-) double mutants. Compared with young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc(-/-) and Wrn(-/-)Terc(-/-) mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc(-/-) and Wrn(-/-)Terc( /-) mice have increased cortical thinning, and increased porosity relative to age matched WT mice. These trabecular and cortical changes were accelerated with age in Terc(-/-) and Wrn(-/-)Terc(-/-) mice compared with older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc(-/-) and Wrn(-/-)Terc(-/-) bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn(-/-) single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy and moment of inertia) of the Terc(-/-) and Wrn(-/-)Terc(-/-) femurs compared with WT mice were also observed. Young Wrn(-/-)Terc(-/-) mice had a statistically significant increase in bone-marrow fat content compared with young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc(-/ ) and Wrn(-/-)Terc(-/-) mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis. PMID- 24626991 TI - LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition. AB - Wolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder - a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are major co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes a mitochondrial inner-membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism, principally for seizures but also for other core features of WHS, including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from individuals with WHS. Here, using a unique panel of WHS-patient-derived cell lines with deletions of differing sizes, incorporating LETM1 or not, we show, for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS-patient cells. Furthermore, we show that this is associated with distinct mitochondrial phenotypes, including altered intracellular [Ca(2+)] levels, dysfunctional mitochondrial transition-pore opening, hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression level; these phenotypes could underlie and/or contribute to some of the core clinical features of this condition. PMID- 24626992 TI - RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. AB - RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER)/progesterone receptor (PR)/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV) promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context dependent role in breast cancer. PMID- 24626994 TI - Physical activity patterns and risk of depression in young adulthood: a 20-year cohort study since childhood. AB - PURPOSE: Little is known about how physical activity patterns during childhood and adolescence are associated with risk of subsequent depression. We examined prospective and retrospective associations between leisure physical activity patterns from childhood to adulthood and risk of clinical depression in young adulthood. METHODS: Participants (759 males, 871 females) in a national survey, aged 9-15 years, were re-interviewed approximately 20 years later. Leisure physical activity was self-reported at baseline (1985) and follow-up (2004-2006). To bridge the interval between the two time-points, historical leisure activity from age 15 years to adulthood was self-reported retrospectively at follow-up. Physical activity was categorized into groups that, from a public health perspective, compared patterns that were least beneficial (persistently inactive) with those increasingly beneficial (decreasing, increasing and persistently active). Depression (major depressive or dysthymic disorder) was assessed using the Composite International Diagnostic Interview. RESULTS: Compared with those persistently inactive, males who were increasingly and persistently active had a 69 and 65 % reduced risk of depression in adulthood, respectively (all p < 0.05). In retrospective analyses, females who were persistently active had a 51 % reduced risk of depression in adulthood (p = 0.01). Similar but non-significant trends were observed for leisure physical activity in females and historical leisure activity in males. Results excluded those with childhood onset of depression and were adjusted for various sociodemographic and health covariates. CONCLUSIONS: Findings from both prospective and retrospective analyses indicate a beneficial effect of habitual discretionary physical activity since childhood on risk of depression in young adulthood. PMID- 24626995 TI - Is early postpartum HbA1c an appropriate risk predictor after pregnancy with gestational diabetes mellitus? AB - Compared to the 2-h oral glucose tolerance test (OGTT), the assessment of HbA1c was proposed as a less time-consuming alternative to detect pathologies in carbohydrate metabolism. This report aims to assess the predictive accuracy of HbA1c to detect alterations in glucose disposition early after gestational diabetes mellitus (GDM) pregnancy. A detailed metabolic characterization was performed in 77 women with previous GDM (pGDM) and 41 controls 3-6 month after delivery: 3-h OGTT, frequently sampled intravenous glucose tolerance test. Follow up examinations of pGDMs were performed up to 10 years. HbA1c (venous samples, HPLC) was assessed at baseline as well as during the follow-up period (475 patient contacts). Moderate associations were observed between HbA1c and measurements of plasma glucose during the OGTT at the baseline examination: The strongest correlation was found for FPG (r = 0.40, p < 0.001), decreasing after ingestion. No associations were detected between HbA1c and OGTT dynamics of insulin or C-peptide. Moreover, baseline HbA1c showed only modest correlation with insulin sensitivity (r = -0.25, p = 0.010) and disposition index (r = -0.26, p = 0.007). A linear model including fasting as well as post-load glucose levels was not improved by HbA1c. However, pGDM females with overt diabetes manifestation during the follow-up period showed more pronounced increasing HbA1c in contrast to females remaining normal glucose tolerant or developing prediabetes. It is suggested that the performance of HbA1c assessed early after delivery is inferior to the OGTT for the detection of early alterations in glucose metabolism. However, an increase in HbA1c levels could be used as an indicator of risk for diabetes manifestation. PMID- 24626996 TI - The incidence, diagnosis, and management of pulmonary vein stenosis as a complication of atrial fibrillation ablation. AB - PURPOSE: Pulmonary vein isolation (PVI) during ablation of atrial fibrillation (AF) is associated with pulmonary vein stenosis (PVS). Although the reported incidence of PVS has fallen in recent years, the precise rate of PVS is unknown. Coherent guidelines for screening and treatment of PVS are not established. We reviewed literature to investigate the incidence, diagnosis, and management of PVS as a complication of PVI. METHODS: We reviewed 41 manuscripts that described a total of 4,615 subjects (median, 84 subjects/study). RESULTS: The incidence of PVS after PVI reported in literature from 1999 to 2004 ranges from 0 to 44% (mean, 6.3%; median, 5.4%), whereas studies after 2004 report an incidence of 0 19% (mean, 2%; median, 3.1%; p < 0.001). PVS symptoms typically occur with reduction of lung perfusion by 20-25%. Variable criteria exist for diagnosis of PVS by magnetic resonance imaging, computed tomography, and perfusion imaging. The restenosis rate for treatment with balloon angioplasty ranges from 30 to 87% (mean, 60%; median, 47%), compared with immediate stenting that ranges from 14 to 57% (mean, 34%; median, 33%). CONCLUSIONS: Recent peer-reviewed articles suggest that PVI carries a 3-8% risk of developing PVS, but they likely underestimate the incidence of PVS, as specific screening and diagnostic guidelines are not established. Imaging modalities should be used to screen patients after ablation of AF since early recognition of PVS improves treatment outcomes. Treatment with angioplasty and stent placement can improve symptoms and lung perfusion but the benefit of treatment with immediate stent placement remains controversial. It is critical to maintain a high clinical index of suspicion for PVS in at-risk individuals to ensure timely detection and treatment. PMID- 24626997 TI - Mapping and ablation of ventricular fibrillation-how and for whom? AB - The involvement of the Purkinje system in a subset of patients with idiopathic ventricular fibrillation or polymorphic VT/VF related to structural heart disease was first demonstrated in the pioneering work of Michel Haissaguerre and co workers (Circulation 106:962-967, 2002 and Lancet 359:677-678, 2002). It is very important to identify these patients with recurrent episodes of ventricular fibrillation and/or ICD shocks with regard to the presence of triggering premature ventricular contractions (PVC), which may be amenable to mapping and catheter ablation by screening Holter and ICD recordings. The practical problem, which is frequently encountered, is the absence of these PVCs when the patients are brought to the EP lab. However, catheter ablation is an important adjunctive tool to antiarrhythmic drug treatment, beta blocker therapy, and general anesthesia in this setting. Local electrogram criteria related to this phenomenon have been identified guiding mapping and ablation (e.g., low amplitude, high frequency Purkinje potentials preceding a closely coupled ventricular signal (Fig. 1a)). The favorable long-term follow-up after catheter ablation has been demonstrated in the setting of right and left ventricular Purkinje-related PVCs leading to polymorphic VT/VF (Leenhardt et al., Circulation 89:206-215, 1994) and also following myocardial infarction (Baensch et al., Circulation 108:3011-3016, 2003) and right ventricular outflow tract-associated VF (Noda et al., Journal of the American College of Cardiology 46:1288-1294, 2005). Most recently, epicardial ablation strategies leading to suppression of polymorphic VT/VF episodes related to the Brugada syndrome have been described irrespective to the presence of premature ventricular beats (Nademanee et al., Circulation 123:1270-1279, 2011). PMID- 24626998 TI - Contrast-induced acute kidney injury in patients undergoing cardiac resynchronization therapy-incidence and prognostic importance. Sub-analysis of data from randomized TRUST CRT trial. AB - INTRODUCTION: Because data on contrast-induced acute kidney injury (CI-AKI) in patients undergoing cardiac resynchronization therapy (CRT-D) are scarce, we aimed to assess the incidence, natural course and prognostic importance of this syndrome in CRT recipients. METHODS: Study population consisted of 100 consecutive patients enrolled into the Triple Site Versus Standard Cardiac Resynchronization (TRUST CRT) trial, who were treated with CRT-D. Two patients were excluded up to 3 months after randomization and not analysed further. CI-AKI was defined as a rise in serum creatinine of at least 26.5 MUmol/L (0.3 mg/dL) within 48 h after contrast exposure, or at least 50% increase from the baseline value during index hospital stay with CRT-D implantation according to KDIGO Clinical Practice Guideline for Acute Kidney Injury. RESULTS: Among 98 subjects of TRUST CRT trial, 10 patients (10.2%) developed CI-AKI after CRT-D implantation. In patients with glomerular filtration rate (GFR) <60 mL/min/1.73 m(2) on admission, the incidence of CI-AKI was almost twofold (15.4%) higher than in subjects with GFR >=60 (8.3%). CRT-D recipients with CI-AKI had significantly higher mortality rate (50.0%) compared to those without CI-AKI (17.0%) during 30 months of follow-up (logrank p = 0.012). Multivariate Cox regression analysis showed CI-AKI as significant and independent risk factor for death in CRT-D recipients (hazard ratio 5.71; 95% CI 5.16-6.26; p = 0.001). CONCLUSIONS: Contrast-induced acute kidney injury is a serious and frequent procedural complication of CRT-D implantation with a significant negative influence on long term survival. The results suggest that clinical evaluation regarding renal function should be considered in CRT-D recipients, both before and after device implantation. PMID- 24626999 TI - Improvement in acute contractility and hemodynamics with multipoint pacing via a left ventricular quadripolar pacing lead. AB - INTRODUCTION: A quadripolar left ventricular (LV) pacing can deliver multipoint pacing (MPP). It is unknown if this confers improved cardiac function compared to conventional cardiac resynchronization therapy (CRT). METHODS AND RESULTS: We aimed to characterize changes in acute cardiac contractility and hemodynamics with multisite left ventricular "multipoint" pacing (MPP) in a prospective multicenter study in patients implanted with a CRT-defibrillator incorporating a quadripolar LV lead. The device was programmed to deliver MPP acutely pacing with eight configurations of varying timing delays. Global peak LV radial strain and LV outflow velocity time integral (LVOT VTI) were measured for conventional CRT and each MPP configuration. Out of the eight tested MPP configurations, the one that yielded the best echocardiographic measurement for each patient was defined as "optimal MPP". Forty CRT recipients had complete radial strain datasets suitable for analysis. Compared to conventional CRT, the mean peak radial strain was significantly higher for the optimal MPP configuration (18.3 +/- 7.4 vs. 9.3 +/- 5.3%, p < 0.001), and at least one MPP configuration was significantly superior (>20%) in 63% of patients. LVOT VTI data were collected in a subset of 13 patients. In these patients, mean VTI was significantly higher for optimal MPP compared to conventional CRT (13.5 +/- 2.7 vs. 10.9 +/- 3.3 cm, p < 0.01). CONCLUSION: MPP delivered via a quadripolar LV lead resulted in a significant improvement in acute cardiac contractility and hemodynamics compared to conventional CRT in the majority of patients studied. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01044784. PMID- 24627000 TI - Tau as a biomarker of concussion. PMID- 24627001 TI - Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury. AB - Dexmedetomidine (DEX), a highly specific alpha2-adrenergic agonist, which exhibits anaesthetic-sparing, analgesia and sympatholytic properties. DEX modulates gene expression, channel activation, transmitter release, inflammatory processes and apoptotic and necrotic cell death. It has also been demonstrated to have protective effects in a variety of animal models of ischemia/reperfusion (I/R) injury, including the intestine, myocardial, renal, lung, cerebral and liver. The broad spectrum of biological activities associated with DEX continues to expand, and its diverse effects suggest that it may offer a novel therapeutic approach for the treatment of human diseases with I/R involvement. PMID- 24627002 TI - Primary adenocarcinoma of the jejunum in elderly patient. PMID- 24627004 TI - Ki-67 as an independent prognostic factor in an unselected cohort of patients with ovarian cancer: results of an explorative, retrospective study. AB - The identification of prognostic markers has clinical implications in epithelial ovarian carcinoma (EOC). Here, we studied markers for proliferation (Ki-67), endocrine regulation [progesterone receptor (PR), estrogen receptor (ER)], and invasion [urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1)]. All patients with available follow-up information and EOC tissue, who were treated at our institution between 1997 and 2004, were enrolled in the present study. Expression of Ki-67, PR and ER was determined by immunohistochemical analyses. uPA and PAI-1 antigen levels were determined using enzyme-linked immunosorbent assays. One hundred and eight patients entered the present study. The median follow-up time was 43.3 (range 11.4-68.0) months. In multivariable Cox regression analyses, Ki-67 expression showed an independent negative impact on disease-free survival (DFS) and overall survival (OS) [hazard ratio (HR) for DFS, 11.5; 95% confidence interval (CI), 2.64-49.7; p=0.001 and HR for OS, 21.2; 95% CI, 9.9-113.1; p<0.001]. After cut-off optimization, PR expression showed an independent positive impact on prognosis (HR for DFS, 0.15; 95% CI, 0.03-0.68; p=0.014 and HR for OS, 0.13; 95% CI, 0.03-0.68; p=0.016). Furthermore, postoperative residual tumor burden and completeness of chemotherapy determined the prognosis. ER, uPA and PAI-1 were not associated with survival. PR and ER, and postoperative residual tumor burden and tumor stage showed a strong correlation in an explorative Spearman's rank correlation coefficient (rho=0.759 and rho=0.426, respectively). Ki-67 and cut-off optimized PR are independently associated with the prognosis of EOC. Further prospective studies are warranted to confirm these associations and to elucidate the underlying mechanisms. PMID- 24627003 TI - StarD13 is a tumor suppressor in breast cancer that regulates cell motility and invasion. AB - Breast cancer is one of the most commonly diagnosed cancers in women around the world. In general, the more aggressive the tumor, the more rapidly it grows and the more likely it metastasizes. Members of the Rho subfamily of small GTP binding proteins (GTPases) play a central role in breast cancer cell motility and metastasis. The switch between active GTP-bound and inactive GDP-bound state is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine-nucleotide dissociation inhibitors (GDIs). We studied the role of StarD13, a recently identified Rho-GAP that specifically inhibits the function of RhoA and Cdc42. We aimed to investigate its role in breast cancer proliferation and metastasis. The levels of expression of this Rho-GAP in tumor tissues of different grades were assayed using immunohistochemistry. We observed that, while the level of StarD13 expression decreases in cancer tissues compared to normal tissues, it increases as the grade of the tumor increased. This was consistent with the fact that although StarD13 was indeed a tumor suppressor in our breast cancer cells, as seen by its effect on cell proliferation, it was needed for cancer cell motility. In fact, StarD13 knockdown resulted in an inhibition of cell motility and cells were not able to detach their tail and move forward. Our study describes, for the first time, a tumor suppressor that plays a positive role in cancer motility. PMID- 24627005 TI - Soleus muscle injury: sensitivity of ultrasound patterns. AB - OBJECTIVE: To assess the sensitivity of ultrasound in detecting soleus muscle lesions diagnosed on magnetic resonance imaging (MRI) and to characterize their location, ultrasound pattern, and evolution. MATERIALS AND METHODS: Ultrasound and MRI studies were performed between May 2009 and February 2013 on all patients who presented to the Medical Services Clinic of the Catalan Sport Council with the initial onset of sharp pain in the calf compatible with injury of the soleus muscle. An inter-observer ultrasound reliability study was also performed. RESULTS: A total of 55 cases of soleus injury were studied prospectively (22 with right leg involvement, 33 left) by ultrasound and MRI, which was utilized as the "gold standard." In MRI studies, 24 cases (43.7%) had myofascial injuries that were localized in the posterior aponeurosis (PMF) in 15 cases (27.3%) and in the anterior aponeurosis (AMF) in 9 (16.4%). Thirty-one cases (56.3%) were musculotendinous injuries, with 9 cases (16.4%) in the medial aponeurosis (MMT), 11 cases (20%) in the lateral aponeurosis (LMT), and 11 cases (20%) in the central tendon (CMT). In comparison to MRI, ultrasound was able to detect injury to the soleus in 27.2% of cases. No injuries were detected by ultrasound alone. Posterior myofascial injuries were more likely to be detected by ultrasound than anterior myofascial injuries or all types of musculotendinous injuries. Ultrasound patterns for each type of injury were described. CONCLUSION: Ultrasound is not a sensitive technique for detecting and assessing soleus traumatic tears compared with MRI, although the sensitivity is enhanced by a thorough anatomically based ultrasound examination. Timing of the ultrasound examination may be of importance. Each type of soleus injury appears to have a characteristic ultrasound pattern based on a defect of connective expansions, the existence of small myofascial filiform collections, and the rarefaction of the fibrillar area. PMID- 24627007 TI - [The British pay-for-performance in primary health care]. PMID- 24627006 TI - Jak-2 positive myeloproliferative neoplasms. AB - Originally described by Dameshek in 1951, myeloproliferative disorders are today classified as myeloproliferative Neoplasms (MPNs) in WHO's Classification of Tumors of Hematopoietic and Lymphoid Tissues. The term includes a range of conditions, [ie, BCR-ABL-positive chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), polycythemia vera (PV), primary myelofibrosis (PMF), essential thromobocythemia (ET), chronic eosinophilic leukemia not otherwise specified (CEL-NOS), mastocytosis, and unclassifiable myeloproliferative neoplasm]. In the specific case of CML, a better understanding of the pathogenesis and pathophysiology of the disease has led to a targeted therapy. The presence of chromosome Philadelphia, t(9;22)(q34;11) results in the oncogene BCR-ABL, which characterizes the disease; this molecular rearrangement gives rise to a tyrosine-kinase, which in turn triggers the proliferation of the myeloid line through the activation of the signaling pathways downstream. Tyrosine-kinase inhibitors (TKIs) have altered the therapy and monitoring of CML patients and improved both their prognosis and quality of life. In 2005, various groups of investigators described a new point mutation of the gene JAK2 associated to MPNs. Although the presence of this mutation has led to a modification in the diagnostic criteria of these conditions, the impact of the use of JAK2 inhibitors on the prognosis and course of the disease continues to be controversial. PMID- 24627008 TI - [The Olympic legacy for Brazil: is it a public health issue?]. PMID- 24627009 TI - Characterization of epidemiological surveillance systems for healthcare associated infections (HAI) in the world and challenges for Brazil. AB - Surveillance systems for healthcare-associated infections (HAI) are essential for planning actions in prevention and control. Important models have been deployed in recent decades in different countries. This study aims to present the historical and operational characteristics of these systems and discuss the challenges for Brazil. Various models around the world have drawn on the experience of the United States, which pioneered this process. In Brazil, several initiatives have been launched, but the country still lacks a full national information system on HAI, thus indicating the need to promote action strategies, strengthen the role of States in communication between the Federal and local levels, pursue a national plan to organize surveillance teams with the necessary technological infrastructure, besides updating the relevant legislation for dealing with these challenges. Such measures are essential in the Brazilian context for the unified surveillance of HAI, aimed at healthcare safety and quality. PMID- 24627010 TI - Bias of using odds ratio estimates in multinomial logistic regressions to estimate relative risk or prevalence ratio and alternatives. AB - Recent studies have emphasized that there is no justification for using the odds ratio (OR) as an approximation of the relative risk (RR) or prevalence ratio (PR). Erroneous interpretations of the OR as RR or PR must be avoided, as several studies have shown that the OR is not a good approximation for these measures when the outcome is common (> 10%). For multinomial outcomes it is usual to use the multinomial logistic regression. In this context, there are no studies showing the impact of the approximation of the OR in the estimates of RR or PR. This study aimed to present and discuss alternative methods to multinomial logistic regression based upon robust Poisson regression and the log-binomial model. The approaches were compared by simulating various possible scenarios. The results showed that the proposed models have more precise and accurate estimates for the RR or PR than the multinomial logistic regression, as in the case of the binary outcome. Thus also for multinomial outcomes the OR must not be used as an approximation of the RR or PR, since this may lead to incorrect conclusions. PMID- 24627011 TI - [Access to medium and high-complexity procedures in the Brazilian Unified National Health System: a matter of judicialization]. AB - Lawsuits in healthcare have increased exponentially in Brazil. However, the judicialization of healthcare procedures has not been sufficiently discussed, although such a discussion could broaden the scope of healthcare assessment. This study aimed to analyze the use of court action to ensure access to outpatient and hospital procedures from 1999 to 2009 in the State of Minas Gerais, Brazil. This was a retrospective descriptive study. Procedures were classified according to the Brazilian Unified National Health System (SUS) and the Table on Unified Terminology for Private Healthcare. Coverage by the SUS was 93.5%. The largest proportions of beneficiaries of such lawsuits lived in the Central and Western regions of the country (26.4% and 24%, respectively). The most common procedures involved in such cases were clinical admissions, admission to intensive care, and cardiovascular surgery. The study highlights the emerging need for access to medium and high-complexity procedures through extensive rules for coverage. PMID- 24627012 TI - [Dietary patterns of children under five years of age living in the State capital and other counties of Bahia State, Brazil, 1996 and 1999-2000]. AB - This cross-sectional study included 3,817 preschool children, of whom 1,770 in Salvador, Bahia State, Brazil, and 2,047 in urban and rural areas from nine other municipalities (counties) in the same State. The study used 24-hour recall and principal components analysis to identify and compare dietary patterns. The sample was stratified by age and area. In the first six months of life, breast milk composed the second and third patterns, with positive loadings for children in all 10 municipalities. For children under 17 months of age, pattern 1 was characterized by cow's milk, flour, and sugar, except in rural areas. Pattern 2 was similar for children aged 6-17 months and consisted of bread/cookies, rice, beans, and meat. For children 18-23 months of age in urban areas, pattern 1 showed negative loadings for sugar, cow's milk, and flour. In children over 24 months of age, fruits were not part of the first pattern. The study showed low consumption of milk and low variety of fruits and vegetables. This food consumption profile indicates the need for early interventions to promote healthy eating habits. PMID- 24627013 TI - The payment for performance model and its influence on British general practitioners' principles and practice. AB - This article explores some effects of the British payment for performance model on general practitioners' principles and practice, which may contribute to issues related to financial incentive modalities and quality of primary healthcare services in low and middle-income countries. Aiming to investigate what general practitioners have to say about the effect of the British payment for performance on their professional ethos we carried out semi-structured interviews with 13 general practitioner educators and leaders working in academic medicine across the UK. The results show a shift towards a more biomedical practice model and fragmented care with nurse practitioners and other health care staff focused more on specific disease conditions. There has also been an increased medicalisation of the patient experience both through labelling and the tendency to prescribe medications rather than non-pharmacological interventions. Thus, the British payment for performance has gradually strengthened a scientific-bureaucratic model of medical practice which has had profound effects on the way family medicine is practiced in the UK. PMID- 24627014 TI - [Discourses on the role and representativeness of municipal health conferences in Brazil]. AB - Society's participation in health policymaking is an underlying principle of the Brazilian public health system. The study analyzed participants' discourses on the role and representativeness of municipal health conferences. The study was conducted in five municipalities (counties) in Mato Grosso State, Brazil, in 2009 2010. Thirty social actors were interviewed, including municipal health council members and health system administrators, planners, city council members, and members of the office of the public prosecutor. Data were analyzed using the Qualiquantisoft software for the elaboration of the collective subject's discourse. The discourses identified by the study showed a consensus on the importance of the municipal health council, even among those who questioned the effectiveness of its planning and administrative decisions. The studied revealed discourses resulting from interpretations based on different theoretical traditions. The collective discourses presented both complementary and conflicting arguments, seeking greater resonance and influence in the public health sphere and political system and greater administrative power. PMID- 24627015 TI - Personal and behavioral factors associated with bicycling in adults from Curitiba, Parana State, Brazil. AB - Bicycling is an important form of physical activity that can promote health benefits. The objective of this study was to analyze the association between personal and behavioral aspects in transportation bicycling and leisure time bicycling in adults. Data was drawn from a household survey involving 677 adults (53.1% female) in Curitiba, Parana State, Brazil. The prevalence of bicycling was 11.2% for transportation and 16.7% for leisure. The frequency of leisure time bicycling was higher among men (PR = 2.08; p < 0.001), young people < 30 and adults aged between 30 and 39.9, bicycle owners (PR = 8.76; p < 0.001) and among the physically active. Transportation bicycling occurred more frequently among men (PR = 3.63; p < 0.001), individuals aged 30 to 39.9, those with a low socioeconomic status (PR = 5.00; p = 0.006), bicycle owners (PR = 10.2; p < 0.001) and individuals with a negative perception of their quality of life. The prevalence of bicycling is low in Curitiba considering its potential as a means of physical activity. Personal and behavioral factors were associated with each form of bicycling. PMID- 24627016 TI - [Equity in access to breast cancer screening in a mobile mammography program in southern Rio Grande do Sul State, Brazil]. AB - This study aimed to evaluate a program for the prevention and early diagnosis of breast cancer in a mobile mammography unit that visited several cities in Rio Grande do Sul, the southernmost State in Brazil, where the test was not available through routine services. The authors compared the characteristics of these patients with a group of women referred for mammography in the city of Pelotas, where such equipment is widely available. The mobile unit examined 8,607 women residing in 33 municipalities. The study identified 37 cases of breast cancer, or 4.7 cases per 1,000 tests. In Pelotas, 1,312 patients underwent mammography, and breast cancer prevalence was 6.9 cases per 1,000 tests. There were no statistical differences between the two prevalence rates, even after adjusting for potential confounders. The proposed intervention demonstrates that the availability of tests is needed for prevention and early diagnosis of breast cancer, determining the identification of cases when diagnosis would have been delayed without the mobile unit. PMID- 24627017 TI - [Adolescents' diet quality and associated factors]. AB - The aim of this study was to analyze adolescents' diet quality and associated factors using the Revised Diet Quality Index (DQI-R). A cross-sectional study was performed with 1,326 adolescents from public and private schools. Food intake was measured using a food frequency questionnaire. Crude prevalence ratio was used to evaluate the association between high DQI-R (>= 75th percentile) and independent variables. Variables with p-value < 0.20 were included in the Poisson regression analysis. Mean DQI-R was 75.1 points (95%CI: 74.8-75.5). Higher DQI-R scores were associated with <= 2 hours per day of sedentary activities (e.g., TV, computer, and videogames), >= 300 minutes per week of physical activity, and overweight. Healthy lifestyle was associated with better diet quality. The results emphasize the importance of encouraging physical activity, reducing the number of daily hours in sedentary activities, and intervening in adolescents' eating habits. PMID- 24627018 TI - [Depressive symptoms and work-related stress in Chilean workers: differential conditions for males and females]. AB - This article assessed depressive symptoms associated with work-related psychosocial risk factors according to gender in Chile, using the demand-control model (Karasek) and effort-reward imbalance (Siegrist). A cross-sectional study was conducted in a random sample of 3,010 workers (35% female and 65% male) from the country. Data analysis determined prevalence and associations through various statistical techniques (chi2, logistic regression). Exposure to psychosocial risk factors at work and prevalence of depressive symptoms were higher in women than men (15% vs. 5%). The adjusted analysis highlighted that female workers exposed to Isostrain (OR = 2.34; 95%CI: 1.42-3.85) and low rewards (OR = 2.13; 95%CI: 1.41-3.21) and male workers exposed to psychological demands (OR = 3.04; 95%CI: 1.94-4.76) and effort-reward imbalance (OR = 2.19; 95%CI: 1.39-3.46) had increased risk of depressive symptoms. Exposure to work-related psychosocial risk factors was associated with depressive symptoms in Chilean workers. Effective prevention in key aspects of work organization is thus needed. PMID- 24627019 TI - Socioeconomic inequalities and exposure to traffic-related air pollution in the city of Sao Paulo, Brazil. AB - Air pollution is a leading public health concern. In addition, poor populations have been reported as showing increased exposure to such pollution. The current study thus aimed to evaluate the socioeconomic status of the population exposed to vehicle-related air pollution in the city of Sao Paulo, Brazil. The study used data from the 2010 Census on head-of-household's mean monthly income and the percentage of households connected to the sewage system. Exposure to air pollutants was estimated according to traffic density in the census tract plus a 200m surrounding buffer. The relationship between exposure and socioeconomic variables was analyzed by the Kruskal-Wallis test. Exposure increased with increasing socioeconomic status (p < 0.001). The population with the highest socioeconomic status lives in the most polluted areas of the city. However, place of residence alone is not capable of measuring exposure. The study suggests that future epidemiological studies include other indicators of vulnerability. PMID- 24627020 TI - [Non-adherence to continuous treatment and associated factors: prevalence and determinants in adults 40 years and older]. AB - This study investigates factors associated with non-adherence to continuous drug therapy in individuals 40 years and older. A population-based survey was conducted in Cambe, Parana State, Brazil. Treatment adherence was assessed with the four-item Morisky et al. medication adherence scale. The study also assessed socio-demographic variables and health services access and use of medication. Among 1,180 interviewees, 78% reported use of medication, with continuous use in 55%. The study analyzed 639 individuals, the majority female, ranging from 40 to 59 years of age, with low schooling, and from socioeconomic stratum C (on a scale from A to E). Prevalence of non-adherence was 63.5%. Mean therapeutic complexity was 8.1. After adjusted analysis, the following factors remained associated with non-adherence: not being assisted by community health workers, discontinuous access to medication, and high frequency of medication throughout the day. The results indicate high prevalence of non-adherence, with potentially negative impacts for individuals and society. PMID- 24627021 TI - [Assessment of adherence to the WHO surgical safety checklist in urological and gynecological surgeries at two teaching hospitals in Natal, Rio Grande do Norte State, Brazil]. AB - The WHO surgical safety checklist is a useful tool for decreasing the number of adverse events in hospitals, but its implementation is still a challenge. This study aimed to assess adherence to the checklist in urological and gynecological surgeries at two teaching hospitals in Natal, Rio Grande do Norte, Brazil. A cross-sectional observational design was used, elective surgeries were selected, and data were collected from medical charts. Adherence was based on the quality and proper completion of the checklist, and the association of structural and socio-professional factors was analyzed using multiple regression. Of the 375 surgeries reviewed, 61% included a checklist and 4% were correctly filled out. The existence of a checklist was associated with gynecological surgeries (OR = 130.18) and longer operating time (OR = 2.13), while quality of the checklist was related to urological surgeries (beta = 26.36). Adherence to the checklist needs to be improved, and the observed differences suggest the influence of distinct implementation strategies at the two institutions. PMID- 24627022 TI - [Primary health care reform and implications for the organizational culture of Health Center Groups in Portugal]. AB - The health sector's increasing complexity poses major challenges for administrators. There is considerable consensus on workforce quality as a key determinant of success for any health reform. This study aimed to explore the changes introduced by an action-training intervention in the organizational culture of the 73 executive directors of Health Center Groups (ACES) in Portugal during the primary health care reform. The study covers two periods, before and after the one-year ACES training, during which the data were collected and analyzed. The Competing Values Framework allowed observing that after the ACES action-training intervention, the perceptions of the executive directors regarding their organizational culture were more aligned with the practices and values defended by the primary health care reform. The study highlights the need to continue monitoring results over different time periods to elaborate further conclusions. PMID- 24627023 TI - [Food insecurity in the Northeast and South of Brazil: magnitude, associated factors, and per capita income patterns for reducing inequities]. AB - This article addresses food insecurity among urban Brazilian families with children under seven years. A cross-sectional study in areas covered by primary health care centers identified 5,419 families in the Northeast and 5,081 in the South of the country. Food insecurity was assessed by the Brazilian Food Insecurity Scale. Prevalence of moderate or severe food insecurity was 22.9% in the Northeast and 7.5% in the South. According to the adjusted analysis, increased likelihood of moderate or severe food insecurity was associated with families headed by women, black or brown maternal skin color, low maternal education, low family income, and enrollment in the Bolsa Familia program (conditional income transfer). Moderate or severe food insecurity would be reduced by 59.5% in the Northeast and 45.4% in the South with a per capita income of at least BRL 175.00 per month. Increased family income for the poorest families and better targeting of Bolsa Familia are essential for reducing food insecurity in the country. PMID- 24627024 TI - Age, class and race discrimination: their interactions and associations with mental health among Brazilian university students. AB - Although research on discrimination and health has progressed significantly, it has tended to focus on racial discrimination and US populations. This study explored different types of discrimination, their interactions and associations with common mental disorders among Brazilian university students, in Rio de Janeiro in 2010. Associations between discrimination and common mental disorders were examined using multiple logistic regression models, adjusted for confounders. Interactions between discrimination and socio-demographics were tested. Discrimination attributed to age, class and skin color/race were the most frequently reported. In a fully adjusted model, discrimination attributed to skin color/race and class were both independently associated with increased odds of common mental disorders. The simultaneous reporting of skin color/race, class and age discrimination was associated with the highest odds ratio. No significant interactions were found. Skin color/race and class discrimination were important, but their simultaneous reporting, in conjunction with age discrimination, were associated with the highest occurrence of common mental disorders. PMID- 24627025 TI - Federal funding of health policy in Brazil: trends and challenges. AB - The article analyzes Federal funding of health policy in Brazil in the 2000s, focusing on the Ministry of Health's budget implementation. Federal spending on health was less unstable between 2000 and 2002 and has expanded since 2006. However, it fluctuated as a share of both the Gross Domestic Product and Gross National Revenue. Federal intergovernmental transfers increased, exceeding 70% in 2007. Meanwhile, the proportion of Federal investments remained low, varying from 3.4% to 6.3%. The highest absolute amount of spending was on specialized outpatient and hospital care. The decade showed a proportionally greater increase in spending on pharmaceutical care. The growing allocation of Federal funds to States in the North and Northeast, especially for primary care and epidemiological surveillance, failed to offset the sharp regional inequalities in per capita Federal spending. The main characteristics of health funding limit Federal health policy governance and pose several challenges for the Brazilian Unified National Health System. PMID- 24627026 TI - [Autonomy for financial management in public and private healthcare facilities in Brazil]. AB - Autonomy in financial management is an advantage in public administration. A 2009 National Healthcare Facility Survey showed that 3.9% of Brazil's 52,055 public healthcare facilities had some degree of financial autonomy. Such autonomy was more common in inpatient facilities (17.8%), those managed by State governments (26.3%), and in Southern Brazil (6.6%). Autonomy was mainly partial (for resources in specific areas, relating to small outlays, consumables and capital goods, and outsourced services or personnel). 74.3% of 2,264 public facilities with any financial autonomy were under direct government administration. Financial autonomy in public healthcare facilities appears to be linked to local political decisions and not necessarily to the facility's specific legal and administrative status. However, legal status displays distinct scopes of autonomy - those under direct government administration tend to be less autonomous, and those under private businesses more autonomous; 85.8% of the 45,394 private healthcare facilities reported that they were financially autonomous. PMID- 24627027 TI - Use of medicines by homeless people in Porto, Portugal. AB - The objective of this study was to describe patterns of medication use among homeless adults from the city of Porto, Portugal. We recruited 146 homeless participants in four social services institutions. Data on the use of medicines in the previous week were collected using face-to-face interviews. We described the prevalence and main correlates of use of medicines from different Anatomical Therapeutic Chemical classification (ATC) groups. A total of 56.8% of the homeless reported to have used at least one medicine in the previous week. The most frequently reported were benzodiazepines (21.9%) and antipsychotics (15.1%); socio-demographic characteristics, lifestyle variables and use of health care were not found to be significantly associated with their use. The prevalence was 1.4% for anti-inflammatory and antirheumatic products, and 6.2% for antihypertensives, diuretics and beta-blocking agents. Medicines pertaining to the nervous system ATC group were by far the most frequently used, while those for the treatment of other common chronic and acute conditions seem to be underused. PMID- 24627028 TI - [Utilitarian managerism in academic output in public health: the importance of critical essays]. PMID- 24627029 TI - [Letter to the editors regarding the editorial published in the volume 29, number 11]. PMID- 24627030 TI - Relationship of late arteriovenous fistula stenosis with soluble E-selectin and soluble EPCR in chronic hemodialysis patients with arteriovenous fistula. AB - BACKGROUND/AIMS: Vascular access dysfunction caused by stenosis is a major complication for hemodialysis (HD) patients. However, physiopathology of late arteriovenous fistula (AVF) stenosis is still under investigation. The aim of the present study was to evaluate the association between plasma soluble EPCR (sEPCR) with serum soluble E-selectin (sE-selectin) concentration and late AVF stenosis in HD patients. METHODS: Plasma sEPCR and serum sE-selectin concentrations were measured in 94 HD patients. Using these data, we studied the association of sEPCR and sE-selectin with the presence and degree of AVF stenosis using ultrasonography and fistulogram. RESULTS: Fifty-one patients have AVF stenosis, and the others (n = 43) have patent AVF. The degree of AVF stenosis was correlated with serum sE-selectin levels (r = 0.351, p = 0.01), but not sEPCR (r = 0.075, p = 0.702). The median level of sE-selectin was statistically higher in the group of AVF stenosis than in the group of patent AVF [463.2 pg/ml (275.4 671.4) vs. 162.5 pg/ml (96.7-285.3), p = 0.001]. Increased sE-selectin levels [OR (OR) = 6.356, p = 0.015] and high levels of LDL (OR = 4.321, p = 0.044) were independent predictors of late AVF stenosis in the multivariate model. CONCLUSIONS: sE-selectin and the LDL were the most important predictors of late AVF stenosis. In addition, sE-selectin correlated with the degree of AVF stenosis. We suggested that atherosclerosis might be contributing factor for development of late AVF stenosis. PMID- 24627031 TI - Tumor necrosis factor-alpha synergistically enhances polyinosinic-polycytidylic acid-induced toll-like receptor 3 signaling in cultured normal human mesangial cells: possible involvement in the pathogenesis of lupus nephritis. AB - AIM: It has been reported that tumor necrosis factor (TNF)-alpha plays dual controversial roles, beneficial or detrimental, in the pathogenesis of murine lupus nephritis (LN). However, its precise role in the development of human LN remains to be determined. METHODS: We examine the effect of pretreatment with TNF alpha on the toll-like receptor 3 (TLR3) signaling induced by polyinosinic polycytidylic acid (poly IC), a synthetic analog of viral dsRNA that makes "pseudoviral" infection in cultured normal human mesangial cells, and analyzed the expression of CC chemokine ligand 5 (CCL5) via TLR3/interferon (IFN) beta/retinoic acid-inducible gene-I (RIG-I) pathway by reverse transcriptase polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay. RESULTS: We found synergistic effect of TNF-alpha, even at low level, on the expression of CCL5 induced by poly IC in a concentration-dependent manner, in comparison with that by poly IC alone. Knockdown of either IFN-beta or RIG-I decreased CCL5 expression induced by TNF-alpha followed by poly IC. CONCLUSION: Pretreatment with TNF-alpha leads marked activation of the TLR3/IFN-beta/RIG I/CCL5 axis induced by "pseudoviral" infection. Since chronic local activation of proinflammatory cytokines including TNF-alpha in resident renal cells may exist in patients with active lupus, synergistic effect of TNF-alpha and "pseudoviral" infection is possibly involved in the development of LN. PMID- 24627032 TI - Algal omics: unlocking bioproduct diversity in algae cell factories. AB - Rapid advances in "omic" technologies are helping to unlock the full potential of microalgae as multi-use feedstocks, with utility in an array of industrial biotechnology, biofuel, and biomedical applications. In turn, algae are emerging as highly attractive candidates for development as microbial cell factories. In this review, we examine the wide array of potential algal bioproducts, with a focus upon the role of omic technologies in driving bioproduct discovery and optimization in microalgal systems. PMID- 24627033 TI - Comparative genomics of the pine pathogens and beetle symbionts in the genus Grosmannia. AB - Studies on beetle/tree fungal symbionts typically characterize the ecological and geographic distributions of the fungal populations. There is limited understanding of the genome-wide evolutionary processes that act within and between species as such fungi adapt to different environments, leading to physiological differences and reproductive isolation. Here, we assess genomic evidence for such evolutionary processes by extending our recent work on Grosmannia clavigera, which is vectored by the mountain pine beetle and jeffrey pine beetle. We report the genome sequences of an additional 11 G. clavigera (Gc) sensu lato strains from the two known sibling species, Grosmannia sp. (Gs) and Gc. The 12 fungal genomes are structurally similar, showing large-scale synteny within and between species. We identified 103,430 single-nucleotide variations that separated the Grosmannia strains into divergent Gs and Gc clades, and further divided each of these clades into two subclades, one of which may represent an additional species. Comparing variable genes between these lineages, we identified truncated genes and potential pseudogenes, as well as seven genes that show evidence of positive selection. As these variable genes are involved in secondary metabolism and in detoxifying or utilizing host-tree defense chemicals (e.g., polyketide synthases, oxidoreductases, and mono-oxygenases), their variants may reflect adaptation to the specific chemistries of the host trees Pinus contorta, P. ponderosa, and P. jeffreyi. This work provides a comprehensive resource for developing informative markers for landscape population genomics of these ecologically and economically important fungi, and an approach that could be extended to other beetle-tree-associated fungi. PMID- 24627034 TI - The doubly conditioned frequency spectrum does not distinguish between ancient population structure and hybridization. AB - Distinguishing between hybridization and population structure in the ancestral species is a key challenge in our understanding of how permeable species boundaries are to gene flow. The doubly conditioned frequency spectrum (dcfs) has been argued to be a powerful metric to discriminate between these two explanations, and it was used to argue for hybridization between Neandertal and anatomically modern humans. The shape of the observed dcfs for these two species cannot be reproduced by a model that represents ancient population structure in Africa with two populations, while adding hybridization produces realistic shapes. In this letter, we show that this result is a consequence of the spatial coarseness of the demographic model and that a spatially structured stepping stone model can generate realistic dcfs without hybridization. This result highlights how inferences on hybridization between recently diverged species can be strongly affected by the choice of how population structure is represented in the underlying demographic model. We also conclude that the dcfs has limited power in distinguishing between the signals left by hybridization and ancient structure. PMID- 24627035 TI - Are growth factor receptors modulated by metformin in human endometrial stromal cells after stimulation with androgen and insulin? AB - OBJECTIVE: To assess the effect of metformin on gene and protein expression of insulin receptor (IR) and IGF-1 (IGF-1R) receptor in human endometrial stromal cells after stimulation with androgen and insulin. STUDY DESIGN: Primary culture of endometrial stromal cells stimulated with estrogen, progesterone with or without androgen or insulin, and treated with metformin for 24 and 48 h, followed by RNA (qRT-PCR) and protein (Western blot) extraction and analysis. RESULTS: IR gene expression was increased after treatment with insulin (2.9-fold change, p = 0.027) and further after metformin treatment (4.7-fold change, p < 0.001), and in IGF-1R, the group treated with insulin (1.83-fold change) and metformin (1.78 fold change) showed more expression, than control group (p < 0.001). Similarly, IR protein expression was increased after addition of metformin and insulin (249,869 +/- 15,878) in relation to the other groups (p < 0.001). Furthermore, cells treated with insulin (153,634 +/- 29,123) and androgen plus insulin (162,854 +/- 86,258) had a higher IR protein expression compared to control (104,654 +/- 5,634) and androgen group (71,595 +/- 3,439, (p = 0.045 and 0.021). In groups treated with insulin (127,711 +/- 4,591) and androgen plus insulin (151,098 +/- 5,194) the protein IGF-1R was increased compared to control (79,355 +/- 3,470) and the androgen-only group (79,326 +/- 3,114) (p < 0.001). CONCLUSION: Metformin in combination with insulin increased IR protein and gene expressions, while it had no influence on the protein expression of IGF-1R in endometrial stromal cells. PMID- 24627036 TI - Blood biomarkers for brain injury in concussed professional ice hockey players. AB - IMPORTANCE: Lack of objective biomarkers for brain damage hampers acute diagnosis and clinical decision making about return to play after sports-related concussion. OBJECTIVES: To determine whether sports-related concussion is associated with elevated levels of blood biochemical markers of injury to the central nervous system and to assess whether plasma levels of these biomarkers predict return to play in professional ice hockey players with sports-related concussion. DESIGN, SETTING, AND PARTICIPANTS: Multicenter prospective cohort study involving all 12 teams of the top professional ice hockey league in Sweden, the Swedish Hockey League. Two hundred eighty-eight professional ice hockey players from 12 teams contesting during the 2012-2013 season consented to participate. All players underwent clinical preseason baseline testing regarding concussion assessment measures. Forty-seven players from 2 of the 12 ice hockey teams underwent blood sampling prior to the start of the season. Thirty-five players had a concussion from September 13, 2012, to January 31, 2013; of these players, 28 underwent repeated blood sampling at 1, 12, 36, and 144 hours and when the players returned to play. MAIN OUTCOMES AND MEASURES: Total tau, S-100 calcium-binding protein B, and neuron-specific enolase concentrations in plasma and serum were measured. RESULTS: Concussed players had increased levels of the axonal injury biomarker total tau(median, 10.0 pg/mL; range, 2.0-102 pg/mL) compared with preseason values (median, 4.5pg/mL; range, 0.06-22.7 pg/mL) (P < .001). The levels of the astroglial injury biomarker S-100 calcium-binding protein B were also increased in players with sports-related concussion(median, 0.075 MUg/L; range, 0.037-0.24 MUg/L) compared with preseason values (median,0.045 MUg/L; range, 0.005-0.45 MUg/L) (P < .001). The highest biomarker concentrations of total tau and S-100 calcium-binding protein B were measured immediately after a concussion, and they decreased during rehabilitation. No significant changes were detected in the levels of neuron-specific enolase from preseason values (median, 6.5 MUg/L; range,3.45-18.0 MUg/L) to postconcussion values (median, 6.1 MUg/L; range, 3.6-12.8 MUg/L) (P = .10). CONCLUSIONS AND RELEVANCE: Sports-related concussion in professional ice hockey players is associated with acute axonal and astroglial injury. This can be monitored using blood biomarkers, which may be developed into clinical tools to guide sport physicians in the medical counseling of athletes in return-to-play decisions. PMID- 24627037 TI - Indocyanine green videoangiography for assessment of postoperative hyperperfusion in moyamoya disease. AB - BACKGROUND: Postoperative cerebral hyperperfusion (HP) is a notable complication that occurs more frequently in moyamoya disease (MMD) than in atherosclerosis. This study aimed to clarify the characteristics of intraoperative indocyanine green (ICG) videoangiography in MMD and atherosclerotic disease in terms of postoperative HP. METHODS: This prospective study included 47 patients with 60 sides that underwent superior temporal artery (STA)-middle cerebral artery (MCA) single bypass. ICG videoangiography was performed after revascularization. The ICG time intensity curve was recorded in the STA, proximal MCA, distal MCA, and superficial Sylvian vein, and the angiographic differences among adult MMD, pediatric MMD, and atherosclerosis were analyzed. RESULTS: Twenty-two patients (27 sides) had adult MMD, 14 patients (22 sides) had pediatric MMD, and 11 patients (11 sides) had atherosclerosis. Postoperative HP was significantly higher in adult MMD (40.7 %) than in pediatric MMD (18.2 %) and atherosclerosis (0 %). Adult MMD with HP was associated with a longer ICG peak time (P < 0.001). There was no correlation between the ICG peak time and preoperative cerebral blood flow or vascular reserve. The ratio of the vessel caliber was also higher in adult MMD with HP (P < 0.001). CONCLUSIONS: ICG videoangiography provides different characteristics of bypass flow among adult MMD, pediatric MMD, and atherosclerosis. Poor run-off and stagnation of blood flow from the STA might contribute to postoperative HP in MMD. The occurrence of postoperative HP in MMD could depend on two factors: donor STA size and poor run-off and integrity of the blood brain barrier in the recipient MCA. PMID- 24627038 TI - Long-lived spin state of a tripeptide in stretched hydrogel. AB - The longitudinal (T 1), transverse (T 2), and singlet state (T s) relaxation times of the geminal backbone protons (CH2) of L-Leu-Gly-Gly were studied by NMR spectroscopy at 9.4 T in a bovine hide gelatin gel composed in D2O at 25 degrees C. Gelatin granules were dissolved in a hot solution of the tripeptide and then the solution was allowed to gel inside a flexible silicone tubing. With increases in gelatin content, the T 2 and T s of the CH2 protons correspondingly decreased (T s/T 2 ~ constant), while the change in T 1 was relatively small. The largest observed T s/T 1 value was 3.3 at 46% w/v gelatin that was the lowest gelatin content examined. Stretching the tubing, and hence the gel, brought about anisotropic alignment of the constituents resulting in residual quadrupolar splitting of the resonance from D2O in (2)H NMR spectra, and residual dipolar splitting of the CH2 resonance in (1)H NMR spectra. WALTZ-16 decoupling during the relaxation intervals extended the singlet state relaxation time, but the efficacy diminished as the gels were stretched. Theoretically predicted T 1, T 2, and T s values, assuming intramolecular dipolar coupling as the only source of relaxation, were within the same order of magnitude as the experimentally observed values. Overall we showed that it is possible to observe a long-lived spin state in an anisotropic medium when T 2 is shorter than T 1 in the presence of non-zero residual dipolar couplings. PMID- 24627039 TI - [Guided growth in children and adolescents. Correction of leg length discrepancies and leg axis deformities]. AB - The treatment of crooked legs and unequal leg length is one of the key tasks of orthopedic surgery. While mature patients usually require complex and invasive surgical interventions, the growth potential of the physes can be used to advantage for correction of these leg length discrepancies and axis deformities of the legs in growing children and adolescents. This guided growth is induced by temporary or permanent and partial or complete arrest of the growth plate, depending on the indications. This technique is called epiphysiodesis. Although these procedures are principally less invasive with few complications, accurate preoperative indications and planning, precise surgical techniques and careful postoperative follow-up examinations are mandatory prerequisites to achieve the desired therapeutic target. PMID- 24627040 TI - Downregulation of VEGF expression attenuates malignant biological behavior of C6 glioma stem cells. AB - Several lines of direct evidence show that gliomas express high levels of vascular endothelial growth factor (VEGF). VEGF can promote the growth of gliomas through angiogenesis. It is believed that gliomas originate in the brain tumor stem cells (BTSCs). However, the direct effect of VEGF on the biological behavior of BTSCs has not been completely elucidated. In this study, we established C6 glioma stem cells (C6GSCs) from the C6 glioma cells. Furthermore, we suppressed the VEGF expression of C6GSCs using lentiviral vector-VEGF shRNA. After transfection, the VEGF expression of C6GSCs was downregulated significantly. The proliferation and invasion capacity of transfected C6GSCs was impaired and the ability of differentiation was enhanced. The data demonstrate that downregulation of VEGF expression attenuates malignant biological behavior of C6GSCs. RNA interference of VEGF expression implies an effective anti-gliomas strategy. PMID- 24627041 TI - [Resistance to first-line drugs and major genotypic lineages of Mycobacterium tuberculosis in the 3 French Department of the Americas: Profiles, evolution, and trends (1995-2011)]. AB - This is the first overview on resistant and multidrug resistant isolates of Mycobacterium tuberculosis circulating in the French Department of the Americas (Guadeloupe, Martinique, and French Guiana) over 17 years (January 1995-December 2011). A total of 1,239 cases were studied: 1,199 new cases (primary and multidrug resistance of 11.8 and 1.6% respectively), and 40 persistent (defined as cases with a previous history of positive culture over 6 months interval and whose spoligotypes remain unchanged), in which significantly higher proportions of resistance to at least isoniazid (22.5%, P = 0.002), rifampicin (20.0%, P < 0.001), and multidrug resistance (17.5%, P < 0.001) were observed as compared to new cases. The 281 spoligotypes obtained showed the presence of five major lineages, T (29.9%), LAM (23.9%), Haarlem (22.1%), EAI (7.1%), and X (6.7%). Two of these lineages, X and LAM, predominate among resistant and multidrug resistant isolates respectively (X: 10.5% of resistant isolates, P = 0.04; LAM: 42.3% of multidrug resistant isolates, P = 0.02). Four of the 19 major spoligo-profiles, corresponding to SIT 20, 64, 45, and 46, were significantly associated with drug resistance. Among them, genotype SIT 20, associated with monoresistance to isoniazid and multidrug resistance, would be actively and persistently in circulation, since 1999, in French Guiana, department in which one may also observe the presence of strains of M. tuberculosis phylogeographically associated to Guiana and Suriname (SIT 131 and SIT 1340). PMID- 24627042 TI - The BRCA2 gene is a potential molecular target during 5-fluorouracil therapy in human oral cancer cells. AB - 5-Fluorouracil (5-FU) is widely used in clinical cancer therapy. It is commonly used either alone or in combination with other drugs and/or radiation for head and neck, and other types of cancers. 5-FU induces DNA double-strand breaks (DSBs). Inhibition of the repair of 5-FU-induced DSBs may improve the therapeutic response in many tumors to this anticancer agent. The aim of the present study was to further our understanding of the pathways which are involved in the repair of 5-FU-induced DSBs. Cell survival after drug treatment was examined with colony forming assays using Chinese hamster lung fibroblast cells or Chinese hamster ovary cell lines which are deficient in DSB repair pathways involving the homologous recombination repair-related genes BRCA2 and XRCC2, and the non homologous end joining repair-related genes DNA-PKcs and Ku80. It was found that BRCA2 was involved in such repair, and may be effectively targeted to inhibit the repair of 5-FU-induced damage. Observations showed that knockdown of BRCA2 using small interference RNA suppression increased the sensitivity to 5-FU of human oral cancer cell lines (SAS and HSC3). These findings suggest that downregulation of BRCA2 may be useful for sensitizing tumor cells during 5-FU chemotherapy. PMID- 24627043 TI - Cross-sectional imaging of perforated gallbladder. AB - Gallbladder perforation is a potentially life-threatening condition commonly seen as a complication of acute cholecystitis. Urgent surgical intervention is often needed to reduce serious morbidity and mortality. It presents a diagnostic challenge due to nonspecific symptoms, leading to a delay in diagnosis. Imaging plays a vital role in early identification of this potentially fatal condition and evaluation by more than one imaging modality may be required to make the diagnosis. Knowledge of specific and ancillary imaging findings is crucial to avoid misdiagnosis. In this article, we will review the risk factors, pathophysiology, and surgical classification of gallbladder perforation and discuss the role of multimodality imaging in its diagnosis. Differential diagnoses on imaging will also be discussed. PMID- 24627044 TI - Neuroscience and humanistic psychiatry: a residency curriculum. AB - OBJECTIVE: Psychiatry residencies with a commitment to humanism commonly prioritize training in psychotherapy, cultural psychiatry, mental health policy, promotion of human rights, and similar areas reliant upon dialogue and collaborative therapeutic relationships. The advent of neuroscience as a defining paradigm for psychiatry has challenged residencies with a humanistic focus due to common perceptions that it would entail constriction of psychiatric practice to diagnostic and psychopharmacology roles. The author describes a neuroscience curriculum that has taught psychopharmacology effectively, while also advancing effectiveness of language-based and relationship-based therapeutics. METHODS: In 2000, the George Washington University psychiatry residency initiated a neuroscience curriculum consisting of (1) a foundational postgraduate year 2 seminar teaching cognitive and social neuroscience and its integration into clinical psychopharmacology, (2) advanced seminars that utilized a neuroscience perspective in teaching specific psychotherapeutic skill sets, and (3) case-based teaching in outpatient clinical supervisions that incorporated a neuroscience perspective into traditional psychotherapy supervisions. Curricular assessment was conducted by (1) RRC reaccreditation site visit feedback, (2) examining career trajectories of residency graduates, (3) comparing PRITE exam Somatic Treatments subscale scores for 2010-2012 residents with pre-implementation residents, and (4) postresidency survey assessment by 2010-2012 graduates. RESULTS: The 2011 RRC site visit report recommended a "notable practice" citation for "innovative neurosciences curriculum." Three of twenty 2010-2012 graduates entered neuroscience research fellowships, as compared to none before the new curriculum. PRITE Somatic Treatments subscale scores improved from the 23rd percentile to the 62nd percentile in pre- to post-implementation of curriculum (p < .001). Recent graduates rated effectiveness of clinical psychopharmacology training as 8.6 on ten-point Likert scale. CONCLUSIONS: From multiple vantage points of assessment, these outcome results support effectiveness of this neuroscience curriculum for a residency committed to humanistic psychiatry as its primary mission. As a naturalistic study, further examination of its methods in pretest and posttest assessments and a multisite comparison is warranted. PMID- 24627046 TI - Changes in the solubility of corn proteins through interaction with the arabinoxylans in extruded nixtamalized corn flour treated with xylanase. AB - The extrusion process allows the production of nixtamalized corn flour rich in arabinoxylans, which help to prevent cardiovascular and intestinal diseases. During extrusion, physiochemical properties of nixtamalized corn flour are negatively modified. The use of enzymes such as xylanase in order to obtain nixtamalized corn flour using extrusion has been studied as an alternative to reduce these changes in corn flour tortilla. The aim of this research was to evaluate changes in protein solubility of extruded nixtamalized corn flour with and without different concentrations of xylanase enzyme (0.05, 0.075, and 0.1%, w/w). Soluble proteins of each corn flour were extracted and analyzed by SE-HPLC, while insoluble proteins were determined by the combustion method. In addition, each corn flour was analyzed by scanning electron microscopy (SEM). Results showed that the extruded nixtamalized corn flour, with and without xylanase, increased the protein solubility, and this effect was lower in extruded nixtamalized corn flour with xylanase. Insoluble protein diminished in corn flours either with or without xylanase enzyme. The addition of xylanase reduces the effect that the extrusion process has on the solubility proteins of extruded nixtamalized corn flour. PMID- 24627045 TI - 6-Hydroxydopamine impairs mitochondrial function in the rat model of Parkinson's disease: respirometric, histological, and behavioral analyses. AB - Mitochondrial defects have been shown to be associated with the pathogenesis of Parkinson's disease (PD). Yet, experience in PD research linking mitochondrial dysfunction, e.g., deregulation of oxidative phosphorylation, with neuronal degeneration and behavioral changes is rather limited. Using the 6 hydroxydopamine (6-OHDA) rat model of PD, we have investigated the potential role of mitochondria in dopaminergic neuronal cell death in the substantia nigra pars compacta by high-resolution respirometry. Mitochondrial function was correlated with the time course of disease-related motor behavior asymmetry and dopaminergic neuronal cell loss, respectively. Unilateral 6-OHDA injections (>2.5 MUg/2 MUl) into the median forebrain bundle induced an impairment of oxidative phosphorylation due to a decrease in complex I activity. This was indicated by increased flux control coefficient. During the period of days 2-21, a progressive decrease in respiratory control ratio of up to -58 % was observed in the lesioned compared to the non-lesioned substantia nigra of the same animals. This decrease was associated with a marked uncoupling of oxidative phosphorylation. Mitochondrial dysfunction, motor behavior asymmetry, and dopaminergic neuronal cell loss correlated with dosage (1.25-5 MUg/2 MUl). We conclude that high resolution respirometry may allow the detection of distinct mitochondrial dysfunction as a suitable surrogate marker for the preclinical assessment of potential neuroprotective strategies in the 6-OHDA model of PD. PMID- 24627047 TI - Development of an industrializable fermentation process for propionic acid production. AB - Propionic acid (PA) is a short-chain fatty acid with wide industrial application including uses in pharmaceuticals, herbicides, cosmetics, and food preservatives. As a three-carbon building block, PA also has potential as a precursor for high volume commodity chemicals such as propylene. Currently, most PA is manufactured through petrochemical routes, which can be tied to increasing prices and volatility due to difficulty in demand forecasting and feedstock availability. Herein described are research advancements to develop an industrially feasible, renewable route to PA. Seventeen Propionibacterium strains were screened using glucose and sucrose as the carbon source to identify the best platform strain. Propionibacterium acidipropionici ATCC 4875 was selected as the platform strain and subsequent fermentation optimization studies were performed to maximize productivity and yield. Fermentation productivity was improved three-fold to exceed 2 g/l/h by densifying the inoculum source. Byproduct levels, particularly lactic and succinic acid, were reduced by optimizing fermentor headspace pressure and shear. Following achievement of commercially viable productivities, the lab grade medium components were replaced with industrial counterparts to further reduce fermentation costs. A pure enzymatically treated corn mash (ECM) medium improved the apparent PA yield to 0.6 g/g (PA produced/glucose consumed), but it came at the cost of reduced productivity. Supplementation of ECM with cyanocobalamin restored productivity to near lab-grade media levels. The optimized ECM recipe achieved a productivity of 0.5 g/l/h with an apparent PA yield of 0.60 g/g corresponding to a media cost <1 USD/kg of PA. These improvements significantly narrow the gap between the fermentation and incumbent petrochemical processes, which is estimated to have a manufacturing cost of 0.82 USD/kg in 2017. PMID- 24627048 TI - Engineering of Yarrowia lipolytica lipase Lip8p by circular permutation to alter substrate and temperature characteristics. AB - Applications of lipases are mainly based on their catalytic efficiency and substrate specificity. In this study, circular permutation (CP), an unconventional protein engineering technique, was employed to acquire active mutants of Yarrowia lipolytica lipase Lip8p. A total of 21 mutant lipases exhibited significant shifts in substrate specificity. Cp128, the most active enzyme mutant, showed higher catalytic activity (14.5-fold) and higher affinity (4.6-fold) (decreased K m) to p-nitrophenyl-myristate (pNP-C14) than wild type (WT). Based on the three-dimensional (3D) structure model of the Lip8p, we found that most of the functional mutation occurred in the surface-exposed loop region in close proximity to the lid domain (S112-F122), which implies the steric effect of the lid on lipase activity and substrate specificity. The temperature properties of Cp128 were also investigated. In contrast to the optimal temperature of 45 degrees C for the WT enzyme, Cp128 exhibited the maximal activity at 37 degrees C. But it is noteworthy that there is no change in thermostability. PMID- 24627049 TI - Molecular epidemiology of methicillin-resistant S. aureus in the ICU setting. PMID- 24627051 TI - Collaborative scientific research networks. PMID- 24627050 TI - FTO and obesity: mechanisms of association. AB - The Fat mass and obesity associated (FTO) gene is a newly identified genetic factor for obesity. However, the exact molecular mechanisms responsible for the effect of FTO on obesity remain largely unknown. Recent studies from genome-wide associated studies reveal that genetic variants in the FTO gene are associated not only with human adiposity and metabolic disorders, but also with cancer, a highly obesity-associated disease as well. Data from animal and cellular models further demonstrate that the perturbation of FTO enzymatic activity dysregulates genes related to energy metabolism, causing the malfunction of energy and adipose tissue homeostasis in mice. The most significant advance about FTO research is the recent discovery of FTO as the first N6-methyl-adenosine (m(6)A) RNA demethylase that catalyzes the m(6)A demethylation in alpha-ketoglutarate - and Fe(2+)-dependent manners. This finding provides the strong evidence that the dynamic and reversible chemical m(6)A modification on RNA may act as a novel epitranscriptomic marker. Furthermore, the FTO protein was observed to be partially localized onto nuclear speckles enriching mRNA processing factors, implying a potential role of FTO in regulating RNA processing. This review summarizes the recent progress about biological functions of FTO through disease association studies as well as the data from in vitro and in vivo models, and highlights the biochemical features of FTO that might be linked to obesity. PMID- 24627052 TI - Legal highs: a public health problem. PMID- 24627053 TI - [Towards a theoretical framework for rethinking cultural accessibility]. AB - Health services accessibility is a key health policy issue. However, few in-depth studies have addressed it theoretically. Most distinguish between availability, accessibility, and acceptability, or between geographic, financial, administrative, and cultural accessibility. We discuss and analyze the concept of accessibility as conflictive articulation between supply and demand in health. The article addresses the importance of cultural accessibility, rethinking it as a social interface, i.e., a social arena with clashing worldviews (namely, those of physicians and patients). The approach sheds light on the complex processes of grasping, translating, and reshaping knowledge and recommendations within such interaction. PMID- 24627054 TI - Applying the Fuzzy Delphi Method for determining socio-ecological factors that influence adherence to mammography screening in rural areas of Mexico. AB - In Mexico, regular participation in mammography screening is low, despite higher survival rates. The objective of our research is to highlight healthcare procedures to be optimized and target areas to encourage investment and to raise awareness about the benefits of early diagnosis. Those socio-ecological factors (community, interpersonal and individual) were collected through a review of literature and based on the spatial interaction model of mammography use developed by Mobley et al. The opinion of diverse groups of experts on the importance of those factors was collected by survey. The Fuzzy Delphi Method helped to solve the inherent uncertainty of the survey process. Our findings suggest that population health behaviors, proximity-density to facilities/ physicians and predisposing factors are needed to increase the screening rate. Variations in expert group size could affect the accuracy of the conclusions. However, the application of the enhanced aggregation method provided a group consensus that is less susceptible to misinterpretation and that weighs the opinion of each expert according to their clinical experience in mammography research. PMID- 24627055 TI - Social geography of AIDS in Brazil: identifying patterns of regional inequalities. AB - The trend towards decline and stabilization of the AIDS epidemic in Brazil should be analyzed carefully, since aggregate data can mask regional or local inequalities in such a large and diverse country. The current study reevaluates the epidemic's spatial dissemination and the AIDS-related mortality pattern in Brazil. The study considered all AIDS cases diagnosed in individuals over 18 years of age and living in Brazil, as well as AIDS deaths recorded in 1998-2008. Three-year moving average rates were estimated, and a spatial analysis was conducted using a local empirical Bayesian method. The epidemic was only found to be expanding in the North and Northeast regions, while declining in the rest of the country, especially in the Southeast. According to the findings, the apparent stabilization of AIDS mortality tends to mask regional disparities. Social determinants of health and regional disparities should be taken into account in program development and policymaking. PMID- 24627056 TI - [Validation of psychosocial scales for change in the consumption of fruits and vegetables]. AB - The objective of this study was to translate, adapt, and test the psychometric properties of psychosocial scales on fruits and vegetable consumption. A multidimensional questionnaire based on constructs of Social Cognitive Theory and the Transtheoretical Model was administered to 717 university students. Validation procedures included conceptual, item, semantic, operational, measurement, and functional equivalence. Exploratory factor analysis and temporal stability were performed using SPSS (17.0). Small differences between the translated versions were observed, and a few adjustments were made. The explained variance ranged from 57.3% to 63.2%, and alpha values ranged from 0.77 to 0.88, showing good internal consistency. Average temporal stability was good, and all constructs correlated with the stages of behavior change (p < 0.05). All validation steps were satisfactory and deemed appropriate for application in the population. PMID- 24627058 TI - [Reliability of cancer as the underlying cause of death according to the Mortality Information System and Population-Based Cancer Registry in Goiania, Goias State, Brazil]. AB - This study assessed the reliability of cancer as the underlying cause of death using probabilistic linkage between the Mortality Information System and Population-Based Cancer Registry (PBCR) in Goiania, Goias State, Brazil, from 2000 to 2005. RecLink III was used for probabilistic linkage, and reliability was assessed by Cohen's kappa and prevalence-adjusted and bias-adjusted kappa (PABAK). In the probabilistic linkage, 2,874 individuals were identified for the reliability analysis. Cohen's kappa ranged from 0.336 to 0.846 and PABAK from 0.810 to 0.990 for 14 neoplasm groups defined in the study. For reliability of the 35 leading cancers, 12(34.3%) presented kappa values under 0.600 and PABAK over 0.981. Among the neoplasms common to both sexes, crude agreement ranged from 0.672 to 0.790 and adjusted agreement from 0.894 to 0.961. Sixty-seven percent of cases classified by the Mortality Information System as "cancer of ill-defined sites" were reclassified according to the PBCR. This study was useful for the classification of cancer mortality estimates in areas covered by the PBCR. PMID- 24627057 TI - [Treatment of rheumatoid arthritis in the Brazilian Unified National Health System: expenditures on infliximab compared to synthetic disease-modifying anti rheumatic drugs, 2003-2006]. AB - This study aimed to characterize the profile of users and related expenses with infliximab and synthetic disease-modifying anti-rheumatic drugs (DMARD) for rheumatoid arthritis treatment in the Brazilian Unified National Health System (SUS). We constructed a cohort from 2003 to 2006 drawing on databases of the SUS Outpatient Information System. Analyses were stratified by clinical and socio demographic characteristics. We calculated average monthly expenditure per individual follow-up year and the factors that influenced it. The cohort consisted of 26,228 patients, mostly female, between 40 and 59 years of age, living in the Southeast of Brazil, and diagnosed with Felty's syndrome. Medicines for rheumatoid arthritis totalized BRL 74,306,087.18, of which infliximab accounted for 70%. Median monthly per capita expenditure was BRL 3,466.03 for patients receiving infliximab compared to BRL 143.85 for patients treated with synthetic DMARD. Drug treatment for rheumatoid arthritis was the main expense in SUS, with high economic impact from infliximab. Sex, diagnosis, age, and region of residence were factors that influenced expenditures. PMID- 24627059 TI - Does life-course socioeconomic position influence racial inequalities in the occurrence of uterine leiomyoma? Evidence from the Pro-Saude Study. AB - We aimed to investigate whether life-course socioeconomic position mediates the association between skin color/race and occurrence of uterine leiomyomas. We analyzed 1,475 female civil servants with baseline data (1999-2001) of the Pro Saude Study in Rio de Janeiro State, Brazil. Life-course socioeconomic position was determined by parental education (early life socioeconomic position), participant education (socioeconomic position in early adulthood) and their combination (cumulative socioeconomic position). Gynecological/breast exams and health insurance status were considered markers of access to health care. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using Cox proportional hazards models. Compared with white women, black and parda ("brown") women had higher risk of reporting uterine leiomyomas, respectively HR: 1.6, 95%CI: 1.2-2.1; HR: 1.4, 95%CI: 0.8-2.5. Estimates were virtually identical in models including different variables related to life-course socioeconomic position. This study corroborated previous evidence of higher uterine leiomyomas risk in women with darker skin color, and further suggest that life-course socioeconomic position adversity does not influence this association. PMID- 24627060 TI - [An oral health care network organized by large municipalities in Santa Catarina State, Brazil]. AB - This study aims to analyze the oral health care network in Santa Catarina State, Brazil, in municipalities with 100,000 inhabitants or more, focusing on the identification and integration of the network's essential elements. Primary data were obtained through a structured questionnaire applied to oral health care administrators. Secondary data were collected from official databases and provided by the Municipal and State Health Departments. The municipalities offer oral health services at all levels of care, but they are in different stages in implementation of the network. They have taken some measures to consolidate the network, such as inclusion of tools for integration of primary services to specialized care and reorientation of primary health care as the network's central coordinating element. Limitations include difficulty in defining the network's clientele based on epidemiological criteria, insufficient logistics and governance systems, and the need to expand oral health teams in the family health strategy, operating under health surveillance principles. PMID- 24627061 TI - Assessing maternal healthcare inequities among migrants: a qualitative study. AB - Considering pregnancy and motherhood as periods of increased vulnerability in migrant women, to characterize the healthcare provided to this collective, we sought to identify and understand patterns of satisfaction and demand of maternal and child healthcare, assessing women's perceptions about its quality. The study followed a qualitative methodology (semi-structured interviews) for collecting and analysing data (content analysis) and was conducted in Porto, the second largest city of Portugal. Participants were 25 recent immigrant mothers from Eastern European countries, Brazil, Portuguese-speaking African countries and six native Portuguese recent mothers (for comparison), contacted through social associations and institutions. Data suggests that healthcare depends not only on accessibility but especially on social opportunities. Equitable public health action must provide individuals and groups the equal opportunity to meet their needs, which may not be achieved by providing the same standard if care to all. PMID- 24627062 TI - [Overweight and abdominal obesity in adults in aquilombocommunity in Bahia State, Brazil]. AB - This study analyzes nutritional status, estimates the prevalence of overweight and abdominal obesity, and investigates factors associated with these outcomes in a two-stage random sample of adults (> 20 years) in quilombos (communities that descend from African slaves) in Vitoria da Conquista, Bahia State, Brazil, in 2011. Among 739 participants, prevalence rates were 31.8% and 10.2% for overweight and obesity, respectively, and 55.7% for increased waist-to-height ratio (> 0.50). Prevalence of overweight was higher among 30-39-year-olds, while abdominal obesity was more frequent among older individuals. Female sex, eating chicken or beef with untrimmed fat, and hypertension were associated with higher odds of overweight and abdominal obesity, while smoking and single marital status were associated with lower odds. The results show high prevalence rates for overweight and abdominal obesity in these very poor and socially isolated communities. Specific preventive and control measures are urgently needed. PMID- 24627063 TI - [Factors associated with neonatal death in high-risk infants: a multicenter study in High-Risk Neonatal Units in Northeast Brazil]. AB - This study aimed to identify factors associated with in-hospital mortality in High-Risk Neonatal Units (NICU) belonging to the North-Northeast Perinatal Health Network in Northeast Brazil. The explanatory variables were individual maternal characteristics, prenatal care, childbirth and neonatal care, and infant characteristics. This was a longitudinal, multicenter hospital-based study. The study population consisted of 3,623 live born infants admitted to 34 NICUs. After adjusting for the three hierarchical levels in the model for determination of death in the NICU up to the 27 th day of life, the following showed statistically significant association: type of delivery - cesarean section (OR = 0.72; 95%CI: 0.56-0.95), non-use of prenatal steroids (OR =1.51; 95%CI: 1.01-2.25), preeclampsia (OR = 0.73; 95%CI: 0.56-0.95), oligohydramnios (OR = 1.57; 95%CI: 1, 17-2.10), birth weight < 2500g (OR = 1.40; 95%CI: 1.03-1.90), 5-minute Apgar score < 7 (OR = 2.63; 95%CI: 2.21-3.14), endotracheal intubation (OR = 1.95; 95%CI: 1.31-2.91), and non-use of surfactant (OR = 0.54; 95%CI: 0.43-0.69). Death during NICU care is determined by conditions of the pregnancy, childbirth, and the newborn. PMID- 24627064 TI - Health research networks on the web: an analysis of the Brazilian presence. AB - In order to map Brazilian institutions' web presence in an international network of health research institutions, a study was conducted in 2009, including 190 institutions from 42 countries. The sample was based on WHO (World Health Organization) collaborating centers, and the methodology used webometric analyses and techniques, especially interlinks, and social network analysis. The results showed the presence of five Brazilian institutions, featuring the Oswaldo Cruz Foundation (Fiocruz), showing links to 20 countries and 42 institutions. Through the interface between the health field and the web, the study aims to contribute to future analyses and a plan for strategic repositioning of these institutions in the virtual world, as well as to the elaboration of public policies and recognition of webometrics as an area to be explored and applied to various other fields of knowledge. PMID- 24627065 TI - [Cost analysis of18F-FDG PET-CT from the perspective of the Brazilian Unified National Health System as healthcare provider: a study in a public healthcare center in Rio de Janeiro, Brazil]. AB - Positron emission tomography (PET) has been introduced recently in Brazil and requires costs analysis to support economic evaluation studies on its use. The current study analyzed the use of 18 F-FDG PET-CT and estimated its costs from the perspective of a public healthcare provider. The micro-costing technique was used, identifying, quantifying, and valuing all the inputs used to perform the procedure. Cost estimates considered 85 tests performed at the Brazilian National Cancer Institute from March to June 2012. Reference cases were defined as adult cancer patients, output of five tests per day, and one dose of 18 F-FDG per patient. Unit cost for the procedure was BRL 3,150.30 based on career wages under the Ministry of Science and Technology and BRL 2,927.19 based on Ministry of Health career wages. The factor with the heaviest cost impact was daily output of tests. Other factors that could impact the test's cost in public healthcare institutions were also examined. PMID- 24627066 TI - [Food security, income, and the Bolsa Familia program: a cohort study of municipalities in Paraiba State, Brazil, 2005-2011]. AB - This study aims to evaluate the impact of the conditional cash transfer program known as Bolsa Familia in overcoming food insecurity. A cohort study was conducted in 2005 and 2011 in a sample of families in Sao Jose dos Ramos and Nova Floresta, Paraiba State, Brazil. In 2005, 609 households were interviewed, and in 2011 we located and re-interviewed 406 families. There had been an increase in food security and mild food insecurity and an improvement in socioeconomic indicators. A significant association was observed between higher income and improved food security. The program showed a positive impact by increasing income and providing improved levels of food security and mild food insecurity. Other socioeconomic variables may be contributing to this improvement. The fight against food insecurity and malnutrition thus requires additional policies and programs that act on other determinants. PMID- 24627067 TI - Serum cadmium levels in a sample of blood donors in the Western Amazon, Brazil, 2010-2011. AB - A cross-sectional study was conducted to determine the distribution of serum cadmium (Cd) levels in blood donors in Rio Branco, Acre State, Brazil. Blood samples were obtained from 922 volunteer blood donors from 18 to 65 years of age at the Hemoacre blood center in 2010-2011. Mean serum Cd was 0.37ug/L (95%CI: 0.33-0.41). Increased serum Cd was associated with lower schooling; individuals with less than five years of schooling showed a mean Cd of 0.61ug/L (95%CI: 0.34 0.89), compared to 0.34ug/L (95%CI: 0.28-0.40) among those with more than nine years of schooling. Mean serum Cd was three times higher among smokers. Smoking showed a positive association with Cd level, with an OR of 12.36 (95%CI: 7.70 19.84). Meanwhile, serum Cd was lower among individuals that regularly drank tea, as compared to non-tea drinkers. Serum Cd levels were mostly below the reference value (88.3% of participants). Mean serum Cd in the current study indicates that in general the population studied here is not exposed to worrisome Cd levels. PMID- 24627068 TI - [Translation of knowledge on cervical cancer: is there a gap between research on causes and research on patient care?]. AB - This article constructs a map on the translation of knowledge concerning cervical cancer, based on citation networks analysis and the use of Gene Ontology terms and Medical Subject Headings. We identified two areas of research that are poorly interconnected and differ in structure, content, and evolution. One focuses on causes of cancer and the other on patient care. The first research area showed a knowledge translation process where basic research and clinical research are communicated through a set of articles that consolidate human papillomavirus infection as the necessary cause of cervical cancer. The first area aims to prevent HPV infection and the development of cervical cancer, while the second aims to stage and treat the disease. PMID- 24627069 TI - [Alcohol consumption patterns among patients in primary health care and detection by health professionals]. AB - This cross-sectional study investigated patterns of alcohol consumption among patients enrolled in the Family Health Program (FHP) in a city in Southeast Brazil, as well as the detection of such consumption by FHP professionals. A total of 932 adult patients were evaluated from November 2010 to November 2011. Of this total, 17.5% were considered at risk for hazardous drinking (AUDIT >= 8); increased risk was associated with male gender, younger age, and chronic illness. The CAGE questionnaire was positive in 98 patients (10.5%), with a higher proportion in men. Health professionals were more likely to ask about alcohol consumption in men, individuals aged >= 55 years, those with chronic illnesses, and heavier drinkers (438/932; 47.8%). Positive diagnosis of alcoholism was more frequent in men, individuals aged 35-54 years, and those with serious alcohol abuse (22/175; 12.6%). The study concluded that alcohol consumption is common among patients treated by FHP teams (although insufficiently recognized by professionals) and that a minority of alcoholics is instructed on the risks of drinking. PMID- 24627070 TI - HIV/AIDS coinfection with the hepatitis B and C viruses in Brazil. AB - The aim of this study is to estimate the prevalence of HIV/HBV and HIV/HCV coinfections among AIDS cases reported in Brazil, and to describe the epidemiological profile of these cases. Coinfection was identified through probabilistic record linkage of the data of all patients carrying the HIV virus recorded as AIDS patients and of those patients reported as carriers of hepatitis B or C virus in various databases from the Brazilian Ministry of Health from 1999 to 2010. In this period 370,672 AIDS cases were reported, of which 3,724 were HIV/HBV coinfections. Women are less likely to become coinfected than men and the chance of coinfection increases with age. This study allowed an important evaluation of HBV/HIV and HCV/HIV coinfections in Brazil using information obtained via merging secondary databases from the Ministry of Health, without conducting seroprevalence research. The findings of this study might be important for planning activities of the Brazilian epidemiologic surveillance agencies. PMID- 24627073 TI - Expression of hypoxic signaling markers in head and neck squamous cell carcinoma and its clinical significance. AB - Hypoxia is a consistent finding in fast-growing tumors; it contributes to tumor progression and therapeutic responses. We explored the expression of hypoxia associated biomarkers in head and neck squamous cell carcinoma (HNSCC) to assess their relationship with clinical factors in HNSCC. In total, 90 patients with HNSCC were enrolled. Expression of HIF-1alpha, HSP70, HSP90, VEGF, IGF-1R, and P16 was investigated by immunohistochemistry. Their correlations with clinical factors, including location of primary sites, T stage, N stage, M stage, HPV status, primary treatment success/failure, recurrences, disease-free survival (DFS), and overall survival, were analyzed. HIF-1alpha, HPS70, HPS90, VEGF, and IGF-1R were positive in 33 of 89 (37.1 %), 62 of 87 (71.3 %), 83 of 89 (93.3 %), 41 of 87 (47.1 %), and 50 of 56 (89.3 %) cases, respectively. Expression levels of some of these markers were correlated. High HIF-1alpha or HSP 70 correlated with poor DFS, and expression of HSP70 correlated with LN metastasis. HPV-related carcinomas showed high HSP 70 and IGF-1R expression. Hypoxia-associated proteins were highly expressed and associated with aggressive clinical features in HNSCC. Expression of HIF-1alpha or HSP70 can be considered poor prognostic indicator in HNSCC. Our results suggest that hypoxic signaling is activated in HNSCC, especially in HPV-related tumors. PMID- 24627074 TI - A genotype-phenotype correlation in Sicilian patients with GJB2 biallelic mutations. AB - The aim of this work was to study the genotype distribution of Sicilian patients with biallelic GJB2 mutations; to correlate genotype classes and/or specific mutations of GJB2 gene (35delG-non-35delG) with audiologic profiles. A total of 10 different mutations and 11 different genotypes were evidenced in 73 SNHL subjects; 35delG (90.36 % of cases) and IVS1+1 (13.69 %) were the most common mutations found in the cohort with a significant difference in the distribution between North and South Sicily. Audiological evaluation revealed a severe (16/73) to profound (47/73) hearing loss (HL) in 86.13 % of cases without significant difference between the degree of HL and the province of origin of the subjects (P = 0.727). The homozygous truncating (T/T) genotype was the most widespread (89.04 % of cases), with a severe-to-profound hearing impairment in 90.36 % of T/T class with respect to truncating/non-truncating (T/NT) and non-truncating/non truncating (NT/NT) genotypes (P = 0.012). From the comparison of homozygous 35delG and 35delG/non-35delG genotypes, a more profound HL in the homozygous 35delG than in compound heterozygous 35delG/non-35delG (p < 0.0001) resulted. This study confirms that 35delG is the most common mutation in the Mediterranean area with a heterogeneous distribution of the genotypes between North and South Sicily; probands homozygotes for 35delG or presenting a T/T genotype are more apt to have a severe-to-profound HL. PMID- 24627075 TI - How often do head and neck cancer patients raise concerns related to intimacy and sexuality in routine follow-up clinics? AB - Intimacy and sexuality problems are underreported in head and neck cancer patients. The aim of this study was to collate the various prompts available in a routine follow-up clinic through the use of an intimacy screening question and Patient's Concerns Inventory (PCI), and to identify how often these problems were raised by patients and what possible actions took place as a consequence. 177 patients completed the intimacy screening question, PCI and UW-QOLv.4 at follow up clinics, from October 2008 to January 2011. Case note review identified if intimacy was mentioned in clinic letters and if referral for support was made. On the intimacy screening question, 15 % (26) reported problems of considerable/some concern (24) or selected intimacy/sexuality on the PCI (2). The PCI identified that 9 of the 24 reporting the worst problems wanted the topic discussed in clinic, and clinic letters suggested that 5 of these discussed the issue in clinic with 4 being referred on, 3 to a clinical psychologist and 1 to a clinical nurse specialist. Intimacy problems are underreported in clinic reviews. It is a difficult subject to discuss. It will remain a potential unmet need unless attempts are made to advance the opportunities for patient screening, information leaflets, staff training on how to talk about such sensitive issues and referral for counselling. PMID- 24627076 TI - Topographic bone thickness maps for Bonebridge implantations. AB - BonebridgeTM (BB) implantation relies on optimal anchoring of the bone-conduction implant in the temporal bone. Preoperative position planning has to account for the available bone thickness minimizing unwanted interference with underlying anatomical structures. This study describes the first clinical experience with a planning method based on topographic bone thickness maps (TBTM) for presigmoid BB implantations. The temporal bone was segmented enabling three-dimensional surface generation. Distances between the external and internal surface were color encoded and mapped to a TBTM. Suitable implant positions were planned with reference to the TBTM. Surgery was performed according to the standard procedure (n = 7). Computation of the TBTM and consecutive implant position planning took 70 min on average for a trained technician. Surgical time for implantations under passive TBTM image guidance was 60 min, on average. The sigmoid sinus (n = 5) and dura mater (n = 1) were exposed, as predicted with the TBTM. Feasibility of the TBTM method was shown for standard presigmoid BB implantations. The projection of three-dimensional bone thickness information into a single topographic map provides the surgeon with an intuitive display of the anatomical situation prior to implantation. Nevertheless, TBTM generation time has to be significantly reduced to simplify integration in clinical routine. PMID- 24627077 TI - Analysis of acute impact of oleoresin capsicum on rat nasal mucosa using scanning electron microscopy. AB - Analysis of acute cellular changes seen in nasal mucosa of Wistar-Albino rats exposed to different doses of oleoresin capsicum for various time periods by means of scanning electron microscopy. Thirty-five Wistar-Albino rats were divided into five groups of seven rats each. 6-gram oleoresin capsicum per second was sprayed into cages of the groups except group 1. Spray times and duration of exposure to pepper gasses were different for each group. Thirty minutes after the exposure, the animals were killed and specimens from their nasal mucosas were harvested and examined under scanning electron microscope. Mucosal damage was scored from 0-4 points. Mean values of nasal mucosa damage scores of the groups were calculated and compared statistically. Average damage scores of the groups exposed to identical doses of oleoresin capsicum for various exposure times were compared and a statistically significant difference was seen between Groups 2 and 3 (p < 0.05), however the difference between Groups 4 and 5 was insignificant (p > 0.05). Average damage scores of the groups exposed to various doses for identical exposure times were compared, and statistically significant differences were observed between Groups 2 and 4 and also Groups 3 and 5 (p < 0.05). Outcomes of our study have demonstrated that pepper gas exerts destructive changes on rat nasal mucosa. The extent of these destructive changes increases with the prolonged exposure to higher doses. Besides, exposure time also stands out as an influential factor on the extent of the destructive changes. PMID- 24627078 TI - Is type 1 diabetes mellitus a cause for subtle hearing loss in pediatric patients? AB - The objective of this study is to investigate the effects of IDDM on the function of the auditory pathway from the cochlea to the auditory cortex in child patients. Totally, 140 ears of 70 children with IDDM and 60 ears of 30 age and gender-matched healthy controls were included in the study. The ages of patients and controls ranged from 4 to 14 years. Audiological assessment including pure tone audiometry, otoacoustic emission testing (OAE) and auditory brainstem response testing (ABR) has been performed to all participants. There was no significant difference between the patients and controls regarding pure-tone thresholds on audiometry (p > 0.05). The latencies of waves I, III and V on ABR were not significantly different between the patients and controls (p > 0.05). The amplitudes on DPOAE testing obtained from both groups were not significantly different at the frequencies of 2,000 and 4,000 Hz (p > 0.05). However, the DPOAE amplitudes of the patients at 1,000 Hz were significantly lower than those of controls at the same frequency (p = 0.03). There was no difference between the patients who had chronic disease (>5 years) and healthy controls regarding pure tone audiometry, ABR and DPOAE testing results (p > 0.05). In the light of the findings obtained with pure-tone audiometry, and OAE and ABR testing, it seems that auditory system is spared in children with IDDM at clinical level. Diabetes control and chronicity of the disease do not impact on the auditory system except for a subclinical involvement in the apical portion of the cochlea. PMID- 24627079 TI - Novel STAT3 mutation causing hyper-IgE syndrome: studies of the clinical course and immunopathology. AB - PURPOSE: Reporting a clinical case with a novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene resulting in autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES). Here we also had the opportunity to perform in-depth immunologic investigations to further understand the immunopathology of this primary immunodeficiency. METHODS: The patient, a baby boy, was clinically assessed according to the scoring system developed by Grimbacher et al. and STAT3 was investigated by DNA sequencing. Immunologic work up consisted of lymphocyte phenotyping and proliferation assays, measurement of soluble mediators and routine investigations. RESULTS: According to the Grimbacher score the patient was likely to have AD-HIES and a novel heterozygous STAT3 mutation (c.1110-3C>A), causing a splice error, was identified. Lymphocyte phenotyping revealed decreased numbers of interleukin (IL)-17 producing T-helper lymphocytes and aberrant B-lymphocyte subsets. Proliferative in vitro lymphocyte responses against C. albicans, staphylococcal enterotoxins and pokeweed mitogen were supernormal at presentation, whereas only the elevated response to pokeweed mitogen persisted. The soluble mediators IL-5, -10, -12, -13, -15 and granulocyte colony stimulatory factor were elevated in serum. CONCLUSION: A novel heterozygous STAT3 mutation causing defective splicing of exon 12 was identified. Lymphocyte phenotyping revealed deranged subpopulations. Despite the clinical picture with severe C. albicans and staphylococcal infections, the patient's lymphocytes mounted responses to these pathogens. The hypereosinophilia and high immunoglobulin E levels might partly be explained by elevated IL-5 and -13 as a result of lack of negative feedback from defective STAT3 signaling. PMID- 24627080 TI - Good's syndrome and pure white cell aplasia complicated by cryptococcus infection: A case report and review of the literature. AB - Thymomas can present with a variety of paraneoplastic manifestations, mostly of autoimmune origin, including Good's syndrome when there is associated hypogammaglobulinemia. Although pure red cell aplasia is a recognised complication of thymoma, selective white cell aplasia is very rare, particularly in Good's syndrome. Lethal opportunistic infections are a feature of Good's syndrome, usually occurring in those patients with associated severe T lymphocyte defects. Although the cryptococcus is a recognised fungal pathogen in patients with other causes of CD4+ T cell lymphopenia, surprisingly this complication has not been reported in patients with Good's syndrome. We now describe a 70 year old man with Good's syndrome and pure white cell aplasia who presented with disseminated cryptococcosis, and provide an up-to-date review of the relevant literature. Despite meningeal involvement our patient recovered after combined treatment with intravenous globulin, granulocyte stimulating growth, corticosteroids and antifungal therapy. PMID- 24627081 TI - Proteomic and functional analyses demonstrate the involvement of oxidative stress in the anticancer activities of oridonin in HepG2 cells. AB - Oridonin exhibits a curative effect on liver carcinoma in patients and experimental animals. In the present study, we performed proteomic and functional analyses to explore the mechanism involved in the anticancer activity of oridonin. Oridonin treatment for 24 h resulted in a dose-dependent decrease in cell viability with an IC50 value of 37.90 uM. Treatment with 40 uM oridonin for 24 h induced apoptosis as typical apoptotic nuclear alterations were observed following DAPI staining. Using a 2-DE-based proteomic approach, 3 upregulated oxidative stress markers, Hsp70-1, Hop and Prdx2, were identified in the HepG2 cells treated with 40 uM oridonin for 24 h. A pattern of alteration in Hsp70-1 was verified by western blotting. The mRNA expression patterns of Hsp70-1 and Hop as determined by qPCR were comparable to their protein expression patterns. Further investigations showed that oridonin treatment for 24 h resulted in reactive oxygen species (ROS) generation, and ROS scavenger N-acetylcysteine (NAC) completely inhibited ROS production and restored cell viability, suggesting that oxidative stress contributed to oridonin-induced HepG2 cell death. Western blot analysis of oxidative stress pathway-related proteins demonstrated that oridonin treatment increased p-JNK, p-p38 and p-p53, and decreased Bcl-2 protein expression levels, promoted cytochrome c release, decreased mitochondrial membrane potential, and activated caspase-9 and caspase-3. Furthermore, knockdown of Hsp70-1 expression with specific shRNA significantly decreased the viability of the cells treated with oridonin, suggesting a protective role of Hsp70-1 in oridonin-mediated oxidative stress. The results of the present study provide evidence for a link between oxidative stress and oridonin-induced apoptosis in HepG2 cells. PMID- 24627082 TI - Biological characterization and analysis of metastasis-related genes in cell lines derived from the primary lesion and lymph node metastasis of a squamous cell carcinoma arising in the mandibular gingiva. AB - Controlling metastatic lesions is an important part of improving cancer prognosis, in addition to controlling the primary lesion. There have been numerous histological studies on primary and metastatic lesions, but little basic research has been performed using cell lines from primary and metastatic lesions belonging to the same patient. In this study, we successfully established a cell line derived from lower gingival carcinoma (WK2) as well as a line derived from secondary cervical lymph node metastasis (WK3F) through primary cultures of tissue from a patient with oral squamous cell carcinoma. We then investigated the biological characteristics of the cancer cell lines from these primary and metastatic lesions and analyzed metastasis-related genes. Comparison of the biological characteristics in vitro showed that WK3F had higher cell proliferation ability and shorter cell doubling time than WK2. WK3F also had increased cell migratory ability and higher invasive and self-replication abilities. Heterotransplantation into nude mice resulted in high tumor formation rates in the tongue and high metastasis rates in the cervical lymph nodes. Changes in WK2 and WK3F gene expression were then comprehensively analyzed using microarrays. Genes with increased expression in WK3F compared to WK2 were extracted when the Z-score was >=2.0 and the ratio was >=5.0, while genes with reduced expression in WK3F compared to WK2 were extracted when the Z-score was <= 2.0 and the ratio was <=0.2; differences were found in 604 genes. From these, MAGEC1 (88.0-fold), MMP-7 (18.6-fold), SNAI1 (6.6-fold), MACC1 (6.2-fold), and HTRA1 (0.012-fold) were selected as metastasis-related candidate genes. The results suggest that these molecules could be important for clarifying the mechanisms that regulate metastasis and provide new therapeutic targets for inhibiting tumor invasion. PMID- 24627083 TI - Improvements in undergraduate oncology education introduced at Polish medical universities between 2004 and 2010 under Poland's "National Program for Combating Neoplastic Diseases". AB - Cancer patient treatment in Poland remains unsatisfactory when compared to that in other countries. In 2005, this alarming situation prompted the Polish government to launch the "National Program for Combating Neoplastic Diseases" (NPCND). One part of this project was to improve the quality of oncology instruction at the undergraduate level over the years 2006 and 2007 (subsequently extended until 2010 thanks to promising results and the relatively small financial outlay). The program's main aims were to improve existing oncology therapy and to ameliorate the quality of undergraduate oncology education. To evaluate the changes in the quality of undergraduate education as a result of the NPCND program, medical universities were asked to fill out a questionnaire. Responses indicate that the program had a major positive impact on the quality of cancer education mainly as a result of the introduction of a uniform program of training and an increase in the number of classes devoted to oncology. The main unresolved problem is that university hospitals seldom have integrated units catering in-house for surgery, radiotherapy, chemotherapy, etc., and most such "hands-on" teaching still has to be done externally. PMID- 24627084 TI - Reflections: the other half. PMID- 24627085 TI - Dynamic regulation of Rad51 by E2F1 and p53 in prostate cancer cells upon drug induced DNA damage under hypoxia. AB - Intratumoral hypoxia has been proposed to create a "mutator" phenotype through downregulation of DNA repair, leading to increased genomic instability and drug resistance. Such downregulation of DNA repair has been proposed to sensitize hypoxic cancer cells to DNA-damaging agents and inhibitors of DNA repair. Here, we showed that prostate cancer cells with mutant p53 were resistant to the poly(ADP-ribose) polymerase inhibitor, veliparib (2-[(2R)-2-methylpyrrolidin-2 yl]-1H-benzimidazole-4-carboxamide, dihydrochloride; Abbott Laboratories, Abbott Park, IL), and the DNA-damaging topoisomerase I inhibitor camptothecin-11 (CPT 11) or SN38 (7-ethyl-10-hydroxycamptothecin) under hypoxia. Upregulation of Rad51 by E2F1 upon DNA damage under hypoxia contributed to such resistance, which was reversed by either inhibiting RAD51 transcription with small interfering RNA or by expressing wild-type p53 in the p53 null prostate cancer line. Accumulation of endogenous p53 but not E2F1 and suppressed RAD51 transcription was observed in prostate cancer line with wild-type p53 after DNA damage under hypoxia. Combining veliparib with CPT-11 significantly enhanced DNA damage and apoptosis under both hypoxic and normoxic culture conditions. Such enhanced DNA damage and antitumor activities were seen in the presence of Rad51 upregulation and confirmed in vivo with PC3 mouse xenografts. These data illustrate a dynamic regulation of Rad51 by E2F1 and p53 in prostate cancer cells' response to hypoxia and DNA damage. The veliparib and CPT-11 combination can be further explored as a treatment of metastatic castration-resistant prostate cancers that have frequent p53 mutations and enriched genomic instability. PMID- 24627086 TI - Non-physician performance of lower and upper endoscopy: a systematic review and meta-analysis. AB - BACKGROUND AND STUDY AIMS: Demand for endoscopic procedures worldwide has increased while the number of physicians trained to perform endoscopy has remained relatively constant. The objective of this study was to characterize non physician performance of lower and upper endoscopic procedures. PATIENTS AND METHODS: Bibliographical searches were conducted in Medline, EMBASE, and Cochrane Library databases. Studies were included where patients underwent flexible sigmoidoscopy, colonoscopy, or upper endoscopy done by a non-physician (nurse, nurse practitioner, physician assistant) and outcome measures were reported (detection of polyps, adenomas, cancer, and/or adverse events). Pooled rates were calculated for specific outcomes and rate ratios were determined for selected comparison groups. RESULTS: Most studies involved nurses performing flexible sigmoidoscopies for colorectal cancer screening. Nurses and nurse practitioners/physician assistants performing flexible sigmoidoscopies showed pooled polyp detection rates of 9.9 % and 23.7 %, adenoma detection rates of 2.9 % and 7.2 %, colorectal cancer detection rates of 1.3 % and 1.2 %, and adverse event rates of 0.3 and 0 per 1000 sigmoidoscopies, respectively. There was no significant difference between polyp and adenoma detection rates in sigmoidoscopy performance studies comparing nurses or nurse-practitioners/physician assistants with physicians. For the 3 studies of non-physician performance of colonoscopy, pooled adenoma detection rate was 26.4 %, cecal intubation rate was 93.5 %, and adverse event rate was 2.2 /1000 colonoscopies. In the few studies examining upper endoscopies, 99.4 % of upper endoscopy procedures performed by nurses were successful with no reported adverse events. CONCLUSION: Available studies suggest that when non-physicians perform endoscopic procedures, especially lower endoscopies, outcomes and adverse events are in line with those of physicians. PMID- 24627088 TI - Patient's response to a simple question on recovery after hemodialysis session strongly associated with scores of comprehensive tools for quality of life and depression symptoms. AB - PURPOSE: Many maintenance hemodialysis patients do not feel well after the hemodialysis session and need a time to recover. The main objective of the study was to investigate whether a simple question about the need of some time to recover from hemodialysis was associated with scores of comprehensive tools of depression symptoms and health-related quality of life (HRQOL). METHODS: Cross sectional evaluation of 800 Brazilian patients enrolled in the Prospective Study of the Prognosis of Chronic Hemodialysis Patients (PROHEMO). The KDQOL-SF was used for HRQOL and the 20-item CES-D and BDI for depression symptoms. Linear and logistic models were used for multivariable adjustments. RESULTS: Patients who reported some time to recover (30%) had significantly (P < 0.001) higher depression symptoms scores (mean difference = 4.75 for CES-D and 4.48 for BDI). HRQOL scores were, in general, lower for patients who referred a time to recover, with mean differences larger than 4.0 (P < 0.05) both for physical and mental components. Strong associations of needing a time to recover and lower scores of several kidney disease-targeted HRQOL components were also observed. Differences in depression symptoms and HRQOL were largely reduced after adjustments for symptoms (muscle pain/cramps, faintness, fatigue, nausea/vomiting). CONCLUSIONS: The results support the validity of a simple question on post-hemodialysis recovery as a proxy for scores of complex instruments for depression symptoms and HRQOL. The results suggest that the poorer HRQOL and higher depression probability in patients who need a time to recover from hemodialysis could be partially explained by the presence of hemodialysis-related symptoms. PMID- 24627089 TI - Using WOMAC Index scores and personal characteristics to estimate Assessment of Quality of Life utility scores in people with hip and knee joint disease. AB - PURPOSE: To determine whether Assessment of Quality of Life (AQoL) utility scores can be reliably estimated from Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in people with hip and knee joint disease (arthritis or osteoarthritis). METHODS: WOMAC and AQoL data were analysed from 219 people recruited for a national population-based study. Generalised linear models were used to estimate AQoL utility scores based on WOMAC total and subscale scores and personal characteristics. Goodness of fit was assessed for each model, and plots of prediction errors versus actual AQoL utility scores were used to gauge bias. RESULTS: Each model closely predicted the average AQoL utility score for the overall sample (actual mean AQoL 0.64, range of predicted means 0.63-0.64; actual median AQoL 0.71, range of predicted medians 0.68-0.69). No clear preferred model was identified, and overall, the models predicted 40-46% of the variance in AQoL utility scores. The WOMAC function subscale model performed similarly to the total score model. The models functioned best at the mid-range of AQoL scores, with greater bias observed for extreme scores. Inaccuracies in individual-level estimates and low/high health-related quality of life (HRQoL) subgroup estimates were evident. CONCLUSION: Reliable overall group level estimates were produced, supporting the application of these techniques at a population level. Using WOMAC scores to predict individual AQoL utility scores is not recommended, and the models may produce inaccurate estimates in studies targeting patients with low/high HRQoL. Where pain and stiffness data are unavailable, the WOMAC function subscale can be used to generate a reasonable utility estimate. PMID- 24627090 TI - Comparison between the EQ-5D-5L and the EQ-5D-3L in patients with hepatitis B. AB - OBJECTIVES: The purpose of the study was to compare psychometric properties of the EQ-5D-5L (5L) and the EQ-5D-3L (3L) health outcomes assessment instruments in patients with hepatitis B in China. METHODS: Patients, including hepatitis B virus carriers and those with active or inactive chronic hepatitis B, compensated cirrhosis, decompensated cirrhosis or hepatocellular carcinoma, answered a questionnaire composed of 5L, socio-demographic information, 3L, and the visual analog scale (VAS), respectively. After 1 week, a retest was conducted for inpatients. We compared acceptability, face validity, redistribution properties, convergent validity, known-group validity, discriminatory power, ceiling effect, test-retest reliability, and responsiveness of 5L and 3L. RESULTS: A total of 369 outpatients and 276 inpatients were recruited for the first interview. Of the inpatients, 183 were used in the retest. Most patients preferred 5L-3L. The 3L-5L response pairs had an inconsistency rate of 2.4%. Correlation with the VAS was greater with 5L than with 3L. Age, education, and comorbidity were associated with health-related quality of life (HRQoL). 5L discriminated more infectious conditions than 3L. In all dimensions, the Shannon's index from 5L was larger while in three dimensions the Shannon's evenness index from 5L was slightly larger. The ceiling effect was reduced in 5L. In patients with stable health states, no significant difference was detected in the weighted kappa between 5L and 3L, but intraclass correlation coefficient of 5L was higher than that of 3L. In patients with improved health states, HRQoL was seen as increased in both 5L and 3L, without significant difference. CONCLUSIONS: The EQ-5D-5L was more suitable than the EQ-5D-3L in the patients with hepatitis B in China. PMID- 24627092 TI - Involvement of a specific chemosensory protein from Bactrocera dorsalis in perceiving host plant volatiles. AB - Insects have evolved many physiological and behavioral adaptations to recognize external complex chemicals. Olfaction plays an important role in perceiving volatile chemicals, utilizing them to locate host sites, conspecifics, and enemies. Chemosensory proteins (CSPs) are present in high concentrations within the sensory sensilla of insects and are endowed with a heterogeneous range of functions. However, direct evidence for the involvement of CSPs in olfactory function is still lacking. In this study, a fluorescence-based ligand binding assay using Bdor-CSP2 illustrated its ability to bind the majority of the selected ligands of different shapes and chemical structures that are ecologically significant, host plant volatiles of Bactrocera dorsalis. RNAi mediated silencing coupled with electrophysiological tests showed lower electrophysiological responses to (3Z)-hex-3-en-1-ol, trans-2-hexenal, 6 methylhept-5-en-2-one, and 3-methylbutyl acetate in dsBdor CSP2 treated flies compared with the untreated controls. The reduced expression of Bdor-CSP2 by RNA interference was confirmed by semi-quantitative PCR, real-time quantitative PCR and Western blot, which suggested the RNAi-treatment was responsible for the observed reduction of antennal responses in EAG recordings. These data suggest that the expression of Bdor-CSP2 is necessary for the recognition of antennal responses to some plant host volatiles by B. dorsalis. PMID- 24627093 TI - Vaccination with vascular progenitor cells derived from induced pluripotent stem cells elicits antitumor immunity targeting vascular and tumor cells. AB - Vaccination of BALB/c mice with dendritic cells (DCs) loaded with the lysate of induced vascular progenitor (iVP) cells derived from murine-induced pluripotent stem (iPS) cells significantly suppressed the tumor of CMS-4 fibrosarcomas and prolonged the survival of CMS-4-inoculated mice. This prophylactic antitumor activity was more potent than that of immunization with DCs loaded with iPS cells or CMS-4 tumor cells. Tumors developed slowly in mice vaccinated with DCs loaded with iVP cells (DC/iVP) and exhibited a limited vascular bed. Immunohistochemistry and a tomato-lectin perfusion study demonstrated that the tumors that developed in the iVP-immunized mice showed a marked decrease in tumor vasculature. Immunization with DC/iVP induced a potent suppressive effect on vascular-rich CMS-4 tumors, a weaker effect on BNL tumors with moderate vasculature, and nearly no effect on C26 tumors with poor vasculature. Treatment of DC/iVP-immunized mice with a monoclonal antibody against CD4 or CD8, but not anti-asialo GM1, inhibited the antitumor activity. CD8(+) T cells from DC/iVP vaccinated mice showed significant cytotoxic activity against murine endothelial cells and CMS-4 cells, whereas CD8(+) T cells from DC/iPS-vaccinated mice did not. DNA microarray analysis showed that the products of 29 vasculature associated genes shared between genes upregulated by differentiation from iPS cells into iVP cells and genes shared by iVP cells and isolated Flk-1(+) vascular cells in CMS-4 tumor tissue might be possible targets in the immune response. These results suggest that iVP cells from iPS cells could be used as a cancer vaccine targeting tumor vascular cells and tumor cells. PMID- 24627094 TI - Sequential treatment of HPV E6 and E7-expressing TC-1 cells with bortezomib and celecoxib promotes apoptosis through p-p38 MAPK-mediated downregulation of cyclin D1 and CDK2. AB - Interruption of the cell cycle is accompanied by changes in several related molecules that result in the activation of apoptosis. The present study was performed to verify the apoptotic effects of sequential treatment with bortezomib and celecoxib in TC-1 cells expressing the human papillomavirus (HPV) E6 and E7 proteins. In TC-1 cells sequentially treated with bortezomib and celecoxib, apoptosis was induced through decreased expression of signal transducer and activator of transcription-3 (STAT3), cyclin D1 and cyclin-dependent kinase (CDK) 2, which are major regulators of the G0/G1 cell cycle checkpoint. In addition, increased levels of p21, CHOP, BiP and p-p38 MAPK were identified in these cells. The treatment-induced apoptosis was effectively inhibited by treatment with SB203580, an inhibitor of p-p38. Moreover, the growth of tumors sequentially treated with bortezomib and celecoxib was retarded compared to the growth of tumors exposed to a single treatment with either bortezomib or celecoxib in vivo. We demonstrated that sequential treatment with bortezomib and celecoxib induced apoptosis via p-p38-mediated G0/G1 cell cycle arrest and endoplasmic reticulum (ER) stress. Sequential treatment with these two drugs could therefore be a useful therapy for cervical cancer. PMID- 24627096 TI - Molecular epidemiology of rabies virus in Poland. AB - The paper describes a phylogenetic study of 58 Polish isolates of rabies virus collected between 1992 and 2010. Sequences of the nucleoprotein (N) and glycoprotein (G) genes approximately 600 bp long were compared with reference sequences (GenBank) of European rabies viruses from neighbouring countries. The study confirmed a very high level of homology (94.4-100 %) of the Polish rabies virus strains irrespective of the date of isolation. Two variants of rabies virus: NEE (Northeastern Europe variant) and CE (Central Europe variant), depending on the geographical place of isolation, were circulating in Poland from 1992 to 2010. The Polish rabies virus isolates showed high similarity to European RABV strains, especially those collected in Ukraine and Romania. They were clearly different from vaccine strains SAD B19 and SAD Bern, which have been used for oral vaccination of foxes against rabies in Poland since 1993. PMID- 24627095 TI - Epigenetic reprogramming, gene expression and in vitro development of porcine SCNT embryos are significantly improved by a histone deacetylase inhibitor--m carboxycinnamic acid bishydroxamide (CBHA). AB - Insufficient epigenetic reprogramming of donor nuclei is believed to be one of the most important causes of low development efficiency of mammalian somatic cell nuclear transfer (SCNT). Previous studies have shown that both the in vitro and in vivo development of mouse SCNT embryos could be increased significantly by treatment with various histone deacetylase inhibitors (HDACi), including Trichostatin A, Scriptaid, and m-carboxycinnamic acid bishydroxamide (CBHA), in which only the effect of CBHA has not yet been tested in other species. In this paper we examine the effect of CBHA treatment on the development of porcine SCNT embryos. We have discovered the optimum dosage and time for CBHA treatment: incubating SCNT embryos with 2 MUmol/L CBHA for 24 h after activation could increase the blastocyst rate from 12.7% to 26.5%. Immunofluorescence results showed that the level of acetylation at histone 3 lysine 9 (AcH3K9), acetylation at histone 3 lysine 18 (AcH3K18), and acetylation at histone 4 lysine 16 (AcH4K16) was raised after CBHA treatment. Meanwhile, CBHA treatment improved the expression of development relating genes such as pou5f1, cdx2, and the imprinted genes like igf2. Despite these promising in vitro results and histone reprogramming, the full term development was not significantly increased after treatment. In conclusion, CBHA improves the in vitro development of pig SCNT embryos, increases the global histone acetylation and corrects the expression of some developmentally important genes at early stages. As in mouse SCNT, we have shown that nuclear epigenetic reprogramming in pig early SCNT embryos can be modified by CBHA treatment. PMID- 24627097 TI - Influence of dialysis on the glucose profile in patients with diabetes: usefulness of continuous glucose monitoring. AB - We sought to investigate the impact of dialysis on glucose profiles of diabetic patients using continuous glucose monitoring (CGM). The study included 33 hemodialyzed patients with diabetes (14 females and 19 males; mean age: 66+/-8 years; patients with type 2 diabetes: 30; mean duration of dialysis: 3.8+/-2.6 years) who were under insulin treatment. After a run-in period, CGM was performed for 48 h, including a dialysis session. Three CGM sessions were proposed for each patient over a 3-month period. CGM results were analyzed during and after dialysis at 6 different time points. Moreover, data were analyzed in 7 different day periods according to meals. Of the 99 CGM available, 21 were excluded because of technical issues or patient refusal. The CGM results indicated that mean glucose values (7.5+/-2.5 mmol/l vs. 9.4+/-1.9 mmol/l; p<0.001) and variability indices (p<0.001) were lower, whereas the frequency of hypoglycemia (4.4+/-9.6% vs. 2.1+/-7.9%; p<0.001) was higher during hemodialysis sessions. Significant differences were observed in glucose values only before and 2 h after breakfast (p<0.001). Compared with other day periods, glucose values were lower during the second half of the night and higher before and after dinner (p<0.001). In summary, CGM allows the identification of a particular glucose profile in hemodialyzed diabetic patients. CGM seems feasible and clinically useful for the analysis of glucose profiles in this group of patients. PMID- 24627098 TI - Acute post-exercise oxygen uptake, hormone and plasma metabolite response in obese men. AB - This study aimed to compare oxygen uptake ( VO2), hormone and plasma metabolite responses during the 30 min after submaximal incremental exercise (Incr) performed at the same relative/absolute exercise intensity and duration in lean (L) and obese (O) men. Eight L and 8 O men (BMI: 22.9 +/- 0.4; 37.2 +/- 1.8 kg . m(-2)) completed Incr and were then seated for 30 min. VO2 was monitored during the first 10 min and from the 25-30(th) minutes of recovery. Blood samples were drawn for the determination of hormone (catecholamines, insulin) and plasma metabolite (NEFA, glycerol) concentrations. Excess post-exercise oxygen consumption (EPOC) magnitude during the first 10 min was similar in O and in L (3.5 +/- 0.4; 3.4 +/- 0.3 liters, respectively, p=0.86). When normalized to percent change ( VO2END=100%), % VO2END during recovery was significantly higher from 90-120 s in O than in L (p <= 0.04). There were no significant differences in catecholamines (p >= 0.24), whereas insulin was significantly higher in O than in L during recovery (p=0.01). The time-course of glycerol was similar from 10-30 min of recovery (-42% for L; -41% for O, p=0.85), whereas significantly different patterns of NEFA were found from 10-30 min of recovery between groups (-18% for L; +8% for O, p=0.03). Despite similar EPOC, a difference in VO2 modulation between groups was observed, likely due to faster initial rates of VO2 decline in L than in O. The different patterns of NEFA between groups may suggest a lower NEFA reesterification during recovery in O, which was not involved in the rapid EPOC component. PMID- 24627099 TI - Hair cortisol measurement in mitotane-treated adrenocortical cancer patients. AB - The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (beta=0.03, p=0.93), hair cortisol levels were associated with BMI (beta=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (beta=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane treated ACC patients. PMID- 24627100 TI - Extracellular visfatin activates gluconeogenesis in HepG2 cells through the classical PKA/CREB-dependent pathway. AB - Adipokines reportedly affect hepatic gluconeogenesis, and the adipokine visfatin is known to be related to insulin resistance and type 2 diabetes. However, whether visfatin contributes to hepatic gluconeogenesis remains unclear. Visfatin, also known as nicotinamide phosphoribosyltransferase (NAMPT), modulates sirtuin1 (SIRT1) through the regulation of nicotinamide adenine dinucleotide (NAD). Therefore, we investigated the effect of extracellular visfatin on glucose production in HepG2 cells, and evaluated whether extracellular visfatin affects hepatic gluconeogenesis via an NAD+-SIRT1-dependent pathway. Treatment with visfatin significantly increased glucose production and the mRNA expression and protein levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6 phosphatase (G6Pase) in HepG2 cells in a time- and concentration-dependent manner. Knockdown of SIRT1 had no remarkable effect on the induction of gluconeogenesis by visfatin. Subsequently, we evaluated if extracellular visfatin stimulates the production of gluconeogenic enzymes through the classical protein kinase A (PKA)/cyclic AMP-responsive element (CRE)-binding protein (CREB) dependent process. The phosphorylation of CREB and PKA increased significantly in HepG2 cells treated with visfatin. Additionally, knockdown of CREB and PKA inhibited visfatin-induced gluconeogenesis in HepG2 cells. In summary, extracellular visfatin modulates glucose production in HepG2 cells through the PKA/CREB pathway, rather than via SIRT1 signaling. PMID- 24627101 TI - Bone structure and strength are enhanced in rats programmed by early overfeeding. AB - Childhood obesity is growing in prevalence. Obesity and bone dysfunctions may be related disorders, and therefore our aim was to study the impact of the early overfeeding (EO) in offspring bone health since weaning up to adulthood. To induce EO during lactation, litter size was adjusted to 3 male rats per litter (SL). Litter containing 10 pups per mother was the control (NL). Bone tissue was evaluated by dual-energy X-ray absorptiometry, computed tomography, microcomputed tomography, biomechanical tests, and serum analyses. SL offspring presented higher body weight, fat mass, lean mass from 21 up to 180 days, hyperphagia, and higher visceral fat mass. Bone analysis showed that SL offspring presented higher total bone mineral density (BMD) only at 180 days, and higher total bone mineral content and higher bone area from 21 until 180 days. At 180 days, SL offspring presented higher femur BMD and fourth lumbar vertebra (LV4) BMD, higher femoral head radiodensity and LV4 vertebral body radiodensity, lower trabecular pattern factor and trabecular separation, however with higher trabecular number, higher maximal load, resilience, stiffness and break load, and lower break deformation. SL group had, at 180 days, higher osteocalcin and lower C-terminal cross-linked telopeptide of type I collagen (CTX I). We have shown that the excess of fat mass contributed to an increased bone mass, and hypothesized that this increase could be mediated by the hypothyroidism and previous higher thyroid hormone action and hyperleptinemia at weaning. Furthermore, the increased biomechanical loading due to increased body weight probably help us to understand the protective effects obesity exerts upon bone health. PMID- 24627102 TI - The effect of thyroidectomy and propylthiouracil-induced hypothyroidism on insulin secretion in male rats. AB - Data available on thyroid dysfunction and insulin secretion are inconsistent. The aim of this study was to assess the effect of hypothyroidism on insulin secretion, in vivo and in vitro, in rats. Adult Wistar male rats were divided into 4 groups, the control, the propylthiouracyl (PTU)-treated hypothyroid, the surgically thyroidectomized, and the sham-operated thyroidectomized. After 5 weeks, intravenous glucose tolerance test (IVGTT) was performed and 3 weeks later pancreatic islets were isolated to assess glucose induced insulin secretion and insulin content. Fasting serum glucose and insulin levels did not differ between the groups, but serum glucose concentration during IVGTT in the PTU-induced hypothyroid group was significantly higher as compared to controls, throughout 5 60 min. The serum glucose concentration during IVGTT in the thyroidectomized rats was also significantly higher than in the sham-operated ones, except at 10 and 60 min. The area under the curve of the serum insulin was significantly lower during IVGTT in the PTU-treated (10,010 +/- 1,380 pmol/l/60 min) and thyroidectomized (13,930 +/- 2,786) groups vs. their comparable groups (19,150 +/- 2,110), p<0.01 and (20,650 +/- 1,601), p<0.05, respectively. In the PTU-treated, but not in thyroidectomized animals, insulin secretion in response to glucose 8.3 and 16.7 mM was significantly lower than their comparable group. The results show that PTU and thyroidectomy-induced hypothyroidism leads to impaired glucose tolerance due to reduced glucose stimulated insulin secretion. Islets insulin secretion is positively correlated with serum T3 and T4 concentrations. PMID- 24627103 TI - The antidiabetic action of camel milk in experimental type 2 diabetes mellitus: an overview on the changes in incretin hormones, insulin resistance, and inflammatory cytokines. AB - Folk medicine stories accredited the aptitude of camel milk (CMK) as a hypoglycemic agent and recent studies have confirmed this in the diabetic patients and experimental animals. However, the mechanism(s) by which CMK influences glucose homeostasis is yet unclear. The current study investigated the changes in the glucose homeostatic parameters, the incretin hormones, and the inflammatory cytokines in the CMK-treated diabetic animals. A model of type 2 diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin 40 mg/kg/day for 4 repeated doses. Camel milk treatment was administered for 8 weeks. The changes in glucagon like peptide-1 (GLP-1), glucose dependent insulinotropic peptide (GIP), glucose tolerance, fasting and glucose stimulated insulin secretion, insulin resistance (IR), TNF-alpha, TGF-beta1, lipid profile, atherogenic index (AI), and body weight were investigated. The untreated diabetic animals showed hyperglycemia, increased HOMA-IR, hyperlipidemia, elevated AI, high serum incretins [GLP-1 and GIP], TNF-alpha, and TGF-beta1 levels and weight loss as compared with the control group. Camel milk treatment to the diabetic animals resulted in significant lowered fasting glucose level, hypolipidemia, decreased HOMA-IR, recovery of insulin secretion, weight gain, and no mortality during the study. Additionally, CMK inhibits the diabetes induced elevation in incretin hormones, TNF-alpha and TGF-beta1 levels. The increase in glucose-stimulated insulin secretion, decreased HOMA-IR, modulation of the secretion and/or the action of incretins, and the anti-inflammatory effect are anticipated mechanisms to the antidiabetic effect of CMK and suggest it as a valuable adjuvant antidiabetic therapy. PMID- 24627104 TI - A role for resistin in the ovary during the estrous cycle. AB - In a previous study, we showed that resistin expression increased during ovarian follicle development in prepubertal pigs and had direct effects on steroidogenesis, suggesting an important role for resistin in the ovary during puberty. To determine its potential regulatory role in the ovary during the estrous cycle, using real-time PCR, immunoblotting, immunohistochemistry, and ELISA methods, we quantified the expression, immunolocalization and concentration of resistin in different sized ovarian follicles (small, 2-4 mm; medium, 4-6 mm; and large, 8-12 mm) in mature pigs. We then determined the effects of recombinant resistin (0.1, 1, and 10 ng/ml) on steroid hormone (progesterone-P4, androstendione-A4, testosterone-T, and estradiol-E2) secretion and steroidogenic enzyme (3betaHSD, CYP17A1, 17betaHSD, and CYP19A1) gene and protein expression in ovarian follicles. We found no differences in the resistin expression between all of the examined follicles. Immunostaining analysis also showed resistin expression in the cytoplasm of both granulosa and theca cells, where it was localized more abundantly in the granulosa cells compared to the theca cells. Recombinant resistin direct stimulated P4, A4, and T secretion via increased expression of 3betaHSD, CYP17A1, and 17betaHSD, suggesting an autocrine and/or paracrine regulatory role in the porcine ovary during the estrous cycle. PMID- 24627105 TI - A key role for interferon regulatory factors in mediating early-life metabolic defects in male offspring of maternal protein restricted rats. AB - An adverse intra-uterine environment, induced by maternal consumption of diets high in saturated fat or low in protein have been implicated as a potential trigger for development of metabolic disease in later life. However, the underlying mechanisms responsible for this programming of obesity have yet to be described. Recent studies have demonstrated that interferon regulatory factors 3 (IRF3) and 4 (IRF4) function to repress adipogenesis. We investigated whether impaired IRF3 and IRF4 function may predispose to development of metabolic disease in a model of programmed obesity. Changes in IRF3 and IRF4 levels, adipogenic gene expression, and adiponectin signalling were measured in white adipose tissue from programmed male offspring of rat dams fed a low-protein diet (MLP), which are predisposed to obesity. 3T3L1 adipocytes were used to determine novel regulatory mechanisms governing IRF expression. IRF3 and IRF4 levels were suppressed in MLP rats, together with raised lipogenic and adipogenic gene expression. Adiponectin and adiponectin receptor 1 and 2 mRNA levels were reduced in MLP rats, along with levels of PPARalpha and activity of AMP-activated protein kinase (AMPK), 2 downstream targets of adiponectin. Further studies determined that both IRF3 and IRF4 are induced by adiponectin, with adiponectin-AMPK and adiponectin-PPARalpha signalling regulating IRF3 and IRF4, respectively. We have demonstrated that impaired ability to repress adipogenesis and lipogenesis, through dysregulated adiponectin-PPARalpha-AMPK-IRF signalling, may play a causal role in predisposing MLP offspring to development of obesity and metabolic disease in later life. PMID- 24627106 TI - Relationship of angiotensinase and vasopressinase activities between hypothalamus, heart, and plasma in L-NAME-treated WKY and SHR. AB - The renin-angiotensin system (RAS), vasopressin, and nitric oxide (NO) interact to regulate blood pressure at central and peripheral level. To improve our understanding of their interaction and their relationship with the hypothalamus and the cardiovascular system, we analyzed angiotensin- and vasopressin metabolizing activities in hypothalamus (HT), left ventricle (LV), and plasma, collected from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) treated or not with L-NAME [N(G)-nitro-L-arginine methyl ester], which inhibits the formation of NO and over-activates the sympathetic nervous system. Previous observations in WKY suggested higher formation of Ang III and Ang IV in the HT and higher availability of Ang II in plasma after L-NAME treatment. Our current results show higher formation of Ang IV and higher metabolism of vasopressin after treatment with L-NAME in the LV of WKY rats. In SHR treated with L-NAME, there is higher availability of Ang III in the HT leading to higher release of vasopressin together with lower formation of Ang 2-10. In their LV, however, there is an increase of vasopressinase. Interestingly, while the enzymatic activities in the HT and LV of WKY rats and control SHR are poorly correlated, they are well but inversely correlated in the L-NAME treated SHR. On the other hand, no significant correlations between enzymatic activities in HT or LV and plasma were noticed. Our results suggest that eNOS inhibition in SHR induces or enhances an inverse reciprocal interaction between HT and LV involving the RAS and vasopressin, which may be mediated by the autonomic nervous system. PMID- 24627107 TI - Autologous transobturator midurethral sling placement: a novel outpatient procedure for female stress urinary incontinence. AB - INTRODUCTION: We present a novel outpatient transobturator autologous rectus fascia midurethral sling procedure. METHODS: A 55-year old woman presented with stress urinary incontinence (SUI) as documented by history, physical exam, and 24 h pad test. Conservative and surgical treatment options were discussed. The patient was interested only in outpatient surgical options, however, and was adamantly opposed to any mesh procedures due to concerns regarding complications. Therefore, following an in-depth discussion and informed consent, a transobturator, autologous sling procedure was performed. The vaginal dissection was performed in the standard fashion. A rectus fascial strip measuring 7 * 1 cm rectus fascia was harvested. A trocar was passed through each obturator foramen. Fascial stay sutures were retracted through the skin incisions. The sling was then appropriately tensioned and the stay sutures tied together. RESULTS: The patient had an uncomplicated perioperative course. She voided spontaneously with low postvoid residual. At follow-up, she had no urinary leakage. CONCLUSIONS: The transobturator autologous midurethral sling procedure is technically feasible and, in the short term, effective. Longer follow-up and larger series are needed to validate this procedure, which, however, may become a suitable option for patients and surgeons concerned with potential mesh complications. PMID- 24627108 TI - Whole-exome sequencing in patients with inherited neuropathies: outcome and challenges. AB - Inherited peripheral neuropathies (IPN) are one of the most frequent inherited causes of neurological disability characterized by considerable phenotypic and genetic heterogeneity. Based on clinical and electrophysiological properties, they can be subdivided into three main groups: HMSN, dHMN, and HSN. At present, more than 50 IPN genes have been identified. Still, many patients and families with IPN have not yet received a molecular genetic diagnosis because clinical genetic testing usually only covers a subset of IPN genes. Moreover, a considerable proportion of IPN genes has to be identified. Here we present results of WES in 27 IPN patients excluded for mutations in many known IPN genes. Eight of the patients received a definite diagnosis. While six of these patients carried bona fide pathogenic mutations in known IPN genes, two patients had mutations in genes known to be involved in other types of neuromuscular disorders. A further group of eight patients carried sequence variations in IPN genes that could not unequivocally be classified as pathogenic. In addition, combining data of WES and linkage analysis identified SH3BP4, ITPR3, and KLHL13 as novel IPN candidate genes. Moreover, there was evidence that particular mutations in PEX12, a gene known to cause Zellweger syndrome, could also lead to an IPN phenotype. We show that WES is a useful tool for diagnosing IPN and we suggest an expanded phenotypic spectrum of some genes involved in other neuromuscular and neurodegenerative disorders. Nevertheless, interpretation of variants in known and potential novel disease genes has remained challenging. PMID- 24627110 TI - When myasthenia gravis is not all. PMID- 24627109 TI - Dopamine receptor mapping with PET imaging in Parkinson's disease. AB - Parkinson's disease (PD) is a chronic neurodegenerative disorder characterised pathologically by the loss of dopaminergic neurons in the substantia nigra pars compacta. These neurons project to the striatum, and their loss leads to alterations in the activity of the neural circuits that regulate movement. The striatal output of the circuit related to the control of movement is mediated by two pathways: the direct striatal pathway, which is mediated through facilitation of D1 receptors, and the indirect striatal pathway, mediated through D2 receptors. Positron emission tomography (PET) molecular imaging is a powerful in vivo technique in which using selective dopaminergic radioligands has been employed to investigate the dopaminergic system in humans. In this article we aim to review the role of PET imaging in understanding the postsynaptic dopaminergic mechanisms in PD. PET studies have allowed us to gain important insights into the functions of the dopaminergic system, the mechanisms of drug-induced motor and non-motor complications, and the placebo effect in PD. PMID- 24627111 TI - Response to letter regarding article, "Balloon guide catheter improves revascularization and clinical outcomes with the solitaire device: analysis of the North American Solitaire Acute Stroke Registry". PMID- 24627112 TI - Neurological, functional, and cognitive stroke outcomes in Mexican Americans. AB - BACKGROUND AND PURPOSE: Our objective was to compare neurological, functional, and cognitive stroke outcomes in Mexican Americans (MAs) and non-Hispanic whites using data from a population-based study. METHODS: Ischemic strokes (2008-2012) were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) Project. Data were collected from patient or proxy interviews (conducted at baseline and 90 days poststroke) and medical records. Ethnic differences in neurological (National Institutes of Health Stroke Scale: range, 0-44; higher scores worse), functional (activities of daily living/instrumental activities of daily living score: range, 1-4; higher scores worse), and cognitive (Modified Mini-Mental State Examination: range, 0-100; lower scores worse) outcomes were assessed with Tobit or linear regression adjusted for demographics and clinical factors. RESULTS: A total of 513, 510, and 415 subjects had complete data for neurological, functional, and cognitive outcomes and covariates, respectively. Median age was 66 (interquartile range, 57-78); 64% were MAs. In MAs, median National Institutes of Health Stroke Scale, activities of daily living/instrumental activities of daily living, and Modified Mini-Mental State Examination score were 3 (interquartile range, 1-6), 2.5 (interquartile range, 1.6-3.5), and 88 (interquartile range, 76-94), respectively. MAs scored 48% worse (95% CI, 23%-78%) on National Institutes of Health Stroke Scale, 0.36 points worse (95% CI, 0.16-0.57) on activities of daily living/instrumental activities of daily living score, and 3.39 points worse (95% CI, 0.35-6.43) on Modified Mini Mental State Examination than non-Hispanic whites after multivariable adjustment. CONCLUSIONS: MAs scored worse than non-Hispanic whites on all outcomes after adjustment for confounding factors; differences were only partially explained by ethnic differences in survival. These findings in combination with the increased stroke risk in MAs suggest that the public health burden of stroke in this growing population is substantial. PMID- 24627113 TI - High-sensitivity C-reactive protein and interleukin-6-dominant inflammation and ischemic stroke risk: the northern Manhattan study. AB - BACKGROUND AND PURPOSE: Interleukin-6 (IL-6) is a proinflammatory cytokine with known autoregulatory feedback mechanisms. We hypothesized that elevated high sensitivity C-reactive protein (hsCRP) relative to IL-6 confers an increased risk of ischemic stroke (IS), and low hsCRP relative to IL-6 a decreased risk, for individuals in the prospective, multiethnic, population-based Northern Manhattan Study (NOMAS). METHODS: Serum hsCRP and IL-6 were measured in NOMAS participants at baseline. We created a trichotomized predictor based on the dominant biomarker in terms of quartiles: hsCRP-dominant, IL-6-dominant, and codominant groups. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for the association between inflammatory biomarker group status and risk of incident IS. RESULTS: Of 3298 participants, both hsCRP and IL 6 were available in 1656 participants (mean follow-up, 7.8 years; 113 incident IS). The hsCRP-dominant group had increased risk of IS (adjusted hazard ratio, 2.62; 95% confidence interval, 1.56-4.41) and the IL-6-dominant group had decreased risk (adjusted hazard ratio, 0.38; 95% confidence interval, 0.18-0.82) when compared with the referent group, after adjusting for potential confounders. Model fit was improved using the inflammation-dominant construct, over either biomarker alone. CONCLUSIONS: In this multiethnic cohort, when hsCRP-quartile was higher than IL-6 quartile, IS risk was increased, and conversely when IL-6 quartiles were elevated relative to hsCRP, IS risk was decreased. Construct validity requires confirmation in other cohorts. PMID- 24627114 TI - Stroke thrombolysis: save a minute, save a day. AB - BACKGROUND AND PURPOSE: Stroke thrombolysis is highly time-critical, but data on long-term effects of small reductions in treatment delays have not been available. Our objective was to quantify patient lifetime benefits gained from faster treatment. METHODS: Observational prospective data of consecutive stroke patients treated with intravenous thrombolysis in Australian and Finnish centers (1998-2011; n=2258) provided distributions of age, sex, stroke severity, onset-to treatment times, and 3-month modified Rankin Scale in daily clinical practice. Treatment effects derived from a pooled analysis of thrombolysis trials were used to model the shift in 3-month modified Rankin Scale distributions with reducing treatment delays, from which we derived the expected lifetime and level of long term disability with faster treatment. RESULTS: Each minute of onset-to-treatment time saved granted on average 1.8 days of extra healthy life (95% prediction interval, 0.9-2.7). Benefit was observed in all groups: each minute provided 0.6 day in old severe (age, 80 years; National Institutes of Health Stroke Scale [NIHSS] score, 20) patients, 0.9 day in old mild (age, 80 years; NIHSS score, 4) patients, 2.7 days in young mild (age, 50 years; NIHSS score, 4) patients, and 3.5 days in young severe (age, 50 years; NIHSS score, 20) patients. Women gained slightly more than men over their longer lifetimes. In the whole cohort, each 15 minute decrease in treatment delay provided an average equivalent of 1 month of additional disability-free life. CONCLUSIONS: Realistically achievable small reductions in stroke thrombolysis delays would result in significant and robust average health benefits over patients' lifetimes. The awareness of concrete importance of speed could promote practice change. PMID- 24627115 TI - Letter by Simonsen et al regarding article, "Balloon guide catheter improves revascularization and clinical outcomes with the solitaire device: analysis of the North American Solitaire Acute Stroke Registry". PMID- 24627116 TI - Time course of early postadmission hematoma expansion in spontaneous intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Early hematoma expansion (EHE) in patients with intracerebral hematoma is a promising treatment target. To date, the time course of EHE has remained poorly described. We prospectively investigated the time course of EHE. METHODS: We included consecutive patients presenting spontaneous intracerebral hematoma within 4.5 hours. On admission, patients underwent noncontrast computed tomography (CT) and CT angiography. Serial hematoma volume estimations by transcranial B-mode ultrasound were effected through the contralateral transtemporal bone window by obtaining sagittal, transversal, and coronal diameter and calculating the ABC/2-formula. National Institute of Health Stroke Scale and transcranial B-mode ultrasound were performed consecutively every 30 minutes during the first 6 hours and from 6 to 12 hours every 2 hours. Follow-up CT and ultrasound were performed after ~24 hours. RESULTS: Twenty-five patients with intracerebral hematoma were included; mean (SD) time from onset to CT was 108.6 (45.7) minutes. Ten (40%) patients had EHE. In patients with a final clinically significant hematoma expansion >12.5 mL, all EHE occurred within 6 hours after admission scan. EHE in spot sign positive patients continued during the first 5 hours after CT angiography. In spot sign-negative patients, no significant EHE was observed (Friedman test, P=0.476). Neurological deterioration occurred in 5 (20%) patients and was well temporally correlated with EHE. Transcranial B-mode ultrasound demonstrated good volume estimation compared with the follow-up CT with a maximum absolute volume deviation within 7 mL and minimal systematic error (mean deviation, 1.3 [confidence interval, -0.1 to 2.6] mL). CONCLUSIONS: EHE was reliably reflected by transcranial B-mode ultrasound and mainly occurred within the first 7 to 8 hours after symptom onset. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472224. PMID- 24627117 TI - Optimal perfusion computed tomographic thresholds for ischemic core and penumbra are not time dependent in the clinically relevant time window. AB - BACKGROUND AND PURPOSE: This study aims to determine whether perfusion computed tomographic (PCT) thresholds for delineating the ischemic core and penumbra are time dependent or time independent in patients presenting with symptoms of acute stroke. METHODS: Two hundred seventeen patients were evaluated in a retrospective, multicenter study. Patients were divided into those with either persistent occlusion or recanalization. All patients received admission PCT and follow-up imaging to determine the final ischemic core, which was then retrospectively matched to the PCT images to identify optimal thresholds for the different PCT parameters. These thresholds were assessed for significant variation over time since symptom onset. RESULTS: In the persistent occlusion group, optimal PCT parameters that did not significantly change with time included absolute mean transit time, relative mean transit time, relative cerebral blood flow, and relative cerebral blood volume when time was restricted to 15 hours after symptom onset. Conversely, the recanalization group showed no significant time variation for any PCT parameter at any time interval. In the persistent occlusion group, the optimal threshold to delineate the total ischemic area was the relative mean transit time at a threshold of 180%. In patients with recanalization, the optimal parameter to predict the ischemic core was relative cerebral blood volume at a threshold of 66%. CONCLUSIONS: Time does not influence the optimal PCT thresholds to delineate the ischemic core and penumbra in the first 15 hours after symptom onset for relative mean transit time and relative cerebral blood volume, the optimal parameters to delineate ischemic core and penumbra. PMID- 24627118 TI - Extravascular optical coherence tomography: evaluation of carotid atherosclerosis and pravastatin therapy. AB - BACKGROUND AND PURPOSE: Extravascular optical coherence tomography (OCT), as a noninvasive imaging methodology with micrometer resolution, was evaluated in a murine model of carotid atherosclerosis by way of assessing the efficacy of pravastatin therapy. METHODS: An OCT device was engineered for extravascular plaque imaging. Wild-type mice and apolipoprotein E-deficient (ApoE(-/-)) mice were randomized to 3 treatment groups: (1) wild-type on a diet of standard rodent chow (n=13); (2) ApoE(-/-) on a high-fat, atherosclerotic diet (HFD; n=13); and (3) ApoE(-/-) on a HFD given daily pravastatin (n=13). Mice were anesthetized and the left common carotid was surgically exposed. Three-dimensional (3D; 2 spatial dimensions+time) and 4D (3 spatial dimensions+time) OCT images of the vessel lumen patency were evaluated. After perfusion, in situ OCT imaging was performed for statistical comparison with the in vivo results and final histology. RESULTS: Intraoperative OCT imaging positively identified carotid plaque in 100% of ApoE( /-) mice on HFD. ApoE(-/-) mice on HFD had a significantly decreased lumen patency when compared with that in wild-type mice (P<0.001). Pravastatin therapy was found to increase lumen patency significantly in ApoE(-/-) mice on HFD (P<0.01; compared with ApoE(-/-) on HFD). The findings were confirmed with OCT imaging after perfusion and histology. CONCLUSIONS: OCT imaging offers the potential for real-time, detailed vessel lumen evaluation, potentially improving surgical accuracy and outcomes during cerebrovascular neurosurgical procedures. Pravastatin significantly increases vessel lumen patency in the ApoE(-/-) mouse on HFD. PMID- 24627119 TI - Perylene diimide appended with 8-hydroxyquinoline for ratiometric detection of Cu2+ ions and metal displacement driven "turn on" cyanide sensing. AB - Perylene diimide (PDI) 3 and 4 appended with 8-hydroxyquinoline derivatives have been synthesized and their photophysical and spectroscopic properties have been experimentally determined. Moreover, PDIs 3 and 4 show ratiometric behavior to detect Cu(2+) colorimetrically with visible color change from coral red to light pink, whereas 3 and 4 show "turn-off" behavior in fluorescence with lowest limit of detection 5 * 10(-7) M. The PDI 3 could be further utilized for ratiometric CN(-) detection colorimetrically and as "turn-on" sensor for CN(-) detection fluorometrically with lowest limit of detection 8 * 10(-6) M. The comparison of spectroscopic properties of PDI 1-4 highlights the importance of linking 8 hydroxyquinoline units on the PDI core at bay position for achieving Cu(2+) recognition event into ratiometric signal. PMID- 24627120 TI - Transition metals and organic ligands influence biodegradation of 1,4-dioxane. AB - 1,4-Dioxane, a contaminant increasingly detected in water supplies, is a public health concern because it is classified as a possible human carcinogen. 1,4 Dioxane can be biodegraded by aerobic bacteria via monooxygenase-catalyzed reactions. While these metalloenzymes require trace metals as cofactors in their catalytic sites, these metals may be toxic at elevated concentrations. In this study, the effects of transition metals on 1,4-dioxane biodegradation by Pseudonocardia dioxanivorans CB1190, a monooxygenase-expressing bacterium, were investigated. Dose-dependent inhibition of 1,4-dioxane biodegradation by Cd(II), Cu(II), and Ni(II) was observed, whereas Zn(II) had no measurable effect on biodegradation rates. 1,4-Dioxane biodegradation in cultures exposed to 2 mg/L Cu(II) was restored in the presence of 0.005, 0.05, and 0.5 mM alginin, 0.05, and 0.5 mM cysteine, and 0.005 mM tannin. These results indicated that specific ligands bind with transition metals and alleviate bacterial toxicity. In parallel experiments, tannin and cysteine inhibited 1,4-dioxane biodegradation, but alginin, BSA, and SRNOM did not affect the biodegradation rates. Thus, monooxygenase-catalyzed biodegradation rates are subject to interactions among transition metals and natural organic ligands in the environment. Mechanistic insights and quantitative data obtained in this study will be useful for designing bioremediation strategies at sites simultaneously contaminated with metals and organic pollutants. PMID- 24627121 TI - A novel beta-glucosidase from Humicola insolens with high potential for untreated waste paper conversion to sugars. AB - Humicola insolens produced a new beta-glucosidase (BglHi2) under solid-state fermentation. The purified enzyme showed apparent molecular masses of 116 kDa (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and 404 kDa (gel filtration), suggesting that it is a homotetramer. Mass spectrometry analysis showed amino acid sequence similarity with a beta-glucosidase from Chaetomium thermophilum. Optima of pH and temperature were 5.0 and 65 degrees C, respectively, and the enzyme was stable for 60 min at 50 degrees C, maintaining 71 % residual activity after 60 min at 55 degrees C. BglHi2 hydrolyzed p nitrophenyl-beta-D-glucopyranoside and cellobiose. Cellobiose hydrolysis occurred with high apparent affinity (K M = 0.24 +/- 0.01 mmol L(-1)) and catalytic efficiency (k cat/K M = 1,304.92 +/- 53.32 L mmol(-1) s(-1)). The activity was insensitive to Fe(+3), Cr(+2), Mn(+2), Co(+2), and Ni(2+), and 50-60 % residual activities were retained in the presence of Pb(2+), Hg(2+), and Cu(2+). Mixtures of pure BglHi2 or H. insolens crude extract (CE) with crude extracts from Trichoderma reesei fully hydrolyzed Whatman no. 1 paper. Mixtures of H. insolens CE with T. reesei CE or Celluclast 1.5 L fully hydrolyzed untreated printed office paper, napkin, and magazine papers after 24-48 h, and untreated cardboard was hydrolyzed by a H. insolens CE/T. reesei CE mixture with 100 % glucose yield. Data revealed the good potential of BglHi2 for the hydrolysis of waste papers, promising feedstocks for cellulosic ethanol production. PMID- 24627122 TI - Bone union rate with recombinant human bone morphogenic protein-2 versus autologous iliac bone in PEEK cages for anterior lumbar interbody fusion. AB - PURPOSE: Autologous iliac crest bone graft (ICBG) is the gold standard material for spinal fusion. Bone graft substitutes, such as recombinant human bone morphogenic protein 2 (rhBMP-2) have been developed to promote spinal fusion and address morbidity issues related to ICBG harvesting. The objective of this study was to compare bone fusion rates after anterior lumbar interbody fusion (ALIF) between ICBG and rhBMP-2 by examining thin-cut computed tomography (CT) images at the one year follow-up. METHODS: Fifty one patients (62 levels) who underwent single- or two-level ALIF via the video-assisted minimally invasive anterior approach in our institution were assessed. Radiolucent cages were inserted in all cases. Each cage has a middle beam delimiting two chambers. Grafting was performed as follows: one chamber was filled with autologous ICBG, and the other chamber was filled with 6 mg of rhBMP-2. Thin-cut CT-scan multiplanar reconstruction analyses were performed to assess the rate and quality of bone fusion at one year of follow-up. RESULTS: Fusion was observed in 55 levels (88.7 %), with significant differences in fusion rates with rhBMP-2 and ICBG (71 % vs. 88.7 %) (P=0.001). Osteogenesis in the rhBMP-2 chamber had a centripetal pattern in all cases, leaving a central void in 97.7 % of cases representing 38.3 % of the surface of its chamber (range 0-80.3 %). In ICBG chambers, graft resorption was present in 44.4 %, representing 9.8 % of the chamber surface (range 0-52.2 %). CONCLUSION: RhBMP-2 was inferior to ICBG in terms of rate and quality of bone fusion in one- or two-level ALIF. PMID- 24627123 TI - Endometrial cancer: diagnostic value of quantitative measurements of microvascular changes with DCE-MR imaging. AB - OBJECT: To assess the diagnostic value of dynamic contrast-enhanced (DCE) perfusion-magnetic resonance imaging (MRI) in detection, characterization and grading of endometrial cancer, using histopathological analysis as the standard of reference. MATERIALS AND METHODS: Eighty patients with histologically proven endometrial carcinoma who underwent MRI (1.5 T magnet) of the pelvis for staging purposes were enrolled in the study. Each MR examination consisted of multiplanar T2 and T1-weighted turbo spin echo (TSE) sequences and T1-weighted gradient echo sequences before, during and after the administration of contrast medium. For each patient colour perfusion maps were derived from the dynamic sequences using a dedicated workstation. On the maps a region of interest was manually drawn both on normal myometrium and on the endometrial lesion. Then the following perfusion parameters were automatically calculated: relative enhancement (RE, %), maximum enhancement (ME, %), maximum relative enhancement (MRE, %) and time to peak (TTP, s). RESULTS: All patients underwent total hysterectomy. Histopathological analysis documented: G1 tumour in 21 patients, G2 tumour in 44 patients, G3 tumour in 14 patients and one squamous cell carcinoma. The following mean value perfusion parameters, with corresponding mean standard deviation, were obtained for endometrial cancer: RE (%) = 59.3 +/- 36.3; ME (%) = 862.7 +/- 475.9; MRE (%) = 75.3 +/- 37.6 and TTP (s) = 164.7 +/- 78. RE, ME and MRE were lower in tumour lesions than in normal myometrium (p < 0.001) and significantly higher values (p < 0.001) of perfusion parameters were obtained for G1 (well-differentiated) tumours as compared to those in G2 and G3 (moderately and poorly differentiated) lesions. CONCLUSION: DCE perfusion-MRI can provide quantitative information on tissue vascularity, which may be of help in detecting endometrial cancer and in the assessment of tumour grading. PMID- 24627124 TI - An RF-induced voltage sensor for investigating pacemaker safety in MRI. AB - OBJECT: Magnetic resonance imaging (MRI) is inadvisable for patients with pacemakers, as radiofrequency (RF) voltages induced in the pacemaker leads may cause the device to malfunction. Our goal is to develop a sensor to measure such RF-induced voltages during MRI safety tests. MATERIALS AND METHODS: A sensor was designed (16.6 cm(2)) for measuring voltages at the connection between the pacemaker lead and its case. The induced voltage is demodulated, digitized, and transferred by optical fibres. The sensor was calibrated on the bench using RF pulses of known amplitude and duration. Then the sensor was tested during MRI scanning at 1.5 T in a saline gel filled phantom. RESULTS: Bench tests showed measurement errors below 5% with a (-40 V; +40 V) range, a precision of 0.06 V, and a temporal resolution of 24.2 MUs. In MRI tests, variability in the measured voltages was below 3.7% for 996 measurements with different sensors and RF exposure. Coupling between the sensor and the MRI electromagnetic environment was estimated with a second sensor connected and was below 6.2%. For a typical clinical MRI sequence, voltages around ten Vp were detected. CONCLUSION: We have built an accurate and reproducible tool for measuring RF-induced voltages in pacemaker leads during MR safety investigations. The sensor might also be used with other conducting cables including those used for electrocardiography and neurostimulation. PMID- 24627125 TI - beta-elemene reverses the drug resistance of lung cancer A549/DDP cells via the mitochondrial apoptosis pathway. AB - beta-elemene (beta-ELE) is a new anticancer drug extracted from Curcuma zedoaria Roscoe and has been widely used to treat malignant tumors. Recent studies have demonstrated that beta-ELE reverses the drug resistance of tumor cells. To explore the possible mechanisms of action of beta-ELE, we investigated its effects on cisplatin-resistant human lung adenocarcinoma A549/DDP cells. The effects of beta-ELE on the growth of A549/DDP cells in vitro were determined by MTT assay. Apoptosis was assessed by fluorescence microscopy with Hoechst 33258 staining and flow cytometry with Annexin V-FITC/PI double staining. Mitochondrial membrane potential was assessed using JC-1 fluorescence probe and laser confocal scanning microscopy, and intracellular reactive oxygen species levels were measured by 2',7'-dichlorofluorescein-diacetate staining and flow cytometry. Cytosolic glutathione content was determined using GSH kits. The expression of cytochrome c, caspase-3, procaspase-3 and the Bcl-2 family proteins was assessed by western blotting. The results demonstrated that beta-ELE inhibited the proliferation of A549/DDP cells in a time- and dose-dependent manner. Furthermore, beta-ELE enhanced the sensitivity of A549/DDP cells to cisplatin and reversed the drug resistance of A549/DDP cells. Consistent with a role in activating apoptosis, beta-ELE decreased mitochondrial membrane potential, increased intracellular reactive oxygen species concentration and decreased the cytoplasmic glutathione levels in a time- and dose-dependent manner. The combination of beta-ELE and cisplatin enhanced the protein expression of cytochrome c, caspase-3 and Bad, and reduced protein levels of Bcl-2 and procaspase-3 in the A549/DDP lung cancer cells. These results define a pathway of procaspase-3-beta-ELE function that involves decreased mitochondrial membrane potential, leading to apoptosis triggered by the release of cytochrome c into the cytoplasm and the modulation of apoptosis-related genes. The reversal of drug resistance of the A549/DDP cell line by beta-ELE may be derived from its effect in inducing apoptosis. PMID- 24627126 TI - Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia. AB - The distinction between a monogenic dyslipidemia and a polygenic/environmental dyslipidemia is important for the cardiovascular risk assessment, counseling, and treatment of these patients. The present work aims to perform the cardiovascular risk assessment of dyslipidemic children to identify useful biomarkers for clinical criteria improvement in clinical settings. Main cardiovascular risk factors were analyzed in a cohort of 237 unrelated children with clinical diagnosis of familial hypercholesterolemia (FH). About 40% carried at least two cardiovascular risk factors and 37.6% had FH, presenting mutations in LDLR and APOB. FH children showed significant elevated atherogenic markers and lower concentration of antiatherogenic particles. Children without a molecular diagnosis of FH had higher levels of TGs, apoC2, apoC3, and higher frequency of BMI and overweight/obesity, suggesting that environmental factors can be the underlying cause of their hypercholesterolem>=ia. An apoB/apoA1 ratio >=0.68 was identified as the best biomarker (area under the curve = 0.835) to differentiate FH from other dyslipidemias. The inclusion in clinical criteria of a higher cut off point for LDL cholesterol or an apoB/apoA1 ratio >=0.68 optimized the criteria sensitivity and specificity. The correct identification, at an early age, of all children at-risk is of great importance so that specific interventions can be implemented. apoB/apoA1 can improve the identification of FH patients. PMID- 24627127 TI - Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families. AB - Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS. PMID- 24627128 TI - Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack. AB - Sterols are an essential class of lipids in eukaryotes, where they serve as structural components of membranes and play important roles as signaling molecules. Sterols are also of high pharmacological significance: cholesterol lowering drugs are blockbusters in human health, and inhibitors of ergosterol biosynthesis are widely used as antifungals. Inhibitors of ergosterol synthesis are also being developed for Chagas's disease, caused by Trypanosoma cruzi. Here we develop an in silico pipeline to globally evaluate sterol metabolism and perform comparative genomics. We generate a library of hidden Markov model-based profiles for 42 sterol biosynthetic enzymes, which allows expressing the genomic makeup of a given species as a numerical vector. Hierarchical clustering of these vectors functionally groups eukaryote proteomes and reveals convergent evolution, in particular metabolic reduction in obligate endoparasites. We experimentally explore sterol metabolism by testing a set of sterol biosynthesis inhibitors against trypanosomatids, Plasmodium falciparum, Giardia, and mammalian cells, and by quantifying the expression levels of sterol biosynthetic genes during the different life stages of T. cruzi and Trypanosoma brucei. The phenotypic data correlate with genomic makeup for simvastatin, which showed activity against trypanosomatids. Other findings, such as the activity of terbinafine against Giardia, are not in agreement with the genotypic profile. PMID- 24627129 TI - A simple and accurate HPLC method for fecal bile acid profile in healthy and cirrhotic subjects: validation by GC-MS and LC-MS. AB - We have developed a simple and accurate HPLC method for measurement of fecal bile acids using phenacyl derivatives of unconjugated bile acids, and applied it to the measurement of fecal bile acids in cirrhotic patients. The HPLC method has the following steps: 1) lyophilization of the stool sample; 2) reconstitution in buffer and enzymatic deconjugation using cholylglycine hydrolase/sulfatase; 3) incubation with 0.1 N NaOH in 50% isopropanol at 60 degrees C to hydrolyze esterified bile acids; 4) extraction of bile acids from particulate material using 0.1 N NaOH; 5) isolation of deconjugated bile acids by solid phase extraction; 6) formation of phenacyl esters by derivatization using phenacyl bromide; and 7) HPLC separation measuring eluted peaks at 254 nm. The method was validated by showing that results obtained by HPLC agreed with those obtained by LC-MS/MS and GC-MS. We then applied the method to measuring total fecal bile acid (concentration) and bile acid profile in samples from 38 patients with cirrhosis (17 early, 21 advanced) and 10 healthy subjects. Bile acid concentrations were significantly lower in patients with advanced cirrhosis, suggesting impaired bile acid synthesis. PMID- 24627130 TI - The combined use of serum neurotensin and IL-8 as screening markers for colorectal cancer. AB - This pilot study aimed to determine the feasibility of serum neurotensin/IL-8 values being used as a screening tool for colorectal cancer. Fifty-six patients and 15 healthy controls were assigned to seven groups according to their disease entity based on theater records and histology report. Blood samples for neurotensin and IL-8 were measured using an enzyme-linked immunosorbent assay. There were no differences in the clinical and biochemical parameters of patients and controls. Group (p=0.003) and age (p=0.059, marginally significant) were independent predictors of neurotensin plasma values. Neurotensin (p=0.004) and IL 8 (p=0.029) differed between healthy and colorectal cancer patients. Neurotensin values differentiate the control group from all remaining groups. The value of plasma neurotensin <= 54.47 pg/ml at enrollment selected by receiver operating characteristic (ROC) curves demonstrated a sensitivity of 77 %, specificity of 90 %, and an estimate of area under ROC curve (accuracy) of 85 % in predicting colorectal cancer. At enrollment, the value of plasma IL-8 >= 8.83 pg/ml had a sensitivity of 85 %, specificity 80 %, and an estimate of area under ROC curve (accuracy) of 81 % in predicting colorectal cancer. IL-8 should be used complementary to neurotensin due to its lower specificity. None of the colorectal cancer patients displayed a combination of high neurotensin and low IL-8 values (beyond cutoffs). It seems that a blood neurotensin/IL-8 system may be used as a screening tool for colorectal cancer, but much has to be done before it is validated in larger-scale prospective studies. PMID- 24627131 TI - NRP-1 expression in bladder cancer and its implications for tumor progression. AB - Neuropilin-1 (NRP-1) overexpression has been reported in a variety of human cancers. However, the role of NRP-1 in bladder cancer (BC) remains unclear. The aim of present study was to analyze NRP-1 protein expression in BC tissues and to assess its prognostic significance for BC. NRP-1 messenger ribonucleic acid (mRNA) and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry in specimens of primary cancer and their adjacent noncancerous tissues in BC patients. Additionally, NRP-1 protein expression in 139 archived paraffin embedded BC samples was analyzed by immunohistochemistry and correlated with clinicopathological characteristics and survival. Student's t test, Spearman's rank correlation, Kaplan-Meier plots, and Cox's proportional hazards regression model were used to analyze the data. By qRT-PCR and immunohistochemistry, the levels of NRP-1 mRNA and protein were significantly higher in BC, compared to that in adjacent noncancerous tissues (P<0.001). High expression of NRP-1 was significantly associated with histologic grade (P=0.016) and tumor stage (P=0.001). Multivariate analysis showed that high expression of NRP-1 was an independent prognostic factor for overall survival. Our study suggests that overexpression of NRP-1 may play an important role in the progression of BC, and NRP-1 expression may serve as a biomarker for poor prognosis for BC. PMID- 24627132 TI - Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. AB - CA125, human epididymis secretary protein 4 (HE4) and the Risk of Ovarian Malignancy Algorithm (ROMA) could be used for diagnosing ovarian cancer (OCa). However, it has not been conclusively determined which of these markers yields the best diagnostic accuracy. Therefore, we conducted a meta-analysis to evaluate the diagnostic value of these markers. We systematically searched the PubMed and ScienceDirect databases and identified 32 studies that evaluated the role of CA125, HE4 and ROMA in diagnosing OCa. The bivariate random-effects approach was used to calculate the pooled estimates by considering the heterogeneity of major related parameters such as the menopausal status, International Federation of Gynecology and Obstetrics stages, detection method and blinded design. Three tests yielded similar discriminatory performances in the OCa diagnosis (AUC [95 % CI]-0.89 [0.86-0.92] for HE4; 0.87 [0.84-0.90] for CA125; 0.91 [0.88-0.93] for ROMA). HE4 yielded a higher specificity than CA125 and ROMA (HE4 93.60 [90.00 95.90] >CA125 82.10 [76.60-86.50] and ROMA 82.40 [77.40-86.50]), especially in the premenopausal subgroup (HE4 93.80 [88.40-96.80] >CA125 76.30 [63.30-85.70] and ROMA 85.10 [80.40-88.80]). In contrast, CA125 and ROMA performed significantly better in the postmenopausal subgroup than in the premenopausal subgroup (AUC [95 % CI]-CA125-premenopausal 0.85 [0.82-0.88]1 month.(1,2) It causes clinically significant distress or impairment in social, occupational or other important functions.(1) Acute stress disorder (ASD) occurs within 4 weeks of the event and comprises similar symptoms to PTSD, lasting 2 days to 4 weeks.(3,4) Recognition and treatment of PTSD may be complicated by symptom overlap or comorbidity with disorders such as anxiety and depression.(5) Here we discuss recognition of PTSD and evidence for trauma-focused psychological treatment (generally considered to be first-line therapy). Part II of this article will discuss drugs, self-help and complementary therapy options. PMID- 24627137 TI - Orthogonal polarization spectral imaging of conjunctival microcirculation. AB - PURPOSE: Orthogonal polarization spectral (OPS) imaging is an optical imaging technique that uses a handheld microscope and green polarized light to visualize the red blood cells in the microcirculation of organ surfaces. The purpose of this study was to evaluate whether OPS imaging can be used for the functional and morphological evaluation of microcirculation in the conjunctiva. METHODS: To accomplish the aforementioned purpose, 21 eyes of 21 volunteer patients were examined. OPS images of the vasculature of the inferior conjunctiva and the nasal part of the bulbar conjunctiva were taken from each eye. The images were subsequently analyzed using a computer, and the following parameters were assessed: red blood cell velocity, blood vessel diameter, and functional capillary density. In addition, distinct qualitative aspects of the conjunctival microvasculature were characterized. RESULTS: OPS imaging facilitated both the observation of red blood cells that were flowing through conjunctival vessels on a white background, and the measurement of other quantitative and qualitative microvascular parameters. Significant differences between several measures of the inferior and nasal bulbar conjunctival microcirculations were found, including differences in the configurations of the vessel segments, the number of vessel segments, the number of bifurcations, the mean diffusion distance, and the functional capillary density. CONCLUSIONS: OPS imaging can be used to measure the diameters of microvessels, functional capillary density, and other parameters. Significant differences between the microcirculations of the inferior conjunctiva and the nasal bulbar conjunctiva were found, which indicates the necessity of using a standardized approach to examine the conjunctival vasculature. OPS imaging is suitable for both the functional and morphological evaluation of the conjunctival microcirculation. PMID- 24627139 TI - An Examination of a Proposed DSM-IV Pathological Gambling Hierarchy in a Treatment Seeking Population: Similarities with Substance Dependence and Evidence for Three Classification Systems. AB - Toce-Gerstein et al. (Addiction 98:1661-1672, 2003) investigated the distribution of Diagnostic and Statistical Manual for Mental Disorders, 4th edition (DSM-IV) pathological gambling criteria endorsement in a U.S. community sample for those people endorsing a least one of the DSM-IV criteria (n = 399). They proposed a hierarchy of gambling disorders where endorsement of 1-2 criteria were deemed 'At Risk', 3-4 'Problem gamblers', 5-7 'Low Pathological', and 8-10 'High Pathological' gamblers. This article examines these claims in a larger Australian treatment seeking population. Data from 4,349 clients attending specialist problem gambling services were assessed for meeting the ten DSM-IV pathological gambling criteria. Results found higher overall criteria endorsement frequencies, three components, a direct relationship between criteria endorsement and gambling severity, clustering of criteria similar to the Toce-Gerstein et al. taxonomy, high accuracy scores for numerical and criteria specific taxonomies, and also high accuracy scores for dichotomous pathological gambling diagnoses. These results suggest significant complexities in the frequencies of criteria reports and relationships between criteria. PMID- 24627138 TI - Accuracy of spinal curvature assessed by a computer-assisted device and anthropometric indicators in discriminating vertebral fractures among individuals with back pain. AB - This study examined the accuracy of thoracic and lumbar kyphotic angles as well as anthropometric indicators for discriminating patients with vertebral fracture among Japanese women >50 years old with back pain. Along with region-specific kyphotic angles and anthropometric indicators, the combination of thoracic and lumbar kyphotic angles offered the highest accuracy. INTRODUCTION: Vertebral fractures have been associated with thoracic kyphosis. However, reports on lumbar kyphotic changes in association with vertebral fracture are scarce. This study investigated the accuracy of thoracic kyphotic angle (TKA) and lumbar kyphotic angle (LKA) measurements as well as anthropometric indicators (wall-occiput distance (WOD) and rib-pelvis distance (RPD)) in discriminating patients with vertebral fracture. METHODS: Lateral radiographs of the spine were obtained in 70 postmenopausal Japanese women who visited an orthopedic clinic with low back pain (mean age, 76.2 +/- 9.0 years). Radiographic vertebral fracture was diagnosed using quantitative measurement according to Japanese criteria. Osteoarthritis (OA) was defined as Kellgren-Lawrence (KL) grade 3 or higher. TKA and LKA were measured using SpinalMouse(r). WOD and RPD were also measured. RESULTS: At least one vertebral fracture was present in 49 subjects (70 %). Women with vertebral fractures showed significant increases in LKA, TKA + LKA, and WOD and decreases in RPD. Logistic regression analysis showed significant association between TKA + LKA and vertebral fracture independent of the presence of OA. Receiver operating characteristic analysis revealed that TKA was useful for discriminating thoracic fractures (area under the curve (AUC), 0.730) and LKA was useful for lumbar fractures (AUC, 0.691). The combination of TKA + LKA offered the highest accuracy for detecting thoracic, lumbar, and any vertebral fractures, with AUCs of 0.779, 0.728, and 0.783, respectively. WOD and RPD showed low-to-moderate accuracies for thoracic, lumbar, and any vertebral fractures. CONCLUSIONS: Assessment of spinal kyphosis by SpinalMouse(r) as well as anthropometric indicators proved useful in discriminating subjects with vertebral fractures. These convenient and radiation free methods could contribute to early diagnosis of vertebral fractures and subsequent appropriate treatment, thus preventing additional osteoporotic fractures. PMID- 24627140 TI - Economic values for production and functional traits of Small East African goat using profit functions. AB - Economic values for production traits (milk yield, MY, g; 12-month live weight, yLW, kg; consumable meat percentage, CM, %) and functional traits (mature doe live weight, DoLW, kg; mature buck live weight, LWb, kg; kidding frequency, KF; pre-weaning survival rate, PrSR, %; post-weaning survival rate, PoSR,%; doe survival rate, DoSR, %; and residual feed intake, RFI, kg) were estimated using profit functions for the Small East African goat. The scenario evaluated was a fixed flock size, and the resultant economic values (Kes per doe per year) were 34.46 (MY), 62.35 (yLW), 40.69 (CM), 0.15 (DoLW), 2.84 (LWb), 8.69 (KF), 17.38 (PrSR), 16.60 (PoSR), 16.69 (DoSR) and -3.00 (RFI). Similarly, the economic values decreased by -14.7 % (MY), -2.7 % (yLW), -23.9 % (CM), -6.6 % (DoLW), -98 % (LWb), -8.6 % (KF), -8.2 % (PrSR), -8.9 % (PoSR), -8.1 % (DoSR) and 0 % (RFI) when they were risk rated. The economic values for production and functional traits, except RFI, were positive, which implies that genetic improvement of these traits would have a positive effect on the profitability in the pastoral production systems. The application of an Arrow-Pratt coefficient of absolute risk aversion (lambda) at the level of 0.02 resulted in a decrease on the estimated economic values, implying that livestock keepers who were risk averse were willing to accept lower expected returns. The results indicate that there would be improvement in traits of economic importance, and, therefore, easy-to manage genetic improvement programmes should be established. PMID- 24627141 TI - Expanded flap to repair facial scar left by radiotherapy of hemangioma. AB - This study explored the feasibility and clinical efficacy of expanded flap to repair facial scar left by radiotherapy of hemangioma. From March 2000 to April 2011, 13 cases of facial cicatrices left by radiotherapy of hemangioma have been treated with implantation surgery of facial skin dilator under local anesthesia. After water flood expansion for 1-2 months, resection of facial scar was performed, and wound repairing with expansion flap transfer was done. Thirteen patients were followed up from 5 months to 3 years. All patients tolerated flap transfer well; no contracture occurred during the facial expansion flap transfer. The incision scar was not obvious, and its color and texture were identical to surrounding skin. In conclusion, the use of expanded flap transfer to repair the facial scar left by radiotherapy of hemangioma is advantageous due to its simplicity, flexibility, and large area of repairing. This method does not affect the subsequent facial appearance. PMID- 24627142 TI - Oriental nose elongation using an L-shaped polyethylene sheet implant for combined septal spreading and extension. AB - BACKGROUND: The currently recommended strategies for short nose elongation were designed primarily for the Caucasian nasal framework. For Oriental patients, more elongation often is required because a hypoplastic septal cartilage requires more elongation, resulting in a higher risk of complications. This report proposes a modified technique for Oriental nose elongation, which adjusts the pressure points after nasal elongation using an L-shaped implant. METHODS: Between January 2007 and December 2009, 58 patients underwent Oriental nose elongation using an L shaped, porous, high-density polyethylene sheet implant. Augmentation rhinoplasty and conchal cartilage shield grafts were performed depending on the nasal shape. Pre- and postoperative nasal length, height, and projection as well as columella labial angle, columella-lobular angle, and nasal tip angle were measured and compared. A patient satisfaction survey was performed postoperatively. All occurring complications were recorded. RESULTS: The postoperative nasal length was significantly elongated from 47.0+/-10.4 mm to 49.3+/-10.1 mm (p=0.003), and the nasal height increased significantly from 48.5+/-9.1 mm to 50.4+/-8.5 mm (p=0.011). The initially obtuse columella-labial angle improved significantly from 100.8 degrees +/-12.1 degrees to 92.5 degrees +/-15.5 degrees (p=0.014). No significant changes were found regarding nasal projection, nasal tip angle, or columella-lobular angle. The majority of the patients (91.3%) were highly satisfied or satisfied with the aesthetic results. A major complication in terms of implant exposure was observed in one case. The minor complications included stiffness of the nasal tip (3 patients) and tip redness (1 patient). CONCLUSIONS: In Oriental nose elongation, the use of an L-shaped graft is a feasible and safe treatment option that allows for an excellent aesthetic outcome and reduces the incidence of complications. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24627143 TI - Effect of motion artifacts and scan circle displacements on Cirrus HD-OCT retinal nerve fiber layer thickness measurements. AB - PURPOSE: To evaluate the effect of scan circle displacements on retinal nerve fiber layer thickness (RNFLT) measurements in Cirrus HD-OCT scans with motion artifacts affecting the optic disc. METHODS: In this cross-sectional study, 70 scans from 18 healthy eyes and 100 scans from 26 glaucomatous eyes were divided into 85 pairs, each composed by a scan with one motion artifact affecting the optic disc, and a scan from the same eye without motion artifacts. En face images underwent automated realignment, and horizontal/vertical scan circle displacements were determined. Multiple regression analysis evaluated the relationship between scan circle displacements and RNFLT change. RESULTS: Scans with motion artifacts showed similar displacements in healthy and glaucomatous eyes (P values >= 0.08). Average RNFLT and quadrants were relatively unchanged, while clock-hours showed more changes (e.g., in glaucomatous eyes, clock-hour-7 RNFLT was lower in scans with motion artifacts, P = 0.05). Scan circle displacements produced average RNFLT changes above test-retest variability in 3/85 cases (3.53%). Retinal nerve fiber layer thickness tended to decrease in sectors moved away from the disc and to increase in sectors closer to the disc (R(2) <= 0.40 and R(2) <= 0.22 in healthy and glaucomatous eyes, respectively). In healthy eyes, horizontal displacements >= 423 and 325 MUm were associated with average and quadrant RNFLT changes above test-retest variability, respectively. CONCLUSIONS: Scan circle displacements occurred in all scans with motions artifacts affecting the optic disc. Average RNFLT and quadrants were more robust than clock-hours. Because motion artifacts may be difficult to detect, clinicians should carefully inspect en face OCT images for their presence and interpret clock-hour results cautiously. PMID- 24627144 TI - Conditional knockout of CTGF affects corneal wound healing. AB - PURPOSE: This study aimed to elucidate the role of connective tissue growth factor (CTGF) in healthy eyes and wounded corneas of mice and rabbits. Conditional knockout mice were used to determine the role of CTGF in corneal healing. METHODS: CTGF expression was determined using transgenic mice carrying CTGF promoter driven-eGFP, quantitative RT-PCR, and immunofluorescent staining. Mice that carried two floxed CTGF alleles and a Cre/ERT2 transgene under the control of human ubiquitin C (ubc) promoter were used to conditionally delete CTGF gene in a tamoxifen-inducible manner. Phototherapeutic keratectomy (PTK) was used to generate an acute corneal wound and corneal re-epithelialization was assessed by fluorescein staining. RESULTS: Connective tissue growth factor expression was found in multiple ocular tissues with relatively high levels in the corneal endothelium, lens subcapsular epithelium, and in the vasculature of the iris and retina. Wounded corneas responded with an immediate upregulation of CTGF in the epithelium at the wound margin and a sustained CTGF induction during re-epithelialization. At the onset of haze formation, CTGF protein becomes more focused in the basal epithelium. Deletion of the CTGF gene caused a 40% reduction (P < 0.01) in the cornea re-epithelialization rate in knockout mice compared with wild-type mice. CONCLUSIONS: Connective tissue growth factor is expressed in the naive cornea, lens, iris, and retina, and is expressed immediately after epithelial injury. Loss of CTGF impairs efficient re-epithelialization of corneal wounds. PMID- 24627145 TI - The spatial profile of macular pigment in subjects from a Singapore Chinese population. AB - PURPOSE: To examine the spatial profile of macular pigment (MP) and its relationship with serum concentrations of lutein (L) and zeaxanthin (Z) in subjects from a Singapore Chinese population. METHODS: In this cross-sectional study, the following details were recorded in 95 healthy subjects: sociodemographic, lifestyle information, body mass index (BMI), visual acuity, MP spatial profile using a macular densitometer, and serum L and Z. RESULTS: The mean (SD) age of the population was 42.40 (+/- 13) years, ranging from 21 to 68 years. Females demonstrated significantly lower MP optical density (MPOD) than males (MPOD: females = 0.52 +/- 0.17; males = 0.61 +/- 0.21, P = 0.03). MP spatial profile was typical and atypical with central dip in 68 (85%) and 12 (15%) subjects, respectively. Age and BMI were found to be significant predictors for atypical MP spatial profile (age: odds ratio, OR = 1.06, 95% confidence interval, CI = 1.01-1.13, P = 0.04; BMI: OR = 1.17, 95% CI = 1.01-1.34, P = 0.03). A positive relationship was observed between MPOD and serum concentrations of L and Z, but only the latter relationship reached statistical significance (serum L: r = 0.12, P = 0.30; serum Z: r = 0.26, P = 0.02). CONCLUSIONS: A central dip in MP spatial profile was observed with older age and higher BMI, the two known risk factors for AMD, suggesting that atypical MP spatial profile may be associated with an increased risk of AMD. Further studies with larger sample sizes are required to confirm these observations. PMID- 24627146 TI - Pirfenidone attenuates the IL-1beta-induced hyaluronic acid increase in orbital fibroblasts from patients with thyroid-associated ophthalmopathy. AB - PURPOSE: This study aimed to investigate the effect of pirfenidone on the IL 1beta-induced hyaluronic acid (HA) increase in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO). METHODS: Primary cultured orbital fibroblasts were obtained from patients with TAO, and the excreted levels of HA from IL-1beta-treated cells with or without pirfenidone were measured. The effect of pirfenidone on IL-1beta-induced hyaluronic acid synthase (HAS) expression was evaluated. The relevance of the mitogen-activated protein kinase (MAPK)-mediated signaling pathway in IL-1beta-induced HAS expression was assessed using specific inhibitors to p38, extracellular signal-regulated kinase (ERK), or c-Jun N terminal kinase (JNK). The phosphorylation level of each MAPK in IL-1beta-treated cells with or without pirfenidone and the level of AP-1 DNA binding were measured. The inhibitory potency of pirfenidone on HA production was evaluated using dexamethasone as a reference agent. RESULTS: Pirfenidone strongly attenuated the IL-1beta-induced HA release in a dose-dependent manner. The IL 1beta-induced HAS expression was decreased significantly following cotreatment with pirfenidone at the mRNA and protein levels. The production of mRNAs was halted by cotreatment with inhibitors of ERK and p38, but not by inhibitors of JNK. The IL-1beta-induced ERK and p38 phosphorylation, and AP-1 DNA binding were attenuated in the presence of pirfenidone. Pirfenidone showed greater potency than dexamethasone in inhibiting increases in IL-1beta-induced HA. CONCLUSIONS: Pirfenidone attenuates the IL-1beta-induced HA production in orbital fibroblasts from patients with TAO, at least in part, through suppression of the MAPK mediated HAS expression. These results support the potential use of pirfenidone for treatment of patients with TAO. PMID- 24627147 TI - Significance of ectodomain shedding of TNF receptor 1 in ocular surface. AB - PURPOSE: We evaluated an anti-inflammatory effect of TNF receptor 1 (TNFR1) ectodomain shedding in ocular surface. METHODS: Human corneal epithelial cell (HCEC) was first pretreated by TNF-alpha. Ectodomain shedding was stimulated by uridine triphosphate (UTP) or peptidoglycan (PGN), with or without shedding inhibition using TNF-alpha processing inhibitor (TAPI). The phosphorylation of the NF-kappaB inhibitory protein, IkappaB, was assessed by Western blotting and concentrations of soluble TNFR1 (sTNFR1) in culture medium were analyzed by ELISA. Tear fluid from patients with Sjogren syndrome and graft-versus-host disease (GVHD) was collected and analyzed by ELISA for sTNFR1 concentration. Five dry eye patients underwent topical treatment using diquafosol sodium eye drops, a purinergic P2Y2 receptor agonist, and the tear fluid of the patients was sampled before and 4 weeks after the treatment for sTNFR1 ELISA. RESULTS: Phosphorylation of IkappaB was diminished by adding UTP or PGN, and this down-regulation of IkappaB phosphorylation was reversed by adding TAPI. In HCEC medium, sTNFR1 release was increased significantly by adding UTP or PGN, and inhibited significantly by adding TAPI. In the tears of the patients with Sjogren syndrome and GVHD, sTNFR1 expression was upregulated. In the tears of the patients with short breakup time (BUT) dry eye, sTNFR1 concentrations (ng/mL) in the tears were 1.30 +/- 0.58 ng/mL for the pretreatment baseline, and 1.64 +/- 0.70 after treatment, statistically significantly higher than those for the pretreatment (P < 0.01). CONCLUSIONS: Ectodomain shedding of sTNFR1 blocked TNF-alpha-induced intracellular signaling in corneal epithelium. The upregulation of sTNFR1 in inflamed ocular surfaces suggests an anti-inflammatory role of sTNFR1 ectodomain shedding at the ocular surface. PMID- 24627148 TI - Anti-apoptotic effect of caspase inhibitors on H2O2-treated HeLa cells through early suppression of its oxidative stress. AB - Oxidative stress-induced cytotoxicity in cervical cancer cells may be of toxicological interest. In the present study, the effects of exogenous H2O2 on cell growth and death in HeLa cervical cancer cells were investigated, and the anti-apoptotic effects of various caspase (pan-caspase, caspase-3, -8 or -9) inhibitors on H2O2-treated HeLa cells were also evaluated with regard to reactive oxygen species (ROS) and glutathione (GSH) levels. Based on MTT assays, H2O2 inhibited the growth of HeLa cells with an IC50 value of ~75 uM at 24 h. H2O2 increased the number of dead cells and Annexin V-FITC-positive cells in the HeLa cells, which was accompanied by the activation of caspase-3 and the loss of mitochondrial membrane potential (MMP; DeltaPsim). However, relatively higher doses of H2O2 induced necrosis in HeLa cells. Caspase inhibitors significantly prevented H2O2-induced HeLa cell death. H2O2 increased ROS including O2*- at 24 h and increased the activity of catalase in HeLa cells. H2O2 also increased the ROS level at 1 h, and several caspase inhibitors attenuated the increased level at 1 h but not at 6, 12 and 24 h. H2O2 decreased the GSH level in HeLa cells at 1 h, and several caspase inhibitors attenuated the decreased level of GSH at this time. H2O2 induced GSH depletion at 24 h. In conclusion, H2O2 inhibited the growth of HeLa cells via apoptosis and/or necrosis, which was accompanied by intracellular increases in ROS levels and GSH depletion. Caspase inhibitors are suggested to suppress H2O2-induced oxidative stress to rescue HeLa cells at the early time point of 1 h. PMID- 24627149 TI - Posture-induced changes in intraocular pressure: comparison of pseudoexfoliation glaucoma and primary open-angle glaucoma. AB - PURPOSE: The objective of this study was to evaluate and compare the IOP values in the sitting and supine positions in primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG) patients. We also investigated possible relationships between the level of visual field damage and postural IOP change. METHODS: Twenty-nine patients with POAG and 32 patients with PXG were recruited to the study. An Icare PRO tonometer was used to measure IOP in the sitting and supine positions. Intraocular pressure in the sitting position was also measured with a Goldmann applanation tonometer (GAT). Humphrey field analyzer 750 data taken within the previous 3 months were obtained and analyzed. RESULTS: The mean difference between the GAT and the Icare PRO tonometer readings was 0.12 +/- 0.8 mmHg, and the tonometers were in close agreement (r = 0.964; P < 0.0001). The mean Icare PRO IOP in the sitting position was 16.6 +/- 3.3 mmHg in the POAG group and 14.9 +/- 2.7 mmHg in the PXG group. The average rise was 1.7 +/- 1.2 mmHg in the POAG group and 2.9 +/- 1.9 mmHg in the PXG group. The difference in IOP between the sitting and supine positions was significant between the groups (P = 0.001). The ?IOP was negatively correlated with both the mean deviation and the visual field index (P < 0.0001 for both). The ?IOP and pattern standard deviation were positively correlated (P < 0.0001). CONCLUSIONS: A higher increase in IOP was observed in PXG patients from the sitting to the supine position than in POAG patients. Postural variation in IOP was found to be associated with the severity of visual field damage. PMID- 24627150 TI - An up-date on newly discovered immunohistochemical biomarkers for the diagnosis of human testicular germ cell tumors. AB - Although testicular germ cell tumors (TGCTs) are relatively uncommon, they are particularly important, as they tend to affect children and young men, the most common tumor being in males aged from 20 to 40 years, and the incidence has been increasing in the last years. TGCTs comprise two major histologic groups: seminomas and non-seminomas germ cell tumors (NSGCTs). NSGCTs can be further divided into embryonal, carcinoma, Teratoma, yolk sac tumor, and choriocarcinoma. Seminomas and NSGCTs present significant differences in clinical features, therapy, and prognosis, and both show characteristics of the Primordial Germ Cells (PGCs). For proper diagnosis of the different histological subgroups, immunohistochemistry is required using different molecular markers, such as Aurora B, GPR30, Nek2, HMGA1, HMGA2, and others, and they could represent useful novel molecular targets for antineoplastic strategies. More insight into the pathogenesis of TGCTs is likely to contribute not only to better treatment of these tumors but also to a better understanding of stem cells and oncogenesis. PMID- 24627151 TI - Pattern and predictors of interpersonal violence among adolescent female students in Egypt. AB - Violence among female adolescents is a major public health problem. The objective of this study is to detect the pattern and predicting factors of interpersonal violence among adolescent female students in a nursing high school in Cairo. A cross-sectional study was conducted during the academic year 2011-2012 and included a total of 220 students using a self-administered questionnaire. Physical violence exposure at home, school and community among studied adolescents were 65.5, 30.4 and 25.9% respectively. Verbal violence was found in 55, 69 and 60% at home, school and community respectively. Finally 5 and 41.3% of studied students were exposed to sexual violence at home and community respectively. The highest violence exposure score was at school from teachers while the highest score of being violent was mainly towards the community. Multivariate regression analysis for violence scores revealed that younger students, students from urban residence and higher crowding index were significant predictors for total violence exposure and being violent scores. Prevention programmes should be given for all students especially high risk ones (young age, urban residence and high crowdness index families) and their families to address and overcome this problem. PMID- 24627152 TI - Edentulism associates with worse cognitive performance in community-dwelling elders in rural Ecuador: results of the Atahualpa project. AB - Studies in industrialized nations suggest that severe edentulism correlates with cognitive impairment, but there is little information on this association in underserved populations. We conducted a community-based study to assess whether edentulism associates with cognitive impairment in elders living in rural Ecuador. Atahualpa residents aged >=60 years were identified during a door-to door census and evaluated using the Montreal Cognitive Assessment (MoCA). Persons were classified into two groups according to whether they have severe edentulism (<10 remaining teeth) or not. In addition, a questionnaire allowed self-rating of oral health. A total of 274 persons (mean age 69.6 +/- 7.7 years; 59% women) were included. Persons with <10 remaining teeth (n = 116) have significantly lower MoCA scores than those with >=10 teeth (n =158), after adjusting for demographics, cardiovascular risk factors, depression and dementia (beta = -1.06, p = 0.03). Self-rated poor oral health was more prevalent among persons with <10 teeth (p < 0.0001), but did not correlate with MoCA scores (good vs. poor, beta = -0.89, p = 0.89). Severe edentulism is associated with poor cognitive performance in elders living in rural Ecuador. Public health campaigns directed to improve oral health may facilitate early recognition of persons with cognitive impairment in underserved populations. PMID- 24627153 TI - Predicting outdoor recreation area use in a Southeastern US county: a signal detection analysis. AB - Use of outdoor recreation areas (ORAs) is correlated with physical activity (PA) in community-dwelling adults. Additionally, the wide spread availability of ORAs, including their placement in disadvantaged neighborhoods, make them an especially promising venue through which to promote PA. The purpose of this study was to examine the combination of individual-level factors associated with ORA use in a socioeconomically diverse Southeastern US county. A 2011 random digit-dial survey included 829 adults aged 18+ years with complete data; questions assessed PA level and use/perceived safety of ORAs. Signal detection analysis, a non parametric recursive partitioning technique, identified cutpoints for defining subgroups of respondents based on ORA use. Seven subgroups were defined ranging from 77.2 % ORA use (younger, met PA recommendations) to 31.8 % ORA use (older, perceived ORAs to be less safe). Signal detection did not identify gender or race as important for defining subgroups. Results suggest that gendered and ethnically focused ORA promotion campaigns might be unnecessary. Instead, efforts could focus on increasing awareness of ORA facilities among older, less active adults. PMID- 24627154 TI - T-type Ca(2+) channels facilitate NO-formation, vasodilatation and NO-mediated modulation of blood pressure. AB - Voltage-gated calcium channels are involved in the vascular excitation contraction mechanism and regulation of arterial blood pressure. It was hypothesized that T-type channels promote formation of nitric oxide from the endothelium. The present experiments determine the involvement of T-type channels in depolarization-dependent dilatation of mesenteric arteries and blood pressure regulation in Cav3.1 knock-out mice. Nitric oxide-dependent vasodilatation following depolarization-mediated vasoconstriction was reduced significantly in mesenteric arteries from Cav3.1(-/-) compared to wild type mice. Four days of systemic infusion of a nitric oxide (NO)-synthase-inhibitor to conscious wild type elicited a significant increase in mean arterial blood pressure that was absent in Cav3.1(-/-) mice. Immunoprecipitation and immunofluorescence labeling showed co-localization of Cav3.1 and endothelial nitric oxide synthase (eNOS) in arteries from wild type mice. Nitric oxide release measured as DAF fluorescence and cGMP levels were significantly lower in depolarized Cav3.1(-/-) compared to wild type arteries. In summary, the absence of T-type Cav3.1 channels attenuates NO-dependent dilatation in mesenteric arteries in vitro, as well as the hypertension after L-NAME infusion in vivo. Furthermore, Cav3.1 channels cluster with eNOS and promote formation of nitric oxide by the endothelium. The present findings suggest that this mechanism is important for the systemic impact of NO on peripheral resistance. PMID- 24627155 TI - Bacteriocinogenic properties and in vitro probiotic potential of enterococci from Tunisian dairy products. AB - The aim of this study was to isolate new bacteriocinogenic strains with putative probiotic potential from various Tunisian fermented milks. A total of 44 Gram positive catalase-negative isolates were colony-purified and screened for antimicrobial activity. Of inhibitory isolates, four were identified as Enterococcus durans and one as Enterococcus faecalis using 16S rRNA gene sequence. The five strains were sensitive to penicillin G, all aminoglycosides tested, to the vancomycin, tetracycline, and chloramphenicol, and E. durans 42G and E. faecalis 61B were resistant to erythromycin. The antimicrobial substances were sensitive to proteolytic enzymes and had good biochemical stability. E. durans 61A showed a good resistance to gastric and small intestinal secretions, but were more sensitive to the duodenal conditions. Considering the safety and the stability under simulated gastrointestinal tract, it appears that the bacteriocinogenic strain E. durans 61A is a good candidate for its application as novel probiotic strain in the food industry. PMID- 24627156 TI - Adjuvant chemotherapy for stage II colon cancer: everyone still needs a tailor. PMID- 24627157 TI - AFP-producing urothelial carcinoma of the bladder: a case report. AB - We report a case of urothelial carcinoma of the urinary bladder with concurrent alpha-fetoprotein (AFP) elevation. A 60-year-old male was admitted for gross hematuria. Subsequent analyses revealed elevated serum AFP levels (970.20 ng/ml). He had no history of hepatitis, and hepatobiliary disease was not detected on computed tomography or ultrasound. Carcino-embryonic antigen was normal. The patient underwent radical cystectomy and was found to have a high-grade urothelial carcinoma of bladder on pathology. In addition, immunohistochemical staining of the tumor cells showed strong AFP positivity. Postoperatively, serum AFP levels decreased gradually to normal. In summary, urothelial carcinoma of the urinary bladder with AFP elevation is rare, and the mechanism and prognosis require further exploration. PMID- 24627158 TI - A narrative policy approach to environmental conservation. AB - Due to the urgency and seriousness of the loss of biological diversity, scientists from across a range of disciplines are urged to increase the salience and use of their research by policy-makers. Increased policy nuance is needed to address the science-policy gap and overcome divergent views of separate research and policy worlds, a view still relatively common among conservation scientists. Research impact considerations should recognize that policy uptake is dependent on contextual variables operating in the policy sphere. We provide a novel adaptation of existing policy approaches to evidence impact that accounts for non evidentiary "societal" influences on decision-making. We highlight recent analytical tools from political science that account for the use of evidence by policy-makers. Using the United Kingdom's recent embrace of the ecosystem approach to environmental management, we advocate analyzing evidence research impact through a narrative lens that accounts for the credibility, legitimacy, and relevance of science for policy. PMID- 24627159 TI - Arsenic hexoxide enhances TNF-alpha-induced anticancer effects by inhibiting NF kappaB activity at a safe dose in MCF-7 human breast cancer cells. AB - Arsenic hexoxide (As4O6) has been used in Korean folk remedy for the treatment of cancer since the late 1980s. Evidence suggests that the anticancer effects of As4O6 are different from those of As2O3. Tumor necrosis factor-alpha (TNF-alpha) is generally increased in advanced cancer and is closely related to cancer progression, although it has cancer-killing effects. The reason is that TNF-alpha activates nuclear factor-kappaB (NF-kappaB) that is involved in cell proliferation, invasion, drug resistance and metastasis. In the present study, we investigated the effects of As4O6 on NF-kappaB activity, NF-kappaB-mediated cellular responses, and NF-kappaB-regulated gene expressions involved in metastasis at the concentrations of As4O6 where no cytotoxicity was observed. As4O6 suppressed NF-kappaB activation in both TNF-alpha-treated and control cells, and also suppressed IkappaB phosphorylation in a time-dependent manner, suggesting the suppression of NF-kappaB results, in part, from the inhibition of IkappaB degradation. We also confirmed the anti-NF-kappaB activity of As4O6 with synergism with TNF-alpha by augmenting caspase-8 activation. As4O6 also suppressed NF-kappaB activation induced by TNF-alpha, and some of the downstream NF-kappaB-regulated proteins involved in cancer proliferation, anti-apoptosis and metastasis. In conclusion, the present study demonstrated that As4O6 has anticancer properties by inhibiting NF-kappaB activation and NF-kappaB-regulated proteins at least in part through the inhibition of IkappaB phosphorylation, especially in the conditions of advanced cancer where TNF-alpha is highly secreted. PMID- 24627161 TI - Percutaneous bone biopsies: comparison between flat-panel cone-beam CT and CT scan guidance. AB - PURPOSE: This study was designed to compare the accuracy of targeting and the radiation dose of bone biopsies performed either under fluoroscopic guidance using a cone-beam CT with real-time 3D image fusion software (FP-CBCT-guidance) or under conventional computed tomography guidance (CT-guidance). METHODS: Sixty eight consecutive patients with a bone lesion were prospectively included. The bone biopsies were scheduled under FP-CBCT-guidance or under CT-guidance according to operating room availability. Thirty-four patients underwent a bone biopsy under FP-CBCT and 34 under CT-guidance. We prospectively compared the two guidance modalities for their technical success, accuracy, puncture time, and pathological success rate. Patient and physician radiation doses also were compared. RESULTS: All biopsies were technically successful, with both guidance modalities. Accuracy was significantly better using FP-CBCT-guidance (3 and 5 mm respectively: p = 0.003). There was no significant difference in puncture time (32 and 31 min respectively, p = 0.51) nor in pathological results (88 and 88 % of pathological success respectively, p = 1). Patient radiation doses were significantly lower with FP-CBCT (45 vs. 136 mSv, p < 0.0001). The percentage of operators who received a dose higher than 0.001 mSv (dosimeter detection dose threshold) was lower with FP-CBCT than CT-guidance (27 vs. 59 %, p = 0.01). CONCLUSIONS: FP-CBCT-guidance for bone biopsy is accurate and reduces patient and operator radiation doses compared with CT-guidance. PMID- 24627162 TI - Sac angiography and glue embolization in emergency endovascular aneurysm repair for ruptured abdominal aortic aneurysm. AB - PURPOSE: The purpose of this study was to demonstrate a sac angiography technique and evaluate the feasibility of N-butyl cyanoacrylate (NBCA) embolization of the ruptured abdominal aortic aneurysm (AAA) sac in emergency endovascular aneurysm repair (EVAR) in hemodynamically unstable patients. METHODS: A retrospective case series of three patients in whom sac angiography was performed during emergency EVAR for ruptured AAA was reviewed. After stent graft deployment, angiography within the sac of aneurysm (sac angiography) was performed by manually injecting 10 ml of contrast material through a catheter to identify the presence and site of active bleeding. In two patients, sac angiography revealed active extravasation of the contrast material, and NBCA embolization with a coaxial catheter system was performed to achieve prompt sealing. RESULTS: Sac angiography was successful in all three patients. In the two patients who underwent NBCA embolization for aneurysm sac bleeding, follow-up computed tomography (CT) images demonstrated the accumulation of NBCA consistent with the bleeding site in preprocedural CT images. CONCLUSIONS: EVAR is associated with a potential risk of ongoing bleeding from type II or IV endoleaks into the disrupted aneurysm sac in patients with severe coagulopathy. Therefore, sac angiography and NBCA embolization during emergency EVAR may represent a possible technical improvement in the treatment of ruptured AAA in hemodynamically unstable patients. PMID- 24627160 TI - Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner. AB - Cells encountering hypoxic stress conserve resources and energy by downregulating the protein synthesis. Here we demonstrate that one mechanism in this response is the translational repression of TOP mRNAs that encode components of the translational apparatus. This mode of regulation involves TSC and Rheb, as knockout of TSC1 or TSC2 or overexpression of Rheb rescued TOP mRNA translation in oxygen-deprived cells. Stress-induced translational repression of these mRNAs closely correlates with the hypophosphorylated state of 4E-BP, a translational repressor. However, a series of 4E-BP loss- and gain-of-function experiments disprove a cause-and-effect relationship between the phosphorylation status of 4E BP and the translational repression of TOP mRNAs under oxygen or growth factor deprivation. Furthermore, the repressive effect of anoxia is similar to that attained by the very efficient inhibition of mTOR activity by Torin 1, but much more pronounced than raptor or rictor knockout. Likewise, deficiency of raptor or rictor, even though it mildly downregulated basal translation efficiency of TOP mRNAs, failed to suppress the oxygen-mediated translational activation of TOP mRNAs. Finally, co-knockdown of TIA-1 and TIAR, two RNA-binding proteins previously implicated in translational repression of TOP mRNAs in amino acid starved cells, failed to relieve TOP mRNA translation under other stress conditions. Thus, the nature of the proximal translational regulator of TOP mRNAs remains elusive. PMID- 24627163 TI - Adiponectin exerts its negative effect on bone metabolism via OPG/RANKL pathway: an in vivo study. AB - To explore the effects of adiponectin on the bone metabolism in vivo. Bone mineral density (BMD), bone microstructure, serum adiponectin levels, and biochemical markers of the bone turnover were measured in 12-week-old male Adipo /- and WT mice. In addition, the osteoclast formation, osteoprotegerin (OPG), and the receptor activator of nuclear factor-kappaB ligand (RANKL) expression were examined. The serum adiponectin levels were normal in the WT mice while undetectable in the Adipo-/- mice. Compared with the WT mice, the Adipo-/- mice had higher BMD, more trabecular bone, greater bone volume fraction, and trabecular thickness in the left femur. On the contrary, fewer osteoclasts were observed in the Adipo-/- mice when compared with the WT mice. Meanwhile, the Adipo-/- mice had a significantly decreased serum carboxyl-terminal telopeptide of type 1 collagen (CTX)/osteocalcin (OC) ratio. Interestingly, both the adiponectin and RANKL would cause a significant increase of CTX/OC ratio in the co-culture of the CD14+ peripheral blood mononuclear cells and the osteoblasts from Adipo-/- mice. Further, immunohistochemistry assays in tibias and both the RT-PCR and immunoblot analyses in the cultured osteoblasts showed the Adipo-/- mice expressed lower levels of RANKL but higher levels of OPG. Adiponectin had a negative effect on the bone metabolism, and this negative effect might be mediated, at least in part, by the OPG/RANKL pathway. PMID- 24627164 TI - PTH-C1: a rat continuous cell line expressing the parathyroid phenotype. AB - The lack of a continuous cell line of epithelial parathyroid cells able to produce parathyroid hormone (PTH) has hampered the studies on in vitro evaluation of the mechanisms involved in the control of parathyroid cell function and proliferation. The PT-r cell line was first established from rat parathyroid tissue in 1987, but these cells were known to express the parathyroid hormone related peptide (Pthrp) gene, but not the Pth gene. In an attempt to subclone the PT-r cell line, a rat parathyroid cell strain was isolated and named PTH-C1. During 3 years, in culture, PTH-C1 cells maintained an epithelioid morphology, displaying a diploid chromosome number, a doubling time around 15 h during the exponential phase of growth, and parathyroid functional features. PTH-C1 cell line produces PTH and expresses the calcium sensing receptor (Casr) gene and other genes known to be involved in parathyroid function. Most importantly, the PTH-C1 cells also exhibit an in vitro secretory response to calcium. Altogether these findings indicate the uniqueness of the PTH-C1 cell line as an in vitro model for cellular and molecular studies on parathyroid physiopathology. PMID- 24627165 TI - STEAP4 and insulin resistance. AB - Obesity is a multifactorial disease that caused by the interactions between genetic susceptibility genes and environmental cues. Obesity is considered as a major risk factor of insulin resistance. STEAP4 is a novel anti-obesity gene that is significantly down-regulated in adipose tissue of obese patients. Over expression of STEAP4 can improve glucose uptake and mitochondrial function, and increase insulin sensitivity. STEAP4 expression is regulated by a variety of inflammatory cytokines, hormones, or adipokines. In this review, we discuss function of STEAP4 in regulating insulin resistance in adipose tissue in vivo, as well as in adipocytes in vitro. PMID- 24627166 TI - Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives. AB - Somatostatin (SST) is abundantly produced by the human retina, and the main source is the retinal pigment epithelium (RPE). SST exerts relevant functions in the retina (neuromodulation, angiostatic, and anti-permeability actions) by interacting with SST receptors (SSTR) that are also expressed in the retina. In the diabetic retina, a downregulation of SST production does exist. In this article, we give an overview of the mechanisms by which this deficit of SST participates in the main pathogenic mechanisms involved in diabetic retinopathy (DR): neurodegeneration, neovascularization, and vascular leakage. In view of the relevant SST functions in the retina and the reduction of SST production in the diabetic eye, SST replacement has been proposed as a new target for treatment of DR. This could be implemented by intravitreous injections of SST analogs or gene therapy, but this is an aggressive route for the early stages of DR. Since topical administration of SST has been effective in preventing retinal neurodegeneration in STZ-induced diabetic rats, it seems reasonable to test this new approach in humans. In this regard, the results of the ongoing clinical trial EUROCONDOR will provide useful information. In conclusion, SST is a natural neuroprotective and antiangiogenic factor synthesized by the retina which is downregulated in the diabetic eye and, therefore, its replacement seems a rational approach for treating DR. However, clinical trials will be needed to establish the exact position of targeting SST in the treatment of this disabling complication of diabetes. PMID- 24627167 TI - Analyzing distributional properties of interference effects across modalities: chances and challenges. AB - In research investigating Stroop or Simon effects, data are typically analyzed at the level of mean response time (RT), with results showing faster responses for compatible than for incompatible trials. However, this analysis provides only limited information as it glosses over the shape of the RT distributions and how they may differ across tasks and experimental conditions. These limitations have encouraged the analysis of RT distributions using delta plots. In the present review, we aim to bring together research on distributional properties of auditory and visual interference effects. Extending previous reviews on distributional properties of the Simon effect, we additionally review studies reporting distributional analyses of Stroop effects. We show that distributional analyses of sequential effects (i.e., taking into account congruency of the previous trial) capture important similarities and differences of interference effects across tasks (Simon, Stroop) as well as across sensory modalities, despite some challenges associated to this approach. PMID- 24627168 TI - Encoding and choice in the task span paradigm. AB - Cognitive control during sequences of planned behaviors requires both plan-level processes such as generating, maintaining, and monitoring the plan, as well as task-level processes such as selecting, establishing and implementing specific task sets. The task span paradigm (Logan in J Exp Psychol Gen 133:218-236, 2004) combines two common cognitive control paradigms, task switching and working memory span, to investigate the integration of plan-level and task-level processes during control of sequential behavior. The current study expands past task span research to include measures of encoding processes and choice behavior with volitional sequence generation, using the standard task span as well as a novel voluntary task span paradigm. In two experiments, we consider how sequence complexity, defined separately for plan-level and task-level complexity, influences sequence encoding (Experiment 1), sequence choice (Experiment 2), sequence memory, and task performance of planned sequences of action. Results indicate that participants were sensitive to sequence complexity, but that different aspects of behavior are most strongly influenced by different types of complexity. Hierarchical complexity at the plan level best predicts voluntary sequence generation and memory; while switch frequency at the task level best predicts encoding of externally defined sequences and task performance. Furthermore, performance RTs were similar for externally and internally defined plans, whereas memory was improved for internally defined sequences. Finally, participants demonstrated a significant sequence choice bias in the voluntary task span. Consistent with past research on choice behavior, volitional selection of plans was markedly influenced by both the ease of memory and performance. PMID- 24627169 TI - A comparative evaluation between new ternary zirconium alloys as alternative metals for orthopedic and dental prosthetic devices. AB - PURPOSE: We assessed in vitro the corrosion behavior and biocompatibility of four Zr-based alloys (Zr97.5 Nb1.5VM1.0 ; VM, valve metal: Ti, Mo, W, Ta; at%) to be used as implant materials, comparing the results with grade-2 titanium, a biocompatible metal standard. METHODS: Corrosion resistance was investigated by open circuit potential and electrochemical impedance spectroscopy measurements as a function of exposure time to an artificial physiological environment (Ringer's solution). Human bone marrow stromal cells were used to evaluate biocompatibility of the alloys and their influence on growth kinetics and cell osteogenic differentiation through histochemical and gene expression analyses. RESULTS: Open circuit potential values indicated that Zr-based alloys and grade-2 Ti undergo spontaneous passivation in the simulated aggressive environment. High impedance values for all samples demonstrated improved corrosion resistance of the oxide film, with the best protection characteristics displayed by Zr97.5 Nb1.5Ta1.0. Cells seeded on all surfaces showed the same growth kinetics, although matrix mineralization and alkaline phosphatase activity were maximal on Zr97.5 Nb1.5Mo1.0 and Zr97.5 Nb1.5Ta1.0. Markers of ongoing proliferation, however, such as podocalyxin and CD49f, were still overexpressed on Zr97.5 Nb1.5 Mo1.0 even upon osteoinduction. No relevant effects were noted for the CD146-expressing population of bone progenitors. Nonetheless, the presence of a more differentiated cell population on Zr97.5Nb1.5Ta1.0 samples was inferable by comparing mineralization data and transcript levels of osteogenic markers (osteocalcin, osteopontin, bone sialoprotein, and RUNX2). CONCLUSIONS: The combination of passivation, corrosion resistance and satisfactory biotolerance to bone progenitors make the Zr-based alloys promising implant materials. Among those we tested, Zr97.5Nb1.5Ta1.0 seems to be the most appealing. PMID- 24627170 TI - Severing your lifeline: the impact of neuropsychiatric conditions after left ventricular assist device implantation. PMID- 24627172 TI - A longitudinal study of changes in asylum seekers ability regarding activities of daily living during their stay in the asylum center. AB - The aim was to assess change in activities of daily living (ADL) ability amongst asylum seekers and if there were any difference between tortured and non-torture following a 10 months post-arrival period, and if self-reported health and exposure to torture were factors related to change in ADL-ability. The study was a combined baseline, follow-up correlational study amongst individuals from Afghanistan, Iran and Syria, living in Danish asylum centers. Forty-three persons aged 20-50, were invited and participated in the baseline study. Twenty-two were still in asylum center at the follow-up and 17 of them participated. ADL-ability was measured using Assessment of Motor and Process Skills and questionnaires about exposure to torture, self-reported mental health and pain. ADL motor and process measures, well-being and self-rated health declined from baseline to follow-up. Measures of pain and depression increased. Exposure to physical torture and change in ADL motor (r = 0.525) measures were associated, as well as change in current pain and change in ADL process (r = 0.525) measures. Due to preponderance of torture survivors analysis of group difference was not applicable. Health care workers should be aware of ADL concerns and exposure to torture in this population to best address their needs within rehabilitation settings. PMID- 24627173 TI - The influence of socio-demographic factors on miscarriage incidence among Italian and immigrant women: a critical analysis from Italy. AB - Miscarriage is one of the most relevant adverse events in women's reproductive life. The purpose of the study was to describe miscarriage trend in Italy during the last years among Italian and immigrant women, to compare miscarriage rates of the two groups and to evaluate the effect of age, nationality and educational level on the incidence of having a miscarriage. Then, a brief critical review of other miscarriage risk factors was performed. This study is based on ISTAT database. All data were analyzed through the statistical software SPSS and the following analytical techniques were used: multivariate logistic regression, factorial analysis of variance and Chi square test. Immigrant miscarriage rates resulted higher than Italian ones and they decreased from 2003 to 2009 unlike Italian ones, which remained unchanged. The effect of maternal age on the miscarriage incidence resulted different, depending on the nationality; for Italian women it increased with increasing of age and for immigrant women the opposite trend was found. Moreover, miscarriage incidence resulted significantly different depending on the maternal educational level. Whereas immigrant women considered did not belong to the same ethnic group, biological or genetic factors underlying these differences were excluded and a socioeconomic explanation was provided. Finally, in order to provide more complete information, other miscarriage risk factors were discussed through a brief review of the literature. PMID- 24627174 TI - Lung cancer screening with low-dose CT (LDCT) is ready for prime time in the USA. PMID- 24627175 TI - Omalizumab decreases exacerbations and allows a step down in daily inhaled corticosteroid dose in adults and children with moderate-to-severe asthma. PMID- 24627176 TI - The incidence and the risk factors of venous thromboembolism in Korean patients with pelvic or acetabular fractures. AB - BACKGROUND: Pelvic ring and acetabular fractures are the results of high energy trauma, but there is a paucity of information available regarding the incidence and risk factors of venous thromboembolism (VTE) after these injuries in Asians. This study was undertaken to evaluate the incidence of VTE after a pelvic or an acetabular fracture and to identify predictive factors. METHODS: A prospective evaluation was performed by indirect computed tomography (CT) venography in patients with pelvic or acetabular fractures. Ninety-five patients were examined by indirect CT venography. Fifty-five patients suffered from a pelvic ring injury (anteroposterior compression 5, lateral compression 25, vertical shear 25), and the remaining 40 from acetabular fractures (simple 18, complex 22). Indirect CT venography was performed within 1-2 weeks of initial trauma. Relationships between VTE and sex, age, fracture pattern, body mass index, injury severity score, period of immobilization, and need for surgical treatment were analyzed. Deep vein thrombosis (DVT) in a more proximal to popliteal vein and the existence of PE were considered clinically significant. RESULTS: Thirty-two patients (33.7 %) were found to have VTE at an average of 11 days after initial injury. Clinically significant DVT was found 20 cases (21.1 %). No statistical difference was found between pelvic ring injuries and acetabular fractures with respect to the development of VTE. For those with pelvic ring injury, the incidence of VTE in those with a vertical shear injury (52 %) was significantly greater than in others with a pelvic ring injury (p = 0.014). Patients with an age >50 were found to be at greater risk of VTE (p = 0.032). CONCLUSION: Our findings demonstrate that Korean patients with pelvic or acetabular fractures have a higher risk of VTE than is generally believed, and caution should be taken to prevent and treat VTE, especially in high energy pelvic ring injury and elderly patients. PMID- 24627177 TI - Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats. AB - Hepatic fibrosis is a significant health problem that may progress to cirrhosis and cancer. It may be caused by viruses or chemicals such as dimethylnitrosamine, which is used as a preservative in processed meats and industrial products. The present study was designed to investigate the antifibrotic effect of hesperidin (100 or 200 mg/kg, a flavanone glycoside with potent anti-inflammatory and antioxidant activities) against liver fibrosis in rats compared to silymarin (100 mg/kg). Liver fibrosis was induced in rats using dimethylnitrosamine (10 mg/kg/day, i.p.) three times per week on alternating days for 4 weeks. After 28 days, tissue and blood samples were collected to assess the protective effect of hesperidin. Dimethylnitrosamine caused liver fibrosis as evidenced by the elevation in the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total and direct bilirubin, as well as hepatic malondialdehyde content, gene expression of inducible nitric oxide synthase, alpha-smooth muscle actin and caspase-3. In addition, dimethylnitrosamine caused a reduction in serum total protein, albumin and hepatic glutathione content. Treatment with hesperidin (100 or 200 mg/kg) successfully ameliorated the deleterious effects of dimethylnitrosamine on all tested parameters. Our study indicates a novel protective effect of hesperidin against dimethylnitrosamine-induced liver fibrosis. Interestingly, the protection evoked by hesperidin (200 mg/kg) was superior to that of the standard silymarin. PMID- 24627178 TI - Mycosynthesis and characterization of silver nanoparticles and their activity against some human pathogenic bacteria. AB - The aim of this study was to biosynthesis silver nanoparticles from the fungus Nigrospora sphaerica isolated from soil samples and to examine their activity against five human pathogenic strains of bacteria viz. Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhi and Staphylococcus aureus using disc diffusion method. The synergistic effect of silver nanoparticles in combination with commonly used antibiotic Gentamycin against the selected bacteria was also examined. The synthesized silver nanoparticles from free-cell filtrate were characterized by using UV-Vis spectrophotometer analysis, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). UV Vis spectrophotometer analysis showed a peak at 420 nm indicating the synthesis of silver nanoparticles, FTIR analysis verified the detection of protein capping of silver nanoparticles while SEM micrographs revealed that the silver nanoparticles are dispersed and aggregated and mostly having spherical shape within the size range between 20 and 70 nm. The synthesized silver nanoparticles exhibited a varied growth inhibition activity (15-26 mm diam inhibition zones) against the tested pathogenic bacteria. A remarkable increase of bacterial growth inhibition (26-34 mm diam) was detected when a combination of silver nanoparticles and Gentamycin was used. A significant increase in fold area of antibacterial activity was observed when AgNPs in combination with Gentamycin was applied. The synthesized silver nanoparticles produced by the fungus N. sphaerica is a promising to be used as safe drug in medical therapy due to their broad spectrum against pathogenic bacteria. PMID- 24627179 TI - Estimating cell concentration in three-dimensional engineered tissues using high frequency quantitative ultrasound. AB - Histology and biochemical assays are standard techniques for estimating cell concentration in engineered tissues. However, these techniques are destructive and cannot be used for longitudinal monitoring of engineered tissues during fabrication processes. The goal of this study was to develop high-frequency quantitative ultrasound techniques to nondestructively estimate cell concentration in three-dimensional (3-D) engineered tissue constructs. High frequency ultrasound backscatter measurements were obtained from cell-embedded, 3 D agarose hydrogels. Two broadband single-element transducers (center frequencies of 30 and 38 MHz) were employed over the frequency range of 13-47 MHz. Agarose gels with cell concentrations ranging from 1 * 10(4) to 1 * 10(6) cells mL(-1) were investigated. The integrated backscatter coefficient (IBC), a quantitative ultrasound spectral parameter, was calculated and used to estimate cell concentration. Accuracy and precision of this technique were analyzed by calculating the percent error and coefficient of variation of cell concentration estimates. The IBC increased linearly with increasing cell concentration. Axial and lateral dimensions of regions of interest that resulted in errors of less than 20% were determined. Images of cell concentration estimates were employed to visualize quantitatively regional differences in cell concentrations. This ultrasound technique provides the capability to rapidly quantify cell concentration within 3-D tissue constructs noninvasively and nondestructively. PMID- 24627181 TI - Mutational analysis of the HIV-1 auxiliary protein Vif identifies independent domains important for the physical and functional interaction with HIV-1 reverse transcriptase. PMID- 24627180 TI - Novel functional small RNAs are selectively loaded onto mammalian Ago1. AB - Argonaute (Ago) proteins function in RNA silencing as components of the RNA induced silencing complex (RISC). In lower organisms, the small interfering RNA and miRNA pathways diverge due in part to sorting mechanisms that direct distinct small RNA (sRNA) duplexes onto specific Ago-RISCs. However, such sorting mechanisms appear to be lost in mammals. miRNAs appear not to distinguish among Ago1-4. To determine the effect of viral infection on the sorting system, we compared the content of deep-sequenced RNA extracted from immunoprecipitation experiments with the Ago1 and Ago2 proteins using Epstein-Barr virus (EBV) infected cells. Consistent with previous observations, sequence tags derived from miRNA loci in EBV and humans globally associate in approximately equivalent amounts with Ago1 and Ago2. Interestingly, additional sRNAs, which have not been registered as miRNAs, were associated with Ago1. Among them, some unique sequence tags derived from tandem loci in the human genome associate exclusively with Ago1 but not, or rarely, with Ago2. This is supported by the observation that the expression of the unique sRNAs in the cells is highly dependent on Ago1 proteins. When we knocked down Ago1, the expression of the Ago1-specific sRNAs decreased dramatically. Most importantly, the Ago1-specific sRNAs bound to mRNAs and regulated target genes and were dramatically upregulated, depending on the EBV life cycle. Therefore, even in mammals, the sorting mechanism in the Ago1-4 family is functional. Moreover, the existence of Ago1-specific sRNAs implies vital roles in some aspects of mammalian biology. PMID- 24627182 TI - Honoring Dr. Jean H. Futrell. PMID- 24627183 TI - Species delimitation using genome-wide SNP data. AB - The multispecies coalescent has provided important progress for evolutionary inferences, including increasing the statistical rigor and objectivity of comparisons among competing species delimitation models. However, Bayesian species delimitation methods typically require brute force integration over gene trees via Markov chain Monte Carlo (MCMC), which introduces a large computation burden and precludes their application to genomic-scale data. Here we combine a recently introduced dynamic programming algorithm for estimating species trees that bypasses MCMC integration over gene trees with sophisticated methods for estimating marginal likelihoods, needed for Bayesian model selection, to provide a rigorous and computationally tractable technique for genome-wide species delimitation. We provide a critical yet simple correction that brings the likelihoods of different species trees, and more importantly their corresponding marginal likelihoods, to the same common denominator, which enables direct and accurate comparisons of competing species delimitation models using Bayes factors. We test this approach, which we call Bayes factor delimitation (*with genomic data; BFD*), using common species delimitation scenarios with computer simulations. Varying the numbers of loci and the number of samples suggest that the approach can distinguish the true model even with few loci and limited samples per species. Misspecification of the prior for population size theta has little impact on support for the true model. We apply the approach to West African forest geckos (Hemidactylus fasciatus complex) using genome-wide SNP data. This new Bayesian method for species delimitation builds on a growing trend for objective species delimitation methods with explicit model assumptions that are easily tested. [Bayes factor; model testing; phylogeography; RADseq; simulation; speciation.]. PMID- 24627184 TI - Inferring heterogeneous evolutionary processes through time: from sequence substitution to phylogeography. AB - Molecular phylogenetic and phylogeographic reconstructions generally assume time homogeneous substitution processes. Motivated by computational convenience, this assumption sacrifices biological realism and offers little opportunity to uncover the temporal dynamics in evolutionary histories. Here, we propose an evolutionary approach that explicitly relaxes the time-homogeneity assumption by allowing the specification of different infinitesimal substitution rate matrices across different time intervals, called epochs, along the evolutionary history. We focus on an epoch model implementation in a Bayesian inference framework that offers great modeling flexibility in drawing inference about any discrete data type characterized as a continuous-time Markov chain, including phylogeographic traits. To alleviate the computational burden that the additional temporal heterogeneity imposes, we adopt a massively parallel approach that achieves both fine- and coarse-grain parallelization of the computations across branches that accommodate epoch transitions, making extensive use of graphics processing units. Through synthetic examples, we assess model performance in recovering evolutionary parameters from data generated according to different evolutionary scenarios that comprise different numbers of epochs for both nucleotide and codon substitution processes. We illustrate the usefulness of our inference framework in two different applications to empirical data sets: the selection dynamics on within-host HIV populations throughout infection and the seasonality of global influenza circulation. In both cases, our epoch model captures key features of temporal heterogeneity that remained difficult to test using ad hoc procedures. [Bayesian inference; BEAGLE; BEAST; Epoch Model; phylogeography; Phylogenetics.]. PMID- 24627186 TI - Comment on: double, synchronous pituitary adenomas causing acromegaly and Cushing's disease. A case report and review of literature. Endocr Pathol 2013;24:92-99. PMID- 24627185 TI - Global biodiversity assessment and hyper-cryptic species complexes: more than one species of elephant in the room? AB - Several recent estimates of global biodiversity have concluded that the total number of species on Earth lies near the lower end of the wide range touted in previous decades. However, none of these recent estimates formally explore the real "elephant in the room", namely, what proportion of species are taxonomically invisible to conventional assessments, and thus, as undiagnosed cryptic species, remain uncountable until revealed by multi-gene molecular assessments. Here we explore the significance and extent of so-called "hyper-cryptic" species complexes, using the Australian freshwater fish Galaxias olidus as a proxy for any organism whose taxonomy ought to be largely finalized when compared to those in little-studied or morphologically undifferentiated groups. Our comprehensive allozyme (838 fish for 54 putative loci), mtDNA (557 fish for 605 bp of cytb), and morphological (1963-3389 vouchers for 17-58 characters) assessment of this species across its broad geographic range revealed a 1500% increase in species level biodiversity, and suggested that additional taxa may remain undiscovered. Importantly, while all 15 candidate species were morphologically diagnosable a posteriori from one another, single-gene DNA barcoding proved largely unsuccessful as an a priori method for species identification. These results lead us to draw two strong inferences of relevance to estimates of global biodiversity. First, hyper-cryptic complexes are likely to be common in many organismal groups. Second, no assessment of species numbers can be considered "best practice" in the molecular age unless it explicitly includes estimates of the extent of cryptic and hyper-cryptic biodiversity. [Galaxiidae; global estimates; hyper-diverse; mountain galaxias; species counts; species richness.]. PMID- 24627187 TI - Impact of technological innovation on a nursing home performance and on the medication-use process safety. AB - Despite the fact that since 1985 the government of Quebec increased by 5.75 % on average the amount of money spent on healthcare per year, little improvement was noted. It is obvious that an optimal use of resources is essential to reduce waiting times and provide safer and faster services to patients. The use of new technology can contribute to improve the healthcare system efficiency. Our study aims to assess the impact of a medication distribution technology on 1) the performance of a health and social services center's pharmacy, 2) the performance of one care unit in a nursing home and on 3) the medication-use process safety. To measure performance we were inspired by the Lean approach. The results show that medication distribution technology is considered as an effective way to significantly detect medication errors, to allow nurses to focus more on patients and pharmacy to react more rapidly to changes in patient medications. PMID- 24627189 TI - Online child pornography offenders are different: a meta-analysis of the characteristics of online and offline sex offenders against children. AB - The current meta-analysis compared the characteristics of online child pornography-only offenders, typical (offline) sex offenders against children, and offenders with both child pornography and contact sex offences against children (mixed). Based on 30 unique samples (comparison ns ranging from 98 to 2,702), the meta-analysis found key differences between groups. Offenders who committed contact sex offences were more likely to have access to children than those with only child pornography offences. In contrast, offenders who used the internet to commit sexual offences had greater access to the internet than those with contact sex offenders. Differences between the groups, however, were not limited to differential opportunities. Sex offenders against children and mixed offenders were found to score higher on indicators of antisociality than online child pornography offenders (CPOs). CPOs were also more likely to have psychological barriers to sexual offending than sex offenders against children and mixed offenders (e.g., greater victim empathy). Mixed offenders were found to be the most pedophilic, even more than CPOs. The findings suggest that offenders who restricted their offending behavior to online child pornography offences were different from mixed offenders and offline sex offenders against children, and that mixed offenders were a particularly high risk group. PMID- 24627188 TI - Different roles of two transcription factor B proteins in the hyperthermophilic archaeon Thermococcus kodakarensis. AB - Two genes, TK1280 and TK2287, encode orthologous transcription factor B proteins (TFB1 and TFB2, respectively) in the hyperthermophilic archaeon Thermococcus kodakarensis. The functional difference between their TFBs remains unknown. While TFB1 and TFB2 displayed equivalent thermostability, mRNA levels of tfb1 at 93 degrees C were eightfold higher than those at 60 or 85 degrees C, and were 4- to 10-fold greater than those of tfb2 at all temperatures. This suggests that TFB1 is the abundant TFB in T. kodakarensis and is heat-inducible. By contrast, the mRNA level of tfb2 increased at 93 degrees C, but the levels were less than twofold of those at 60 or 85 degrees C. No significant differences in growth were observed among the DTF1 (?tfb1, ?pyrF), DTF2 (?tfb2 ?pyrF), and parental host strain KU216 (?pyrF) at 60 degrees C. However, DTF2 showed a decrease in cell yield at 85 degrees C, and both DTF1 and DTF2 showed growth defects at 93 degrees C. Comparative transcriptome analysis between KU216 and DTF1 or DTF2 indicated that TFB1 apparently controls the expression of genes essential for motility/adhesion, whereas TFB2 regulates genes involved in mevalonate/lipid biosynthesis. In DTF1, the ratio of cells with flagella decreased at 85 and 93 degrees C, and reporter studies indicated that flaB1 transcription is dependent on TFB1 at 85 degrees C but not at 60 degrees C. PMID- 24627190 TI - The relationship between intact parathyroid hormone levels and daily physical activity in hemodialysis patients. AB - PURPOSE: Poor physical activity and decreased daily activities are commonly seen in hemodialysis (HD) patients. Along with the progression of chronic kidney disease (CKD), various abnormalities of mineral and bone metabolism develop, such as osteitis fibrosa and adynamic bone disease, which are related with intact parathyroid hormone (intact-PTH). Surprisingly, scarce data exists regarding the relationship between intact-PTH and daily physical activity in HD patients. METHODS: Demographics, clinical parameters, laboratory data were recorded for all patients. Depressive symtoms, quality of life and daily activities of HD patients were measured by Beck Depression Inventory, SF-36, and Nottingham Extended Activities of Daily Living Scale (NEADLS), respectively. RESULTS: In total 114 patients (male/female: 63/51, aged: 53.0 +/- 13.8 years) were enrolled. The value of intact-PTH for <25th (Group 1), < 25th-50th (Group 2), 50th-75th (Group 3) and >75th (Group 4) quartiles were <132.5 pg/ml, >=132.5 <261.0, >=261.0 <510.4 and >=510.4, respectively. The NEADLS scores were 25.3 +/- 10.8, 35.0 +/- 9.4, 27.2 +/- 13.9 and 26.4 +/- 12.9 as going from Group 1 to Group 4 (p = 0.009). Post-hoc analysis of these four groups revealed that only Group 1 and Group 2 (p = 0.012), and Group 2 and Group 4 (p = 0.034) were different with respect to NEADLS scores. CONCLUSIONS: Intact-PTH levels were inversely associated with daily activities in whole group. However, the post hoc analysis demonstrated that the association between intact PTH and daily activity is not linear and daily physical activity was lower only in patients with lowest and highest quartiles of intact-PTH. PMID- 24627191 TI - Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells. AB - Extracellular nucleotides, such as ATP, are released from cells and play roles in various physiological and pathological processes through activation of P2 receptors. Here, we show that autocrine signaling through release of ATP and activation of P2X7 receptor influences migration of human lung cancer cells. Release of ATP was induced by stimulation with TGF-beta1, which is a potent inducer of cell migration, in human lung cancer H292 cells, but not in noncancerous BEAS-2B cells. Treatment of H292 cells with a specific antagonist of P2X7 receptor resulted in suppression of TGF-beta1-induced migration. PC-9 human lung cancer cells released a large amount of ATP under standard cell culture conditions, and P2X7 receptor-dependent dye uptake was observed even in the absence of exogenous ligand, suggesting constitutive activation of P2X7 receptor in this cell line. PC-9 cells showed high motile activity, which was inhibited by treatment with ecto-nucleotidase and P2X7 receptor antagonists, whereas a P2X7 receptor agonist enhanced migration. PC-9 cells also harbor a constitutively active mutation in epidermal growth factor receptor (EGFR). Treatment with EGFR tyrosine kinase inhibitor AG1478 suppressed both cell migration and P2X7 receptor expression in PC-9 cells. Compared to control PC-9 cells, cells treated with P2X7 antagonist exhibited broadened lamellipodia around the cell periphery, while AG1478-treated cells lacked lamellipodia. These results indicate that P2X7 mediated signaling and EGFR signaling may regulate migration of PC-9 cells through distinct mechanisms. We propose that autocrine ATP-P2X7 signaling is involved in migration of human lung cancer cells through regulation of actin cytoskeleton rearrangement. PMID- 24627192 TI - Association of a single-nucleotide polymorphism from chromosome 17q12 with the aggressiveness of prostate cancer in a Hispanic population. AB - PURPOSE: To study the association between the polymorphisms, rs1859962 and rs4430796, from the chromosomes 17q24 and 17q12, respectively, with the risk of prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population. METHODS: This study included 33 controls and 167 patients diagnosed with PCa. The polymorphisms, rs1859962 and rs4430796, were analyzed on blood specimens using quantitative PCR. The genetic analysis of the qPCR data was performed using the SNPStats program. A comparison between the clinical characteristics of the prostate cancers from the patients and the presence of the different polymorphism genotypes detected in blood specimens obtained from these patients was performed using the IBM SPSS v20.0 software. RESULTS: We observed no association of the SNPs and the risk of developing PCa (OR 0.84, 95 % CI 0.30 2.38, p = 1.0 to rs1859962 and OR 1.94, 95 % CI 0.57-6.52, p = 0.28 to rs4430796), both sporadic and hereditary. However, patients carrying the genotype G/G from the polymorphism rs4430796 had significantly higher PSA levels than patients carrying the other genotypes (15.05 ng/ml to G/G, 10 and 8.11 ng/ml to genotypes A/G y A/A, respectively, p = 0.01). Furthermore, patients with the genotype G/G of rs4430796 had higher tumor volume than other genotypes (9.45 cc to G/G and 5.22 cc to A/G + A/A, p = 0.04). CONCLUSION: The polymorphism rs4430796 of the chromosome 17q12 appears to be a biomarker for cancer aggressiveness, increased PSA and tumor volume of PCa. PMID- 24627193 TI - Myelodysplastic syndromes with 5q deletion: pathophysiology and role of lenalidomide. AB - Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder primarily affecting CD34+ cells, characterized by ineffective hematopoiesis, often transforming into acute myelogenous leukemia (AML). A subset of patients has 5q deletion (del(5q)) as the culprit pathogenetic trigger. Del(5q) affects critical regions 5q31 and 5q33, leading to gene haplodeficiency with subsequent RPS14 haplodeficiency and P53 activation. Subsequent to P53 activation, erythroid cell apoptosis and ineffective erythropoiesis occur. Other pathogenetic elements include protein phosphatase 2a and CDC25C haplodeficiency and decreased miR-145 and miR-146a expression. Lenalidomide is an immunomodulatory agent that selectively suppresses the del(5q) clone. While the mechanism is not fully understood, it is associated with diverse molecular changes including stabilization of MDM2 with subsequent enhanced P53 degradation. Lenalidomide showed success in low- and intermediate-1-risk MDS as reported in the 002, 003, and 004 trials. However, in higher-risk MDS, the results of lenalidomide monotherapy were modest, mandating the use of combination therapy. The role and priority of lenalidomide varies between different guidelines, and accordingly, future efforts are necessary to reach a unified therapeutic algorithm. TP53 mutations are important predictors of AML progression and possible resistance to lenalidomide. It is recommended to identify TP53 mutation early in the disease since it may change the decision regarding choice of therapy. Challenges with lenalidomide therapy remain the long-term effects and timing of its discontinuation. PMID- 24627194 TI - Flow cytometry CD4(+)CD26(-)CD38(+) lymphocyte subset in the microenvironment of Hodgkin lymphoma-affected lymph nodes. AB - Hodgkin lymphoma (HL) is traditionally diagnosed by the presence of neoplastic Hodgkin and Reed-Sternberg (HRS) cells found in minority within a typical inflammatory microenvironment. It is now recognized that the majority of these T CD4 cells are T regulatory (Treg) and play an important immunosuppressive role and contribute to tumour persistence. Flow cytometric immunophenotyping of lymphocytes was performed on lymph node samples over a 12-year period (2000-2012) to identify the Hodgkin-specific subset and potential biomarkers related to Treg cells. CD3, CD19 and T CD4(+)CD26(-)CD38(+) subsets were measured in the lymphocytic infiltrate of 108 consecutive lymph node samples concurrently diagnosed histologically as HL and in 43 cases of benign reactive lymphoid hyperplasia (BRLH). HL, compared to BRLH, shows statistically significant differences within the reactive microenvironmental population: decreased CD19(+) cells (23 % vs 39 %; p < 0.001), increased CD3(+) (74 % vs 58 %; p < 0.001) and CD4(+)CD26(-)CD38(+) cells (38 % vs 11.5 %; p < 0.001). By using the co-expressed markers CD38 and CD26 for logistic analysis, the obtained receiver operating characteristic (ROC) curves confirm that the CD4(+)CD26(-)CD38(+) subset is strongly expressed in HL (ROC AUC = 0,8639). Flow cytometric detection of CD4(+)CD26(-)CD38(+) cells seems able to identify the cellular microenvironmental pattern in HL and to distinguish it from BRLH. Although there is extensive experience in flow cytometric analysis of non-HL, it is not routinely applied in cases of HL and our findings suggest that it may be useful in quickly and easily characterizing its cellular para-neoplastic inflammatory background. PMID- 24627195 TI - Association between matrix metalloproteinase 2 (MMP2) promoter polymorphisms and the susceptibility to non-Hodgkin's lymphoma in Egyptians. AB - Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases capable of extracellular matrix degradation. MMP2 is the key molecule that control invasion, tumor growth, and metastasis, and has been associated with poor prognosis in several tumors. Several epidemiological studies have focused on the associations between MMP2 promoter polymorphisms and cancer susceptibility; however, little is known about their role in hematological malignancies. The present study aimed to investigate the association of MMP2 -735C/T and -1306C/T promoter polymorphisms with B-NHL susceptibility and their clinicopathological characteristics. The study included 100 B-NHL patients and 100 healthy controls. Genotyping of MMP2 735C/T and MMP2 -1306C/T was done by polymerase chain reaction restricted fragment length polymorphism (PCR-RFLP) technique. MMP2 -735C/T heteromutant genotype (CT) was detected in 23 % of patients, and the homomutant genotype (TT) was detected in 7 % of patients. The polymorphic allele, T allele, was associated with susceptibility to B-NHL (OR = 2.8:95 %CI = 1.48-5.28). For MMP2 -1306C/T, the frequencies of the polymorphic variants were 5 % for the heteromutant genotype (CT) and 3 % for the homomutant genotype (TT). The polymorphic allele, T allele, conferred almost fourfold increased risk of B-NHL (OR = 3.8, 95 %CI = 1.05-13.9), and the risk elevated to be almost eight folds when confined to diffuse large B-cell lymphoma (DLBCL) (OR = 7.9, 95 %CI = 1.67-32.27). MMP2 735C/T polymorphic genotypes were correlated with advanced clinical stages of the disease (stages III and IV). In conclusion, the study revealed that the variant alleles of MMP2 -735C/T and MMP2 -1306C/T can be considered as molecular risk factors for B-NHL among Egyptians. PMID- 24627196 TI - Tribute to Jean-Francois Narbonne. PMID- 24627197 TI - Brain glutathione redox system significance for the control of silica-coated magnetite nanoparticles with or without mercury co-exposures mediated oxidative stress in European eel (Anguilla anguilla L.). AB - This in vitro study investigates the impact of silica-coated magnetite particles (Fe3O4@SiO2/SiDTC, hereafter called IONP; 2.5 mg L(-1)) and its interference with co-exposure to persistent contaminant (mercury, Hg; 50 MUg L(-1)) during 0, 2, 4, 8, 16, 24, 48, and 72 h on European eel (Anguilla anguilla) brain and evaluates the significance of the glutathione (GSH) redox system in this context. The extent of damage (membrane lipid peroxidation, measured as thiobarbituric acid reactive substances, TBARS; protein oxidation, measured as reactive carbonyls, RCs) decreased with increasing period of exposure to IONP or IONP + Hg which was accompanied with differential responses of glutathione redox system major components (glutathione reductase, GR; glutathione peroxidase, GPX; total GSH, TGSH). The occurrence of antagonism between IONP and Hg impacts was evident at late hour (72 h), where significantly decreased TBARS and RC levels and GR and glutathione sulfo-transferase (GST) activity imply the positive effect of IONP + Hg concomitant exposure against Hg-accrued negative impacts [vs. early (2 h) hour of exposure]. A period of exposure-dependent IONP alone and IONP + Hg joint exposure-accrued impact was perceptible. Additionally, increased susceptibility of the GSH redox system to increased period of exposure to Hg was depicted, where insufficiency of elevated GR for the maintenance of TGSH required for membrane lipid and cellular protein protection was displayed. Overall, a fine-tuning among brain glutathione redox system components was revealed controlling IONP + Hg interactive impacts successfully. PMID- 24627198 TI - Vertical and horizontal distributions of microbial abundances and enzymatic activities in propylene-glycol-affected soils. AB - The natural microbial activity in the unsaturated soil is vital for protecting groundwater in areas where high loads of biodegradable contaminants are supplied to the surface, which usually is the case for airports using aircraft de-icing fluids (ADF) in the cold season. Horizontal and vertical distributions of microbial abundance were assessed along the western runway of Oslo Airport (Gardermoen, Norway) to monitor the effect of ADF dispersion with special reference to the component with the highest chemical oxygen demand (COD), propylene glycol (PG). Microbial abundance was evaluated by several biondicators: colony-forming units (CFU) of some physiological groups (aerobic and anaerobic heterotrophs and microscopic fungi), most probable numbers (MPN) of PG degraders, selected catabolic enzymatic activities (fluorescein diacetate (FDA) hydrolase, dehydrogenase, and beta-glucosidase). High correlations were found between the enzymatic activities and microbial counts in vertical soil profiles. All microbial abundance indicators showed a steep drop in the first meter of soil depth. The vertical distribution of microbial abundance can be correlated by a decreasing exponential function of depth. The horizontal trend of microbial abundance (evaluated as total aerobic CFU, MPN of PG-degraders, and FDA hydrolase activity) assessed in the surface soil at an increasing distance from the runway is correlated negatively with the PG and COD loads, suggesting the relevance of other chemicals in the modulation of microbial growth. The possible role of potassium formate, component of runway de-icers, has been tested in the laboratory by using mixed cultures of Pseudomonas spp., obtained by enrichment with a selective PG medium from soil samples taken at the most contaminated area near the runway. The inhibitory effect of formate on the growth of PG degraders is proven by the reduction of biomass yield on PG in the presence of formate. PMID- 24627200 TI - 7th International PCB Workshop: Chemical mixtures in a complex world. PMID- 24627199 TI - Risk assessment of antibiotic residues in different water matrices in India: key issues and challenges. AB - Global detection of antibiotic substances in water matrices has considerably increased in the recent past. However, in India research on this issue is limited or generalised in the literature. Risks associated with the presence of antibiotics in the environment can be quantified using a hazard quotient (HQ) approach. Here, HQs were developed using the measured environmental concentration (MEC) approach for antibiotic residues in Indian water matrices previously reported in the literature. In the present study, environmental risk assessment, using the HQ index [HQ = measured environmental concentration (MEC)/predicted no effect concentration (PNEC)] for different antibiotics, was performed according to the guidelines of European Medicine Evaluation Agency (EMEA). MEC and PNEC levels were obtained from the literature. PNEC values were also calculated from EC50 using a safety factor when no PNECs were reported in the literature. HQs were obtained for industrial effluents (HQ = 10(4)) that were greater than any previously reported values. Ciprofloxacin, a fluoroquinolone antibiotic, seemed to present the greatest risk in India. The HQ indices for Indian water matrices were in the following order: industrial effluents > lake water > river water > hospital effluents > treated sewage ? groundwater. A very high HQ represents a potential environmental concern for aquatic environments in India and demands that immediate attention be devoted to regulating these compounds, especially in pharmaceutical industrial wastewater. PMID- 24627201 TI - Solar CPC pilot plant photocatalytic degradation of bisphenol A in waters and wastewaters using suspended and supported-TiO2. Influence of photogenerated species. AB - Photocatalytic degradation of bisphenol A (BPA) in waters and wastewaters in the presence of titanium dioxide (TiO2) was performed under different conditions. Suspensions of the TiO2 were used to compare the degradation efficiency of BPA (20 mg L(-1)) in batch and compound parabolic collector (CPC) reactors. A TiO2 catalyst supported on glass spheres was prepared (sol-gel method) and used in a CPC solar pilot plant for the photodegradation of BPA (100 MUg L(-1)). The influence of OH., O2 (.-), and h (+) on the BPA degradation were evaluated. The radicals OH. and O2 (.-) were proved to be the main species involved on BPA photodegradation. Total organic carbon (TOC) and carboxylic acids were determined to evaluate the BPA mineralization during the photodegradation process. Some toxicological effects of BPA and its photoproducts on Eisenia andrei earthworms were evaluated. The results show that the optimal concentration of suspended TiO2 to degrade BPA in batch or CPC reactors was 0.1 g L(-1). According to biological tests, the BPA LC50 in 24 h for E. andrei was of 1.7 * 10(-2) mg cm(-2). The photocatalytic degradation of BPA mediated by TiO2 supported on glass spheres suffered strong influence of the water matrix. On real municipal wastewater treatment plant (MWWTP) secondary effluent, 30 % of BPA remains in solution; nevertheless, the method has the enormous advantage since it eliminates the need of catalyst removal step, reducing the cost of treatment. PMID- 24627202 TI - Nitric acid recycling and copper nitrate recovery from effluent. AB - The recycling of nitric acid and copper nitrate contained in an industrial effluent was studied. The experiments conducted on such a medium showed that the presence of copper nitrate significantly improves nitric acid-water separation during distillation in an azeotropic medium. At the temperature of the azeotrope, however, this metal salt starts to precipitate, making the medium pasty, thus inhibiting the nitric acid extraction process. The optimisation of parameters such as column efficiency and adding water to the boiler at the azeotrope temperature are recommended in this protocol in order to collect the various components while avoiding the formation of by-products: NOx compounds. Thus, the absence of column, along with the addition of a small volume of water at a temperature of 118 degrees C, significantly increases the yield, allowing 94 % nitric acid to be recovered at the end of the process, along with the residual copper nitrate. The resulting distillate, however, is sufficiently dilute to not be used as is. Rectification is required to obtain concentrated nitric acid at 15 mol.l(-1), along with a weakly acidic distillate from the distillation front. This latter is quenched using potassium hydroxide and is used as a fertiliser solution for horticulture or sheltered market gardening. This process thus allows complete recycling of all the medium's components, including that of the distillate resulting from the nitric acid rectification operation. PMID- 24627203 TI - Heterogeneous Fenton degradation of bisphenol A catalyzed by efficient adsorptive Fe3O4/GO nanocomposites. AB - A new method for the degradation of bisphenol A (BPA) in aqueous solution was developed. The oxidative degradation characteristics of BPA in a heterogeneous Fenton reaction catalyzed by Fe3O4/graphite oxide (GO) were studied. Transmission electron microscopic images showed that the Fe3O4 nanoparticles were evenly distributed and were ~6 nm in diameter. Experimental results suggested that BPA conversion was affected by several factors, such as the loading amount of Fe3O4/GO, pH, and initial H2O2 concentration. In the system with 1.0 g L(-1) of Fe3O4/GO and 20 mmol L(-1) of H2O2, almost 90% of BPA (20 mg L(-1)) was degraded within 6 h at pH 6.0. Based on the degradation products identified by GC-MS, the degradation pathways of BPA were proposed. In addition, the reused catalyst Fe3O4/GO still retained its catalytic activity after three cycles, indicating that Fe3O4/GO had good stability and reusability. These results demonstrated that the heterogeneous Fenton reaction catalyzed by Fe3O4/GO is a promising advanced oxidation technology for the treatment of wastewater containing BPA. PMID- 24627204 TI - Chemical composition and mass closure of ambient coarse particles at traffic and urban-background sites in Thessaloniki, Greece. AB - Concentrations and chemical composition of the coarse particle fraction (PMc) were investigated at two urban sites in the city of Thessaloniki, Greece, through concurrent sampling of PM10 and PM2.5 during the warm and the cold months of the year. PMc levels at the urban-traffic site (UT) were among the highest found in literature worldwide exhibiting higher values in the cold period. PMc levels at the urban-background site (UB) were significantly lower exhibiting a reverse seasonal trend. Concentration levels of minerals and most trace metals were also higher at the UT site suggesting a stronger impact from traffic-related sources (road dust resuspension, brake and tire abrasion, road wear). According to the chemical mass closure obtained, minerals (oxides of Si, Al, Ca, Mg, Fe, Ti, and K) dominated the PMc profile, regardless of the site and the period, with organic matter and secondary inorganic aerosols (mainly nitrate) also contributing considerably to the PMc mass, particularly in the warm period. The influence of wind speed to dilution and/or resuspension of coarse particles was investigated. The source of origin of coarse particles was also investigated using surface wind data and atmospheric back-trajectory modeling. Finally, the contribution of resuspension to PMc levels was estimated for air quality management perspectives. PMID- 24627205 TI - The pattern of proline, glutamic acid, and leucine-rich protein 1 expression in Chinese women with primary breast cancer. AB - BACKGROUND: Disparities of biomarkers' expression in breast cancer across different races and ethnicities have been well documented. Proline, glutamic acid, and leucine-rich protein 1 (PELP1), a novel ER coregulator, has been considered as a promising biomarker of breast cancer prognosis; however, the pattern of PELP1 expression in Chinese women with breast cancer has never been investigated. This study aims to provide useful reference on possible racial or ethnic differences of PELP1 expression in breast cancer by exploring the pattern of PELP1 expression in Chinese women with primary breast cancer. METHODS: The expression of PELP1 in primary breast cancer samples from 130 Chinese female patients was detected by immunohistochemistry and correlated to other clinicopathological parameters; for comparison, the expression of PELP1 in 26 benign breast fibroadenomas was also examined. RESULTS: The overall value of the PELP1 H-score in breast cancer was significantly higher than that in breast fibroadenoma (p<0.001). In our breast cancer patients, the ER/HER-2-positive group had significantly higher PELP1 H-scores than their negative counterparts (p=0.003 for ER and p=0.022 for HER-2); the Ki-67-high group also showed significantly higher PELP1 H-scores than the Ki-67-low group (p=0.008). No significant association between PELP1 H-scores and other clinicopathological parameters was found. Finally, the PELP1 H-score in breast cancers of the luminal B subtype was significantly higher than that in the triple negative subtype (p=0.002). CONCLUSION: Overexpression of PELP1 in Chinese women with primary breast cancer appears to be associated with biomarkers of poor outcome; these results are similar to other reports based on Western populations. PMID- 24627206 TI - Work Ability Index as tool to identify workers at risk of premature work exit. AB - PURPOSE: To investigate the Work Ability Index (WAI) as tool for identifying workers at risk of premature work exit in terms of disability pension, unemployment, or early retirement. METHODS: Prospective cohort study of 11,537 male construction workers (mean age 45.5 years), who completed the WAI at baseline and reported their work status (employed, unemployed, disability pension, or retired) after mean 2.3 years of follow-up. Associations between WAI scores and work status were investigated by multinomial logistic regression analysis. The ability of the WAI to discriminate between workers at high and low risk of premature work exit was analyzed by the area (AUC) under the receiver operating characteristic curve. RESULTS: 9,530 (83 %) construction workers had complete data for analysis. At follow-up, 336 (4 %) workers reported disability pension, 125 (1 %) unemployment, and 255 (3 %) retirement. WAI scores were prospectively associated with the risk of disability pension at follow-up, but not with the risk of unemployment and early retirement. The WAI showed fair discrimination to identify workers at risk of disability pension [AUC = 0.74; 95 % confidence interval (CI) 0.70-0.77]. The discriminative ability decreased with age from AUC = 0.78 in workers aged 30-39 years to AUC = 0.69 in workers >=50 years of age. Discrimination failed for unemployment (AUC = 0.51; 95 % CI 0.47 0.55) and early retirement (AUC = 0.58; 95 % CI 0.53-0.61). CONCLUSIONS: The WAI can be used to identify construction workers <50 years of age at increased risk of disability pension and invite them for preventive interventions. PMID- 24627207 TI - Intraventricular tissue plasminogen activator in subarachnoid hemorrhage patients: a prospective, randomized, placebo-controlled pilot trial. AB - BACKGROUND: The quantity of subarachnoid (SAH) and intraventricular hemorrhage (IVH) occurring in the setting of a ruptured cerebral aneurysm is strongly associated with subsequent complications and poor outcomes. METHODS: We randomly allocated aneurysmal SAH patients with a modified Fisher score of 4, who had been treated with endovascular coil embolization and ventricular drainage, to receive either 2 mg intraventricular tissue plasminogen activator (TPA) every 12 h (maximum 10 mg) or placebo. Computed tomography scans were performed 12, 48, and 72 h after administration. Primary outcomes included feasibility (enrollment and consent rates), safety (assessed by prospectively screening for complications), and rate of intracranial blood clearance (measured using sequential IVH, modified Graeb, and SAH sum scores). Secondary outcomes included angiographic vasospasm, delayed cerebral ischemia, need for ventriculoperitoneal shunting, and 6-month neurological outcomes. RESULTS: Seventy-seven patients were screened, 17 were eligible, and 12 were randomized. The consent rate was 87 %. There were no cases of new intracranial hemorrhage complicating use of TPA. Models fit using generalized estimating equations demonstrated more rapid reduction in IVH volume (p = 0.009), modified Graeb score (p < 0.001), and SAH sum score (p < 0.001) among patients treated with TPA. SAH clearance at 48 h was enhanced by earlier drug administration (p = 0.02). There were no differences in secondary outcomes. CONCLUSIONS: Intraventricular TPA accelerates clearance of SAH and IVH, especially when administered early. A larger-scale clinical trial of intraventricular TPA is feasible, will need to be conducted at multiple centers, and is required to determine whether this practice reduces complications and improves outcomes. PMID- 24627208 TI - The influence of training on the attentional blink and psychological refractory period. AB - A growing body of research suggests that dual-task interference in sensory consolidation (e.g., the attentional blink, AB) and response selection (e.g., the psychological refractory period, PRP) stems from a common central bottleneck of information processing. With regard to response selection, it is well known that training reduces dual-task interference. We tested whether training that is known to be effective for response selection can also reduce dual-task interference in sensory consolidation. Over two experiments, performance on a PRP paradigm (Exp. 1) and on AB paradigms (differing in their stimuli and task demands, Exps. 1 and 2) was examined after participants had completed a relevant training regimen (T1 practice for both paradigms), an irrelevant training regimen (comparable sensorimotor training, not related to T1 for both tasks), a visual-search training regimen (Exp. 2 only), or after participants had been allocated to a no training control group. Training that had shown to be effective for reducing dual task interference in response selection was also found to be effective for reducing interference in sensory consolidation. In addition, we found some evidence that training benefits transferred to the sensory consolidation of untrained stimuli. Collectively, these findings show that training benefits can transfer across cognitive operations that draw on the central bottleneck in information processing. These findings have implications for theories of the AB and for the design of cognitive-training regimens that aim to produce transferable training benefits. PMID- 24627209 TI - Multisensory processing of redundant information in go/no-go and choice responses. AB - In multisensory research, faster responses are commonly observed when multimodal stimuli are presented, as compared to unimodal target presentations. This so called redundant-signals effect can be explained by several frameworks, including separate-activation and coactivation models. The redundant-signals effect has been investigated in a large number of studies; however, most of those studies have been limited to the rejection of separate-activation models. Coactivation models have been analyzed in only a few studies, primarily using simple response tasks. Here, we investigated the mechanism of multisensory integration underlying go/no-go and choice responses to redundant auditory-visual stimuli. In the present study, the mean and variance of response times, as well as the accuracy rates of go/no-go and choice responses, were used to test a coactivation model based on the linear superposition of diffusion processes (Schwarz, 1994) within two absorbing barriers. The diffusion superposition model accurately describes the means and variances of response times as well as the proportions of correct responses observed in the two tasks. Linear superposition thus seems to be a general principle in the integration of redundant information provided by different sensory channels, and is not restricted to simple responses. The results connect existing theories of multisensory integration with theories on choice behavior. PMID- 24627210 TI - Display-wide influences on figure-ground perception: the case of symmetry. AB - Past research has demonstrated that convex regions are increasingly likely to be perceived as figures as the number of alternating convex and concave regions in test displays increases. This region-number effect depends on both a small preexisting preference for convex over concave objects and the presence of scene characteristics (i.e., uniform fill) that allow the integration of the concave regions into a background object/surface. These factors work together to enable the percept of convex objects in front of a background. We investigated whether region-number effects generalize to another property, symmetry, whose effectiveness as a figure property has been debated. Observers reported which regions they perceived as figures in black-and-white displays with alternating symmetric/asymmetric regions. In Experiments 1 and 2, the displays had articulated outer borders that preserved the symmetry/asymmetry of the outermost regions. Region-number effects were not observed, although symmetric regions were perceived as figures more often than chance. We hypothesized that the articulated outer borders prevented fitting a background interpretation to the asymmetric regions. In Experiment 3, we used straight-edge framelike outer borders and observed region-number effects for symmetry equivalent to those observed for convexity. These results (1) show that display-wide information affects figure assignment at a border, (2) extend the evidence indicating that the ability to fit background as well as foreground interpretations is critical in figure assignment, (3) reveal that symmetry and convexity are equally effective figure cues and, (4) demonstrate that symmetry serves as a figural property only when it is close to fixation. PMID- 24627211 TI - Attention meets binding: only attended distractors are used for the retrieval of event files. AB - Response-irrelevant stimuli can be encoded with, and later on retrieve, a response given to a relevant stimulus, an effect that is called distractor response binding. In three experiments using a prime-probe design, we investigated whether the allocation of attention modulates the processes contributing to distractor-response binding. Participants identified letters via keypresses while attending to one of two sets of simultaneously presented but response-irrelevant number stimuli. In different experiments, both spatial attention and feature-based attention were allocated to the response-irrelevant stimuli. The results showed that only attended response-irrelevant stimuli elicited effects of distractor-response binding. In particular, while the encoding of response-irrelevant stimuli and responses was not particularly affected by attention during prime processing, only attended response-irrelevant stimuli in the probe retrieved previous responses. Hence, we show that attention affects action regulation due to modulating the influence of stimulus-response binding on behavior. PMID- 24627212 TI - Decomposing the action effect: how simple actions affect subsequent perception. AB - Simple actions toward an object cause people to allocate attention preferentially toward properties of that object in subsequent unrelated tasks. We show here that it is not necessary to process or attend to any properties of the object in order to obtain the effect: Even when participants knew prior to the object's onset that they would be acting, the effects of the object remained. Furthermore, the effect remained when the action had no visible effect on the object. In addition, we examined the extent to which the effect may be due to goal updating (which is necessary only on trials that require action) and found that the effect remained even when goal updating was not necessary. The results reveal that a simple action does, indeed, affect perception and have implications for understanding vision as individuals make actions in naturally occurring behavior. PMID- 24627213 TI - Expertise for upright faces improves the precision but not the capacity of visual working memory. AB - Considerable research has focused on how basic visual features are maintained in working memory, but little is currently known about the precision or capacity of visual working memory for complex objects. How precisely can an object be remembered, and to what extent might familiarity or perceptual expertise contribute to working memory performance? To address these questions, we developed a set of computer-generated face stimuli that varied continuously along the dimensions of age and gender, and we probed participants' memories using a method-of-adjustment reporting procedure. This paradigm allowed us to separately estimate the precision and capacity of working memory for individual faces, on the basis of the assumptions of a discrete capacity model, and to assess the impact of face inversion on memory performance. We found that observers could maintain up to four to five items on average, with equally good memory capacity for upright and upside-down faces. In contrast, memory precision was significantly impaired by face inversion at every set size tested. Our results demonstrate that the precision of visual working memory for a complex stimulus is not strictly fixed but, instead, can be modified by learning and experience. We find that perceptual expertise for upright faces leads to significant improvements in visual precision, without modifying the capacity of working memory. PMID- 24627214 TI - Response inhibition and adaptations to response conflict in 6- to 8-year-old children: evidence from the Simon effect. AB - Several studies have shown that the Simon effect, which is the advantage of spatial correspondence between stimulus and response locations when the stimulus location is task-irrelevant, decreases with increasing response times and is affected by preceding-trial correspondence. These modulations suggest the existence of control mechanisms that adapt our behavior to current goals by responding to the conflict experienced within a trial and by preventing the recurrence of a conflict in the subsequent trial. The aim of the present study was to assess whether these control mechanisms, which are well consolidated in adults and in children older than 8 years of age, are present in children between 6 and 8 years old. To this end, we tested 32 first-grade (6-7 years) and 34 second-grade (7-8 years) children on a Simon task in which correspondence sequence was manipulated on a trial-by-trial basis. The Simon effect was larger for first- than for second-graders and decreased with increasing response times only in second-graders. Crucially, for both groups, the effect was reduced when the preceding trial was noncorresponding, and the reductions were comparable for the two groups, indicating that trial-by-trial control mechanisms are already present in first-grade children and may be dissociated from within-trial control adjustments. PMID- 24627215 TI - Effects of direct and averted gaze on the subsequent saccadic response. AB - The saccadic latency to visual targets is susceptible to the properties of the currently fixated objects. For example, the disappearance of a fixation stimulus prior to presentation of a peripheral target shortens saccadic latencies (the gap effect). In the present study, we investigated the influences of a social signal from a facial fixation stimulus (i.e., gaze direction) on subsequent saccadic responses in the gap paradigm. In Experiment 1, a cartoon face with a direct or averted gaze was used as a fixation stimulus. The pupils of the face were unchanged (overlap), disappeared (gap), or were translated vertically to make or break eye contact (gaze shift). Participants were required to make a saccade toward a target to the left or the right of the fixation stimulus as quickly as possible. The results showed that the gaze direction influenced saccadic latencies only in the gaze shift condition, but not in the gap or overlap condition; the direct-to-averted gaze shift (i.e., breaking eye contact) yielded shorter saccadic latencies than did the averted-to-direct gaze shift (i.e., making eye contact). Further experiments revealed that this effect was eye contact specific (Exp. 2) and that the appearance of an eye gaze immediately before the saccade initiation also influenced the saccadic latency, depending on the gaze direction (Exp. 3). These results suggest that the latency of target elicited saccades can be modulated not only by physical changes of the fixation stimulus, as has been seen in the conventional gap effect, but also by a social signal from the attended fixation stimulus. PMID- 24627216 TI - The F-actin and adherence-dependent mechanical differentiation of normal epithelial cells after TGF-beta1-induced EMT (tEMT) using a microplate measurement system. AB - The epithelial to mesenchymal transition (EMT) is known to involve several physiological and pathological phenomena. In this study, we utilized a microplate measurement system (MMS) approach based on the deflection of a flexible micro cantilever to measure cell stiffness (in Pa) and adhesion force (in nN) of a single cell during EMT with nN resolution. Our results demonstrated that after transforming growth factor-beta1 (TGF-beta1) induced EMT (tEMT), NMuMG cells became stiffer due to thicker and more abundant F-actin and displayed stronger vinculin accumulation after long-term cell-substrate adhesion. The MMS could distinguish differences in compressive stiffness (219 +/- 10 and 287 +/- 14 Pa), tensile stiffness (114 +/- 14 and 132 +/- 12 Pa), and adhesion force (150 +/- 42 and 192 +/- 31 nN) between cells before and after tEMT. However, without proper development of the F-actin structure and adequate adherent time, the mechanical differences were diminished. After tEMT, the cells with increased stiffness and a cell-substrate adhesion force benefited by migrating more rapidly and had more invasiveness. Thus, this technology has the potential to benefit research focused on cancer diagnosis, drug development, and cell-substrate interactions. PMID- 24627217 TI - Small molecule-folic acid modification on nanopatterned PDMS and investigation on its surface property. AB - Folic acid (or folate, FA) has attracted considerable attention for cancer therapy. As one small molecule, its receptor (folate receptor, FR) is significantly overexpressed on the surface of many human tumor cells compared with normal cells. In this work, physical and chemical coupled modification method, that is the combination of nanoimprinting technique and graft polymerization, was adopted to modify FA on nanopatterned polydimethylsiloxane (PDMS) surface for possible application in micro-nanofluidic cytology. The surface property of differently treated PDMS was characterized by FTIR, AFM and contact angle measurement. AO/PI double staining, cell counting and MTT method were performed to examine the potential influence of FA modified nanopatterned PDMS on human cervical carcinoma (HeLa) cell behavior. Both FA modification and nanostructure have positive effect on the growth and viability of HeLa cells. It is the first time that the small molecule-folic acid was used to immobilize on the surface of PDMS in order to improve its surface property. PMID- 24627218 TI - The interactions of lenalidomide with human uptake and efflux transporters and UDP-glucuronosyltransferase 1A1: lack of potential for drug-drug interactions. AB - PURPOSE: Lenalidomide is an immunomodulatory agent used for the treatment of myelodysplastic syndromes and multiple myeloma. Renal clearance of lenalidomide is the predominant elimination route and is approximately twofold greater than the glomerular filtration rate (GFR), suggesting the potential contribution of an active secretory mechanism. In vitro studies were conducted to examine whether lenalidomide is a substrate of drug transporters, namely P-glycoprotein (P-gp), human breast cancer resistance protein (BCRP), multidrug resistance proteins (MRP1, MRP2, MRP3), organic anion transporters (OAT1, OAT3), organic cation transporters (OCT1 and OCT2), human organic cation transporter novel 1 and 2 (OCTN1 and OCTN2), multidrug and toxin extrusion (MATE1) and organic anion transporting polypeptide (OATP1B1). Lenalidomide was also evaluated as an inhibitor of P-gp, BCRP, MRP2, OCT2, OAT1, OAT3, OATP1B1, OATP1B3 and bile salt export pump (BSEP). In addition, inhibition of UDP-glucuronosyltransferase 1A1 (UGT1A1) variants by lenalidomide was also assessed. METHOD: Cells or vesicles expressing each of the human transporters were used for uptake and inhibition studies, with appropriate probe substrates and known inhibitors. RESULTS: Results of these studies indicate that the lenalidomide is not a substrate for the transporters examined, except that it is weak substrate of P-gp. None of the transporters studied were inhibited by lenalidomide. Lenalidomide is not an inhibitor of UGT1A1*1/*1 or its polymorphic variants UGT1A1*1/*28 and UGT1A1*28/*28. CONCLUSIONS: Drug interactions are unlikely to occur when lenalidomide is co-administered with substrates or inhibitors of these transporters. In addition, lenalidomide is unlikely to cause interactions when co administered with substrates of UGT1A1. PMID- 24627219 TI - A phase I clinical and pharmacokinetic study evaluating vinflunine in combination with epirubicin as first-line treatment in metastatic breast cancer. AB - BACKGROUND: Vinflunine (VFL) is a bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with epirubicin (EPR) to establish the recommended dose (RD), to evaluate the safety and efficacy profiles and to investigate potential pharmacokinetic (PK) drug-drug interaction (DDI). PATIENTS AND METHODS: Two schedules (day 1 every 3 weeks; days 1 and 8 every 3 weeks) were investigated as first-line chemotherapy of metastatic breast cancer patient. PK DDI was evaluated through population PK approaches. RESULTS: Thirty-nine patients received a total of 197 cycles of the VFL-EPR combination (median 6). The RDs were VFL 250 mg/m(2) + EPR 75 mg/m(2) every 3 weeks for schedule 1 and VFL 170 mg/m(2) + EPR 35 mg/m(2) every 3 weeks for schedule 2. The PK analysis demonstrated no clinically relevant mutual DDI between VFL and EPR. The main dose limiting toxicity was neutropenia. The most frequent non-haematological adverse events were nausea, fatigue, constipation, vomiting, anorexia and stomatitis. Objective response rate was achieved in 45.9 % of the patients. CONCLUSION: VFL EPR combination is feasible with manageable toxicity. The antitumour activity was promising and supports further evaluation. PMID- 24627220 TI - The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation. AB - The selective Aurora-A kinase inhibitor MLN8237 is in clinical trials for hematologic malignancies, ovarian cancer and other solid tumors. We previously showed that MLN8237 is potently antiproliferative toward standard monolayer cultured glioblastoma cells. We have now investigated the effect of MLN8237 with and without temozolomide or ionizing radiation on the proliferation of glioblastoma tumor stem-like cells (neurospheres) using soft agar colony formation assays and normal human astrocytes by MTT assay. Western blotting was utilized to compare MLN8237 IC50s to cellular Aurora-A and phosphoThr(288)Aurora A levels. MLN8237 was more potently antiproliferative to neurosphere cells than to standard monolayer glioma cells, and was non-toxic to normal human astrocytes. Western blot analysis revealed that MLN8237 treatment inhibits phosphoThr(288)Aurora-A levels providing proof of drug target-hit in glioblastoma cells. Furthermore, phosphoThr(288)Aurora-A levels partially predicted the antiproliferative efficacy of MLN8237. We also found that Aurora-A inhibition by MLN8237 was synergistic with temozolomide and potentiated the effects of ionizing radiation on colony formation in neurosphere glioblastoma tumor stem-like cells. These results further support the potential of Aurora-A inhibitors as primary chemotherapy agents or biologic response modifiers in glioblastoma patients. PMID- 24627221 TI - Single nucleotide polymorphism-specific regulation of matrix metalloproteinase-9 by multiple miRNAs targeting the coding exon. AB - Microribonucleic acids (miRNAs) work with exquisite specificity and are able to distinguish a target from a non-target based on a single nucleotide mismatch in the core nucleotide domain. We questioned whether miRNA regulation of gene expression could occur in a single nucleotide polymorphism (SNP)-specific manner, manifesting as a post-transcriptional control of expression of genetic polymorphisms. In our recent study of the functional consequences of matrix metalloproteinase (MMP)-9 SNPs, we discovered that expression of a coding exon SNP in the pro-domain of the protein resulted in a profound decrease in the secreted protein. This missense SNP results in the N38S amino acid change and a loss of an N-glycosylation site. A systematic study demonstrated that the loss of secreted protein was due not to the loss of an N-glycosylation site, but rather an SNP-specific targeting by miR-671-3p and miR-657. Bioinformatics analysis identified 41 SNP-specific miRNA targeting MMP-9 SNPs, mostly in the coding exon and an extension of the analysis to chromosome 20, where the MMP-9 gene is located, suggesting that SNP-specific miRNAs targeting the coding exon are prevalent. This selective post-transcriptional regulation of a target messenger RNA harboring genetic polymorphisms by miRNAs offers an SNP-dependent post transcriptional regulatory mechanism, allowing for polymorphic-specific differential gene regulation. PMID- 24627222 TI - miR-Synth: a computational resource for the design of multi-site multi-target synthetic miRNAs. AB - RNAi is a powerful tool for the regulation of gene expression. It is widely and successfully employed in functional studies and is now emerging as a promising therapeutic approach. Several RNAi-based clinical trials suggest encouraging results in the treatment of a variety of diseases, including cancer. Here we present miR-Synth, a computational resource for the design of synthetic microRNAs able to target multiple genes in multiple sites. The proposed strategy constitutes a valid alternative to the use of siRNA, allowing the employment of a fewer number of molecules for the inhibition of multiple targets. This may represent a great advantage in designing therapies for diseases caused by crucial cellular pathways altered by multiple dysregulated genes. The system has been successfully validated on two of the most prominent genes associated to lung cancer, c-MET and Epidermal Growth Factor Receptor (EGFR). (See http://microrna.osumc.edu/mir-synth). PMID- 24627223 TI - Internally labeled Cy3/Cy5 DNA constructs show greatly enhanced photo-stability in single-molecule FRET experiments. AB - DNA constructs labeled with cyanine fluorescent dyes are important substrates for single-molecule (sm) studies of the functional activity of protein-DNA complexes. We previously studied the local DNA backbone fluctuations of replication fork and primer-template DNA constructs labeled with Cy3/Cy5 donor-acceptor Forster resonance energy transfer (FRET) chromophore pairs and showed that, contrary to dyes linked 'externally' to the bases with flexible tethers, direct 'internal' (and rigid) insertion of the chromophores into the sugar-phosphate backbones resulted in DNA constructs that could be used to study intrinsic and protein induced DNA backbone fluctuations by both smFRET and sm Fluorescent Linear Dichroism (smFLD). Here we show that these rigidly inserted Cy3/Cy5 chromophores also exhibit two additional useful properties, showing both high photo-stability and minimal effects on the local thermodynamic stability of the DNA constructs. The increased photo-stability of the internal labels significantly reduces the proportion of false positive smFRET conversion 'background' signals, thereby simplifying interpretations of both smFRET and smFLD experiments, while the decreased effects of the internal probes on local thermodynamic stability also make fluctuations sensed by these probes more representative of the unperturbed DNA structure. We suggest that internal probe labeling may be useful in studies of many DNA-protein interaction systems. PMID- 24627224 TI - WITHDRAWN: EMLA and Amethocaine for reduction of children's pain associated with needle insertion. PMID- 24627225 TI - A Closer Look at Phonology as a Predictor of Spoken Sentence Processing and Word Reading. AB - The goal of this study was to tease apart the roles of phonological awareness (pA) and phonological short-term memory (pSTM) in sentence comprehension, sentence production, and word reading. Children 6- to 10-years of age (N = 377) completed standardized tests of pA ('Elision') and pSTM ('Nonword Repetition') from the Comprehensive Test of Phonological Processing. Concepts and Following Directions (CFD) and Formulated Sentences (FS) were taken from the Clinical Evaluation of Language Fundamentals-Fourth Edition, as measures of sentence comprehension and production, respectively. Children also completed the Word Identification (Word Id) and Word Attack (Word Att) subtests of the Woodcock Reading Mastery Test-Third Edition. Hierarchical multiple regression analyses controlling for age and nonverbal IQ revealed that Elision was the only significant predictor of CFD and FS. While Elision was the strongest predictor of Word Id and Word Att, Nonword Repetition accounted for additional variance in both reading measures. These results emphasize the usefulness of breaking down phonological processing into multiple components and they also have implications language and reading disordered populations. PMID- 24627226 TI - Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist. AB - Cancer cachexia is defined as a multifactorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass and progressive functional impairment. It is postulated that cardiac dysfunction/atrophy parallels skeletal muscle atrophy in cancer cachexia. Cardiotoxic chemotherapy may additionally result in cardiac dysfunction and heart failure in some cancer patients. Heart failure thus may be a consequence of either ongoing cachexia or chemotherapy-induced cardiotoxicity; at the same time, heart failure can result in cachexia, especially muscle wasting. Therefore, the subsequent heart failure and cardiac cachexia can exacerbate the existing cancer-induced cachexia. We discuss these bilateral effects between cancer cachexia and heart failure in cancer patients. Since cachectic patients are more susceptible to chemotherapy induced toxicity overall, this may also include increased cardiotoxicity of antineoplastic agents. Patients with cachexia could thus be doubly unfortunate, with cachexia-related cardiac dysfunction/heart failure and increased susceptibility to cardiotoxicity during treatment. Cardiovascular risk factors as well as pre-existing heart failure seem to exacerbate cardiac susceptibility against cachexia and increase the rate of cardiac cachexia. Hence, chemotherapy induced cardiotoxicity, cardiovascular risk factors, and pre-existing heart failure may accelerate the vicious cycle of cachexia-heart failure. The impact of cancer cachexia on cardiac dysfunction/heart failure in cancer patients has not been thoroughly studied. A combination of serial echocardiography for detection of cachexia-induced cardiac remodeling and computed tomography image analysis for detection of skeletal muscle wasting would appear a practical and non-invasive approach to develop an understanding of cardiac structural/functional alterations that are directly related to cachexia. PMID- 24627227 TI - Novel mutations in the amyloid precursor protein gene within Moroccan patients with Alzheimer's disease. AB - In Morocco, Alzheimer's disease (AD) affects almost 30,000 individuals, and this number could increase to 75,000 by 2020. To our knowledge, the genes predisposing individuals to AD and predicting disease incidence remain elusive. In this study, we aimed to evaluate the genetic contribution of mutations in the amyloid precursor protein (APP) gene exons 16 and 17 to familial and sporadic AD cases. Seventeen sporadic cases and eight family cases were seen at the memory clinic of the University of Casablanca Neurology Department. These patients underwent standard somatic neurological examination, cognitive function assessment, brain imaging, and laboratory tests. Direct sequencing of exons 16 and 17 of the APP gene was performed on genomic DNA of AD patients. In this original Moroccan study, we identified seven novel frameshift mutations in exons 16 and 17 of the APP gene. Interestingly, only one novel splice mutation was detected in a family case. There is a strong correlation between clinical symptoms and genetic factors in Moroccan patients with a family history of AD. Therefore, mutations in APP gene exons 16 and 17 may eventually become genetic markers for AD predisposition. PMID- 24627228 TI - Histopathological effects of different therapy strategies in experimental sinus thrombosis. AB - The optimal treatment for cerebral venous thrombosis is still under debate. The histological consequences of different treatments have not been systematically studied and may be of value in this debate. Thrombosis of the superior sagittal sinus was induced in rats by topical application of ferric chloride. Animals were treated 6 h after operation with subcutaneous injection of 450 IU/kg enoxaparin twice daily (n = 10), with 10 mg recombinant tissue plasminogen activator (rt PA)/kg (n = 12), and with 6 mg abciximab/kg (n = 10). Eleven animals were treated with saline (controls), and four animals were sham-operated without thrombosis induction. Animals were killed on day 7. Coronal brain slices were stained with hematoxylin-eosin (HE) and against glial fibrillary acidic protein (GFAP), and factor VIII. Histology was quantified in parasagittal and temporal regions of interest. Compared with controls, counts of pyknotic neurons on HE stain were significantly lower in the enoxaparin group. Counts for GFAP-expressing astrocytes were highest in the enoxaparin (p < 0.001) and rt-PA (p < 0.05) treated groups. Angiogenesis defined as factor VIII-expressing vessels was significantly (p < 0.01) higher in the enoxaparin and significantly lower (p < 0.01) in the rt-PA group compared with controls. In this animal model, we found histological differences related to the different treatments, which cannot be explained by recanalization and its speed alone. PMID- 24627229 TI - CSF biomarkers in superficial siderosis: a new tool for diagnosis and evaluation of therapeutic efficacy of deferiprone--a case report. PMID- 24627231 TI - Integrodifference models for persistence in temporally varying river environments. AB - To fully understand population persistence in river ecosystems, it is necessary to consider the effect of the water flow, which varies tremendously with seasonal fluctuations of water runoff and snow melt. In this paper, we study integrodifference models for growth and dispersal in the presence of advective flow with both periodic (alternating) and random kernel parameters. For the alternating kernel model, we obtain the principal eigenvalue of the linearization operator to determine population persistence and derive a boundary value problem to calculate it. For the random model, we establish two persistence metrics: a generalized spectral radius and the asymptotic growth rate, which are mathematically equivalent but can be understood differently, to determine population persistence or extinction. The theoretical framework and methods for calculations are provided, and the framework is applied to calculating persistence in highly variable river environments. PMID- 24627230 TI - Association of conventional risk factors for cardiovascular disease with IMT in middle-aged and elderly Chinese. AB - To study the association between known risk factors for cardiovascular disease and intima-media thickness (IMT) in the carotid and popliteal arteries in middle aged and elderly Chinese adults. 686 middle aged and elderly Chinese adults from the China Da Qing Diabetes Prevention Study who had full clinical, laboratory, ultrasound examination results were enrolled in the study. Common carotid artery (CCA) and popliteal artery (PA) IMT were obtained using high resolution ultrasound machine. Pearson's or Spearman's correlation analysis and logistic regression analysis were used to determine association between risk factors [age, gender, tobacco smoking, body mass index (BMI), diabetes mellitus (DM), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, total triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, glycosylated hemoglobin (HbA1c)] and CCA- or PA-IMT. The age range of the study population was 45-87 years, 384 of them (56 %) were women. The prevalence of high blood pressure and DM was 60.6 and 68.8 %, respectively. Participants in DM group tended to be older, had greater value for SBP, HbA1c and PA-IMT, but smaller value for DBP than those in control group. Smoke status, BMI, blood lipids and CCA-IMT were not statistically different between groups. Pearson's or Spearman's rank correlation analysis showed that CCA-IMT had a positive correlation with age, gender, DM, SBP, BMI and HbA1c, negative correlation with HDL-C. PA-IMT showed a positive correlation with age, gender and SBP. Univariate logistic regression analysis showed that elevation of age, SBP, BMI, HbA1c and having DM were significant predictors of CCA-IMT thickening, so was reduction of HDL-C. Risk factors that predicted significant thickening of PA IMT were age, gender, tobacco smoking. After adjusted for age and gender, except HDL-C, the other four risk factors (SBP, BMI, HbA1c and having DM) that predicted CCA-IMT thickening remained significant; however none of the risk factors predicted PA-IMT thickening after adjusted for age and gender. The current results provide evidence that CCA-IMT is a superior marker for atherosclerosis compared with PA-IMT. Aggressive control of SBP, HbA1c and proper control of weight may postpone thickening of CCA-IMT. PMID- 24627232 TI - Can an electronic health record system be used for preconception health optimization? AB - To explore the potential of an integrated outpatient electronic health record (EHR) for preconception health optimization. An automated case-finding EHR derived algorithm was designed to identify women of child-bearing age having outpatient encounters in an 85-site, integrated health system. The algorithm simultaneously cross-referenced multiple discrete data fields to identify selected preconception factors (obesity, hypertension, diabetes, teratogen use including ACE inhibitors, multivitamin supplementation, anemia, renal insufficiency, untreated sexually transmitted infection, HIV positivity, and tobacco, alcohol or illegal drug use). Surveys were mailed to a random sample of patients to obtain their self-reported health profiles for these same factors. Concordance was assessed between the algorithm output, survey results, and manual data abstraction. Between 8/2010-2/2012, 107,339 female outpatient visits were identified, from which 29,691 unique women were presumed to have child-bearing potential. 19,624 (66 %) and 8,652 (29 %) had 1 or >=2 health factors, respectively while only 1,415 (5 %) had none. Using the patient survey results as a reference point, health-factor agreement was similar comparing the algorithm (85.8 %) and the chart abstraction (87.2 %) results. Incorrect or missing data entries in the EHR encounters were largely responsible for discordances observed. Preconception screening using an automated algorithm in a system-wide EHR identified a large group of women with potentially modifiable preconception health conditions. The issue most responsible for limiting algorithm performance was incomplete point of care documentation. Accurate data capture during patient encounters should be a focus for quality improvement, so that novel applications of system-wide data mining can be reliably implemented. PMID- 24627233 TI - Improving gestational weight gain counseling through meaningful use of an electronic medical record. AB - The purpose of this study was to test the effectiveness of an intervention to improve the consistency and accuracy of antenatal gestational weight gain counseling through introduction of a "best practice alert" into an electronic medical record (EMR) system. A best practice alert was designed and implemented in the EMR. Based on each patient's pre-gravid body mass index (BMI), fetal number, and 2009 Institute of Medicine (IOM) guidelines, the alert provides an individualized total gestational weight gain goal, the weight gain goal per week of gestation, a template for scripted provider counseling and documentation, and a patient handout containing personalized gestational weight gain information. Retrospective chart reviews of 388 pre-intervention patients and 345 post intervention patients were used to evaluate effectiveness. Introduction of a gestational weight gain best practice alert into the EMR improved the rate of antenatal gestational weight gain counseling that was consistent with current IOM guidelines (p < 0.001). Improvement in IOM-consistent gestational weight gain counseling was seen across all provider types, including obstetricians, family practice physicians, and certified nurse midwives. The intervention also resulted in significant improvement in documentation of pre-gravid weights and BMIs within the EMR. The EMR is an effective tool for improving the consistency and accuracy of antenatal gestational weight gain counseling in accord with 2009 IOM guidelines. PMID- 24627234 TI - Effectiveness of a Brief Care Management Intervention for Reducing Psychiatric Hospitalization Readmissions. AB - This study examines a recovery-focused care management bridging strategy implemented during time of inpatient stay with the goal to increase engagement in aftercare and reduce early psychiatric readmissions. The sample included 195 individuals who received care from a large psychiatric specialty hospital. Eighty seven individuals were assigned to receive the intervention, while 108 individuals were assigned to the control group. Individuals in the intervention group received a brief interview prior to inpatient discharge plus usual care, and individuals in the control group received usual care. After controlling for age, living situation, and utilization, individuals in the control group were more likely to be readmitted within 30 days of an index readmission than individuals in the intervention group (OR = 2.44, p = .02). Bridging strategies utilized prior to discharge for individuals at higher risk of early mental health inpatient readmission may be used as an effective alternative to more costly interventions. PMID- 24627235 TI - Community Readiness Within Systems of Care: The Validity and Reliability of the System of Care Readiness and Implementation Measurement Scale (SOC-RIMS). AB - Establishing a system of care requires communities to identify ways to successfully implement strategies and support positive outcomes for children and their families. Such community transformation is complex and communities vary in terms of their readiness for implementing sustainable community interventions. Assessing community readiness and guiding implementation, specifically for the funded communities implementing a system of care, requires a well-designed tool with sound psychometric properties. This scale development study used the results of a previously published concept mapping study to create, administer, and assess the psychometric characteristics of the System of Care Readiness and Implementation Measurement Scale (SOC-RIMS). The results indicate the SOC-RIMS possesses excellent internal consistency characteristics, measures clearly discernible dimensions of community readiness, and demonstrates the target constructs exist within a broad network of content. The SOC-RIMS can be a useful part of a comprehensive assessment in communities where system of care practices, principles, and philosophies are implemented and evaluated. PMID- 24627236 TI - Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy. AB - BACKGROUND: The optimal timing to initiate bevacizumab (BV) therapy for recurrent glioblastoma (GBM) is currently unclear. To address this issue, we examined progression-free survival (PFS) and survival time (ST) in a large retrospective cohort of GBM patients treated with BV at different recurrences. METHODS: We identified 468 primary GBM patients who underwent biopsy or surgery followed by radiation therapy and temozolomide (RT/TMZ), and then received BV. PFS and ST were compared between patients stratified by the recurrence that BV was initiated (upfront, first recurrence, second recurrence, or 3+ recurrences). We also examined the effect on PFS and ST of the addition of chemotherapy to BV. In a larger cohort of GBM patients, we determined overall treatment continuation rates at each recurrence and identified variables predictive of inability to continue treatment. RESULTS: BV PFS was similar for all 3 recurrence groups (median, 4.1 months). There were no differences in BV ST (median, 9.8 months). The addition of chemotherapy to BV improved PFS but not ST. Analysis of treatment continuation rates indicated that the number of patients unable to undergo further treatments is modest, and that patients unable to tolerate BV delay can be identified by age >=60 years and low extent of resection. CONCLUSIONS: Deferred use of bevacizumab is not associated with diminished efficacy. Analysis of treatment continuation rates identified patients who may be unable to delay BV therapy. Our findings suggest that there is a fixed survival after BV initiation and that delayed BV treatment is preferable for most patients. PMID- 24627237 TI - Quality of life in patients with advanced gastric cancer sequentially treated with docetaxel and irinotecan with 5-fluorouracil and folinic acid (leucovin). AB - With a median overall survival of only 9-13 months in patients with advanced gastric cancer (GC), the quality of life (QoL) during the palliative treatment remains a key issue. Furthermore, when combinations of two or three drugs are used, the impact on QoL should be carefully evaluated. This was studied within the GATAC trial in patients sequentially treated with docetaxel and irinotecan with 5-fluorouracil and leucovorin (5-Fu/Lv). Patients with previously untreated advanced GC were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus and 44 h infusion of 5-Fu/Lv (D1, q2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses. QoL was measured with the EORTC QLQ-C30 questionnaire at the start of the treatment, at crossover and after completing treatment with both regimens. Eighty-one patients were randomized, and 78 patients started treatment. A total of 191 completed QoL questionnaires were collected. There were no statistically significant differences in QoL scores between the two treatment groups and no changes in mean scores during the 16 weeks of treatment. During the last 8 weeks of treatment, a significantly larger portion of patients with radiological response reported sustained or better QoL scores than those with no radiological response (82 vs. 50%, p = 0.007). Chemotherapy in advanced GC did not affect QoL average scores. Patients with non responding tumours reported more often a decline in the global QoL score. The concept of the pre-scheduled switch of chemotherapy regimens prior to progression should be further studied in this disease, as it appears effective, tolerable and not to negatively affect QoL. PMID- 24627238 TI - Organ preservation for muscle-invasive bladder cancer by preoperative intra arterial chemotherapy and transurethral resection. AB - The aim of this study was to evaluate the clinical outcomes achieved by use of preoperative intra-arterial chemotherapy and transurethral resection of bladder tumors as bladder preservation therapy in treatment of muscle-invasive bladder cancer. Patients with clinical stage T2-T4aN0M0 muscle-invasive bladder cancer were treated with 3 courses of preoperative cisplatin-based intra-arterial chemotherapy at 4-week intervals. Following treatment, the tumors were completely removed by transurethral resection, and all patients received epirubicin for intra-vesical instillation as a maintenance strategy. Patients showing a complete response received continuous monitoring, and radical cystectomy was strongly recommended for patients who did not achieve a complete response. Between August 2005 and October 2012, a total of 127 patients completed treatment with a bladder preservation therapy, and the median follow-up time for all patients was 31.9 months (range 5-87 months). Among these patients, 91 (71.7%) achieved a complete response, and the 5-year overall survival and disease-specific survival rates for all patients were 50.2 and 59.5%, respectively. Among the patients who demonstrated a complete response, 10 experienced a superficial relapse and 15 experienced an invasive cancer relapse. The 5-year recurrence-free and progression-free survival rates were 62.2 and 76.9%, respectively. An analysis of tumor-related factors suggested that clinical stage was significant for predicting both complete response and overall survival. These results suggest that preoperative intra-arterial chemotherapy combined with transurethral resection of the bladder tumor is useful for bladder preservation in certain patients with invasive bladder cancer. Patients with stage T2 tumors are best suited for this type of therapy. PMID- 24627239 TI - The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. AB - Clostridium difficile infection (CDI) is one of the most frequent causes of healthcare-associated infections, and its rates are also increasing in the community. The management of CDI has become a major challenge, given growing rates of recurrences and failures with standard antibiotic therapy. Mounting evidence suggests that fecal microbiota transplantation (FMT) may be effective; however, as there is a paucity of data with regard to repeat FMT for primary non response to this treatment, this study examined the outcome of multiple FMTs for recurrent CDI. Case records were reviewed for 94 patients who underwent FMT via retention enema for recurrent or refractory CDI during the period 2008-2012. Demographic information, treatment data, and clinical resolution rates were examined for single FMT and cumulative resolution was assessed for multiple FMTs in the context of ongoing symptoms. The cumulative clinical resolution following four or more FMTs was 86%. When antibiotic therapy was used between FMTs, the clinical resolution rate increased to 92%. There were no reported adverse events and no patients who were cured with FMT had further episodes of CDI at 6-24 months follow-up. Multiple FMTs administered through enemas is an effective, safe, and simple therapy for the management of recurrent or refractory CDI. PMID- 24627240 TI - Relations among behavioral inhibition, shame- and guilt-proneness, and anxiety disorders symptoms in non-clinical children. AB - This study examined relationships between the self-conscious emotions of shame and guilt, behavioral inhibition (as an index of anxiety proneness), and anxiety disorder symptoms in non-clinical children aged 8-13 years (N = 126), using children's self-report data. Results showed that there were positive and significant correlations between shame and guilt, behavioral inhibition, and anxiety disorders symptoms. When controlling for the overlap between shame and guilt, it was found that shame (but not guilt) remained significantly associated with higher levels of anxiety proneness and anxiety symptoms. Further, when controlling for the effect of behavioral inhibition, shame still accounted for a significant proportion of the variance of total anxiety and generalized anxiety scores. For these anxiety problems, support emerged for a model in which shame acted as a partial mediator in the relation between behavioral inhibition and anxiety. These results indicate that the self-conscious emotion of shame is a robust correlate of anxiety pathology in children. PMID- 24627241 TI - Spindle and kinetochore-associated protein 1 is overexpressed in gastric cancer and modulates cell growth. AB - Spindle and kinetochore-associated protein 1 (SKA1) is a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation. SKA1 is required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint. Recently, SKA1 has been highlighted as a biomarker in some types of cancers, however, the precise role of SKA1 in gastric cancer remains unknown. In order to investigate the role of SKA1 in gastric cancer, the expression levels of SKA1 were analyzed in 56 gastric cancer samples and 54 non-neoplastic samples by immunohistochemistry, and we found SKA1 was significantly overexpressed in gastric cancer tissues. Moreover, we employed lentivirus-mediated short hairpin RNA to knockdown SKA1 in the human gastric cancer cell line MGC80-3. Functional analysis indicated that SKA1 silencing significantly inhibited cell proliferation and colony formation, as determined by MTT and colony formation assays. The depletion of SKA1 in MGC80-3 cells also led to S phase cell cycle arrest. These results suggest that SKA1 could be used for gastric cancer early diagnosis as a biomarker. It is possible to enable a potential therapy based on targeting SKA1. PMID- 24627242 TI - Effect of hydrogen peroxide on contractility and citrate synthase activity of the rabbit urinary bladder in the presence and absence of resveratrol and a whole grape suspension. AB - One etiology related directly to obstructive urinary bladder dysfunction is ischemia/reperfusion resulting in significant oxidative stress to the bladder. Grapes, a natural source of antioxidants, have been proven effective in preventing obstructive and ischemic bladder dysfunction. Many investigators believe that resveratrol is the primary active antioxidant ingredient in grapes. We compared the ability of a whole-grape suspension with pure resveratrol in their ability to protect the bladder from in vitro oxidative stress mediated by hydrogen peroxide (H2O2). Four male rabbit bladders were used. Two strips from each bladder were incubated in the presence of 1 mg/mL grape suspension for 30 min, another two strips were incubated in the presence of 1 mg/mL resveratrol solution, and the last two strips were incubated in the presence of 1 mg/mL sucrose/and fructose as controls. The rest of the bladder was separated into muscle and mucosa, frozen and stored for biochemical evaluation. (1) Chemically, resveratrol has about 20 times the antioxidant capacity of the grape suspension. (2) The grape suspension had significant protective effects when the rate of tension was quantitated at all concentrations of H2O2, while the resveratrol had no effect. (3) Citrate synthase activities of the muscle and mucosa were significantly protected by the grape suspension but not by resveratrol. These data demonstrate that the grape suspension protects the mitochondria to a significantly greater degree than resveratrol, which suggests that the antioxidant activities are due to the combination of active components found in the grape suspension and not just resveratrol. PMID- 24627243 TI - L-Cysteine supplementation reduces high-glucose and ketone-induced adhesion of monocytes to endothelial cells by inhibiting ROS. AB - Type 1 diabetic (T1D) patients are hyperglycemic and also show elevated blood levels of ketone bodies, particularly acetoacetate (AA) and beta-hydroxybutyrate (BHB). T1D patients have a greater risk of developing endothelial dysfunction and cardiovascular disease (CVD). Supplementation with cysteine-rich milk proteins has been shown to be beneficial in improving various biomarkers of endothelial dysfunction and CVD. This study examines whether L-cysteine (LC) per se prevents monocyte adhesion to endothelial cells, a critical step in endothelial dysfunction. Human umbilical vein endothelial cells and THP-1 monocytes were pretreated with and without LC (500 MUM) for 2 h and then exposed to ketones (AA or BHB, 0-4 mM) and/or high glucose (HG) (25 mM) for 24 h. This study shows that LC reduces HG and ketone-induced ROS production, ICAM-1 expression, and the adhesion of monocytes to endothelial cells. This study provides a biochemical mechanism by which milk protein supplementation can be beneficial in preventing the excess endothelial dysfunction and CVD seen in diabetic patients. PMID- 24627244 TI - Forward subtractive libraries containing genes transactivated by dexamethasone in ataxia-telangiectasia lymphoblastoid cells. AB - Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder caused by biallelic mutations in the Ataxia Telangiectasia-mutated gene. A-T shows a complex phenotype ranging from early-onset progressive neurodegeneration to immunodeficiencies, high incidence of infections, and tumors. Unfortunately, no therapy is up to now available for treating this condition. Recently, the short term treatment of ataxia-telangiectasia patients with glucocorticoids was shown to improve their neurological symptoms and possibly reverse cerebellar atrophy. Thus, corticosteroids represent an attractive approach for the treatment of this neurodegenerative disease. However, the molecular mechanism involved in glucocorticoid action in A-T is yet unknown. The aim of our work is to construct cDNA libraries containing those genes which are transactivated by the glucocorticoid analogue, dexamethasone, in A-T human cells. For this purpose, suppression subtractive hybridization has been performed on ATM-null lymphoblastoid cell transcriptome extracted following drug administration. Annotation of whole genes contained in the libraries has been obtained by coupling subtractive hybridization with microarray analysis. Positive transcripts have been validated by quantitative PCR. Through in silico analyses, identified genes have been classified on the basis of the pathway in which they are involved, being able to address signaling required for dexamethasone action. Most of the induced transcripts are involved in metabolic processes and regulation of cellular processes. Our results can help to unravel the mechanism of glucocorticoid action in the reversion of A-T phenotype. Moreover, the induction of a specific region of the ATM transcript has been identified as putative biomarker predictive of dexamethasone efficacy on ataxic patients. PMID- 24627245 TI - Actinic keratosis: rationale and management. AB - Actinic keratoses (AKs) are common skin lesions heralding an increased risk of developing squamous cell carcinoma (SCC) and other skin malignancies, arising principally due to excessive ultraviolet (UV) exposure. They are predominantly found in fair-skinned individuals, and increasingly, are a problem of the immunosuppressed. AKs may regress spontaneously, remain stable or transform to invasive SCC. The risk of SCC increases for those with more than 5 AKs, and the majority of SCCs arise from AKs. The main mechanisms of AK formation are inflammation, oxidative stress, immunosuppression, impaired apoptosis, mutagenesis, dysregulation of cell growth and proliferation, and tissue remodeling. Human papilloma virus has also been implicated in the formation of some AKs. Understanding these mechanisms guides the rationale behind the current available treatments for AKs. One of the main principles underpinning the management of AKs is that of field cancerization. Wide areas of skin are exposed to increasing amounts of UV light and other environmental insults as we age. This is especially true for the head, neck and forearms. These insults do not target only the skin where individual lesions develop, but also large areas where crops of AKs may appear. The skin between lesions is exposed to the same insults and is likely to contain as-yet undetectable preclinical lesions or areas of dysplastic cells. The whole affected area is known as the 'field'. Management is therefore divided into lesion-directed and field-directed therapies. Current therapies include lesion-directed cryotherapy and/or excision, and topical field-directed creams: 5-fluorouracil, imiquimod, diclofenac, photodynamic therapy and ingenol mebutate. Combining lesion- and field-directed therapies has yielded good results and several novel therapies are under investigation. Treatment is variable and tailored to the individual making a gold standard management algorithm difficult to design. This literature review article aims to describe the rationale behind the best available therapies for AKs in light of current understanding of pathophysiology and epidemiology. A PubMed and MEDLINE search of literature was performed between January 1, 2000 and September 18, 2013. Where appropriate, articles published prior to this have been referenced. This is not a systematic review or meta-analysis, but aims to highlight the most up to date understanding of AK disease and its management. PMID- 24627247 TI - Intraocular pressure fluctuation and glaucoma progression: what do we know? AB - While mean intraocular pressure (IOP) has long been known to correlate with glaucomatous damage, the role of IOP fluctuation is less clearly defined. There is extensive evidence in the literature for and against the value of short-term and long-term IOP fluctuation in the evaluation and prognosis of patients with glaucoma. We present here the arguments made by both sides, as well as a discussion of the pitfalls of prior research and potential directions for future studies. Until a reliable method is developed that allows for constant IOP monitoring, many variables will continue to hinder us from drawing adequate conclusions regarding the significance of IOP variation. PMID- 24627246 TI - Frequency of abnormal retinal nerve fibre layer and ganglion cell layer SDOCT scans in healthy eyes and glaucoma suspects in a prospective longitudinal study. AB - BACKGROUND/AIMS: To examine the frequency of abnormal retinal nerve fibre layer thickness (RNFLT) and ganglion cell complex (GCC) measurements among healthy and glaucoma suspect and preperimetric glaucoma (GSPPG) eyes in a prospective longitudinal study. METHODS: Normal and GSPPG eyes with >= 18 months follow-up were included. Spectral-domain optical coherence tomography (SDOCT) was performed annually in normal and biannually in GSPPG eyes. One eye was randomly selected for inclusion. RNFLT and GCC parameters with p>5% were classified as 'within normal limits (WNL)' and p<1% were classified as 'outside normal limits (ONL)'. RESUlts: 23 normal and 74 GSPPG eyes were followed for a mean 43.4 +/- 9.6 months. During serial follow-up, 100% and 91% of normal eyes had all RNFLT and GCC parameters classified as WNL, respectively. 27 (37%) and 17 (23%) of GSPPG eyes had an ONL classification in at least one RNFLT and GCC parameter, respectively. A high percentage (41%-56%) of RNFLT and GCC measurements classified as ONL were not replicated on subsequent scans. The rates of loss for all parameters were similar (p>0.05) between the groups. CONCLUSIONS: Specificity in this sample of healthy eyes was very high for RNFLT and GCC parameters. Confirmation of suspected SDOCT abnormalities is recommended to differentiate reproducible loss from long-term variability. PMID- 24627248 TI - Change in choroidal thickness and axial length with change in intraocular pressure after trabeculectomy. AB - BACKGROUND/AIMS: We studied the change in choroidal thickness (CT) and axial length (AL) after intraocular (IOP) changes produced by trabeculectomy. METHODS: Twenty-one eyes of 20 patients were studied preoperatively, and then postoperatively at 1 week, 1, 3, and 6 months. Variables measured included IOP, AL, keratometry, refractive error, central corneal thickness, and average CT in the posterior 6 mm centred on the fovea using enhanced depth imaging spectral domain optical coherence tomography (OCT). RESULTS: OCT images in 17 eyes (58 images, preoperatively and postoperatively) were of sufficient quality to determine CT. In every patient, CT increased with IOP lowering postoperatively. For each 1 mmHg decrease in IOP, there was a mean increase of 3.4 um in CT (p<0.0001; univariate regression, 95% CI 2.5 to 4.3). This represented a CT increase of 1.7% per mm Hg decrease (p<0.0001; 95% CI 1.3 to 2.0%). AL decreased by 6.8 um per mm Hg decrease in IOP (p<0.0001, univariate regression, 95% CI 4.9 to 8.6). CONCLUSIONS: The dynamic relationship between change in IOP and the state of sclera and choroid was confirmed by sequential measurements in postoperative trabeculectomy patients, providing estimates of the magnitude of choroidal swelling and scleral volume decrease with IOP lowering. PMID- 24627249 TI - Effects of corrective surgery on social phobia, psychological distress, disease related disability and quality of life in adult strabismus patients. AB - BACKGROUND: Corrective surgery is done for ocular alignment and disrupted facial expression in some cases of adult strabismus patients. The effects of corrective surgery on the presence of social phobia (SP) diagnosis, the severity of social anxiety symptoms, the disease-related disability and the quality of life (QoL) among strabismus patients have not been thoroughly studied yet. METHODS: The study sample was composed of patients who had undergone corrective surgery for strabismus. Preoperative and postoperative evaluations made by using standardised measures of social phobia diagnosis (DSM-IV-TR) and severity (Liebowitz Social Anxiety Scale (LSAS)), anxiety and depression (Hospital Anxiety and Depression Scale (HADS)), disability (Sheehan Disability Scale) and quality of life (short form-36). RESULTS: Preoperatively, SP diagnosis was detected in 17 of 31 (54.8%) patients, whereas postoperatively 6 of 31 (19.4%) patients had SP (p=0.001). Participants showed a significant decrease in all subscale scores and total score of both LSAS and HADS compared with their preoperative scores. Significant improvements were observed in QoL and disability scores as well. CONCLUSIONS: Adult strabismus patients seem to gain benefits from corrective surgery not only for their ocular misalignment but also for social anxiety levels that may be associated with improvements in their QoL and disability levels. PMID- 24627250 TI - Optical coherence tomography in the preoperative and postoperative management of macular hole and epiretinal membrane. AB - Optical coherence tomography (OCT) imaging plays an essential role in the diagnosis and treatment of macular diseases, including those of the vitreomacular interface. OCT enables accurate diagnosis and differentiation of full thickness macular hole, lamellar macular hole and epiretinal membrane, with or without the presence of vitreomacular adhesion. This information enables earlier diagnosis and treatment when necessary, and can guide the choice of therapy. OCT is useful to facilitate discussions with patients and manage the visual expectations. Postoperatively, OCT can be helpful to optimise patient comfort and visual outcomes. As the technology continues to improve, OCT will become increasingly critical for all aspects of care for patients with macular hole and epiretinal membrane. PMID- 24627251 TI - Optical coherence tomography shows retinal abnormalities associated with optic nerve disease. AB - Optical coherence tomography (OCT) of the macula in patients with primary optic neuropathy has revealed the presence of structural changes in the neurosensory retina in addition to the nerve fibre layer. Subretinal fluid has been documented in papilloedema and non-arteritic ischaemic optic neuropathy, and may account for decreased visual acuity in affected patients. Subretinal fluid has also been described from other causes of optic nerve head swelling including diabetic papillopathy and papillitis. Drugs used in the treatment of multiple sclerosis, such as corticosteroids and fingolimod can cause decreased vision due to central serous and cystoid macular oedema sometimes confused with recurrent optic neuritis. A subset of patients with various types of optic atrophy show microcystic changes in the inner nuclear layer on spectral domain OCT imaging. The pathophysiology and visual significance of these retinal changes remain unclear, but may affect the diagnosis and management of optic nerve disorders. PMID- 24627252 TI - Diagnosing the severity of dry eye: a clear and practical algorithm. AB - Dry eye disease (DED) is a distressing ocular condition. Due to its multifactorial nature, clinical and biological signs of DED can be inconsistent and sometimes discordant with symptomatology. Consequently, no gold-standard model for determining DED severity exists. This can impact treatment decisions and complicate evaluation of disease progression, particularly within the stringent context of clinical trials. The multinational ODISSEY European Consensus Group is comprised of ophthalmologists who contend with ocular surface disease issues on a daily basis. This group convened to establish a clear and practical algorithm for evaluation and diagnosis of severe DED. Using a consensus based approach, they assessed 14 commonly used DED severity criteria. The panel agreed that following confirmed DED diagnosis, just two criteria, symptom-based assessment and corneal fluorescein staining were sufficient to diagnose the presence of severe DED in the majority of patients. In the event of discordance between signs and symptoms, further evaluation using additional determinant criteria was recommended. This report presents the ODISSEY European Consensus Group recommended algorithm for DED evaluation, which facilitates diagnosis of severe disease even in the event of discordance between signs and symptoms. It is intended that this algorithm will be useful in a clinical and developmental setting. PMID- 24627253 TI - Cavernous venous malformations of the orbit (so-called cavernous haemangioma): a comprehensive evaluation of their clinical, imaging and histologic nature. AB - PURPOSE: The purpose of this investigation is to describe the clinical, imaging, histologic and flow dynamic characteristics of orbital cavernous haemangioma. METHODS: In this clinicopathologic series, clinical features were obtained from patient records. All imaging studies were reviewed. All specimens were reviewed with haematoxylin and eosin, and 10 were subject to a staining protocol including: Movat Pantachrome, periodic acid Schiff, D2-40, CD31, GLUT-1, Ki-67, vascular endothelial growth factor receptor 1 (VEGF-r1) (flt-1), VEGF-r2 (Flk-1), VEGF, anti-smooth muscle actin (SMA), CD20, CD4, CD8 and CD68. Imaging and pathology were reviewed in a systematic fashion. RESULTS: Clinically, lesions were more common in middle-aged females presenting with axial proptosis and pain. One-third demonstrated signs of optic nerve dysfunction. Dynamic imaging revealed focal early and diffuse late enhancement. Lesions demonstrated slow growth at 0.2 cm3/year. Histologically, all lesions demonstrated large vascular channels with mature-appearing endothelium and abundant stroma. Three salient features were noted and characterised: thrombosis, nests of perivascular hypercellularity and expanded stromal elements. Acute thrombosis was a feature of each specimen (<10% of channels). Fibrin clots were lined by a layer of CD31+ endothelium. Perivascular hypercellular areas stained uniformly with CD31 and less so with VEGFr2. Additionally, focal areas of Ki67+ and CD68+ cells were found in these regions. Expanded stroma contained CD31+ microcapillary networks and stained diffusely with anti-SMA. CONCLUSIONS: Cavernous haemangioma demonstrate clinical features and growth characteristics of a benign mass. Dynamic imaging highlights their slow flow vascular nature. Histologically, the hypercellularity and stromal changes identified can be understood within the pathogenic context of thrombosis and recanalisation in an organised lesion. PMID- 24627254 TI - Consecutive esotropia after surgery for intermittent exotropia: the clinical course and factors associated with the onset. AB - BACKGROUND: To analyse the incidence and factors associated with the onset of consecutive esotropia after surgery for intermittent exotropia, and to investigate its clinical course. METHODS: We retrospectively reviewed the medical records of 526 patients who had undergone exotropia surgery. We evaluated the risk factors for consecutive esotropia, defined as esodeviation >= 10 prism dioptres (PD) at postoperative month 1 or later. We also evaluated the clinical course of consecutive esotropia with non-surgical and surgical management. RESULTS: Consecutive esotropia occurred in 26 (4.94%) of 526 patients. Divergence excess type of exotropia (p=0.036), amblyopia (p=0.046), bilateral lateral rectus recession (p=0.008), esodeviation of >= 20 PD at postoperative day 1 (p=0.000), younger age at diagnosis and surgery (p=0.010, p=0.003) and shorter duration from onset to surgery (p=0.039) showed significant association with consecutive esotropia. Among 26 patients, 15 became orthophoric with full-time patching +/- Fresnel prism glasses. Eleven patients failed to show improvement of the esodeviation with non-surgical management; seven of these underwent surgery for sustained esotropia. Among these patients, five showed orthophoria at the final follow-up. CONCLUSIONS: Divergence excess type, bilateral lateral rectus recession, amblyopia, younger age at diagnosis and surgery, shorter duration from onset to surgery and overcorrection of >= 20 PD at postoperative day 1 were predisposing factors for consecutive esotropia. In less than half the consecutive esotropia patients (11/26), esodeviation persisted with non-surgical management. Surgery for consecutive esotropia showed relatively favourable outcomes. PMID- 24627255 TI - Outcomes and cost of diverted versus undiverted restorative proctocolectomy. AB - BACKGROUND: Some observational studies suggest that diversion during restorative proctocolectomy mitigates the risk of anastomotic complications. However, diversion has its own costs and complications. The aim of this study was to compare the cost and outcomes of diverted to undiverted restorative proctocolectomy. METHODS: This study took advantage of a natural experiment within one surgical department to understand the clinical and financial implications of diversion during restorative proctocolectomy. For the last 10 years, two surgeons routinely diverted all patients undergoing restorative proctocolectomy, and two other surgeons routinely did not. The medical records of 288 consecutive restorative proctocolectomy patients were reviewed. Minimum follow-up time was 1 year, with an average of 4.7 years. Complications rates and costs of care were collected. RESULTS: There were no significant differences between rates of anastomotic leak, fistula, or hernias in diverted versus undiverted patients. The odds of having stricture (odds ratio (OR) = 17.08, P < 0.001) and small bowel obstruction (OR = 5.05, P = 0.02) were both significantly higher in diverted patients. The average cost per patient was $43,000 more in the routinely diverted patients. CONCLUSION: Undiverted restorative proctocolectomy may be the highest value procedure with the most favorable outcomes at the lowest cost. PMID- 24627256 TI - Early oral feeding vs. traditional feeding in patients undergoing elective open bowel surgery-a randomized controlled trial. AB - OBJECTIVE: This prospective randomized controlled trial was conducted to compare the safety, tolerability and outcome of early oral feeding vs. traditional feeding in patients undergoing elective open bowel surgery. METHODS: A total of 120 consecutive patients who underwent elective open bowel surgeries were randomized into either early feeding (n = 60) or traditional feeding group (n = 60). Patients in the early feeding group were started on oral fluids on post operative day 1, while those in the traditional feeding group were started orals after the resolution of ileus. Patient characteristics, surgical procedures, co morbidity, first flatus, first defecation, time of starting solid diet, complications and length of hospitalization were assessed between the two groups. RESULTS: The two groups were similar in demographic and baseline data. The number of days to first flatus (p < 0.0001), first defecation (p < 0.0001), length of post-operative stay (p = 0.011) and time of starting solid diet (p < 0.0001) were significantly earlier in the early feeding group. Anastomotic leak, wound infection, fever, vomiting, abdominal distention and other complications were similar. Multivariate analysis showed that patients in the early oral feeding group were discharged 3.4 days earlier (p = 0.037). CONCLUSION: In patients undergoing elective open bowel surgeries, early post-operative feeding is safe, is well tolerated and reduces the length of hospitalization. PMID- 24627257 TI - Surgical outcome of hilar plate resection: extended hilar bile duct resection without hepatectomy. AB - BACKGROUND: We have done curative or palliative extended extrahepatic bile duct resection at the level of the hilar plate for selected patients with cholangiocarcinoma with hilar spreading, calling this procedure "hilar plate resection" (HPR), but the results of evaluating the clinical benefits of HPR for cholangiocarcinoma with hilar spreading have not been reported. PATIENTS AND METHODS: Fifty-two patients with cholangiocarcinoma underwent HPR: the curative procedure was performed in 28 patients (cHPR group) and the palliative in 24 patients (pHPR group). In the same period, 128 patients with cholangiocarcinoma underwent major hepatectomy with intrahepatic cholangiojejunostomy (Hx group). These groups were compared in terms of post-operative complications and survival. RESULTS: There were no significant differences in the rate of patients with post operative complications and in post-operative hospital stay. The overall cumulative 5-year survival rates for each procedure (Hx group, cHPR group and pHPR group) were 40, 38 and 11 %, respectively. There was no significant difference between the Hx and cHPR groups in survival rates (p = 0.87). CONCLUSION: In conclusion, HPR appears to be safe and feasible for selected patients with cholangiocarcinoma. However, the indications for HPR should be restricted. PMID- 24627258 TI - The best surgical approach for left colectomy: a comparative study between transverse laparotomy, midline laparotomy and laparoscopy. AB - AIM: To compare the early and late complications after left colectomy (LC) by left transverse laparotomy (LTL), midline laparotomy (ML) and laparoscopy (La). METHODS: From 1998 to 2003, 328 patients underwent an LC by LTL, ML or La. After matching patients for age, ASA score and indication, 159 patients were divided into three groups of 53 patients each according to the surgical approach performed. The median follow-up was 8 years. Early and late complications were compared by univariate and multivariate analysis. RESULTS: Early morbidity rates after LTL, ML and La were 52%, 45% and 21%, respectively (p = 0.002). Extra digestive complication rates after LTL, ML and La were 36%, 34% and 13.2%, respectively (p = 0.02). Respiratory complication rates were 15%, 21% and 2% (p = 0.01). The rate of wound infection was higher after LTL (15% vs. 6% and 6%, p = 0.06). Length of stay was significantly shorter after La (median: LTL, 10 days; ML, 9 days; La, 6 days; p < 0.0001). At a median follow-up of 8 years, the obstruction rate was 6.3%, regardless of the surgical approach. The rates of incisional hernia after LTL, ML and La were 8%, 23% and 3% (p = 0.004), respectively, with odds ratio (OR) = 4.47 (1.2 to 16). CONCLUSION: Our study shows that although La has a significant lower rate of complications, LTL, with fewer respiratory complications and hernia than ML, should be considered as the reference incision in case of conversion or contra-indication for laparoscopy. PMID- 24627259 TI - Short- and long-term results of laparoscopic versus open anti-reflux surgery: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: There is an ongoing debate about whether laparoscopic anti-reflux surgery (LARS) or open anti-reflux surgery (OARS) is the better option for the surgical treatment of gastroesophageal reflux disease (GERD). This study was aimed to evaluate and compare the short- and long-term results of both surgical strategies by means of a systematic review and meta-analysis. METHODS: A systematic search of electronic databases (PubMed, Embase, The Cochrane Library) for studies published from 1970 to 2013 was performed. All randomized controlled trials (RCTs) that compared LARS with OARS were included. We analyzed the outcomes of each type of surgery over short- and long-term periods. RESULTS: Twelve studies met final inclusion criteria (total n = 1,067). A total of 510 patients underwent OARS and 557 had LARS. The pooled analyses showed, despite of longer operation time, the hospital stay and sick leave were significantly reduced in the LARS group. Significant reductions were also observed in complication rates for the LARS group in both short (odds ratio (OR) 0.31, 95 % CI 0.17 to 0.56) and long-term periods (OR 0.24, 95 % CI 0.07 to 0.80). Although complaints of reflux symptoms were more frequent among LARS patients in the short term follow-up, LARS achieved better control of reflux symptoms in the long-term period (P < 0.05). Reoperation rate, patient's satisfaction, and 24-h pH monitoring were all comparable between the two groups (all P > 0.05). CONCLUSIONS: LARS is an effective and safe alternative of OARS for the surgical treatment of GERD, which enables a faster convalescence, better control of long term reflux symptoms, and with reduced risk of complications. PMID- 24627261 TI - Priming the (proton) pump. PMID- 24627260 TI - Upregulation of HIF-1alpha via activation of ERK and PI3K pathway mediated protective response to microwave-induced mitochondrial injury in neuron-like cells. AB - Microwave-induced learning and memory deficits in animal models have been gaining attention in recent years, largely because of increasing public concerns on growing environmental influences. The data from our group and others have showed that the injury of mitochondria, the major source of cellular adenosine triphosphate (ATP) in primary neurons, could be detected in the neuron cells of microwave-exposed rats. In this study, we provided some insights into the cellular and molecular mechanisms behind mitochondrial injury in PC12 cell derived neuron-like cells. PC12 cell-derived neuron-like cells were exposed to 30 mW/cm(2) microwave for 5 min, and damages of mitochondrial ultrastructure could be observed by using transmission electron microscopy. Impairments of mitochondrial function, indicated by decrease of ATP content, reduction of succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) activities, decrease of mitochondrial membrane potential (MMP), and increase of reactive oxygen species (ROS) production, could be detected. We also found that hypoxia-inducible factor-1 (HIF-1alpha), a key regulator responsible for hypoxic response of the mammalian cells, was upregulated in microwave-exposed neuron-like cells. Furthermore, HIF-1alpha overexpression protected mitochondria from injury by increasing the ATP contents and MMP, while HIF-1alpha silence promoted microwave induced mitochondrial damage. Finally, we demonstrated that both ERK and PI3K signaling activation are required in microwave-induced HIF-1alpha activation and protective response. In conclusion, we elucidated a regulatory connection between impairments of mitochondrial function and HIF-1alpha activation in microwave exposed neuron-like cells. By modulating mitochondrial function and protecting neuron-like cells against microwave-induced mitochondrial injury, HIF-1alpha represents a promising therapeutic target for microwave radiation injury. PMID- 24627262 TI - Contrasting responses of silver birch VOC emissions to short- and long-term herbivory. AB - There is a need to incorporate the effects of herbivore damage into future models of plant volatile organic compound (VOC) emissions at leaf or canopy levels. Short-term (a few seconds to 48 h) changes in shoot VOC emissions of silver birch (Betula pendula Roth) in response to feeding by geometrid moths (Erannis defoliaria Hubner) were monitored online by proton transfer reaction time-of flight mass spectrometry (PTR-TOF-MS). In addition, two separate field experiments were established to study the effects of long-term foliage herbivory (FH, 30-32 days of feeding by geometrids Agriopis aurantiaria (Clerck) and E. defoliaria in two consecutive years) and bark herbivory (BH, 21 days of feeding by the pine weevil (Hylobius abietis L.) in the first year) on shoot and rhizosphere VOC emissions of three silver birch genotypes (gt14, gt15 and Hausjarvi provenance). Online monitoring of VOCs emitted from foliage damaged by geometrid larvae showed rapid bursts of green leaf volatiles (GLVs) immediately after feeding activity, whereas terpenoid emissions had a tendency to gradually increase during the monitoring period. Long-term FH caused transient increases in total monoterpene (MT) emissions from gt14 and sesquiterpene (SQT) emissions from Hausjarvi provenance, mainly in the last experimental season. In the BH experiment, genotype effects were detected, with gt14 trees having significantly higher total MT emissions compared with other genotypes. Only MTs were detected in the rhizosphere samples of both field experiments, but their emission rates were unaffected by genotype or herbivory. The results suggest that silver birch shows a rapid VOC emission response to short-term foliage herbivory, whereas the response to long-term foliage herbivory and bark herbivory is less pronounced and variable at different time points. PMID- 24627263 TI - Failure of aneurysm occlusion by flow diverter: a role for surgical bypass and parent artery occlusion. AB - Flow diverters represent a paradigm shift in the treatment of aneurysms. However, unusual and poorly understood complications are being reported. We present a case of a giant internal carotid artery terminus aneurysm treated with flow diversion that progressively and symptomatically enlarged despite a reduction in the filling portion. Complete occlusion of the aneurysm and reduction in mass effect occurred through superficial temporal artery- middle cerebral artery bypass and parent artery occlusion. Incomplete aneurysm occlusion following flow diversion has been reported, but mechanisms and predisposing factors are speculative and definitive solutions have not been described. This case illustrates a potential solution. PMID- 24627264 TI - Harms and deprivation of benefits for nonhuman primates in research. AB - The risks of harm to nonhuman primates, and the absence of benefits for them, are critically important to decisions about nonhuman primate research. Current guidelines for review and practice tend to be permissive for nonhuman primate research as long as minimal welfare requirements are fulfilled and human medical advances are anticipated. This situation is substantially different from human research, in which risks of harms to the individual subject are typically reduced to the extent feasible. A risk threshold is needed for the justification of research on nonhuman primates, comparable to the way risk thresholds are set for vulnerable human subjects who cannot provide informed consent. Much of the laboratory research conducted today has inadequate standards, leading to common physical, psychological, and social harms. PMID- 24627265 TI - Moving beyond the welfare standard of psychological well-being for nonhuman primates: the case of chimpanzees. AB - Since 1985, the US Animal Welfare Act and Public Health Service policy have required that researchers using nonhuman primates in biomedical and behavioral research develop a plan "for a physical environment adequate to promote the psychological well-being of primates." In pursuing this charge, housing attributes such as social companionship, opportunities to express species-typical behavior, suitable space for expanded locomotor activity, and nonstressful relationships with laboratory personnel are dimensions that have dominated the discussion. Regulators were careful not to direct a specific set of prescriptions (i.e., engineering standards) for the attainment of these goals, but to leave the design of the programs substantially up to "professional judgment" at the local level. Recently, however, the Institute of Medicine, in its path-finding 2011 report on the necessity of chimpanzee use in research, bypassed this flexible and contingent concept, and instead, required as a central precondition that chimpanzees be housed in "ethologically appropriate" environments. In so doing, obligations of ethical treatment of one great ape species were elevated above the needs of some research. The evolution and significance of this change are discussed. PMID- 24627266 TI - Evaluation of treatment outcomes for Stenotrophomonas maltophilia bacteraemia. AB - OBJECTIVE: The goal of this study was to retrospectively collect data about treatment outcomes in patients diagnosed with Stenotrophomonas maltophilia bacteraemia over a period of 20 years and evaluate these data with respect to the efficacy of treatment options. METHODS: The setting was a 700-bed tertiary care hospital in a large urban area. Hospital databases and medical records provided information about episodes of S. maltophilia, patient characteristics and treatment outcomes. Patients with at least one positive blood culture for S. maltophilia were included in the study. Data were analysed with respect to clinical improvement and mortality <=30 days after the onset of infection. We compared patient characteristics, laboratory values and treatments by using the Chi-square or Fisher's exact tests and the Mann-Whitney test. RESULTS: We investigated 27 patients with S. maltophilia bacteraemia. The focus of infection was a central venous catheter in 18 (67 %) cases. The 30-day mortality rate was 11 %. All patients who were treated with an antibiotic that was effective in vitro against the pathogen recovered clinically and survived >=30 days after the onset of infection. The most frequently used antibiotic was trimethoprim sulfamethoxazole administered alone or in combination with a fluoroquinolone. CONCLUSIONS: Despite the fact that S. maltophilia is resistant to multiple antibiotics, the prognosis for patients with S. maltophilia bacteraemia is good when they are treated with antibiotics that are effective against this pathogen in vitro. PMID- 24627267 TI - Progressive disseminated histoplasmosis in the HIV population in Europe in the HAART era. Case report and literature review. AB - INTRODUCTION: In highly endemic areas, up to 20 % of human immunodeficiency virus (HIV)-infected persons will develop progressive disseminated histoplasmosis (PDH). Europe is not endemic to histoplasmosis, and the disease is mainly found in immigrants often co-infected with HIV. METHODS: We present a case of a patient with HIV and PDH highlighting the possible diagnostic difficulties that may arise in a non-endemic area and review the literature of histoplasmosis in the context of HIV infection with special focus on Europe. DISCUSSION: When cellular immunity wanes (usually at CD4 T-lymphocyte counts <150 cells/MUL) histoplasma infection, acquired earlier, can reactivate and disseminate. PDH is an acquired immune deficiency syndrome(AIDS)-defining disease and a life-threatening infection, with a clinical spectrum ranging from an acute, fatal course with lung infiltrates and respiratory failure, shock, coagulopathy and multi-organ failure, to a more subacute disease with focal organ involvement, pancytopenia and hepatosplenomegaly. Mortality rates remain high for untreated patients, but early diagnosis, proper antifungal treatment and early initiation of antiretroviral therapy have improved the prognosis. CONCLUSION: European infectious diseases physicians, microbiologists and pathologists must be aware of histoplasmosis, particularly when facing HIV-infected immigrants from endemic areas. This is increasingly important due to migration and travel activities from these areas. PMID- 24627268 TI - Do we get what we pay for? Transitioning physician payments towards value and efficiency. PMID- 24627269 TI - Teaching commentary on "A primary care-based multidisciplinary readmission prevention program": essential aspects of comparability and context in practice based program evaluation. PMID- 24627270 TI - Masking epistasis between MYC and TGF-beta pathways in antiangiogenesis-mediated colon cancer suppression. AB - BACKGROUND: The c-Myc oncoprotein is activated in the majority of colorectal cancers (CRCs), whereas the TGF-beta pathway is frequently affected by loss-of function mutations, for example in SMAD2/3/4 genes. The canonical model places Myc downstream of inhibitory TGF-beta signaling. However, we previously demonstrated that Myc also inhibits TGF-beta signaling through the miR-17~92 microRNA cluster, raising the question about functional relationships between these two pathways. METHODS: We engineered a series of genetically complex murine and human CRC cell lines in which Myc and TGF-beta activities could be manipulated simultaneously. This was achieved through retroviral expression of the Myc-estrogen receptor fusion protein and through Smad4 short hairpin RNA knockdown. Cell lines thus modified were injected subcutaneously in immunocompromised mice, and the resultant tumors (n = 5-10 per treatment group) were analyzed for overall growth and neovascularization. Additionally, the distribution of MYC and TGF-beta pathway mutations was analyzed in previously profiled human CRC samples. RESULTS: In kras-mutated/trp53-deleted murine colonocytes, either Myc activation or TGF-beta inactivation increased tumor sizes and microvascular densities approximately 1.5- to 2.5-fold, chiefly through downregulation of thrombospondin-1 and related type I repeat-containing proteins. Combining Myc activation with TGF-beta inactivation did not further accelerate tumorigenesis. This redundancy and the negative effect of TGF-beta signaling on angiogenesis were also demonstrated using xenografts of human CRC cell lines. Furthermore, the analysis of the Cancer Genome Atlas data revealed that in CRC without microsatellite instability, overexpression of Myc and inactivation of Smads (including acquired mutations in SMAD2) are mutually exclusive, with odds ratio less than 0.1. CONCLUSIONS: In human CRC, gain-of-function alterations in Myc and loss-of-function alterations in TGF-beta exhibit a masking epistatic interaction and are functionally redundant. PMID- 24627271 TI - Promoting quality and evidence-based care in early-stage breast cancer follow-up. AB - Evidence-based guidelines for long-term follow-up of early-stage breast cancer patients developed by oncology societies in the United States and Europe recommend that breast cancer survivors undergo regular evaluation with history and physical examination, as well as annual mammography. Routine blood tests, circulating tumor markers, and/or surveillance imaging studies beyond mammography are not recommended in the absence of concerning symptoms or physical examination findings because of lack of supportive clinical evidence. Despite these guidelines, studies have shown that 20% to 40% of oncologists assess serum tumor markers as part of routine monitoring of early-stage breast cancer patients. As part of efforts to both address the financial challenges confronting the health care system and optimize patient outcomes, the American Society of Clinical Oncology's Cost of Care Task Force identified adherence to breast cancer surveillance guidelines as an opportunity to improve care and reduce cost. However, these recommendations are based on trials done in an era of outdated technology and limited therapeutic options. It is possible that recent improvements in diagnostics and treatments could make earlier detection of recurrent disease important for improving both survival and quality of life outcomes. Research is necessary to further inform optimal breast cancer follow-up strategies, which could impact these recommendations. At this time, outside of well-conducted clinical trials, there is no role for ordering routine serial blood or imaging tests in monitoring for recurrence in early-stage breast cancer patients. PMID- 24627272 TI - Better therapeutic trials in ovarian cancer. AB - The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28-29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy. PMID- 24627273 TI - Change in peripheral blood leukocyte telomere length and mortality in breast cancer survivors. AB - BACKGROUND: Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors. METHODS: We measured peripheral blood leukocyte telomere length at two time points in women enrolled in a multiethnic, prospective cohort of stage I to stage IIIA breast cancer survivors diagnosed between 1995 and 1999 with a median follow-up of 11.2 years. We evaluated associations between telomere length measured at mean 6 (baseline; LTL0; n = 611) and 30 months (LTL30; n = 478) after diagnosis and the change between those time points (n = 478), with breast cancer specific and all-cause mortality using Cox proportional hazards models adjusted for possible confounders. Statistical tests were two-sided. RESULTS: There were 135 deaths, of which 74 were due to breast cancer. Neither baseline nor 30-month telomere length was associated with either all-cause or breast cancer-specific mortality (LTL0: hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.67 to 1.02; HR = 0.88; 95% CI = 0.67 to 1.15; LTL30: HR = 0.78, 95% CI = 0.59 to 1.05; HR = 0.86; 95% = CI = 0.58 to 1.26, respectively). However, participants whose telomeres shortened between baseline and 30 months were at a statistically significantly increased risk of breast cancer-specific (HR = 3.03; 95% CI = 1.11 to 8.18) and all-cause mortality (HR = 2.38; 95% CI = 1.28 to 4.39) compared with participants whose telomeres lengthened. When follow-up was censored at 5-years after diagnosis, LTL0 (HR = 0.66; 95% CI = 0.45 to 0.96), LTL30 (HR = 0.51; 95% CI = 0.29 to 0.92), and change in telomere length (HR = 3.45; 95% CI = 1.11 to 10.75) were statistically significantly associated with all-cause mortality. CONCLUSIONS: Telomere shortening was associated with increased risk of breast cancer-specific and all-cause mortality, suggesting that change in blood telomere length over time could be a biomarker of prognosis. Research on determinants of telomere length and change is needed. PMID- 24627274 TI - Therapeutic properties of aerobic training after a cancer diagnosis: more than a one-trick pony? PMID- 24627277 TI - In and out, good and bad news, of generalizability of SWOG treatment trial results. PMID- 24627275 TI - Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. AB - BACKGROUND: Previous studies have hypothesized that tumor blood flow may be elevated or reduced during exercise, which could impact the tumor microenvironment. However, to date technical limitations have precluded the measurement of tumor blood flow during exercise. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that during exercise tumors would experience 1) diminished vascular resistance, 2) augmented blood flow, 3) increased numbers of perfused vessels, and 4) decreased tissue hypoxia and, furthermore, that the increased perfusion would be associated with diminished vasoconstriction in prostate tumor arterioles. METHODS: Dunning R-3327 MatLyLu tumor cells were injected into the ventral prostate of male Copenhagen rats aged 4 to 6 months randomly assigned to tumor-bearing (n = 42) or vehicle control (n = 14) groups. Prostate tumor blood flow, vascular resistance, patent vessel number, and hypoxia were measured in vivo in conscious rats at rest and during treadmill exercise, and vasoconstrictor responsiveness of resistance arterioles was investigated in vitro. RESULTS: During exercise there was a statistically significant increase in tumor blood flow (approximately 200%) and number of patent vessels (rest mean +/- standard deviation [SD] = 12.7+/-1.3; exercise mean +/- SD = 14.3+/-0.6 vessels/field; Student t test two-sided P = .02) and decreased hypoxia compared with measurements made at rest. In tumor arterioles, the maximal constriction elicited by norepinephrine was blunted by approximately 95% vs control prostate vessels. CONCLUSIONS: During exercise there is enhanced tumor perfusion and diminished tumor hypoxia due, in part, to a diminished vasoconstriction. The clinical relevance of these findings are that exercise may enhance the delivery of tumor-targeting drugs as well as attenuate the hypoxic microenvironment within a tumor and lead to a less aggressive phenotype. PMID- 24627276 TI - Comparison of survival outcomes among cancer patients treated in and out of clinical trials. AB - BACKGROUND: Clinical trials test the efficacy of a treatment in a select patient population. We examined whether cancer clinical trial patients were similar to nontrial, "real-world" patients with respect to presenting characteristics and survival. METHODS: We reviewed the SWOG national clinical trials consortium database to identify candidate trials. Demographic factors, stage, and overall survival for patients in the standard arms were compared with nontrial control subjects selected from the Surveillance, Epidemiology, and End Results program. Multivariable survival analyses using Cox regression were conducted. The survival functions from aggregate data across all studies were compared separately by prognosis (>=50% vs <50% average 2-year survival). All statistical tests were two sided. RESULTS: We analyzed 21 SWOG studies (11 good prognosis and 10 poor prognosis) comprising 5190 patients enrolled from 1987 to 2007. Trial patients were younger than nontrial patients (P < .001). In multivariable analysis, trial participation was not associated with improved overall survival for all 11 good prognosis studies but was associated with better survival for nine of 10 poor prognosis studies (P < .001). The impact of trial participation on overall survival endured for only 1 year. CONCLUSIONS: Trial participation was associated with better survival in the first year after diagnosis, likely because of eligibility criteria that excluded higher comorbidity patients from trials. Similar survival patterns between trial and nontrial patients after the first year suggest that trial standard arm outcomes are generalizable over the long term and may improve confidence that trial treatment effects will translate to the real-world setting. Reducing eligibility criteria would improve access to clinical trials. PMID- 24627278 TI - The role and reliability of rapid bedside diagnostic test in early diagnosis and treatment of bacterial meningitis. AB - OBJECTIVE: To evaluate the role and reliability of rapid bedside diagnostic test in early diagnosis and treatment of bacterial meningitis in children using reagent strips. METHODS: This prospective, single blinded study was conducted in the Department of Pediatrics of VMMC & Safdarjung Hospital, New Delhi in collaboration with the Department of Microbiology of VMMC & Safdarjung Hospital, New Delhi, over a period of 15 mo (August 2009 to Nov 2010). Seventy-five children aged 3 mo to 12 y admitted in the pediatric ward with suspected diagnosis of acute meningitis were included. All enroled patients underwent lumbar puncture. CSF samples were taken and divided in 2 parts for laboratory evaluation and rapid strip analysis. The sensitivity, specificity, positive predictive value and the negative predictive values of the reagent strips for the diagnosis of bacterial meningitis were calculated. Accuracy of the reagent strips was established using kappa statistics. Latex agglutination for antigen detection and microbiological culture were also done. RESULTS: Highly significant association was observed between CSF examination in routine laboratory method and dipstick method. The number of laboratory values that correlated were- for cells 71(94.63%), for protein 68 (90.67%), for glucose 68(90.67%) out of total 75 cases. The sensitivity and specificity of reagent strip in diagnosing acute bacterial meningitis were 96.7% and 97.8% respectively. The positive predictive and negative predictive values of reagent strip in diagnosing acute bacterial meningitis were 96.7% and 97.8% respectively. Staphylococcus aureus was found to be the most common organism isolated (50%). CONCLUSIONS: Thus reagent strip analysis is a very rapid, reliable and effective method for diagnosis of acute bacterial meningitis in children. Staphylococcus aureus was the most common organism isolated. PMID- 24627279 TI - Stroke as a rare manifestation of classical citrullinemia. PMID- 24627280 TI - Facial nerve palsy caused by parotid abscess in an infant. PMID- 24627281 TI - Comparison of two new generation pulse oximeters with arterial oxygen saturation in critically ill children. AB - OBJECTIVES: To compare the performance of two new generation pulse oximeters, one with enhanced signal extraction technology (SET) and other without enhanced SET in detecting hypoxemia and to correlate it with arterial blood gas analysis. METHODS: Forty-eight patients, admitted to pediatric intensive care unit (PICU) of a teritiary care teaching hospital in India for critical care and support during the study period, who had an arterial catheter in situ were included. Children with those disease conditions known to interfere with pulse oximetry and blood gas analysis were excluded.184 set of observations were made during the study period. Each set had oxygen saturation (SpO2) measured from both the pulse oximeters and the corresponding arterial oxygen saturation (SaO2). The values were compared for occurrence of true and false alarms during periods of normal BP, hypotension and varying degrees of hypoxia. RESULTS: The mean arterial SaO2 in the study was 94.4 % +/- 4.9. The mean SpO2 recorded in conventional and enhanced signal extraction technology (SET) pulse oximeters were 94.9 % +/- 4.5 and 97.2 % +/- 4.7 respectively. Enhanced signal extraction technology pulse oximeter detected 4/27 (15 %) of true hypoxemic events and 1 event was a false alarm. Conventional pulse oximeter detected 11/27 (41 %) true hypoxemic events but recorded 6 false alarms. CONCLUSIONS: Both pulse oximeters were not found to be performing satisfactorily in picking up hypoxemia in the study. There was good correlation with mean SpO2 from pulse oximeters and arterial SaO2. The reliability of pulse oximetry decreases with worsening hypoxemia and hypotension, and the sensitivity for picking up hypoxemia can be as low as 15 %. PMID- 24627282 TI - Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair. AB - The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present a novel benzoxazine, 8-methyl-2-(morpholine-4yl)-7-(pyridine-3-methoxy) 4H-1,3-benzoxacine-4-one (LTU27) and analyse its ability to cause sensitization of lung cancer and colon cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them concomitantly with both radiation and LTU27. The mechanism of action appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis. PMID- 24627283 TI - Numerical simulations on conformable laser-induced interstitial thermotherapy through combined use of multi-beam heating and biodegradable nanoparticles. AB - Clinically, precisely heating and thus completely ablating diseased tumor tissue through laser beam is still facing many technical challenges. In this study, numerical simulation of a conformal heating modality based on multi-beam laser along with biodegradable magnesium nanoparticles (Mg-NPs) was put forward to treat liver tumor with large size or irregular shape. Further, a Gaussian-like distribution was proposed to investigate the influence of Mg-NP deposition on the nanoenhanced laser-induced interstitial thermotherapy (LITT). A temperature feedback system was adopted to control the temperature range to avoid overheating. To preliminarily validate the heating enhancement induced by the applied multi-beam laser and Mg-NPs, a conceptual experiment was performed. Both theoretical simulation and experimental measurements demonstrated that multi-beam laser with Mg-NPs could improve efficiency in the conformal heating of tumors with irregular shape or large size. In addition, the distribution and content of Mg-NPs produced significant impact on thermotherapy: (1) The adjustable parameter sigma in the Gaussian-like distribution could reflect various practical situations and diffusivities of Mg-NPs; (2) under the premise of the same concentration of Mg-NPs and short time to heat a small-sized target, the whole liver tumor containing Mg-NPs could not improve the efficiency as the nanoparticles limited the photons to be absorbed only around the fibers, while liver tumor partially containing Mg-NPs could improve the thermotherapy efficiency up to 20 %; and (3) the addition of Mg-NPs was rather beneficial for realizing a conformal heating as the residual thermal energy was much less than that without Mg-NPs. This study suggests a feasible and promising modality for planning a high-performance LITT in future clinics. PMID- 24627285 TI - Editor's Note. PMID- 24627284 TI - Do laser/LED phototherapies influence the outcome of the repair of surgical bone defects grafted with biphasic synthetic microgranular HA + beta-tricalcium phosphate? A Raman spectroscopy study. AB - The treatment of bone loss is difficult. Many techniques are proposed to improve repair, including biomaterials and, recently, phototherapies. This work studied bone mineralization by Raman spectroscopy assessing intensities of Raman peaks of both inorganic (~ 960, ~ 1,070 cm(-1)) and organic (~ 1,454 cm(-1)) contents in animal model. Six groups were studied: clot, laser, light-emitting diode (LED), biomaterial (HA + beta-tricalcium phosphate), laser + biomaterial, and LED + biomaterial. Defects at right tibia were performed with a drill. When indicated, defects were further irradiated at a 48-h interval during 2 weeks. At the 15th and 30th days, the tibias were withdrawn and analyzed. The ~ 960-cm(-1) peak was significantly affected by phototherapy on both clot- and biomaterial-filled defects. The ~ 1,070-cm(-1) peak was affected by both time and the use of the LED light on clot-filled defects. On biomaterial-filled defects, only the use of the laser light significantly influenced the outcome. No significant influence of either the time or the use of the light was detected on clot-filled defects as regards the ~ 1,454-cm(-1) peak. Raman intensities of both mineral and matrix components indicated that the use of laser and LED phototherapies improved the repair of bone defects grafted or not with biphasic synthetic microgranular HA + beta-tricalcium phosphate. PMID- 24627286 TI - Management of mantle cell leukemia with cardiac involvement leading to cardiogenic shock. AB - Mantle cell lymphoma is an aggressive subtype of B cell non-Hodgkin lymphoma. It can progress to leukemic phase but frank leukemic picture at initial presentation is not common. Leukemic phase indicates advance stage of the disease and generally associated with extensive extra-nodal involvement. Pericardial invasion has been reported, however we could not find a report of myocardial infiltration by this disease since the appraisal of the term "mantle cell lymphoma" in 1992. Here we report a case of cardiac involvement by mantle cell leukemia leading to cardiogenic shock which complicates the treatment decisions. PMID- 24627287 TI - Ventricular tachycardia in a disseminated MDR-TB patient: a case report and brief review of literature. AB - Although significant breakthroughs have been achieved in tuberculosis management, we still encounter numerous difficulties in diagnosis and treatment of the disease. Additionally, a new challenge, multidrug-resistant tuberculosis (MDR-TB) with unspecific clinical presentation, often results in delayed diagnosis. In this paper, we reported a case of disseminated tuberculosis with rare presentation of ventricular fibrillation, which proved resistant to both isoniazid and rifampicin. A review of literature showed that ventricular fibrillation or tachycardia in tuberculosis patients with pericarditis or myocarditis has been sporadically reported in the past, but none has been conducted involving patients with MDR-TB infections. PMID- 24627288 TI - Paratesticular fibrous pseudotumor: a report of five cases and literature review. AB - Paratesticular fibrous pseudotumor is a rare benign tumor that originates from intrascrotal tissue, such as tunica vaginalis, epididymis, or spermatic cord. Five cases of fibrous pseudotumor in our hospital were reviewed retrospectively, and the clinical manifestations were analyzed. Three cases of unilateral nodules, comprising one case located in the tunica vaginalis and two cases located in the epididymis, underwent local excision of the unilateral nodule. Two cases of diffuse incrassation in the tunica vaginalis underwent right radical orchiectomy. Postoperative pathological examination showed that all were fibrous pseudotumors. An average follow-up of 26 months showed uneventful results without recurrence for all patients. Fibrous pseudotumor is not a neoplasm but a reactive fibrous inflammatory hyperplasia. Definitive diagnosis requires pathological examination. Radical orchiectomy should be avoided when possible, and local excision should be performed because of the lack of obvious evidence of potential malignancy. PMID- 24627289 TI - Telling truth from Ys: an evaluation of whether the accuracy of self-reported semen exposure assessed by a semen Y-chromosome biomarker predicts pregnancy in a longitudinal cohort study of pregnancy. AB - OBJECTIVES: Adolescents may use condoms inconsistently or incorrectly, or may over-report condom use. This study used a semen exposure biomarker to evaluate the accuracy of female adolescents' reports of condom use and predict subsequent pregnancy. METHODS: The sample comprised 715 sexually active African-American female adolescents, ages 15-21 years. At baseline, 6 months and 12 months, participants completed a 40-min interview and were tested for semen Y-chromosome with PCR from a self-administered vaginal swab. We predicted pregnancy from semen exposure under-report using multivariate regression controlling for oral contraception, reported condom use and coital frequency. RESULTS: At the 3 surveys, 30%, 20% and 15% of adolescents who reported always using condoms tested positive for semen exposure. At 6 month follow-up, 20.4% and 16.2% of the adolescents who under-reported semen exposure reported pregnancy, a higher pregnancy rate than accurate reporters of semen exposure, even accurate reporters who reported never using condoms (14.2% and 11.8%). Under-reporters of semen exposure were 3.23 (95% CI (1.61, 6.45)) times as likely to become pregnant at 6 month follow-up and 2.21 (0.94, 5.20) times as likely to become pregnant at 12 month follow-up as accurate reporters who reported not using contraception, adjusting for self-reported coital frequency. CONCLUSIONS: Adolescents who under report semen exposure may be at uniquely high risk for unplanned pregnancy and STIs, and may also under-report coital frequency. Condom efficacy trials that rely on self-report may yield inaccurate results. Adapted to a clinical setting, the Y-chromosome PCR could alert women to incorrect or inconsistent condom use. PMID- 24627290 TI - Pharmacokinetic and pharmacodynamic interaction between gemigliptin and metformin in healthy subjects. AB - BACKGROUND AND OBJECTIVE: Gemigliptin is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor used in the treatment of type 2 diabetes mellitus. This study evaluated possible pharmacodynamic and pharmacokinetic interactions between gemigliptin and metformin and investigated their tolerability. METHODS: A randomized, open-label, multiple-dose, three-treatment, three-period, three-sequence crossover study was conducted in healthy male subjects. Twenty-seven subjects received gemigliptin (50 mg once daily), metformin (1,000 mg twice a day), or both drugs for 7 days per dosing period. Blood samples were drawn over 24 h on the seventh day of each period for pharmacokinetic and pharmacodynamic evaluations, including plasma DPP 4 activity and total/active glucagon-like peptide-1 (GLP-1) levels. Meal tolerance tests were conducted for pharmacodynamic assessment on the eighth day. Safety and tolerability were evaluated using adverse events, vital signs, ECGs, and clinical laboratory tests. RESULTS: Coadministration of gemigliptin and metformin had no significant effect on the pharmacokinetics of gemigliptin or metformin. The inhibition of DPP-4 by gemigliptin was not affected by coadministration with metformin. Co-therapy of gemigliptin and metformin showed additional effects by increasing plasma active GLP-1 concentrations and lowering serum glucose levels. The plasma glucagon level was lower in co-therapy than with metformin monotherapy. The coadministration of gemigliptin and metformin was well tolerated without serious adverse events. CONCLUSIONS: Coadministration of gemigliptin and metformin showed beneficial anti-diabetic effects without pharmacokinetic drug-drug interactions. PMID- 24627292 TI - Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy. AB - BACKGROUND: While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons for delayed discharge after day surgery and overnight stay laparoscopic cholecystectomy. The safety and effectiveness of intraperitoneal local anaesthetic instillation in people undergoing laparoscopic cholecystectomy is unknown. OBJECTIVES: To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded to March 2013 to identify randomised clinical trials of relevance to this review. SELECTION CRITERIA: We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing local anaesthetic intraperitoneal instillation versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy for the review with regards to benefits while we considered quasi randomised studies and non-randomised studies for treatment-related harms. DATA COLLECTION AND ANALYSIS: Two review authors collected the data independently. We analysed the data with both fixed-effect and random-effects models using Review Manager 5 analysis. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included 58 trials, of which 48 trials with 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) versus control (1291 participants) contributed data to one or more of the outcomes. All the trials except one trial with 30 participants were at high risk of bias. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Various intraperitoneal local anaesthetic agents were used but bupivacaine in the liquid form was the most common local anaesthetic used. There were considerable differences in the methods of local anaesthetic instillation including the location (subdiaphragmatic, gallbladder bed, or both locations) and timing (before or after the removal of gallbladder) between the trials. There was no mortality in either group in the eight trials that reported mortality (0/236 (0%) in local anaesthetic instillation versus 0/210 (0%) in control group; very low quality evidence). One participant experienced the outcome of serious morbidity (eight trials; 446 participants; 1/236 (0.4%) in local anaesthetic instillation group versus 0/210 (0%) in the control group; RR 3.00; 95% CI 0.13 to 67.06; very low quality evidence). Although the remaining trials did not report the overall morbidity, three trials (190 participants) reported that there were no intra-operative complications. Twenty trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation. None of the trials reported participant quality of life, return to normal activity, or return to work.The effect of local anaesthetic instillation on the proportion of participants discharged as day surgery between the two groups was imprecise and compatible with benefit and no difference of intervention (three trials; 242 participants; 89/160 (adjusted proportion 61.0%) in local anaesthetic instillation group versus 40/82 (48.8%) in control group; RR 1.25; 95% CI 0.99 to 1.58; very low quality evidence). The MD in length of hospital stay was 0.04 days (95% CI -0.23 to 0.32; five trials; 335 participants; low quality evidence). The pain scores as measured by the visual analogue scale (VAS) were significantly lower in the local anaesthetic instillation group than the control group at four to eight hours (32 trials; 2020 participants; MD -0.99 cm; 95% CI -1.10 to -0.88 on a VAS scale of 0 to 10 cm; very low quality evidence) and at nine to 24 hours (29 trials; 1787 participants; MD -0.53 cm; 95% CI -0.62 to -0.44; very low quality evidence). Various subgroup analyses and meta-regressions to investigate the influence of the different local anaesthetic agents, different methods of local anaesthetic instillation, and different controls on the effectiveness of local anaesthetic intraperitoneal instillation were inconsistent. AUTHORS' CONCLUSIONS: Serious adverse events were rare in studies evaluating local anaesthetic intraperitoneal instillation (very low quality evidence). There is very low quality evidence that it reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is unknown and likely to be small. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment. PMID- 24627293 TI - Synthesis and evaluation of Tc-99m DTPA-glutathione as a non-invasive tumor imaging agent in a mouse colon cancer model. AB - PURPOSE: Glutathione (GSH) plays a critical role in detoxification reactions by reducing the levels of reactive oxygen species in cancer cells. This study aimed to develop technetium (Tc)-99m diethylenetriaminepentaacetic acid (DTPA)-GSH as a tumor imaging agent, and to evaluate the diagnostic performance of Tc-99m DTPA GSH in terms of its ability to differentiate tumors from inflammatory lesions. METHODS: DTPA-GSH was synthesized by reaction of GSH with DTPA anhydride under anhydrous conditions in a nitrogen atmosphere. DTPA-GSH was then reacted with Tc 99m sodium pertechnetate in a tin (II) chloride (SnCl2) solution. Gamma camera imaging was performed after intravenous injection of Tc-99m DTPA-GSH into a mouse CT-26 colon cancer model, or a mouse model of inflammation induced by the intramuscular injection of Freund's complete adjuvant. RESULTS: DTPA-GSH was successfully prepared via a straightforward synthetic procedure and radiolabeled with Tc-99m at a high labeling efficiency (>95%). Tc-99m DTPA-GSH was strongly internalized by tumors in colon cancer model mice, with the tumor-to-normal muscle ratio of the complex reaching 4.3+/-0.9 at 4 h. By contrast, Tc-99m DTPA GSH showed relatively weak uptake in inflammatory lesions (target-to-non-target ratio=2.0+/-0.3 at 4 h). A competition study showed that the uptake of Tc-99m DTPA-GSH into tumors was blocked by co-injection with high concentrations of free GSH. CONCLUSIONS: The results of this work indicate that Tc-99m DTPA-GSH is a good candidate for development as a non-invasive tumor imaging agent. Furthermore, Tc-99m DTPA-GSH effectively distinguished between cancerous tissue and inflammatory lesions. PMID- 24627296 TI - Daily stressors and negative life events in children at elevated risk of developing schizophrenia. AB - BACKGROUND: Psychological stress is implicated in the development of schizophrenia, but little is known about experiences of stress among children at elevated risk for the disorder. AIMS: To examine stressor exposure and reactivity in children with different vulnerability profiles for schizophrenia: (a) children presenting multiple antecedents of schizophrenia (ASz group), (b) children with a family history of schizophrenia (FHx group) and (c) typically developing low-risk (TD) children. METHOD: Ninety-five children (ASz = 29; FHx = 19; ASz+FHx = 5; TD = 42), identified aged 9-12 years using a community-based screening procedure or as relatives of individuals with schizophrenia, completed questionnaires assessing environmental stressors and psychopathology at age 11-14 years. RESULTS: Relative to their typically developing peers, children in the FHx and ASz groups were exposed to a greater number of negative life events and a higher frequency of daily stressors, respectively; and were more distressed by these experiences. CONCLUSIONS: Stress exposure and reactivity may constitute useful targets of early intervention for psychosis. PMID- 24627295 TI - Estimated effects of projected climate change on the basic reproductive number of the Lyme disease vector Ixodes scapularis. AB - BACKGROUND: The extent to which climate change may affect human health by increasing risk from vector-borne diseases has been under considerable debate. OBJECTIVES: We quantified potential effects of future climate change on the basic reproduction number (R0) of the tick vector of Lyme disease, Ixodes scapularis, and explored their importance for Lyme disease risk, and for vector-borne diseases in general. METHODS: We applied observed temperature data for North America and projected temperatures using regional climate models to drive an I. scapularis population model to hindcast recent, and project future, effects of climate warming on R0. Modeled R0 increases were compared with R0 ranges for pathogens and parasites associated with variations in key ecological and epidemiological factors (obtained by literature review) to assess their epidemiological importance. RESULTS: R0 for I. scapularis in North America increased during the years 1971-2010 in spatio-temporal patterns consistent with observations. Increased temperatures due to projected climate change increased R0 by factors (2-5 times in Canada and 1.5-2 times in the United States), comparable to observed ranges of R0 for pathogens and parasites due to variations in strains, geographic locations, epidemics, host and vector densities, and control efforts. CONCLUSIONS: Climate warming may have co-driven the emergence of Lyme disease in northeastern North America, and in the future may drive substantial disease spread into new geographic regions and increase tick-borne disease risk where climate is currently suitable. Our findings highlight the potential for climate change to have profound effects on vectors and vector-borne diseases, and the need to refocus efforts to understand these effects. PMID- 24627297 TI - Adversity, cannabis use and psychotic experiences: evidence of cumulative and synergistic effects. AB - BACKGROUND: There is robust evidence that childhood adversity is associated with an increased risk of psychosis. There is, however, little research on intervening factors that might increase or decrease risk following childhood adversity. AIMS: To investigate main effects of, and synergy between, childhood abuse and life events and cannabis use on odds of psychotic experiences. METHOD: Data on psychotic experiences and childhood abuse, life events and cannabis use were collected from 1680 individuals as part of the South East London Community Health Study (SELCoH), a population-based household survey. RESULTS: There was strong evidence that childhood abuse and number of life events combined synergistically to increase odds of psychotic experiences beyond the effects of each individually. There was similar, but weaker, evidence for cannabis use (past year). CONCLUSIONS: Our findings are consistent with the hypothesis that childhood abuse creates an enduring vulnerability to psychosis that is realised in the event of exposure to further stressors and risk factors. PMID- 24627298 TI - Efficacy of a triage system to reduce length of hospital stay. AB - BACKGROUND: Attempts have been made to improve the efficiency of in-patient acute care. A novel method has been the development of a 'triage system' in which patients are assessed on admission to develop plans for discharge or transfer to an in-patient ward. AIMS: To compare a triage admission system with a traditional system. METHOD: Length of stay and readmission data for all admissions in a 1 year period between the two systems were compared using the participating trust's anonymised records. RESULTS: Despite reduced length of stay on the actual triage ward, the average length of stay was not reduced and the triage system did not lead to a greater number of readmissions. There was no significant difference in costs between the two systems. CONCLUSIONS: Based on our findings we cannot conclude that the triage system reduced length of stay, but we can conclude that it does not increase the number of readmissions as some have feared. PMID- 24627299 TI - Effects of a diet rich in n-3 polyunsaturated fatty acids on hepatic lipogenesis and beta-oxidation in mice. AB - Here, we investigate whether a diet rich in fish oil can lead to the development of hepatic alterations associated with non-alcoholic fatty liver disease (NAFLD). To achieve this goal, we provided, for 8 weeks, four different diets to 3-month old C57BL/6 mice: (a) standard-chow diet (SC; 40 g soybean oil/kg diet, 10 % of the total energy content from lipids), (b) fish oil diet (FO; 4 g soybean oil and 36 g fish oil/kg diet, 10 % of the total energy content from lipids), (c) high fat diet (HF; 40 g soybean oil and 238 g lard/kg diet, 50 % of the total energy content from lipids), and (d) high-fish oil diet (HFO; 40 g soybean oil and 238 g fish oil/kg diet, 50 % of the total energy content from lipids). Biochemical analyses, stereology, western-blotting and RT-qPCR were used. In the HF group, we found evidence of obesity, metabolic syndrome, and liver damage, along with hypertriglyceridemia, hepatic insulin resistance, and steatosis. On the other hand, the HFO group did not present these alterations and remained similar to the controls. The changes observed in the animals fed the HF diet were accompanied by an increase in hepatic lipogenesis and a decrease in beta-oxidation; meanwhile, in the HFO group, the opposite results were found, that is, reduced lipogenesis and elevated beta-oxidation, were most likely responsible for the prevention of deleterious hepatic alterations and liver damage. In conclusion, a diet rich in fish oil has beneficial effects on hepatic insulin resistance, lipogenesis and beta-oxidation and prevents hepatic tissue from liver damage and NAFLD. PMID- 24627300 TI - Lifestyle intervention for improving school achievement in overweight or obese children and adolescents. AB - BACKGROUND: The prevalence of overweight and obesity in childhood and adolescence is high. Excessive body fat at a young age is likely to persist into adulthood and is associated with physical and psychosocial co-morbidities, as well as lower cognitive, school and later life achievement. Lifestyle changes, including reduced caloric intake, decreased sedentary behaviour and increased physical activity, are recommended for prevention and treatment of child and adolescent obesity. Evidence suggests that lifestyle interventions can benefit cognitive function and school achievement in children of normal weight. Similar beneficial effects may be seen in overweight or obese children and adolescents. OBJECTIVES: To assess whether lifestyle interventions (in the areas of diet, physical activity, sedentary behaviour and behavioural therapy) improve school achievement, cognitive function and future success in overweight or obese children and adolescents compared with standard care, waiting list control, no treatment or attention control. SEARCH METHODS: We searched the following databases in May 2013: CENTRAL, MEDLINE, EMBASE, CINAHL Plus, PsycINFO, ERIC, IBSS, Cochrane Database of Systematic Reviews, DARE, ISI Conference Proceedings Citation Index, SPORTDiscus, Database on Obesity and Sedentary Behaviour Studies, Database of Promoting Health Effectiveness Reviews (DoPHER) and Database of Health Promotion Research. In addition, we searched the Network Digital Library of Theses and Dissertations (NDLTD), three trials registries and reference lists. We also contacted researchers in the field. SELECTION CRITERIA: We included (cluster) randomised and controlled clinical trials of lifestyle interventions for weight management in overweight or obese children three to 18 years of age. Studies in children with medical conditions known to affect weight status, school achievement and cognitive function were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data, assessed quality and risk of bias and cross-checked extracts to resolve discrepancies when required. Authors were contacted to obtain further study details and were asked to provide data on the overweight and obese study population when they were not reported separately. MAIN RESULTS: Of 529 screened full-text articles, we included in the review six studies (14 articles) of 674 overweight and obese children and adolescents, comprising four studies with multicomponent lifestyle interventions and two studies with physical activity only interventions. We conducted a meta-analysis when possible and a sensitivity analysis to consider the impact of cluster-randomised controlled trials and/or studies at 'high risk' of attrition bias on the intervention effect. We prioritised reporting of the sensitivity analysis when risk of bias and differences in intervention type and duration were suspected to have influenced the findings substantially. Analysis of a single study indicated that school-based healthy lifestyle education combined with nutrition interventions can produce small improvements in overall school achievement (mean difference (MD) 1.78 points on a scale of zero to 100, 95% confidence interval (CI) 0.8 to 2.76; P < 0.001; N = 321; moderate-quality evidence). Single component physical activity interventions produced small improvements in mathematics achievement (MD 3.00 points on a scale of zero to 200, 95% CI 0.78 to 5.22; P value = 0.008; one RCT; N = 96; high-quality evidence), executive function (MD 3.00, scale mean 100, standard deviation (SD) 15, 95% CI 0.09 to 5.91; P value = 0.04; one RCT; N = 116) and working memory (MD 3.00, scale mean 100, SD 15, 95% CI 0.51 to 5.49; P value = 0.02; one RCT; N = 116). No evidence suggested an effect of any lifestyle intervention on reading, vocabulary and language achievements, attention, inhibitory control and simultaneous processing. Pooling of data in meta-analyses was restricted by variations in study design. Heterogeneity was present within some meta-analyses and may have been explained by differences in types of interventions. Risk of bias was low for most assessed items; however in half of the studies, risk of bias was detected for attrition, participant selection and blinding. No study provided evidence of the effect of lifestyle interventions on future success. Whether changes in academic and cognitive abilities were connected to changes in body weight status was unclear because of conflicting findings and variations in study design. AUTHORS' CONCLUSIONS: Despite the large number of childhood obesity treatment trials, evidence regarding their impact on school achievement and cognitive abilities is lacking. Existing studies have a range of methodological issues affecting the quality of evidence. Multicomponent interventions targeting physical activity and healthy diet could benefit general school achievement, whereas a physical activity intervention delivered for childhood weight management could benefit mathematics achievement, executive function and working memory. Although the effects are small, a very large number of children and adolescents could benefit from these interventions. Therefore health policy makers may wish to consider these potential additional benefits when promoting physical activity and healthy eating in schools. Future obesity treatment trials are needed to examine overweight or obese children and adolescents and to report academic and cognitive as well as physical outcomes. PMID- 24627301 TI - Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users. AB - BACKGROUND: Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. METHODS: In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects. RESULTS: Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p<0.001). Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p<0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p<0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. CONCLUSION: This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction. PMID- 24627302 TI - Efficient recovery of whole cell proteins in Oenococcus oeni--a comparison of different extraction protocols for high-throughput malolactic starter applications. AB - In this study, we compared different total protein extraction protocols to achieve highly efficient isolation and purification of total proteins for the specific protein profiling of Oenococcus oeni. The sodium dodecyl sulfate polyacrylamide gel electrophoresis patterns obtained for the different extraction protocols revealed not only a qualitative similar protein pattern but also quantitative variations with different intensity bands depending on the extraction method used. The selected extraction method added with sonication proved to work extremely well and efficiently and was able to obtain a high resolution 2-D electrophoresis (2-DE) map. Prominent spots were successfully identified by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry and corresponded to 76 different proteins involved in the main metabolic pathways. The approach allowed to achieve a protein profiling specific for O. oeni from Aglianico wine with numerous characterized protein products corresponding to many different O. oeni genes and associated with main cellular pathways. Further investigations of the 2-DE protein expression profile will provide useful and interesting information on the molecular mechanisms at the protein level responsible for growth and survival of O. oeni in wine. PMID- 24627303 TI - A community study of the effect of polycyclic aromatic hydrocarbon metabolites on heart rate variability based on the Framingham risk score. AB - OBJECTIVES: To investigate the effects of the urinary metabolite profiles of background exposure to the atmospheric pollutants polycyclic aromatic hydrocarbon (PAH) and Framingham risk score (FRS), which assesses an individual's cardiovascular disease risk, on heart rate variability (HRV). METHODS: The study conducted from April to May 2011 in Wuhan, China, included 1978 adult residents with completed questionnaires, physical examinations, blood and urine samples, and 5-min HRV indices (including SD of all normal to normal intervals (SDNN), root mean square successive difference (rMSSD), low frequency (LF), high frequency (HF) and their ratio (LF/HF), and total power) obtained from 3-channel Holter monitor. 12 urinary PAH metabolites were measured by gas chromatography mass spectrometry. FRS was calculated by age, sex, lipid profiles, blood pressure, diabetes and smoking status. Linear regression models were constructed after adjusting for potential confounders. RESULTS: Elevated total concentration of hydroxynaphthalene (SigmaOHNa) was significantly associated, in a dose responsive manner, with decreased SDNN and LF/HF (ptrend=0.014 and 0.007, respectively); elevated total concentration of hydroxyfluorene (SigmaOHFlu) was significantly associated with reduced SDNN, LF and LF/HF (ptrend=0.027, 0.003, and <0.0001, respectively); and elevated total concentration of all PAH metabolites (SigmaOH-PAHs) was associated with decreased LF and LF/HF (ptrend=0.005 and <0.0001, respectively). Moreover, increasing quartiles of FRS were significantly associated with decreased HRV indices, except LF/HF (all ptrend<0.0001). Interestingly, individuals in low-risk subgroups had greater decreases in SDNN, LF and LF/HF in relation to SigmaOH-PAHs, SigmaOHNa and SigmaOHFlu than those in high-risk subgroups (all p<0.05). CONCLUSIONS: Environmental PAH exposure may differentially affect HRV based on individual coronary risk profiles. PMID- 24627304 TI - The role of mental health problems and common psychotropic drug treatments in accidental injury at work: a case-control study. AB - OBJECTIVES: Mental illness and psychotropic drugs have been linked with workplace injury, but few studies have measured exposures and outcomes independently or established their relative timings. To address this shortcoming, we conducted a case-control study nested within a database prospectively recording injury consultations, diagnoses and drug prescriptions. METHODS: The Clinical Practice Research Datalink logs primary care data for 6% of the British population, coding all consultations (by the Read system) and drug prescriptions. We identified 1348 patients aged 16-64 years from this database who had consulted a family doctor or hospital over a 20-year period for workplace injury (cases, 479 diagnostic codes) and 6652 age, sex and practice-matched controls with no such consultation. Groups were compared in terms of consultations for mental health problems (1328 codes) and prescription of psychotropic drugs prior to the case's injury consultation using conditional logistic regression. RESULTS: In total, 1846 (23%) subjects had at least one psychiatric consultation before the index date and 1682 (21%) had been prescribed a psychotropic drug. The OR for prior mental health consultation was 1.44 (p<0.001) and that for psychotropic drug treatment was 1.57 (p<0.001). Risks were significantly elevated for several subclasses of mental health diagnosis (eg, psychosis, neurosis) and for each of the drug classes analysed. Assuming causal relationships, about 9-10% of all workplace injuries leading to medical consultation were attributable to mental illness or psychotropic medication. CONCLUSIONS: Mental health problems and psychotropic treatments may account for an important minority of workplace injuries. PMID- 24627305 TI - Airline crew cohorts: is there more to learn regarding their cancer risk? PMID- 24627306 TI - Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment. AB - Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8 1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-kappaB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-kappaB and STAT3 also contribute to epithelial-mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy. PMID- 24627307 TI - Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. AB - Evidence relating dietary patterns to obesity and related disorders such as non alcoholic fatty liver disease (NAFLD) is limited in pediatric age. Aim of this study was to analyze the association between dietary patterns, obesity and development of severe steatosis and the metabolic syndrome in a series of children and adolescents referred for suspected NAFLD, and the interaction with the rs738409 I148M PNPLA3 polymorphism. Two hundred patients (112 females) had completed a food frequency and demographic questionnaire. Nearly 58 % were obese, and 32 % were overweight. Mild, moderate, and severe fatty liver was present in 60 (30 %), 87 (44 %), and 51 (26 %) participants, respectively. A great proportion of overweight/obese children and adolescents reported a correct dietary pattern. At multivariate ordinal regression analysis considering demographic, anthropometric, genetic, and behavioral determinants, the major determinant of steatosis severity was PNPLA3 I148M genotype (p < 0.0001), followed by older age (p = 0.017), higher waist circumference (p = 0.016), and less time spent practising physical exercise (p = 0.034). Furthermore, there was a significant interaction between PNPLA3 I148M and intake of sweetened beverages (p = 0.033) and of vegetables (p = 0.038). In conclusion, although dietary pattern was reportedly correct in at-risk overweight adolescents with NAFLD, we report a novel interaction between PNPLA3 I148M and dietary components with the severity of steatosis. PMID- 24627308 TI - Bisphosphonates for osteoporosis in people with cystic fibrosis. AB - BACKGROUND: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.Additional searches of PubMed were performed on 13 January 2014. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. MAIN RESULTS: Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival. PMID- 24627309 TI - EPOS 33rd Annual Meeting. PMID- 24627310 TI - Performance of probabilistic method to detect duplicate individual case safety reports. AB - BACKGROUND: Individual case reports of suspected harm from medicines are fundamental for signal detection in postmarketing surveillance. Their effective analysis requires reliable data and one challenge is report duplication. These are multiple unlinked records describing the same suspected adverse drug reaction (ADR) in a particular patient. They distort statistical screening and can mislead clinical assessment. Many organisations rely on rule-based detection, but probabilistic record matching is an alternative. OBJECTIVES: The aim of this study was to evaluate probabilistic record matching for duplicate detection, and to characterise the main sources of duplicate reports within each data set. RESEARCH DESIGN: vigiMatchTM, a published probabilistic record matching algorithm, was applied to the WHO global individual case safety reports database, VigiBase((r)), for reports submitted between 2000 and 2010. Reported drugs, ADRs, patient age, sex, country of origin, and date of onset were considered in the matching. Suspected duplicates for the UK, Denmark, and Spain were reviewed and classified by the respective national centre. This included evaluation to determine whether confirmed duplicates had already been identified by in-house, rule-based screening. Furthermore, each confirmed duplicate was classified with respect to the likely source of duplication. MEASURES: For each country, the proportions of suspected duplicates classified as confirmed duplicates, likely duplicates, otherwise related, and unrelated were obtained. The proportions of confirmed or likely duplicates that were not previously known by the national organisation were determined, and variations in the rates of suspected duplicates across subsets of reports were characterised. RESULTS: Overall, 2.5 % of the reports with sufficient information to be evaluated by vigiMatch were classified as suspected duplicates. The rates for the three countries considered in this study were 1.4 % (UK), 1.0 % (Denmark), and 0.7 % (Spain). Higher rates of suspected duplicates were observed for literature reports (11 %) and reports with fatal outcome (5 %), whereas a lower rate was observed for reports from consumers and non-health professionals (0.5 %). The predictive value for confirmed or likely duplicates among reports flagged as suspected duplicates by vigiMatch ranged from 86 % for the UK, to 64 % for Denmark and 33 % for Spain. The proportions of confirmed duplicates that were previously unknown to national centres ranged from 89 % for Spain, to 60 % for the UK and 38 % for Denmark, despite in-house duplicate detection processes in routine use. The proportion of unrelated cases among suspected duplicates were below 10 % for each national centre in the study. CONCLUSIONS: Probabilistic record matching, as implemented in vigiMatch, achieved good predictive value for confirmed or likely duplicates in each data source. Most of the false positives corresponded to otherwise related reports; less than 10 % were altogether unrelated. A substantial proportion of the correctly identified duplicates had not previously been detected by national centre activity. On one hand, vigiMatch highlighted duplicates that had been missed by rule-based methods, and on the other hand its lower total number of suspected duplicates to review improved the accuracy of manual review. PMID- 24627312 TI - An unusual class of anthracyclines potentiate Gram-positive antibiotics in intrinsically resistant Gram-negative bacteria. AB - OBJECTIVES: An orthogonal approach taken towards novel antibacterial drug discovery involves the identification of small molecules that potentiate or enhance the activity of existing antibacterial agents. This study aimed to identify natural-product rifampicin adjuvants in the intrinsically resistant organism Escherichia coli. METHODS: E. coli BW25113 was screened against 1120 actinomycete fermentation extracts in the presence of subinhibitory (2 mg/L) concentrations of rifampicin. The active molecule exhibiting the greatest rifampicin potentiation was isolated using activity-guided methods and identified using mass and NMR spectroscopy. Susceptibility testing and biochemical assays were used to determine the mechanism of antibiotic potentiation. RESULTS: The anthracycline Antibiotic 301A(1) was isolated from the fermentation broth of a strain of Streptomyces (WAC450); the molecule was shown to be highly synergistic with rifampicin (fractional inhibitory concentration index = 0.156) and moderately synergistic with linezolid (FIC index = 0.25) in both E. coli and Acinetobacter baumannii. Activity was associated with inhibition of efflux and the synergistic phenotype was lost when tested against E. coli harbouring mutations within the rpoB gene. Structure-activity relationship studies revealed that other anthracyclines do not synergize with rifampicin and removal of the sugar moiety of Antibiotic 301A(1) abolishes activity. CONCLUSIONS: Screening only a subsection of our natural product library identified a small-molecule antibiotic adjuvant capable of sensitizing Gram-negative bacteria to antibiotics to which they are ordinarily intrinsically resistant. This result demonstrates the great potential of this approach in expanding antibiotic effectiveness in the face of the growing challenge of resistance in Gram-negatives. PMID- 24627311 TI - Potential approaches to ameliorate hepatic fat accumulation seen with MTP inhibition. AB - Microsomal triglyceride transfer protein (MTP) is one of the promising targets for the therapy of dyslipidemia and MTP inhibition can lead to robust plasma low density lipoprotein cholesterol (LDL-C) reduction. Lomitapide, a small-molecule MTP inhibitor, was recently approved by the US FDA as an additional treatment for homozygous familial hypercholesterolemia (hoFH). However, liver-related side effects, including hepatic fat accumulation and transaminase elevations, are the main safety concerns associated with MTP inhibitors. Here, we review recent knowledge on the mechanisms underlying liver toxicity of MTP inhibitors. The contribution of altered levels of intracellular triglycerides, cholesteryl esters, and free cholesterols toward cellular dysfunction is specifically addressed. On this basis, therapies targeted to attenuate cellular lipid accumulation, to reduce risk factors for non-alcoholic fatty liver disease (NAFLD) (i.e., insulin resistance and oxidative stress) and to specifically inhibit intestinal MTP may be useful for ameliorating liver damage induced by MTP inhibitors. In particular, weight loss through lifestyle interventions is expected to be the most effective and safest way to minimize the undesirable side effects. Specific dietary supplementation might also have protective effects against hepatosteatosis. Despite that, to date, few clinical data support these therapeutic options in MTP inhibition-related liver damage, such proposed approaches may be further explored in the future for their use in preventing unwanted effects of MTP inhibitors. PMID- 24627314 TI - Vascunet registry validated. PMID- 24627313 TI - Autoantibodies and biomarkers of endothelial cell activation in atherosclerosis. PMID- 24627315 TI - Pathogenesis of varicose veins - lessons from biomechanics. AB - The development of varicose veins or chronic venous insufficiency is preceded by and associated with the pathophysiological remodelling of the venous wall. Recent work suggests that an increase in venous filling pressure is sufficient to promote varicose remodelling of veins by augmenting wall stress and activating venous endothelial and smooth muscle cells. In line with this, known risk factors such as prolonged standing or an obesity-induced increase in venous filling pressure may contribute to varicosis. This review focuses on biomechanically mediated mechanisms such as an increase in wall stress caused by venous hypertension or alterations in blood flow, which may be involved in the onset of varicose vein development. Finally, possible therapeutic options to counteract or delay the progress of this venous disease are discussed. PMID- 24627316 TI - Technique and clinical evidence of neuroprotection in carotid artery stenting. AB - Carotid artery stenting has been advocated as an effective alternative to carotid endarterectomy. Periprocedural embolization of debris during endovascular treatment of carotid artery disease may result in neurological deficit. Different strategies are being developed and evaluated for their ability to minimize the clinical embolic risk. Distal filter devices, proximal and distal balloon occlusion systems are increasingly used in carotid artery stenting, because they seem to be safe and effective in preventing distal embolization, according to several uncontrolled studies. However the use of embolic protection devices is a subject of controversy and no data on their benefit are available from randomized controlled multi-center trials. The technique and clinical evidence of cerebral protection systems during carotid angioplasty and stenting for stroke prevention are reviewed. PMID- 24627317 TI - In arterial occlusive disease autoantibodies against ETAR and AT(1)R correlate with each other but are not associated with classical cardiovascular risk factors. AB - BACKGROUND: Autoantibodies (Abs) against angiotensin-II type 1 (AT(1)R) and endothelin-1 type A receptors (ETAR) are investigated in the present study as B cell originated humoral factors that may activate the respective receptors on endothelial cells. The prevalence of the Abs was determined in patients with peripheral arterial occlusive disease (PAD). PATIENTS AND METHODS: In a prospective observational study 200 patients undergoing angiography and proven advanced PAD were enrolled. Serum samples, clinical data and laboratory values for classical cardiovascular risk factors were collected. Autoantibody titers for AT(1)R and ETAR were determined by solid-phase ELISA and correlative analyses with laboratory parameters and clinical data for common cardiovascular risk factors were performed. RESULTS: Anti-ETAR antibody titers were detected in 57 % of the patients, elevated anti-AT(1)R titers in 61.5 %. About 50 % were positive for both Abs. A strong intercorrelation between ETAR and AT(1)R titers was present (r2 0.79). In patients with positive titers for both Abs females presented significantly higher titers for ETAR (p = 0.045) and AT(1)R (p = 0.02). Autoantibody titers directed against surface receptors ETA and AT(1) are highly correlated in PAD. Titers were independent from classical risk factors in any patient subgroup. CONCLUSIONS: This study opens a new perspective on the involvement of the immune system, hereby represented by functional autoantibodies, in the atherosclerotic pathophysiology, leaving behind the common background of classical risk factors. PMID- 24627318 TI - Effects of enoxaparin and dalteparin on proliferation and migration of patient derived vascular smooth muscle cells. AB - BACKGROUND: Proliferation and migration are the two main processes of intimal hyperplasia: the primary cause of intermediate and late vascular graft failure. Low-molecular-weight heparins (LMWHs) inhibit these processes on vascular smooth muscle cells (VSMCs) in animal models, but have failed to improve patency of vascular grafts in clinical trials. Despite these findings, they are still used therapeutically to reduce intimal hyperplasia following vascular interventions. This study was designed to investigate the effects of LMWHs compared to unfractioned heparin in patient-derived VSMCs. MATERIAL AND METHODS: Arterial patient-derived VSMCs were used to study the effects of enoxaparin and dalteparin on proliferation, migration and mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) signal transduction. The VSMCs were treated with the LMWHs in a range of concentrations and evaluated using image based cell enumeration, real time migration monitoring and flow cytometry. Series treated with unfractioned heparin were included as positive controls and untreated series as negative controls. RESULTS: Neither enoxaparin nor dalteparin influenced proliferation and MAPK-ERK phosphorylation. Migration was reduced slightly by both LMWHs. Unfractioned heparin exhibited dose-dependent effects different from those of the LMWHs in all analyses. CONCLUSIONS: This study demonstrated a difference in proliferative and migratory effects between the two LMWHs and unfractioned heparin in patient-derived VSMCs. The effects corresponded to the MAPK-ERK activation, suggesting different mechanisms of action. These results can explain why clinical trials using LMWHs to prevent intimal hyperplasia have failed to observe a reduced incidence of restenosis and do not support prolonged therapeutic use to prevent intimal hyperplasia. PMID- 24627319 TI - Abdominal aortic calcification and its distribution in normal-sized and aneurysmatic abdominal aortas. AB - BACKGROUND: Multi-detector computed tomography (MDCT) is more and more used for evaluation and quantification of coronary artery calcification, but correlation between the degree of calcification and occurrence of clinical events is also known for other vascular beds such as the aorta. PURPOSE: To assess possible differences in amount and pattern of calcification in aneurysmatic and non aneurysmatic abdominal aortas. PATIENTS AND METHODS: Thirty-four subjects displayed infrarenal abdominal aneurysm (AAA) and were compared to 33 patients with normal-sized aortas using MDCT. Quantitative and qualitative analysis was performed by two radiologists. Calcium scores were assessed for the whole abdominal aorta as well as separately for the supra- and infrarenal segments. Moreover, plaque patterns were evaluated and classified according to their thickness and size. Furthermore, calcium scores were correlated with a number of cardiovascular risk factors. RESULTS: Total calcium scores were comparable in patients with and without AAA (1,213 +/- 1,351 and 1,211 +/- 1,535, respectively), but significant differences were found regarding plaque density that was considerably higher both in the supra- and infrarenal segments in the non-aneurysmatic group (AAA: suprarenal, 0.01, infrarenal, 0.07; non-AAA: suprarenal, 0.06, infrarenal, 0.16). Plaque pattern were considerably different in the infrarenal segments in aneurysmatic aortas: they were thinner (1 and 2 mm) and smaller (< 100 mm2) than in normal-sized aortas (mainly > 3mm and > 100 mm2). Distribution of risk factors was similar in both groups with the highest mean calcium score being present in patients with 4 risk factors. Pearson's correlation coefficient indicating correlation between total calcium score and number of risk factors was almost the same in both groups: AAA, r = 0.67; non AAA, r = 0.65. CONCLUSIONS: Compared to normal-sized aortas thinner and smaller plaques are present in AAA, which may be due to degenerative processes. PMID- 24627320 TI - Validation of the VASCUNET registry - pilot study. AB - BACKGROUND: VASCUNET is an international registry of vascular surgical (open and endovascular) procedures since 1997. The aim of this paper is to describe a pilot validation performed at three hospitals in Hungary in September 2012. PATIENTS AND METHODS: Three core indications were checked: abdominal aortic aneurysm, carotid artery disease and limb ischemia with infrainguinal treatment. RESULTS: 2439 registered procedures had been reported with between 94 and 109 per cent agreement with hospital administrative numbers. In a random sample of 29 patients the VASCUNET data were compared with the patient records regarding risk factors, procedures performed and in hospital results. Only few discrepancies were found. CONCLUSIONS: The conclusions are that validation is feasible, that this pilot project in Hungary showed good agreement between registry and local patient records. For a registry to be accepted and used both for practical and scientific purposes regular validation by senior surgeons should be undertaken and the vascular surgical community must have a budget for such a process. PMID- 24627321 TI - Acute ischemia of the lower leg caused by granulomatosis with polyangiitis. PMID- 24627322 TI - An uncommon cause of abdominal pain and weight loss: the superior mesenteric artery syndrome. PMID- 24627323 TI - A giant pulmonary arteriovenous malformation without hereditary hemorrhagic telangiectasia: successful interventional embolization using a PDA occluder. PMID- 24627325 TI - Rehabilitation after lumbar disc surgery. AB - BACKGROUND: Several rehabilitation programmes are available for individuals after lumbar disc surgery. OBJECTIVES: To determine whether active rehabilitation after lumbar disc surgery is more effective than no treatment, and to describe which type of active rehabilitation is most effective. This is the second update of a Cochrane Review first published in 2002.First, we clustered treatments according to the start of treatment.1. Active rehabilitation that starts immediately postsurgery.2. Active rehabilitation that starts four to six weeks postsurgery.3. Active rehabilitation that starts longer than 12 months postsurgery.For every cluster, the following comparisons were investigated.A. Active rehabilitation versus no treatment, placebo or waiting list control.B. Active rehabilitation versus other kinds of active rehabilitation.C. Specific intervention in addition to active rehabilitation versus active rehabilitation alone. SEARCH METHODS: We searched CENTRAL (2013, Issue 4) and MEDLINE, EMBASE, CINAHL, PEDro and PsycINFO to May 2013. SELECTION CRITERIA: We included only randomised controlled trials (RCTs). DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed studies for eligibility and risk of bias. Meta-analyses were performed if studies were clinically homogeneous. The GRADE approach was used to determine the overall quality of evidence. MAIN RESULTS: In this update, we identified eight new studies, thereby including a total of 22 trials (2503 participants), 10 of which had a low risk of bias. Most rehabilitation programmes were assessed in only one study. Both men and women were included, and overall mean age was 41.4 years. All participants had received standard discectomy, microdiscectomy and in one study standard laminectomy and (micro)discectomy. Mean duration of the rehabilitation intervention was 12 weeks; eight studies assessed six to eight week exercise programmes, and eight studies assessed 12 to 13-week exercise programmes. Programmes were provided in primary and secondary care facilities and were started immediately after surgery (n = 4) or four to six weeks (n = 16) or one year after surgery (n = 2). In general, the overall quality of the evidence is low to very low. Rehabilitation programmes that started immediately after surgery were not more effective than their control interventions, which included exercise. Low- to very low-quality evidence suggests that there were no differences between specific rehabilitation programmes (multidisciplinary care, behavioural graded activity, strength and stretching) that started four to six weeks postsurgery and their comparators, which included some form of exercise. Low-quality evidence shows that physiotherapy from four to six weeks postsurgery onward led to better function than no treatment or education only, and that multidisciplinary rehabilitation co-ordinated by medical advisors led to faster return to work than usual care. Statistical pooling was performed only for three comparisons in which the rehabilitation programmes started four to six weeks postsurgery: exercise programmes versus no treatment, high- versus low-intensity exercise programmes and supervised versus home exercise programmes. Very low quality evidence (five RCTs, N = 272) shows that exercises are more effective than no treatment for pain at short-term follow-up (standard mean difference (SMD) -0.90; 95% confidence interval (CI) -1.55 to -0.24), and low-quality evidence (four RCTs, N = 252) suggests that exercises are more effective for functional status on short-term follow-up (SMD -0.67; 95% CI -1.22 to -0.12) and that no difference in functional status was noted on long-term follow-up (three RCTs, N = 226; SMD -0.22; 95% CI -0.49 to 0.04). None of these studies reported that exercise increased the reoperation rate. Very low-quality evidence (two RCTs, N = 103) shows that high-intensity exercise programmes are more effective than low-intensity exercise programmes for pain in the short term (weighted mean difference (WMD) -10.67; 95% CI -17.04 to -4.30), and low-quality evidence (two RCTs, N = 103) shows that they are more effective for functional status in the short term (SMD -0.77; 95% CI -1.17 to -0.36). Very low-quality evidence (four RCTs, N = 154) suggests no significant differences between supervised and home exercise programmes for short-term pain relief (SMD -0.76; 95% CI -2.04 to 0.53) or functional status (four RCTs, N = 154; SMD -0.36; 95% CI -0.88 to 0.15). AUTHORS' CONCLUSIONS: Considerable variation was noted in the content, duration and intensity of the rehabilitation programmes included in this review, and for none of them was high- or moderate-quality evidence identified. Exercise programmes starting four to six weeks postsurgery seem to lead to a faster decrease in pain and disability than no treatment, with small to medium effect sizes, and high-intensity exercise programmes seem to lead to a slightly faster decrease in pain and disability than is seen with low-intensity programmes, but the overall quality of the evidence is only low to very low. No significant differences were noted between supervised and home exercise programmes for pain relief, disability or global perceived effect. None of the trials reported an increase in reoperation rate after first-time lumbar surgery. High-quality randomised controlled trials are strongly needed. PMID- 24627326 TI - Therapeutic ultrasound for chronic low-back pain. AB - BACKGROUND: Chronic non-specific low-back pain (LBP) has become one of the main causes of disability in the adult population around the world. Therapeutic ultrasound is frequently used by physiotherapists in the treatment of LBP and is one of the most widely used electro-physical agents in clinical practice. OBJECTIVES: The objective of this review is to determine the effectiveness of therapeutic ultrasound in the management of chronic non-specific LBP. SEARCH METHODS: Electronic searches were performed using CENTRAL, MEDLINE, EMBASE, PEDro, and PsycLIT databases in October 2013. Reference lists of eligible studies and relevant systematic reviews were checked and forward citation searching was also performed. SELECTION CRITERIA: Randomised controlled trials on therapeutic ultrasound for non-specific chronic LBP were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias of each trial and extracted the data. When sufficient clinical and statistical homogeneity existed, a meta-analysis was performed. The quality of the evidence for each comparison was determined using the GRADE approach. MAIN RESULTS: Seven small randomised controlled trials involving a total of 362 participants with chronic LBP were included. Two of the studies had a low risk of bias, meeting six or more of the 12 criteria used for assessing risk of bias. All studies were carried out in secondary care settings and most applied therapeutic ultrasound in addition to exercise therapy, at various intensities for six to 18 treatment sessions. There was moderate quality evidence that therapeutic ultrasound improves back-specific function (standardised mean difference (SMD) [95%CI] -0.45 [-0.84 to -0.05]) compared with placebo in the short term. There was low quality evidence that therapeutic ultrasound is no better than placebo for short-term pain improvement (mean difference (MD) [95%CI] -7.12 [-17.99 to 3.75]; zero to100 point scale). There was low quality evidence that therapeutic ultrasound plus exercise is no better than exercise alone for short-term pain improvement (MD [95%CI] -2.16 [-4.66 to 0.34]; zero to 50-point scale), or functional disability (MD [95%CI] -0.41 [-3.14 to 2.32]; per cent). The studies comparing therapeutic ultrasound versus placebo or versus exercise alone did not report on overall satisfaction with treatment, or quality of life. There was low quality evidence that spinal manipulation reduces pain and functional disability more than ultrasound over the short to medium term. There is also very low quality evidence that there is no clear benefit on any outcome measure between electrical stimulation and therapeutic ultrasound; and that phonophoresis results in improved SF-36 scores compared to therapeutic ultrasound. None of the included studies reported on adverse events related to the application of therapeutic ultrasound. AUTHORS' CONCLUSIONS: No high quality evidence was found to support the use of ultrasound for improving pain or quality of life in patients with non specific chronic LBP. There is some evidence that therapeutic ultrasound has a small effect on improving low-back function in the short term, but this benefit is unlikely to be clinically important. Evidence from comparisons between other treatments and therapeutic ultrasound for chronic LBP were indeterminate and generally of low quality. Since there are few high quality randomised trials and the available trials are very small, future large trials with valid methodology are likely to have an important impact on our confidence in the estimate of effect and may change the estimate. PMID- 24627327 TI - Practical considerations for volumetric wear analysis of explanted hip arthroplasties. AB - OBJECTIVES: Wear debris released from bearing surfaces has been shown to provoke negative immune responses in the recipient. Excessive wear has been linked to early failure of prostheses. Analysis using coordinate measuring machines (CMMs) can provide estimates of total volumetric material loss of explanted prostheses and can help to understand device failure. The accuracy of volumetric testing has been debated, with some investigators stating that only protocols involving hundreds of thousands of measurement points are sufficient. We looked to examine this assumption and to apply the findings to the clinical arena. METHODS: We examined the effects on the calculated material loss from a ceramic femoral head when different CMM scanning parameters were used. Calculated wear volumes were compared with gold standard gravimetric tests in a blinded study. RESULTS: Various scanning parameters including point pitch, maximum point to point distance, the number of scanning contours or the total number of points had no clinically relevant effect on volumetric wear calculations. Gravimetric testing showed that material loss can be calculated to provide clinically relevant degrees of accuracy. CONCLUSIONS: Prosthetic surfaces can be analysed accurately and rapidly with currently available technologies. Given these results, we believe that routine analysis of explanted hip components would be a feasible and logical extension to National Joint Registries. Cite this article: Bone Joint Res 2014;3:60-8. PMID- 24627328 TI - Regulation of alternative splicing of tau exon 10. AB - The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer's disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4Rtau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology) only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies. PMID- 24627329 TI - Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease. AB - Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer's disease (AD); however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented. PMID- 24627330 TI - Dementia studies in Chinese populations. AB - Variations in the prevalence of dementia in different ethnic groups have been reported worldwide, and a number of reviews have provided a picture of epidemiological studies in dementia research. However, little is known about epidemiological studies in Chinese populations. In this review, we searched PubMed and the Web of Science for original research articles published in English up to July 2013 on the prevalence, incidence, risk factors, and prognosis of dementia in Chinese populations worldwide. Except for the prevalence, we included only population-based follow-up studies. We identified 25 studies in elderly Chinese residents in Mainland China, Hong Kong, Taiwan, and Singapore, and found a higher prevalence of dementia in Mainland China than in the other locations, which may be due to that the studies from Mainland China are more recent than those from other locations. A notable increase in incidence was observed when dementia cases were diagnosed using 10/66 diagnostic criteria compared to other criteria. Studies on risk factors for dementia were limited and mostly from Mainland China. Age, gender, education, smoking, and alcohol consumption were related to the risk of dementia in Chinese populations. Only two prognostic studies were identified, and age, gender, and residential area were related to the prognosis of dementia. In conclusion, the prevalence, incidence, and risk factors for dementia found in Chinese populations were comparable to other ethnic groups, but no conclusive results on prognosis were found. The differences in prevalence and incidence were influenced by the diagnostic criteria and the time of study. Longitudinal population-based studies on the incidence, risk factors, and prognosis of dementia in Chinese populations are required. PMID- 24627331 TI - Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: results from the TRACER trial. AB - BACKGROUND: This study characterized a medically managed population in a non-ST segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo. METHODS: In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization. RESULTS: Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15). CONCLUSIONS: NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results. PMID- 24627332 TI - First case of atypical takotsubo cardiomyopathy in a bilateral lung-transplanted patient due to acute respiratory failure. AB - Takotsubo cardiomyopathy which is characterised by a transient left ventricular wall motion abnormality was first described in 1990. The disease is still not well known, and as such it is suggested that an emotional trigger is mandatory in this disease. We present the case of a 51-year old female patient seven years after bilateral lung transplantation, who developed acute respiratory distress syndrome and subsequently suffered from atypical takotsubo cardiomyopathy with transient severe reduction of ejection fraction and haemodynamic instability needing acute intensive care treatment. Acute respiratory failure has emerged as an important physical trigger factor in takotsubo cardiomyopathy. Little is known about the association of hypoxia and takotsubo cardiomyopathy which can elicit a life-threatening condition requiring acute intensive care. Therefore, experimental studies are needed to investigate the role of hypoxia in takotsubo cardiomyopathy. PMID- 24627333 TI - Bilateral priming before wii-based movement therapy enhances upper limb rehabilitation and its retention after stroke: a case-controlled study. AB - BACKGROUND: Motor deficits after a stroke are thought to be compounded by the development of asymmetric interhemispheric inhibition. Bilateral priming was developed to rebalance this asymmetry and thus improve therapy efficacy. OBJECTIVE: This study investigated the effect of bilateral priming before Wii based Movement Therapy to improve rehabilitation after stroke. METHODS: Ten patients who had suffered a stroke (age, 23-77 years; 3-123 months after stroke) underwent a 14-day program of Wii-based Movement Therapy for upper limb rehabilitation. Formal Wii-based Movement Therapy sessions were immediately preceded by 15 minutes of bilateral priming, whereby active flexion-extension of the less affected wrist drove mirror-symmetric passive movements of the more affected wrist through a custom device. Functional movement was assessed at weeks 0 (before therapy), 3 (after therapy), and 28 (follow-up) using the Wolf Motor Function Test (WMFT), upper limb Fugl-Meyer Assessment (FMA), upper limb range of motion, and Motor Activity Log (MAL). Case-matched controls were patients who had suffered a stroke who received Wii-based Movement Therapy but not bilateral priming. RESULTS: Upper limb functional ability improved for both groups on all measures tested. Posttherapy improvement on the FMA for primed patients was twice that of the unprimed patients (37.3% vs 14.6%, respectively) and was significantly better maintained at 28 weeks (P = .02). Improvements on the WMFT and MAL were similar for both groups, but the pattern of change in range of motion was strikingly different. CONCLUSIONS: Bilateral priming before Wii-based Movement Therapy led to a greater magnitude and retention of improvement compared to control, especially measured with the FMA. These data suggest that bilateral priming can enhance the efficacy of Wii-based Movement Therapy, particularly for patients with low motor function after a stroke. PMID- 24627334 TI - Measurement properties of streamlined wolf motor function test in patients at subacute to chronic stages after stroke. AB - BACKGROUND. Previous research using the streamlined Wolf Motor Function Test (SWMFT) has focused either on the 3- to 9-month period or on the >12-month period after stroke and lacked the information for those at 9 to 12 months. Whether SWMFT scores reflect motor deficit and recovery from early to late stages after stroke remains unclear. OBJECTIVE: A retrospective study using the Functional Ability Scale (FAS) was conducted to evaluate whether all SWMFTs items measure the poststroke recovery of upper extremity (UE) motor function and if they could be used for patients within 9 to 12 months after a stroke. METHODS: Rasch analysis was conducted, and data were drawn from patients 3 months to years after a stroke. RESULTS: The continuum of UE motor function in SWMFT-FAS was supported. Subacute patients had the best motor function, followed by the 9- to 12-month group, and then chronic patients. Variation in UE motor function was large (2.35 2.72 logits), and motor abilities of these 3 groups overlapped. The 8 SWMFT items could target a broad range of UE motor function, from -8.28 to 7.80 logits. The average difficulty of these 8 items also matched the UE motor ability of the subgroup at 9 to 12 months after stroke, and individual versions of the SWMFT performed well to assess the motor ability of this group. CONCLUSIONS: The SWMFTs had sound hierarchical properties. The SWMFT-Chronic or the SWMFT-Subacute could be used to evaluate UE function of this subgroup at 9 to 12 months after stroke. PMID- 24627335 TI - Is the recovery of functional balance and mobility accompanied by physiological recovery in people with severe impairments after stroke? AB - BACKGROUND: Rehabilitation after severe stroke is often limited because of impairments in sensorimotor function. Functional and physiological recovery after severe stroke is poorly understood and has not been studied extensively. OBJECTIVE: This study's purpose was to examine functional and physiological recovery of standing balance during inpatient rehabilitation in people with severe impairments after stroke. METHODS: A total of 10 participants with severe impairments after stroke were evaluated monthly in a stroke rehabilitation unit with the following functional outcome measures: Berg Balance Scale (BBS), Clinical Outcome Variables Scale (COVS), and Chedoke McMaster Stroke Assessment (CMSA). Weight bearing (WB), center of pressure (COP) velocity, and electromyography (EMG) data were collected during quiet standing and during internal perturbation with a rapid nonparetic arm raise. RESULTS: Cross sectionally, there were moderate to strong correlations for EMG area and WB with CMSA and COVS. Additionally, the BBS was correlated with WB on the paretic side. Longitudinally, statistically significant improvement was found for functional measures but not for physiological measures. The mean BBS and COVS improved by 23 and 21 points, respectively. COP velocity decreased by 60.1% on the paretic leg but not significantly. CONCLUSIONS: During stroke rehabilitation, all participants improved functionally. Some patients improved physiologically, though near discharge, all participants remained very impaired. Future studies with larger sample sizes are needed to explore the capacity for physiological recovery in this population. PMID- 24627336 TI - Two common tests of dexterity can stratify upper limb motor function after stroke. AB - BACKGROUND: Neurological deficits after a stroke are commonly classified according to motor function for clinical decision making regarding discharge and rehabilitation. Participants in clinical stroke studies are also stratified by motor function to avoid a sampling bias. OBJECTIVE: This post hoc analysis examined a suite of upper limb functional assessment tools to test the hypothesis that motor function of survivors of stroke can be stratified using 2 simple tests of manual dexterity despite the heterogeneity of the population. METHODS: The functional ability of the more affected hand and arm was assessed for 67 hemiparetic patients, aged 18 to 83 years (mean +/- standard deviation, 59.8 +/- 14.0 years), at 1 to 264 months after a stroke (23.6 +/- 39.6 months) using the Wolf Motor Function Test (WMFT), upper limb motor Fugl-Meyer Assessment (F-M), Box and Block Test (BBT), grooved pegboard test, and wrist range of motion. We tested the strength of our proposed stratification scheme with a hypothesis driven hierarchical cluster analysis using standardized raw scores and dichotomous BBT and grooved pegboard test values. RESULTS: The most salient discriminator between low and higher motor function was the ability to move >1 block on the BBT. Within the higher function group, the ability to place all 25 pegs on the grooved pegboard test discriminated between moderate and high motor function. The derived scheme was congruent with clinical observations. The WMFT timed tasks, F-M scores, and range of motion did not discriminate functional groups. CONCLUSIONS: Two simple unambiguous and objective tests of gross (BBT) and fine (grooved pegboard test) manual dexterity discriminated 3 groups of motor function ability for a heterogeneous group of patients after stroke. PMID- 24627337 TI - Stability of etoposide solutions in disposable infusion devices for day hospital cancer practices. AB - In a context of day hospital care of cancer patients, a protocol combining etoposide and carboplatin is used in paediatrics. Disposable infusion devices can be used to improve patient quality of life and to optimize nursing time. Stability data are available for carboplatin in these devices but not for etoposide. The aim of this study was to determine the stability of etoposide solutions in these devices by monitoring the changing etoposide concentration. To study the changing etoposide concentration, we investigated three different concentrations, each in two different solvents: sodium chloride (NaCl) 0.9 % and dextrose 5 %, in Intermate((r)) disposable infusion devices. Quantitative analyses were performed by high-performance liquid chromatography coupled with ultraviolet (UV) detection on samples collected over a 24-h study period. The results showed that 100 mg/L etoposide solutions were stable for 24 h in NaCl 0.9 % and for 12 h in dextrose 5 %, whatever the temperature. The 400-mg/L solutions were stable for 24 h in both diluents, whatever the temperature, whereas the 600 mg/L solutions when diluted in NaCl 0.9 % and dextrose 5 % in water were stable for 8 and 6 h, respectively. We found that precipitation was the main phenomenon responsible for decreased etoposide concentrations. This study allowed us to conclude that etoposide solutions prepared in Intermate((r)) infusion devices are stable for day hospital administration in paediatrics. It will also allow us to conduct a future clinical study that will focus on the medico-economic feasibility of this protocol and on the evaluation of patient and nurse satisfaction. PMID- 24627338 TI - Inhibition of matrix metalloproteinase-1 and type-I procollagen expression by phenolic compounds isolated from the leaves of Quercus mongolica in ultraviolet irradiated human fibroblast cells. AB - The aim of this study was to investigate the effect of Quercus mongolica (QM) which induce anti-photoaging process of skin in vitro. Bioassay-guided isolation of 80 % Me2CO extract of the leaves of QM led to the isolation and identification of six known phenolic compounds: pedunculagin (1), (-)-epigallocatechin (2), (+) catechin (3), quercetin 3-O-(6"-O-galloyl)-beta-D-glucopyranoside (4), kaempferol 3-O-beta-D-glucopyranoside-7-O-alpha-L-rhamnopyranoside (5) and kaempferol 3-O (6"-galloyl)-beta-D-glucopyranoside (6). The effects of compounds 1-6 on expression of matrix metalloproteinase-1 (MMP-1) and type-I procollagen were further evaluated. Among them, compound 1 showed potent inhibitory effect on MMP 1 and the increased type-I procollagen synthesis in ultraviolet B-induced human fibroblast. These results suggest that pedunculagin, an ellagitannin, is a potential candidate for the prevention and treatment of skin aging. PMID- 24627339 TI - Bioequivalence of tacrolimus formulations with different dynamic solubility and in-vitro dissolution profiles. AB - This study was to evaluate the pharmacokinetics and bioequivalence of two tacrolimus formulations which had different in vitro drug release profiles. Dynamic solubility, in vitro dissolution profiles of the two formulations, and their influence on pharmacokinetics were examined. The male volunteers were randomly assigned to receive a single 1-mg capsule of the test or reference formulation and pharmacokinetic parameters were determined using a noncompartmental method. The two formulations released >85 % of tacrolimus in water within 30 min, which passed the criterion of evaluating the test formulation. However, the test formulation produced a faster initial release rate and plateaued in about 15 min, while the reference showed almost zero order initial release profiles. The AUC0-infinity values were 145.92 (reference) and 140.49 ng h/mL (test). The mean Cmax was 15.70 (reference) and 16.08 ng/mL (test) with Tmax values of 1.63 and 1.60 h, respectively. The t1/2 for the reference and test formulations was 29.12 and 27.85 h, respectively. Relative bioavailability was calculated to be 96.28 %. The point estimates for the mean ratio of the test to reference for the AUC0-t and Cmax were 0.969 and 1.026, respectively, satisfying the criterion for bioequivalence. The results suggest that the test formulation is pharmacokinetically equivalent to the reference in terms of both rate and extent of absorption. Even though the in vitro dissolution profiles of the formulations might not be equivalent, the pharmacokinetics indicated bioequivalence. Therefore, when developing poorly soluble drugs, it might be beneficial to pay attention to the dynamic solubility as well as dissolution profiles. PMID- 24627340 TI - An integrative 'omics' solution to the detection of recombinant human erythropoietin and blood doping. AB - Administration of recombinant human erythropoietin (rHumanEPO) improves sporting performance and hence is frequently subject to abuse by athletes, although rHumanEPO is prohibited by the WADA. Approaches to detect rHumanEPO doping have improved significantly in recent years but remain imperfect. A new transcriptomic based longitudinal screening approach is being developed that has the potential to improve the analytical performance of current detection methods. In particular, studies are being funded by WADA to identify a 'molecular signature' of rHumanEPO doping and preliminary results are promising. In the first systematic study to be conducted, the expression of hundreds of genes were found to be altered by rHumanEPO with numerous gene transcripts being differentially expressed after the first injection and further transcripts profoundly upregulated during and subsequently downregulated up to 4 weeks postadministration of the drug; with the same transcriptomic pattern observed in all participants. The identification of a blood 'molecular signature' of rHumanEPO administration is the strongest evidence to date that gene biomarkers have the potential to substantially improve the analytical performance of current antidoping methods such as the Athlete Biological Passport for rHumanEPO detection. Given the early promise of transcriptomics, research using an 'omics' based approach involving genomics, transcriptomics, proteomics and metabolomics should be intensified in order to achieve improved detection of rHumanEPO and other doping substances and methods difficult to detect such a recombinant human growth hormone and blood transfusions. PMID- 24627341 TI - When to use discrete event simulation (DES) for the economic evaluation of health technologies? A review and critique of the costs and benefits of DES. AB - Modelling in economic evaluation is an unavoidable fact of life. Cohort-based state transition models are most common, though discrete event simulation (DES) is increasingly being used to implement more complex model structures. The benefits of DES relate to the greater flexibility around the implementation and population of complex models, which may provide more accurate or valid estimates of the incremental costs and benefits of alternative health technologies. The costs of DES relate to the time and expertise required to implement and review complex models, when perhaps a simpler model would suffice. The costs are not borne solely by the analyst, but also by reviewers. In particular, modelled economic evaluations are often submitted to support reimbursement decisions for new technologies, for which detailed model reviews are generally undertaken on behalf of the funding body. This paper reports the results from a review of published DES-based economic evaluations. Factors underlying the use of DES were defined, and the characteristics of applied models were considered, to inform options for assessing the potential benefits of DES in relation to each factor. Four broad factors underlying the use of DES were identified: baseline heterogeneity, continuous disease markers, time varying event rates, and the influence of prior events on subsequent event rates. If relevant, individual level data are available, representation of the four factors is likely to improve model validity, and it is possible to assess the importance of their representation in individual cases. A thorough model performance evaluation is required to overcome the costs of DES from the users' perspective, but few of the reviewed DES models reported such a process. More generally, further direct, empirical comparisons of complex models with simpler models would better inform the benefits of DES to implement more complex models, and the circumstances in which such benefits are most likely. PMID- 24627342 TI - Unraveling vitamin B12-responsive gene regulation in algae. AB - Photosynthetic microalgae play a vital role in primary productivity and biogeochemical cycling in both marine and freshwater systems across the globe. However, the growth of these cosmopolitan organisms depends on the bioavailability of nutrients such as vitamins. Approximately one-half of all microalgal species requires vitamin B12 as a growth supplement. The major determinant of algal B12 requirements is defined by the isoform of methionine synthase possessed by an alga, such that the presence of the B12-independent methionine synthase (METE) enables growth without this vitamin. Moreover, the widespread but phylogenetically unrelated distribution of B12 auxotrophy across the algal lineages suggests that the METE gene has been lost multiple times in evolution. Given that METE expression is repressed by the presence of B12, prolonged repression by a reliable source of the vitamin could lead to the accumulation of mutations and eventually gene loss. Here, we probe METE gene regulation by B12 and methionine/folate cycle metabolites in both marine and freshwater microalgal species. In addition, we identify a B12-responsive element of Chlamydomonas reinhardtii METE using a reporter gene approach. We show that complete repression of the reporter occurs via a region spanning -574 to -90 bp upstream of the METE start codon. A proteomics study reveals that two other genes (S-Adenosylhomocysteine hydrolase and Serine hydroxymethyltransferase2) involved in the methionine-folate cycle are also repressed by B12 in C. reinhardtii. The strong repressible nature and high sensitivity of the B12-responsive element has promising biotechnological applications as a cost-effective regulatory gene expression tool. PMID- 24627343 TI - Recurrent metastatic anal cancer treated with modified paclitaxel, ifosfamide, and cisplatin and third-line mitomycin/cetuximab. AB - PURPOSE: Squamous cell carcinoma represents approximately 75% of all anal cancers. Squamous cell carcinoma of the anal canal is a rare malignancy often curable in the early stages with the combined modality therapy of chemoradiation. Treatment in the metastatic setting is challenging due to the rarity of metastatic disease with the majority of patients presenting with curative locally advanced disease, and the ability to design clinical trials for metastatic disease has yet to be explored. There are no established chemotherapy guidelines for patients with metastatic anal cancer after the failure of cisplatin and fluorouracil. METHODS: We used PubMed and OVID research engines to identify publications in English literature addressing treatments/therapeutics using the following keywords "metastatic anal cancer" and "metastatic squamous cell carcinoma of anus" in addition to reviewing related clinical trials in clinicaltrials.gov. RESULTS: We hereby report our experience in using aggressive combinations in the second- and third-line settings. A 49-year-old white male diagnosed with T3 N3 M0 Stage IIIB anal cancer was treated initially with surgical excision and adjuvant fluorouracil/cisplatin due unavailability of mitomycin. He developed metastatic disease to the skin and perianal region, was treated with four cycles of paclitaxel, ifosfamide, and cisplatin with growth factor support, and achieved minimal residual disease. On progression five months after finishing therapy, we treated him with mitomycin and cetuximab with mixed response after two cycles. The patient later elected to proceed with hospice care only and succumbed to his disease 16 months after first cycle of paclitaxel, ifosfamide, and cisplatin and 24 months from diagnosis. CONCLUSIONS: Paclitaxel, ifosfamide, and cisplatin is highly active in metastatic setting in selected patients. Cetuximab based regimen can be valuable option as second or third line. Paclitaxel, ifosfamide, and cisplatin and mitomycin and cetuximab can be available options for unmet need in metastatic anal cancer. PMID- 24627344 TI - Differential effects of variation in athletes training on myocardial morphophysiological adaptation in men: focus on 123I-MIBG assessed myocardial sympathetic activity. AB - PURPOSE: High intensity systematic physical training leads to myocardial morphophysiological adaptations. The goal of this study was to investigate if differences in training were correlated with differences in cardiac sympathetic activity. METHODS: 58 males (19-47 years), were divided into three groups: strength group (SG), (20 bodybuilders), endurance group (EG), (20 endurance athletes), and a control group (CG) comprising 18 healthy non-athletes. Cardiac sympathetic innervation was assessed by planar myocardial (123)I metaiodobenzylguanidine scintigraphy using the early and late heart to mediastinal (H/M) ratio, and washout rate (WR). RESULTS: Left ventricular mass index was significantly higher both in SG (P < .001) and EG (P = .001) compared to CG without a statistical significant difference between SG and EG (P = .417). The relative wall thickness was significantly higher in SG compared to CG (P < .001). Both left ventricular ejection fraction and the peak filling rate showed no significant difference between the groups. Resting heart rate was significantly lower in EG compared to CG (P = .006) and SG (P = .002). The late H/M ratio in CG was significantly higher compared to the late H/M for SG (P = .003) and EG (P = .004). However, WR showed no difference between the groups. There was no significant correlation between the parameters of myocardial sympathetic innervation and parameters of left ventricular function. CONCLUSIONS: Strength training resulted in a significant increase in cardiac dimensions. Both strength and endurance training seem to cause a reduction in myocardial sympathetic drive. However, myocardial morphological and functional adaptations to training were not correlated with myocardial sympathetic activity. PMID- 24627345 TI - Atherosclerotic plaque uptake of a novel integrin tracer 18F-Flotegatide in a mouse model of atherosclerosis. AB - INTRODUCTION: Rupture of unstable atherosclerotic plaque that leads to stroke and myocardial infarction may be induced by macrophage infiltration and neovessel formation. A tracer that selectively binds to integrin alphavbeta3 a protein expressed by macrophages and neovascular endothelium may identify rupture prone plaque. METHODS: (18)F-labeled "R-G-D" containing tripeptide (Flotegatide), a click chemistry derived radiotracer that binds to integrin alphavbeta3 was injected in ApoE knockout mice fed a high fat diet. Uptake of Flotegatide by atherosclerotic plaque was visualized by micro-PET, autoradiography, and correlated to histologic markers of inflammation and angiogenesis. RESULTS: We found that Flotegatide preferentially binds to aortic plaque in an ApoE knockout mouse model of atherosclerosis. The tracer's uptake is strongly associated with presence of histologic markers for macrophage infiltration and integrin expression. There is a weaker but detectable association between Flotegatide uptake and presence of an immunohistochemical marker for neovascularization. DISCUSSION: We hypothesize that Flotegatide may be a useful tracer for visualization of inflamed plaque in clinical subjects with atherosclerosis and may have potential for detecting vulnerable plaque. PMID- 24627346 TI - Inappropriate utilization of SPECT myocardial perfusion imaging on the USA-Mexico border. AB - BACKGROUND: The American College of Cardiology/American Society of Nuclear Cardiology published revised appropriate use criteria (AUC) for SPECT MPI in 2009. We assessed adherence to these guidelines and factors associated with inappropriate utilization at the University Medical Center. METHODS: The AUC was applied retrospectively to 420 SPECT MPI studies. Two-sample t test, Fisher's exact test, and multivariable logistic regression models were used for analysis. RESULTS: There were 322 appropriate (86%) and 54 (14%) inappropriate studies. The odds of having an inappropriate test increased with younger age (P < .001) and female gender (P < .001). Subjects with diabetes (P = .007) and chest pain (P < .001) were less likely to have an inappropriate test. Academic outpatients were three times more likely to have an inappropriate study (P = .123), while community PCPs were 5.6 times (P = .011) and community cardiologists eight times more likely to order inappropriate tests (P = .031). CONCLUSIONS: Inappropriate SPECT MPI in low risk younger women is an important issue on the USA-Mexico border. Initiatives to reduce inappropriate SPECT MPI should focus on a few indications and evaluation of cardiovascular symptoms in younger age women in outpatient/community practices. PMID- 24627347 TI - Experience of low-dose aminophylline use to relieve minor adverse effects of dipyridamole in patients undergoing stress myocardial perfusion imaging. AB - BACKGROUND: Intravenous administration of aminophylline is widely adopted to reverse dipyridamole-related adverse effects (AEs) during stress myocardial perfusion imaging (MPI). The study aimed to investigate the efficacy of lower dose aminophylline to relieve minor AEs. METHODS: 2,250 consecutive patients undergoing dipyridamole-stressed MPI were enrolled. Information concerning AE occurrence and dosages of aminophylline was collected to evaluate the efficacy of lower-dose aminophylline. A logistic regression was used to determine independent predictors of dipyridamole-related AE occurrence. RESULTS: No severe AE was noted. Overall mild AE incidence was 37.0% (833/2,250 patients). Initial low-dose (25 mg) aminophylline relieved symptoms in 98.8% of patients with mild AEs (823/833 patients). An extra 25 mg aminophylline sufficed to reverse all such AEs. Mean body mass index (BMI) differed significantly between patients with and without any AE [25.6 vs 25.1 (P = .009)]. There was no significant difference between two subgroups in mean age, male gender prevalence, body height and weight, dipyridamole dose/BMI, or prevalence of significant perfusion defect(s) on MPI. Multivariable logistic regression demonstrated BMI remained the independent predictor of dipyridamole-related AE occurrence (odds ratio 1.028, 95% confidence interval 1.007-1.049, P = .01). CONCLUSION: Low-dose (?50 mg, and usually 25 mg) aminophylline seems sufficient to relieve mild dipyridamole related AEs during stress MPI. PMID- 24627348 TI - Modulation of the secretory pathway rescues zebrafish polycystic kidney disease pathology. AB - Mutations in polycystin 1 and polycystin 2 are responsible for autosomal dominant polycystic kidney disease, the most common heritable human disease. Polycystins function as calcium ion channels, but their impact on cell physiology is not fully known. Recent findings suggest that polycystins could function in the maintenance of extracellular matrix integrity. In zebrafish, polycystin 2 knockdown induces kidney cysts, hydrocephalus, left/right asymmetry defects, and strong dorsal axis curvature. Here, we show that increased notochord sheath collagen deposition in polycystin 2-deficient embryos is directly linked to axis defects. Increased collagen II protein accumulation did not associate with increased col2a1 mRNA or a decrease in matrix metalloproteinase activity but, instead, it associated with increased expression of the endoplasmic reticulum/Golgi transport coat protein complex II Sec proteins. sec24D knockdown prevented dorsal axis curvature and kidney cystogenesis in polycystin 2 morphants. Nontoxic doses of brefeldin A also prevented the dorsal axis curvature formation in polycystin 2 morphants and curly up polycystin 2 mutants. Brefeldin A treatment after the onset of polycystin deficiency phenotypes reversed the curved axis phenotype but not kidney cyst progression. Our results suggest that polycystin 2 deficiency causes increased collagen II synthesis with upregulation of secretory pathway coat protein complex II components. Restoration of normal rates of secretory protein synthesis and secretion may be a new target in the treatment of autosomal dominant polycystic kidney disease. PMID- 24627349 TI - BP, cardiovascular disease, and death in the Folic Acid for Vascular Outcome Reduction in Transplantation trial. AB - The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52+/-9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136+/-20 mmHg and mean diastolic BP was 79+/-12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial. PMID- 24627350 TI - BP targets in renal transplant recipients: too high or too low? PMID- 24627351 TI - Does the greater omentum ("policeman of the abdomen") possess therapeutic utility in CKD? PMID- 24627353 TI - How to present statistics in medical journals. PMID- 24627352 TI - Activated omentum slows progression of CKD. AB - Stem cells show promise in the treatment of AKI but do not survive long term after injection. However, organ repair has been achieved by extending and attaching the omentum, a fatty tissue lying above the stomach containing stem cells, to various organs. To examine whether fusing the omentum to a subtotally nephrectomized kidney could slow the progression of CKD, we used two groups of rats: an experimental group undergoing 5/6 nephrectomy only and a control group undergoing 5/6 nephrectomy and complete omentectomy. Polydextran gel particles were administered intraperitoneally before suture only in the experimental group to facilitate the fusion of the omentum to the injured kidney. After 12 weeks, experimental rats exhibited omentum fused to the remnant kidney and had lower plasma creatinine and urea nitrogen levels; less glomerulosclerosis, tubulointerstitial injury, and extracellular matrix; and reduced thickening of basement membranes compared with controls. A fusion zone formed between the injured kidney and the omentum contained abundant stem cells expressing stem cell antigen-1, Wilms' tumor 1 (WT-1), and CD34, suggesting active, healing tissue. Furthermore, kidney extracts from experimental rats showed increases in expression levels of growth factors involved in renal repair, the number of proliferating cells, especially at the injured edge, the number of WT-1-positive cells in the glomeruli, and WT-1 gene expression. These results suggest that contact between the omentum and injured kidney slows the progression of CKD in the remnant organ, and this effect appears to be mediated by the presence of omental stem cells and their secretory products. PMID- 24627354 TI - Older patients have the most to gain from orthopaedic enhanced recovery programmes. AB - BACKGROUND: Between August 2007 and May 2009, 2128 consecutive patients underwent either primary hip or knee joint replacement surgery at our institute on an enhanced recovery pathway. We aimed to investigate the potential benefits of this pathway in patients over the age of 85 years. METHODS: Data extracted from Hospital Episode Statistics were analysed. This data are prospectively collected and independently collated. RESULTS: In all patients median length of stay was reduced when compared with both our own data before the introduction of the pathway (6 to 4 days) and national averages over the same time period for both hip and knee replacements (5 to 4 days). Difference in length of stay was most pronounced in the group of patients aged 85 years and over (9 to 5 days for total hip replacement and 8 to 5 days for total knee replacement). Nearly all patients were discharged directly home (97.4%). Readmission rates were over 45% lower in patients aged 85 and over when compared with national averages (5.2 vs. 9.4%). CONCLUSIONS: This is the first series in the literature to assess the role of enhanced recovery pathways in the very elderly. This study not only shows that successful fast track rehabilitation can be achieved in the very elderly population undergoing elective joint replacement surgery, but that it is this cohort of vulnerable patients who have the most to gain from such multidisciplinary recovery programmes. PMID- 24627355 TI - Exercise- and hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses is reduced in older adults. AB - Mean pulmonary arterial pressure (Ppa) during exercise is significantly higher in individuals aged >=50 yr compared with their younger counterparts, but the reasons for this are unknown. Blood flow through intrapulmonary arteriovenous anastomoses (IPAVA) can be detected during exercise or while breathing hypoxic gas mixtures using saline contrast echocardiography in almost all healthy young individuals. It has been previously hypothesized that a lower degree of exercise induced blood flow through IPAVA is associated with high Ppa during exercise. This association may suggest that individuals who are known to have high Ppa during exercise, such as those >=50 yr of age, may have lower blood flow through IPAVA, but the presence and degree of exercise-induced blood flow through IPAVA has not been specifically studied in older populations. Using transthoracic saline contrast echocardiography, we investigated the potential effects of age on exercise-induced blood flow through IPAVA in a cross-section of subjects aged 19 72 yr. To verify our findings, we assessed the effects of age on hypoxia-induced blood flow through IPAVA. Age groups were <=41 yr (younger, n = 16) and >=50 yr (older, n = 14). Qualitatively measured exercise- and hypoxia-induced blood flow through IPAVA was significantly lower in older individuals compared with younger controls. Older individuals also had significantly higher pulmonary arterial systolic pressure and total pulmonary resistance (TPR) during exercise. Low blood flow through IPAVA was independently associated with high TPR. The reasons for the age-related decrease in blood flow through IPAVA are unknown. PMID- 24627356 TI - Time courses of central hemodynamics during rapid changes in posture. AB - Changes in posture cause blood volume redistribution, affecting cardiac filling and stroke volume (SV). We hypothesized that the time courses of ventricular filling would differ between the right and left ventricle during a rapid (2 s) tilt and that changes in right ventricular filling pressure would be more swift because of the direct coupling to the systemic circulation. We further hypothesized that the transient imbalance between right and left ventricular filling pressure would influence left ventricular SV changes. Right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), left ventricular stroke volume, heart rate, and arterial pressure were recorded beat-by-beat during rapid tilts from supine to upright positions and back again, during rest and dynamic 100-W leg exercise. RAP changes had a faster time course than PCWP during down-tilts, both during rest and exercise (1 +/- 1 vs. 6 +/- 2 s and 2 +/- 2 vs. 6 +/- 2 s, respectively; P < 0.05). This discrepancy caused a transient decrease in the end-diastolic pressure difference between the right and left ventricle. The decreased pressure difference in diastole impeded left ventricular filling because of ventricular interdependence, causing SV to fall transiently. The mechanisms of ventricular interdependence were also involved in reverse during up-tilt, where SV was maintained for 2-3 s despite falling PCWP. Furthermore, the decrease in RAP during up-tilt in the resting condition was biphasic with an initial fast and a second slower component, which might suggest the effect of venous valves. This was not seen during dynamic leg exercise where blood pooling is prevented by the venous muscle pump. PMID- 24627357 TI - Acid-base balance in the developing marsupial: from ectotherm to endotherm. AB - Marsupial joeys are born ectothermic and develop endothermy within their mother's thermally stable pouch. We hypothesized that Tammar wallaby joeys would switch from alpha-stat to pH-stat regulation during the transition from ectothermy to endothermy. To address this, we compared ventilation (Ve), metabolic rate (Vo2), and variables relevant to blood gas and acid-base regulation and oxygen transport including the ventilatory requirements (Ve/Vo2 and Ve/Vco2), partial pressures of oxygen (PaO2), carbon dioxide (PaCO2), pHa, and oxygen content (CaO2) during progressive hypothermia in ecto- and endothermic Tammar wallabies. We also measured the same variables in the well-studied endotherm, the Sprague-Dawley rat. Hypothermia was induced in unrestrained, unanesthetized joeys and rats by progressively dropping the ambient temperature (Ta). Rats were additionally exposed to helox (80% helium, 20% oxygen) to facilitate heat loss. Respiratory, metabolic, and blood-gas variables were measured over a large body temperature (Tb) range (~15-16 degrees C in both species). Ectothermic joeys displayed limited thermogenic ability during cooling: after an initial plateau, Vo2 decreased with the progressive drop in Tb. The Tb of endothermic joeys and rats fell despite Vo2 nearly doubling with the initiation of cold stress. In all three groups the changes in Vo2 were met by changes in Ve, resulting in constant Ve/Vo2 and Ve/Vco2, blood gases, and pHa. Thus, although thermogenic capability was nearly absent in ectothermic joeys, blood acid-base regulation was similar to endothermic joeys and rats. This suggests that unlike some reptiles, unanesthetized mammals protect arterial blood pH with changing Tb, irrespective of their thermogenic ability and/or stage of development. PMID- 24627360 TI - Structural insights into the assembly of a monomeric class V myosin. PMID- 24627358 TI - Variability in anesthetic care for total knee arthroplasty: an analysis from the anesthesia quality institute. AB - Anesthetic practice utilization and related characteristics of total knee arthroplasties (TKAs) are understudied. The research team sought to characterize anesthesia practice patterns by utilizing National Anesthesia Clinical Outcomes Registry data of the Anesthesia Quality Institute. The proportions of primary TKAs performed between January 2010 and June 2013 using general anesthesia (GA), neuraxial anesthesia (NA), and regional anesthesia (RA) were determined. Utilization of anesthesia types was analyzed using anesthesiologist and patient characteristics and facility type. In all, 108 625 eligible TKAs were identified; 10.9%, 31.3%, and 57.9% were performed under RA, NA, and GA, respectively. Patients receiving RA had higher median age and higher frequency of American Society of Anesthesiology score >=3 compared with those receiving other anesthesia types under study. Relative to GA (45.0%), when NA or RA were used, the anesthesiologist was more frequently board certified (75.5% and 62.1%, respectively; P < .0001). Anesthetic technique differences for TKAs exist, with variability associated with patient and provider characteristics. PMID- 24627361 TI - Bioinformatics analysis of time-series genes profiling to explore key genes affected by age in fracture healing. AB - The present study was aimed to explore possible key genes and bioprocess affected by age during fracture healing. GSE589, GSE592 and GSE1371 were downloaded from gene expression omnibus database. The time-series genes of three age levels rats were firstly identified with hclust function in R. Then functional and pathway enrichment analysis for selected time-series genes were performed. Finally, the VennDiagram package of R language was used to screen overlapping n time-series genes. The expression changes of time-series genes in the rats of three age levels were classified into two types: one was higher expressed at 0 day, decreased at 3 day to 2 week, and increased from 4 to 6 week; the other was the opposite. Functional and pathways enrichment analysis showed that 12 time-series genes of adult and old rats were significantly involved in ECM-receptor interaction pathway. The expression changes of 11 genes were consistent with time axis, 10 genes were up-regulated at 3 days after fracture, and increased slowly in 6 week, while Itga2b was down-regulated. The functions of 106 overlapping genes were all associated with growth and development of bone after fracture. The key genes in ECM-receptor interaction pathway including Spp1, Ibsp, Tnn and Col3a1 have been reported to be related to fracture in literatures. The difference during fracture healing in three age levels rats is mainly related to age. The Spp1, Ibsp, Tnn and Col3a1 are possible potential age-related genes and ECM-receptor interaction pathway is the potential age-related process during fracture healing. PMID- 24627366 TI - Unremitting abdominal pain: obscure until the first CT. PMID- 24627367 TI - Supporting continuing professional development. PMID- 24627365 TI - The GABA synapse as a target for antiepileptic drugs: a historical overview focused on GABA transporters. AB - It is clear that normal neuronal function relies on a tight balance between excitatory and inhibitory neurotransmission. Inhibitory signaling through the GABAergic system can be tightly regulated at the level of GABA uptake via GABA transporters (GAT). As such, selectively modulating the GABA uptake process through pharmacological agents has been an area of active investigation over several decades. These studies have demonstrated that inhibition of astroglial, but not neuronal, GATs may be preferred for anticonvulsant action. To date, four distinct GAT subtypes have been identified and efforts to selectively target these transporters have led to the proliferation of pharmacological agents aimed at augmenting extrasynaptic GABA levels. These pharmacological tools have provided novel and informative insight into the role of GABA and GABAergic signaling in the brain, but have also provided critical information concerning the regulation of CNS disorders associated with an imbalance in inhibitory tone, such as epilepsy. One such compound with notable inhibitory effects at GATs, tiagabine, has demonstrated clinical anticonvulsant efficacy, and is, to date, the only approved GAT inhibitor for clinical use. Thus, efforts to identify and develop GAT subtype-specific compounds continue to be an area of active investigation for the management of epilepsy and other CNS disorders. Herein, the historical efforts to elucidate the role of GABA in the synapse, as well as the role of GAT inhibitors as anticonvulsants, are described. PMID- 24627369 TI - Socially repugnant or the standard of care: Is there a distinction between sex selective and ability-selective abortion? PMID- 24627370 TI - Imaging appropriateness criteria: why Canadian family physicians should care. PMID- 24627371 TI - Advancing preventive care with clinical tobacco intervention. PMID- 24627372 TI - Using evidence for the care of practice team populations. PMID- 24627373 TI - Evidence versus expectations. PMID- 24627374 TI - Physicians receiving gifts. PMID- 24627377 TI - Patient therapeutic education: placing the patient at the centre of the WHO analgesic ladder. PMID- 24627378 TI - Risks of untreated depression in pregnancy. AB - QUESTION: In my family practice, I tell my female patients of reproductive age who have depression that untreated depression in pregnancy might be more harmful than the unproven risks of antidepressants. However, I recently read in a national news magazine that there is actually no evidence for this advice. Have I missed something? ANSWER: You did not miss anything, so you should continue to advise your pregnant patients as before. News magazines can have substantial bias, as the reporters often only interview "experts" who support their beliefs, as was probably the case in this article. Most glaringly, in this instance, no perinatal psychiatrists were interviewed and none of the experts were clinically involved with pregnant women. We believe that media statements like the one you mentioned might lead women to abruptly discontinue their antidepressants, putting themselves at risk of relapse, hospitalization, and even suicide. Your balancing role in providing your patient with evidence-based information is critical. PMID- 24627376 TI - Canadian guidelines for acute bacterial rhinosinusitis: clinical summary. AB - OBJECTIVE: To provide a clinical summary of the Canadian clinical practice guidelines for acute bacterial rhinosinusitis (ABRS) that includes relevant considerations for family physicians. QUALITY OF EVIDENCE: Guideline authors performed a systematic literature search and drafted recommendations. Recommendations received both strength of evidence and strength of recommendation ratings. Input from external content experts was sought, as was endorsement from Canadian medical societies (Association of Medical Microbiology and Infectious Disease Canada, Canadian Society of Allergy and Clinical Immunology, Canadian Society of Otolaryngology-Head and Neck Surgery, Canadian Association of Emergency Physicians, and the Family Physicians Airways Group of Canada). MAIN MESSAGE: Diagnosis of ABRS is based on the presence of specific symptoms and their duration; imaging or culture are not needed in uncomplicated cases. Treatment is dependent on symptom severity, with intranasal corticosteroids (INCSs) recommended as monotherapy for mild and moderate cases, although the benefit might be modest. Use of INCSs plus antibiotics is reserved for patients who fail to respond to INCSs after 72 hours, and for initial treatment of patients with severe symptoms. Antibiotic selection must account for the suspected pathogen, the risk of resistance, comorbid conditions, and local antimicrobial resistance trends. Adjunct therapies such as nasal saline irrigation are recommended. Failure to respond to treatment, recurrent episodes, and signs of complications should prompt referral to an otolaryngologist. The guidelines address situations unique to the Canadian health care environment, including actions to take during prolonged wait periods for specialist referral or imaging. CONCLUSION: The Canadian guidelines provide up-to-date recommendations for diagnosis and treatment of ABRS that reflect an evolving understanding of the disease. In addition, the guidelines offer useful tools to help clinicians discern viral from bacterial episodes, as well as optimally manage their patients with ABRS. PMID- 24627379 TI - Effectiveness of riboflavin in pediatric migraine prevention. AB - QUESTION: The rate of migraine diagnosed among children is increasing. Is riboflavin, an alternative to traditional pharmacologic agents, effective and safe for prevention of migraine in children? ANSWER: Because migraine is a very common condition in childhood and adolescence, often contributing to substantial burden of illness, there is increased interest in alternatives to traditional pharmacologic prevention. The expectation is that over-the-counter alternative medication will be less toxic, better tolerated, and have fewer side effects. A few studies in adults show that riboflavin (vitamin B2) might decrease frequency of migraine headaches. It has become common practice to recommend that children try riboflavin to prevent migraine; however, research on riboflavin use in children is inconclusive. PMID- 24627380 TI - Managing patients with a history of substance abuse. PMID- 24627381 TI - Schiotz tonometry. PMID- 24627382 TI - Making your office accessible for patients with mobility impairments. PMID- 24627383 TI - Red reflex: Procedures and assessments video series. PMID- 24627385 TI - Collegial conversations with a Balinese doctor. PMID- 24627386 TI - Manuela Pattison-Bacon MD CCFP. PMID- 24627384 TI - "My approach to this job is...one person at a time": Perceived discordance between population-level quality targets and patient-centred care. AB - OBJECTIVE: To understand the usefulness of audit and feedback among family physicians and examine the barriers to using it to improve quality of care. DESIGN: Qualitative study using in-depth interviews. SETTING: Family physicians across Ontario participating in audit and feedback initiatives describing the proportion of patients meeting quality targets for chronic disease. PARTICIPANTS: Purposive sampling was conducted to ensure variation in sex, years of experience, and baseline performance for quality metrics. All participants used electronic medical records and worked in multidisciplinary primary care practices. METHODS: Semistructured interviews were conducted with family physicians. The interview guide and initial coding framework were adjusted iteratively in keeping with the constant comparative method. Sampling continued until saturation was reached. Interviews were analyzed using the framework approach. MAIN FINDINGS: Participants reported that the feedback increased their awareness of gaps between ideal and actual performance. This resulted mainly in efforts to "try harder" patient by patient. Key barriers to acting upon feedback in a systematic manner included a perceived discordance between population-level quality targets and patient-centred care, as well as competing priorities at both the patient and organizational levels. Although all participants had electronic medical records, participants reported a lack of quality improvement infrastructure in their practices. CONCLUSION: Family physicians were not highly motivated to achieve evidence-based population-level quality targets for diabetes; many competing organizational and clinical goals took priority. Additional human resources might be needed to translate data in feedback reports into systematic changes that could lead to sustained improvements in quality of care. PMID- 24627387 TI - Persona-scenario exercise for codesigning primary care interventions. PMID- 24627388 TI - The CFPC and the SRPC: making a difference for rural Canadians. PMID- 24627391 TI - It's report card time!: the CFPC's role in health policy. PMID- 24627399 TI - Cardiovascular safety of NSAIDs. PMID- 24627400 TI - Laboratory tests, interpretation, and use of resources: a program to introduce the basics. AB - PROBLEM ADDRESSED: The overuse of laboratory testing has increased rapidly and is contributing to the financial strain on the health care system in Canada. Moreover, a substantial proportion of ordered tests are unnecessary. In a search of all the Canadian family physician residency programs, none lists laboratory training as mandatory or as an optional elective in its curriculum. OBJECTIVE OF PROGRAM: To introduce family medicine residents to appropriate and efficient use of laboratory tests. PROGRAM DESCRIPTION: The program was run as a series of identical 4-hour small group sessions to facilitate discussion and laboratory tours. The curriculum focused on 7 key topics: problems associated with laboratory testing, sources of laboratory errors, definitions of normal and abnormal test results, appropriate use of laboratory requisition forms, laboratory quality assurance methods, laboratory collection processes, and costs of common laboratory tests. Residents were taken to a patient specimen collection site for a tour and introduction, followed by approximately 2 hours of didactic sessions, and ending with a tour of a large tertiary care testing facility. CONCLUSION: The program was very well received by family medicine residents and resulted in a substantial increase in residents' self-assessed knowledge of the 7 topics covered in the curriculum. It is hoped that this program will fill an important gap in residency training and support residents' competency in the "selectivity" domain of training. PMID- 24627402 TI - Teaching primary care obstetrics: insights and recruitment recommendations from family physicians. AB - OBJECTIVE: To explore the experiences and recommendations for recruitment of family physicians who practise and teach primary care obstetrics. DESIGN: Qualitative study using in-depth interviews. SETTING: Six primary care obstetrics groups in Edmonton, Alta, that were involved in teaching family medicine residents in the Department of Family Medicine at the University of Alberta. PARTICIPANTS: Twelve family physicians who practised obstetrics in groups. All participants were women, which was reasonably representative of primary care obstetrics providers in Edmonton. METHODS: Each participant underwent an in-depth interview. The interviews were audiotaped and transcribed verbatim. The investigators independently reviewed the transcripts and then analyzed the transcripts together in an iterative and interpretive manner. MAIN FINDINGS: Themes identified in this study include lack of confidence in teaching, challenges of having learners, benefits of having learners, and recommendations for recruiting learners to primary care obstetrics. While participants described insecurity and challenges related to teaching, they also identified positive aspects, and offered suggestions for recruiting learners to primary care obstetrics. CONCLUSION: Despite describing poor confidence as teachers and having challenges with learners, the participants identified positive experiences that sustained their interest in teaching. Supporting these teachers and recruiting more such role models is important to encourage family medicine learners to enter careers such as primary care obstetrics. PMID- 24627401 TI - Atrial fibrillation anticoagulation care in a large urban family medicine practice. AB - OBJECTIVE: To determine the proportion of patients with atrial fibrillation (AF) in primary care achieving guideline-concordant stroke prevention treatment based on both the previous (2010) and the updated (2012) Canadian guideline recommendations. DESIGN: Retrospective chart review. PARTICIPANTS: Primary care patients (N = 204) with AF. The mean age was 71.3 years and 53.4% were women. SETTING: Large urban community family practice in Toronto, Ont. MAIN OUTCOME MEASURES: Patient demographic characteristics such as sex and age; a list of current cardiac medications including anticoagulants and antiplatelets; the total number of medications; relevant current and past medical history including presence of diabetes, stroke or transient ischemic attack, hypertension, and vascular disease; number of visits to the family physician and cardiologist in the past year and past 5 years, and how many of these were for AF; the number of visits to the emergency department or hospitalizations for AF, congestive heart failure, or stroke; if patients were taking warfarin, how often their international normalized ratios were recorded, and how many times they were in the reference range; CHADS2 (congestive heart failure, hypertension, age >= 75, diabetes mellitus, and stroke or transient ischemic attack) score, if recorded; and reason for not taking oral anticoagulants when they should have been, if recorded. RESULTS: Among those who had CHADS2 scores of 0, 64 patients (97.0%) were receiving appropriate stroke prevention in AF (SPAF) treatment according to the 2010 guidelines. When the 2012 guidelines were applied, 39 patients (59.1%) were receiving appropriate SPAF treatment (P < .001). For those with CHADS2 scores of 1, 88.4% of patients had appropriate SPAF treatment according to the 2010 guidelines, but only 55.1% were adequately treated according to the 2012 guidelines (P < .001). Of the patients at the highest risk (CHADS2 score > 1), 68.1% were adequately treated with anticoagulation and an additional 8.7% (6 of 69) had documented reasons why they were not taking anticoagulants. CONCLUSION: When assessed using the 2012 Canadian Cardiovascular Society AF guidelines, the proportion of patients receiving appropriate SPAF therapy in this primary care setting decreased substantially. All patients with CHADS2 scores of 0 or 1 should be reassessed to ensure that they are receiving optimal stroke prevention treatment. PMID- 24627403 TI - Immunization delivery in British Columbia: perspectives of primary care physicians. AB - OBJECTIVE: To explore the experiences of family physicians and pediatricians delivering immunizations, including perceived barriers and supports. DESIGN: Qualitative study using focus groups. SETTING: Ten cities throughout British Columbia. PARTICIPANTS: A total of 46 family physicians or general practitioners, 10 pediatricians, and 2 residents. METHODS: A semistructured dialogue guide was used by a trained facilitator to explore participants' experiences and views related to immunization delivery in British Columbia. Verbatim transcriptions were independently coded by 2 researchers. Key themes were analyzed and identified in an iterative manner using interpretive description. MAIN FINDINGS: Physicians highly valued vaccine delivery. Factors facilitating physician delivered immunizations included strong beliefs in the value of vaccines and having adequate information. Identified barriers included the large time commitment and insufficient communication about program changes, new vaccines, and the adult immunization program in general. Some physicians reported good relationships with local public health, while others reported the opposite experience, and this varied by geographic location. CONCLUSION: These findings suggest that physicians are supportive of delivering vaccines. However, there are opportunities to improve the sustainability of physician-delivered immunizations. While compensation schemes remain under the purview of the provincial governments, local public health authorities can address the information needs of physicians. PMID- 24627404 TI - Short report: How family physicians can support discussions about menstrual issues. PMID- 24627405 TI - Effectiveness of domain-based intervention for language development in Japanese hearing-impaired children: a multicenter study. AB - OBJECTIVE: Decreasing language delay in hearing-impaired children is a key issue in the maintenance of their quality of life. Language training has been presented mainly by experience-based training; effective intervention programs are crucially important for their future. The aim of this study was to confirm the efficacy of 6-month domain-based language training of school-age, severe-to profound hearing-impaired children. METHODS: We conducted a controlled before after study involving 728 severe-to-profound prelingual hearing-impaired children, including an intervention group (n = 60), control group (n = 30), and baseline study group (n = 638). Language scores of the participants and questionnaires to the caregivers/therapists were compared before and after the intervention. Average monthly increase in each language score of the control group and baseline study group were compared with those of the intervention group. RESULTS: Language scores and the results of the questionnaire of the intervention group showed a significant improvement (P < .05). The average monthly language growth of the intervention group was twice that of the control group and 3 to 4 times that of the baseline study group (P < .05). The effect size was largest in communication (1.914), followed by syntax (0.931). CONCLUSION: Domain-based language training improved the language development and daily communication of hearing-impaired children without any adverse effects. PMID- 24627406 TI - Neuroregeneration in the nucleus ambiguus after recurrent laryngeal nerve avulsion in rats. AB - OBJECTIVES: The objective was to investigate neuroregeneration, the origins of newborn cells and the proliferation of neuronal and glial cells in the nucleus ambiguus (NA) after ipsilateral recurrent laryngeal nerve (RLN) avulsion. METHODS: All of the animals received a CM-Dil injection in the left lateral ventricle. Forty-five adult rats were subjected to a left RLN avulsion injury, while 9 rats were used as controls. 5-Bromo-2-deoxyuridine (BrdU) was injected intraperitoneally. Neuron quantification and immunohistochemical analysis were performed in the brain stems at different time points after RLN injury. RESULTS: After RLN avulsion, CM-Dil labeled neural progenitor cells (NPCs) migrated to the ipsilateral NA and differentiated into astrocytes but not into neurons. In the NA, the neuronal cells re-expressed nestin. Only a small number of neuronal and glial cells in the NA showed BrdU immunoreactivity. CONCLUSIONS: After RLN avulsion, the NPCs in the ependymal layer of the fourth ventricle or central canal are activated, migrate to the lesion in the NA and differentiate exclusively into astrocytes. The newborn neural stem cells in the NA may arise from the mature region neurons. The presence of both cell types in the NA may play a role in repairing RLN injuries. PMID- 24627407 TI - Immunomodulatory Effect of Mesenchymal Stem Cells on T Lymphocyte and Cytokine Expression in Nasal Polyps. AB - OBJECTIVES: Adipose tissue-derived stem cells (ASCs) have been reported to have immunomodulatory effects in various inflammatory diseases, including asthma and allergic rhinitis, through the induction of T cell anergy. Nasal polyps (NPs) are a chronic inflammatory disease in the nose and paranasal sinus characterized histologically by the infiltration of inflammatory cells, such as eosinophils or lymphocytes. This study was performed to investigate whether ASCs have immunomodulatory effects on T lymphocyte and cytokine expression in eosinophilic NPs. STUDY DESIGN: Basic science experimental study. SETTING: University tertiary care facility. SUBJECTS AND METHODS: NP specimens were obtained from 20 patients with chronic rhinosinusitis and eosinophilic NPs. ASCs were isolated and cultured from the abdominal fat of 15 subjects undergoing intra-abdominal surgery. Infiltrating cells (1 * 10(6)) were isolated from NP tissue and co-cultured with 1 * 10(5) ASCs. To determine whether ASCs affect infiltrating T lymphocyte and cytokine expression in eosinophilic NP, T lymphocyte subsets and cytokine expression were analyzed before and after ASC treatment. RESULTS: ASC treatment significantly decreased the proportions of CD4(+) and CD8(+) T cells. After ASC treatment, Th2 cytokine (interleukin [IL]-4 and IL-5) levels decreased significantly. In contrast, levels of Th1 (interferon-gamma and IL-2) and regulatory cytokines (transforming growth factor-beta and IL-10) increased significantly after ASC treatment. CONCLUSIONS: ASCs have immunomodulatory effects in the eosinophilic inflammation of NPs, characterized by down-regulation of activated T lymphocytes and a Th2 immune response. These effects would be expected, over time, to significantly contribute to the control of eosinophilic inflammation and, possibly, growth of eosinophilic NPs. PMID- 24627408 TI - Impact of Otitis Media Severity on Children's Quality of Life. AB - OBJECTIVE: Children with otitis media (OM) suffer sleep disturbances, loss of appetite, earache, and behavioral problems. Our objective was to quantitate the average burden of OM and to compare the associated impact of tympanostomy tubes on infant health related quality of life (HR-QoL). STUDY DESIGN: Multi institutional prospective cross-sectional study. SETTING: Otolaryngology, family practice, and pediatric clinics. SUBJECTS AND METHODS: Children ages 6 to 24 months of age with or without recurrent OM. Patient history, the PedsQL Infant QoL survey, and the 6-item child with OM survey (Otitis Media 6 [OM-6]) were collected from providers and parents. RESULTS: Data from 1208 patients were analyzed. Mean age was 14.7 months, and 54% were male. The mean OM-6 score of children with recurrent OM was 3.3, whereas similarly aged well-children had a mean OM-6 score of 2.5. The mean PedsQL Infant scores of recurrent OM patients were significantly worse than those of children from well-child visits. Worse OM 6 scores were correlated with poorer PedsQL Infant scores, Pearson r = -0.581 (1 12 months) and -0.558 (13-24 months), P < .001. Otolaryngology patients who were recommended to undergo ear tube placement had significantly poorer OM-6 scores and worse PedsQL Infant scores, whereas patients with prior tube placement had significantly better OM-6 and PedsQL Infant scores. CONCLUSION: Children with recurrent OM had significantly worse HR-QoL than similarly aged healthy children. Increased burden of OM strongly affected HR-QoL, and recommendation for tube placement was associated with increased disease burden and poorer HR-QoL. The presence of tympanostomy tubes was associated with better OM-6 and PedsQL Infant scores. PMID- 24627409 TI - Systematic Review: Efficacy of Gufoni Maneuver for Treatment of Lateral Canal Benign Paroxysmal Positional Vertigo with Geotropic Nystagmus. AB - OBJECTIVE: In this rapid systematic review, we studied the efficacy of the Gufoni maneuver for the treatment of lateral canal benign paroxysmal positional vertigo (BPPV) with geotropic nystagmus. METHODS: A comprehensive search, including PubMed, Embase, Web of Science, and Cochrane as data sources, resulted in 44 original papers for randomized trials that compared the Gufoni maneuver with other maneuvers (date of search: April 23, 2013). Three studies (389 patients) remained after screening of title, abstract, and full text. RESULTS: After method assessment, 2 of these 3 studies were considered to have a low risk of bias and a high level of validity. The third study did not properly report the treatment allocation and blinding; moreover, outcome data were incomplete. The first 2 studies compared the Gufoni maneuver with a sham maneuver (and the barbecue roll in one study). The third study compared the Gufoni maneuver with a treatment with vestibular suppressants and with the barbecue roll (plus forced prolonged positioning). All 3 studies reported short-term results. Midterm results (1 month) were reported in 2 studies. CONCLUSION AND RECOMMENDATION: Given the variety in the comparative treatments and follow-up duration, all 3 studies showed that the Gufoni maneuver was more effective than the sham maneuver or treatment with vestibular suppressants. All agreed that the maneuver was easy to perform, which made it suitable for older, immobile, and obese patients. However, there were insufficient data to establish the relative efficacy of the Gufoni maneuver compared with other maneuvers. PMID- 24627410 TI - Surgery for Otitis Media in a Universal Health Care Model: Socioeconomic Status and Race/Ethnicity Effects. AB - OBJECTIVES: (1) To determine the association between socioeconomic status (SES), race/ethnicity, and other demographic risk factors in surgically managed otitis media within a model of universal health care. 2) To determine quality of life (QOL) outcomes of surgically managed otitis media in this model. SETTING: Tertiary academic medical center. STUDY DESIGN: Prospective cohort study. METHODS: A prospective study was conducted between June 2011 and December 2012 with dependent children of military families. TRICARE provides equal access to care among all beneficiaries regardless of a wide range of annual incomes. Caretakers of children scheduled for bilateral myringotomy and tympanostomy tube (BMT) placement were administered a demographic survey, as well as OM-6 QOL instrument preoperatively and 6 weeks postoperatively. A control group who did not undergo BMT was also administered both the survey and OM-6 for comparison. RESULTS: Two hundred forty patients were enrolled (120 surgical patients and 120 controls). Logistic regression demonstrated age younger than 6 years old (P < .001), day care attendance (P < .001), and non-Hispanic Caucasian race (P = .022) to be associated with surgery. Surgical QOL outcomes demonstrated a significant improvement in otitis media-6 (OM-6) scores after surgical management from 3.00 (95% confidence interval [CI], 2.79-3.20) to 1.35 (95% CI, 1.22-1.47). CONCLUSION: In a universal health care model serving more than 2 million children, previously reported proxies of low SES as well as minority race/ethnicity were not associated with surgically managed otitis media contrary to reported literature. Caucasian race, young age, and day care attendance were associated with surgery. Surgery improved QOL outcomes 6 weeks postoperatively. PMID- 24627411 TI - Evaluation of an Objective Striatal Analysis Program for Determining Laterality in Uptake of 123I-Ioflupane SPECT Images: Comparison to Clinical Symptoms and to Visual Reads. AB - An automated objective striatal analysis (OSA) software program was applied to dopamine transporter (123)I-ioflupane images acquired on subjects with varying severities of parkinsonism. The striatal binding ratios (SBR) of the left and right putamina (relative to the occipital lobe) were computed, and the laterality of that measure was compared with clinical symptoms and visual reads. The objective over-read of OSA was evaluated as an aid in confirming the laterality of disease onset. METHODS: One hundred one (123)I-ioflupane scans were acquired on clinically referred subjects. SPECT images were analyzed using the OSA software, which locates the slices containing the striatal and background (occipital) structures, positions regions over the left and right caudate nuclei and putamina, and calculates the background-subtracted SBR. Seven images were uninterpretable because of patient motion or lack of visualization of the striatum. The remaining 94 scans were analyzed with OSA. Differences between left and right putaminal SBR ranged from 0% to 36.6%, with a mean of 11.4%. When the difference between the SBR of the left and right putamina was greater than 6%, the lower side was taken as the side of onset. Left-to-right differences less than 6% were considered to be nonlateralizing (symmetric). The 94 scans were reviewed independently by 3 masked expert readers. By majority consensus, abnormal findings were seen on 67 of the 94 scans, of which 46 had available clinical findings. RESULTS: Clinically, 34 subjects presented with lateralized tremors and 12 with symmetric or no tremors. Of the 34 cases of clinically lateralized tremors, 26 (76%) were concordant with the OSA findings, 5 were disparate with OSA (15%), and in 3 the OSA results were symmetric (9%). For the same 34 patients, the visual reads were concurrent with clinical tremor findings in 24 cases (71%), 1 was disparate (3%), and 9 visual reads were symmetric (26%). Of the 9 scans deemed symmetric by readers, 4 were correctly lateralized by OSA, and of the 3 symmetric OSA results, 2 were correctly lateralized visually. CONCLUSION: The OSA program may be a helpful aid in the interpretation of (123)I ioflupane SPECT images for determining laterality representing the asymmetric loss of dopamine transporters in the striata. OSA offers an objective, reproducible over-read evaluation for the laterality of onset in Parkinson disease. PMID- 24627412 TI - Painful knee arthroplasty. AB - A triple-tracer nuclear medicine study that incorporates (99m)Tc-sulfur colloid, (111)In-labeled leukocytes, and (99m)Tc-methylene diphosphonate can be useful for the diagnosis of aseptic loosening in a patient after total-knee arthroplasty, as demonstrated in this case study. The triple-tracer technique takes less time and is more accurate than a bone scan alone. PMID- 24627413 TI - Atypical Presentation of Sarcoidosis on 18F-FDG PET/CT. AB - On (18)F-FDG PET, inflammatory processes can be one of the most confounding factors for interpretation, particularly when the presentation of the process is atypical, as it was in the case of sarcoidosis reported here. Clinicians should be aware that sarcoidosis may mimic lung malignancies and lymphomas, regardless of typical or atypical appearance on (18)F-FDG PET. PMID- 24627414 TI - Sweating the small stuff: pitfalls in the use of radiation detection instruments. AB - Nuclear medicine technologists use nonimaging radiation detection instruments on a daily basis and routinely assess their performance in several ways. These instruments are simple to operate compared with imaging instruments but are also susceptible to misuse. After reviewing the theoretic basis for common mistakes and the importance of routine quality control, this continuing education article discusses pitfalls in the operation of dose calibrators, survey meters, scintillation detectors, and semiconductors. The article also reviews quality control procedures and ways in which these can be performed incorrectly. The goal of the article is to help technologists to spot and correct problems before they lead to errant results. PMID- 24627415 TI - Nanoparticles based on a hydrophilic polyester with a sheddable PEG coating for protein delivery. AB - PURPOSE: To investigate the effect of polyethylene glycol (PEG) in nanoparticles based on blends of hydroxylated aliphatic polyester, poly(D,L-lactic-co-glycolic co-hydroxymethyl glycolic acid) (PLGHMGA) and PEG-PLGHMGA block copolymers on their degradation and release behavior. METHODS: Protein-loaded nanoparticles were prepared with blends of varying ratios of PEG-PLGHMGA (molecular weight of PEG 2,000 and 5,000 Da) and PLGHMGA, by a double emulsion method with or without using poly(vinyl alcohol) (PVA) as surfactant. Bovine serum albumin and lysozyme were used as model proteins. RESULTS: PEGylated particles prepared without PVA had a zeta potential ranging from ~ -3 to ~-35 mV and size ranging from ~200 to ~600 nm that were significantly dependent on the content and type of PEG-block copolymer. The encapsulation efficiency of the two proteins however was very low (<30%) and the particles rapidly released their content in a few days. In contrast, all formulations prepared with PVA showed almost similar particle properties (size: ~250 nm, zeta potential: ~-1 mV), while loading efficiency for both model proteins was rather high (80-90%). Unexpectedly, independent of the type of formulation, the nanoparticles had nearly the same release and degradation characteristics. NMR analysis showed almost a complete removal of PEG in 5 days which explains these marginal differences. CONCLUSIONS: Protein release and particle degradation are not substantially influenced by the content of PEG, likely because of the fast shedding of the PEG blocks. These PEG shedding particles are interesting system for intracellular delivery of drugs. PMID- 24627417 TI - Interaction of inflammation, hyperuricemia, and the prevalence of hypertension among adults free of metabolic syndrome: NHANES 2009-2010. AB - BACKGROUND: Hyperuricemia and markers of inflammation are correlated with the risk for hypertension. Whether hyperuricemia has any impact on the association between C-reactive protein (CRP) and hypertension is not known. METHODS AND RESULTS: We analyzed cross-sectional data from the National Health and Nutrition Examination Survey, 2009-2010, using ordinary least squares and logistic regression models. Those who met the criteria for metabolic syndrome, had self reported gout, or were <20 years old were excluded. For each 1-SD increase in serum urate, the serum CRP concentration was 20% higher in unadjusted linear regression models and 13% higher in multivariable linear regression models, after accounting for the effects of age, sex, race, socioeconomic and educational strata, renal function, lipids, smoking, and body mass index. In multivariable models adjusting for the same covariates, hyperuricemia was associated with hypertension with an odds ratio of 2.21 (1.71 to 2.85). When analyzed separately, this was observed in men and women. In multivariable analyses of the overall sample, elevated CRP levels were not associated with hypertension. CONCLUSIONS: Among adults free of metabolic syndrome, elevated uric acid, but not elevated CRP, is independently associated with prevalent hypertension. PMID- 24627418 TI - Coronary heart disease risks associated with high levels of HDL cholesterol. AB - BACKGROUND: The association between high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) events is not well described in individuals with very high levels of HDL-C (>80 mg/dL). METHODS AND RESULTS: Using pooled data from 6 community-based cohorts we examined CHD and total mortality risks across a broad range of HDL-C, including values in excess of 80 mg/dL. We used Cox proportional hazards models with penalized splines to assess multivariable, adjusted, sex-stratified associations of HDL-C with the hazard for CHD events and total mortality, using HDL-C 45 mg/dL and 55 mg/dL as the referent in men and women, respectively. Analyses included 11 515 men and 12 925 women yielding 307 245 person-years of follow-up. In men, the association between HDL-C and CHD events was inverse and linear across most HDL-C values; however at HDL-C values >90 mg/dL there was a plateau effect in the pattern of association. In women, the association between HDL-C and CHD events was inverse and linear across lower values of HDL-C, however at HDL-C values >75 mg/dL there were no further reductions in the hazard ratio point estimates for CHD. In unadjusted models there were increased total mortality risks in men with very high HDL-C, however mortality risks observed in participants with very high HDL-C were attenuated after adjustment for traditional risk factors. CONCLUSIONS: We did not observe further reductions in CHD risk with HDL-C values higher than 90 mg/dL in men and 75 mg/dL in women. PMID- 24627419 TI - Changes in mipomersen dosing regimen provide similar exposure with improved tolerability in randomized placebo-controlled study of healthy volunteers. AB - BACKGROUND: Mipomersen, an apolipoprotein B synthesis inhibitor, demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B in 4 phase 3 studies at the FDA-approved subcutaneous dose of 200 mg once weekly. METHODS AND RESULTS: A short-term phase 1 study in healthy volunteers was conducted to evaluate the relative bioavailability, safety, and tolerability of mipomersen in 2 test dose regimens in reference to the 200 mg weekly dose regimen. Eighty-four adults were randomized to 1 of 3 cohorts (30 mg once daily, 70 mg 3 times weekly, or 200 mg once weekly) and then mipomersen or placebo (3:1 ratio) for 3 weeks of treatment. Comparable mipomersen post-distribution phase plasma concentrations were observed across the 3 dose regimens suggesting similar tissue exposure. Injection site reactions were reported, but did not lead to treatment discontinuation. The median incidence of these responses per injection was decreased by lowering the dose. Signals from a diverse panel of systemic inflammation markers were essentially indistinguishable between dose regimens and placebo treatment. The one exception was a modest transient post-dose elevation of C-reactive protein (CRP) in the mipomersen 200 mg weekly group. This elevation was not associated with an increase in other proinflammatory markers. CONCLUSIONS: This study demonstrated a similar drug exposure and overall safety profile between the 3 dosing regimens. Exploratory assessment of a diverse panel of biomarkers found no indication of a systemic inflammatory response to mipomersen treatment. These results support assessment of alternative dose regimens in longer-term studies. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061814. PMID- 24627416 TI - Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type. AB - AIM: To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). METHODS AND RESULTS: Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for >= 3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). CONCLUSION: A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957). PMID- 24627422 TI - How important are Dipteran vectors of disease in Africa? PMID- 24627420 TI - Gender-specific risk factors for peripheral artery disease in a voluntary screening population. AB - BACKGROUND: Women have high rates of peripheral artery disease (PAD) despite fewer cardiovascular disease (CVD) risk factors, compared to men. We sought to determine the gender-specific prevalence of low ankle brachial index (ABI) and the relationship to C-reactive protein (CRP) levels and CVD risk factors in the Life Line Screening population. METHODS AND RESULTS: Between April 2005 and August 2011, 133 750 women and 71 996 men had ABI and CRP measured at a Life Line Screening Center. Women were slightly older than men, whereas men were more likely to be current smokers, have diabetes mellitus (DM), and coronary artery disease (CAD) (P<0.001 for each). Women were more likely to have ABI<=1.0, compared to men (26.6% versus 14.4%, respectively; P<0.001), as well as ABI<=0.9 (4.1% women versus 2.6% men; P<0.001). Women had higher median CRP levels (1.94 mg/L; interquartile range [IQR], 0.89, 4.44 mg/L), compared to men (1.35 mg/L; IQR, 0.73, 2.80 mg/L; P<0.001). Men and women shared similar risk factors for ABI<=0.9, including older age, black race, smoking, DM, hypertension, hypercholesterolemia, CAD, and elevated CRP levels. In an adjusted model, there were significant interactions between gender and age (P<0.001), CRP (P<0.001), CAD (P=0.03), and DM (P=0.06) with ABI as the outcome. The associations between age, CRP, CAD, and DM with ABI<=0.9 were stronger in men than in women. CONCLUSIONS: Women participating in the Life Line Screening had higher CRP levels and a higher prevalence of PAD, compared to men. Neither higher CRP levels nor conventional CVD risk factors explained the excess prevalence of PAD in women. PMID- 24627421 TI - Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells. AB - BACKGROUND: Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we show that inhibition of the mitochondrial permeability transition pore (mPTP) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSCs. METHODS AND RESULTS: We induced cardiomyocyte differentiation from mouse and human PSCs and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from mPTP inhibition rather than from calcineurin inhibition. The mPTP inhibitor NIM811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK506 only slightly increased cardiomyocyte differentiation. CsA-treated cells showed an increase in mitochondrial calcium, mitochondrial membrane potential, oxygen consumption rate, ATP level, and expression of genes related to mitochondrial function. Furthermore, inhibition of mitochondrial oxidative metabolism reduced the cardiomyogenic effect of CsA while antioxidant treatment augmented the cardiomyogenic effect of CsA. CONCLUSIONS: Our data show that mPTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSCs. PMID- 24627423 TI - A country-wide field evaluation of rapid diagnostic test for meningococcal meningitis. AB - We comment on a unique country-wide scale field evaluation of rapid diagnostic test (RDT) for meningococcal meningitis in Niger. The authors reported the good sensitivity and specificity of the test, and the reliability of results obtained in the field by non-specialized health staff. This finding allows us to consider RDT as a good candidate laboratory tool to be used for the case-based surveillance system, post introduction of the new conjugate A vaccine (MenAfriVac) in the African meningitis belt countries. In addition, RDT is also a potential point of care test to improve the management of meningitis patients. PMID- 24627424 TI - Survival probability and predictors of mortality and retention in care among patients enrolled for first-line antiretroviral therapy, Andhra Pradesh, India, 2008-2011. AB - BACKGROUND: The national antiretroviral therapy (ART) initiative in India began in 2004. In order to better inform the national program, we estimated the mean cumulative survival probability and loss to follow-up (LFU) rate among patients initiated on ART. METHODS: We identified a cohort of people living with HIV (PLHIV) aged >=15 years initiated on ART in two ART centres in Hyderabad city, Andhra Pradesh state, India between January 2008 and December 2008. The cohort was followed-up until 31 December 2011 and death and/or LFU were the primary endpoints. Death from any cause during the study period was considered to be the result of HIV infection. We used the Kaplan-Meier estimation method for survival probability and Cox proportional hazard model to identify the predictors. RESULTS: Of the 1690 patients initiated on ART, 259 (15.3%) were transferred out during the study period. Mortality rate was 7.6/100 person-years. Male gender, low CD4 count, history of tuberculosis before initiation of ART, and weight <48 kg were the predictors of mortality. Patients who were LFU were more likely to be males, unemployed, widowed, and had weight below 48 kg. CONCLUSION: Survival rates on ART were higher compared to other resource-limited settings. Delayed diagnosis and initiation of ART and co-infection with TB were important predictors for both mortality and retention in care. PMID- 24627425 TI - Predisposing factors associated with uncomplicated type 2 diabetes among adults in a diabetic clinic, Enugu State, Nigeria. AB - BACKGROUND: The role of micronutrients and other predisposing factors associated with the aetiology of type 2 diabetes in Nigeria is not well established. The objectives of this study were to investigate predisposing factors associated with uncomplicated type 2 diabetes among a Nigerian adult population. METHODS: Predisposing factors associated with uncomplicated type 2 diabetes were investigated in 60 Igbo (a major tribe in Eastern Nigeria) adults aged 30-90 years. This study was carried out at the Diabetic Clinic, University of Nigeria Teaching Hospital (UNTH) Ituku-Ozalla, Enugu. Packed cell volume (PCV), serum ferrtin and some anthropometric parameters were measured alongside fasting blood sugar (FBS). RESULTS: PCV recorded a statistically significant lower (p<0.001) mean value at 32.94+/-0.61% in the patients when compared with the control group with a mean value of 39.06+/-1.02%. Serum ferritin revealed a statistically significant higher (p<0.01; 110.20+/-15.17 ng/ml) mean value in the patients when compared with the control group (20.4+/-5.64 ng/ml). However, PCV (32.00+/-0.88%) and body mass index (BMI) (31.99+/-1.12 Kg/m(2)) recorded a statistically significant lower (p<0.05) mean value in female patients when compared with their corresponding males. There was no significant correlation (p>0.05) between serum iron ferritin, FBS and all other anthropometric predictors of incidence of type 2 diabetes. CONCLUSION: Type 2 diabetes is not associated with elevated levels of serum iron ferritin. Hence, serum ferritin may not be a better predictor of type 2 diabetes, especially in uncomplicated cases. PMID- 24627426 TI - Surveillance of influenza from household to community in Taiwan. AB - BACKGROUND: We propose a chain binomial model to elucidate the transmission modes of influenza within households and with which to further evaluate the spread of influenza in a community. METHODS: Data on the surveillance of influenza in Taiwan were collected from July 2001 to March 2002. A series of chain binomial models were fitted to estimate the escape probability. This parameter together with accumulated cases of the first episode were further applied to derive the transmission probability, the contact rate and the recovery rate, yielding an estimate of the basic reproductive number and providing a simulation approach with which to assess the spread of influenza in the community. RESULTS: Of the 6 391 614 cases identified during the study period, 4 451 046 were from 3 654 320 households consisting of two to five people, with at least one case used to estimate the escape probabilities within households. The escape probability within households was 92.4%, which, in turn, led to a contact rate estimate of 7.7 per day. The transmission probability was estimated as 8.3%. These three parameters yielded 2.56 as the basic reproductive number. CONCLUSIONS: The proposed method provides a means for using household data to evaluate the transmissibility of influenza within a community. PMID- 24627427 TI - Implicit and explicit Theory of Mind reasoning in autism spectrum disorders: the impact of experience. AB - This study aimed to investigate the relationship between explicit and implicit forms of Theory of Mind reasoning and to test the influence of experience on implicit Theory of Mind reasoning in individuals with autism spectrum disorders and in neurotypical adults. Results from two standard explicit Theory of Mind tasks are mixed: Individuals with autism spectrum disorders did not differ from neurotypical adults in their performance in the Strange Stories Test, but scored significantly lower on the Reading the Mind in the Eyes Test. Furthermore, in an implicit false-belief task, individuals with autism spectrum disorders differed from neurotypical adults in false belief-congruent anticipatory looking. However, this group difference disappeared by (1) providing participants with the outcome of a false belief-based action and (2) subsequently repeating this test trial. Although the tendency to fixate the false belief-congruent location significantly increased from the first to the second test trial in individuals with autism spectrum disorders, it differed in neither test trial from chance. These findings support the notion of an implicit Theory of Mind deficit in autism spectrum disorders, but give rise to the idea that anticipatory looking behaviors in autism spectrum disorders may be affected by experience. Additionally, the pattern of results from implicit and explicit Theory of Mind measures supports the theory of two independent Theory of Mind reasoning systems. PMID- 24627428 TI - Effects of dynamic stepping training on nonlocomotor tasks in individuals poststroke. AB - BACKGROUND: During the physical rehabilitation of individuals poststroke, therapists are challenged to provide sufficient amounts of task-specific practice in order to maximize outcomes of multiple functional skills within limited visits. Basic and applied studies have suggested that training of one motor task may affect performance of biomechanically separate tasks that utilize overlapping neural circuits. However, few studies have explicitly investigated the impact of training one functional task on separate, nonpracticed tasks. OBJECTIVE: The purpose of this preliminary study was to investigate the potential gains in specific nonlocomotor assessments in individuals poststroke following only stepping training of variable, challenging tasks at high aerobic intensities. METHODS: Individuals with locomotor deficits following subacute and chronic stroke (n=22) completed a locomotor training paradigm using a repeated-measures design. Practice of multiple stepping tasks was provided in variable environments or contexts at high aerobic intensities for >=40 sessions over 10 weeks. The primary outcome was timed Five-Times Sit-to-Stand Test (5XSTS) performance, with secondary measures of sit-to-stand kinematics and kinetics, clinical assessment of balance, and isometric lower limb strength. RESULTS: Participants improved their timed 5XSTS performance following stepping training, with changes in selected biomechanical measures. Statistical and clinically meaningful improvements in balance were observed, with more modest changes in paretic leg strength. CONCLUSIONS: The present data suggest that significant gains in selected nonlocomotor tasks can be achieved with high-intensity, variable stepping training. Improvements in nonpracticed tasks may minimize the need to practice multiple tasks within and across treatment sessions. PMID- 24627429 TI - Physical therapy 2.0: leveraging social media to engage patients in rehabilitation and health promotion. AB - Care for chronic conditions and noncommunicable diseases is dominating health systems around the globe. For physical therapists, this strain presents a substantial opportunity for engaging patients in health promotion and disease management in the years to come. Examples of social media being used to engage consumers in the business landscape are pervasive, and research reports suggest that patients are ready for social media to be incorporated into the way health care systems deliver care. We propose that leveraging the power and utility of existing technologies, such as social media, could innovate the way physical therapists engage patients in rehabilitation and health promotion practices, thus contributing to the evolution of the profession: Physical Therapy 2.0. To continue to be relevant in the community, physical therapist practice must respond to patients' needs and expectations. Incorporating social media into how physical therapists are both designing and delivering care holds potential for enhancing patient engagement in prescribed health behaviors and improving treatment outcomes. This conceptual article presents the perspective that physical therapists can utilize social media to enhance care delivery and treatment outcomes. PMID- 24627430 TI - The human movement system: our professional identity. AB - The 2013 House of Delegates of the American Physical Therapy Association adopted a vision statement that addresses the role of physical therapy in transforming society through optimizing movement. The accompanying guidelines address the movement system as key to achieving this vision. The profession has incorporated movement in position statements and documents since the early 1980s, but movement as a physiological system has not been addressed. Clearly, those health care professions identified with a system of the body are more easily recognized for their expertise and role in preventing, diagnosing, and treating dysfunctions of the system than health professions identified with intervention but not a system. This perspective article provides a brief history of how leaders in the profession have advocated for clear identification of a body of knowledge. The reasons are discussed for why movement can be considered a physiological system, as are the advantages of promoting the system rather than just movement. In many ways, a focus on movement is more restrictive than incorporating the concept of the movement system. Promotion of the movement system also provides a logical context for the diagnoses made by physical therapists. In addition, there is growing evidence, particularly in relation to musculoskeletal conditions, that the focus is enlarging from pathoanatomy to pathokinesiology, further emphasizing the timeliness of promoting the role of movement as a system. Discussion also addresses musculoskeletal conditions as lifestyle issues in the same way that general health has been demonstrated to be clearly related to lifestyle. The suggestion is made that the profession should be addressing kinesiopathologic conditions and not just pathokinesiologic conditions, as would be in keeping with the physical therapist's role in prevention and as a life-span practitioner. PMID- 24627431 TI - In reply to Rodriguez-Osorio et al. PMID- 24627432 TI - Enhanced pain-induced activity of pain-processing regions in a case-control study of episodic migraine. AB - OBJECTIVE: The objective of this study was to identify brain regions having aberrant pain-induced activation in migraineurs, thereby gaining insight into particular aspects of pain processing that are atypical in migraineurs. METHODS: Functional magnetic resonance imaging assessed whole brain responses to painful heat in 24 adult episodic migraineurs who were at least 48 hours pain free and 27 healthy controls. Regions differentially activated in migraineurs compared to controls were identified. Activation intensities in these regions were correlated with headache frequency, number of migraine years, and time to next migraine attack. RESULTS: Migraineurs had greater pain-induced activation of lentiform nucleus, fusiform gyrus, subthalamic nucleus, hippocampus, middle cingulate cortex, premotor cortex, somatosensory cortex, and dorsolateral prefrontal cortex, and less activation in precentral gyrus and superior temporal gyrus. There were significant correlations between activation strength and headache frequency for middle cingulate (r = 0.627, p = 0.001), right dorsolateral prefrontal cortex (r = 0.568, p = 0.004), left fusiform gyrus (r = 0.487, p = 0.016), left precentral gyrus (r = 0.415, p = 0.044), and left hippocampus (r = 0.404, p = 0.050) and with number of migraine years for left fusiform gyrus (r = 0.425, p = 0.038). There were no significant correlations between activation strength and time to next migraine attack. CONCLUSIONS: The majority of regions with enhanced pain-induced activation in headache-free migraineurs participate in cognitive aspects of pain perception such as attending to pain and pain memory. Enhanced cognitive pain processing by migraineurs might reflect cerebral hypersensitivity related to high expectations and hypervigilance for pain. PMID- 24627433 TI - PET imaging analysis with 64Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model. AB - Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with (64)Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). METHODS: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and d-penicillamine, a hydrophilic chelator) 30 min before (64)CuCl2 injection. After (64)CuCl2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with gamma counting and autoradiography. RESULTS: After copper injection alone, marked accumulation of radioactivity ((64)Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 +/- 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 +/ 0.26 %ID/g) and brain (0.96 +/- 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 +/- 2.68 %ID/g) and increased copper transport into the liver (29.42 +/- 0.98 %ID/g) and brain (5.12 +/- 0.95 %ID/g) of MD model mice. Copper injection with d-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. CONCLUSION: PET studies with (64)Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of (64)Cu PET for the treatment of MD and other copper-related disorders may be useful in clinical settings. PMID- 24627434 TI - Glypican-3-targeted 89Zr PET imaging of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a devastating malignancy in which imperfect imaging plays a primary role in diagnosis. Glypican-3 (GPC3) is an HCC-specific cell surface proteoglycan overexpressed in most HCCs. This paper presents the use of (89)Zr-conjugated monoclonal antibody against GPC3 ((89)Zr-alphaGPC3) for intrahepatic tumor localization using PET. METHODS: Polymerase chain reaction confirmed relative GPC3 expression in cell lines. In vitro binding, in vivo biodistribution, and small-animal PET studies were performed on GPC3-expressing HepG2 and non-GPC3-expressing HLF and RH7777 cells and orthotopic xenografts. RESULTS: (89)Zr-alphaGPC3 demonstrated antibody-dependent, antigen-specific tumor binding. HepG2 liver tumors exhibited high peak uptake (836.6 +/- 86.6 percentage injected dose [%ID]/g) compared with background liver (27.5 +/- 1.6 %ID/g). Tumor to-liver contrast ratio was high and peaked at 32.5. The smallest HepG2 tumor (<1 mm) showed lower peak uptake (42.5 +/- 6.4 %ID/g) and tumor-to-liver contrast (1.57) but was still clearly visible on PET. Day 7 tissue activity was still substantial in HepG2 tumors (466.4 +/- 87.6 %ID/g) compared with control RH7777 tumors (3.9 +/- 1.3 %ID/g, P < 0.01), indicating antigen specificity by (89)Zr alphaGPC3. HepG2 tumor treated with unlabeled alphaGPC3 or heat-denatured (89)Zr alphaGPC3 demonstrated tumor activity (2.1 %ID/g) comparable to that of control xenografts, confirming antibody dependency. CONCLUSION: This study demonstrated the feasibility of using (89)Zr-alphaGPC3 to image HCC in the liver, as well as the qualitative determination of GPC3 expression via small-animal PET. The ability to clarify the identity of small liver lesions with an HCC-specific PET probe would provide clinicians with vital information that could significantly alter patient management, warranting further investigation for clinical translation. PMID- 24627435 TI - Theranostics of malignant melanoma with 64CuCl2. AB - Human copper transporter 1 (CTR1) is overexpressed in a variety of cancers. This study aimed to evaluate the use of (64)CuCl2 as a theranostic agent for PET and radionuclide therapy of malignant melanoma. METHODS: CTR1 expression levels were detected by Western blot analysis of a group of tumor cell lines. Two melanoma cell lines (B16F10 and A375M) that highly expressed CTR1 were then selected to study the uptake and efflux of (64)CuCl2. Mice bearing B16F10 or A375M tumors (n = 4 for each group) were subjected to 5 min of static whole-body PET scans at different time points after intravenous injection of (64)CuCl2. Dynamic scans were also obtained for B16F10 tumor-bearing mice. All mice were sacrificed at 72 h after injection of (64)CuCl2, and biodistribution studies were performed. Mice bearing B16F10 or A375M tumors were further subjected to (64)CuCl2 radionuclide therapy. Specifically, when the tumor size reached 0.5-0.8 cm in diameter, tumor bearing mice were systemically administered (64)CuCl2 (74 MBq) or phosphate buffered saline, and tumor sizes were monitored over the treatment period. RESULTS: CTR1 was found to be overexpressed in the cancer cell lines tested at different levels, and high expression levels in melanoma cells and tissues were observed (melanotic B16F10 and amelanotic A375M). (64)CuCl2 displayed high and specific uptake in B16F10 and A375M cells. In vivo (64)CuCl2 PET imaging demonstrated that both B16F10 and A375M tumors were clearly visualized. Radionuclide treatment studies showed that the tumor growth in both the B16F10 and the A375M models under (64)CuCl2 treatment were much slower than that of the control group. CONCLUSION: Both melanotic and amelanotic melanomas (B16F10 and A375M) tested were found to overexpress CTR1. The tumors can be successfully visualized by (64)CuCl2 PET and further treated by (64)CuCl2, highlighting the high potential of using (64)CuCl2 as a theranostic agent for the management of melanoma. PMID- 24627436 TI - Phase-1 clinical trial results of high-specific-activity carrier-free 123I iobenguane. AB - A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of (123)I-iobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. METHODS: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. RESULTS: A reference clinical imaging database acquired over time for healthy men and women injected with high-specific-activity (123)I iobenguane showed organ distribution and whole-body retention similar to those of conventional (123)I-iobenguane. The heart-to-mediastinum ratios for the high specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. CONCLUSION: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity (123)I iobenguane. PMID- 24627438 TI - Neonatal Ross-Konno operation and endocardial fibroelastosis resection after foetal percutaneous aortic valve balloon valvuloplasty: a complex approach to rescue the left heart. AB - We report a case of a patient who presented with aortic stenosis and a borderline left ventricle during foetal life. A balloon aortic valve valvuloplasty was performed in uterus, and in the postnatal period for relief of the left ventricular outflow tract obstruction followed by a Ross-Konno procedure with fibroelastosis resection. These successful interventions allowed left ventricular growth and the conversion to a biventricular circulation after a single-stage surgery. PMID- 24627437 TI - A new strategy in the treatment of chemoresistant lung adenocarcinoma via specific siRNA transfection of SRF, E2F1, Survivin, HIF and STAT3. AB - OBJECTIVES: According to the actual treatment strategies of lung cancer, the current therapeutic regimen is an individualized, multidisciplinary concept. The development of chemoresistance in the last decade represents the most important obstacle to an effective treatment. In our study, we examined a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA specific transfection of six crucial molecules involved in lung carcinogenesis [serum response factor(SFR), E2F1, Survivin, hypoxia inducible factor1 (HIF1), HIF2 and signal transducer and activator of transcription (STAT3)]. METHODS: Three chemoresistant A549 adenocarcinoma cells were cultured under standard conditions at 37 degrees C and 5% CO2. The chemoresistance against Vinflunine, Vinorelbine and Methotrexate was induced artificially. The A549 cells were transfected for 2 h at 37 degrees C with specific siRNA targeting SRF, E2F1, Survivin, HIF1, HIF2 and STAT3 in a non-viral manner. The efficiency of siRNA silencing was evaluated via quantitative real-time polymerase chain reaction, whereas the surviving cells after siRNA transfection as predictor factor for tumoural growth were analysed with a CASY cell counter 3 days after transfection. RESULTS: The response of the chemotherapeutic resistant adenocarcinoma cells after siRNA transfection was concentration-dependent at both 25 and 100 nM. The CASY analysis showed a very effective suppression of adenocarcinoma cells in Vinorelbine, Vinflunine and Methotrexate groups, with significantly better results in comparison with the control group. CONCLUSIONS: In our study, we emphasized that siRNA interference might represent a productive platform for further research in order to investigate whether a new regimen in the treatment of multiresistant non-small-cell lung cancer could be established in vivo in the context of a multimodal cancer therapy. PMID- 24627439 TI - Elective use of femoro-femoral cardiopulmonary bypass during transcatheter aortic valve implantation. AB - OBJECTIVES: Elective use of normothermic cardiopulmonary bypass (CPB) may reduce the risks associated with the transcatheter aortic valve implantation (TAVI) procedure in selected high-risk TAVI patients. METHODS: Between April 2008 and August 2013, 1177 consecutive patients underwent TAVI. Elective normothermic femoro-femoral CPB was used in 3.7% of patients (n=43, 27 males, 16 females; mean age 75+/-10 [range 38-90] years). The EuroSCORE I was 65+/-23%, the EuroSCORE II was 39+/-24% and the Society of Thoracic Surgeons Predicted Risk of Mortality score was 31+/-24%. The mean left ventricular ejection fraction (LVEF) was 24+/ 12% (range 5-50%). RESULTS: The device success rate (Valve Academic Research Consortium-2 criteria) was 98% in this study group. The median duration of CPB was 20 (range 5-297) min. In 20 patients with pulmonary hypertension combined with an enlarged right ventricle (RV), or with poor RV ejection fraction or LVEF (mean LVEF: 18+/-3% [range 10-20%]), CPB was used to prevent haemodynamic instability during valve deployment and to eliminate the adverse effects of possible ventricular fibrillation. Additionally, it was used to promote cardiac recovery by unloaded failing hearts in 23 patients (53%) with cardiogenic shock. Whereas the 30-day mortality rate in the group of patients in cardiogenic shock was 28.6%, no patient in the other group died. The 1-year survival rate was 36+/ 11 and 86+/-9.5%, respectively. CONCLUSIONS: The use of preoperatively planned CPB may increase the safety of the TAVI procedure in patients with severely reduced heart function or in cardiogenic shock. PMID- 24627440 TI - Long-term results of sequential vein coronary artery bypass grafting compared with totally arterial myocardial revascularization: a propensity score-matched follow-up study?. AB - OBJECTIVES: The aim of the study was to analyse the early and long-term outcomes of a consecutive series of patients who underwent sequential coronary artery bypass grafting (CABG) and to compare them with a matched population of totally arterial revascularized patients. METHODS: From January 1994 to December 1996, 209 patients underwent total arterial myocardial revascularization at our institution [arterial (ART) group]. In the same period, 2097 patients underwent CABG with left internal thoracic artery on left anterior descending and great saphenous vein on the right and circumflex branches sequentially [sequential vein (SV) group]. The propensity score methodology was used to obtain risk-adjusted outcome comparisons between the two groups (209 vs 243 patients in the ART group and SV group, respectively). RESULTS: In-hospital mortality was 1% in the ART group and 0.4% in the SV group (P = 0.86). Mean follow-up was 14 +/- 4 years. Long-term survival was comparable among the two study groups [actuarial 5- and 15 year survival rates were 97 vs 93% and 82 vs 79% in the ART group and the SV group, respectively (P = 0.29)]. At follow-up, recurrence of angina (17 vs 18%; P = 0.99), acute myocardial infarction (MI) (3 vs 5%; P = 0.72) and repeated percutaneous coronary intervention (19 vs 21%; P = 0.69) were similar in the ART group compared with the SV group. In the Cox regression analysis, type of revascularization was not an independent predictor of any long-term outcomes (death or major adverse cardiac events). In asymptomatic patients, exercise stress test at follow-up was comparable between the two groups (P = 0.14). CONCLUSIONS: Sequential vein CABG appears to have good early and long-term clinical outcomes. Also, early and long-term incidence of acute MI was not significantly higher in the SV group. However, further studies with a larger population are warranted in order to confirm the present results. PMID- 24627441 TI - Yet another study reports poor control of elevated blood pressure. PMID- 24627442 TI - Prevalence of hypertension, awareness, treatment, and control in the Hispanic Community Health Study/Study of Latinos. AB - BACKGROUND: The prevention and control of hypertension is an essential component for reducing the burden of cardiovascular diseases. Here we describe the prevalence of hypertension in diverse Hispanic/Latino background groups and describe the proportion who are aware of their diagnosis, receiving treatment, and having their hypertension under control. METHODS: The Hispanic Community Health Study/Study of Latinos is a longitudinal cohort study of 16,415 Hispanics/Latinos, aged 18-74 years from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). At baseline (2008-2011) the study collected extensive measurements and completed questionnaires related to research on cardiovascular diseases. Hypertension was defined as measured blood pressure >=140/90mm Hg or use of antihypertensive medication. RESULTS: The total age adjusted prevalence of hypertension in this study was 25.5% as compared with 27.4% in non-Hispanic whites in the National Health and Nutrition Examination Survey. Prevalence of hypertension increased with increasing age groups and was highest in Cuban, Puerto Rican, and Dominican background groups. The percent with hypertension who were aware, being treated with medication, or had their hypertension controlled was lower compared with US non-Hispanic whites with hypertension and it was lowest in those without health insurance. CONCLUSIONS: These findings indicate a significant deficit in treatment and control of hypertension among Hispanics/Latinos residing in the United States, particularly those without health insurance. Given the relative ease of identification of hypertension and the availability of low-cost medications, enabling better access to diagnostic and treatment services should reduce the burden of hypertension in Hispanic populations. PMID- 24627443 TI - Seven-day remote ischemic preconditioning improves local and systemic endothelial function and microcirculation in healthy humans. AB - BACKGROUND: Ischemic preconditioning (IPC) protects tissue against ischemia induced injury inside and outside ischemic areas. The purpose was to examine the hypothesis that daily IPC leads to improvement in endothelial function and skin microcirculation not only in the arm exposed to IPC but also in the contralateral arm. METHODS: Thirteen healthy, young, normotensive male individuals (aged 22+/-2 years) were assigned to 7-day daily exposure of the arm to IPC (4*5 minutes). Assessment of brachial artery endothelial function (using flow-mediated dilation (FMD)) and forearm microcirculation (cutaneous vascular conductance (CVC) at baseline and during local heating) was performed before and after 7 days to examine the local (i.e., intervention arm) and remote (i.e., control arm) effect of IPC. We repeated the assessment tests 8 days after the intervention (Post+8). RESULTS: FMD increased after repeated IPC (P = 0.03) and remained significantly elevated at Post+8 in the intervention (5.0+/-2.2%, 6.1+/-2.2%, and 6.6+/-2.3%) and contralateral arms (5.4+/-2.2%, 6.0+/-2.2%, and 7.5+/-2.2%). Forearm CVC also increased following repeated IPC (P = 0.006) and remained elevated at Post+8 in both arms (intervention: 0.12+/-0.03, 0.14+/-0.04, 0.16+/-0.04 mV/mm Hg; contralateral: 0.14+/-0.04, 0.015+/-0.04, 0.17+/-0.07). No interaction between IPC arm and time was evident for FMD and CVC (both P > 0.05). IPC intervention did not alter CVC responses to local heating (P > 0.05). CONCLUSIONS: Daily exposure to IPC for 7 days leads to local and remote improvements in brachial artery FMD and resting skin microcirculation that remain after cessation of the intervention and beyond the late phase of protection. These findings may have clinical relevance for micro- and macrovascular improvements. PMID- 24627444 TI - Central hemodynamics are associated with cardiovascular disease and albuminuria in type 1 diabetes. AB - BACKGROUND: We sought to investigate associations between central hemodynamic parameters (estimated from radial pulse wave analyses (PWAs)), cardiovascular disease (CVD), and albuminuria in type 1 diabetes. METHODS: We conducted an observational study of 636 type 1 diabetes patients. Central hemodynamics were measured by PWA as central aortic systolic pressure (CASP), central aortic pulse pressure (CPP), central aortic diastolic pressure (CADP), and subendocardial viability ratio (SEVR). CVD included revascularization, myocardial infarction, peripheral arterial disease, and stroke. Albuminuria was urinary albumin excretion rate >=30 mg/24 hours. We computed standardized odds ratios (ORs) adjusted for sex, age, mean arterial pressure (MAP), heart rate, height, estimated glomerular filtration rate, glycated hemoglobin (HbA1c) total cholesterol, antihypertensive medication, and smoking. At follow-up, development of end-stage renal disease (ESRD) and mortality was traced through electronic medical records. RESULTS: Patients were aged a mean of 54+/-13 years, and 289 (45%) were women. The mean +/- SD was 118+/-17 mm Hg for CASP, 75+/-10 mm Hg for CADP, 43+/-14 mm Hg for CPP, and 150+/-32 for SEVR. In fully adjusted models, increased CASP and CPP and decreased CADP and SEVR were associated with presence of CVD (n = 132; P <= 0.02) and presence of albuminuria (n = 335; P < 0.001). During follow-up, median (range) (2.8 (0.7-3.8) years), SEVR predicted ESRD or mortality combined (n = 26) after adjustment for sex, age, and MAP (P = 0.001), whereas CASP, CPP, and CADP did not (P >= 0.13). CONCLUSIONS: In type 1 diabetes patients, increased CASP and CPP and decreased CADP and SEVR were independently associated with history of CVD and albuminuria. Furthermore, SEVR predicted mortality and ESRD during follow-up. Future studies are needed to determine whether targeting central hemodynamics improves outcome. PMID- 24627445 TI - Arterial applanation tonometry: feasibility and reproducibility in children and adolescents. AB - BACKGROUND: Aortic pulse wave velocity (PWV) and augmentation index (AIx) are markers of vascular health and have recently been used in pediatric clinical trials. However, there are limited data on standardization of these measurements in pediatrics. The objective of this study was to prospectively test the feasibility and reproducibility of PWV and AIx in children and adolescents. METHODS: We performed arterial tonometry on 2 different days within 2 weeks in 40 healthy subjects aged 10-19 years. PWV and AIx were measured in triplicate on each visit. RESULTS: The visits were separated by a mean of 3.08+/-3.7 days. We obtained PWV in 77 of 80 (96%) visits and AIx in 76 of 80 (95%) visits in triplicate. Intraclass correlation coefficients (ICCs) for PWV were 0.61 (95% confidence interval (CI) = 0-0.86) when at least 2 measurements and 0.92 (95% CI = 0-1) when 3 measurements were obtained at each visit that met the quality criteria established for adults by the manufacturer (n = 17 and 3 paired visits, respectively). For AIx, ICCs were 0.78 (95% CI = 0.58-0.88) and 0.81 (95% CI = 0.63-0.90) when measurements with an operator index >=80, a measure of the quality of the waveform, were included (n = 39 and 36 paired visits, respectively). CONCLUSIONS: Arterial applanation tonometry is feasible and reproducible in healthy children and adolescents. AIx has excellent intervisit reproducibility, whereas the intervisit reproducibility of PWV relies on acquisition of multiple measurements that meet quality criteria established for adults. These results have implications for the methodology of future pediatric clinical trials in a population at increasingly higher risk for premature atherosclerosis. PMID- 24627446 TI - Uptake and metabolic effects of 3-iodothyronamine in hepatocytes. AB - 3-Iodothyronamine (T1AM) is an endogenous relative of thyroid hormone with profound metabolic effects. In different experimental models, T1AM increased blood glucose, and it is not clear whether this effect is entirely accounted by changes in insulin and/or glucagone secretion. Thus, in the present work, we investigated the uptake of T1AM by hepatocytes, which was compared with the uptake of thyroid hormones, and the effects of T1AM on hepatic glucose and ketone body production. Two different experimental models were used: HepG2 cells and perfused rat liver. Thyronines and thyronamines (T0AMs) were significantly taken up by hepatocytes. In HepG2 cells exposed to 1 MUM T1AM, at the steady state, the cellular concentration of T1AM exceeded the medium concentration by six- to eightfold. Similar accumulation occurred with 3,5,3'-triiodothyronine and thyroxine. Liver experiments confirmed significant T1AM uptake. T1AM was partly catabolized and the major catabolites were 3-iodothyroacetic acid (TA1) (in HepG2 cells) and T0AM (in liver). In both preparations, infusion with 1 MUM T1AM produced a significant increase in glucose production, if adequate gluconeogenetic substrates were provided. This effect was dampened at higher concentration (10 MUM) or in the presence of the amine oxidase inhibitor iproniazid, while TA1 was ineffective, suggesting that T1AM may have a direct gluconeogenetic effect. Ketone body release was significantly increased in liver, while variable results were obtained in HepG2 cells incubated with gluconeogenetic substrates. These findings are consistent with the stimulation of fatty acid catabolism, and a shift of pyruvate toward gluconeogenesis. Notably, these effects are independent from hormonal changes and might have physiological and pathophysiological importance. PMID- 24627448 TI - Standards, scales and chronic illness: a brief introduction. PMID- 24627447 TI - Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats. AB - There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset. PMID- 24627449 TI - Effects of exercise training on different quality of life dimensions in heart failure with preserved ejection fraction: the Ex-DHF-P trial. AB - BACKGROUND: Despite suffering from poor prognosis, progressive exercise intolerance, and impaired quality of life (QoL), effective therapeutic strategies in heart failure with preserved ejection fraction (HFpEF) are sparse. Exercise training (ET) improves physical QoL in HFpEF, but the effects on other aspects of QoL are unknown. METHODS: The multicentre, prospective, randomized, controlled Exercise training in Diastolic Heart Failure Pilot study included 64 HFpEF patients (65 +/- 7 years, 56% female). They were randomized to supervised endurance/resistance training in addition to usual care (ET, n = 44) or usual care alone (UC, n = 20). At baseline and after 3 months, QoL was assessed (36 item Short-form Health Survey (SF-36), Minnesota Living With Heart Failure Questionnaire (MLWHFQ), and Patient Health Questionnaire (PHQ-9). RESULTS: Exercise improved the following SF-36 dimensions: physical functioning (p < 0.001, p = 0.001 vs. UC), bodily pain (p = 0.046), general health perception (p < 0.001, p = 0.016 vs. UC), general mental health (p = 0.002), vitality (p = 0.003), social functioning (p < 0.001) physical (p < 0.001, p = 0.001 vs. UC), and mental component score (p = 0.030). ET did not improve role limitations due to physical and emotional problems. The MLWHFQ total scale (p < 0.001) and the MLWHFQ physical limitation scale (p < 0.001, p = 0.04 vs. UC) also improved with ET. The MLWHFQ emotional limitation scale did not change with ET. With ET, also the PHQ-9 total score improved significantly (p = 0.004, p = 0.735 vs. UC). CONCLUSIONS: In patients with HFpEF, exercise training improved emotional status, physical and social dimensions of QoL as well as symptoms of depression from pre to post test. Physical dimensions of QoL and general health perception also improved significantly with exercise in comparison to usual care. PMID- 24627450 TI - Risk factors of hematomyelia recurrence and clinical outcome in children with intradural spinal cord arteriovenous malformations. AB - BACKGROUND AND PURPOSE: Few published data are available concerning the risk of re-bleeding of spinal cord AVM after an hematomyelia and concerning the long-term clinical outcome. Our aim was to assess the risk of recurrence and long-term clinical outcome after hematomyelia in children with spinal cord AVMs. MATERIALS AND METHODS: This single-center retrospective study reviewed the clinical and radiologic data of 28 children younger than 18 years of age with arteriovenous malformation who had experienced at least 1 episode of hematomyelia between 1988 and 2012. Long-term clinical outcome was assessed by the American Spinal Injury Association Impairment Scale, and radiologic review included MR imaging and angioarchitecture on angiography (blinded to clinical information) before treatment and at recurrence. RESULTS: Sixteen children (57%) experienced 1 episode of hematomyelia, while 12 children (43%) experienced recurrence. Girls and boys were equally affected (sex ratio, 1:1), and mean clinical follow-up was 5.7 +/- 4.4 years. The risk of recurrence was higher for AVMs of the cervical and upper thoracic spine, 12 (100%) versus 11 (69%) (P = .01). A high American Spinal Injury Association scale score at last follow-up was reported for 11 children (39%), and the risk of recurrence tended to be associated with poorer functional prognosis (7 [64%] versus 5 [29%], P = .07). At the time of recurrence, perimedullary venous drainage was the main factor associated with recurrence (P = .002). Occlusion rate >=50% was associated with a decreased risk of recurrence (P = .047). CONCLUSIONS: In the present series, cervical and upper thoracic spinal cord AVMs and microarchitecture were predictive of the risk of hematomyelia recurrence. Perimedullary venous drainage was one of the main parameters associated with recurrence. Functional prognosis was better in patients with a single episode of hematomyelia. PMID- 24627451 TI - Osteoradionecrosis after radiation therapy for head and neck cancer: differentiation from recurrent disease with CT and PET/CT imaging. AB - BACKGROUND AND PURPOSE: Our aim was to compare the CT and PET/CT imaging features of osteoradionecrosis with those of recurrent disease after treatment of head and neck malignancy. MATERIALS AND METHODS: We retrospectively reviewed maxillofacial and neck CT scans obtained for suspected osteoradionecrosis or tumor recurrence for the presence of the following: 1) discrete solid mass, 2) cystic mass, 3) interruption of the bony cortex, 4) bony fragmentation, 5) bony trabecular loss, 6) intraosseous gas, and 7) bony sclerosis. Trabecular bone loss was further categorized as permeative (<75% loss of trabecula) or lucent (>75% loss). PET/CT studies performed for suspected osteoradionecrosis or tumor recurrence were evaluated for mean standard uptake value and maximum standard uptake value. RESULTS: Ten maxillofacial CT, 53 neck CT, and 23 PET/CT studies were performed in 63 patients. Osteoradionecrosis was diagnosed by pathology or imaging stability in 46 patients, and tumor recurrence, in 17 patients. Bony sclerosis was found to be significantly more prevalent in osteoradionecrosis and was never seen with tumor recurrence (P = .013). Patients with tumor recurrence were more likely to have a solid (P < .001) or cystic mass (P = .025), which was rare in osteoradionecrosis. While patients with tumor recurrence had significantly higher mean standard uptake values and maximum standard uptake values, there was significant overlap in mean standard uptake values and maximum standard uptake values between the 2 groups. CONCLUSIONS: There is significant overlap of standard uptake values in patients with osteoradionecrosis and tumor recurrence. CT findings provide more reliable diagnostic tools, with a solid or cystic mass strongly associated with tumor recurrence and bony sclerosis seen only with osteoradionecrosis. PMID- 24627452 TI - Influence of patient age on angioarchitecture of brain arteriovenous malformations. AB - BACKGROUND AND PURPOSE: The imaging characteristics and modes of presentation of brain AVMs may vary with patient age. Our aim was to determine whether clinical and angioarchitectural features of brain AVMs differ between children and adults. MATERIALS AND METHODS: A prospectively collected institutional data base of all patients diagnosed with brain AVMs since 2001 was queried. Demographic, clinical, and angioarchitecture information was summarized and analyzed with univariable and multivariable models. RESULTS: Results often differed when age was treated as a continuous variable as opposed to dividing subjects into children (18 years or younger; n = 203) versus adults (older than 18 years; n = 630). Children were more likely to present with AVM hemorrhage than adults (59% versus 41%, P < .001). Although AVMs with a larger nidus presented at younger ages (mean of 26.8 years for >6 cm compared with 37.1 years for <3 cm), this feature was not significantly different between children and adults (P = .069). Exclusively deep venous drainage was more common in younger subjects when age was treated continuously (P = .04) or dichotomized (P < .001). Venous ectasia was more common with increasing age (mean, 39.4 years with ectasia compared with 31.1 years without ectasia) and when adults were compared with children (52% versus 35%, P < .001). Patients with feeding artery aneurysms presented at a later average age (44.1 years) than those without such aneurysms (31.6 years); this observation persisted when comparing children with adults (13% versus 29%, P < .001). CONCLUSIONS: Although children with brain AVMs were more likely to come to clinical attention due to hemorrhage than adults, venous ectasia and feeding artery aneurysms were under-represented in children, suggesting that these particular high-risk features take time to develop. PMID- 24627453 TI - Immunoglobulin G4-related disease of the orbit: imaging features in 27 patients. AB - BACKGROUND AND PURPOSE: Immunoglobulin G4-related disease is a systemic fibroinflammatory process of unknown etiology, characterized by tissue infiltration by immunoglobulin G4 plasma cells. The purpose of this study was to retrospectively identify the spectrum of imaging features seen in immunoglobulin G4-related disease of the orbit. MATERIALS AND METHODS: This study included 27 patients with biopsy-proved immunoglobulin G4-related disease of the orbit and either a CT or MR imaging of the orbits. These CT or MR imaging examinations were evaluated for the following: extraocular muscle size, extraocular muscle tendon enlargement, lacrimal gland enlargement, infiltrative process in the orbital fat (increased attenuation on CT or abnormal signal on MR imaging), infraorbital nerve enlargement, mucosal thickening in the paranasal sinuses, and extension of orbital findings intracranially. RESULTS: Extraocular muscles were enlarged in 24 of 27 (89%) patients, 21 (88%) bilaterally. In 32 of 45 (71%) affected orbits, the lateral rectus was the most enlarged muscle. In 26 (96%) patients, the tendons of the extraocular muscles were spared. Nineteen (70%) patients had lacrimal gland enlargement. Twelve (44%) patients had an infiltrative process within the orbital fat. Infraorbital nerve enlargement was seen in 8 (30%) patients. Twenty-four (89%) patients had sinus disease. Cavernous sinus or Meckel cave extension was seen in 3 (11%) patients. CONCLUSIONS: In patients with extraocular muscle enlargement, particularly when the tendons are spared and the lateral rectus is the most enlarged, and even more so when other noted findings are present, immunoglobulin G4-related disease should be a leading differential consideration, even over more commonly known etiologies of extraocular muscle enlargement. PMID- 24627454 TI - Brain radiation doses to patients in an interventional neuroradiology laboratory. AB - BACKGROUND AND PURPOSE: In 2011, the International Commission on Radiologic Protection established an absorbed-dose threshold to the brain of 0.5 Gy as likely to produce cerebrovascular disease. In this paper, the authors investigated the brain doses delivered to patients during clinical neuroradiology procedures in a university hospital. MATERIALS AND METHODS: The radiation dose delivered to the brain was investigated in 99 diagnostic and therapeutic interventional neuroradiology procedures. Brain doses were calculated in a mathematic model of an adult standard anthropomorphic phantom by using the technical and radiation dose data of an x-ray biplane system submitted to regular quality controls and calibration programs. RESULTS: For cerebral embolizations, brain doses resulted in a maximum value of 1.7 Gy, with an average value of 500 mGy. Median and third quartile resulted in 400 and 856 mGy, respectively. For cerebral angiography, the average dose in the brain was 100 mGy. CONCLUSIONS: This work supports the International Commission on Radiologic Protection recommendation on enhancing optimization when doses to the brain could be higher than 0.5 Gy. Radiation doses should be recorded for all patients and kept as low as reasonably achievable. For pediatric patients and young adults, an individual evaluation of brain doses could be appropriate. PMID- 24627455 TI - Bone mineral density values derived from routine lumbar spine multidetector row CT predict osteoporotic vertebral fractures and screw loosening. AB - BACKGROUND AND PURPOSE: Established methods of assessing bone mineral density are associated with additional radiation exposure to the patient. In this study, we aimed to validate a method of assessing bone mineral density in routine multidetector row CT of the lumbar spine. MATERIALS AND METHODS: In 38 patients, bone mineral density was assessed in quantitative CT as a standard of reference and in sagittal reformations derived from standard multidetector row CT studies without IV contrast. MDCT-to-quantitative CT conversion equations were calculated and then applied to baseline multidetector row scans of another 62 patients. After a mean follow-up of 15 +/- 6 months, patients were re-assessed for incidental fractures and screw loosening after spondylodesis (n = 49). RESULTS: We observed conversion equations bone mineral densityMDCT = 0.78 * Hounsfield unitMDCTmg/mL (correlation with bone mineral densityquantitative CT, R(2) = 0.92, P < .001) for 120 kV(peak) tube voltage and bone mineral densityMDCT = 0.86 * Hounsfield unitMDCTmg/mL (R(2) = 0.81, P < .001) for 140 kVp, respectively. Seven patients (11.3%) had existing osteoporotic vertebral fractures at baseline, while 8 patients (12.9%) showed incidental osteoporotic vertebral fractures. Screw loosening was detected in 28 patients (57.1% of patients with spondylodesis). Patients with existing vertebral fractures showed significantly lower bone mineral densityMDCT than patients without fractures (P < .01). At follow-up, patients with incidental fractures and screw loosening after spondylodesis, respectively, showed significantly lower baseline bone mineral densityMDCT (P < .001 each). CONCLUSIONS: This longitudinal study demonstrated that converted bone mineral density values derived from routine lumbar spine multidetector row CT adequately differentiated patients with and without osteoporotic fractures and could predict incidental fractures and screw loosening after spondylodesis. PMID- 24627456 TI - Creating a duet: The Couples Life Story Approach in the United States and Japan. AB - There is a global need for interventions that help couples who are dealing with dementia. This paper describes the way in which interventionists from the United States and Japan participated in the development of an intervention for dyads in which one person is experiencing memory loss. The 5-week intervention, the Couples Life Story Approach, helps dyads to reminisce about their life together as a couple, to work on their patterns of communication, and to develop a Life Story Book. Based on an analysis of cases conducted in the United States (n = 20 couples) and Japan (n = 9 couples), this paper highlights the cross-fertilization process that has occurred as interventionists from the two countries have shared their experiences with one another. Using case illustrations, the discussion focuses on the clinical themes that have emerged for couples in the United States and Japan. PMID- 24627457 TI - Looking against the light: how perception of translucency depends on lighting direction. AB - Translucency is an important aspect of material appearance. To some extent, humans are able to estimate translucency in a consistent way across different shapes and lighting conditions, i.e., to exhibit translucency constancy. However, Fleming and Bulthoff (2005) have shown that that there can be large failures of constancy, with lighting direction playing an important role. In this paper, we explore the interaction of shape, illumination, and degree of translucency constancy more deeply by including in our analysis the variations in translucent appearance that are induced by the shape of the scattering phase function. This is an aspect of translucency that has been largely neglected. We used appearance matching to measure how perceived translucency depends on both lighting and phase function. The stimuli were rendered scenes that contained a figurine and the lighting direction was represented by spherical harmonic basis function. Observers adjusted the density of a figurine under one lighting condition to match the material property of a target figurine under another lighting condition. Across the trials, we varied both the lighting direction and the phase function of the target. The phase functions were sampled from a 2D space proposed by Gkioulekas et al. (2013) to span an important range of translucent appearance. We find the degree of translucency constancy depends strongly on the phase function's location in the same 2D space, suggesting that the space captures useful information about different types of translucency. We also find that the geometry of an object is important. We compare the case of a torus, which has a simple smooth shape, with that of the figurine, which has more complex geometric features. The complex shape shows a greater range of apparent translucencies and a higher degree of constancy failure. In summary, humans show significant failures of translucency constancy across changes in lighting direction, but the effect depends both on the shape complexity and the translucency phase function. PMID- 24627458 TI - Statistical templates for visual search. AB - How do we find a target embedded in a scene? Within the framework of signal detection theory, this task is carried out by comparing each region of the scene with a "template," i.e., an internal representation of the search target. Here we ask what form this representation takes when the search target is a complex image with uncertain orientation. We examine three possible representations. The first is the matched filter. Such a representation cannot account for the ease with which humans can find a complex search target that is rotated relative to the template. A second representation attempts to deal with this by estimating the relative orientation of target and match and rotating the intensity-based template. No intensity-based template, however, can account for the ability to easily locate targets that are defined categorically and not in terms of a specific arrangement of pixels. Thus, we define a third template that represents the target in terms of image statistics rather than pixel intensities. Subjects performed a two-alternative, forced-choice search task in which they had to localize an image that matched a previously viewed target. Target images were texture patches. In one condition, match images were the same image as the target and distractors were a different image of the same textured material. In the second condition, the match image was of the same texture as the target (but different pixels) and the distractor was an image of a different texture. Match and distractor stimuli were randomly rotated relative to the target. We compared human performance to pixel-based, pixel-based with rotation, and statistic-based search models. The statistic-based search model was most successful at matching human performance. We conclude that humans use summary statistics to search for complex visual targets. PMID- 24627459 TI - Noise and adaptation in multistable perception: noise drives when to switch, adaptation determines percept choice. AB - We study the dynamics of perceptual switching in ambiguous visual scenes that admit more than two interpretations/percepts to gain insight into the dynamics of perceptual multistability and its underlying neural mechanisms. We focus on visual plaids that are tristable and we present both experimental and computational results. We develop a firing-rate model based on mutual inhibition and adaptation that involves stochastic dynamics of multiple-attractor systems. The model can account for the dynamic properties (transition probabilities, distributions of percept durations, etc.) observed in the experiments. Noise and adaptation have both been shown to play roles in the dynamics of bistable perception. Here, tristable perception allows us to specify the roles of noise and adaptation in our model. Noise is critical in considering the time of a switch. On the other hand, adaptation mechanisms are critical in considering perceptual choice (in tristable perception, each time a percept ends, there is a possible choice between two new percepts). PMID- 24627460 TI - A new two-alternative forced choice method for the unbiased characterization of perceptual bias and discriminability. AB - Perception is often biased by secondary stimulus attributes (e.g., stimulus noise, attention, or spatial context). A correct quantitative characterization of perceptual bias is essential for testing hypotheses about the underlying perceptual mechanisms and computations. We demonstrate that the standard two alternative forced choice (2AFC) method can lead to incorrect estimates of perceptual bias. We present a new 2AFC method that solves this problem by asking subjects to judge the relative perceptual distances between the test and each of two reference stimuli. Naive subjects can easily perform this task. We successfully validated the new method with a visual motion-discrimination experiment. We demonstrate that the method permits an efficient and accurate characterization of perceptual bias and simultaneously provides measures of discriminability for both the reference and test stimulus, all from a single stimulus condition. This makes it an attractive choice for the characterization of perceptual bias and discriminability in a wide variety of psychophysical experiments. PMID- 24627461 TI - Prevalence of peripheral vascular disease and its association with carotid intima media thickness and arterial stiffness in type 2 diabetes: the Chennai urban rural epidemiology study (CURES 111). AB - We investigated the prevalence of peripheral vascular disease (PVD) and its association with preclinical atherosclerotic markers [intima-media thickness (IMT)] and arterial stiffness among 1755 urban south Indian type 2 diabetic subjects recruited from the Chennai Urban Rural Epidemiology Study (CURES). Doppler studies were performed, and PVD was defined as ankle-brachial index (ABI) of <=0.9. IMT of the common carotid artery was determined using high-resolution B mode ultrasonography, and augmentation index (AGI) was measured using the Sphygmocor apparatus. The overall prevalence of PVD was 8.3% (age-standardized 6.5%). The prevalence of PVD was higher among known diabetic subjects (n = 1401) compared to newly detected diabetic subjects (n = 354) (8.6% vs 6.8%, p = 0.250). The mean IMT and AGI in subjects with PVD were significantly higher compared to subjects without PVD (IMT: 0.99 +/- 0.26 mm vs 0.83 +/- 0.19 mm; AGI: 28.1 +/- 9.6% vs 25.7 +/- 9.8%, respectively). IMT was independently associated with PVD even after adjusting for age [odds ratio (OR) = 2.9 (1.2-6.7), p = 0.016 for second tertile and OR = 3.9 (1.7-9.3), p = 0.002 for third tertile compared to first tertile]. AGI was also associated with PVD in the unadjusted model [OR = 1.8 (1.1-3.1), p = 0.027 for second tertile compared to first tertile]. However, when adjusted for age, the significance was lost. In conclusion, among urban south Indian type 2 diabetic subjects, the prevalence of PVD is 8.3% and IMT is more strongly associated with PVD than AGI. PMID- 24627462 TI - Medical, ethical and personal dimensions of parent-offspring conflicts. PMID- 24627463 TI - The evolution of bacterial social life: From the ivory tower to the front lines of public health. AB - Drug-resistant bacteria are a huge and growing threat to public health. A solution exists in theory, but had not yet been put to a practical test. The accompanying paper by Ross-Gillespie et al., the theory is put to a test and performs successfully. As predicted, using a drug that targets bacteria's shared secreted 'public goods' molecules instead of cell components did not drive the bacterial evolution of drug resistance, and therefore retained its effectiveness. This result holds great promise for better drugs and vaccines against many infectious diseases, and also for better cancer therapies. PMID- 24627464 TI - Night waking among breastfeeding mothers and infants: Conflict, congruence or both? PMID- 24627466 TI - Follistatin: a novel therapeutic for the improvement of muscle regeneration. AB - Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. The objective of this study was to explore the use of an engineered follistatin therapeutic created by fusing FST315 lacking heparin binding activity to the N terminus of a murine IgG1 Fc (FST315-DeltaHBS-Fc) as a systemic therapeutic agent in models of muscle injury. Systemic administration of this molecule was found to increase body weight and lean muscle mass after weekly administration in normal mice. Subsequently, we tested this agent in several models of muscle injury, which were chosen based on their severity of damage and their ability to reflect clinical settings. FST315-DeltaHBS-Fc treatment proved to be a potent inducer of muscle remodeling and regeneration. FST315-DeltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. Collectively, these data demonstrate the benefits of a therapeutically viable form of FST that can be leveraged as an alternate means of ameliorating muscle regeneration. PMID- 24627465 TI - Working memory abilities among children treated for medulloblastoma: parent report and child performance. AB - OBJECTIVE: We investigated the 5-year postsurgical developmental trajectory of working memory (WM) in children with medulloblastoma using parent and performance based measures. METHOD: This study included 167 patients treated for medulloblastoma. Serial assessments of WM occurred at predetermined time points for 5 years. RESULTS: There was a subtle, statistically significant increase in parental concern about WM, coupled with a statistically significant decrease in age-standardized scores on performance-based measures. However, whole-group mean scores on both parent and performance-based measures remained in the age-expected range. Posterior fossa syndrome was consistently associated with poorer WM. Younger age at treatment and higher treatment intensity were associated with greater negative change in WM performance only. CONCLUSIONS: Most children treated for medulloblastoma display WM within the age-appropriate range according to parent report and performance. However, the subtle negative changes over time and identified subgroups at increased risk highlight the need for ongoing monitoring of this population. PMID- 24627467 TI - Activation of alpha4beta2*/alpha6beta2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors. AB - Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for alpha4beta2, ABT-089 [2-methyl-3-[2(S) pyrrolidinylmethoxy]pyridine], and alpha7, ABT-107 [5-(6-[(3R)-1 azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole] (AbbVie, North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and beta2-containing nAChRs were measured using [(3)H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotine-dependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids. PMID- 24627472 TI - Molecular basis for impaired DNA damage response function associated with the RAP80 DeltaE81 defect. AB - Signal transduction within the DNA damage response is driven by the flux of protein-protein interaction cascades that ultimately recruit repair complexes to sites of damage. The protein RAP80 plays a central role in the damage response by targeting BRCA1/BRCA2 tumor suppressors to DNA damage foci through multivalent binding of Lys-63-linked polyubiquitin chains. Mutations within the high penetrance BRCA1/BRCA2 genes account for ~20% of familial breast cancers. The genetic basis for the remaining cancers remains unknown, but may involve defects in binding partners for BRCA1 and BRCA2 that lead to impaired targeting to foci and a concomitant role in the pathogenesis of cancer. Recently, an in-frame deletion mutation (DeltaE81) in a conserved region from the first ubiquitin interaction motif of RAP80 has been linked to an increase in chromosomal abnormalities. Using NMR spectroscopy, we demonstrate that the N-cap motif within the alpha-helix of the first ubiquitin interaction motif from DeltaE81 undergoes a structural frameshift that leads to abolishment of multivalent binding of polyubiquitin chains. Loss of this single glutamate residue disrupts favorable electrostatic interactions between RAP80 and ubiquitin, establishing a plausible molecular basis for a potential predisposition to cancer unrelated to mutations within BRCA1/BRCA2 genes. PMID- 24627473 TI - Phosphorylation of the antiviral protein interferon-inducible transmembrane protein 3 (IFITM3) dually regulates its endocytosis and ubiquitination. AB - Interferon-inducible transmembrane protein 3 (IFITM3) is essential for innate defense against influenza virus in mice and humans. IFITM3 localizes to endolysosomes where it prevents virus fusion, although mechanisms controlling its trafficking to this cellular compartment are not fully understood. We determined that both mouse and human IFITM3 are phosphorylated by the protein-tyrosine kinase FYN on tyrosine 20 (Tyr(20)) and that mouse IFITM3 is also phosphorylated on the non-conserved Tyr(27). Phosphorylation led to a cellular redistribution of IFITM3, including plasma membrane accumulation. Mutation of Tyr(20) caused a similar redistribution of IFITM3 and resulted in decreased antiviral activity against influenza virus, whereas Tyr(27) mutation of mouse IFITM3 showed minimal effects on localization or activity. Using FYN knockout cells, we also found that IFITM3 phosphorylation is not a requirement for its antiviral activity. Together, these results indicate that Tyr(20) is part of an endocytosis signal that can be blocked by phosphorylation or by mutation of this residue. Further mutagenesis narrowed this endocytosis-controlling region to four residues conforming to a YXXPhi (where X is any amino acid and Phi is Val, Leu, or Ile) endocytic motif that, when transferred to CD4, resulted in its internalization from the cell surface. Additionally, we found that phosphorylation of IFITM3 by FYN and mutagenesis of Tyr(20) both resulted in decreased IFITM3 ubiquitination. Overall, these results suggest that modification of Tyr(20) may serve in a cellular checkpoint controlling IFITM3 trafficking and degradation and demonstrate the complexity of posttranslational regulation of IFITM3. PMID- 24627474 TI - Mapping interactions between myosin relay and converter domains that power muscle function. AB - Intramolecular communication within myosin is essential for its function as motor, but the specific amino acid residue interactions required are unexplored within muscle cells. Using Drosophila melanogaster skeletal muscle myosin, we performed a novel in vivo molecular suppression analysis to define the importance of three relay loop amino acid residues (Ile(508), Asn(509), and Asp(511)) in communicating with converter domain residue Arg(759). We found that the N509K relay mutation suppressed defects in myosin ATPase, in vitro motility, myofibril stability, and muscle function associated with the R759E converter mutation. Through molecular modeling, we define a mechanism for this interaction and suggest why the I508K and D511K relay mutations fail to suppress R759E. Interestingly, I508K disabled motor function and myofibril assembly, suggesting that productive relay-converter interaction is essential for both processes. We conclude that the putative relay-converter interaction mediated by myosin residues 509 and 759 is critical for the biochemical and biophysical function of skeletal muscle myosin and the normal ultrastructural and mechanical properties of muscle. PMID- 24627475 TI - Channel-anchored protein kinase CK2 and protein phosphatase 1 reciprocally regulate KCNQ2-containing M-channels via phosphorylation of calmodulin. AB - M-type potassium channels, encoded by the KCNQ family genes (KCNQ2-5), require calmodulin as an essential co-factor. Calmodulin bound to the KCNQ2 subunit regulates channel trafficking and stabilizes channel activity. We demonstrate that phosphorylation of calmodulin by protein kinase CK2 (casein kinase 2) rapidly and reversibly modulated KCNQ2 current. CK2-mediated phosphorylation of calmodulin strengthened its binding to KCNQ2 channel, caused resistance to phosphatidylinositol 4,5-bisphosphate depletion, and increased KCNQ2 current amplitude. Accordingly, application of CK2-selective inhibitors suppressed KCNQ2 current. This suppression was prevented by co-expression of CK2 phosphomimetic calmodulin mutants or pretreatment with a protein phosphatase inhibitor, calyculin A. We also demonstrated that functional CK2 and protein phosphatase 1 (PP1) were selectively tethered to the KCNQ2 subunit. We identified a functional KVXF consensus site for PP1 binding in the N-terminal tail of KCNQ2 subunit: mutation of this site augmented current density. CK2 inhibitor treatment suppressed M-current in rat superior cervical ganglion neurons, an effect negated by overexpression of phosphomimetic calmodulin or pretreatment with calyculin A Furthermore, CK2 inhibition diminished the medium after hyperpolarization by suppressing the M-current. These findings suggest that CK2-mediated phosphorylation of calmodulin regulates the M-current, which is tonically regulated by CK2 and PP1 anchored to the KCNQ2 channel complex. PMID- 24627476 TI - Thioredoxin-interacting protein promotes islet amyloid polypeptide expression through miR-124a and FoxA2. AB - Thioredoxin-interacting protein (TXNIP) is up-regulated by glucose and diabetes and plays a critical role in glucotoxicity, inflammation, and beta-cell apoptosis, whereas we have found that TXNIP deficiency protects against diabetes. Interestingly, human islet amyloid polypeptide (IAPP) is also induced by glucose, aggregates into insoluble amyloid fibrils found in islets of most individuals with type 2 diabetes and promotes inflammation and beta-cell cytotoxicity. However, so far no connection between TXNIP and IAPP signaling had been reported. Using TXNIP gain and loss of function experiments, INS-1 beta-cells and beta-cell specific Txnip knock-out mice, we now found that TXNIP regulates IAPP expression. Promoter analyses and chromatin-immunoprecipitation assays further demonstrated that TXNIP increases IAPP expression at the transcriptional level, and we discovered that TXNIP-induced FoxA2 (forkhead box A2) transcription factor expression was conferring this effect by promoting FoxA2 enrichment at the proximal FoxA2 site in the IAPP promoter. Moreover, we found that TXNIP down regulates miR-124a expression, a microRNA known to directly target FoxA2. Indeed, miR-124a overexpression led to decreased FoxA2 expression and IAPP promoter occupancy and to a significant reduction in IAPP mRNA and protein expression and also effectively inhibited TXNIP-induced IAPP expression. Thus, our studies have identified a novel TXNIP/miR-124a/FoxA2/IAPP signaling cascade linking the critical beta-cell signaling pathways of TXNIP and IAPP and thereby provide new mechanistic insight into an important aspect of transcriptional regulation and beta-cell biology. PMID- 24627477 TI - Inhibition of pancreatic beta-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance. AB - Glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells is caused by Ca(2+) entry via voltage-dependent Ca(2+) channels. CaMKII is a key mediator and feedback regulator of Ca(2+) signaling in many tissues, but its role in beta cells is poorly understood, especially in vivo. Here, we report that mice with conditional inhibition of CaMKII in beta-cells show significantly impaired glucose tolerance due to decreased GSIS. Moreover, beta-cell CaMKII inhibition dramatically exacerbates glucose intolerance following exposure to a high fat diet. The impairment of islet GSIS by beta-cell CaMKII inhibition is not accompanied by changes in either glucose metabolism or the activities of KATP and voltage-gated potassium channels. However, glucose-stimulated Ca(2+) entry via voltage-dependent Ca(2+) channels is reduced in islet beta-cells with CaMKII inhibition, as well as in primary wild-type beta-cells treated with a peptide inhibitor of CaMKII. The levels of basal beta-cell cytoplasmic Ca(2+) and of endoplasmic reticulum Ca(2+) stores are also decreased by CaMKII inhibition. In addition, CaMKII inhibition suppresses glucose-stimulated action potential firing frequency. These results reveal that CaMKII is a Ca(2+) sensor with a key role as a feed-forward stimulator of beta-cell Ca(2+) signals that enhance GSIS under physiological and pathological conditions. PMID- 24627478 TI - Fat-specific protein 27 (FSP27) interacts with adipose triglyceride lipase (ATGL) to regulate lipolysis and insulin sensitivity in human adipocytes. AB - In adipocytes, lipolysis is a highly regulated process involving hormonal signals, lipid droplet-associated proteins, and lipases. The discovery of new lipid droplet-associated proteins added complexity to the current model of lipolysis. In this study, we used cultured human adipocytes to demonstrate that fat-specific protein 27 (FSP27), an abundantly expressed protein in adipocytes, regulates both basal and stimulated lipolysis by interacting with adipose triglyceride lipase (ATGL, also called desnutrin or PNPLA2). We identified a core domain of FSP27, amino acids 120-220, that interacts with ATGL to inhibit its lipolytic function and promote triglyceride storage. We also defined the role of FSP27 in free fatty acid-induced insulin resistance in adipocytes. FSP27 depletion in human adipocytes increased lipolysis and inhibited insulin signaling by decreasing AKT phosphorylation. However, reducing lipolysis by either depletion of ATGL or expression of exogenous full-length FSP27 or amino acids 120 220 protected human adipocytes against the adverse effects of free fatty acids on insulin signaling. In embryonic fibroblasts derived from ATGL KO mice, exogenous free fatty acids did not affect insulin sensitivity. Our results demonstrate a crucial role for FSP27-ATGL interactions in regulating lipolysis, triglyceride accumulation, and insulin signaling in human adipocytes. PMID- 24627479 TI - Chemical organization of the cell wall polysaccharide core of Malassezia restricta. AB - Malassezia species are ubiquitous residents of human skin and are associated with several diseases such as seborrheic dermatitis, tinea versicolor, folliculitis, atopic dermatitis, and scalp conditions such as dandruff. Host-Malassezia interactions and mechanisms to evade local immune responses remain largely unknown. Malassezia restricta is one of the most predominant yeasts of the healthy human skin, its cell wall has been investigated in this paper. Polysaccharides in the M. restricta cell wall are almost exclusively alkali insoluble, showing that they play an essential role in the organization and rigidity of the M. restricta cell wall. Fractionation of cell wall polymers and carbohydrate analyses showed that the polysaccharide core of the cell wall of M. restricta contained an average of 5% chitin, 20% chitosan, 5% beta-(1,3)-glucan, and 70% beta-(1,6)-glucan. In contrast to other yeasts, chitin and chitosan are relatively abundant, and beta-(1,3)-glucans constitute a minor cell wall component. The most abundant polymer is beta-(1,6)-glucans, which are large molecules composed of a linear beta-(1,6)-glucan chains with beta-(1,3)-glucosyl side chain with an average of 1 branch point every 3.8 glucose unit. Both beta glucans are cross-linked, forming a huge alkali-insoluble complex with chitin and chitosan polymers. Data presented here show that M. restricta has a polysaccharide organization very different of all fungal species analyzed to date. PMID- 24627480 TI - Blockade of Fas signaling in breast cancer cells suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation. AB - Mechanisms for cancer-related inflammation remain to be fully elucidated. Non apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFkappaB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer. PMID- 24627481 TI - Glycosylphosphatidylinositol anchoring directs the assembly of Sup35NM protein into non-fibrillar, membrane-bound aggregates. AB - In prion-infected hosts, PrPSc usually accumulates as non-fibrillar, membrane bound aggregates. Glycosylphosphatidylinositol (GPI) anchor-directed membrane association appears to be an important factor controlling the biophysical properties of PrPSc aggregates. To determine whether GPI anchoring can similarly modulate the assembly of other amyloid-forming proteins, neuronal cell lines were generated that expressed a GPI-anchored form of a model amyloidogenic protein, the NM domain of the yeast prion protein Sup35 (Sup35(GPI)). We recently reported that GPI anchoring facilitated the induction of Sup35(GPI) prions in this system. Here, we report the ultrastructural characterization of self-propagating Sup35(GPI) aggregates of either spontaneous or induced origin. Like membrane bound PrPSc, Sup35(GPI) aggregates resisted release from cells treated with phosphatidylinositol-specific phospholipase C. Sup35(GPI) aggregates of spontaneous origin were detergent-insoluble, protease-resistant, and self propagating, in a manner similar to that reported for recombinant Sup35NM amyloid fibrils and induced Sup35(GPI) aggregates. However, GPI-anchored Sup35 aggregates were not stained with amyloid-binding dyes, such as Thioflavin T. This was consistent with ultrastructural analyses, which showed that the aggregates corresponded to dense cell surface accumulations of membrane vesicle-like structures and were not fibrillar. Together, these results showed that GPI anchoring directs the assembly of Sup35NM into non-fibrillar, membrane-bound aggregates that resemble PrPSc, raising the possibility that GPI anchor-dependent modulation of protein aggregation might occur with other amyloidogenic proteins. This may contribute to differences in pathogenesis and pathology between prion diseases, which uniquely involve aggregation of a GPI-anchored protein, versus other protein misfolding diseases. PMID- 24627483 TI - Regulation of PSMB5 protein and beta subunits of mammalian proteasome by constitutively activated signal transducer and activator of transcription 3 (STAT3): potential role in bortezomib-mediated anticancer therapy. AB - The ubiquitin-proteasome system facilitates the degradation of ubiquitin-tagged proteins and performs a regulatory role in cells. Elevated proteasome activity and subunit expression are found in several cancers. However, the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear despite the well investigated and defined role of the mammalian proteasome. This study was initiated to elucidate the mechanisms involved in the regulation of beta subunits of the mammalian proteasome. Suppression of STAT3 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the beta subunits of the 20 S core complex in DU145 cells. Notably, PSMB5, a molecular target of bortezomib, was shown to be a target of STAT3. Knockdown of STAT3 decreased PSMB5 protein. Inhibition of phospho-STAT3 substantially reduced PSMB5 protein levels in cells expressing constitutively active-STAT3. Accumulation of activated STAT3 resulted in the induction of PSMB5 promoter and protein levels. In addition, a direct correlation was observed between the endogenous levels of PSMB5 and constitutively active STAT3. PSMB5 and STAT3 protein levels remained unaltered following the inhibition of proteasome activity. The EGF-induced concerted increase of beta subunits was blocked by inhibition of the EGF receptor or STAT3 but not by the PI3K/AKT or MEK/ERK pathways. Decreased proteasome activities were due to reduced protein levels of catalytic subunits of the proteasome in STAT3-inhibited cells. Combined treatments with bortezomib and inhibitor of STAT3 abrogated proteasome activity and enhanced cellular apoptosis. Overall, we demonstrate that aberrant activation of STAT3 regulates the expression of beta subunits, in particular PSMB5, and the catalytic activity of the proteasome. PMID- 24627482 TI - The BiP molecular chaperone plays multiple roles during the biogenesis of torsinA, an AAA+ ATPase associated with the neurological disease early-onset torsion dystonia. AB - Early-onset torsion dystonia (EOTD) is a neurological disorder characterized by involuntary and sustained muscle contractions that can lead to paralysis and abnormal posture. EOTD is associated with the deletion of a glutamate (DeltaE) in torsinA, an endoplasmic reticulum (ER) resident AAA(+) ATPase. To date, the effect of DeltaE on torsinA and the reason that this mutation results in EOTD are unclear. Moreover, there are no specific therapeutic options to treat EOTD. To define the underlying biochemical defects associated with torsinADeltaE and to uncover factors that might be targeted to offset defects associated with torsinADeltaE, we developed a yeast torsinA expression system and tested the roles of ER chaperones in mediating the folding and stability of torsinA and torsinADeltaE. We discovered that the ER lumenal Hsp70, BiP, an associated Hsp40, Scj1, and a nucleotide exchange factor, Lhs1, stabilize torsinA and torsinADeltaE. BiP also maintained torsinA and torsinADeltaE solubility. Mutations predicted to compromise specific torsinA functional motifs showed a synthetic interaction with the DeltaE mutation and destabilized torsinADeltaE, suggesting that the DeltaE mutation predisposes torsinA to defects in the presence of secondary insults. In this case, BiP was required for torsinADeltaE degradation, consistent with data that specific chaperones exhibit either pro degradative or pro-folding activities. Finally, using two independent approaches, we established that BiP stabilizes torsinA and torsinADeltaE in mammalian cells. Together, these data define BiP as the first identified torsinA chaperone, and treatments that modulate BiP might improve symptoms associated with EOTD. PMID- 24627485 TI - The nuclear pore complex function of Sec13 protein is required for cell survival during retinal development. AB - Sec13 is a dual function protein, being a core component of both the COPII coat, which mediates protein trafficking from the endoplasmic reticulum to the Golgi apparatus, and the nuclear pore complex (NPC), which facilitates nucleo cytoplasmic traffic. Here, we present a genetic model to differentiate the roles of these two functions of Sec13 in vivo. We report that sec13(sq198) mutant embryos develop small eyes that exhibit disrupted retinal lamination and that the mutant retina contains an excessive number of apoptotic cells. Surprisingly, we found that loss of COPII function by oligonucleotide-mediated gene knockdown of sec31a and sec31b or brefeldin A treatment did not disrupt retinal lamination, although it did result in digestive organ defects similar to those seen in sec13(sq198), suggesting that the digestive organ defects observed in sec13(sq198) are due to loss of COPII function, whereas the retinal lamination defects are due to loss of the NPC function. We showed that the retinal cells of sec13(sq198) failed to form proper nuclear pores, leading to a nuclear accumulation of total mRNA and abnormal activation of the p53-dependent apoptosis pathway, causing the retinal defect in sec13(sq198). Furthermore, we found that a mutant lacking Nup107, a key NPC-specific component, phenocopied the retinal lamination phenotype as observed in sec13(sq198). Our results demonstrate a requirement for the nuclear pore function of Sec13 in development of the retina and provide the first genetic evidence to differentiate the contributions of the NPC and the COPII functions of Sec13 during organogenesis. PMID- 24627484 TI - The lantibiotic NAI-107 binds to bactoprenol-bound cell wall precursors and impairs membrane functions. AB - The lantibiotic NAI-107 is active against Gram-positive bacteria including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. To identify the molecular basis of its potency, we studied the mode of action in a series of whole cell and in vitro assays and analyzed structural features by nuclear magnetic resonance (NMR). The lantibiotic efficiently interfered with late stages of cell wall biosynthesis and induced accumulation of the soluble peptidoglycan precursor UDP-N-acetylmuramic acid-pentapeptide (UDP-MurNAc pentapeptide) in the cytoplasm. Using membrane preparations and a complete cascade of purified, recombinant late stage peptidoglycan biosynthetic enzymes (MraY, MurG, FemX, PBP2) and their respective purified substrates, we showed that NAI-107 forms complexes with bactoprenol-pyrophosphate-coupled precursors of the bacterial cell wall. Titration experiments indicate that first a 1:1 stoichiometric complex occurs, which then transforms into a 2:1 (peptide: lipid II) complex, when excess peptide is added. Furthermore, lipid II and related molecules obviously could not serve as anchor molecules for the formation of defined and stable nisin-like pores, however, slow membrane depolarization was observed after NAI-107 treatment, which could contribute to killing of the bacterial cell. PMID- 24627486 TI - Molecular dissection of phage endolysin: an interdomain interaction confers host specificity in Lysin A of Mycobacterium phage D29. AB - Mycobacterium tuberculosis has always been recognized as one of the most successful pathogens. Bacteriophages that attack and kill mycobacteria offer an alternate mechanism for the curtailment of this bacterium. Upon infection, mycobacteriophages produce lysins that catalyze cell wall peptidoglycan hydrolysis and mycolic acid layer breakdown of the host resulting in bacterial cell rupture and virus release. The ability to lyse bacterial cells make lysins extremely significant. We report here a detailed molecular dissection of the function and regulation of mycobacteriophage D29 Lysin A. Several truncated versions of Lysin A were constructed, and their activities were analyzed by zymography and by expressing them in both Escherichia coli and Mycobacterium smegmatis. Our experiments establish that Lysin A harbors two catalytically active domains, both of which show E. coli cell lysis upon their expression exclusively in the periplasmic space. However, the expression of only one of these domains and the full-length Lysin A caused M. smegmatis cell lysis. Interestingly, full-length protein remained inactive in E. coli periplasm. Our data suggest that the inactivity is ensued by a C-terminal domain that interacts with the N-terminal domain. This interaction was affirmed by surface plasmon resonance. Our experiments also demonstrate that the C-terminal domain of Lysin A selectively binds to M. tuberculosis and M. smegmatis peptidoglycans. Our methodology of studying E. coli cell lysis by Lysin A and its truncations after expressing these proteins in the bacterial periplasm with the help of signal peptide paves the way for a large scale identification and analysis of such proteins obtained from other bacteriophages. PMID- 24627487 TI - C18 ORF1, a novel negative regulator of transforming growth factor-beta signaling. AB - Transforming growth factor (TGF)-beta signaling is deliberately regulated at multiple steps in its pathway from the extracellular microenvironment to the nucleus. However, how TGF-beta signaling is activated or attenuated is not fully understood. We recently identified transmembrane prostate androgen-induced RNA (TMEPAI), which is involved in a negative feedback loop of TGF-beta signaling. When we searched for a family molecule(s) for TMEPAI, we found C18ORF1, which, like TMEPAI, possesses two PY motifs and one Smad-interacting motif (SIM) domain. As expected, C18ORF1 could block TGF-beta signaling but not bone morphogenetic protein signaling. C18ORF1 bound to Smad2/3 via its SIM and competed with the Smad anchor for receptor activation for Smad2/3 binding to attenuate recruitment of Smad2/3 to the TGF-beta type I receptor (also termed activin receptor-like kinase 5 (ALK5)), in a similar fashion to TMEPAI. Knockdown of C18ORF1 prolonged duration of TGF-beta-induced Smad2 phosphorylation and concomitantly potentiated the expression of JunB, p21, and TMEPAI mRNAs induced by TGF-beta. Consistently, TGF-beta-induced cell migration was enhanced by the knockdown of C18ORF1. These results indicate that the inhibitory function of C18ORF1 on TGF-beta signaling is similar to that of TMEPAI. However, in contrast to TMEPAI, C18ORF1 was not induced upon TGF-beta signaling. Thus, we defined C18ORF1 as a surveillant of steady state TGF-beta signaling, whereas TMEPAI might help C18ORF1 to inhibit TGF beta signaling in a coordinated manner when cells are stimulated with high levels of TGF-beta. PMID- 24627488 TI - Evidence for steric regulation of fibrinogen binding to Staphylococcus aureus fibronectin-binding protein A (FnBPA). AB - The adjacent fibrinogen (Fg)- and fibronectin (Fn)-binding sites on Fn-binding protein A (FnBPA), a cell surface protein from Staphylococcus aureus, are implicated in the initiation and persistence of infection. FnBPA contains a single Fg-binding site (that also binds elastin) and multiple Fn-binding sites. Here, we solved the structure of the N2N3 domains containing the Fg-binding site of FnBPA in the apo form and in complex with a Fg peptide. The Fg binding mechanism is similar to that of homologous bacterial proteins but without the requirement for "latch" strand residues. We show that the Fg-binding sites and the most N-terminal Fn-binding sites are nonoverlapping but in close proximity. Although Fg and a subdomain of Fn can form a ternary complex on an FnBPA protein construct containing a Fg-binding site and single Fn-binding site, binding of intact Fn appears to inhibit Fg binding, suggesting steric regulation. Given the concentrations of Fn and Fg in the plasma, this mechanism might result in targeting of S. aureus to fibrin-rich thrombi or elastin-rich tissues. PMID- 24627489 TI - Transient contraction of mitochondria induces depolarization through the inner membrane dynamin OPA1 protein. AB - Dynamin-related membrane remodeling proteins regulate mitochondrial morphology by mediating fission and fusion. Although mitochondrial morphology is considered an important factor in maintaining mitochondrial function, a direct mechanistic link between mitochondrial morphology and function has not been defined. We report here a previously unrecognized cellular process of transient contraction of the mitochondrial matrix. Importantly, we found that this transient morphological contraction of mitochondria is accompanied by a reversible loss or decrease of inner membrane potential. Fission deficiency greatly amplified this phenomenon, which functionally exhibited an increase of inner membrane proton leak. We found that electron transport activity is necessary for the morphological contraction of mitochondria. Furthermore, we discovered that silencing the inner membrane associated dynamin optic atrophy 1 (OPA1) in fission deficiency prevented mitochondrial depolarization and decreased proton leak without blocking mitochondrial contraction, indicating that OPA1 is a factor in coupling matrix contraction to mitochondrial depolarization. Our findings show that transient matrix contraction is a novel cellular mechanism regulating mitochondrial activity through the function of the inner membrane dynamin OPA1. PMID- 24627490 TI - Complex formation between S100B protein and the p90 ribosomal S6 kinase (RSK) in malignant melanoma is calcium-dependent and inhibits extracellular signal regulated kinase (ERK)-mediated phosphorylation of RSK. AB - S100B is a prognostic marker for malignant melanoma. Increasing S100B levels are predictive of advancing disease stage, increased recurrence, and low overall survival in malignant melanoma patients. Using S100B overexpression and shRNA(S100B) knockdown studies in melanoma cell lines, elevated S100B was found to enhance cell viability and modulate MAPK signaling by binding directly to the p90 ribosomal S6 kinase (RSK). S100B-RSK complex formation was shown to be Ca(2+) dependent and to block ERK-dependent phosphorylation of RSK, at Thr-573, in its C terminal kinase domain. Additionally, the overexpression of S100B sequesters RSK into the cytosol and prevents it from acting on nuclear targets. Thus, elevated S100B contributes to abnormal ERK/RSK signaling and increased cell survival in malignant melanoma. PMID- 24627491 TI - Specificity protein 1 (Sp1) maintains basal epithelial expression of the miR-200 family: implications for epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is required for the specification of tissues during embryonic development and is recapitulated during the metastatic progression of tumors. The miR-200 family plays a critical role in enforcing the epithelial state with their expression lost in cells undergoing EMT. EMT can be mediated by activation of the ZEB1 and ZEB2 (ZEB) transcription factors, which repress miR-200 expression via a self-reinforcing double negative feedback loop to promote the mesenchymal state. However, it remains unclear what factors drive and maintain epithelial-specific expression of miR-200 in the absence of EMT inducing factors. Here, we show that the transcription factor Specificity Protein 1 (Sp1) binds to the miR-200b~200a~429 proximal promoter and activates miR-200 expression in epithelial cells. In mesenchymal cells, Sp1 expression is maintained, but its ability to activate the miR-200 promoter is perturbed by ZEB mediated repression. Reduction of Sp1 expression caused changes in EMT-associated markers in epithelial cells. Furthermore, we observed co-expression of Sp1 and miR-200 during mouse embryonic development wherein miR-200 expression was only lost in regions with high ZEB expression. Together, these findings indicate that miR-200 family members require Sp1 to drive basal expression and to maintain an epithelial state. PMID- 24627492 TI - High resolution structure and double electron-electron resonance of the zebrafish voltage-dependent anion channel 2 reveal an oligomeric population. AB - In recent years, there has been a vast increase in structural and functional understanding of VDAC1, but VDAC2 and -3 have been understudied despite having many unique phenotypes. One reason for the paucity of structural and biochemical characterization of the VDAC2 and -3 isoforms stems from the inability of obtaining purified, functional protein. Here we demonstrate the expression, isolation, and basic characterization of zebrafish VDAC2 (zfVDAC2). Further, we resolved the structure of zfVDAC2 at 2.8 A resolution, revealing a crystallographic dimer. The dimer orientation was confirmed in solution by double electron-electron resonance spectroscopy and by cross-linking experiments disclosing a dimer population of ~20% in lauryldimethine amine oxide detergent micelles, whereas in lipidic bicelles a higher population of dimeric and higher order oligomers species were observed. The present study allows for a more accurate structural comparison between VDAC2 and its better-studied counterpart VDAC1. PMID- 24627493 TI - Yeast AMP-activated protein kinase monitors glucose concentration changes and absolute glucose levels. AB - Analysis of the time-dependent behavior of a signaling system can provide insight into its dynamic properties. We employed the nucleocytoplasmic shuttling of the transcriptional repressor Mig1 as readout to characterize Snf1-Mig1 dynamics in single yeast cells. Mig1 binds to promoters of target genes and mediates glucose repression. Mig1 is predominantly located in the nucleus when glucose is abundant. Upon glucose depletion, Mig1 is phosphorylated by the yeast AMP activated kinase Snf1 and exported into the cytoplasm. We used a three-channel microfluidic device to establish a high degree of control over the glucose concentration exposed to cells. Following regimes of glucose up- and downshifts, we observed a very rapid response reaching a new steady state within less than 1 min, different glucose threshold concentrations depending on glucose up- or downshifts, a graded profile with increased cell-to-cell variation at threshold glucose concentrations, and biphasic behavior with a transient translocation of Mig1 upon the shift from high to intermediate glucose concentrations. Fluorescence loss in photobleaching and fluorescence recovery after photobleaching data demonstrate that Mig1 shuttles constantly between the nucleus and cytoplasm, although with different rates, depending on the presence of glucose. Taken together, our data suggest that the Snf1-Mig1 system has the ability to monitor glucose concentration changes as well as absolute glucose levels. The sensitivity over a wide range of glucose levels and different glucose concentration-dependent response profiles are likely determined by the close integration of signaling with the metabolism and may provide for a highly flexible and fast adaptation to an altered nutritional status. PMID- 24627497 TI - BVA reiterates its position on non-stun slaughter. PMID- 24627494 TI - A histidine-rich linker region in peptidylglycine alpha-amidating monooxygenase has the properties of a pH sensor. AB - Decreasing luminal pH is thought to play a role in the entry of newly synthesized and endocytosed membrane proteins into secretory granules. The two catalytic domains of peptidylglycine alpha-amidating monooxygenase (PAM), a type I integral membrane protein, catalyze the sequential reactions that convert peptidyl-Gly substrates into amidated products. We explored the hypothesis that a conserved His-rich cluster (His-Gly-His-His) in the linker region connecting its two catalytic domains senses pH and affects PAM trafficking by mutating these His residues to Ala (Ala-Gly-Ala-Ala; H3A). Purified recombinant wild-type and H3A linker peptides were examined using circular dichroism and tryptophan fluorescence; mutation of the His cluster largely eliminated its pH sensitivity. An enzymatically active PAM protein with the same mutations (PAM-1/H3A) was expressed in HEK293 cells and AtT-20 corticotrope tumor cells. Metabolic labeling followed by immunoprecipitation revealed more rapid loss of newly synthesized PAM 1/H3A than PAM-1; although release of newly synthesized monofunctional PHM/H3A was increased, release of soluble bifunctional PAM/H3A, a product of the endocytic pathway, was decreased. Surface biotinylation revealed rapid loss of PAM-1/H3A, with no detectable return of the mutant protein to secretory granules. Consistent with its altered endocytic trafficking, little PAM-1/H3A was subjected to regulated intramembrane proteolysis followed by release of a small nuclear targeted cytosolic fragment. AtT-20 cells expressing PAM-1/H3A adopted the morphology of wild-type AtT-20 cells; secretory products no longer accumulated in the trans-Golgi network and secretory granule exocytosis was more responsive to secretagogue. PMID- 24627495 TI - A Golgi-localized mannosidase (MAN1B1) plays a non-enzymatic gatekeeper role in protein biosynthetic quality control. AB - Conformation-based disorders are manifested at the level of protein structure, necessitating an accurate understanding of how misfolded proteins are processed by the cellular proteostasis network. Asparagine-linked glycosylation plays important roles for protein quality control within the secretory pathway. The suspected role for the MAN1B1 gene product MAN1B1, also known as ER mannosidase I, is to function within the ER similar to the yeast ortholog Mns1p, which removes a terminal mannose unit to initiate a glycan-based ER-associated degradation (ERAD) signal. However, we recently discovered that MAN1B1 localizes to the Golgi complex in human cells and uncovered its participation in ERAD substrate retention, retrieval to the ER, and subsequent degradation from this organelle. The objective of the current study was to further characterize the contribution of MAN1B1 as part of a Golgi-based quality control network. Multiple lines of experimental evidence support a model in which neither the mannosidase activity nor catalytic domain is essential for the retention or degradation of the misfolded ERAD substrate Null Hong Kong. Instead, a highly conserved, vertebrate-specific non-enzymatic decapeptide sequence in the luminal stem domain plays a significant role in controlling the fate of overexpressed Null Hong Kong. Together, these findings define a new functional paradigm in which Golgi localized MAN1B1 can play a mannosidase-independent gatekeeper role in the proteostasis network of higher eukaryotes. PMID- 24627499 TI - Contingency planning: Exercise Walnut provides reassurance, says AHVLA. PMID- 24627500 TI - More women than men to stand for RCVS Council. PMID- 24627501 TI - Horsemeat in 'beef' products: European Commission summarises progress. PMID- 24627502 TI - Partnership to advance broiler genetics. PMID- 24627503 TI - Glasgow research centre wins Queen's Anniversary Prize. PMID- 24627504 TI - UK researchers win canine health awards. PMID- 24627506 TI - All SET: postdocs prepare for competition final. PMID- 24627507 TI - Getting together on One Health. PMID- 24627509 TI - 'Unbreakable bond' celebrated by Friends for Life competition. PMID- 24627508 TI - Animal-assisted interventions: making better use of the human-animal bond. PMID- 24627510 TI - Economic decision-making in animal health and welfare. PMID- 24627511 TI - Economics and One Health. PMID- 24627512 TI - History of One Health and One Medicine. PMID- 24627513 TI - Focus on behaviour. PMID- 24627514 TI - Feedback sought on BVD type 2 outbreaks. PMID- 24627515 TI - Seeking insights into antibiotic use. PMID- 24627516 TI - Plasma factor XIII: understanding the 99%. PMID- 24627517 TI - TTP and pregnancy. PMID- 24627518 TI - Refining prognosis in BCR-ABL1-positive ALL. PMID- 24627519 TI - The DNA methylome: a novel biomarker. PMID- 24627520 TI - No contact, no thrombosis? PMID- 24627521 TI - FXa takes center stage in vascular inflammation. PMID- 24627522 TI - Does rFVIIa work solo in hemophilia? PMID- 24627524 TI - Forgoing artificial nutrition or hydration at the end of life: a large cross sectional survey in Belgium. AB - OBJECTIVES: To examine the frequency and characteristics of decisions to forgo artificial nutrition and/or hydration (ANH) at the end of life. DESIGN: Postal questionnaire survey regarding end-of-life decisions (including ANH) to physicians certifying a large representative sample (n=6927) of Belgian death certificates in 2007. SETTING: Flanders, Belgium, 2007. PARTICIPANTS: Treating physicians of deceased patients. RESULTS: Response rate was 58.4%. A decision to forgoANH occurred in 6.6% of all deaths (4.2% withheld,3.0% withdrawn). Being female, dying in a care home or hospital and suffering from nervous system diseases(including dementia) or malignancies were the most important patient related factors positively associated with a decision to forgo ANH. Physicians indicated that the decision to forgo ANH had had some life-shortening effects in 77% of cases. There had been no consultation with the patient in 81%, mostly due to incapacity (coma or dementia). The family, colleague physicians and nurses were involved in decision making in 76%,41% and 62%, respectively. CONCLUSIONS: A substantial number of deaths are preceded by a decision to forgo ANH in Belgium. These decisions, ethically laden and involving a considerable chance of life shortening, are mostly not preceded by discussion with the patient despite existing patient rights legislation. It is recommended that physicians and patients and their families alike dedicate ample time to the discussion of treatment options and communication about the possibility of forgoing ANH and that this discussion takes place earlier as part of overall end-of life care planning rather than at the very end of life. PMID- 24627525 TI - The CD47-SIRPalpha signalling system: its physiological roles and therapeutic application. AB - Signal regulatory protein alpha (SIRPalpha), also known as SHPS-1/BIT/ CD172a, is an immunoglobulin superfamily protein that binds to the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region. CD47, another immunoglobulin superfamily protein, is a ligand for SIRPalpha, with the two proteins constituting a cell-cell communication system (the CD47-SIRPalpha signalling system). SIRPalpha is particularly abundant in the myeloid-lineage hematopoietic cells such as macrophages or dendritic cells (DCs), whereas CD47 is expressed ubiquitously. Interaction of CD47 (on red blood cells) with SIRPalpha (on macrophages) is thought to prevent the phagocytosis by the latter cells of the former cells, determining the lifespan of red blood cells. Recent studies further indicate that this signalling system plays important roles in engraftment of hematopoietic stem cells as well as in tumour immune surveillance through regulation of the phagocytic activity of macrophages. In the immune system, the CD47-SIRPalpha interaction is also important for the development of a subset of CD11c(+)DCs as well as organization of secondary lymphoid organs. Finally, the CD47-SIRPalpha signalling system likely regulates bone homeostasis by osteoclast development. Newly emerged functions of the CD47-SIRPalpha signalling system thus provide multiple therapeutic strategies for cancer, autoimmune diseases and bone disorders. PMID- 24627523 TI - A second-generation protein-protein interaction network of Helicobacter pylori. AB - Helicobacter pylori infections cause gastric ulcers and play a major role in the development of gastric cancer. In 2001, the first protein interactome was published for this species, revealing over 1500 binary protein interactions resulting from 261 yeast two-hybrid screens. Here we roughly double the number of previously published interactions using an ORFeome-based, proteome-wide yeast two hybrid screening strategy. We identified a total of 1515 protein-protein interactions, of which 1461 are new. The integration of all the interactions reported in H. pylori results in 3004 unique interactions that connect about 70% of its proteome. Excluding interactions of promiscuous proteins we derived from our new data a core network consisting of 908 interactions. We compared our data set to several other bacterial interactomes and experimentally benchmarked the conservation of interactions using 365 protein pairs (interologs) of E. coli of which one third turned out to be conserved in both species. PMID- 24627526 TI - How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. AB - Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is a relatively common and potentially severe complication seen in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and/or arsenic trioxide. The full-blown syndrome consists of unexplained fever, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, hypotension, and renal failure. Most measures currently used for management of DS have very little evidence-based support, and therefore, many remain controversial. Despite the lack of evidence supporting DS prophylaxis, several groups have adopted a preventive strategy with corticosteroids, especially for patients with leukocyte levels higher than from 5 to 10 * 10(9)/L. DS diagnosis should be suspected in the presence of any of the above-mentioned signs and symptoms, and preemptive treatment with dexamethasone should be started immediately. Other supportive measures can also be crucial for the correct management of DS, especially in those patients with life-threatening complications. Temporary discontinuation of all-trans retinoic acid or arsenic trioxide is indicated only for patients in very poor clinical condition or with severe renal or pulmonary dysfunction, sometimes requiring admission to the intensive care unit. Recognition of specific biomarkers and a better understanding of DS pathogenesis can be helpful for the development of specific therapies to counteract DS in a timely manner. PMID- 24627527 TI - Vessel wall BAMBI contributes to hemostasis and thrombus stability. AB - Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a transmembrane protein related to the transforming growth factor-beta superfamily, and is highly expressed in platelets and endothelial cells. We previously demonstrated its positive role in thrombus formation using a zebrafish thrombosis model. In the present study, we used Bambi-deficient mice and radiation chimeras to evaluate the function of this receptor in the regulation of both hemostasis and thrombosis. We show that Bambi(-/-) and Bambi(+/-) mice exhibit mildly prolonged bleeding times compared with Bambi(+/+) littermates. In addition, using 2 in vivo thrombosis models in mesenterium or cremaster muscle arterioles, we demonstrate that Bambi-deficient mice form unstable thrombi compared with Bambi(+/+) mice. No defects in thrombin generation in Bambi(-/-) mouse plasma could be detected ex vivo. Moreover, the absence of BAMBI had no effect on platelet counts, platelet activation, aggregation, or platelet procoagulant function. Similar to Bambi(-/-) mice, Bambi(-/-) transplanted with Bambi(+/+) bone marrow formed unstable thrombi in the laser-induced thrombosis model that receded more rapidly than thrombi that formed in Bambi(+/+) mice receiving Bambi( /-) bone marrow transplants. Taken together, these results provide strong evidence for an important role of endothelium rather than platelet BAMBI as a positive regulator of both thrombus formation and stability. PMID- 24627528 TI - Atypical chronic myeloid leukemia is clinically distinct from unclassifiable myelodysplastic/myeloproliferative neoplasms. AB - Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) largely defined morphologically. It is, unclear, however, whether aCML-associated features are distinctive enough to allow its separation from unclassifiable MDS/MPN (MDS/MPN U). To study these 2 rare entities, 134 patient archives were collected from 7 large medical centers, of which 65 (49%) cases were further classified as aCML and the remaining 69 (51%) as MDS/MPN-U. Distinctively, aCML was associated with many adverse features and an inferior overall survival (12.4 vs 21.8 months, P = .004) and AML-free survival (11.2 vs 18.9 months, P = .003). The aCML defining features of leukocytosis and circulating myeloid precursors, but not dysgranulopoiesis, were independent negative predictors. Other factors, such as lactate dehydrogenase, circulating myeloblasts, platelets, and cytogenetics could further stratify MDS/MPN-U but not aCML patient risks. aCML appeared to have more mutated RAS (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]), but was not statistically significant. Somatic CSF3R T618I (0/54) and CALR (0/30) mutations were not detected either in aCML or MDS/MPN-U. In conclusion, within MDS/MPN, the World Health Organization 2008 criteria for aCML identify a subgroup of patients with features clearly distinct from MDS/MPN-U. The MDS/MPN-U category is heterogeneous, and patient risk can be further stratified by a number of clinicopathological parameters. PMID- 24627529 TI - Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism. AB - The optimal N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off value for risk stratification of pulmonary embolism remains controversial. In this study we validated and compared different proposed NT-proBNP cut-off values in 688 normotensive patients with pulmonary embolism. During the first 30 days, 28 (4.1%) patients reached the primary outcome (pulmonary embolism-related death or complications) and 29 (4.2%) patients died. Receiver operating characteristic analysis yielded an area under the curve of 0.70 (0.60-0.80) for NT-proBNP. A cut off value of 600 pg.mL(-1) was associated with the best prognostic performance (sensitivity 86% and specificity 50%) and the highest odds ratio (6.04 (95% CI 2.07-17.59), p=0.001) compared to the cut-off values of 1000, 500 or 300 pg.mL( 1). Using multivariable logistic regression analysis, NT-proBNP >= 600 pg.mL(-1) had a prognostic impact on top of that of the simplified Pulmonary Embolism Severity Index and right ventricular dysfunction on echocardiography (OR 4.27 (95% CI 1.22-15.01); p=0.024, c-index 0.741). The use of a stepwise approach based on the simplified Pulmonary Embolism Severity Index, NT-proBNP >= 600 pg.mL(-1) and echocardiography helped optimise risk assessment. Our findings confirm the prognostic value of NT-proBNP and suggest that a cut-off value of 600 pg.mL(-1) is most appropriate for risk stratification of normotensive patients with pulmonary embolism. NT-proBNP should be used in combination with a clinical score and an imaging procedure for detecting right ventricular dysfunction. PMID- 24627530 TI - Whole-body magnetic resonance imaging in extrathoracic sarcoidosis. PMID- 24627531 TI - Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium. AB - Th17-mediated neutrophilic airway inflammation has been implicated in decreased response to glucocorticoids in asthma. We aimed to investigate the effect of glucocorticoids on the airway epithelial release of the neutrophilic and Th17 cell chemoattractant CCL20. We studied CCL20 and CXCL8 sputum levels in asthmatic subjects using inhaled glucocorticoids or not, and the effect of budesonide on CCL20 and CXCL8 production in primary bronchial epithelial cells. The mechanism behind the effect of budesonide-induced CCL20 production was studied in 16HBE14o- cells using inhibitors for the glucocorticoid receptor, intracellular pathways and metalloproteases. We observed higher levels of CCL20, but not CXCL8, in the sputum of asthmatics who used inhaled glucocorticoids. CCL20 levels correlated with inhaled glucocorticoid dose and sputum neutrophils. Budesonide increased tumour necrosis factor (TNF)-alpha-induced CCL20 by primary bronchial epithelium, while CXCL8 was suppressed. In 16HBE14o- cells, similar effects were observed at the CCL20 protein and mRNA levels, indicating transcriptional regulation. Although TNF-alpha-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the increase by budesonide was not. Inhibition of glucocorticoid receptor or ADAM17 abrogated the budesonide-induced increase in CCL20 levels. We show that glucocorticoids enhance CCL20 production by bronchial epithelium, which may constitute a novel mechanism in Th17-mediated glucocorticoid-insensitive inflammation in asthma. PMID- 24627532 TI - Microparticles and vascular dysfunction in obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is independently associated with various cardiovascular diseases, including myocardial infarction and stroke. OSA may promote atherosclerosis risk factors such as hypertension, diabetes and dyslipidaemia, and may have direct proatherogenic effects on the vascular wall. A growing number of studies have recently focused on the role of microparticles (MPs) in the atherogenic process. MPs are small plasma membrane vesicles that can be released by a variety of vascular or blood cells, and contain both membrane and cytosolic elements. Case-control studies have shown that platelet-, endothelium- and leukocyte-derived MP levels are increased in OSA. Experimental evidence has demonstrated that MPs from OSA patients induce endothelial dysfunction, inflammation and vascular hyperreactivity when injected into mice. In this review, we provide an overview of the main characteristics of MPs, their expression in OSA and their potential role in the atherogenic process associated with OSA. PMID- 24627533 TI - Middle East respiratory syndrome coronavirus: epidemic potential or a storm in a teacup? PMID- 24627534 TI - Bronchial obstruction and reversibility in children: inspiratory or expiratory resistance? PMID- 24627535 TI - Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. AB - Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean +/- sd 32 +/- 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68 82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH. PMID- 24627536 TI - Right ventricular reverse remodelling after balloon pulmonary angioplasty. AB - Balloon pulmonary angioplasty (BPA) has been reported to improve haemodynamics and functional capacity, with an acceptable risk, in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not candidates for pulmonary endarterectomy. However, right ventricular (RV) function, an important predictor in CTEPH, remains to be elucidated. We aimed to examine the impact of BPA on RV remodelling and dysfunction relative to haemodynamic improvements in patients with inoperable CTEPH. 20 consecutive patients with inoperable CTEPH who underwent BPA with cardiovascular magnetic resonance before and after BPA were retrospectively studied. BPA led to significant amelioration of the mean pulmonary arterial pressure, cardiac index and pulmonary vascular resistance (PVR), without death or major complications. Furthermore, BPA significantly ameliorated right-sided heart failure symptoms and signs, and exercise capacity. Cardiovascular magnetic resonance revealed a marked improvement in RV end diastolic and end-systolic volume index, with concomitant improvements in RV ejection fraction, mass and interventricular septal bowing after BPA. Changes in RV volumes strongly correlated with changes in cardiac index and PVR. BPA induced RV reverse remodelling and improved systolic dysfunction safely by ameliorating haemodynamics in patients with inoperable CTEPH. Evaluating RV function with cardiovascular magnetic resonance may be effective for noninvasively monitoring BPA efficacy. PMID- 24627537 TI - Human rhinovirus infection during naturally occurring COPD exacerbations. AB - Human rhinovirus (HRV) infection is an important trigger of exacerbations of chronic obstructive pulmonary disease (COPD) but its role in determining exacerbation frequency phenotype or the time-course of HRV infection in naturally occurring exacerbations is unknown. Sputum samples from 77 patients were analysed by real-time quantitative PCR for both HRV (388 samples), and Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (89 samples). Patients recorded worsening of respiratory symptoms on daily diary cards, from which exacerbations were identified. HRV prevalence and load at exacerbation presentation were significantly higher than in the stable state (prevalence 53.3% versus 17.2%, respectively; p<0.001) but 0% by day 35 post-exacerbation. HRV load was higher in patients with cold symptoms (p=0.046) or sore throats (p=0.006) than those without. 73% of bacterium-negative but HRV-positive exacerbations were bacterium-positive by day 14. Patients with HRV detected at exacerbation had a higher exacerbation frequency (interquartile range) of 3.01 (2.02-5.30) per year compared with patients without HRV (2.51 (2.00-3.51)) (p=0.038). HRV prevalence and load increased at COPD exacerbation, and resolved during recovery. Frequent exacerbators were more likely to experience HRV infection. Secondary bacterial infection is common after HRV infection, and provides a possible mechanism for exacerbation recurrence and a potential target for novel therapies. PMID- 24627538 TI - Zonisamide reduces obstructive sleep apnoea: a randomised placebo-controlled study. AB - Carbonic anhydrase inhibition reduces apnoeic events in sleep disordered breathing. Zonisamide inhibits carbonic anhydrase, and induces weight loss in obese patients. This study explored the relative influence of these two properties, which may both alleviate obstructive sleep apnoea (OSA). Continuous positive airway pressure (CPAP) was used as a standard care comparator. 47 patients with moderate-to-severe OSA and a body mass index of 27-35 kg.m(-2) were randomised to receive either zonisamide, placebo or CPAP for 4 weeks. The open extension phase (20 weeks) compared CPAP and zonisamide. Polysomnography, biochemistry and symptoms were evaluated. At 4 weeks, zonisamide reduced apnoea/hypopnoea index (AHI) by a mean+/-sd 33+/-39% and oxygen desaturation index by 28+/-31% (p=0.02 and 0.014, respectively; placebo adjusted). The mean compliance adjusted reduction of AHI after zonisamide and CPAP was 13 and 61%, respectively, (p=0.001) at 24 weeks. Body weight was marginally changed at 4 weeks, but reduced after zonisamide and increased after CPAP at 24 weeks (-2.7+/ 3.0 kg versus 2.3+/-2.0 kg, p<0.001). Zonisamide decreased bicarbonate at 4 and 24 weeks. Side-effects were more common after zonisamide. Zonisamide reduced OSA independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. The effect was less pronounced than that obtained by CPAP. PMID- 24627539 TI - Age-related differences in chest radiographic staging of sarcoidosis in Japan. PMID- 24627540 TI - Rapid diagnosis of tuberculosis using ex vivo host biomarkers in sputum. PMID- 24627541 TI - Patient reported outcome measures for cardiac ablation procedures: a multicentre pilot to develop a new questionnaire. AB - AIM: To assess the feasibility of administering Patient Reported Outcomes Measures (PROMs) in patients treated with ablation for cardiac arrhythmias, and to conduct the first stage of development and testing of a new PROM tool. METHODS AND RESULTS: A new tool was developed by a multidisciplinary team and tested alongside an adaptation of the patient perception of arrhythmia questionnaire (PPAQ) and EQ-5D-5L in a multicentre retrospective audit involving 791 consecutive cardiac arrhythmia patients treated with catheter ablation at three UK centres over 13 months. Data were recorded in the National Cardiac Rhythm Management Database, part of the National Institute for Cardiovascular Outcomes Research. The response rate was 71.9% (n = 569). Patients reported significant improvements across all outcomes and impacts, with reductions in symptoms of 51.7% (heart racing), 33.9% (fatigue) 31.8% (heart flutters), 43.5% (dizziness), 38.6% (breathlessness), 44.2% (chest pressure), 33.1% (trouble concentrating), 15.9% (headache), 28.3% (neck pressure), and 23.4% (fainting) (P < 0.001). The mean number of social days affected reduced by 7.49 days/month (P < 0.001); mean work/school days affected/month reduced by 6.26 (P < 0.001); mean GP/hospital visits reduced by 1.36 days/month (P < 0.001). The procedure met patient expectations in 72% of responders. CONCLUSIONS: The high response rate suggests that the use of PROMs in this patient group is feasible, with rates equalling those of the National PROMs Programme. The results showed that patients experienced significant improvements in their quality of life following ablation, while feedback allowed the tools to be improved. Further work is required to validate these tools; however, the findings suggest that PROMs could be useful in the audit of ablation techniques. PMID- 24627542 TI - DRG systems in Europe: variations in cost accounting systems among 12 countries. AB - BACKGROUND: Diagnosis-related group (DRG)-based hospital payment systems have gradually become the principal means of reimbursing hospitals in many European countries. Owing to the absence or inaccuracy of costs related to DRGs, these countries have started to routinely collect cost accounting data. The aim of the present article was to compare the cost accounting systems of 12 European countries. METHODS: A standardized questionnaire was developed to guide comprehensive cost accounting system descriptions for each of the 12 participating countries. RESULTS: The cost accounting systems of European countries vary widely by the share of hospital costs reimbursed through DRG payment, the presence of mandatory cost accounting and/or costing guidelines, the share of cost collecting hospitals, costing methods and data checks on reported cost data. Each of these aspects entails a trade-off between accuracy of the cost data and feasibility constraints. CONCLUSION: Although a 'best' cost accounting system does not exist, our cross-country comparison gives insight into international differences and may help regulatory authorities and hospital managers to identify and improve areas of weakness in their cost accounting systems. Moreover, it may help health policymakers to underpin the development of a cost accounting system. PMID- 24627543 TI - Electronic medical records: the way forward for primary care research? PMID- 24627544 TI - Functional role of arginine during the peri-implantation period of pregnancy. I. Consequences of loss of function of arginine transporter SLC7A1 mRNA in ovine conceptus trophectoderm. AB - Arginine, the common substrate for production of nitric oxide (NO) and polyamines in mammals, increases in the uterine lumen during the peri-implantation period of pregnancy. However, functional roles of arginine within the uterine lumen for conceptus (embryo and extraembryonic membranes) development have not been elucidated in vivo. To assess roles of arginine in reproductive tissue for survival and development of the conceptus, we conducted an in vivo morpholino antisense oligonucleotide (MAO)-mediated knockdown of SLC7A1 mRNA, the arginine transporter in ovine conceptus trophectoderm (Tr). Translational knockdown of SLC7A1 mRNA resulted in retarded conceptus development and abnormal function compared to MAO control. Use of MAO-SLC7A1 knockdown in conceptuses decreased arginine transport (73%, P<0.01), the abundance of ornithine decarboxylase, and nitric oxide synthase (NOS3) proteins, arginine-related amino acids [citrulline (76%, P<0.05) and ornithine (40%, P<0.05)], and polyamines, which likely accounts for their retarded development. Also, no alternative arginine precursors (glutamine and glutamate), isoforms of nitric oxide synthase (NOS1 and NOS2), or alternative pathways for polyamine biosynthesis via arginine decarboxylase and agmatinase were activated to rescue conceptus development. Collectively, SLC7A1 is the key transporter of arginine by conceptus Tr, and arginine is essential for conceptus survival and development.-Wang, X., Frank, J. W., Little, D. R., Dunlap, K. A., Satterfield, M. C., Burghardt, R. C., Hansen, T. R., Wu, G., and Bazer, F. W. Functional role of arginine during the peri-implantation period of pregnancy. I. Consequences of loss of function of arginine transporter SLC7A1 mRNA in ovine conceptus trophectoderm. PMID- 24627545 TI - New signaling pathways for hepcidin regulation. AB - In this issue of Blood, Mleczko-Sanecka et al used a novel approach based n genome-wide RNA interference knockdown technology to identify the genes involved in the regulation of hepcidin. It showed that hepcidin suppression is linked to the control of mitogen stimulation and nutrient status ia components of well characterized signaling pathways. This indicates novel links between the control of systemic iron homeostasis and critical liver processes such as regeneration, response to injury, carcinogenesis, and nutrient metabolism. PMID- 24627546 TI - Bad liver and a broken heart. AB - In this issue of Blood, the CORDELIA study presented by Pennell and colleagues shows that deferasirox (DFX; Exjade, Novartis) is not inferior to deferoxamine (DFO; Desferal, Novartis) for the removal of cardiac iron in beta-thalassemia. CORDELIA also supports previous findings that efficacy of cardiac iron removal is better if liver iron concentration (LIC) is low. PMID- 24627547 TI - LECT2 makes the amyloid list. AB - In this issue of Blood, Mereuta et al report that we must now add leukocyte cell derived chemotaxin 2 (LECT2) to the list of proteins that can cause systemic amyloidosis, a fibrillar protein deposition disease that leads to end-organ damage and related symptoms and requires a tissue diagnosis demonstrating apple green birefringence in Congo Red-stained sections viewed microscopically under polarized light. When dissected from affected tissue, digested into protein fragments of different lengths for proteomic analysis, and assessed by mass spectrometry for their original constituents, amyloid deposits reveal a unique signature of chaperones such as apolipoprotein E and serum amyloid P-component (arrows) as well as the identity of the critical main culprit: the amyloid forming protein (red boxes). PMID- 24627548 TI - The (miR)e of CTCL. AB - In this issue of Blood, Ito et al demonstrate pathogenic implications of microRNA 150 (miR-150) repression in an aggressive form of cutaneous T-cell lymphoma (CTCL). Noncoding RNAs, such as microRNA, profoundly influence gene transcription and protein translation machinery to change hematopoietic cell fate in physiologic and pathologic conditions. PMID- 24627549 TI - Two faces of ET: CALR and JAK2. AB - In this issue of Blood, Rumi et al and Rotunno et al demonstrate that essential thrombocythemia (ET) patients with calreticulin mutations exhibit lower leukocyte and hemoglobin values, higher platelet counts, and a lower thrombosis risk vs JAK2-mutated ET. Calreticulin-mutated ET appears to be a distinct entity with a more indolent course. PMID- 24627550 TI - BuMPing iron with modified heparins. AB - In this issue of Blood, Poli et al demonstrate that heparin analogs engineered to minimize their anticoagulant properties can potently downregulate hepcidin production in vitro and in vivo, and may potentially be used to treat the anemia of inflammation. PMID- 24627551 TI - A new red cell shape helps the clot. AB - In this issue of Blood, Cines and colleagues discover that red blood cells take up an unusual, and hitherto undiscovered, shape that contributes to blood clotting. PMID- 24627553 TI - Evidence doesn't support home care visits for over 65s. PMID- 24627552 TI - Nicotine patches in pregnant smokers: randomised, placebo controlled, multicentre trial of efficacy. AB - OBJECTIVE: To determine the efficacy of 16 hour nicotine patches among pregnant smokers, with the dose individually adjusted according to saliva cotinine levels (potential range 10-30 mg/day). DESIGN: Randomised, double blind, placebo controlled, parallel group, multicentre trial (Study of Nicotine Patch in Pregnancy, SNIPP) between October 2007 and January 2013. SETTING: 23 maternity wards in France. PARTICIPANTS: 476 pregnant smokers aged more than 18 years and between 12 and 20 weeks' gestation, who smoked at least five cigarettes a day. After exclusions, 402 women were randomised: 203 to nicotine patches and 199 to placebo patches. Data were available on 192 live births in each group. INTERVENTIONS: Nicotine and identical placebo patches were administered from quit day up to the time of delivery. Doses were adjusted to saliva cotinine levels when smoking to yield a substitution rate of 100%. Participants were assessed monthly and received behavioural smoking cessation support. MAIN OUTCOME MEASURES: The primary outcomes were complete abstinence (self report confirmed by carbon monoxide level in expired air <= 8 ppm) from quit date to delivery, and birth weight. The secondary outcomes were point prevalence of abstinence, time to lapse (a few puffs) or relapse, and delivery and birth characteristics. All data were analysed on an intention to treat basis. RESULTS: Complete abstinence was achieved by 5.5% (n=11) of women in the nicotine patch group and 5.1% (n=10) in the placebo patch group (odds ratio 1.08, 95% confidence interval 0.45 to 2.60). The median time to the first cigarette smoked after target quit day was 15 days in both groups (interquartile range 13-18 in the nicotine patch group, 13-20 in the placebo patch group). The point prevalence abstinence ranged from 8% to 12.5% in the nicotine patch group and 8% to 9.5% in the placebo patch group without statistically significant differences. The nicotine substitution rate did not differ from 100%, and the self reported median compliance rate was 85% (interquartile range 56-99%) in the nicotine patch group and 83% (56-95%) in the placebo patch group, assessed at 1016 visits. The mean birth weight was 3065 g (SE 44 g) in the nicotine patch group and 3015 g (SE 44 g) in the placebo patch group (P=0.41). Diastolic blood pressure was significantly higher in the nicotine patch group than in the placebo patch group. The frequency of serious adverse events was similar between the groups, although more non-serious adverse reactions, mainly of skin, occurred in the nicotine patch group. CONCLUSION: The nicotine patch did not increase either smoking cessation rates or birth weights despite adjustment of nicotine dose to match levels attained when smoking, and higher than usual doses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00507975. PMID- 24627554 TI - HIV testing should be offered irrespective of age. PMID- 24627555 TI - Little evidence that primary care providers stop child and teen drug use, US task force says. PMID- 24627556 TI - Breaking barriers in obstructive sleep apnea. Focus on "Intermittent hypoxia induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation". PMID- 24627557 TI - Induced overexpression of OCT4A in human embryonic stem cells increases cloning efficiency. AB - Our knowledge of the molecular mechanisms underlying human embryonic stem cell (hESC) self-renewal and differentiation is incomplete. The level of octamer binding transcription factor 4 (Oct4), a critical regulator of pluripotency, is precisely controlled in mouse embryonic stem cells. However, studies of human OCT4 are often confounded by the presence of three isoforms and six expressed pseudogenes, which has complicated the interpretation of results. Using an inducible lentiviral overexpression and knockdown system to manipulate OCT4A above or below physiological levels, we specifically examine the functional role of the OCT4A isoform in hESC. (We also designed and generated a comparable series of vectors, which were not functional, for the overexpression and knockdown of OCT4B.) We show that specific knockdown of OCT4A results in hESC differentiation, as indicated by morphology changes, cell surface antigen expression, and upregulation of ectodermal genes. In contrast, inducible overexpression of OCT4A in hESC leads to a transient instability of the hESC phenotype, as indicated by changes in morphology, cell surface antigen expression, and transcriptional profile, that returns to baseline within 5 days. Interestingly, sustained expression of OCT4A past 5 days enhances hESC cloning efficiency, suggesting that higher levels of OCT4A can support self-renewal. Overall, our results indicate that high levels of OCT4A increase hESC cloning efficiency and do not induce differentiation (whereas OCT4B expression cannot be induced in hESC), highlighting the importance of isoform-specific studies in a stable and inducible expression system for human OCT4. Additionally, we demonstrate the utility of an efficient method for conditional gene expression in hESC. PMID- 24627559 TI - CFTR and GM1 "gangl-ing" up to heal thy wound. Focus on "Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased beta1-integrin signaling and delayed wound repair". PMID- 24627558 TI - Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. AB - Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are recently found to be present in adult humans, has not been studied. Here we report that mRNA of TLR4, TLR2, NOD1, and NOD2 is upregulated, paralleled with upregulated mRNA of inflammatory cytokines and chemokines in the brown adipose tissue (BAT) of the obese mice. During brown adipocyte differentiation, mRNA and protein expression of NOD1 and TLR4, but not TLR2 and NOD2, is also increased. Activation of TLR4, TLR2, or NOD1 in brown adipocytes induces activation of NF-kappaB and MAPK signaling pathways, leading to inflammatory cytokine/chemokine mRNA expression and/or protein secretion. Moreover, activation of TLR4, TLR2, or NOD1 attenuates both basal and isoproterenol-induced uncoupling protein 1 (UCP-1) expression without affecting mitochondrial biogenesis and lipid accumulation in brown adipocytes. Cellular bioenergetics measurements confirm that attenuation of UCP-1 expression by PRR activation is accompanied by suppression of both basal and isoproterenol-stimulated oxygen consumption rates and isoproterenol-induced uncoupled respiration from proton leak; however, maximal respiration and ATP coupled respiration are not changed. Further, the attenuation of UCP-1 by PRR activation appears to be mediated through downregulation of the UCP-1 promoter activities. Taken together, our results demonstrate the role of selected PRR activation in inducing inflammation and downregulation of UCP-1 expression and mitochondrial respiration in brown adipocytes. Our results uncover novel targets in BAT for obesity treatment and prevention. PMID- 24627560 TI - PHOTO QUIZ. Chronic abdominal pain and intestinal obstruction in a 24-year-old woman. PMID- 24627562 TI - Crossing borders: one world, global health. PMID- 24627563 TI - Prophylactic lead extraction at implantable cardioverter-defibrillator generator change. AB - BACKGROUND: Current implantable cardiac devices have a finite battery life of ~3 to 7 years for implantable cardioverter-defibrillators. It is current practice to reuse all properly functioning intravascular leads. We tested the hypothesis that a strategy of prophylactic lead removal at the time of device change would be superior under some conditions to the current practice of lead reuse. METHODS AND RESULTS: Using currently available data and a Monte Carlo microsimulation trial, we calculated the risks of leaving an indwelling lead until extraction is indicated because of malfunction versus an aggressive management strategy of prophylactic serial extraction at time of generator change. With a serial lead exchange strategy of leads at generator change, there is reduced overall extraction-related mortality because of fewer late complications attributable to extraction of leads with high dwell time because of infection, recall, or subsequent lead failure. This finding is limited to young patients or those with high expected indwell time of lead. This trend reverses for leads with <40 years expected dwell time. Sensitivity analysis shows high dependence on extraction performance and device longevity. In all cases, serial extraction would be expected to lead to increased adverse events related to the more complex procedure. CONCLUSIONS: A strategy of serial lead extraction, given best available current parameters, yields a lower procedural mortality risk in the long-term management of indwelling implantable cardioverter-defibrillator leads in young patients (>40-year estimated dwell time) driven by high aggregate anticipated risk of lifetime lead complication. PMID- 24627564 TI - Gastric and lower esophageal sphincter pressures during nausea: a study using visual motion-induced nausea and high-resolution manometry. AB - Nausea is the subjective unpleasant sensation that immediately precedes vomiting. Studies using barostats suggest that gastric fundus and lower esophageal sphincter (LES) relaxation precede vomiting. Unlike barostat, high-resolution manometry allows less invasive, detailed measurements of fundus pressure (FP) and axial movement of the gastroesophageal junction (GEJ). Nausea was induced in 12 healthy volunteers by a motion video and rated on a visual analog scale. FP was measured as the mean value of the five pressure channels that were clearly positioned below the LES. After intubation, a baseline (BL) recording of 15 min was obtained. This was followed by presentation of the motion video (at least 10 min, maximum 20 min) followed by 30 min recovery recording. Throughout the experiment we recorded autonomic nervous system (ANS) parameters [blood pressure, heart rate (HR), and cardiac vagal tone (CVT), which reflects efferent vagal activity]. Ten out of 12 subjects showed a drop in FP during peak nausea compared with BL (-4.0 +/- 0.8 mmHg; P = 0.005), and 8/10 subjects showed a drop in LES pressure (-8.8 +/- 2.5 mmHg; P = 0.04). Peak nausea preceded peak fundus and LES pressure drop. Nausea was associated with configuration changes at the GEJ such as LES shortening and esophageal lengthening. During nausea we observed a significantly increased HR and decreased CVT. In conclusion, nausea is associated with a drop in fundus and LES pressure, configuration changes at the GEJ as well as changes in the ANS activity such as an increased sympathetic tone (increased HR) and decreased parasympathetic tone (decreased CVT). PMID- 24627565 TI - Neuron-glial communication mediated by TNF-alpha and glial activation in dorsal root ganglia in visceral inflammatory hypersensitivity. AB - Communication between neurons and glia in the dorsal root ganglia (DRG) and the central nervous system is critical for nociception. Both glial activation and proinflammatory cytokine induction underlie this communication. We investigated whether satellite glial cell (SGC) and tumor necrosis factor-alpha (TNF-alpha) activation in DRG participates in a 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced rat model of visceral hyperalgesia. In TNBS-treated rats, TNF-alpha expression increased in DRG and was colocalized to SGCs enveloping a given neuron. These SGCs were activated as visualized under electron microscopy: they had more elongated processes projecting into the connective tissue space and more gap junctions. When nerves attached to DRG (L6-S1) were stimulated with a series of electrical stimulations, TNF-alpha were released from DRG in TNBS-treated animals compared with controls. Using a current clamp, we noted that exogenous TNF-alpha (2.5 ng/ml) increased DRG neuron activity, and visceral pain behavioral responses were reversed by intrathecal administration of anti-TNF-alpha (10 MUg.kg(-1).day(-1)). Based on our findings, TNF-alpha and SGC activation in neuron-glial communication are critical in inflammatory visceral hyperalgesia. PMID- 24627566 TI - Prokinetic effects of mirtazapine on gastrointestinal transit. AB - Mirtazapine is a noradrenergic and specific serotonergic antidepressant. The aim of this study was to investigate the effects of mirtazapine on gastrointestinal motility in dogs, including solid gastric emptying, antral and small intestinal contractions, and small intestinal and colonic transit. Six dogs were implanted with two cannulas located at the duodenum and the ascending colon; another six dogs were implanted with gastric cannula 6 cm proximal to the pylorus. Mirtazapine 45 mg was administered orally 90 min before the study. We found that 1) Mirtazapine accelerated gastric emptying during the entire 3 h in normal dogs (P < 0.04) and accelerated delayed gastric emptying induced by rectal distention (P < 0.04). 2) Mirtazapine restored impaired gastric tone and accommodation induced by rectal distention (P < 0.05). 3) No significant changes were noted in small intestinal contractions or transit with mirtazapine (P > 0.1). 4) Mirtazapine accelerated colonic transit at 2 and 4 h but not 6 h. The geometric center was increased from 1.9 +/- 0.6 to 3.0 +/- 0.5 and 3.9 +/- 0.5 to 4.7 +/- 0.1 at 2 and 4 h respectively (P = 0.04 vs. corresponding control). In conclusion, mirtazapine improves gastric emptying in healthy dogs and normalizes rectal distention-induced delay in gastric emptying and accelerates colon but not small intestinal transit in healthy dogs. Clinical studies are warranted to assess the effects of mirtazapine on gastrointestinal motility and sensory functions in patients with functional gastrointestinal diseases. PMID- 24627567 TI - Conditioned medium from Bifidobacteria infantis protects against Cronobacter sakazakii-induced intestinal inflammation in newborn mice. AB - Necrotizing enterocolitis (NEC) is associated with a high morbidity and mortality in very low birth weight infants. Several hypotheses regarding the pathogenesis of NEC have been proposed but to date no effective treatment is available. Previous studies suggest that probiotic supplementation is protective. We recently reported that probiotic (Bifidobacterium infantis) conditioned medium (PCM) has an anti-inflammatory effect in cultured fetal human intestinal cells (H4) and fetal intestine explants. In this study, we tested in vivo whether PCM protects neonatal mice from developing intestinal inflammation induced by exposure to Cronobacter sakazakii (C. sakazakii), an opportunistic pathogen associated with NEC. We found that infected neonatal mice had a significantly lower body weight than control groups. Infection led to ileal tissue damage including villous rupture, disruption of epithelial cell alignment, intestinal inflammation, apoptotic cell loss, and decreased mucus production. Pretreatment with PCM prevented infection caused decrease in body weight, attenuated enterocyte apoptotic cell death, mitigated reduced mucin production, and maintained ileal structure. Infected ileum expressed reduced levels of IkappaBalpha, which could be restored upon pretreatment with PCM. We also observed a nuclear translocation of NF-kappaB p65 in H4 cells exposed to C. sakazakii, which was prevented in PCM-pretreated cells. Finally, treatment of neonatal mice with PCM prior to infection sustained the capacity of ileal epithelial proliferation. This study suggests that an active component(s) released into the culture medium by B. infantis may prevent ileal damage by a pathogen linked to NEC. PMID- 24627568 TI - Circulating MicroRNAs and the occurrence of acute myocardial infarction in Chinese populations. AB - BACKGROUND: Circulating microRNAs ( miRNAs) are emerging as novel disease biomarkers. We aimed to explore the association between circulating miRNAs and the occurrence of acute myocardial infarction (AMI) in Chinese populations. METHODS AND RESULTS: In the discovery stage, the plasma of 20 patients with AMI and 20 controls were pooled respectively and profiled by massively parallel sequencing. Seventy-seven miRNAs showed differential expression. Selected miRNAs were validated in 178 patients with AMI and 198 controls using quantitative reverse transcriptase polymerase chain reaction assays and further replicated in 150 patients with AMI and 150 controls. Results suggest that miR-320b and miR 125b levels were significantly lower in patients with AMI than in controls in both validation populations (P<0.0001). Lower levels of miR-320b and miR-125b were associated with increased occurrence of AMI (adjusted odds ratio, 4.71; 95% confidence interval, 2.96-7.48 and odds ratio, 4.27; 95% confidence interval, 2.84-6.41, respectively). Addition of the 2 miRNAs to traditional risk factors led to a significant improvement in the area under the curve from 0.822 (95% confidence interval, 0.787-0.856) to 0.871 (95% confidence interval, 0.842 0.900), with a net reclassification improvement of 20.45% (P<0.0001) and an integrated discrimination improvement of 0.16 (P<0.0001) for patients with AMI. A functional study showed that miR-320b and miR-125b could regulate the expression profiles of genes enriched in several signal transduction pathways critical for coronary heart disease in human vascular endothelial cells. CONCLUSIONS: The plasma levels of miR-320b and miR-125b were significantly lower in patients with AMI when compared with controls, and these miRNAs may be involved in the pathogenesis of coronary heart disease. PMID- 24627570 TI - Pellagra and alcoholism: a biochemical perspective. AB - Historical and clinical aspects of pellagra and its relationship to alcoholism are reviewed from a biochemical perspective. Pellagra is caused by deficiency of niacin (nicotinic acid) and/or its tryptophan (Trp) precursor and is compounded by B vitamin deficiencies. Existence on maize or sorghum diets and loss of or failure to isolate niacin from them led to pellagra incidence in India, South Africa, Southern Europe in the 18th century and the USA following the civil war. Pellagra is also induced by drugs inhibiting the conversion of Trp to niacin and by conditions of gastrointestinal dysfunction. Skin photosensitivity in pellagra may be due to decreased synthesis of the Trp metabolite picolinic acid -> zinc deficiency -> decreased skin levels of the histidine metabolite urocanic acid and possibly also increased levels of the haem precursor 5-aminolaevulinic acid (5 ALA) and photo-reactive porphyrins. Depression in pellagra may be due to a serotonin deficiency caused by decreased Trp availability to the brain. Anxiety and other neurological disturbances may be caused by 5-ALA and the Trp metabolite kynurenic acid. Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6. Alcohol dependence can induce or aggravate pellagra by inducing malnutrition, gastrointestinal disturbances and B vitamin deficiencies, inhibiting the conversion of Trp to niacin and promoting the accumulation of 5 ALA and porphyrins. Alcoholic pellagra encephalopathy should be managed with niacin, other B vitamins and adequate protein nutrition. Future studies should explore the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra. PMID- 24627569 TI - Is diabetes mellitus-linked amino acid signature associated with beta-blocker induced impaired fasting glucose? AB - BACKGROUND: The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin resistance. We investigated whether this same AA signature, single-nucleotide polymorphisms in genes in their catabolic pathway, was associated with development of impaired fasting glucose (IFG) after atenolol treatment. METHODS AND RESULTS: Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available for the development of IFG. We assessed the association between baseline circulating levels of isoleucine, leucine, valine, tyrosine, and phenylalanine, as well as single nucleotide polymorphisms in branched-chain amino-acid transaminase 1 (BCAT1) and phenylalanine hydroxylase (PAH) with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the 5 AAs was associated with the following odds ratio and 95% confidence interval for IFG based on a fully adjusted model: isoleucine 2.29 (1.31-4.01), leucine 1.80 (1.10-2.96), valine 1.77 (1.07-2.92), tyrosine 2.13 (1.20-3.78), and phenylalanine 2.04 (1.16-3.59). The composite P value was 2*10( 5). Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (P for trend=0.0003). CONCLUSIONS: Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol-associated adverse metabolic effects. Clinical Trial Registration- http://www.clinicaltrials.gov; Unique Identifier: NCT00246519. PMID- 24627571 TI - Exogenous activation of Wnt/beta-catenin signaling attenuates binge alcohol induced deficient bone fracture healing. AB - AIMS: Excessive alcohol consumption is associated with fracture non-union. Canonical Wnt pathway signaling activity regulates normal fracture healing. We previously demonstrated that binge alcohol exposure modulates beta-catenin levels in the fracture callus of mice. Here, we sought to determine whether exogenous enhancement beta-catenin signaling activity could restore normal fracture healing to binge-exposed mice. METHODS: C57BL/6 male mice were exposed to episodic alcohol or saline for 6 total days of alcohol exposure over a 2-week period. Following alcohol exposure, mice were subjected to a stabilized mid-shaft tibia fracture. Beginning 4 days post-injury, mice received daily injections of either lithium chloride or saline subcutaneously. Protein levels of activated, inactivated, and total beta-catenin and GSK-3beta in fracture calluses were measured at post-injury day 9. Biomechanical strength testing and histology of callus tissue was assessed at post fracture day 14. RESULTS: Binge alcohol was associated with decreased callus biomechanical strength, and reduced cartilaginous callus formation. Alcohol decreased levels of callus-associated activated beta-catenin while concomitantly increasing the levels of inactive beta catenin at post-injury day 9. Alcohol also increased callus associated activated GSK-3beta at post-injury day 9. Lithium chloride (an inhibitor of GSK-3beta) treatment increased activated beta-catenin protein levels, significantly decreased activated GSK-3beta and restored cartilaginous callus formation and endochondral ossification. CONCLUSION: These data link alcohol-impaired fracture healing with deregulation of Canonical Wnt signaling activity in the fracture callus. Exogenous activation of the Wnt pathway using LiCl attenuated the damaging effects of binge alcohol exposure on the fracture healing process by modulating canonical Wnt signaling activity. PMID- 24627573 TI - Accounting for misclassified outcomes in binary regression models using multiple imputation with internal validation data. AB - Outcome misclassification is widespread in epidemiology, but methods to account for it are rarely used. We describe the use of multiple imputation to reduce bias when validation data are available for a subgroup of study participants. This approach is illustrated using data from 308 participants in the multicenter Herpetic Eye Disease Study between 1992 and 1998 (48% female; 85% white; median age, 49 years). The odds ratio comparing the acyclovir group with the placebo group on the gold-standard outcome (physician-diagnosed herpes simplex virus recurrence) was 0.62 (95% confidence interval (CI): 0.35, 1.09). We masked ourselves to physician diagnosis except for a 30% validation subgroup used to compare methods. Multiple imputation (odds ratio (OR) = 0.60; 95% CI: 0.24, 1.51) was compared with naive analysis using self-reported outcomes (OR = 0.90; 95% CI: 0.47, 1.73), analysis restricted to the validation subgroup (OR = 0.57; 95% CI: 0.20, 1.59), and direct maximum likelihood (OR = 0.62; 95% CI: 0.26, 1.53). In simulations, multiple imputation and direct maximum likelihood had greater statistical power than did analysis restricted to the validation subgroup, yet all 3 provided unbiased estimates of the odds ratio. The multiple-imputation approach was extended to estimate risk ratios using log-binomial regression. Multiple imputation has advantages regarding flexibility and ease of implementation for epidemiologists familiar with missing data methods. PMID- 24627574 TI - Three authors reply. PMID- 24627572 TI - Impact of differential attrition on the association of education with cognitive change over 20 years of follow-up: the ARIC neurocognitive study. AB - Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48-67 years (1990-1992) through ages 70-89 years (2011-2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors. PMID- 24627575 TI - Five authors reply. PMID- 24627576 TI - Biomechanical Consequences of Coracoclavicular Reconstruction Techniques on Clavicle Strength. AB - BACKGROUND: Lateral clavicle fractures have been reported after coracoclavicular (CC) ligament reconstructions with bone tunnels through the clavicle. PURPOSE: To biomechanically compare clavicle strength following 2 common CC reconstruction techniques with different bone tunnel diameters. STUDY DESIGN: Controlled laboratory study. METHODS: Testing was performed on 2 groups of matched-pair cadaveric clavicles. Clavicles were prepared with either 2.4-mm tunnels and cortical fixation button (CFB) devices or 6.0-mm tunnels with hamstring tendon grafts (TGs) and tenodesis screws; contralateral clavicles were left intact. A 3 point bending load was applied to the distal clavicles at a rate of 15 mm/min until failure. Ultimate failure load and anterior-posterior width of the clavicles 45 mm medial from the lateral border were recorded. Strength reduction was determined as the percentage reduction in ultimate failure load between paired intact and surgically prepared clavicles. Relative tunnel size was determined as the quotient of tunnel diameter and clavicle width, reported as a percentage. RESULTS: The TG technique significantly reduced clavicle strength relative to intact (P = .011) and caused significantly more strength reduction (mean, -30.7%; range, 8.1% to -62.5%) than the CFB technique (mean, -3.8%; range, 34.2% to -28.1%; P = .031). The CFB technique was not significantly different from intact (P = .314). There was a significant correlation between clavicle width and strength reduction (tau = -0.36, P = .04) and between relative tunnel size and strength reduction (tau = 0.51, P = .005). CONCLUSION: The TG reconstruction technique with 6.0-mm tunnels, grafts, and tenodesis screws caused significantly more reduction of clavicle strength compared with the CFB technique with 2.4-mm tunnels and CFB device. Additionally, relative tunnel width correlated highly with the strength reduction. CLINICAL RELEVANCE: This information can influence intraoperative decision making based on the individual clavicle width and might influence postoperative treatment protocols. Large bone tunnels may predispose patients to clavicle fractures after anatomic CC reconstructions. PMID- 24627577 TI - Return to Sports and Subsequent Injury Rates After Revision Anterior Cruciate Ligament Reconstruction With Patellar Tendon Autograft. AB - BACKGROUND: The return-to-sport and reinjury rates are not well defined after revision anterior cruciate ligament (ACL) reconstruction. HYPOTHESIS: School-age athletes would have a higher rate of return to sports and reinjury to either knee after revision ACL surgery compared with college or recreational athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Patients were prospectively studied after revision ACL reconstruction with bone-patellar tendon-bone (BPTB) autograft. Participants were grouped by competitive sport levels of school age (mean age, 16.6 +/- 0.9 years; n = 84), college (19.6 +/- 1.2 years; n = 58), or recreational adult (27.6 +/- 4.1 years; n = 117). An activity survey was used to determine the specific sport and sport level patients participated in before and after surgery. The International Knee Documentation Committee (IKDC) knee survey and Cincinnati Knee Rating System (CKRS) survey responses were also obtained. RESULTS: The rate of return to the same sport at the same level was 62 of 84 school-age athletes (74%), 43 of 58 college athletes (74%), and 73 of 117 recreational athletes (62%) (P = .1065). The number of patients who had a subsequent ACL graft tear rate after revision surgery was 2 of 84 (2.3%) in the high school group, 3 of 58 (5.1%) in the college group, and 4 of 117 (3.4%) in the recreational group (P = .6706). The number of patients who had a subsequent ACL tear in the contralateral knee was 1 of 84 (1.1%) in the school-age group, 1 of 58 (1.7%) in the college group, and 2 of 117 (1.7%) in the recreational group (P = .9501). At 2 years postoperatively, the mean IKDC subjective total score was 86.1 +/- 11.7 points and the mean CKRS total score was 89.7 +/- 11.1 points. CONCLUSION: Revision ACL reconstruction with BPTB autograft and perioperative rehabilitation allowed high school and college athletes to return to sports at the preinjury level at a rate of 74%; the return rate for recreational-level adults was 62%. Reinjury rates in the first 5 years after revision surgery ranged from 2% to 5%, which is lower than what has been reported for young competitive athletes after primary surgery. PMID- 24627578 TI - Risk-Prone Pitching Activities and Injuries in Youth Baseball: Findings From a National Sample. AB - BACKGROUND: There are relatively few published epidemiological studies that have correlated pitching-related risk factors with increased pitching-related arm problems as well as injuries. HYPOTHESIS: High pitching volume and limited recovery will lead to arm fatigue, thus placing young pitchers at a greater risk for elbow and shoulder problems and, subsequently, an increased risk for arm injuries. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A national survey was conducted among 754 youth pitchers (ages 9 to 18 years) who had pitched in organized baseball leagues during the 12 months before the survey. Self-reported risk-prone pitching activities were identified and compared with recommendations by the American Sports Medicine Institute. Relationships between self-reported pitching activities, shoulder and elbow problems, and injuries were assessed using multivariable logistic regression. RESULTS: Of the 754 participating pitchers, 43.4% pitched on consecutive days, 30.7% pitched on multiple teams with overlapping seasons, and 19.0% pitched multiple games a day during the 12 months before the study. Pitchers who engaged in these activities had increased risk of pitching-related arm pain (odds ratio [OR] = 2.53, 95% confidence interval [CI] = 1.14-5.60; OR = 1.85, 95% CI = 1.02-3.38; OR = 1.89, 95% CI = 1.03-3.49, respectively). Nearly 70% of the sample reported throwing curveballs, which was associated with 1.66 (95% CI = 1.09-2.53) greater odds of experiencing arm pain while throwing. Pitching-related arm tiredness and arm pain were associated with increased risk of pitching-related injuries. Specifically, those who often pitched with arm tiredness and arm pain had 7.88 (95% CI = 3.88 15.99) and 7.50 (95% CI = 3.47-16.21) greater odds of pitching-related injury, respectively. However, pitching on a travel baseball club, playing baseball exclusively, or playing catcher were not associated with arm problems. CONCLUSION: The results of this study, along with those of others, reinforce the importance of avoiding risk-prone pitching activities to prevent pitching-related injuries among youth pitchers. PMID- 24627579 TI - Matrix metalloproteinase content and activity in low-platelet, low-leukocyte and high-platelet, high-leukocyte platelet rich plasma (PRP) and the biologic response to PRP by human ligament fibroblasts. AB - BACKGROUND: Recent work has shown the presence of catabolic cytokines in platelet rich plasma (PRP), but little is known about endogenous catabolic proteases such as matrix metalloproteinases (MMPs). Hypothesis/ PURPOSE: To quantify MMP content in 2 commercially available PRP preparation systems: Arthrex Double Syringe System autologous conditioned plasma (ACP) and Biomet GPS (GPS). The hypothesis was that MMPs are actively secreted from PRP immediately after preparation. STUDY DESIGN: Controlled laboratory study. METHODS: PRP was prepared using either ACP (low platelet, low leukocyte) or GPS (high platelet, high leukocyte). MMP-2, MMP 3, and MMP-9 concentrations were measured using multiplex enzyme-linked immunosorbent assays for up to 6 days in 2 donors, and MMP activity was measured in 3 donors using kinetic activity kits able to detect the enzymatic cleavage of a fluorogenic peptide. Human ligament fibroblasts were cultured and exposed to both ACP and GPS from 1 donor each. MMP-2, -3, and -9 concentrations were assayed in culture media at 24 and 48 hours after exposure. RESULTS: GPS exhibited higher total MMP-2, -3, and -9 concentrations for up to 144 hours of release, while ACP had higher platelet-normalized MMP-2 and MMP-3 concentrations. GPS had significantly higher total and endogenous MMP-2 activity (P = .004 and .014, respectively), MMP-3 activity (P = .020 and .015, respectively), and MMP-9 activity (P = .004 and .002, respectively) compared with ACP. Once normalized to platelet count, differences in MMP activity were not significant between ACP and GPS. Compared with controls, cells stimulated with interleukin-1 beta (IL-1beta) and treated with ACP showed significantly higher fold changes of MMP-2 (P = .001) and MMP-3 (P = .003) concentrations at 24 hours than did cells treated with GPS. Total MMP-9 content was higher in the media of GPS-treated, IL-1beta-stimulated cells compared with ACP-treated cells (P = .001). At 48 hours, IL-1beta stimulated cells treated with GPS exhibited higher fold changes of MMP-2 concentration (P = .002) compared with controls, but no difference in MMP-3 concentration was found. At 48 hours, there was a significantly higher concentration of MMP-9 in the cell culture media of ACP-treated cells compared with GPS-treated cells (P = .003). CONCLUSION: PRP prepared as both ACP and GPS contains MMP-2, -3, and -9, which is released over a period of at least 6 days. Furthermore, a large proportion of these MMPs are in their active form, and MMP activity is dependent on platelet count within the PRP preparation. Once exposed to ligament fibroblasts, both ACP and GPS cause the fibroblasts to release MMPs, most notably 24 hours after PRP exposure, and this release is dependent on prior IL-1beta stimulation. CLINICAL RELEVANCE: The results of this study demonstrate that PRP therapy delivers ng/mL-range concentrations of catabolic proteases, which could perpetuate inflammation and inhibit tissue healing. PMID- 24627580 TI - Intratumoral functional heterogeneity and chemotherapy. AB - Intratumoral heterogeneity including genetic and nongenetic mechanisms refers to biological differences amongst malignant cells originated within the same tumor. Both, cell differentiation hierarchy and stochasticity in gene expression and signaling pathways may result in phenotypic differences of cancer cells. Since a tumor consists of cancer cell clones that display distinct behaviours, changes in clonal proliferative behavior may also contribute to the phenotypic variability of tumor cells. There is a need to reveal molecular actions driving chemotherapeutic resistance in colon cancer cells. In general, it is widely hypothesized that therapeutic resistance in colorectal cancer is a consequence of the preferential survival of cancer stem cells. However, recent data regarding colorectal cancer suggest that resistance to anticancer therapy and post therapeutic tumor reappearence could be related to variations of clonal dynamics. Understanding the interaction of genetic and nongenetic determinants influencing the functional diversity and therapy response of tumors should be a future direction for cancer research. PMID- 24627582 TI - Overgrowth of the indigenous gut microbiome and irritable bowel syndrome. AB - Culture-independent molecular techniques have demonstrated that the majority of the gut microbiota is uncultivable. Application of these molecular techniques to more accurately identify the indigenous gut microbiome has moved with great pace over recent years, leading to a substantial increase in understanding of gut microbial communities in both health and a number of disorders, including irritable bowel syndrome (IBS). Use of culture-independent molecular techniques already employed to characterise faecal and, to a lesser extent, colonic mucosal microbial populations in IBS, without reliance on insensitive, traditional microbiological culture techniques, has the potential to more accurately determine microbial composition in the small intestine of patients with this disorder, at least that occurring proximally and within reach of sampling. Current data concerning culture-based and culture-independent analyses of the small intestinal microbiome in IBS are considered here. PMID- 24627581 TI - Sex hormones in the modulation of irritable bowel syndrome. AB - Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of "microgenderome" related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder. PMID- 24627584 TI - Unraveling the ties between irritable bowel syndrome and intestinal microbiota. AB - Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal disorder. It is a multifactorial disorder. Intestinal microbiota may cause the pathogenesis of IBS by contributing to abnormal gastrointestinal motility, low grade inflammation, visceral hypersensitivity, communication in the gut-brain axis, and so on. Previous attempts to identify the intestinal microbiota composition in IBS patients have yielded inconsistent and occasionally contradictory results. This inconsistency may be due to the differences in the molecular techniques employed, the sample collection and handling methods, use of single samples that are not linked to fluctuating symptoms, or other factors such as patients' diets and phenotypic characterizations. Despite these difficulties, previous studies found that the intestinal microbiota in some IBS patients was completely different from that in healthy controls, and there does appear to be a consistent theme of Firmicutes enrichment and reduced abundance of Bacteroides. Based on the differences in intestinal microbiota composition, many studies have addressed the roles of microbiota-targeted treatments, such as antibiotics and probiotics, in alleviating certain symptoms of IBS. This review summarizes the current knowledge of the associations between intestinal microbiota and IBS as well as the possible modes of action of intestinal microbiota in the pathogenesis of IBS. Improving the current level of understanding of host-microbiota interactions in IBS is important not only for determining the role of intestinal microbiota in IBS pathogenesis but also for therapeutic modulation of the microbiota. PMID- 24627585 TI - Irritable bowel syndrome and small intestinal bacterial overgrowth: meaningful association or unnecessary hype. AB - Irritable bowel syndrome (IBS) is a common condition characterized by abdominal pain or discomfort, bloating, and altered stool form and passage. Small intestinal bacterial overgrowth (SIBO) is a condition in which there is overgrowth of bacteria in small bowel in excess of 105 colony forming units per milliliter on culture of the upper gut aspirate. Frequency of SIBO varied from 4% 78% among patients with IBS and from 1%-40% among controls. Higher frequency in some studies might be due to fallacious criteria [post-lactulose breath-hydrogen rise 20 PPM above basal within 90 min (early-peak)]. Glucose hydrogen breath test (GHBT) has a low sensitivity to diagnose SIBO. Hence, studies based on GHBT might have under-estimated frequency of SIBO. Therefore, it is important to analyze these studies carefully to evaluate whether the reported association between IBS and SIBO is over or under-projected. This review evaluates studies on association between SIBO and IBS, discordance between different studies, their strength and weakness including methodological issues and evidence on therapeutic manipulation of gut flora on symptoms of IBS. PMID- 24627583 TI - Irritable bowel syndrome: emerging paradigm in pathophysiology. AB - Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms. PMID- 24627586 TI - Melatonin for the treatment of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain or discomfort, in combination with disturbed bowel habits in the absence of identifiable organic cause. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland and also large number by enterochromaffin cells of the digestive mucosa. Melatonin plays an important part in gastrointestinal physiology which includes regulation of gastrointestinal motility, local anti-inflammatory reaction as well as moderation of visceral sensation. Melatonin is commonly given orally. It is categorized by the United States Food and Drug Administration as a dietary supplement. Melatonin treatment has an extremely wide margin of safety though it may cause minor adverse effects, such as headache, rash and nightmares. Melatonin was touted as a potential effective candidate for IBS treatment. Putative role of melatonin in IBS treatment include analgesic effects, regulator of gastrointestinal motility and sensation to sleep promoter. Placebo-controlled studies in melatonin suffered from heterogeneity in methodology. Most studies utilized 3 mg at bedtime as the standard dose of trial. However, all studies had consistently showed improvement in abdominal pain, some showed improvement in quality of life of IBS patients. Melatonin is a relatively safe drug that possesses potential in treating IBS. Future studies should focus on melatonin effect on gut mobility as well as its central nervous system effect to elucidate its role in IBS patients. PMID- 24627589 TI - Evaluation of renal function in patients with cirrhosis: where are we now? AB - In the clinical context of the patients with liver cirrhosis, accurate evaluation of the renal function is potentially crucial. Indeed, it can lead to early diagnosis of both acute kidney injury and chronic kidney disease and to reliable characterization of the renal status of the patient before performing a liver transplantation. Despite some limitations, the assay of serum creatinine (SCr) is universally used to estimate glomerular filtration rate (GFR) because of its wide availability, its simplicity and because it is inexpensive. Nevertheless, several reports show that the value of this assay to estimate GFR is strongly challenged in cirrhotic patients, especially in patients with liver failure and/or severely impaired renal function. This has led to seek new alternatives to estimate more reliably the GFR in these patients. Although the reference methods, based on the utilization of exogenous markers, allow measuring GFR and thereby constitute the "gold standard" to evaluate renal function, they are not feasible in routine clinical practice. Several studies have shown that a cystatin C (CysC) based formula perform better than the SCr-based estimates in cirrhotic patients and the estimation of GFR by these formulas could therefore lead to optimize the management of the patients. A new estimate based on CysC has been recently developed using a large number of patients and the first results regarding the evaluation of its performance are promising, making this new formula the best candidate for a reference estimate of the renal function in cirrhotic patients. PMID- 24627587 TI - Irritable bowel syndrome: the evolution of multi-dimensional looking and multidisciplinary treatments. AB - Irritable bowel syndrome (IBS) is common in the society. Among the putative pathogeneses, gut dysmotility results in pain and disturbed defecation. The latter is probably caused by the effect of abnormal gut water secretion. The interaction between abnormal gas accumulation, abdominal pain and bloating remains controversial. Visceral hypersensitivity and its modification along with the central transmission are the characteristics of IBS patients. The identification of biologic markers based on genetic polymorphisms is undetermined. Imbalanced gut microbiota may alter epithelial permeability to activate nociceptive sensory pathways which in turn lead to IBS. Certain food constituents may exacerbate bowel symptoms. The impact of adult and childhood abuses on IBS is underestimated. Using the concept of biopsychosocial dysfunction can integrate multidimensional pathogeneses. Antispasmodics plus stool consistency modifiers to treat the major symptoms and defecation are the first line drug treatment. New drugs targeting receptors governing bowel motility, sensation and secretion can be considered, but clinicians must be aware of their potential serious side effects. Psychiatric drugs and modalities may be the final options for treating intractable subjects. Probiotics of multi-species preparations are safe and worth to be considered for the treatment. Antibiotics are promising but their long-term safety and effectiveness are unknown. Diet therapy including exclusion of certain food constituents is an economic measure. Using relatively safe complementary and alternative medicines (CAMs) may be optional to those patients who failed classical treatment. In conclusion, IBS is a heterogeneous disorder with multidimensional pathogeneses. Personalized medicines with multidisciplinary approaches using different classes of drugs, psychiatric measures, probiotics and antibiotics, dietary therapy, and finally CAMs, can be considered. PMID- 24627588 TI - Hepatic inflammation and progressive liver fibrosis in chronic liver disease. AB - Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease. PMID- 24627590 TI - Risk factors and outcome of bacterial infections in cirrhosis. AB - Viable and non-viable pathological bacterial translocation promote a self perpetuating circle of dysfunctional immune activation and systemic inflammation facilitating infections and organ failure in advanced cirrhosis. Bacterial infections and sepsis are now recognized as a distinct stage in the natural progression of chronic liver disease as they accelerate organ failure and contribute to the high mortality observed in decompensated cirrhosis. The increasing knowledge of structural, immunological and hemodynamic pathophysiology in advanced cirrhosis has not yet translated into significantly improved outcomes of bacterial infections over the last decades. Therefore, early identification of patients at the highest risk for developing infections and infection-related complications is required to tailor the currently available measures of surveillance, prophylaxis and therapy to the patients in need in order to improve the detrimental outcome of bacterial infections in cirrhosis. PMID- 24627591 TI - Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. AB - Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications. PMID- 24627593 TI - Spinal cord involvement in patients with cirrhosis. AB - A severe spinal cord involvement may rarely occur in patients with cirrhosis and other chronic liver diseases; this complication is usually associated with overt liver failure and surgical or spontaneous porto-systemic shunt. Hepatic myelopathy (HM) is characterized by progressive weakness and spasticity of the lower extremities, while sensory and sphincter disturbances have rarely been described and are usually less important. The diagnosis is assigned in the appropriate clinical setting on clinical grounds after the exclusion of other clinical entities leading to spastic paraparesis. Magnetic resonance imaging is often unremarkable; however, also intracerebral corticospinal tract abnormalities have been reported recently. The study of motor evoked potentials may disclose central conduction abnormalities even before HM is clinically manifest. HM responds poorly to blood ammonia-lowering and other conservative medical therapy. Liver transplantation represents a potentially definitive treatment for HM in patients with decompensated cirrhosis of Child-Pugh B and C grades. Other surgical treatment options in HM include surgical ligation, shunt reduction, or occlusion by interventional procedures. PMID- 24627592 TI - Immune dysfunction in cirrhosis. AB - Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID- 24627594 TI - Cirrhosis and hepatopulmonary syndrome. AB - Hepatopulmonary syndrome (HPS) is characterized as a triad: liver disease, intrapulmonary vascular dilatation and arterial hypoxemia. HPS is reported to be present in 4% to 32% of adult patients with end-stage liver disease and in 9%-20% of children. The pathogenesis of HPS has not been clearly identified. Portal hypertension causes impairment in the perfusion of the bowel and increases the enteral translocation of Gram (-) bacteria and endotoxins. This stimulates the release of vasoactive mediators, such as tumor necrosis factor-alpha, heme oxygenase-derived carbon monoxide and nitric oxide. Genetic alterations have not been associated with this syndrome yet; however, cytokines and chemokines have been suggested to play a role. Recently, it was reported that cumulated monocytes lead to the activation of vascular endothelial growth factor-dependent signaling pathways and pulmonary angiogenesis, which plays an important role in HPS pathogenesis. At present, the most effective and only radical treatment is a liver transplant (LT). Cirrhotic patients who are on the waiting list for an LT have a shorter survival period if they develop HPS. Therefore, it is suggested that all cirrhotic cases should be followed closely for HPS and they should have priority in the waiting list. PMID- 24627595 TI - Management of thrombocytopenia due to liver cirrhosis: a review. AB - Thrombocytopenia is a common complication in liver disease and can adversely affect the treatment of liver cirrhosis, limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures because of an increased risk of bleeding. Multiple factors, including splenic sequestration, reduced activity of the hematopoietic growth factor thrombopoietin, bone marrow suppression by chronic hepatitis C virus infection and anti-cancer agents, and antiviral treatment with interferon-based therapy, can contribute to the development of thrombocytopenia in cirrhotic patients. Of these factors, the major mechanisms for thrombocytopenia in liver cirrhosis are (1) platelet sequestration in the spleen; and (2) decreased production of thrombopoietin in the liver. Several treatment options, including platelet transfusion, interventional partial splenic embolization, and surgical splenectomy, are now available for severe thrombocytopenia in cirrhotic patients. Although thrombopoietin agonists and targeted agents are alternative tools for noninvasively treating thrombocytopenia due to liver cirrhosis, their ability to improve thrombocytopenia in cirrhotic patients is under investigation in clinical trials. In this review, we propose a treatment approach to thrombocytopenia according to our novel concept of splenic volume, and we describe the current management of thrombocytopenia due to liver cirrhosis. PMID- 24627596 TI - Autoantibodies in primary biliary cirrhosis: recent progress in research on the pathogenetic and clinical significance. AB - Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research. PMID- 24627597 TI - Non-invasive prediction of forthcoming cirrhosis-related complications. AB - In patients with chronic liver diseases, identification of significant liver fibrosis and cirrhosis is essential for determining treatment strategies, assessing therapeutic response, and stratifying long-term prognosis. Although liver biopsy remains the reference standard for evaluating the extent of liver fibrosis in patients with chronic liver diseases, several non-invasive methods have been developed as alternatives to liver biopsies. Some of these non-invasive methods have demonstrated clinical accuracy for diagnosing significant fibrosis or cirrhosis in many cross-sectional studies with the histological fibrosis stage as a reference standard. However, non-invasive methods cannot be fully validated through cross-sectional studies since liver biopsy is not a perfect surrogate endpoint marker. Accordingly, recent studies have focused on assessing the performance of non-invasive methods through long-term, longitudinal, follow-up studies with solid clinical endpoints related to advanced stages of liver fibrosis and cirrhosis. As a result, current view is that these alternative methods can independently predict future cirrhosis-related complications, such as hepatic decompensation, liver failure, hepatocellular carcinoma, or liver-related death. The clinical role of non-invasive models seems to be shifting from a simple tool for predicting the extent of fibrosis to a surveillance tool for predicting future liver-related events. In this article, we will summarize recent longitudinal studies of non-invasive methods for predicting forthcoming complications related to liver cirrhosis and discuss the clinical value of currently available non-invasive methods based on evidence from the literature. PMID- 24627598 TI - Hepatitis C virus, mitochondria and auto/mitophagy: exploiting a host defense mechanism. AB - Hepatitis C virus (HCV) is the major reason for liver transplantation and the main cause of liver-related morbidity and mortality in a great number of countries. As for the other viruses, this pathogen interferes in more than one process and in more than one way with host cell biology. A mounting body of evidence points, in particular, toward the drastic alterations of mitochondrial physiology and functions that virus is able to induce, albeit the mechanisms have partly remained elusive. Role of the mitochondria in immunity and in quality control systems, as autophagy, as well as the strategies that HCV has evolved to evade and even to manipulate mitochondrial surveillance for its benefit, highlights the importance of deepening the mechanisms that modulate this virus mitochondrion interaction, not only to intensify our knowledge of the HCV infection pathogenesis but also to design efficient antiviral strategies. PMID- 24627599 TI - Serrated pathway in colorectal carcinogenesis. AB - Serrated adenocarcinoma is a recently described subset of colorectal cancer (CRC), which account for about 10% of all CRCs and follows an alternative pathway in which serrated polyps replace the traditional adenoma as the precursor lesion to CRC. Serrated polyps form a heterogeneous group of colorectal lesions that includes hyperplastic polyps (HPs), sessile serrated adenoma (SSA), traditional serrated adenoma (TSA) and mixed polyps. HPs are the most common serrated polyp followed by SSA and TSA. This distinct histogenesis is believed to have a major influence in prevention strategies, patient prognosis and therapeutic impact. Genetically, serrated polyps exhibited also a distinct pattern, with KRAS and BRAF having an important contribution to its development. Two other molecular changes that have been implicated in the serrated pathway include microsatellite instability and the CpG island methylator phenotype. In the present review we will address the current knowledge of serrated polyps, clinical pathological features and will update the most recent findings of its molecular pathways. The understanding of their biology and malignancy potential is imperative to implement a surveillance approach in order to prevent colorectal cancer development. PMID- 24627600 TI - Sodium alginate ameliorates indomethacin-induced gastrointestinal mucosal injury via inhibiting translocation in rats. AB - AIM: To investigate the effects of sodium alginate (AL-Na) on indomethacin induced small intestinal lesions in rats. METHODS: Gastric injury was assessed by measuring ulcerated legions 4 h after indomethacin (25 mg/kg) administration. Small intestinal injury was assessed by measuring ulcerated legions 24 h after indomethacin (10 mg/kg) administration. AL-Na and rebamipide were orally administered. Myeloperoxidase activity in the stomach and intestine were measured. Microvascular permeability, superoxide dismutase content, glutathione peroxidase activity, catalase activity, red blood cell count, white blood cell count, mucin content and enterobacterial count in the small intestine were measured. RESULTS: AL-Na significantly reduced indomethacin-induced ulcer size and myeloperoxidase activity in the stomach and small intestine. AL-Na prevented increases in microvascular permeability, superoxide dismutase content, glutathione peroxidase activity and catalase activity in small intestinal injury induced by indomethacin. AL-Na also prevented decreases in red blood cells and white blood cells in small intestinal injury induced by indomethacin. Moreover, AL-Na suppressed mucin depletion by indomethacin and inhibited infiltration of enterobacteria into the small intestine. CONCLUSION: These results indicate that AL-Na ameliorates non-steroidal anti-inflammatory drug-induced small intestinal enteritis via bacterial translocation. PMID- 24627601 TI - Exenatide improves hepatic steatosis by enhancing lipid use in adipose tissue in nondiabetic rats. AB - AIM: To investigate the metabolic changes in skeletal muscle and/or adipose tissue in glucagon-like peptide-1-induced improvement of nonalcoholic fatty liver disease (NAFLD). METHODS: Male Wistar rats were fed either a control diet (control group) or a high-fat diet (HFD). After 4 wk, the HFD-fed rats were subdivided into two groups; one group was injected with exenatide [HFD-Ex(+) group] and the other with saline [HFD-Ex(-) group] every day for 12 wk. The control group received saline and were fed a control diet. Changes in weight gain, energy intake, and oxygen consumption were analyzed. Glucose tolerance tests were performed after 8 wk of treatment. Histological assessments were performed in liver and adipose tissue. RNA expression levels of lipid metabolism related genes were evaluated in liver, skeletal muscle, and adipose tissue. RESULTS: Exenatide attenuated weight gain [HFD-Ex(-) vs HFD-Ex(+)] and reduced energy intake, which was accompanied by an increase in oxygen consumption and a decrease in the respiratory exchange ratio [HFD-Ex(-) vs HFD-Ex(+)]. However, exenatide did not affect glucose tolerance. Exenatide reduced lipid content in the liver and adipose tissue. Exenatide did not affect the expression of lipid metabolism-related genes in the liver or skeletal muscle. In adipose tissue, exenatide significantly upregulated lipolytic genes, including hormone-sensitive lipase, carnitine palmitoyltransferase-1, long-chain acyl-CoA dehydrogenase, and acyl-CoA oxidase 1 [HFD-Ex(-) vs HFD-Ex(+)]. Exenatide also upregulated catalase and superoxide dismutase 2 [HFD-Ex(-) vs HFD-Ex(+)]. CONCLUSION: In addition to reducing appetite, enhanced lipid use by exenatide in adipose tissue may reduce hepatic lipid content in NAFLD, most likely by decreasing lipid influx into the liver. PMID- 24627602 TI - ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn's disease patients. AB - AIM: To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn's disease (CD). METHODS: In this study, we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls. As both autophagy related like 1 (ATG16L1) and immunity-related guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleotide-binding ligomerization domain-containing protein 2 (NOD2) has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction. The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodoTM Escherichia coli Bioparticles Phagocytosis kit for flowcytometry. RESULTS: In this study, we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity (ratio of mean fluorescence intensity) between the patient groups and the healthy controls. CD patients show a significantly higher phagocytic capacity (ratio mean percentage of phagocytic cells) compared to healthy controls (51.91% +/- 2.85% vs 37.67% +/- 7.06%, P = 0.05). The extend of disease was not of influence. However, variants of ATG16L1 (WT: 2.03 +/- 0.19 vs homozygoot variant: 4.38 +/- 0.37, P < 0.009) as well as NOD2 (C-ins) (heterozygous variant: 42.08 +/- 2.94 vs homozygous variant: 75.58 +/- 4.34 (P = 0.05) are associated with the phagocytic activity in patients with CD. CONCLUSION: Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants. This could be part of the pathophysiological mechanism resulting in the disease. PMID- 24627603 TI - Effect of branched-chain amino acids in patients receiving intervention for hepatocellular carcinoma. AB - AIM: To investigate the usefulness of branched-chain amino acids (BCAA) before transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). METHODS: We investigated the usefulness of pre-intervention with BCAAs by comparing patients treated with BCAAs at 12.45 g/d orally for at least 2 wk before TACE or RFA and those not receiving such pretreatment. A total of 270 patients with hepatocellular carcinoma complicated by cirrhosis were included in the study. Mean changes from baseline (Delta) in serum albumin (Alb), C-reactive protein (CRP), and transaminase levels, as well as peak body temperature were also determined and compared at days 2, 5, and 10 after the start of TACE or RFA. RESULTS: In patients who underwent TACE or RFA, BCAA pre-intervention significantly suppressed the development of post- intervention hypoalbuminemia and reduced inflammatory reactions during the subsequent clinical course. After TACE, the DeltaAlb peaked on day 2, remained constantly lower in BCAA-treated patients, compared to the control group, and was -0.13 +/- 0.42 g/dL in BCAA treated patients and -0.33 +/- 0.51 g/dL in untreated patients on day 10. The DeltaCRP was also significantly lower in BCAA-treated patients on days 2, 5 and 10 after TACE. Like the trends noted after TACE, a similar tendency was noted as to the DeltaAlb and DeltaCRP after RFA. The changes in serum Alb level were inversely correlated with CRP changes; therefore, a possible involvement of the anti-inflammatory effect of BCAAs was inferred as a factor contributory to the suppression of decrease in serum Alb level. CONCLUSION: Pre-intervention with BCAAs may hasten the recovery of serum Alb level and mitigate post-operative complications in patients undergoing TACE or RFA. PMID- 24627604 TI - Forward-viewing radial-array echoendoscope for staging of colon cancer beyond the rectum. AB - AIM: To evaluate feasibility of the novel forward-viewing radial-array echoendoscope for staging of colon cancer beyond rectum as the first series. METHODS: A retrospective study with prospectively entered database. From March 2012 to February 2013, a total of 21 patients (11 men) (mean age 64.2 years) with colon cancer beyond the rectum were recruited. The novel forward-viewing radial array echoendoscope was used for ultrasonographic staging of colon cancer beyond rectum. Ultrasonographic T and N staging were recorded when surgical pathology was used as a gold standard. RESULTS: The mean time to reach the lesion and the mean time to complete the procedure were 3.5 and 7.1 min, respectively. The echoendoscope passed through the lesions in 13 patients (61.9%) and reached the cecum in 10 of 13 patients (76.9%). No adverse events were found. The lesions were located in the cecum (n = 2), ascending colon (n = 1), transverse colon (n = 2), descending colon (n = 2), and sigmoid colon (n = 14). The accuracy rate for T1 (n = 3), T2 (n = 4), T3 (n = 13) and T4 (n = 1) were 100%, 60.0%, 84.6% and 100%, respectively. The overall accuracy rates for the T and N staging of colon cancer were 81.0% and 52.4%, respectively. The accuracy rates among traversable lesions (n = 13) and obstructive lesions (n = 8) were 61.5% and 100%, respectively. Endoscopic ultrasound and computed tomography had overall accuracy rates of 81.0% and 68.4%, respectively. CONCLUSION: The echoendoscope is a feasible staging tool for colon cancer beyond rectum. However, accuracy of the echoendoscope needs to be verified by larger systematic studies. PMID- 24627605 TI - Association of CD14/-260 polymorphism with gastric cancer risk in Highland Tibetans. AB - AIM: To investigate the relationship between CD14-260 and -651 polymorphisms and the risk of developing gastric cancer. METHODS: DNA was extracted from peripheral blood samples obtained from 225 Tibetans with gastric cancer and 237 healthy Tibetans, and analyzed using the polymerase chain reaction/ligase detection (PCR/LDR) method to determine the genotypes at -260 and -651 loci of the CD14 promoter. The allele frequencies, genotype frequencies, and haplotypes were analyzed for their association with gastric cancer risk using online SHEsis software. The luciferase reporter assay and point mutation analysis were used to construct in vitro plasmids expressing a C/T homozygote at the -260 locus of the CD14 promoter. RESULTS: The frequencies of CC, CT and TT genotypes in the CD14 260 C/T locus in gastric cancer patients were 19.1%, 38.7% and 42.2%, respectively, whereas they were 33.3%, 32.5% and 34.2%, respectively, in healthy control subjects. CT genotype carriers were more frequently found among gastric cancer patients than healthy controls (OR = 2.076; 95%CI: 1.282-3.360). Also, TT genotype carriers were more frequently found among gastric cancer patients (OR = 2.155; 95%CI: 1.340-3.466). Compared to the C allele of CD14/-260, the T allele was associated with an increased risk for gastric cancer (OR = 1.574; 95%CI: 1.121-2.045). Furthermore, the frequencies of CC, CT and TT in the CD14-651 C/T locus in gastric cancer patients were 64.4%, 29.3% and 6.2%, respectively, while they were 56.5%, 35.0% and 8.4%, respectively, in the healthy control subjects (P > 0.05). Data obtained using the luciferase reporter assay showed that the p260T homozygote was associated with greater CD14 promoter activity (P < 0.01). CONCLUSION: CD14/-260 polymorphism is associated with gastric cancer risk in Highland Tibetans and affects CD14 promoter activity, thereby regulating CD14 expression. PMID- 24627606 TI - Antiviral therapy in cytomegalovirus-positive ulcerative colitis: a systematic review and meta-analysis. AB - AIM: To evaluate the impact of antiviral treatment on cytomegalovirus (CMV) positive ulcerative colitis patients. METHODS: We performed a systematic review and meta-analysis (MA) of comparative cohort and case-control studies published between January 1966 and March 2013. Studies focusing on colectomy series and studies including only less than 3 patients in the treated or non-treated arm were excluded. The primary outcome was colectomy within 30 d of diagnosis. Secondary outcomes included colectomy during the follow-up period Subgroup analyses by method of detection of CMV, study design, risk of bias and country of origin were performed. Quality of studies was evaluated according to modified New Castle Ottawa Scale. RESULTS: After full-text review, nine studies with a total of 176 patients were included in our MA. All the included studies were of low to moderate quality. Patients who have received antiviral treatment had a higher risk of 30-d colectomy (OR = 2.40; 95%CI: 1.05-5.50; I2 = 37.2%). A subgroup analysis including only patients in whom CMV diagnosis was based did not demonstrate a significant difference between the groups (OR = 3.41; 95%CI: 0.39 29.83; I2 = 56.9%). Analysis of long-term colectomy rates was possible for 6 studies including 110 patients. No statistically significant difference was found between the treated and untreated groups (OR = 1.71; 95%CI: 0.71-4.13; 6 studies, I2 = 0%). Analysis of mortality rate was not possible due to a very limited number of cases. Stratification of the outcomes by disease severity was not possible. CONCLUSION: No positive association between antiviral treatment and a favorable outcome was demonstrated. These findings should be interpreted cautiously due to primary studies' quality and potential biases. PMID- 24627607 TI - TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis. AB - AIM: To compare the liver transplantation-free (LTF) survival rates between patients who underwent transjugular intrahepatic portosystemic shunts (TIPS) and those who underwent paracentesis by an updated meta-analysis that pools the effects of both number of deaths and time to death. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from the inception to October 2012. LTF survival, liver transplantation, liver disease-related death, non-liver disease related death, recurrent ascites, hepatic encephalopathy (HE) and severe HE, and hepatorenal syndrome were assessed as outcomes. LTF survival was estimated using a HR with a 95%CI. Other outcomes were estimated using OR with 95%CIs. Sensitivity analyses were performed to assess the effects of potential outliers in the studies according to the risk of bias and the study characteristics. RESULTS: Six randomized controlled trials with 390 patients were included. In comparison to paracentesis, TIPS significantly improved LTF survival (HR = 0.61, 95%CI: 0.46-0.82, P < 0.001). TIPS also significantly decreased liver disease related death (OR = 0.62, 95%CI: 0.39-0.98, P = 0.04), recurrent ascites (OR = 0.15, 95%CI: 0.09-0.24, P < 0.001) and hepatorenal syndrome (OR = 0.32, 95%CI: 0.12-0.86, P = 0.02). However, TIPS increased the risk of HE (OR = 2.95, 95%CI: 1.87-4.66, P = 0.02) and severe HE (OR = 2.18, 95%CI: 1.27-3.76, P = 0.005). CONCLUSION: TIPS significantly improved the LTF survival of cirrhotic patients with refractory ascites and decreased the risk of recurrent ascites and hepatorenal syndrome with the cost of increased risk of HE compared with paracentesis. Further studies are warranted to validate the survival benefit of TIPS in clinical practice settings. PMID- 24627608 TI - Esophageal stent fracture: case report and review of the literature. AB - Endoscopic esophageal stent placement is widely used in the treatment of a variety of benign and malignant esophageal conditions. Self expanding metal stents (SEMS) are associated with significantly reduced stent related mortality and morbidity compared to plastic stents for treatment of esophageal conditions; however they have known complications of stent migration, stent occlusion, tumor ingrowth, stricture formation, reflux, bleeding and perforation amongst others. A rare and infrequently reported complication of SEMS is stent fracture and subsequent migration of the broken pieces. There have only been a handful of published case reports describing this problem. In this report we describe a case of a spontaneously fractured nitinol esophageal SEMS, and review the available literature on the unusual occurrence of SEMS fracture placed for benign or malignant obstruction in the esophagus. SEMS fracture could be a potentially dangerous event and should be considered in a patient having recurrent dysphagia despite successful placement of an esophageal SEMS. It usually requires endoscopic therapy and may unfortunately require surgery for retrieval of a distally migrated fragment. Early recognition and prompt management may be able to prevent further problems. PMID- 24627609 TI - Pancreaticoduodenectomy following total gastrectomy: a case report and literature review. AB - We present a case of afferent loop syndrome (ALS) occurring after pancreaticoduodenectomy (PD) in a patient who had previously undergone total gastrectomy (TG), and review the English-language literature concerning reconstruction procedures following PD in patients who had undergone TG. The patient was a 69-year-old man who had undergone TG reconstruction by a Roux-en-Y method at age 58 years. The patient underwent PD for pancreas head adenocarcinoma. A jejunal limb previously made at the prior TG was used for pancreaticojejunostomy and hepaticojejunostomy. Despite normal patency of the hepaticojejunostomy, he suffered from repeated postoperative cholangitis which was brought on by ALS due to shortness of the jejunal limb (15 cm in length). We therefore performed receliotomy in which the hepaticojejunostomy was disconnected and reconstructed using a new Y limb 40-cm in length constructed in a double Roux en-Y fashion. The refractory cholangitis resolved immediately after the receliotomy and did not recur. Review of the literature revealed the lack of any current consensus for a standard procedure for reconstruction following PD in patients who had previously undergone TG. This issue warrants further attention, particularly given the expected future increase in the number of PDs in patients with a history of gastric cancer. PMID- 24627610 TI - Huge undifferentiated carcinoma of the pancreas with osteoclast-like giant cells. AB - Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (OGCs) is very rare, less than 1% of all pancreatic malignancies, and shows worse prognosis than that of invasive ductal adenocarcinoma of the pancreas. We present a case of en bloc resection for a huge undifferentiated carcinoma with OGCs that invaded the stomach and transverse mesocolon. A 67-year female was admitted for left upper quadrant pain and computed tomography demonstrated a mass occupying the lesser sac and abutting the stomach and pancreas. There were no distant metastases and the patient underwent subtotal pancreatectomy with splenectomy, total gastrectomy, and segmental resection of the transverse colon. Histopathological examination confirmed an 11 cm-sized undifferentiated carcinoma of the pancreas with OGCs. Immunohistochemical staining revealed reactivity with pan-cytokeratin in adenocarcinoma component, with vimentin in neoplastic multi nucleated cells, with CD45/CD68 in OGCs, and with p53 in tumor cells, respectively. The patient had suffered from multiple bone metastases and survived 9 mo after surgery. This case supports the ductal epithelial origin of undifferentiated carcinoma with OGCs and early diagnosis could result in favorable surgical outcomes. Investigations on the surgical role and prognostic factors need to be warranted in this tumor. PMID- 24627611 TI - Primary malignant melanoma of the esophagus: a case report. AB - Primary malignant melanoma of the esophagus (PMME) is a malignant tumor which occurs in the melanin cells of esophageal mucosal epithelial basal layer. PMME is a rare disease with an extremely poor prognosis. PMME represents only 0.1% to 0.2% of all esophageal malignant tumors. Dysphagia, retrosternal or epigastric discomfort or pain is the most frequent symptom at presentation. Retrosternal, epigastric discomfort, melena or hematemesis are the major clinical manifestations. The tumor is often located from the middle to lower thoracic esophagus. The characteristic endoscopic finding of PMME is a polypoid lesion that is usually pigmented. Immunohistochemical examination with positive results of S100 protein, HMB45 and neuron-specific enolase allow a definitive diagnosis. PMME metastasizes via hematogenic and lymphatic pathways. Esophagectomy is believed to be an effective approach for localized PMME. Five-year survival rates of 37% or higher have been achieved recently. Herein, we report a case of an 65 year-old female admitted for progressive difficulty in swallowing for more than 4 mo. After upper gastrointestinal endoscopy and biopsy, upper gastrointestinal series and computed tomography examination, the patient accepted radical esophagectomy, and the postoperative pathologic and immunohistochemical examination showed PMME. PMID- 24627612 TI - Low levels of serum soluble receptors for advanced glycation end products, biomarkers for disease state: myth or reality. AB - Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) on the membrane and induce deleterious effects via activation of nuclear factor kappa-B, and increased oxidative stress and inflammatory mediators. AGEs also combine with circulating soluble receptors (endogenous secretory RAGE [esRAGE] and soluble receptor for RAGE [sRAGE]) and sequester RAGE ligands and act as a cytoprotective agent. esRAGE is secreted from the cells and is a spliced variant of RAGE. The sRAGE on the other hand is proteolytically cleaved from cell surface receptor via matrix metalloproteinase (MMPs). sRAGE is elevated in type 1 and type 2 diabetes and in patients with decreased renal function. Serum levels of sRAGE are reduced in diseases including coronary artery disease, atherosclerosis, essential hypertension, chronic obstructive lung disease, heart failure, and hypercholesterolemia. Serum levels of AGEs are elevated in patients with coronary artery disease and atherosclerosis. However, the increases in serum AGEs are very high in patients with diabetes and renal disease. There is a positive correlation between serum levels of AGEs and RAGE and sRAGE. The elevated levels of sRAGE in patients with diabetes and impaired renal function may be due to increased levels of MMPs. AGEs increase in the expression and production of MMPs, which would increase the cleavage of sRAGE from cell surface. In conclusion, low level of serum sRAGE is a good biomarker for disease other than diabetes and renal disease. A unified formula that takes into consideration of AGEs, sRAGE, and esRAGE such as AGE/sRAGE or AGEs/esRAGE would be better biomarker than sRAGE or esRAGE for all AGE-RAGE-associated diseases including diabetes and renal disease. PMID- 24627613 TI - Chronic total artery occlusions in noninfarct-related coronary arteries. AB - It has been rarely encountered some patients in clinical practice with coronary artery chronic total occlusion (CTO) on angiography but no any clinical history or electrocardiographic, echocardiographic, or left ventriculographic evidence of previous myocardial infarction. These noninfarct-related artery CTO (non-IRA CTO) lesions may be used as a clinical role model of endogenous cardioprotective mechanisms in addition to continuing the process of atherosclerosis. The objective of this study was to characterize the clinical characteristics of patients with non-IRA CTO patients and compared them to those with infarct related CTO (IRA-CTO). We reviewed our invasive cardiology database searching for the CTO of any major coronary arteries, and assessed whether or not they have the clinical history or electrocardiographic, echocardiographic, and left ventriculographic evidence of previous myocardial infarction. Interestingly, we detected that all these patients with non-IRA CTO had diabetes mellitus, and the clinical and demographic features of these non-IRA CTO patients were compared with age- and sex-matched diabetic IRA-CTO patients with regard to conventional coronary risk factors and the angiographic collateral grading system. There were total 99 CTO patients (49 patients with non-IRA CTO and 50 patients with IRA CTO).All patients with non-IRA CTO had better collateral circulation (96 vs. 40% p < 0.001) compared with those having IRA-CTO. The only significant difference between the groups was the status of current smoking (4 vs. 88%; p < 0.001). The present study showed that the non-IRA CTOs were associated with diabetes mellitus and better collateral development compared with IRA-CTO. In diabetic patients, the concomitant smoking use may be harmful by preventing endogenous cardioprotective mechanisms. PMID- 24627614 TI - Factors associated with completion of pre-kidney transplant evaluations. AB - This study sought to examine various factors that may prevent transplant candidates from completing their transplant workup prior to listing. We reviewed the records of 170 subjects (cases = 100, controls 70) who were either on dialysis or had less than 20 mL/min creatinine clearance and were therefore candidates for preemptive transplantation. Approximately, 56% of preemptive patients completed their workup, while only 36% of patients on dialysis completed their workup. Our data revealed that factors contributing toward completion of workup included intrinsic motivation (four times more likely), lack of specific medical comorbidities (three times more likely), and preemptive status (two times more likely). Among patients on dialysis, intrinsic motivation (five times more likely) and absence of cardiovascular complications (four times more likely) were associated with completion. When comparing patients on dialysis to patients not on dialysis, there were significant differences between the two groups in distance from home to the transplant center, level of education, and presence of medical comorbidities. We believe that targeted interventions such as timely referral, providing appropriate educational resources, and development of adequate support systems, have the potential to improve workup compliance of patients with advanced chronic kidney disease, including those on dialysis. PMID- 24627615 TI - Catheter Aspiration after Every Stage during Primary Percutaneous Angioplasty; ADMIT Trial. AB - We assess the epicardial and microcirculation flow characteristics, and clinical outcome by using catheter aspiration after each stage of primary percutaneous coronary intervention (PPCI). Conflicting data are reported regarding early and late benefit of using aspiration catheter in the initial phase PPCI. A total of 100 patients with ST-segment elevation acute myocardial infarction (STEMI) were included: 51 underwent PPCI without using an aspiration device (SA group) and 49 underwent PPCI by activating an aspiration catheter after each stage of procedure; wiring, ballooning and stenting, respectively (MA group). Thrombolysis in myocardial infarction (TIMI) flow grade, TIMI frame counts and myocardial blush grade (MBG) were evaluated in each group during every stage of procedure. Major adverse cardiac events were evaluated in the index hospitalization and during 30 and 180 days of follow-up. A TIMI flow grade 2-3 was more prevalent in the MA group compared with the SA group only after wiring: 65.9 versus 39.1% (p = 0.01), but TIMI frame counts were lower in the MA versus SA group throughout all procedural steps. MBG 2-3 was statistically higher in the MA group compared with the SA group mainly after wiring. After stenting there were no significant changes in both epicardial and microcirculation flow parameters. There were no significant differences between the groups in early and late clinical outcomes. Improved flow parameters were noticed in the MA group only by activating the aspiration device after wiring. This early advantage disappeared after stenting. The initial better flow characteristic in the MA group was not translated into a better early or late clinical outcome. PMID- 24627616 TI - Is Radial Access and Transradial Cardiac Catheterization Feasible without the Use of Any Vasodilator? AB - This is a "proof of concept" study to assess feasibility of transradial access without use of vasodilators. Radial artery spasm (RAS) is an important cause of patient discomfort and procedural failure with use of radial access. Vasodilators are routinely used to prevent RAS. However, the use of vasodilators may not be appropriate in substantial groups of patients. These include patients with myocardial infarction and low blood pressure who will benefit from radial access the most. No specific recommendations about use of vasodilators in these settings are stated on consensus documents on radial access. During a short period of shortage of verapamil in our country, 15 consecutive patients underwent cardiac catheterization by transradial route without the use of vasodilators. Procedural success, and pain perceived by the patients along with radial occlusion after the procedure were assessed. In 14 of the 15 patients, the procedure was completed successfully without the use of vasodilators. In one patient, RAS developed and the procedure could be completed after injection of verapamil. Mean pain score was 5.3 on a scale of 0 to 10. No radial occlusion was detected early after the procedure. In three of the patients, a reason that would otherwise preclude use of a vasodilator was identified. Radial access can safely and effectively be performed without the use of vasodilators. Consideration of this approach when use of vasodilators is not appropriate should be formally discussed by the interventional cardiology community. PMID- 24627617 TI - Improvements of venous tone with pycnogenol in chronic venous insufficiency: an ex vivo study on venous segments. AB - This study evaluated the stretching and dilatation of venous segments ex vivo in subjects with primary varicose veins in comparison with comparable segments from subjects that used the supplement Pycnogenol (150 mg/d) for 3 months before surgery. Subjects with varicose veins and chronic venous insufficiency voluntarily used Pycnogenol for a period of at least 3 months. The segments of veins removed with surgery (in 30 subjects that had used Pycnogenol and in 10 comparable control subjects that had not used the supplement) were compared with normal, unused vein segments harvested for bypass grafting. The segments were suspended and a weight was attached to the distal part of the veins for 3 minutes and dilated with pressurized water. Digital images were recorded; the veins were measured before and after stretching to evaluate elongation. The manipulation of the vein segment was minimal. Tests were completed within 20 minutes after harvesting the veins. All segments were 4 cm long. The stretching test indicated a significantly higher level of passive elongation in control, varicose segments (2.29; 0.65 mm) in comparison with 1.39; 0.2 mm in vein segments from Pycnogenol using patients. The dilation test showed an average higher dilation (2.19; 0.3 mm) in control varicose veins in comparison with varicose veins from Pycnogenol using patients (1.32; 0.7 mm) (p < 0.05). Stretching and dilatation were lower in veins from Pycnogenol-using subjects (p < 0.05). The measurement of destretching and the recovery after dilatation indicated a better tone and recovery of the original size/shape in varicose segments from patients using Pycnogenol. Varicose segments had a more significant persistent dilatation and elongation in comparison with normal vein segments. Pycnogenol seems to decrease passive dilatation and stretching and gives vein walls a greater tonic recovery and elasticity that allows the vein to recover its original shape after dynamic stresses. PMID- 24627618 TI - Predicting the occurrence of oxygenation impairment in patients with type-B acute aortic dissection. AB - Complicated respiratory failure requiring mechanical ventilation in patients with type-B acute aortic dissection (AAD) has been previously reported, and inflammatory reactions have been found to be associated with the occurrence of oxygenation impairment (OI). However, the possibility of predicting the occurrence of OI in patients with type-B AAD has not yet been evaluated. This study was performed to investigate the possibility of predicting the occurrence of OI in type-B AAD. In this study, 79 type-B AAD patients were enrolled to investigate the possibility of predicting the occurrence of OI. OI was defined as Po2/Fio2 <= 200. Patient characteristics, type of AAD, vital signs on admission, and the presence of inflammatory reactions obtained on admission day were evaluated. OI occurred in 39 patients (49%) on hospital day 2.5 +/- 1.4 on average. Younger age, male gender, nonslender frame (body mass index >= 22 kg/m(2)), a relatively high maximum body temperature on the admission day (>= 36.5 degrees C), DeBakey IIIb type, patent false lumen, and lower Po2/Fio2 on admission were found to be associated with the occurrence of OI. Multivariate analysis revealed that nonslender frame, relatively high body temperature on the admission day, and lower Po2/Fio2 on admission were reliable for predicting the occurrence of oxygen impairment. The occurrence of OI in type-B AAD can be predicted in the clinical setting. PMID- 24627619 TI - Poor outcome of bilateral lower extremity morel-lavallee lesions: a case report. AB - The Morel-Lavallee lesion is a closed, internal degloving injury that results when a strong, shearing force is applied parallel to the plane of injury, as is common in vehicular trauma. It is an underdiagnosed entity that is often missed during the initial trauma workup as symptoms can be subtle. There are few reports of lesions occurring below the knee. Most cases affect the proximal thigh and trochanter, as these tend to be dependent areas in high velocity trauma. To the best of our knowledge, this is the first literature report of bilateral lower extremity Morel-Lavallee lesions. PMID- 24627620 TI - Arterio-enteric fistula in failed enteric-drained pancreas transplants: an impending danger. AB - Enteric drainage is the preferred method of exocrine diversion in simultaneous kidney-pancreas transplantation. Because of improvements in immunosuppression, enteric drainage has become the preferred method of pancreas transplantation in general. Although associated with less potential complications than bladder drained pancreas, potentially lethal arterio-enteric fistulas in the setting of nonfunctioning allografts represent a constant threat. We herein present a case report, a review of the literature, and a call for caution. PMID- 24627621 TI - Successful treatment of myocardial bridge with alcohol septal ablation in hypertrophic obstructive cardiomyopathy. AB - Hypertrophic obstructive cardiomyopathy (HOCM) is characterized by left ventricular hypertrophy of various morphologies, with variety of clinical manifestations and hemodynamic dysfunctions. Myocardial bridge (MB) is frequently seen in HOCM patients and the decrease of flow in the coronary artery segment going intramurally through the myocardium beneath a muscle bridge is also associated with angina, myocardial ischemia, arrhythmia, and sudden death in these patients. We present here a rare case of successful treatment of MB with alcohol septal ablation in hypertrophic cardiomyopathy which has not been reported previously. PMID- 24627622 TI - Renosplenic shunting in the nutcracker phenomenon: a discussion and paradigm shift in options? A novel approach to treating nutcracker syndrome. AB - The nutcracker syndrome is a rare clinical manifestation of symptoms caused by the compression of the left renal vein by an overriding superior mesenteric artery, an anatomical variant otherwise known as the nutcracker phenomenon. Usually present in women and children, when symptomatic, it commonly presents with hematuria, proteinuria, and chronic pelvic pain. Effective modalities of treatment apart from conservative management, include both invasive surgical procedures such as renal vein transposition and autotransplantation of the kidney and more popular recently, the less invasive endovascular stenting. Both options, however, are not without complications, such as, retroperitoneal hematomas or stent migration, thrombosis and restenosis. We now present a case of spontaneous renosplenic shunting in a 68-year-old lady of Chinese descent with the nutcracker syndrome-the first of such cases to be ever reported in a patient with no preexisting predilection for chronic liver disease and portosystemic shunting. Despite having significant pelvic venous congestion as evident on computed tomography scans, she remained asymptomatic. This may present a novel paradigm shift for the treatment of the nutcracker syndrome -surgical creation of a renosplenic bypass instead of current modalities, an alternative solution which can be performed laparoscopically and is without problems related to stent use. The creation of laparoscopic splenorenal bypass has been reported once thus far in Cleveland Ohio by Chung and Gill with good symptomatic improvement but no further studies since to validate its long-term effectiveness. PMID- 24627623 TI - Evaluation of barriers between anterior and posterior compartments during Nd:YAG capsulotomy in diabetic patients. PMID- 24627624 TI - Effect of vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus patients. AB - AIMS: A close association has been demonstrated between increased cardiovascular risk and high asymmetric dimethylarginine (ADMA) levels in type 2 diabetes mellitus (DM) patients. We planned to measure serum ADMA levels in type 2 DM patients using vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. MATERIALS AND METHODS: A total of 68 type 2 DM patients who were on metformin were enrolled in the study. Based on the glycemic levels of patients, vildagliptin was added on to treatment in 33 patients. Patients were followed for 6 months. Serum ADMA, C-reactive protein, and fibrinogen levels were compared in groups of patients using metformin or metformin + vildagliptin, after 6 months. RESULTS: Serum ADMA levels were found to be significantly lower in the group using vildagliptin compared to the group using metformin + vildagliptin (P<0.001). However, serum C-reactive protein and fibrinogen levels were statistically similar in the two study groups (P=0.34 and P=0.23, respectively). CONCLUSION: Metformin + vildagliptin treatment was observed to lower serum ADMA levels in type 2 DM patients. Our findings notwithstanding, large-scale prospective randomized controlled studies are warranted to conclude that vildagliptin provides cardiovascular protection along with diabetes regulation. PMID- 24627625 TI - Results of a human factors experiment of the usability and patient acceptance of a new autoinjector in patients with rheumatoid arthritis. AB - PURPOSE: This study evaluated the human factors affecting the ease of use of a disposable autoinjector developed for subcutaneous self-injections performed by patients with chronic diseases. MATERIALS AND METHODS: This was a randomized, single-center study conducted with 65 patients with rheumatoid arthritis. Patients performed six simulated injections. Assessments of patient device acceptance and device usability were made by patient reports and independent observations of compliance with the device instruction for use (IFU) following single injections and repeated injections. RESULTS: A total of 390 simulated injections were performed. Patient device acceptance was high; more than 90% of patients found each of the tested criteria to be acceptable (>80% was required for statistical significance; P<0.016). Perceived ease of use and simplicity of the three-step process resulted in high acceptance scores: mean scores (+/- standard deviation) were 8.71 (+/-1.18) and 8.05 (+/-0.37), respectively, on a 0 10-point scale. Patients also expressed their acceptance with the ease and usefulness of the detection of the remaining drug in the autoinjector. In addition, 80% of patients declared that they would recommend the device to someone else. Globally, the human factors tested (age, sex, hand disability [Cochin score], extent of previous experience with self-injection [ie, expert or naive]) had no impact on IFU device compliance. In particular, the lack of a Cochin score interaction indicated that the degree of hand disability is not a predictive factor of poor self-injection capability with this autoinjector. CONCLUSION: This study demonstrated a high level of patient acceptance for self injection with this autoinjector among patients with rheumatoid arthritis. In particular, patients with severe hand disability were able to successfully comply with device IFU. PMID- 24627626 TI - Strategies for enhancing information, motivation, and skills for self-management behavior changes: a qualitative study of diabetes care for older adults in Korea. AB - PURPOSE: To describe strategies for enhancing information, motivation, and skills related to changes in diabetes self-management behavior among community-dwelling older adults in Korea. PATIENTS AND METHODS: A total of five focus group interviews (three separate focus groups) were conducted with 12 older adults with type 2 diabetes and five diabetes educators. Qualitative content analysis was used. RESULTS: "One's own willingness and ability" emerged as a fundamental belief about the strategies for diabetes self-management. Six major themes under three categories were identified. Under the information category, the recurrent themes were: 1) repeatedly offering detailed knowledge regarding self-management, 2) providing information about current health status, and 3) identifying experiential knowledge of blood glucose control. The recurrent themes in the motivation category were: 1) ensuring a positive attitude regarding self management, and 2) encouragement or feedback from significant others. Furthermore, in the skills category, we found that the following theme emerged: hands-on skills training with numerical standards. CONCLUSION: This study identified six tailored strategies for enhancing information, motivation, and skills for diabetes self-management behavior changes. These strategies can be used in the development of a culturally sensitive diabetes self-management program for older adults. PMID- 24627627 TI - Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination. AB - Fixed-dose combination (FDC) products represent a widely accepted approach to type 2 diabetes treatment, given that monotherapies sometimes fail to meet the treatment targets - obtaining a sustained reduction in micro- and macrovascular complications. Saxagliptin (SAXA)/metformin (MET) FDC tablets can be used either alone or in combination with glyburide, thiazolidinediones, or insulin. It has been proven that the SAXA/MET combination leads to a significant improvement in glycemic control compared to placebo in patients with type 2 diabetes that is inadequately controlled with MET alone. In addition, this FDC has been proven to be safe for people with diabetes mellitus and established cardiovascular disease, elderly patients, and patients with impaired renal function (>30 mL/minute), with dosage modification. Patient compliance, adherence, and persistence to the therapeutic regimen has been shown to be very good, while the titration of each compound according to the patient's profile is easy, given the availability of different formulations. The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A1c reduction helping the patient to achieve his/her individual glycemic goals. PMID- 24627628 TI - Barriers and facilitators to self-monitoring of blood glucose in people with type 2 diabetes using insulin: a qualitative study. AB - BACKGROUND: Self-monitoring of blood glucose (SMBG) helps to improve glycemic control and empowerment of people with diabetes. It is particularly useful for people with diabetes who are using insulin as it facilitates insulin titration and detection of hypoglycemia. Despite this, the uptake of SMBG remains low in many countries, including Malaysia. PURPOSE: This study aimed to explore the barriers and facilitators to SMBG, in people with type 2 diabetes using insulin. PATIENTS AND METHODS: Qualitative methodology was employed to explore participants' experience with SMBG. Semistructured, individual in-depth interviews were conducted on people with type 2 diabetes using insulin who had practiced SMBG, in the primary care clinic of a teaching hospital in Malaysia. Participants were purposively sampled from different age groups, ethnicity, education level, and level of glycemic control (as reflected by the glycated hemoglobin [HbA1c]), to achieve maximum variation in sampling. All interviews were conducted using a topic guide and were audio-recorded, transcribed verbatim, checked, and analyzed using a thematic approach. RESULTS: A total of 15 participants were interviewed, and thematic saturation was reached. The factors that influenced SMBG were mainly related to cost, participants' emotion, and the SMBG process. The barriers identified included: frustration related to high blood glucose reading; perception that SMBG was only for insulin titration; stigma; fear of needles and pain; cost of test strips and needles; inconvenience; unconducive workplace; and lack of motivation, knowledge, and self-efficacy. The facilitators were: experiencing hypoglycemic symptoms; desire to see the effects of dietary changes; desire to please the physician; and family motivation. CONCLUSION: Participants' perceptions of the purpose of SMBG, the emotions associated with SMBG, and the complexity, pain, and cost related to SMBG as well as personal and family motivation are the key factors that health care providers must consider when advising people with diabetes on SMBG. PMID- 24627629 TI - The perspectives of older women with chronic neck pain on perceived effects of qigong and exercise therapy on aging: a qualitative interview study. AB - Chronic pain is prevalent in elderly populations. The goals of this study were 1) to understand the results of a randomized clinical trial - Qigong and Exercise Therapy for Elderly Patients with Chronic Neck Pain (QIBANE) - that showed no difference between qigong, exercise therapy, and no-treatment on quality of life, and 2) to understand how elderly individuals with chronic pain experience interventions of qigong and exercise therapy. A qualitative interview study was conducted with 20 QIBANE participants. Interviews asked about motivation for and expectations of trial participation, experiences with the exercise classes (qigong or exercise therapy), and changes in pain experience. Interviews were transcribed, entered into the software program ATLAS.ti, and coded thematically by two coders. Content analysis was performed. All interviewees reflected positively on their QIBANE experience and described their participation in QIBANE as helpful. However, what was discussed in both groups when they talked about "positive experiences" in the study differed between the two groups. For example, themes that emerged in the exercise-therapy group related to difficulties associated with aging and staying physically active. In the interviews with qigong group members, emergent themes related to qigong as a method that improved bodily experiences and influenced daily activities. The effects that exercise therapy and qigong have on an elderly population cannot be captured by health related quality-of-life measurements, such as the Short Form (36) Health Survey. Broader concepts of quality of life that include the concepts of self-efficacy and positive affect may be more appropriate. The results presented in this study suggest that for this population group, the approach of patient-centered outcomes is especially pertinent in order to design meaningful intervention studies in the elderly. This means that research questions, interventions, and outcome measurements need to take into account the special situation of elderly people. PMID- 24627630 TI - Novel targeting using nanoparticles: an approach to the development of an effective anti-leishmanial drug-delivery system. AB - The study reported here aimed to develop an optimized nanoparticle delivery system for amphotericin B (AmpB) using a polyelectrolyte complexation technique. For this, two oppositely charged polymers presenting anti-leishmanial activity - chitosan (Cs) and chondroitin sulfate (ChS) - were used: Cs as a positively charged polymer and ChS as a negatively charged polymer. The chitosan (NQ) nanoparticles, chitosan-chondroitin sulfate (NQC) nanoparticles, and chitosan chondroitin sulfate-amphotericin B (NQC-AmpB) nanoparticles presented a mean particle size of 79, 104, and 136 nm, respectively; and a polydispersity index of 0.2. The measured zeta potential of the nanoparticles indicated a positive charge in their surface, while scanning and transmission electron microscopy revealed spherical nanoparticles with a smooth surface. Attenuated total reflectance Fourier transform infrared spectroscopy analysis showed an electrostatic interaction between the polymers, whereas the release profile of AmpB from the NQC-AmpB nanoparticles showed a controlled release. In addition, the Cs; ChS; and NQ, NQC, and NQC-AmpB nanoparticles proved to be effective against promastigotes of Leishmania amazonensis and Leishmania chagasi, with a synergistic effect observed between Cs and ChS. Moreover, the applied NQ, NQC, and NQC-AmpB compounds demonstrated low toxicity in murine macrophages, as well as null hemolytic activity in type O(+) human red blood cells. Pure AmpB demonstrated high toxicity in the macrophages. The results show that cells infected with L. amazonensis and later treated with Cs, ChS, NQ, NQC, NQC-AmpB nanoparticles, or pure AmpB presented with a significant reduction in parasite number in the order of 24%, 31%, 55%, 66%, 90%, and 89%, respectively. The data presented indicate that the engineered NQC-AmpB nanoparticles could potentially be used as an alternative therapy to treat leishmaniasis, mainly due its low toxicity to mammals' cells. PMID- 24627631 TI - In vivo and in vitro investigations of a nanostructured coating material - a preclinical study. AB - Immediate loading of dental implants is only possible if a firm bone-implant anchorage at early stages is developed. This implies early and high bone apposition onto the implant surface. A nanostructured coating material based on an osseoinductive bone grafting is investigated in relation to the osseointegration at early stages. The goal is to transmit the structure (silica matrix with embedded hydroxyapatite) and the properties of the bone grafting into a coating material. The bone grafting substitute offers an osseoinductive potential caused by an exchange of the silica matrix in vivo accompanied by vascularization. X-ray diffraction and transmission electron microscopy analysis show that the coating material consists of a high porous silica matrix with embedded nanocrystalline hydroxyapatite with the same morphology as human hydroxyapatite. An in vitro investigation shows the early interaction between coating and human blood. Energy-dispersive X-ray analysis showed that the silica matrix was replaced by an organic matrix within a few minutes. Uncoated and coated titanium implants were inserted into the femora of New Zealand White rabbits. The bone-to-implant contact (BIC) was measured after 2, 4, and 6 weeks. The BIC of the coated implants was increased significantly at 2 and 4 weeks. After 6 weeks, the BIC was decreased to the level of the control group. A histological analysis revealed high bone apposition on the coated implant surface after 2 and 4 weeks. Osteoblastic and osteoclastic activities on the coating material indicated that the coating participates in the bone-remodeling process. The nanostructure of the coating material led to an exchange of the silica matrix by an autologous, organic matrix without delamination of the coating. This is the key issue in understanding initial bone formation on a coated surface. PMID- 24627633 TI - Screening for autism in preterm children with extremely low and very low birth weight. AB - BACKGROUND: Studies of children with very low birth weight (VLBW, 1,000-1,500 g) and extremely low birth weight (ELBW, less than 1,000 g) indicate that this population seems to be at increased risk of autism spectrum disorder (ASD). METHODS: Parents of 101 VLBW and ELBW children (age 2 years, corrected for prematurity) agreed to participate in the study and signed informed consents; however, parents of only 75 children (44 boys, 31 girls) completed the screening questionnaires. The screening battery included the Modified Checklist for Autism in Toddlers (M-CHAT), Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist (CSBS-DP-ITC), and the Infant/Toddler Sensory Profile (ITSP). Children with disabilities were excluded. All children who screened positive on any of the screening tools were subsequently invited for a detailed assessment. RESULTS: Thirty-two children (42.7%) screened positive on at least one of the screening questionnaires. The screening tool with the most positive results was the CSBS-DP-ITC (26 positive screens), followed by the M CHAT (19 positive screens) and the ITSP (11 positive screens). Of the 32 children who tested positive, 19 participated in the detailed follow-up assessment. A diagnosis of ASD was confirmed in eight of the 19 children. ASD prevalence, calculated from those 19 children and those with negative screening results (43 children), yielded a prevalence of 12.9% in the sample. The difference in frequency of positive screens between the tests was significant (P=0.011). In pair comparisons, ITSP was found to be significantly less positive than CSBS-DP ITC (P=0.032). No significant differences were found between the M-CHAT and CSBS DP-ITC or between the M-CHAT and ITSP. CONCLUSION: The results strongly support the hypothesis of an increased prevalence of autism in children with a birth weight less than 1,500 g. PMID- 24627634 TI - Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation. AB - We propose the possibility of 5-hydroxytryptamine (5-HT)1A receptor involvement in mild serotonin toxicity. A 64-year-old woman who experienced hallucinations was treated with perospirone (8 mg/day). She also complained of depressed mood and was prescribed paroxetine (10 mg/day). She exhibited finger tremors, sweating, coarse shivering, hyperactive knee jerks, vomiting, diarrhea, tachycardia, and psychomotor agitation. After the discontinuation of paroxetine and perospirone, the symptoms disappeared. Another 81-year-old woman, who experienced delusions, was treated with perospirone (8 mg/day). Depressive symptoms appeared and paroxetine (10 mg/day) was added. She exhibited tachycardia, finger tremors, anxiety, agitation, and hyperactive knee jerks. The symptoms disappeared after the cessation of paroxetine and perospirone. Recently, the effectiveness of coadministrating 5-HT1A agonistic psychotropics with selective serotonin reuptake inhibitors (SSRIs) has been reported, and SSRIs with 5-HT1A agonistic activity have been newly approved in the treatment of depression. Perospirone is a serotonin-dopamine antagonist and agonistic on the 5 HT1A receptors. Animal studies have indicated that mild serotonin excess induces low body temperature through 5-HT1A, whereas severe serotonin excess induces high body temperature through 5-HT2A activation. Therefore, it could be hypothesized that mild serotonin excess induces side effects through 5-HT1A, and severe serotonin excess induces lethal side effects with hyperthermia through 5-HT2A. Serotonin toxicity via a low dose of paroxetine that is coadministered with perospirone, which acts agonistically on the 5-HT1A receptor and antagonistically on the 5-HT2A receptor, clearly indicated 5-HT1A receptor involvement in mild serotonin toxicity. Careful measures should be adopted to avoid serotonin toxicity following the combined use of SSRIs and 5-HT1A agonists. PMID- 24627632 TI - Chemotherapeutic potential of curcumin-bearing microcells against hepatocellular carcinoma in model animals. AB - Curcumin (diferuloylmethane) is found in large quantities in the roots of Curcuma longa. It possesses strong antioxidant and anti-inflammatory properties, and inhibits chemically-induced carcinogenesis in the skin, forestomach, colon, and liver. Unfortunately, the poor bioavailability and hydrophobicity of curcumin pose a major hurdle to its use as a potent anticancer agent. To circumvent some of these problems, we developed a novel, dual-core microcell formulation of curcumin. The encapsulation of curcumin in microcells increases its solubility and bioavailability, and facilitates slow release kinetics over extended periods. Besides being safe, these formulations do not bear any toxicity constraints, as revealed by in vitro and in vivo studies. Histopathological analysis revealed that curcumin-bearing microcells helped in regression of hepatocellular carcinoma and the maintenance of cellular architecture in liver tissue. Free curcumin had a very mild effect on cancer suppression. Empty (sham) microcells and microparticles failed to inhibit cancer cells. The novel curcumin formulation was found to suppress hepatocellular carcinoma efficiently in Swiss albino mice. PMID- 24627635 TI - Effect of the coadministration of citalopram with mirtazapine or atipamezole on rat contextual conditioned fear. AB - BACKGROUND: Mirtazapine, a noradrenergic and specific serotonergic antidepressant, which blocks the alpha2-adrenergic autoreceptors and heteroreceptors, has shown anxiolytic properties in clinical trials and preclinical animal experiments. The addition of mirtazapine to selective serotonin reuptake inhibitors (SSRIs) is clinically suggested to be more effective for anxiety disorders. In this study, we examined the combined effects of mirtazapine and citalopram, an SSRI, on the freezing behavior of rats, which was induced by contextual conditioned fear as an index of anxiety or fear. METHODS: Male Sprague Dawley rats individually received footshocks in a shock chamber, and 24 hours later, they were given citalopram and/or mirtazapine injections. One hour after citalopram and 30 minutes after mirtazapine administration, freezing behavior was analyzed in the same shock chamber without shocks. RESULTS: Mirtazapine decreased freezing in a dose-dependent manner, which is consistent with a previous report; it also enhanced an anxiolytic-like effect at a high dose (30 mg/kg) of citalopram. Because mirtazapine blocks alpha2 adrenoreceptors, the combined effect of atipamezole, a selective alpha2 receptor antagonist, with citalopram was also examined. Similar to mirtazapine, atipamezole reduced freezing dose-dependently, but the enhancement of citalopram's effects by atipamezole was not clear when compared with mirtazapine. CONCLUSION: The present findings suggest that mirtazapine has an anxiolytic-like effect and may enhance the anxiolytic-like effect of SSRIs, but this enhancement may not be explained by its anti-alpha2 property alone. PMID- 24627636 TI - Actual preoperative fasting time in Brazilian hospitals: the BIGFAST multicenter study. AB - BACKGROUND: Prolonged fasting increases organic response to trauma. This multicenter study investigated the gap between the prescribed and the actual preoperative fasting times in Brazilian hospitals and factors associated with this gap. METHODS: Patients (18-90-years-old) who underwent elective operations between August 2011 and September 2012 were included in the study. The actual and prescribed times for fasting were collected and correlated with sex, age, surgical disease (malignancies or benign disease), operation type, American Society of Anesthesiologists score, type of hospital (public or private), and nutritional status. RESULTS: A total of 3,715 patients (58.1% females) with a median age of 49 (18-94) years from 16 Brazilian hospitals entered the study. The median (range) preoperative fasting time was 12 (2-216) hours, and fasting time was longer (P<0.001) in hospitals using a traditional fasting protocol (13 [6 216] hours) than in others that had adopted new guidelines (8 [2-48] hours). Almost 80% (n=2,962) of the patients were operated on after 8 or more hours of fasting and 46.2% (n=1,718) after more than 12 hours. Prolonged fasting was not associated with physical score, age, sex, type of surgery, or type of hospital. Patients operated on due to a benign disease had an extended duration of preoperative fasting. CONCLUSION: Actual preoperative fasting time is significantly longer than prescribed fasting time in Brazilian hospitals. Most of these hospitals still adopt traditional rather than modern fasting guidelines. All patients are at risk of long periods of fasting, especially those in hospitals that follow traditional practices. PMID- 24627637 TI - Education and technology used to improve the quality of life for people with diabetes mellitus type II. AB - BACKGROUND: The incidence of type II diabetes mellitus (DMT2) is expected to continue to rise. Current research has analyzed various tools, strategies, programs, barriers, and support in regards to the self-management of this condition. However, past researchers have yet to analyze the education process; including the adaptation of specific strategies in activities of daily living and roles, as well as the influence of health care providers in the integration of these strategies. OBJECTIVES: The purpose of this qualitative case study was to identify the strengths and limitations of the current model of diabetes education in the United States and hypothesize how technology can impact quality of life. METHODS: Key informants on diabetes education were recruited from diabetes education centers through the American Association of Diabetes Educators. Semi structured interviews were conducted with participants. RESULTS: Health care practitioners convey limited knowledge of DMT2. Individuals with DMT2 often have limited understanding of the implications of poor self-management. There appears to be no consistent standard of care for how to effectively incorporate self management strategies. There is limited education for the use of technology in self-management. Diabetes educators describe that technology could be beneficial. CONCLUSION: Findings suggest the importance of the role of care providers in emphasizing the implications of poor self-management strategies; that a multidisciplinary approach may enhance the education process; and a need for further developments in technology to address DMT2 self-management strategies. PMID- 24627638 TI - The relationship between intervention in the CD40 signal pathway and choroidal neovascularization. AB - Age-related macular degeneration, pathologic myopia, ocular trauma, and other eye diseases can cause choroidal neovascularization (CNV). In recent years, photodynamic therapy (PDT), anti-vascular endothelial growth factor (anti-VEGF) medications, laser treatment, and other measures against CNV have been gradually applied in the clinical setting and in some cases have achieved good results. However, the pathogenesis of CNV has not been fully elucidated. The costimulatory system made up of cluster of differentiation 40 protein (CD40) and its ligand (CD40L) is an important signal transduction pathway among immune cells. The activation of CD40 can also stimulate the secretion of a variety of angiogenic growth factors (eg, VEGF) and basic fibroblast growth factors that might lead to CNV. The high level expression of CD40 and CD40L has been detected in CNV diseases. Interference with the CD40 signaling pathway may become a new target for CNV treatment. We review the relationship between CD40, CD40L, and CNV. PMID- 24627639 TI - Nickel nanoparticle-induced dose-dependent cyto-genotoxicity in human breast carcinoma MCF-7 cells. AB - Despite the widespread application of nickel nanoparticles (Ni NPs) in industrial, commercial, and biomedical fields, their response to human cells has not been clearly elucidated. In the study reported here, Ni NPs with a 28 nm diameter were used to study their interaction with human breast carcinoma (MCF-7) cells. Dose-dependent decreased cell viability and damaged cell membrane integrity showed the cytotoxic potential of the Ni NPs. We further found that Ni NPs induce oxidative stress in a dose-dependent manner, as evidenced by glutathione depletion and reactive oxygen species (ROS) generation. Comet assay indicated the dose-dependent induction of DNA damage due to Ni NP exposure. The level of messenger RNA, as well as activity of caspase-3 enzyme, was higher in MCF-7 cells exposed to Ni NPs than in control cells. Moreover, we observed statistically significant correlations of ROS with cell viability (R (2)=0.984), DNA damage (% tail DNA) (R (2)=0.982), and caspase-3 enzyme activity (R (2)=0.991). To the best of our knowledge, this is the first study on human breast cancer cells to have shown the cyto-genotoxicity of Ni NPs, which seems to be mediated through ROS. PMID- 24627640 TI - The value of radiotherapy in breast cancer patients with isolated ipsilateral supraclavicular lymph node metastasis without distant metastases at diagnosis: a retrospective analysis of Chinese patients. AB - BACKGROUND: The purpose of this study was to investigate the prognosis of ipsilateral supraclavicular lymph node metastasis (ISLM) without evidence of distant metastases at diagnosis in Chinese women with breast cancer and to elucidate the clinical value of adjuvant radiotherapy. METHODS: We performed a retrospective analysis of clinical data for 39 patients with ISLM from breast cancer without distant metastasis at diagnosis. Combined modality therapy, consisting of neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy with or without adjuvant radiotherapy, was offered to the patients. RESULTS: The patients in this study accounted for 1% of all breast cancer patients treated during the same time period. The median follow-up was 35 months. The 5-year locoregional recurrence-free survival, distant metastasis-free survival, disease free survival (DFS), and overall survival (OS) were 57.3%, 42.3%, 34.4%, and 46.2%, respectively. Twenty-three patients received postoperative adjuvant radiotherapy. However, there was no significant difference in the 3- and 5-year locoregional recurrence-free survival (P=0.693), ISLM-free recurrence (P=0.964), distant metastasis-free survival (P=0.964), DFS (P=0.234), and OS (P=0.329) rates between the groups of patients who received or did not receive adjuvant radiotherapy (P=0.840). No significant difference in the 3-year locoregional control rate (P=0.900) was found between patients who were treated with adjuvant radiotherapy at <=50 Gy and >50 Gy. Univariate analysis showed that clinical tumor size stage and age were prognostic factors that impacted DFS and OS. CONCLUSION: Combined modality treatment may achieve satisfactory efficacy in Chinese women with ISLM from breast cancer without distant metastasis at the time of diagnosis, suggesting that ISLM might be considered a curable locoregional disease. Adjuvant radiotherapy did not, however, improve the results of these patients. PMID- 24627641 TI - Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report. AB - BACKGROUND: Renal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen. METHODS: We present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy. RESULTS: Six weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not. CONCLUSION: Axitinib might be promising as preoperative or neoadjuvant therapy for locally advanced RCC (>cT3b or >cTanyN1). PMID- 24627642 TI - Direct reprogramming of adult cells: avoiding the pluripotent state. AB - The procedure of using mature, fully differentiated cells and inducing them toward other cell types while bypassing an intermediate pluripotent state is termed direct reprogramming. Avoiding the pluripotent stage during cellular conversions can be achieved either through ectopic expression of lineage-specific factors (transdifferentiation) or a direct reprogramming process that involves partial reprogramming toward the pluripotent stage. Latest advances in the field seek to alleviate concerns that include teratoma formation or retroviral usage when it comes to delivering reprogramming factors to cells. They also seek to improve efficacy and efficiency of cellular conversion, both in vitro and in vivo. The final products of this reprogramming approach could be then directly implemented in regenerative and personalized medicine. PMID- 24627643 TI - Brain repair: cell therapy in stroke. AB - Stroke affects one in every six people worldwide, and is the leading cause of adult disability. Some spontaneous recovery is usual but of limited extent, and the mechanisms of late recovery are not completely understood. Endogenous neurogenesis in humans is thought to contribute to repair, but its extent is unknown. Exogenous cell therapy is promising as a means of augmenting brain repair, with evidence in animal stroke models of cell migration, survival, and differentiation, enhanced endogenous angiogenesis and neurogenesis, immunomodulation, and the secretion of trophic factors by stem cells from a variety of sources, but the potential mechanisms of action are incompletely understood. In the animal models of stroke, both mesenchymal stem cells (MSCs) and neural stem cells (NSCs) improve functional recovery, and MSCs reduce the infarct volume when administered acutely, but the heterogeneity in the choice of assessment scales, publication bias, and the possible confounding effects of immunosuppressants make the comparison of effects across cell types difficult. The use of adult-derived cells avoids the ethical issues around embryonic cells but may have more restricted differentiation potential. The use of autologous cells avoids rejection risk, but the sources are restricted, and culture expansion may be necessary, delaying treatment. Allogeneic cells offer controlled cell numbers and immediate availability, which may have advantages for acute treatment. Early clinical trials of both NSCs and MSCs are ongoing, and clinical safety data are emerging from limited numbers of selected patients. Ongoing research to identify prognostic imaging markers may help to improve patient selection, and the novel imaging techniques may identify biomarkers of recovery and the mechanism of action for cell therapies. PMID- 24627644 TI - Adult human mesenchymal stromal cells and the treatment of graft versus host disease. AB - Graft versus host disease is a difficult and potentially lethal complication of hematopoietic stem cell transplantation. It occurs with minor human leucocyte antigen (HLA) mismatch and is normally treated with corticosteroid and other immunosuppressive therapy. When it is refractory to steroid therapy, mortality approaches 80%. Mesenchymal stromal cells are rare cells found in bone marrow and other tissues. They can be expanded in culture and possess complex and diverse immunomodulatory activity. Moreover, human mesenchymal stromal cells carry low levels of class 1 and no class 2 HLA antigens, making them immunoprivileged and able to be used without HLA matching. Their use in steroid-refractory graft versus host disease was first described in 2004. Subsequently, they have been used in a number of Phase I and II trials in acute and chronic graft versus host disease trials with success. We discuss their mode of action, the results, their production, and potential dangers with a view to future application. PMID- 24627646 TI - My modus operandi. PMID- 24627645 TI - Family structure and risk behaviors: the role of the family meal in assessing likelihood of adolescent risk behaviors. AB - BACKGROUND: Previous literature has asserted that family meals are a key protective factor for certain adolescent risk behaviors. It is suggested that the frequency of eating with the family is associated with better psychological well being and a lower risk of substance use and delinquency. However, it is unclear whether there is evidence of causal links between family meals and adolescent health-risk behaviors. PURPOSE: The purpose of this article is to review the empirical literature on family meals and adolescent health behaviors and outcomes in the US. DATA SOURCES: A SEARCH WAS CONDUCTED IN FOUR ACADEMIC DATABASES: Social Sciences Full Text, Sociological Abstracts, PsycINFO(r), and PubMed/MEDLINE. STUDY SELECTION: We included studies that quantitatively estimated the relationship between family meals and health-risk behaviors. DATA EXTRACTION: Data were extracted on study sample, study design, family meal measurement, outcomes, empirical methods, findings, and major issues. DATA SYNTHESIS: Fourteen studies met the inclusion criteria for the review that measured the relationship between frequent family meals and various risk-behavior outcomes. The outcomes considered by most studies were alcohol use (n=10), tobacco use (n=9), and marijuana use (n=6). Other outcomes included sexual activity (n=2); depression, suicidal ideation, and suicide attempts (n=4); violence and delinquency (n=4); school-related issues (n=2); and well-being (n=5). The associations between family meals and the outcomes of interest were most likely to be statistically significant in unadjusted models or models controlling for basic family characteristics. Associations were less likely to be statistically significant when other measures of family connectedness were included. Relatively few analyses used sophisticated empirical techniques available to control for confounders in secondary data. CONCLUSION: More research is required to establish whether or not the relationship between family dinners and risky adolescent behaviors is an artifact of underlying confounders. We recommend that researchers make more frequent use of sophisticated methods to reduce the problem of confounders in secondary data, and that the scope of adolescent problem behaviors also be further widened. PMID- 24627647 TI - Topical nitroglycerin in neonates with tissue injury: A case report and review of the literature. AB - Peripheral tissue injury is one of the well-described morbidities associated with stays in the neonatal intensive care unit. Despite the potential long-term disability associated with this event, the current available therapeutic options remain very limited. Topical nitroglycerin has emerged as a promising agent for the treatment of tissue injury in infants. The present article includes a review of the currently available evidence on the use of topical nitroglycerin in the neonatal population, and describes a unique case involving successful use of 2% nitroglycerin in the late treatment of prolonged tissue ischemia in a newborn infant. PMID- 24627648 TI - Speech and language support: How physicians can identify and treat speech and language delays in the office setting. AB - Failure to recognize and intervene early in speech and language delays can lead to multifaceted and potentially severe consequences for early child development and later literacy skills. While routine evaluations of speech and language during well-child visits are recommended, there is no standardized (office) approach to facilitate this. Furthermore, extensive wait times for speech and language pathology consultation represent valuable lost time for the child and family. Using speech and language expertise, and paediatric collaboration, key content for an office-based tool was developed. THE TOOL AIMED TO HELP PHYSICIANS ACHIEVE THREE MAIN GOALS: early and accurate identification of speech and language delays as well as children at risk for literacy challenges; appropriate referral to speech and language services when required; and teaching and, thus, empowering parents to create rich and responsive language environments at home. Using this tool, in combination with the Canadian Paediatric Society's Read, Speak, Sing and Grow Literacy Initiative, physicians will be better positioned to offer practical strategies to caregivers to enhance children's speech and language capabilities. The tool represents a strategy to evaluate speech and language delays. It depicts age-specific linguistic/phonetic milestones and suggests interventions. The tool represents a practical interim treatment while the family is waiting for formal speech and language therapy consultation. PMID- 24627649 TI - Case 2: Recurrent lower respiratory tract infections in a child with Down syndrome. PMID- 24627650 TI - Case 1: A 16-year-old female with left lower-quadrant abdominal pain. PMID- 24627651 TI - CPS position statement for prenatal counselling before a premature birth: Simple rules for complicated decisions. PMID- 24627652 TI - Counselling and management for anticipated extremely preterm birth. PMID- 24627653 TI - Epigenetics: What does it mean for paediatric practice? AB - 'Epigenetics' involves the study of gene expression and the environmental exposures that influence expression. In paediatrics, it is recognized that different physiological and developmental stages of the young individual are affected by both genetic control and environmental influence. It appears that changes in gene expression - not changes in the DNA itself - can be passed on from one generation to another. The importance for paediatricians is recognizing disorders involving epigenetics, recording events during childhood that could affect epigenetic control of gene expression, and being aware of new therapies as they become available. Paediatricians need to be able to recognize the relevant risk factors. PMID- 24627654 TI - Going home: Facilitating discharge of the preterm infant. AB - At the time of discharge home, parents of preterm infants in the neonatal intensive care unit often feel apprehensive and may question their ability to care for their baby. The well-planned, comprehensive discharge of a medically stable infant helps to ensure a positive transition to home and safe, effective care after discharge. This statement provides guidance in planning discharge of infants born before 34 weeks' gestational age from tertiary and community settings. Discharge readiness is usually determined by demonstration of functional maturation, including the physiological competencies of thermoregulation, control of breathing, respiratory stability, and feeding skills and weight gain. Supporting family involvement and providing education from the time of admission improve parental confidence and decrease anxiety. Assessing the physical and psychosocial discharge environment is an important part of the discharge process. The clinical team is responsible for ensuring that appropriate investigations and screening tests have been completed, that medical concerns have been resolved and that a follow-up plan is in place at the time of discharge home. PMID- 24627655 TI - Clostridium difficile in paediatric populations. AB - An increase in Clostridium difficile infection incidence has been observed among hospitalized children in the United States. The present statement, targeted at clinicians caring for infants and children in community and institutional settings, summarizes the relevant information relating to the role of C difficile in childhood diarrhea and provides recommendations for diagnosis, prevention and treatment. Significant differences between adult and paediatric risk factors and disease are discussed, along with emerging therapies. The relationship between age and disease severity in children with a newly emergent and more fluoroqinolone-resistant strain of C difficile (North American Pulse-field type-1 [NAP1]) remains unknown. The importance of antimicrobial stewardship as a preventive strategy is highlighted. This statement replaces a previous Canadian Paediatric Society position statement on C difficile published in 2000. PMID- 24627656 TI - Congenital cytomegalovirus infection in Canada: Active surveillance for cases diagnosed by paediatricians. AB - OBJECTIVE: To determine the rate of diagnosis; demographic, clinical and laboratory characteristics; and management of congenital cytomegalovirus (cCMV) cases identified by paediatricians in routine clinical practice in Canada. METHODS: National active monthly surveillance of all clinically practicing general and subspecialty paediatricians in Canada was performed for cCMV from March 1, 2005 to February 28, 2008, through the Canadian Paediatric Surveillance Program. RESULTS: Forty-nine cases of cCMV infection were reported (4.5 per 100,000 births): 40.8% were born before 36 weeks' gestation; 55.1% had a birth weight <2500 g; and 28.6% and 30.6% were below the third percentile for weight and head circumference, respectively. The median maternal age was 23 years, and 18.4% were <20 years of age. Eight mothers (16.3%) were Aboriginal (non Aboriginal birth prevalence 3.9 per 100,000; Aboriginal birth prevalence 15.8 per 100,000; P<0.005). The most common laboratory abnormality was thrombocytopenia (53.1%). Thirty-three (67.3%) infants exhibited neurological manifestations; ganciclovir therapy was administered to 12 (36.4%) and was not administered to 21 (63.6%) of the infants with neurological manifestations. CONCLUSION: Only a minority of the expected number of symptomatic cCMV-infected infants were reported in the present study. The majority of these severely affected infants, including those with neurological disease, are not being treated with ganciclovir. The present description of current diagnosis and practice highlights the need for more complete case identification in the population as well as the need for increased awareness of the optimal therapy for symptomatic cCMV. PMID- 24627657 TI - Teaching ethics in neonatal and perinatal medicine: What is happening in Canada? AB - Ethically challenging clinical situations are frequently encountered in neonatal and perinatal medicine (NPM), resulting in a complex environment for trainees and a need for ethics training during NPM residency. In the present study, the authors conducted a brief environmental scan to investigate the ethics teaching strategies in Canadian NPM programs. Ten of 13 (77%) accredited Canadian NPM residency programs participated in a survey investigating teaching strategies, content and assessment mechanisms. Although informal ethics teaching was more frequently reported, there was significant variability among programs in terms of content and logistics, with the most common topics being 'The medical decision making process: Ethical considerations' and 'Review of bioethics principles' (88.9% each); lectures by staff or visiting staff was the most commonly reported formal strategy (100%); and evaluation was primarily considered to be part of their overall trainee rotation (89%). This variability indicates the need for agreement and standardization among program directors regarding these aspects, and warrants further investigation. PMID- 24627658 TI - Peak and end range eccentric evertor/concentric invertor muscle strength ratios in chronically unstable ankles: comparison with healthy individuals. AB - The aim of this study was to evaluate the alterations in eccentric evertor/concentric invertor strength ratio and their importance in the chronically unstable ankle. Eight patients with chronic ankle instability (CAI) and nine healthy individuals participated in this study. Isokinetic concentric and eccentric invertor and evertor muscle strength measurement was carried out at an angular velocity of 120 degrees .sec(-1) by measuring maximal force moments (torque) during isokinetic ankle inversion and eversion movements. Functionally, evertor/invertor muscle strength ratios (E/I strength ratio) were calculated separately based on peak moment and angle-specific moments obtained at 0 degrees , 5 degrees , 10 degrees , 15 degrees , 20 degrees ankle joint angles. Peak and angle-specific eccentric evertor strength values at 0 degrees , 5 degrees , 10 degrees , 15 degrees , 20 degrees were significantly lower in the chronic ankle instability (CAI) group. In spite of this, no differences were obtained for peak and angle-specific concentric invertor torque values. Eccentric evertor/concentric invertor strength (Eecc/Icon) ratios were also significantly lower in the CAI group, but only at 15 degrees and 20 degrees . Eccentric evertor muscle torque and end range (15 degrees -20 degrees ) Eecc/Icon strength ratio for the chronically unstable ankle were significantly different from those for the healthy ankle. For this reason, measurements of end range eccentric/concentric strength ratios are more valuable in monitoring chronic ankle injuries and rehabilitation should include not only concentric muscle strengthening but also eccentric muscle strengthening, particularly for the evertor muscles. PMID- 24627659 TI - Acute psychological benefits of exercise performed at self-selected workloads: implications for theory and practice. AB - Given that most studies to date examined the connection between exercise and affect without considering the participants' preferred exercise workload, in this research the affective-benefits of jogging or running at a participant-selected pace were investigated in a pilot field and a laboratory experiment. Ninety-six male and female students (19.5 yrs) took part in the pilot field experiment whereas 32 women (20.3 yrs) completed the laboratory experiment. In both experiments, the participants ran/jogged for 20 minutes at a self-selected pace. They completed an abbreviated version of a 'right now form' of the Profile of Mood States (POMS - Grove and Prapavessis, 1992) inventory before and after exercise. In both experiments all dependent measures changed significantly from pre- to post-exercise, except 'fatigue' and 'vigor' that did not change in the laboratory. Total mood disturbance (TMD) decreased significantly in both experiments (68% and 89%). No significant correlations were found between exercise intensity (expressed as percent (%) of maximal heart rate reserve) and the magnitude of changes seen in the dependent measures. It is concluded that exercising at a self-selected workload yields positive changes in affect that are unrelated to exercise intensity. These results suggest that the physiological theories linking exercise with positive changes in affect, in which exercise intensity is instrumental, could not account for the acute affective benefits of exercise. It is proposed that a 'cognitive appraisal hypothesis' may be more appropriate in explaining the acute affective benefits of exercise. PMID- 24627660 TI - The use of varying creatine regimens on sprint cycling. AB - This study aimed to determine the effects of different acute creatine loadings (ACRL) on repeated cycle sprints. Twenty-eight active subjects divided into the control (n=7) and the experimental (n=21) group. The exercise protocol comprised three 30s Anaerobic Wingate Tests (AWT) interspersed with six minutes recovery, without any supplements ingested and following placebo and creatine ingestion, according to each ACRL (40g, 100g and 135g throughout a four-day period). Blood and urinary creatine levels were also determined from the experimental group for each ACRL. Protein intake (across all groups) was held constant during the study. There were no changes in protein intake or performance of the control group. For the experimental group creatine supplementation produced significant (p<0.01) increases in body mass (82.5 +/- 1.4kg pre vs 82.9 +/- 1.2kg post), blood (0.21 +/- 0.04mmol.l(-1) pre vs 2.24 +/- 0.98mmol.l(-1) post), and urinary creatine (0.23 +/- 0.09mmol.l(-1) pre vs 4.29 +/- 1.98mmol.l(-1) post). No significant differences were found between the non-supplement and placebo condition. Creatine supplementation produced an average improvement of 0.7%, 11.8% and 11.1% for the 40g, 100g and 135g ACRL respectively. However, statistics revealed significant (p<0.01) differences only for the 100g and 135g ACRL. Mean +/- SD values for the 100g ACRL for mean and minimum power were 612 +/- 180W placebo vs 693 +/- 221W creatine and 381 +/- 35W placebo vs 415 +/- 11W creatine accordingly. For the 135g ACRL the respective performance values were 722 +/- 215W placebo vs 810 +/- 240W creatine and 405 +/- 59W placebo vs 436 +/- 30W creatine. These data indicate that a 100g compared to 40g ACRL produces a greater potentiation of performance whilst, greater quantities of creatine ingestion (135g ACRL) can not provide a greater benefit. PMID- 24627661 TI - Influence of acute exercise on oxidative stress in chronic smokers. AB - The relative oxidative insult caused by exercise and smoking on biological systems are well documented, however, their cumulative influence needs to be clarified. In order to examine the collective effects of exercise and smoking on oxidant and antioxidant parameters, young male smokers (n=10) and non-smokers (n=10) made to perform a negative slope (10%) cycling exercise for 30 minutes at individual load equivalent to 60% maximal oxygen consumption (VO2max). Pre- and post-exercise (post-ex) haematocrit, haemoglobin, white blood cells, plasma malondialdehyde (MDA) levels, protein carbonyl formation and non-HDL oxidation, erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities, serum ceruloplasmin (CER) and urinary cotinine concentrations were evaluated. Pre-ex CER and urinary cotinine concentrations of smokers were significantly higher (p<0.05 and p<0.01, respectively) compared to that of non smokers and pre-ex CER concentrations were significantly correlated with cotinine levels in all subjects (p<0.05). Significant (p<0.01) increases were observed in non-HDL oxidation following the exercise in both groups and the elevations were more pronounced in smokers. Pre-ex SOD and GPX activities were not different between the two groups, however post-ex enzyme activities were significantly reduced in smokers (p<0.05). MDA and protein carbonyl concentrations were not different between the two groups and there were not any significant changes due to exercise.In conclusion, according to the results of the present study, we suggest that erythrocyte antioxidants SOD and GPX and plasma non-HDL are more prone to the possible oxidant damage of acute physical exercise in chronic smokers. PMID- 24627662 TI - Effect of exercise on learning, memory and levels of epinephrine in rats' hippocampus. AB - The aim of the present study was to investigate effect of exercise on learning and memory, long-term potentiation and levels of epinephrine in the rat hippocampus. Treadmill trained (one hour at 17 m.min(-1) for 10 days) and corresponding control rats went through spatial learning process on a Morris water maze for 8 days. The time to reach the platform (latency), the length of swim path, and the swim speed were used for the evaluation of spatial learning. Our results showed that physical activity produced a significant enhancement in spatial learning, with a decreased path length (p<0.05) and latency (p<0.05) to the platform in Morris water maze, without affecting the swim speed. Furthermore, the levels of the epinephrine were significantly increased (p<0.05) in hippocampus of the exercised rats. In conclusion our findings suggest that the enhanced learning by exercise may be mediated through the activation of adrenoceptors in the hippocampus and epinephrine may play an important role in potentiation of learning. PMID- 24627663 TI - Treadmill and Cycle Ergometer Tests are Interchangeable to Monitor Triathletes Annual Training. AB - The purpose of this study was to verify the use of a single test to obtain annual training guidelines applicable to multiple modes of training. Eight triathletes (4 females, 4 males) were tested 3 times during their training year (Phase I; Phase II; Phase III) on a treadmill and cycle ergometer. Cardio-respiratory variables were calculated at standardized percentages of maximal oxygen uptake (VO2max; 50-100%). VO2max differences between tests reached 6% in every testing session (p <= 0.01). VO2max was stable for both tests throughout the season. The ANOVA (3 phases x 2 tests x 6 intensities) demonstrated that there was a significant difference for heart rate (HRs; p <= 0.05) between tests in Phase I only. However, the nonparametric sign test did not show any significant differences in any phase. These results demonstrated that triathletes could use the relationship between HR and % VO2max collected during a treadmill or a cycle ergometer test to obtain interchangeable reference HRs for monitoring their running and cycling training bouts in high volume and/or high intensity phases of their training year. PMID- 24627664 TI - Aerobic energy expenditure during recreational weight training in females and males. AB - The influence of gender on aerobic energy expenditure (EE) during weight training has not been systematically researched. We determined the absolute and relative EE during the performance of two weight training programs of different intensities, durations and total work in males and females. Eight male and seven female recreational weight trainers (20-29 y) completed two randomly ordered weight training sessions involving 2 sets of 8 standard upper and lower body lifts at a set cadence separated by 45 seconds rest between sets and lifts (48 hrs apart). Heavy (H) at 100% 8 Repetition Maximum (8RM), 8 reps, ~19 min duration and light (L) at 85% 8RM, 15 reps, ~23 min duration. VO2 was determined continuously throughout the training sessions. Lean body mass (LBM) was estimated from skin fold measures and body weight. Energy expenditure was estimated from breath-by-breath metabolic measurements using portable metabolic assessment equipment (Cosmed K4b(2)). Absolute EE (total kJ) and rate of energy expenditure per minute (kJ per min) were not significantly different between H and L intensities and male and female subjects. The rate of EE averaged between approximately 10-12 kJ per min. However, relative EE (J per kg LBM per min per unit work) were significantly higher (p < 0.02) for females compared to males in both H: (26.46+/-8.06 females vs 14.36+/-3.02 males) and L: (19.91+/-4.28 females vs. 9.83+/-3.28 males), intensities. It was concluded that females rely on a greater relative aerobic EE than males when performing recreational type weight lifting programs. PMID- 24627665 TI - A three dimensional kinematic and kinetic study of the golf swing. AB - This paper discusses the three-dimensional kinematics and kinetics of a golf swing as performed by 84 male and one female amateur subjects of various skill levels. The analysis was performed using a variable full-body computer model of a human coupled with a flexible model of a golf club. Data to drive the model was obtained from subject swings recorded using a multi-camera motion analysis system. Model output included club trajectories, golfer/club interaction forces and torques, work and power, and club deflections. These data formed the basis for a statistical analysis of all subjects, and a detailed analysis and comparison of the swing characteristics of four of the subjects. The analysis generated much new data concerning the mechanics of the golf swing. It revealed that a golf swing is a highly coordinated and individual motion and subject-to subject variations were significant. The study highlighted the importance of the wrists in generating club head velocity and orienting the club face. The trajectory of the hands and the ability to do work were the factors most closely related to skill level. Key PointsFull-body model of the golf swing.Mechanical description of the golf swing.Statistical analysis of golf swing mechanics.Comparisons of subject swing mechanics. PMID- 24627666 TI - Work and power analysis of the golf swing. AB - A work and power (energy) analysis of the golf swing is presented as a method for evaluating the mechanics of the golf swing. Two computer models were used to estimate the energy production, transfers, and conversions within the body and the golf club by employing standard methods of mechanics to calculate work of forces and torques, kinetic energies, strain energies, and power during the golf swing. A detailed model of the golf club determined the energy transfers and conversions within the club during the downswing. A full-body computer model of the golfer determined the internal work produced at the body joints during the downswing. Four diverse amateur subjects were analyzed and compared using these two models. The energy approach yielded new information on swing mechanics, determined the force and torque components that accelerated the club, illustrated which segments of the body produced work, determined the timing of internal work generation, measured swing efficiencies, calculated shaft energy storage and release, and proved that forces and range of motion were equally important in developing club head velocity. A more comprehensive description of the downswing emerged from information derived from an energy based analysis. Key PointsFull Body Model of the golf swing.Energy analysis of the golf swing.Work of the body joints dDuring the golf swing.Comparisons of subject work and power characteristics. PMID- 24627667 TI - Do clinical and laboratory parameters effect maternal and fetal outcomes in pregnancies complicated with hemolysis, elevated liver enzymes, and low platelet count syndrome? AB - OBJECTIVE: The aim of the study was to investigate whether the clinical features and laboratory parameters affect maternal and fetal outcomes in pregnancies complicated with HELLP syndrome. MATERIAL AND METHODS: The medical records of pregnant patients complicated with HELLP syndrome were analyzed retrospectively between June 01, 2003 and June 01, 2010. The demographic data, medical history, admission symptoms, clinical and laboratory findings and recovery time were evaluated. The adverse maternal outcomes including eclampsia, placental abruption, disseminated intravascular coagulation, postpartum hemorrhage, pulmonary complications, cerebral edema and visual loss were recorded. Fetal growth restriction, necessity for neonatal intensive care unit admission and perinatal mortality were recorded as an adverse fetal outcome. RESULTS: The incidence of HELLP syndrome was 0.52%. The mean age of the patients was 28.93+/ 7.90 (range 17-45). HELLP syndrome was diagnosed on average in the 33.68+/ 4.41(th) (ranged 24-40) week of gestation. Eighteen cases (40.9%) were nullipara and twenty-six cases (59.1%) multipara. The most common complications were eclampsia (40.9%) and abruption placenta (15.9%). Pregnancy was terminated within 48 hours in all patients. The rate of cesarean section was 90.9%. Perinatal mortality rate in HELLP syndrome was 31.8%. There was no maternal mortality. CONCLUSION: Neither clinical characteristics nor laboratory parameters was found effective for prediction of adverse maternal and fetal outcomes. PMID- 24627668 TI - HPV DNA and Pap smear test results in cases with and without cervical pathology. AB - OBJECTIVE: The aim of the study was to determine the HPV prevalance and its relation to Pap smear, colposcopy and colposcopy directed biopsy in our region of Eskisehir, Turkey. MATERIAL AND METHODS: A total of 615 women who applied to the outpatient clinic between December 2009 and December 2010 constituted our study population. All patients underwent pelvic examination and Pap smear sampling. Patients who had pathological cervical appearance or Pap smear results of ASCUS, AGUS, LSIL or HSIL were referred to colposcopy. Cervical samples for HPV DNA were taken from the patients before Pap smear sampling during the routine examination or before the colposcopic evaluation. RESULTS: Twenty six of 615 patients (4%) were HPV positive. Of these 26 patients, 12 were positive for HPV type 16, 3 for type 18, 3 for type 51, 2 for type 6, 1 for type 52, 1 for type 33, 1 for type 16 and type 31, 1 for type 6 and 52, 1 for type 56 and 90, 1 for type 39 and 66. In 4 patients with cervical cancer, and in 3 of 4 CIN III cases both HPV DNA and Pap smear were positive. In the Pap smear examination of 615 patients, cytology revealed 35 ASCUS (5.6%) 4 AGUS (0.6%), 2 CIN I (0.3%) results who were negative for HPV DNA. These patients with abnormal cytology (n=41) underwent colposcopy directed biopsy, there were 3 CIN I and 1 CIN III and all the other cervical biopsy results of these patients were benign (inflammation, chronic cervicitis). CONCLUSION: HPV positivity in our hospital setting is low which is compatible with other studies in Turkey. In positive HPV cases there is a good correlation between HPV type and positive cervical biopsy results. PMID- 24627669 TI - Evaluation of risk factors in cesarean delivery among multiparous women with a history of vaginal delivery. AB - OBJECTIVE: To predict the risk of cesarean delivery (CS) for multiparous women who have undergone previous vaginal delivery. MATERIAL AND METHODS: A prospective observational study was performed, among multiparous pregnancies that were between 38 and 41 gestational weeks and had a singleton, vertex presentation fetus. Women's physical activity score, obstetric history, intrapartum and postpartum events were assessed. Multivariable logistic regression was used to explore risk factors associated with CS. RESULTS: Of the 245 total 83.7% had spontaneous labor and 16.3% were induced. Seventy-five percent of the induced women required CS, whereas only 19.5% of those with spontaneous labor required CS (p<0.001). The logistic regression analysis model included maternal weight gain, physical activity score, cervical dilatation, and fetal weight as the predictors of CS. We detected 7 (10%) maternal complications in women who underwent intrapartum CS. CONCLUSION: Labor induction is significantly associated with increased risk of cesarean delivery among previously vaginally delivered women and maternal weight gain, physical activity score, cervical dilatation, and fetal weight are most accurate parameters in the prediction of the risk of CS delivery. Intrapartum CS has an increased risk of maternal morbidity. PMID- 24627670 TI - Serum and follicular fluid Anti-Mullerian hormone concentrations at the time of follicle puncture and reproductive outcome. AB - OBJECTIVE: The objective of the study is to determine and compare the levels of Anti-Mullerian hormone (AMH) and estradiol (E2) in serum and follicular fluid (FF) on the day of oocyte pick up (OPU) with the cycle parameters and the outcome of in vitro fertilization (IVF) treatment. MATERIAL AND METHODS: The long stimulation protocol was used in 37 (86%) women; the microdose flare-up protocol was used in 6 (14%) women. Concentrations of AMH and E2 were measured in serum and FF of 43 women undergoing IVF treatment on the day of OPU. RESULTS: Significant positive associations were observed between serum AMH concentrations and the total number of oocytes retrieved (r=0.343, p=0.024). Serum AMH and FF AMH levels on the day of OPU were significantly increased in the group of women who achieved clinical pregnancy (p=0.017, p=0.028). For serum AMH, a cut-off level of 1.64 ng/ml was used for the prediction of clinical pregnancy; for FF AMH, a cut-off level of 3.8 ng/ml was used for the prediction of clinical pregnancy. Serum AMH and FF AMH levels were significantly and positively correlated with implantation rate (r=0.401, p=0.008; r=0.317, p=0.039). No significant correlation was found between serum and FF AMH concentrations and fertilization rate. CONCLUSION: Serum AMH and FF AMH concentrations are positively correlated with implantation and clinical pregnancy rates. PMID- 24627671 TI - Plasma apelin levels in patients with polycystic ovary syndrome. AB - OBJECTIVE: The aim of the study was to evaluate plasma apelin levels in patients with polycystic ovary syndrome (PCOS) and healthy controls. MATERIAL AND METHODS: Plasma apelin levels, serum lipid levels, serum hormone levels, and homeostasis model assessment-insulin resistance (HOMA-IR) values of 32 patients with PCOS and 31 healthy women forming the control group were checked. RESULTS: Plasma apelin levels of the PCOS group (0.350+/-0.083 ng/ml) were significantly higher than those of the control group (0.246+/-0.045 ng/ml) (p<0.001). No significant correlation was detected between apelin levels and biochemical or clinical data in PCOS group. CONCLUSION: Plasma apelin levels were significantly higher in PCOS patients. PMID- 24627673 TI - The investigation of tumoral angiogenesis with HIF-1 alpha and microvessel density in women with endometrium cancer. AB - OBJECTIVE: Hypoxia inducible factor 1 alpha (HIF-1alpha) is a nuclear protein upregulated in response to reduced cellular oxygen concentration which therefore acts as a marker for hypoxia. The aim of this study was to determine tumoral angiogenesis with immunohistochemical markers in endometrium cancer and its relation with stage, grade, survival rates and other prognostic factors. MATERIAL AND METHODS: Using the database in our Gynecologic Oncology clinic, we selected 94 patients who were diagnosed with endometrial cancer and underwent primary surgery at our institution between 2001 and 2010. Tissue microarrays believed to demonstrate the optimum part of the tumor were reprepared from the paraffin blocks. Angiogenesis and microvessel density (MVD) were investigated with the aid of HIF-1alpha and CD34 antibodies. RESULTS: High expression of HIF-1alpha was significantly more frequent in advanced grade endometrial cancers (p=0.044). HIF 1alpha expression was highly correlated with CD34 expression in the tumor cells (p<0.001). However lack of relation among stage, overall survival rates and histological types were analyzed with HIF-1alpha. When we compared HIF-1alpha positive and negative cases with cervical, adnexial, lymphovascular and myometrial invasion, there was no difference between these groups. MVD was evaluated with CD34 and it was remarkable and significantly different on advanced grade tumors (r=0.268; p=0.009). A similar significant difference was observed between the high expression of CD34 and type II endometrial cancer histology (p<0.001). However, there was no relationship between the MVD and stage or survival rates. CONCLUSION: High expression of HIF-1alpha is associated with tumoral angiogenesis in endometrial adenocarcinomas. Further studies targeting HIF-1alpha for disrupting mechanisms essential for tumor growth in endometrium cancer will be significant investigations in the future. PMID- 24627672 TI - Assessment of anxiety and depression levels of pregnant women with hyperemesis gravidarum in a case-control study. AB - OBJECTIVE: The aim of this study was to determine the depression and anxiety levels of pregnant women with hyperemesis gravidarum by using the Beck depression and anxiety inventory scoring system in a Turkish population. MATERIAL AND METHODS: To ascertain this relationship, a case-control study was conducted involving 86 pregnant women in their first trimester of pregnancy. Forty-one subjects had hyperemesis gravidarum, and 45 were healthy pregnant women who served as control subjects. The groups were adjusted for age, parity, and body mass index. All included women were subjected to baseline laboratory investigations including serum TSH and total hCG levels. RESULTS: There were no statistically significant differences between the groups with respect to the demographic and obstetric parameters and baseline laboratory investigations except the mean serum potassium level, which was significantly lower in patients with hyperemesis gravidarum than in the control group (p=0.039). Patients with hyperemesis gravidarum had significantly higher depression and anxiety scores than control cases (p=0.0001 and p=0.049, respectively). CONCLUSION: Our results suggest that increased anxiety and depression levels may be involved in the pathogenesis of hyperemesis gravidarum and extra psychological support may be necessary during the treatment and follow-up of these patients. PMID- 24627674 TI - The effects of immersion in water on labor, birth and newborn and comparison with epidural analgesia and conventional vaginal delivery. AB - OBJECTIVE: To document the practice of labour in water, to assess the effects of water immersion during labor and/or birth (labour stages 1, 2 and 3) on maternal, fetal and neonatal wellbeing and to compare the outcomes and safety with conventional vaginal deliveries and deliveries with epidural analgesia. MATERIAL AND METHODS: Two-hundred and seven women electing for waterbirth (n=207) were compared with women having conventional vaginal deliveries (n=204) and vaginal deliveries with epidural analgesia (n=191). Demographic data, length of 1(st), 2(nd) and 3(rd) stage of labor, induction and episiotomy requirements, perineal trauma, apgar scores, NICU requirements and VAS scores were noted. RESULTS: The 1(st) stage of labor was shorter in waterbirths compared with vaginal delivery with epidural analgesia but the 2(nd) and 3(rd) stage of labor were shortest in patients having waterbirth compared with conventional vaginal delivery and vaginal delivery with epidural analgesia. Patients having waterbirth had less requirement for induction and episiotomy but had more perineal laceration. All women having waterbirths had reduced analgesia requirements and had lower scores on VAS. There was no difference in terms of NICU admission between the groups. Apgar scores were comparable in both groups. There were no neonatal deaths or neonatal infections during the study. CONCLUSION: The study demonstrates the advantages of labor in water in terms of reduction in 2(nd) and 3(rd) stage of labor, reduction in pain and obstetric intervention such as induction or amniotomy. PMID- 24627675 TI - Preimplantation genetic diagnosis (PGD) according to medical ethics and medical law. AB - Assisted reproductive techniques not only nourish great and sometimes illusive hopes of couples who yearn for babies, but also spark new debates by reversing opinions, beliefs and values. Applications made to infertility clinics are increasing due to the influences such as broadcasts made by the media concerning assisted reproductive techniques and other infertility treatments, increase in the knowledge that people have about these problems, late marriages and postponement of childbearing age owing to sociological changes. Pre-implantation genetic diagnosis (PGD) is a technique applied to couples who are known to carry genetic diseases or who have children with genetic diseases. This technique is conducted by doctors in Turkey for its important contribution to decreasing the risk of genetic diseases and in order to raise healthy generations. In this paper, the general ethical debates and the legal situation in Turkey will be discussed. PMID- 24627676 TI - Natural Orifice Surgery (NOS)-the next step in the evolution of minimally invasive surgery. AB - Endoscopy, which was introduced in the 20(th) century, changed the outcome of surgery by reducing the need for analgesia and shortening hospital stay. Any new surgical method should improve safety and outcome. At the beginning of the 21(st) century, the use of natural orifice surgery is a promising progress. The transgastric and transdouglas approaches are currently being investigated and evaluated. The transgastric approach still has a long way to go due to objective problems such as infections, stomach acidity, and the optimal way to ensure the safe closure of gastrotomy. The transdouglas approach, however, is already starting to establish itself and it seems that with the construction of designated instruments it will prevail in the 21(st) century. PMID- 24627677 TI - Extramedullary hematopoiesis in leiomyoma uteri. AB - Extramedullary hematopoiesis (EMH) that often occurs as a compensatory reaction to an underlying hematologic abnormality is a non-neoplastic proliferation of hematopoietic tissue outside the bone marrow and peripheral blood. Rarely, EMH may be seen in hematologically normal individuals. EMH is most commonly (95%) seen in reticuloendothelial organs such as the spleen, liver, and lymph nodes but has rarely been reported in other locations. EMH is extremely rare in the uterus. In this case report, we present EMH in leiomyoma uteri in patients without any underlying hematologic abnormalities. Very rare clinical conditions like EMH can be observed in cases of myoma uteri and therefore should be kept in mind. There is currently no consensus regarding the pathogenesis and clinical management of this uncommon pathology and further reports on this topic are needed. PMID- 24627678 TI - Dichorionic twin pregnancy discordant for fetal anencephaly: a case report. AB - Dichorionic twin pregnancy discordant for fetal anencephaly is a serious condition that threatens the normal co-twin's life by causing polyhydramniosis, preterm labor and sudden death of one or both of the fetuses. We report a case of dichorionic twin pregnancy discordant for fetal anencephaly delivered at the 32(nd) week of gestation because of preterm labor and nonreassuring fetal monitoring. The aim of this case report is to summarize management options in this situation. PMID- 24627679 TI - Isolated fetal liver calcifications. AB - Hepatic calcification in the fetus is considered an uncommon occurrence and the clinical significance is not fully known. We describe five cases with isolated hepatic calcification. The causes and postnatal outcome of the fetal liver calcifications detected by ultrasound imaging are discussed. Isolated fetal liver calcifications with no aneuploidy and infection have a good prognosis. PMID- 24627680 TI - Approach to concomitant rectal and uterine prolapse: case report. AB - The classic description of rectal prolapse is a protrusion of the rectum beyond the anus. Peaks of occurrences are noted in the fourth and seventh decades of life, and most patients (80-90%) are women. The condition is often concurrent with pelvic floor descent and prolapse of other pelvic floor organs, such as the uterus or the bladder. In this study, two cases having contraindication to general anesthesia with rectal and uterine prolapse are presented. These cases were operated on under local anesthesia with support of sedation by Leforte and Delorme's operation at the same time. In conclusion; pelvic floor disorders should be considered as a whole, and surgical correction of rectal prolapse and uterine prolapse may be done at the same time under local anesthesia with the support of sedation. Performance of these operations by experienced and trained pelvic reconstructive surgeons may be advocated. PMID- 24627681 TI - The future of telesurgery: a universal system with haptic sensation. PMID- 24627682 TI - What is your diagnosis? PMID- 24627683 TI - 4-(Naphthalen-1-yl)pyridine. AB - In the title compound, C15H11N, the mean planes of the aromatic moieties are inclined to one another by 72.9 (1) degrees . The crystal is stabilized by pi-pi stacking inter-actions between the pyridine rings of inversion-related mol ecules, with a centroid-centroid distance of 3.772 (2) A. In addition, C-H?pi contacts involving an alpha-C-H group of the pyridine ring and the nonsubstituted ring of the naphthalene unit are observed, giving rise to a herringbone-type supramolecular architecture of the naphthalene moiety being contained in the molecule. PMID- 24627684 TI - A co-crystal of 1,10-phenanthroline with boric acid: a novel aza-aromatic complex. AB - The title compound, C12H8N2.2B(OH)3, is best described as a host-guest complex in which the B(OH)3 mol-ecules form a hydrogen-bonded cyclic network of layers parallel to the ab plane into which the 1,10-phenanthroline mol-ecules are bound. An extensive network of hydrogen bonds are responsible for the crystal stability. No pi-stacking inter-actions occur between the 1,10-phenanthroline mol-ecules. PMID- 24627686 TI - LncRNAs: New Players in Apoptosis Control. AB - The discovery that the mammalian genome is largely transcribed and that almost half of the polyadenylated RNAs is composed of noncoding RNAs has attracted the attention of the scientific community. Growing amount of data suggests that long noncoding RNAs (lncRNAs) are a new class of regulators involved not only in physiological processes, such as imprinting and differentiation, but also in cancer progression and neurodegeneration. Apoptosis is a well regulated type of programmed cell death necessary for correct organ development and tissue homeostasis. Indeed, cancer cells often show an inhibition of the apoptotic pathways and it is now emerging that overexpression or downregulation of different lncRNAs in specific types of tumors sensitize cancer cells to apoptotic stimuli. In this review we summarize the latest studies on lncRNAs and apoptosis with major attention to those performed in cancer cells and in healthy cells upon differentiation. We discuss the new perspectives of using lncRNAs as targets of anticancer drugs. Finally, considering that lncRNA levels have been reported to have a correlation with specific cancer types, we argue the possibility of using lncRNAs as tumor biomarkers. PMID- 24627685 TI - S-nitrosation and ubiquitin-proteasome system interplay in neuromuscular disorders. AB - Protein S-nitrosation is deemed as a prototype of posttranslational modifications governing cell signaling. It takes place on specific cysteine residues that covalently incorporate a nitric oxide (NO) moiety to form S-nitrosothiol derivatives and depends on the ratio between NO produced by NO synthases and nitrosothiol removal catalyzed by denitrosating enzymes. A large number of cysteine-containing proteins are found to undergo S-nitrosation and, among them, the enzymes catalyzing ubiquitination, mainly the class of ubiquitin E3 ligases and the 20S component of the proteasome, have been reported to be redox modulated in their activity. In this review we will outline the processes regulating S nitrosation and try to debate whether and how it affects protein ubiquitination and degradation via the proteasome. In particular, since muscle and neuronal health largely depends on the balance between protein synthesis and breakdown, here we will discuss the impact of S-nitrosation in the efficiency of protein quality control system, providing lines of evidence and speculating about its involvement in the onset and maintenance of neuromuscular dysfunctions. PMID- 24627687 TI - Characterization of NGF, trkA (NGFR) , and p75 (NTR) in Retina of Mice Lacking Reelin Glycoprotein. AB - Both Reelin and Nerve Growth Factor (NGF) exert crucial roles in retinal development. Retinogenesis is severely impaired in E-reeler mice, a model of Reelin deficiency showing specific Green Fluorescent Protein expression in Rod Bipolar Cells (RBCs). Since no data are available on Reelin and NGF cross-talk, NGF and trkA(NGFR)/ p75(NTR) expression was investigated in retinas from E-reeler versus control mice, by confocal microscopy, Western blotting, and real time PCR analysis. A scattered increase of NGF protein was observed in the Ganglion Cell Layer and more pronounced in the Inner Nuclear Layer (INL). A selective increase of p75(NTR) was detected in most of RBCs and in other cell subtypes of INL. On the contrary, a slight trend towards a decrease was detected for trkA(NGFR), albeit not significant. Confocal data were validated by Western blot and real time PCR. Finally, the decreased trkA(NGFR)/ p75(NTR) ratio, representative of p75(NTR) increase, significantly correlated with E-reeler versus E-control. These data indicate that NGF-trkA(NGFR)/ p75(NTR) is affected in E-reeler retina and that p75(NTR) might represent the main NGF receptor involved in the process. This first NGF-trkA(NGFR)/ p75(NTR) characterization suggests that E-reeler might be suitable for exploring Reelin-NGF cross-talk, representing an additional information source in those pathologies characterized by retinal degeneration. PMID- 24627689 TI - Usual interstitial pneumonia with lung cancer: clinicopathological analysis of 43 cases. AB - BACKGROUND: Previous studies have suggested an association between usual interstitial pneumonia (UIP) and lung cancer (Ca). However, clinical and histological information is not enough to determine such an association, due to the low incidence and short survival time of patients with both conditions. METHODS: We retrospectively reviewed the clinical and histological records of Ca patients with UIP between January 1999 and August 2013 at the Samsung Medical Center, Seoul, Korea. We found 43 patients who had Ca with UIP (UIP-Ca). Previously reported data of eighty-four patients with UIP-only were included as a comparison group. RESULTS: Smoking is related to poor prognosis in patients with UIP-Ca, and the number of patients with a high smoking index of more than 30 pack years significantly increased in UIP-Ca patients compared with UIP-only patients. There is no significant prognostic differentiation between UIP-Ca patients and UIP-only patients. Microscopically, UIP-Ca patients showed characteristically heterogeneous histological patterns and degrees of differentiation. There were many foci of squamous metaplasia or dysplasia at the peripheral area of squamous cell carcinomas. CONCLUSIONS: We report 43 cases of UIP-Ca. Our results suggest that smoking is related to cancer occurrence in UIP patients and poor prognosis in UIP-Ca patients. PMID- 24627688 TI - Guideline Recommendations for Testing of ALK Gene Rearrangement in Lung Cancer: A Proposal of the Korean Cardiopulmonary Pathology Study Group. AB - Rearrangement of anaplastic lymphoma kinase (ALK) gene is the best predictor of response to crizotinib, an ALK tyrosine kinase inhibitor. However, the prevalence of the ALK fusion is low, so accurate patient identification is crucial for successful treatment using ALK inhibitors. Furthermore, most patients with lung cancer present with advanced-stage disease at the time of diagnosis, so it is important for pathologists to detect ALK-rearranged patients while effectively maximizing small biopsy or cytology specimens. In this review, we propose a guideline recommendation for ALK testing approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists. PMID- 24627690 TI - Altered Expression of PTEN and Its Major Regulator MicroRNA-21 in Pulmonary Neuroendocrine Tumors. AB - BACKGROUND: Phosphatase and tensin homolog on chromosome ten (PTEN) is one of the most frequently inactivated tumor suppressors in various tumor types. MicroRNA-21 (miR-21) may affect tumor progression by post-transcriptional repression of expression of tumor suppressors, such as PTEN. This study was conducted to evaluate the significance of PTEN expression in pulmonary neuroendocrine (NE) tumors and to analyze the relationship between PTEN and miR-21 expressions. METHODS: Expressions of PTEN and miR-21 were investigated by immunohistochemistry and real time reverse transcription-polymerase chain reaction, respectively, in 75 resected pulmonary NE tumors (23 typical carcinoids [TCs], nine atypical carcinoids [ACs], 22 large cell NE carcinomas [LCNECs], and 21 small cell lung carcinomas [SCLCs]). RESULTS: Loss of PTEN expression was observed in four of 23 TCs (17.4%), four of nine ACs (44.4%), 16 of 22 LCNECs (72.7%) and nine of 21 SCLCs (42.9%) (p=.025). The expression level of miR-21 was significantly higher in high-grade NE carcinomas than in carcinoid tumors (p<.001). PTEN expression was inversely correlated with miR-21 expression (p<.001). CONCLUSIONS: This study suggests that aberrant expression of PTEN in relation to miR-21 may represent an important step in the development and progression of pulmonary NE tumors. PMID- 24627691 TI - Distribution of Human Papillomavirus 52 and 58 Genotypes, and Their Expression of p16 and p53 in Cervical Neoplasia. AB - BACKGROUND: This study investigates the prevalence of human papillomavirus (HPV) 52 and 58 genotypes among women residing in Busan, and the expression of p16 and p53 proteins in cervical neoplasia with HPV 52 and 58 infections. METHODS: A total of three hundred fifteen cases were analyzed using the HPV DNA chip test for HPV genotypes, and of these, we retrospectively examined p16 and p53 expression in 62 cases of cervical tissues infected with HPV 52 and 58 using immunohistochemistry. RESULTS: HPV 52 and 58 genotypes were identified in 62 (54.9%) out of 113 high-risk, HPV-infected cases. Of the cases examined, there were 19 single HPV 52 infections (16.8%), 23 single HPV 58 infections (20.4%), 4 multiple HPV 52 infections (3.5%), and 16 multiple HPV-58 infections (14.2%). Immunoreactivity of p16 and p53 was observed in 41 (66.1%) and 23 (37.1%) of the 62 cases of cervical neoplasia infected with HPV 52 and 58 genotypes, respectively. CONCLUSIONS: This study demonstrates a high prevalence of HPV 52 and 58 genotypes, in addition to HPV 16, among high-risk strains of cervical neoplasia in Korea. These findings suggest that development of more vaccines would be beneficial for the prevention of the various HPV genotypes. PMID- 24627692 TI - P2X7 Receptor Expression in Coexistence of Papillary Thyroid Carcinoma with Hashimoto's Thyroiditis. AB - BACKGROUND: This study was aimed at investigating the relation of P2X7 receptor (P2X7R) expression with the clinicopathological features of papillary thyroid carcinoma (PTC) coexisting with Hashimoto's thyroiditis (HT). METHODS: We examined 170 patients (84, PTC with HT; 86, PTC without HT). P2X7R expression was examined by immunohistochemical methods. The staining intensity and patterns were evaluated and scored using a semi-quantitative method. RESULTS: The PTC with HT group was more likely to contain women and had less extrathyroid extension, lymph node (LN) metastasis, lymphovascular invasion, and recurrence than the PTC without HT group. Patients positive for P2X7R had significantly higher frequencies of lymphovascular invasion, extrathyroid extension, LN metastasis, and absence of HT. As shown by multivariate analysis, the expression of P2X7R was significantly higher if HT was absent and extrathyroid extension was present. In the PTC with HT group, the expression of P2X7R was significantly higher in patients with tumor multifocality, lymphovascular invasion, and extrathyroid extension. In the PTC without HT group, the expression of P2X7R was significantly higher in women and those having tumor multifocality. CONCLUSIONS: Coexistence of PTC with HT is associated with good prognostic factors, and P2X7R expression in PTC was correlated with poor prognostic factors and the absence of HT. PMID- 24627693 TI - Effects of fixation and storage of human tissue samples on nucleic Acid preservation. AB - BACKGROUND: Because of recent advances in the molecular diagnosis of cancer patients, tissue quality has become more important in daily practice. METHODS: To evaluate the effects of fixative, duration of fixation, decalcification, and storage periods on nucleic acid integrity, DNA and RNA were extracted from gastrointestinal cancer tissue. The yield and purity were analyzed, and polymerase chain reaction (PCR) for glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 60 bp), beta-actin (148 bp), and human growth hormone (hGH; 434 bp) and real-time reverse transcription-PCR for beta-actin (97 bp) were performed. RESULTS: All formalin-fixed paraffin-embedded (FFPE) and methacarn-fixed paraffin embedded (MFPE) samples tested positive for GAPDH and beta-actin by PCR. hGH was successfully detected in all MFPE samples, but in only 46.7% of the FFPE samples. Prolonged formalin fixation resulted in fewer GAPDH and beta-actin PCR products, and amplification of hGH was not successful. The PCR and reverse transcription PCR results were significantly affected by the duration of decalcification. The yield, purity, and integrity of mRNA progressively decreased with increased storage periods of paraffin blocks. CONCLUSIONS: Fixation and storage should therefore be standardized in order to improve the quality of molecular pathologic diagnosis. PMID- 24627694 TI - Uncommon and rare human papillomavirus genotypes relating to cervical carcinomas. AB - BACKGROUND: Human papillomavirus (HPV) is an oncogenic virus in cervical cancer and most invasive carcinomas (ICs) are caused by HPV16 and 18. However, the roles and contributions of other uncommon and rare genotypes remain uncertain. METHODS: HPV genotypes were retrospectively assessed using an HPV DNA chip that can specify up to 32 HPV genotypes. We arbitrarily regarded genotypes accounting for less than 6% of the total as uncommon and rare genotypes. RESULTS: A total of 3,164 HPV-positive cases were enrolled. In groups 2A, 2B, 3, and unclassified HPV genotypes, 2.4% of cases with uncommon HPV genotypes (68, 26, 34, 53, 66, 69, 70, 73, 40, 42, 43, 44, 54, 55, 61, 62, 6, and 11) showed high grade squamous intraepithelial lesions and ICs. There were no HPV32- and 57-infected cases. CONCLUSIONS: We found that the uncommon and rare HPV genotypes may provide incremental etiologic contributions in cervical carcinogenesis, especially HPV68, 70, and 53. Further studies on these uncommon and rare HPV genotypes will be of importance in establishing the significance of genotypes in different regions, especially in planning a strategy for further vaccine development as well as follow-up on the effectiveness of the currently used vaccines. PMID- 24627695 TI - Large cell calcifying sertoli cell tumor of the testis: a case study and review of the literature. AB - A 24-year-old man was admitted due to an incidentally detected mass in his left testis, which showed radiopaque calcification on plain X-ray film. Left orchiectomy was performed, and the resected testis contained a well-demarcated, hard mass measuring 1.1 cm. Histological analysis revealed that the tumor was composed of neoplastic cells, fibrotic stroma, and laminated or irregularly shaped calcific bodies. The individual cells had abundant eosinophilic or clear cytoplasm with round nuclei, each of which contained one or two conspicuous nucleoli. They were arranged in cords, trabeculae, clusters, and diffuse sheets. There were several foci of intra-tubular growth patterns, with thickening of the basal lamina. Immunohistochemically, the neoplastic cells were positive for S-100 protein and vimentin, focally positive for inhibin alpha, and negative for cytokeratin, CD10, and Melan-A. In addition to reporting this rare case, we also review the relevant literature regarding large cell calcifying Sertoli cell tumors. PMID- 24627696 TI - Primary myxoid leiomyoma of the liver. AB - Herein, we report a case of primary myxoid leiomyoma of the liver. A 60-year-old woman complained of upper abdominal fullness. Computed tomography showed a solid tumor (8 cm) in the liver. The patient underwent right hepatectomy and histological findings from the resected specimen revealed scattered bland spindle cells in a background of exuberant myxoid material. The tumor cells were immunoreactive for smooth muscle actin and desmin. No other lesions were found elsewhere in the body. Thus, the tumor was diagnosed as a primary myxoid leiomyoma of the liver. PMID- 24627697 TI - Primary sigmoid adenocarcinoma metastasis to the breast in a 28-year-old female: a case study and a review of literature. AB - Metastasis to the breast from colorectal carcinoma is rare, only a few cases have been reported in the literature, and no cases have been reported in a young, 28 year-old patient. This report confirms the occurrence of the disease in a younger age group. The patient was referred to the Breast Clinic with a history of a gradually increasing lump in her right breast for two weeks' duration. On clinical examination, a 2-cm firm lump was noted in the upper inner quadrant of the right breast, which was clinically benign; however, histological examination of the breast core biopsy together with immunohistochemistry confirmed metastatic colorectal adenocarcinoma. The primary colorectal carcinoma was later confirmed to be a stage pT4N2M1 tumor, and the Duke stage was C1. Histology with immunohistochemistry is very important in the diagnosis of cases of this nature, but the clinical correlation should be taken into consideration at multidisciplinary team meetings to decide the final management of the patient. PMID- 24627698 TI - Adenocarcinoma arising in a colonic duplication cyst: a case report and review of the literature. PMID- 24627699 TI - A rare case of pulmonary papillary adenoma in old aged woman: a brief case report. PMID- 24627700 TI - Malignant fat-forming solitary fibrous tumor of the thigh. PMID- 24627701 TI - Benign Indolent CD56-Positive NK-Cell Lymphoproliferative Lesion Involving Gastrointestinal Tract in an Adolescent. PMID- 24627702 TI - Crush cytology of microcystic meningioma with extensive sclerosis. PMID- 24627703 TI - Recent Update of Renin-angiotensin-aldosterone System in the Pathogenesis of Hypertension. AB - The activation of renin-angiotensin-aldosterine system(RAAS) is one of the main pathogenesis of hypertension. All the components of RAAS are present in the kidneys at higher concentrations compared to plasma levels, and intrarenal formation of angiotensin II (Ang II) is independent of the systemic RAAS. There are some unique features in intrarenal RAAS compared to systemic RAAS. Unlike JG cells where Ang II inhibits renin release via the AngII type 1 (AT1) receptor by negative feedback, in the collecting duct Ang II stimulates renin expression via the AT1 receptor. Upregulated renin produced in the distal nephron may be able to support continued intrarenal Ang II formation leading to amplification or maintenance of the hypertensive state.The recently discovered angiotensin converting enzyme-related carboxypeptidase 2 (ACE2)-Angiotensin-(1-7) Ang-(1-7) Mas receptor axis has an opposing function to that of the ACE-Ang II-AT1 receptor axis.The ACE2 deficiency was associated with an increase in blood pressure, and ACE2 knockout mice have highlighted hypertensive response to Ang II infusion associated with exaggerated accumulation of Ang II in the kidney. Recently, several numbers of patients have been evaluated as the activators of ACE2-Ang-(1 7)-Mas receptor axis, which can be divided into two main classes: aimed to increase the activity of ACE2, and directed to stimulate the Ang-(1-7) receptor Mas. In order to investigate new targets for hypertension and kidney disease, further research on the function of the ACE-Ang-(1-7)-Mas receptor axis is required. PMID- 24627704 TI - Obesity associated hypertension: new insights into mechanism. AB - With excess nutrition, the burden of obesity is a growing problem worldwide. The imbalance between energy intake and expenditure leads to variable disorders as all major risk factors for cardiovascular disease. There are many hypothetical mechanisms to explain obesity-associated hypertension. Activation of the RAAS is a key contributing factor in obesity. Particularly, the RAAS in adipose tissue plays a crucial role in adipose tissue dysfunction and obesity-induced inflammation. The phenotypic changes of adipocytes occur into hypertrophy and an inflammatory response in an autocrine and paracrine manner to impair adipocyte function, including insulin signaling pathway. Adipose tissue produce and secretes several molecules such as leptin, resistin, adiponectin, and visfatin, as well as cytokines such as TNF-alpha, IL-6, MCP-1, and IL-1. These adipokines are stimulated via the intracellular signaling pathways that regulate inflammation of adipose tissue. Inflammation and oxidative stress in adipose tissue are important to interact with the microvascular endothelium in the mechanisms of obesity-associated hypertension. Increased microvascular resistance raises blood pressure. Therefore, a regulatory link between microvascular and perivascular adipose tissue inflammation and adipokine synthesis are provided to explain the mechanism of obesity-associated hypertension. PMID- 24627705 TI - Severe hypernatremia by excessive bamboo salt ingestion in healthy young woman. AB - Severe hypernatremia is an important electrolyte disorder that has serious effects. The patient had no medical history. A. 20-year-old ingested bamboo salt for digestion and weight reduction according to the folk remedies posted on an internet website. She presented with vomiting and diarrhea over ten times per day. Her initial serum sodium concentration was 174mEq/L. Her symptoms improved rapidly with hypotonic saline infusion. She recovered completely without any sequelae in three days. Severe hypernatremia in a normal young adult with clear consciousness and normal renal function has not been reported in Korea yet. So we report a case of severe hypernatremia by excessive bamboo salt ingestion in healthy young woman. PMID- 24627706 TI - Severe Hyponatremia Associated with the Use of Angiotensin II Receptor Blocker/thiazide Combinations. AB - There are several widely used combinations of angiotensin II receptor blocker (ARB)/thiazide. The complimentary mechanism of action for such anti-hypertensive therapies is that, while ARB inhibits the vasoconstricting and aldosterone secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and increases excretion of sodium and chloride in the distal tubule, consequently promoting water excretion. In addition, hypokalemia, which may be triggered by a hydrochlorothiazide-induced increase in urinary potassium loss, is resisted by the use of ARB. Hence, the ARB/thiazide combination is safe in terms of potassium imbalance. For these reasons, fixed-dose ARB/thiazide combination anti-hypertensive drugs have been widely used for the treatment of hypertension. However, there have not been many studies done regarding cases where patients under such regimens showed severe hyponatremia, even when the amount of thiazide included was low. Here we report two cases in which severe hyponatremia occurred following treatment with the ARB/thiazide combinations. Upon discontinuation of the regimen, both patients showed recovery from hyponatremia. PMID- 24627707 TI - Biochemia Medica indexed in PubMed Central (PMC). PMID- 24627708 TI - Preanalytical phase - an updated review of the current evidence. PMID- 24627709 TI - Why would medical publishers not incorporate core bioethical values into their Ethics Guidelines? AB - It is quite universally acknowledged by bioethicists, at least in the western world, that respect for the patients' autonomy, non-malevolence, beneficence, and justice (also called equity) are four core ethical values in medicine. The Ethics Guidelines of key journals in laboratory medicine are not explicit about the first three of these values, and even implicitly, they seem to miss values of justice. Health equity being one of the main objectives of public health policy across the world, we suggest that values of equity explicitly become part of the Ethics Guidelines of laboratory medicine journals. Biochemia Medica could show the way to other medical publishers by incorporating into its Ethics Guidelines these very important core bioethical values. PMID- 24627710 TI - Understanding logistic regression analysis. AB - Logistic regression is used to obtain odds ratio in the presence of more than one explanatory variable. The procedure is quite similar to multiple linear regression, with the exception that the response variable is binomial. The result is the impact of each variable on the odds ratio of the observed event of interest. The main advantage is to avoid confounding effects by analyzing the association of all variables together. In this article, we explain the logistic regression procedure using examples to make it as simple as possible. After definition of the technique, the basic interpretation of the results is highlighted and then some special issues are discussed. PMID- 24627711 TI - Hiring a professional medical writer: is it equivalent to ghostwriting? AB - Authors of articles published in medical journals are often busy researchers who cannot afford time devoted to writing. Though they are experts in their own therapeutic area, more often than not, researchers find it difficult to actually write and publish their research. Professional medical writers with their expertise in writing clear, concise, comprehensible, and coherent content are often a great support to researchers. Their contribution to the manuscript is usually focused on getting a manuscript ready for publication. They are not authors unless they make substantial contribution to the study according to the guidelines of the International Committee of Medical Journal Editors (ICMJE). However, medical writing is not the same as ghostwriting. Ghostwriting is unethical. Medical writers can be legitimate contributors to the medical manuscript. Several international guidelines including the ICMJE guidelines require authors to acknowledge the contribution of medical writers in the published article. Medical writers whose name is publicly associated with the article in turn make an extra effort to ensure that all applicable publication ethics and style guidelines are adhered to. This article discusses the current international guidelines about the acknowledgement of writing assistance. It also emphasizes on how acknowledging medical writing support can go a long way in curbing the menace of scientific misconduct including ghostwriting. PMID- 24627712 TI - History of the preanalytical phase: a personal view. AB - In the 70ies of the last century, ther term "preanalytical phase" was introduced in the literature. This term describes all actions and aspects of the "brain to brain circle" of the medical laboratory diagnostic procedure happening before the analytical phase. The author describes his personal experiences in the early seventies and the following history of increasing awareness of this phase as the main cause of "laboratory errors". This includes the definitions of influence and interference factors as well as the first publications in book, internet, CD-Rom and recent App form over the past 40 years. In addition, a short summary of previous developments as prerequesits of laboratory diagnostic actions is described from the middle age matula for urine collection to the blood collection tubes, anticoagulants and centrifuges. The short review gives a personal view on the possible causes of missing awareness of preanalytical causes of error and future aspects of new techniques in regulation of requests to introduction of quality assurance programs for preanalytical factors. PMID- 24627713 TI - Interferences from blood collection tube components on clinical chemistry assays. AB - Improper design or use of blood collection devices can adversely affect the accuracy of laboratory test results. Vascular access devices, such as catheters and needles, exert shear forces during blood flow, which creates a predisposition to cell lysis. Components from blood collection tubes, such as stoppers, lubricants, surfactants, and separator gels, can leach into specimens and/or adsorb analytes from a specimen; special tube additives may also alter analyte stability. Because of these interactions with blood specimens, blood collection devices are a potential source of pre-analytical error in laboratory testing. Accurate laboratory testing requires an understanding of the complex interactions between collection devices and blood specimens. Manufacturers, vendors, and clinical laboratorians must consider the pre-analytical challenges in laboratory testing. Although other authors have described the effects of endogenous substances on clinical assay results, the effects/impact of blood collection tube additives and components have not been well systematically described or explained. This review aims to identify and describe blood collection tube additives and their components and the strategies used to minimize their effects on clinical chemistry assays. PMID- 24627714 TI - The importance of implementing safe sharps practices in the laboratory setting in Europe. AB - Healthcare workers are at risk of sharps injuries and subsequent infection from more than 40 bloodborne pathogens or species. Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) together account for the vast majority of cases. The Directive 2010/32/EU "Prevention from sharp injuries in the hospital and healthcare sector", issued to protect workers from these risks, requires an integrated approach to prevention including awareness-raising, education, training, elimination of unnecessary needles, safe procedures for sharps use and disposal, banning of recapping, vaccination, use of personal protective equipment, provision of safety-engineered devices, and appropriate surveillance, monitoring, response and follow-up. As laboratories represent a high-risk setting both in the preanalytical and analytical phase, we reviewed accidents and prevention in this setting in the light of the new legislation. Phlebotomy is the procedure carrying the highest risk of exposure and infection, involved in 30-50% of HIV and HCV cases detected in nationwide systems following accidental blood exposures implemented since the 1990s in Italy and France. In laboratories, problems in the management of sharps containers, recapping, needle disassembly by hand and blood transfer from syringes into tubes were observed and accounted for two-thirds of injuries. These accidents could be reduced through education and monitoring of behaviours, and introduction of medical devices incorporating safety-engineered protection mechanisms with appropriate training. Laboratory staff should be immunized against HBV, and know policies and procedures for the post-exposure management and prophylaxis. The management commitment to safety is crucial to ensure the necessary support to these changes. PMID- 24627715 TI - Lipemia: causes, interference mechanisms, detection and management. AB - In the clinical laboratory setting, interferences can be a significant source of laboratory errors with potential to cause serious harm for the patient. After hemolysis, lipemia is the most frequent endogenous interference that can influence results of various laboratory methods by several mechanisms. The most common preanalytical cause of lipemic samples is inadequate time of blood sampling after the meal or parenteral administration of synthetic lipid emulsions. Although the best way of detecting the degree of lipemia is measuring lipemic index on analytical platforms, laboratory experts should be aware of its problems, like false positive results and lack of standardization between manufacturers. Unlike for other interferences, lipemia can be removed and measurement can be done in a clear sample. However, a protocol for removing lipids from the sample has to be chosen carefully, since it is dependent on the analytes that have to be determined. Investigation of lipemia interference is an obligation of manufacturers of laboratory reagents; however, several literature findings report lack of verification of the declared data. Moreover, the acceptance criteria currently used by the most manufacturers are not based on biological variation and need to be revised. Written procedures for detection of lipemia, removing lipemia interference and reporting results from lipemic samples should be available to laboratory staff in order to standardize the procedure, reduce errors and increase patient safety. PMID- 24627716 TI - Physical activity - an important preanalytical variable. AB - The concentration of several biochemical and hematological biomarkers is strongly influenced by a number of preanalytical variables. Several lines of evidence attest that short, middle, and long-term exercise, as well as the relative intensity of physical effort (from mild to strenuous), may influence a broad array of laboratory variables. The amount of extracellular release and clearance from blood of most of these biomarkers is markedly influenced by the biological characteristics of the molecule(s), level of training, type, intensity and duration of exercise, and time of recovery after training. It is hence noteworthy that test results that fall outside the conventional reference ranges in athletes not only may reflect the presence of a given disease, but may frequently mirror an adaptation to regular training or changes that have occurred during and/or following strenuous exercise, and which should be clearly acknowledged to prevent misinterpretation of laboratory data. The aim of this narrative review is to provide an update about the most significant changes of some biochemical and hematological biomarkers in response to physical exercise, for appropriate interpretation of these changes in the context of physically active subjects. PMID- 24627717 TI - Interference of medical contrast media on laboratory testing. AB - The use of contrast media such as organic iodine molecules and gadolinium contrast agents is commonplace in diagnostic imaging. Although there is widespread perception that side effects and drug interactions may be the leading problems caused by these compounds, various degrees of interference with some laboratory tests have been clearly demonstrated. Overall, the described interference for iodinate contrast media include inappropriate gel barrier formation in blood tubes, the appearance of abnormal peaks in capillary zone electrophoresis of serum proteins, and a positive bias in assessment of cardiac troponin I with one immunoassay. The interference for gadolinium contrast agents include negative bias in calcium assessment with ortho-cresolphthalein colorimetric assays and occasional positive bias using some Arsenazo reagents, negative bias in measurement of angiotensin converting enzyme (ACE) and zinc (colorimetric assay), as well as positive bias in creatinine (Jaffe reaction), total iron binding capacity (TIBC, ferrozine method), magnesium (calmagite reagent) and selenium (mass spectrometry) measurement. Interference has also been reported in assessment of serum indices, pulse oximetry and methaemoglobin in samples of patients receiving Patent Blue V. Under several circumstances the interference was absent from manufacturer-supplied information and limited to certain type of reagents and/or analytes, so that local verification may be advisable to establish whether or not the test in use may be biased. Since the elimination half-life of these compounds is typically lower than 2 h, blood collection after this period may be a safer alternative in patients who have received contrast media for diagnostic purposes. PMID- 24627718 TI - Preanalytical requirements of urinalysis. AB - Urine may be a waste product, but it contains an enormous amount of information. Well-standardized procedures for collection, transport, sample preparation and analysis should become the basis of an effective diagnostic strategy for urinalysis. As reproducibility of urinalysis has been greatly improved due to recent technological progress, preanalytical requirements of urinalysis have gained importance and have become stricter. Since the patients themselves often sample urine specimens, urinalysis is very susceptible to preanalytical issues. Various sampling methods and inappropriate specimen transport can cause important preanalytical errors. The use of preservatives may be helpful for particular analytes. Unfortunately, a universal preservative that allows a complete urinalysis does not (yet) exist. The preanalytical aspects are also of major importance for newer applications (e.g. metabolomics). The present review deals with the current preanalytical problems and requirements for the most common urinary analytes. PMID- 24627719 TI - Harmonization of pre-analytical quality indicators. AB - Quality indicators (QIs) measure the extent to which set targets are attained and provide a quantitative basis for achieving improvement in care and, in particular, laboratory services. A body of evidence collected in recent years has demonstrated that most errors fall outside the analytical phase, while the pre- and post-analytical steps have been found to be more vulnerable to the risk of error. However, the current lack of attention to extra-laboratory factors and related QIs prevent clinical laboratories from effectively improving total quality and reducing errors. Errors in the pre-analytical phase, which account for 50% to 75% of all laboratory errors, have long been included in the 'identification and sample problems' category. However, according to the International Standard for medical laboratory accreditation and a patient centered view, some additional QIs are needed. In particular, there is a need to measure the appropriateness of all test request and request forms, as well as the quality of sample transportation. The QIs model developed by a working group of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) is a valuable starting point for promoting the harmonization of available QIs, but further efforts should be made to achieve a consensus on the road map for harmonization. PMID- 24627720 TI - How to conduct External Quality Assessment Schemes for the pre-analytical phase? AB - In laboratory medicine, several studies have described the most frequent errors in the different phases of the total testing process, and a large proportion of these errors occur in the pre-analytical phase. Schemes for registration of errors and subsequent feedback to the participants have been conducted for decades concerning the analytical phase by External Quality Assessment (EQA) organizations operating in most countries. The aim of the paper is to present an overview of different types of EQA schemes for the pre-analytical phase, and give examples of some existing schemes. So far, very few EQA organizations have focused on the pre-analytical phase, and most EQA organizations do not offer pre analytical EQA schemes (EQAS). It is more difficult to perform and standardize pre-analytical EQAS and also, accreditation bodies do not ask the laboratories for results from such schemes. However, some ongoing EQA programs for the pre analytical phase do exist, and some examples are given in this paper. The methods used can be divided into three different types; collecting information about pre analytical laboratory procedures, circulating real samples to collect information about interferences that might affect the measurement procedure, or register actual laboratory errors and relate these to quality indicators. These three types have different focus and different challenges regarding implementation, and a combination of the three is probably necessary to be able to detect and monitor the wide range of errors occurring in the pre-analytical phase. PMID- 24627721 TI - Pleural, peritoneal and pericardial effusions - a biochemical approach. AB - The pathological accumulation of serous fluids in the pleural, peritoneal and pericardial space occurs in a variety of conditions. Since patient management depends on right and timely diagnosis, biochemical analysis of extravascular body fluids is considered a valuable tool in the patient management process. The biochemical evaluation of serous fluids includes the determination of gross appearance, differentiation of transudative from exudative effusions and additional specific biochemical testing to assess the effusion etiology. This article summarized data from the most relevant literature concerning practice with special emphasis on usefulness of biochemical tests used for the investigation of pleural, peritoneal and pericardial effusions. Additionally, preanalytical issues concerning serous fluid analysis were addressed and recommendations concerning acceptable analytical practice in serous fluid analysis were presented. PMID- 24627722 TI - Biological variations of ADAMTS13 and von Willebrand factor in human adults. AB - BACKGROUND: The ultra-large von Willebrand factor (vWF) multimers are very active and must be degraded by ADAMTS13 for optimal activity. A severe functional deficiency of ADAMTS13 has been associated with thrombotic thrombocytopenic purpura. The correct interpretation of patient vWF and ADAMTS13 plasma levels requires an understanding of the biological variation associated with these analytes. In the present paper, we aimed to determine the biological variation of ADAMTS13 and vWF in human adults. MATERIALS AND METHODS: Blood samples were collected weekly from 19 healthy subjects for 5 consecutive weeks. vWF activity and antigenicity were determined using aggregometric and immunoturbidimetric methods. ADAMTS13 antigenicity and activity were determined by ELISA. RESULTS: The within-subject biological variations for vWF activity and antigenicity were 8.06% and 14.37%, respectively, while the between-subject biological variations were 18.5% and 22.59%, respectively. The index of individuality for vWF activity was 0.44, while vWF antigenicity was 0.64. Similarly, ADAMTS13 activity and antigenicity within-subject biological variations were 12.73% and 9.75%, respectively, while between-subject biological variations were 9.63% and 6.28%, respectively. The ADAMTS13 indexes of individuality were 1.32 and 1.55, respectively. CONCLUSION: We report high biological variation and individuality in vWF antigenicity and activity levels. However, ADAMTS13 antigenicity and activity displayed high biological variation, but low individuality. Thus, population-based reference intervals may be useful for monitoring ADAMTS13 antigenicity and activity, but not for vWF, which displays high individuality. These findings should be considered when determining the reference interval and other clinical variables associated with ADAMTS13 and vWF levels. PMID- 24627723 TI - Comparison of digoxin concentration in plastic serum tubes with clot activator and heparinized plasma tubes. AB - INTRODUCTION: Sample type recommended by the manufacturer for the digoxin Abbott assay is either serum collected in glass tubes or plasma (sodium heparin, lithium heparin, citrate, EDTA or oxalate as anticoagulant) collected in plastic tubes. In our hospital samples are collected in plastic tubes. Our hypothesis was that the serum sample collected in plastic serum tube can be used interchangeably with plasma sample for measurement of digoxin concentration. Our aim was verification of plastic serum tubes for determination of digoxin concentration. MATERIALS AND METHODS: Concentration of digoxin was determined simultaneously in 26 venous blood plasma (plastic Vacuette, LH Lithium heparin) and serum (plastic Vacuette, Z Serum Clot activator; both Greiner Bio-One GmbH, Kremsmunster, Austria) samples, on Abbott AxSYM analyzer using the original Abbott Digoxin III assay (Abbott, Wiesbaden, Germany). Tube comparability was assessed using the Passing Bablok regression and Bland-Altman plot. RESULTS: Serum and plasma digoxin concentrations are comparable. Passing Bablok intercept (0.08 [95% CI = -0.10 to 0.20]) and slope (0.99 [95% CI = 0.92 to 1.11]) showed there is no constant or proportional error. CONCLUSION: Blood samples drawn in plastic serum tubes and plastic plasma tubes can be interchangeably used for determination of digoxin concentration. PMID- 24627724 TI - Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene. AB - INTRODUCTION: Congenital analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. It is an allelic heterogeneous defect, caused by variety of mutations within the albumin gene in homozygous or compound heterozygous state. Herein we report the clinical and molecular characterization of a new case of congenital analbuminemia diagnosed in a female newborn of consanguineous (first degree cousins) parents from Ankara, Turkey, who presented with a low albumin concentration (< 8 g/L) and severe clinical symptoms. MATERIALS AND METHODS: The albumin gene of the index case was screened by single-strand conformation polymorphism, heteroduplex analysis, and direct DNA sequencing. The effect of the splicing mutation was evaluated by examining the cDNA obtained by reverse transcriptase - polymerase chain reaction (RT-PCR) from the albumin mRNA extracted from proband's leukocytes. RESULTS: DNA sequencing revealed that the proband is homozygous, and both parents are heterozygous, for a novel G>A transition at position c.1652+1, the first base of intron 12, which inactivates the strongly conserved GT dinucleotide at the 5' splice site consensus sequence of this intron. The splicing defect results in the complete skipping of the preceding exon (exon 12) and in a frame-shift within exon 13 with a premature stop codon after the translation of three mutant amino acid residues. CONCLUSIONS: Our results confirm the clinical diagnosis of congenital analbuminemia in the proband and the inheritance of the trait and contribute to shed light on the molecular genetics of analbuminemia. PMID- 24627725 TI - A deep vein thrombosis caused by 20209C>T mutation in homozygosis of the prothrombin gene in a Caucasian patient. AB - INTRODUCTION: Additional nucleotide substitutions in the 3'-untranslated region of prothrombin gene could explain some thrombotic events and also adverse pregnancy outcomes. We describe the first case of a homozygous 20209C>T mutation as the cause of deep vein thrombosis in a Spanish patient. CASE AND METHODS: The 56-year-old male patient with a partial tear of the Achilles tendon developed calf (tibial) deep vein thrombosis after immobilization and was treated with an anticoagulant. To determine if the deep vein thrombosis was of genetic origin, a peripheral blood DNA sample was analysed for the presence of the three most frequent mutations associated with thrombotic events: factor V Leiden (1691G>A), prothrombin (20210G>A) and methylene tetrahydrofolate reductase (677C>T). The presence or absence of the normal allele of prothrombin could not be determined using the PTH-FV-MTHFR StripAssay (Vienna Lab). RESULTS: Comprehensive analysis showed that the patient had a variant interfering with the polymerase chain reaction product, we sequenced the entire prothrombin gene and found that the patient had a homozygous C>T mutation at position 20209; this interfered with the polymerase chain reaction product, which needs a C at this position to be able to bind to the wild-type probe present in the test strip. CONCLUSION: The homozygous 20209C>T mutation and the presence of the mutation 677C>T in heterozygosity explained the patient's deep vein thrombosis because the combination of mutations would increase the risk of thrombosis. Suitable genetic counselling should be provided to the patient and first-degree relatives as it important to detect prothrombin gene variants that could increase risk for thrombotic events. PMID- 24627726 TI - Interaction of hemoglobin Grey Lynn (Vientiane) with a non-deletional alpha(+) thalassemia in an adult Thai proband. AB - Hemoglobin (Hb) Grey Lynn is a Hb variant caused by a substitution of Phe for Leu at position 91 of alpha1-globin chain, originally described in individual of unknown ethnic background. This article addresses the interaction of Hb Grey Lynn with a non-deletional alpha(+)-thalassemia found in Thailand, a hitherto un described condition. The proband was adult Thai woman referred for investigation of mild anemia with Hb 90 g/L. Hb analyses using low pressure liquid chromatography raised a suspicion of abnormal Hb presence, which was failed to demonstrate by cellulose acetate electrophoresis and capillary electrophoresis. DNA sequencing identified a CTT (Leu) to TTT (Phe) mutation at codon 91 corresponding to the Hb Grey Lynn (Vientiane) [alpha91(FG3)Leu>Phe (alpha1) on alpha1-globin gene and a C deletion between codons 36 and 37 on alpha2-globin gene causing alpha(+)-thalassemia. As compared to those observed in a compound heterozygote for Hb Grey Lynn / alpha(0)-thalassemia reported previously, higher MCV (81.7 fL) and MCH (26.3 pg) values with a lower level of Hb Grey Lynn (19.7%) were observed in the proband. The normochromic normocytic anemia observed could be due to the interaction of Hb Grey Lynn with alpha(+)-thalassemia. The two mutations could be identified using PCR-RFLP and allele-specific PCR assays developed. PMID- 24627727 TI - False negativity to carbohydrate-deficient transferrin and drugs: a clinical case. AB - INTRODUCTION: In this work we report on the possible effect of the medical therapy on CDT concentration in a chronic alcohol abuser, with known medical history (July 2007 - April 2012) and alcohol abuse confirmed by relatives. CASE HISTORY: At the end of 2007, patient displayed the following laboratory results: AST 137 U/L, ALT 120 U/L, GGT 434 U/L, MCV 101 fL and CDT 3.3%. On December 2007, after double coronary artery bypass surgery, he began a pharmacological treatment with amlodipine, perindopril, atorvastatin, isosorbide mononitrate, carvedilol, ticlopidine and pantoprazole. In the next months, until may 2011, the patient resumed alcohol abuse, as confirmed by relatives; however, CDT values were repeatedly found negative (0.8% and 1.1%) despite elevated transaminases and GGT, concurrent elevated ethyl glucuronide concentration (> 50 mg/L) and blood alcohol concentration (> 1 g/L). Alcohol consumption still continued despite increasing disulfiram doses ordered by an Alcohol Rehab Center. On May 2011, the patient was transferred to a private medical center where he currently lives. CONCLUSIONS: This study suggests the possibility that a medical therapy including different drugs may hamper the identification of chronic alcohol abusers by CDT. PMID- 24627728 TI - Abnormal gel flotation in a patient with apperant pneumonia diagnosis: a case report. AB - INTRODUCTION: Serum blood collection tubes with separator gel are widely used by many laboratories for chemistry analyses. We describe a case of a primary blood collection tube filled with blood sample and a floating separator gel. MATERIALS AND METHODS: The blood sample was collected from a 51 years old female in intensive care unit with the diagnosis of pneumonia into a BD Vacutainer SST tube (Becton Dickinson, NJ, USA) containing serum separator gel and conveyed to the core laboratory of Marmara University Hospital within 30 minutes from collection. Sample was immediately centrifuged at room temperature at 1500 * g for 10 minutes. RESULTS: The analyses revealed a highly increased total protein concentration of 145 g/L (reference interval 64-83 g/L). The nephelometric analyses showed an elevated serum IgG concentration of 108 g/L (reference interval 6.5-16 g/L) and IgG lambda monoclonal band was determined by serum immunofixation electrophoresis. CONCLUSION: Limitation of the separator gel tubes in patients with a high plasma density and its possible effects on test results and laboratory costs should be remembered. The clinical diagnosis stated in the information system should also reveal known comorbid conditions besides the apparent admission reason. This information would avoid resampling, additional testing, and communication efforts with the clinicians. PMID- 24627729 TI - Essential oils, a new horizon in combating bacterial antibiotic resistance. AB - For many years, the battle between humans and the multitudes of infection and disease causing pathogens continues. Emerging at the battlefield as some of the most significant challenges to human health are bacterial resistance and its rapid rise. These have become a major concern in global public health invigorating the need for new antimicrobial compounds. A rational approach to deal with antibiotic resistance problems requires detailed knowledge of the different biological and non-biological factors that affect the rate and extent of resistance development. Combination therapy combining conventional antibiotics and essential oils is currently blooming and represents a potential area for future investigations. This new generation of phytopharmaceuticals may shed light on the development of new pharmacological regimes in combating antibiotic resistance. This review consolidated and described the observed synergistic outcome between essential oils and antibiotics, and highlighted the possibilities of essential oils as the potential resistance modifying agent. PMID- 24627730 TI - Antibacterial efficacy testing of a bioelectric wound dressing against clinical wound pathogens. AB - Silver-based wound dressings have been developed for the control of bioburden in wounds. However, the popularity and extensive use of silver-based dressings has been associated with emerging microbial resistances to silver. In this study we examined in vitro antibacterial efficacy of a bioelectric dressing containing silver and zinc against various wound pathogens. Antibiotic-sensitive clinical wound isolates showed a 100% reduction in bacterial growth, except that Enterococcus faecalis isolate was shown to survive with a bacterial log10 reduction rate of less than 10(2) CFU. We also investigated antibacterial efficacy against the extended spectrum beta-lactamase (ESBL) bacteria, multidrug resistant (MDR) bacteria, and methicillin-resistant Staphylococcus aureus (MRSA). The bioelectric dressing was effective in killing wound pathogens including ESBL, MDR, and MRSA in vitro. Furthermore, based on the primary results against E. faecalis, we carried out extensive studies against several nosocomial Enterococcus species including vancomycin-resistant species. Overall, the vancomycin-sensitive or -resistant Enterococcus species were resistant to this dressing at up to 48 h, except for the vancomycin-resistant Enterococcus raffinosus isolate only showing a 100% bacterial reduction at 48 h, but not at 24 h. The results demonstrated the effective bactericidal activity of a bioelectric dressing against antibiotic-sensitive and MDR strains, but Enterococcus species are bacteriostatic. PMID- 24627731 TI - Mid term results of distal femoral fractures treated with a polyaxial locking plate: a multi-center study. AB - OBJECTIVE: Locking plates have become a standard implant in the treatment of distal femoral fractures. Newer designs allow polyaxial screw placement as well as the ability to lock the lag screws. METHODS: The consecutive multi-centre study cohort consists of all distal femoral fractures treated with the NCB(r) Distal Femur plate (Zimmer, Warsaw, USA) and a minimum follow-up of twelve months. Fracture classification according the AO/ OTA system and the trauma mechanism radiological evaluation and complications were documented. Clinical evaluation consisted of the Short Form SF12 questionnaire (SF12), the Hospital for Special Surgery Score (HSS) and clinical assessment of range of motion. RESULTS: Twenty-five patients with twenty-six fractures were available for follow up with a minimum required follow-up of twelve months. 81% of the fractures were intra-articular. 48% of the patients were multi-traumatised, 38% having open fractures. All except two went to union (92%) with the primary procedure. The HSS Score was 79 (32-99) and the SF 12 (physical and mental) 40 (19-57) and 54 (21 66) at follow-up. There were five patients requiring surgical revision (19%). CONCLUSION: These fractures are often combined with concomitant injuries. Using modern locked implants high union rates can be achieved with a good function and patient satisfaction when respecting biologic and biomechanical principles. PMID- 24627732 TI - Patient-based outcomes after tibia fracture in children and adolescents. AB - INTRODUCTION: Tibia fractures are common in pediatric patients and time necessary to return to normal function may be underappreciated. The purpose of this study was to assess functional recovery in pediatric patients who sustain tibia fractures, utilizing the Pediatrics Outcome Data Collection Instrument (PODCI), in order to provide evidence-based information on post-injury functional limitations and anticipated recovery times. METHODS: 84patients (out of 264 eligible patients, response rate 32%) age 1.5-18 years treated for a tibia fracture at a large children's hospital between 1/07 and 4/08 completed a PODCI questionnaire at 6 and 12 months post-injury. PODCI questionnaires were compared to previously reportednormal controls using Student's t-test in six categories. RESULTS: At 6 months after injury, the Sports functioning PODCI score was significantly less than healthy controls in both the parent reports for adolescent (mean 88.71 versus 95.4) and adolescent self-report (mean 90.44 versus 97.1); these showed no difference at 12 months. DISCUSSION: For adolescents who sustain fractures of the tibia, there remains a negative impact on their sports functioning after 6 months that resolves by 12 months. Physicians can counsel their patients that although they may be limited in their sports function for some time after injury, it is anticipated that this will resolve by one year from the time of injury. LEVEL OF EVIDENCE: Level II. PMID- 24627733 TI - Modulation of Regulatory T-Cell Subsets in Very Long-Term Treated Aviremic HIV(+) Patients and Untreated Viremic Patients. AB - Naive, central- and effector-like memory regulatory T cells (Tregs) were evaluated in untreated and long-term antiretroviral-treated HIV(+) patients that showed comparable CD4(+) cell levels, while being, respectively, viremic and aviremic. In the untreated patients, the percentage of naive-like Tregs was significantly increased to the detriment of central memory regulatory T cells. This redistribution of regulatory Treg subsets may contribute to explain the partially preserved CD4(+) cell counts seen in these patients despite the ongoing viremia. On the contrary, in the long-term treated patients, the percentages of Treg subsets were similar to those of healthy donors, demonstrating a restored Treg homeostasis. The characterization of Treg subsets, rather than an evaluation of the total Treg population, may lead to a deeper understanding of the Treg role in HIV infection and therapy. PMID- 24627734 TI - Tumor differentiation as related to sentinel lymph node status in gastric cancer. AB - AIM: To investigate the influence of tumor grade on sentinel lymph node (SLN) status in patients with gastric cancer (GC). METHODS: We retrospectively studied 71 patients with GC who underwent SLN mapping during gastric surgery to evaluate the relationship between SLN status and tumor grade. RESULTS: Poorly differentiated tumors were detected in 50/71 patients, while the other 21 patients had moderately differentiated tumors. SLNs were identified in 58/71 patients (82%). In 41 of the 58 patients that were found to have stained nodes (70.7%), the tumor was of the poorly differentiated type (group I), while in the remaining patients with stained nodes 17/58 (29.3%), the tumor was of the moderately differentiated type (group II). Positive SLNs were found in 22/41 patients in group I (53.7%) and in 7/17 patients in group II (41.2%) (P = 0.325). The rate of positivity for the SLNs in the two groups (53.7% vs 41.2%) was not statistically significant (P = 0.514). CONCLUSION: Most of our patients were found to have poorly differentiated adenocarcinoma of the stomach and there was no correlation between tumor grade and SLN involvement. PMID- 24627735 TI - Treatment of perforated giant gastric ulcer in an emergency setting. AB - AIM: To study and assess clinical outcomes of various modes of treatment for perforated giant gastric ulcer in an emergency setting. METHODS: From May 2010 to February 2013, 20 cases of perforated giant gastric ulcer (> 2 cm) were operated on in an emergency setting. All the patients presented with features of peritonitis and were resuscitated aggressively before taking for surgery. In the first 4 cases, primary closure was done after taking a biopsy and among these, the 3(rd) case also underwent partial distal gastrectomy and gastrojejunostomy and the 4(th) case underwent a radical subtotal gastrectomy with D2 lymphadenectomy and gastrojejunostomy for malignancy. All the remaining 16 cases underwent partial distal gastrectomy and gastrojejunostomy. RESULTS: Among the first 4 cases, 2 had an uneventful recovery and were discharged on the 6(th) postoperative day. The 3(rd) and 4(th) patients developed gastric fistula, leading to prolonged hospitalization. For the 3(rd) patient, conservative management was tried for 1 wk, followed by partial distal gastrectomy and gastrojejunostomy, and he was discharged on the 20(th) day after admission, while the 4(th) patient underwent a radical subtotal gastrectomy with D2 lymphadenectomy and gastrojejunostomy. Postoperatively, he developed adult respiratory distress syndrome, multiorgan dysfunction syndrome and expired on the 3(rd) postoperative day of the second surgery. All the remaining 16 patients underwent partial distal gastrectomy and gastrojejunostomy and recovered well. Among these, 4 of them were malignant and the remaining were benign ulcers. All had an uneventful recovery. The percentage of malignancy in our series was 30% (6 out of 20 cases). In our study, 86% had an uneventful recovery, complications were seen in about 10%, and mortality was about 5%. CONCLUSION: In giant gastric ulcer, the chances of malignancy and leak after primary closure are high. So, we feel that partial distal gastrectomy and gastrojejunostomy is better. PMID- 24627736 TI - Implications of the presence of an aberrant right hepatic artery in patients undergoing pancreaticoduodenectomy. AB - AIM: To analyze the differences in outcomes and the clinical impact following pancreatoduodenectomy (PD) in patients with and without aberrant right hepatic artery (aRHA). METHODS: All patients undergoing PD between January 2008 and December 2012 were divided into two groups, one with aRHA and the other without. These groups were compared to identify differences in the intraoperative variables, the oncological clearance and the postoperative morbidity, mortality and hospital stay. RESULTS: A total of 225 patients underwent PD, of which 43 (19.1%) patients were found to have either accessory or replaced right hepatic arteries (aRHA group). The aRHA was preserved in 79% of the patients. There was no significant difference in the intraoperative blood loss but operative time was prolonged, reflecting the complexity of the procedure [420 +/- 44 (240-540) min vs 480 +/- 45 (300-600) min, P < 0.05)]. There were no differences in the incidence of postoperative complications (pancreatic leak, pancreatic fistula, delayed gastric emptying and mortality) and hospital stay. Oncological clearance in the form of positive resection margins [13 (7.1%) vs 3 (6.9%)] and lymph node yield were also similar in the two groups. CONCLUSION: An aRHA is found in approximately one fifth of patients undergoing PD. Preservation is technically possible in most patients and can increase the operative complexity but does not negatively affect the safety or oncological outcomes of the procedure. PMID- 24627737 TI - High time!!! Hold hands against hypertension. PMID- 24627738 TI - Sanctions, Smuggling, and the Cigarette: The Granting of Iran Office of Foreign Asset Control's Licenses to Big Tobacco. AB - BACKGROUND: Presuming that tobacco taxes, levied both as import duties and ad valorem, would financially benefit the Iranian Government, such the introduction of a highly desired US product to the market would be antithetical to the sanctions regime currently in place. METHODS: This paper as a systematic review and documents through Pubmed and webs seeks to understand the politician economy implications of nicotine addiction in Iran, focusing on the US office of foreign asset control's (OFAC) awarding of Iran operations licenses to American tobacco companies. RESULTS: By comparing Iran's tobacco industry and the attendant public health crisis that has arisen from high rates of nicotine addiction, to conditions in Turkey, it can be demonstrated that Iran is uniquely unable to extract revenues from the sale of tobacco products. The primary point of comparison between Iran and Turkey is smoking-attributable annual productivity loses of each country as estimated through the use of smoking-attributable mortality, morbidity and economic costs software (SAMMEC) and the available related literature. Based on the calculations derived from the SAMMEC model, Iran is burdened with an incredible cost to the economy borne by a high prevalence of smokers. CONCLUSIONS: It is concluded that an awareness of this condition enables OFAC to award licenses to big tobacco without fear of undermining current foreign policy initiatives. PMID- 24627739 TI - Efficacy of double dose recombinant hepatitis B vaccination in chronic hepatitis C patients, compared to standard dose vaccination. AB - BACKGROUND: Hepatitis B virus (HBV) vaccination is a well-known, safe and effective way for protection against HBV infection; however, non-responders remain susceptible to infection with HBV. This is so important in patients with any kind of chronic liver disease, especially chronic hepatitis C virus (HCV) patients in whom acute HBV infection may lead to decompensation of liver disease. Some of the studies have shown that immunogenicity of HBV vaccination is decreased in these patients. The aim of this study was to evaluate the efficacy and safety of double dose vaccination of HBV in these patients, compared with standard dose vaccination in similar patients and healthy adults. METHODS: A total of 64 patients with chronic HCV infection were randomized into 2 groups of 32. Group A received standard dose HBV vaccine, at 0, 1, 6 months, whereas group B received double dose HBV vaccine. Group C consisted of 32 healthy adults who also received standard dose vaccination. At 1 month after the end of vaccination, Hepatitis B surface antibody (HBsAb) titer was checked in all participants and the results were compared. RESULTS: There was no significant difference in age or sex among three groups. The response rate in groups B and C was 100% (all had HBsAb titer >10 mIU/mL), while in group A, 4 patients (12.5%) were non-responders (HBsAb titer < 10 mIU/mL). The difference in response rate was statistically significant between Group A and the other two groups (P < 0.05). CONCLUSIONS: The efficacy of standard dose HBV vaccination in patients with chronic HCV infection was suboptimal. Using double dose vaccination in these patients was an effective way to increase the antibody response. PMID- 24627740 TI - Assessment of Functional Capacity in Chagas Heart Disease by Incremental Shuttle Walk Test and its Relation to Quality-of-Life. AB - BACKGROUND: The cardiopulmonary exercise test (CPET) is considered to be the gold standard to evaluate functional capacity (FC) in patients with heart failure. However, field tests such as the 6-min walk test (6MWT) and the incremental shuttle walk test (ISWT) are simple and effective in evaluating the same. Despite the increasing use of ISWT, no studies that used the test in patients with Chagas heart disease (CHD) were found and only few studies have evaluated the health related quality-of-life (HRQoL) in this population. The objective of this study was to correlate the distance walked in the ISWT with distance walked by 6MWT and peak oxygen uptake (VO2peak) by CPET and HRQoL in patients with CHD. METHODS: A total of 35 patients with CHD were evaluated according to the FC and HRQoL. The FC was assessed by CPET, 6MWT and ISWT. HRQoL was assessed by the generic short form health survey (SF-36) and Minnesota Living with Heart Failure Questionnaire (MLHFQ). Descriptive data were shown as mean and standard deviation or median and interquartile range. The correlation was carried out with Pearson or Spearman correlation test. A receiver operating characteristic (ROC) curve was constructed to investigate the accuracy of ISWT for predicting low values of VO2peak. RESULTS: The distance walked in ISWT correlated with VO2peak(r = 0.587; P < 0.001), distance walked in 6MWT (r = 0.484; P = 0.003), MLWHFQ scores (r = 0.460; P = 0.006) and physical functioning and role physical domains of the SF-36 scores (r = 0.435, P = 0.009; r = 0.477, P = 0.008, respectively). There was no significant difference between the distances walked in field tests (P = 0.694). The area under the ROC curve was 0.871 for ISWT in predicts a VO2peak value of, at least, 25 mL/kg/min. CONCLUSIONS: The ISWT showed to be effective in evaluating the FC in CHD and in demonstrate the impact of disease on some aspects of the HRQoL of these patients. PMID- 24627741 TI - Does water hardness have preventive effect on cardiovascular disease? AB - BACKGROUND: The aim of this study is to investigate the association of calcium and magnesium concentration of drinking water with cardiovascular disease (CVDs) in urban and rural areas of a city in Iran. METHODS: This case-control study was conducted in 2012 in Khansar County in Isfahan province, Iran. We used the official data of the Provincial health center regarding the chemical analysis data of urban and rural areas including the hardness, calcium and magnesium content of drinking water. Data of patients hospitalized for CVD in the only specialty hospital of the city was gathered for the years of 2010 and 2011. RESULTS: In 2010, water calcium content above 72 mg/L was associated with reduced number of CVDs in 1000 population; whereas in 2011 this decrease in CVDs was observed for calcium levels of more than 75 mg/L. In 2010, the level of water Mg content ranged from 23 to 57 mg/L. By increasing Mg hardness level above 31 mg/L in 2010 and above 26 mg/L in 2011 were associated with decreased number of CVDs in 1000 people. decrease. CONCLUSIONS: Our study suggests favorable protective effects of water hardness, mainly water magnesium content, on CVDs. Water hardness, as well as calcium and magnesium content of drinking water may have a protective role against CVDs. Further experimental studies are necessary to determine the underlying mechanisms and longitudinal studies are required to study the clinical impacts of the current findings. PMID- 24627742 TI - Iranian audience poll on smoking scenes in persian movies in 2011. AB - BACKGROUND: Scenes depicting smoking are among the causes of smoking initiation in youth. The present study was the first in Iran to collect some primary information regarding the presence of smoking scenes in movies and propagation of tobacco use. METHODS: This cross-sectional study was conducted by polling audience about smoking scenes in Persian movies on theaters in 2011. Data were collected using a questionnaire. A total of 2000 subjects were selected for questioning. The questioning for all movies was carried out 2 weeks after the movie premiered at 4 different times including twice during the week and twice at weekends. RESULTS: A total of 39 movies were selected for further assessment. In general, 2,129 viewers participated in the study. General opinion of 676 subjects (31.8%) was that these movies can lead to initiation or continuation of smoking in viewers. Women significantly thought that these movies can lead to initiation of smoking (37.4% vs. 29%). This belief was stronger among non-smokers as well (33.7% vs. 26%). CONCLUSIONS: Despite the prohibition of cigarette advertisements in the mass media and movies, we still witness scenes depicting smoking by the good or bad characters of the movies so more observation in this field is needed. PMID- 24627743 TI - Comparison of microleakage of two materials used as fissure sealants with different methods: an in vitro study. AB - BACKGROUND: Marginal seal has a principal role in durability and clinical success of fissure sealants. The aim of this study was to compare the microleakage of two materials used as pit and fissure sealant with different methods of application. METHODS: The 55 extracted premolars were assigned randomly to one of the following five groups: Group 1: Acid-etching (ultra-etch) + fissure sealant (conventional method), Group 2: Acid etching + bonding agent (single bond) + fissure sealant, Group 3: Self-etching primer + bonding agent (SE bond) + fissure sealant, Group 4: Acid-etching + bonding agent + flowable composite (Filtek flow), Grope 5: Self-etching primer + bonding agent + flowable composite. Following sealant placement, the teeth were thermocycled (3000 cycles; 5-55 degrees C) and then immersed in 50% silver nitrate solution for 24 h and then immersed in photo developing solution for 4 h under fluorescent light. The teeth were then sectioned in a bucco-lingual direction. Microleakage was scored using a stereomicroscope and a 4-criteria ranking/ordinal scale. Data were analyzed statistically using the Kruskal-Wallis and Mann-Whitney tests. RESULTS: The result of tests showed that there were statistical differences between some groups. Groups 2 and 4 had the lowest and Groups 3 and 5 had the highest microleakage scores and a statistically significant difference could be displayed between them (P < 0.05). Mean microleakage in Group 4 was also significantly lower than in Group 1 (P < 0.05). CONCLUSIONS: Using acid and a bonding agent prior to sealant placement seems to be the best technique for sealing pits and fissures. PMID- 24627744 TI - Efficiency improvement of dentistry clinics: introducing an intervening package for dentistry clinics, isfahan, iran. AB - BACKGROUND: In Isfahan, the second metropolitan in Iran, there are 1448 dentistry treatment centers that most of them are inefficient. Today, efficiency is the most important issue in health care centers as well as dentistry clinics. The goal of this research is to investigate the affordability and efficiency of dentistry clinics in Isfahan province, Iran. METHODS: The current work is a quantitative research, designed in three methodological steps, including two surveys and experimental studies, for understanding current deficiencies of Iranian dentistry clinics. First, we ran a survey. Then, we analyzed the results of the questionnaires which guided us to find a particular intervening package to improve the efficiency of the clinics. At the second step, we chose an inefficient clinic named Mohtasham (Iran, Isfahan) to evaluate our intervening package. RESULTS: Based on what the interviewees answered, we mention the most important issues to be considered for improving the efficiency of dental clinics in Isfahan. By considering mentioned problematic issues, an intervening package was designed. This intervening package was applied in Mohtasham clinic, since June 2010. It improved the clinic's income from 16328 US$ with 4125 clients in 2010, to 420,000 US$ with 14784 patients in 2012. CONCLUSIONS: The proposed intervening package changed this clinic to an efficient and economic one. Its income increased 5.08 times and its patient's numbers grew 4.01 times simultaneously. In other words, Mohtasham's experience demonstrates the reliability of the package and its potentiality to be applied in macro level to improve other dentistry clinics. PMID- 24627746 TI - Concordance between hybrid capture 2 results performed on cervical samples obtained before and immediately after visual inspection with acetic Acid test. AB - BACKGROUND: VIA is a simple, inexpensive test widely advocated for resource limited settings. Major limitation of VIA is its low specificity. HPV DNA testing can be used to triage VIA-positive women if the facilities are available. The major concern for such strategy would be whether sample collection after acetic acid wash will alter HPV test characteristics. This study aimed to evaluate whether samples for HPV testing by Hybrid Capture 2 (HC2) technology can be collected immediately after VIA without altering test performance. METHODS: Total 204 VIA-positive women were recruited. Cervical samples were collected for HC2 test before and after VIA at the same sitting by the same provider. The paired samples were analyzed at the same laboratory by the same technician in the same batch of testing. Agreement in HC2 results between pre-VIA and post-VIA samples was estimated using kappa statistics. All women had colposcopy and biopsies were obtained if colposcopy was suspicious of neoplasia. Sensitivity and specificity of HC2 test in detecting CIN2+ lesions were calculated using negative colposcopy or biopsy as the gold standard and were compared between the pre and post VIA samples. RESULTS: Almost perfect agreement in HC2 results (kappa=0.85) and RLU/Cut off ratios (correlation coefficient=0.92) was observed between samples collected before and after VIA. The sensitivity and specificity to detect CIN2+ lesions remained unaltered even when cervical samples were collected after VIA. This confirmed that acetic acid wash did not alter HC2 performance. CONCLUSIONS: Collection of samples for HC2 test is feasible immediately after VIA. PMID- 24627745 TI - Psycho-social Determinants of Colorectal Cancer Screening in Iran. AB - BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer among Iranians, and threatens them at younger ages. This study was guided by the theoretical concepts of the preventive health model (PHM) to assess the attitudes and beliefs of Iranians towards CRC screening. METHODS: This cross-sectional study was conducted with participation of 200 individuals aged 50 years or older in a Teaching Hospital in Tehran, Iran. Background characteristics (e.g., age, gender, marital status) were assessed and a validated instrument drawn from the PHM was applied to measure cognitive and psychosocial variables (i.e., self efficacy, intention to screening, perceived susceptibility, cancer worries, response efficacy, and social support). Data were collected via face-to-face interviews and analyzed using the SPSS version 13.00 for Windows. RESULTS: The age of the participants ranged from 50 years to 83 years (mean 60.13). Most respondents were married (62.5%), unemployed (42%), and had secondary or higher education (44.5%). Overall, 11% of respondents reported prior screening. Individuals obtained relatively poor scores on self-efficacy, intention to screening, perceived susceptibility, cancer worries, response efficacy, and social support. CONCLUSIONS: In this study, individuals mostly reported poor attitude in regard to CRC screening. The results of the present study could guide policy makers in designing tailored interventions to increase the participation of individuals in screening programs. PMID- 24627747 TI - Factors Associated with Breast Cancer Screening Decision Stage among Women in Tehran, Iran. AB - BACKGROUND: Early detection through screening is the best method to reduce death due to breast cancer. It has been shown, having knowledge and generating positive attitudes, influences the decision of women to participate in the screening programs. The aim of this study was to identify the factors associated with breast cancer screening (BCS) and with an intention to have screening among women in Tehran, Iran. METHODS: A cross-sectional study was carried out from January to July 2011, among women who had attended to primary health-care centers in West Tehran using multi-stage sampling method. We invited 1,240 women sequentially to complete a self-administered survey questionnaire at the beginning of their visit; and 1,012 (82%) completed the survey. The questionnaire included, items drawn from the Preventive Health Model that assess socio-demographic background and perceptions about BCS. Multiple logistic regression analysis was performed to identify factors associated with screening and intention to do screening in the future. RESULTS: The mean age of subjects was 38.2 years. Women who perceived more screening efficacy (odd ratio [OR] =1.63; confidence interval [CI] 95%: 1.12 2.37) and fewer performance barriers (OR = 0.82; CI 95%: 0.68-0.97) were more likely to perform clinical breast exam in the future. The women who reported higher clinical breast exam self-efficacy (OR = 1.82; CI 95%: 1.39-2.37), mammography self-efficacy (OR = 1.31; CI 95%: 1.04-1.65), screening efficacy (OR = 1.53; CI 95%: 1.18-1.97), and family influence (OR = 1.27; CI 95%: 1.05-1.54), and those who reported fewer screening performance barriers (OR = 0.56; CI 95%: 0.48-0.67) were more likely to decide for carried out mammography in the future. Most respondents indicated that they intended to do clinical breast exam and mammography in the future (75.8% and 72.1% respectively). About 65% of women reported they would do both. CONCLUSIONS: We found that women's intention to do BCS was very high and a comprehensive national program is needed to guide their intention. Among different demographic factors, the impact of education level on doing BCS was significant. PMID- 24627748 TI - Psychosocial Determinants of Health-Related Quality of Life of People Living with HIV/AIDS on Antiretroviral Therapy at Udupi District, Southern India. AB - BACKGROUND: Life expectancy of people living with HIV/AIDS (PLHA) on antiretroviral therapy has appreciably increased. However, psychosocial challenges pose a great threat to their health-related quality of life (HRQOL). The aim of this study was to determine psychosocial factors influencing health related quality of life of PLHA on antiretroviral therapy. METHODS: A cross sectional study was conducted using convenience sampling to select 226 PLHA at District hospital. Demographic information was collected using a semistructured questionnaire. HRQOL was assessed using WHOQOL-HIV Bref. The Hospital Anxiety and Depression Scale, CAGE scale, and Multidimensional Scale of Perceived Social Support were used. One-way ANOVA was applied. RESULTS: There was a significant difference in mean quality of life score with respect to level of anxiety in the physical (P < 0.001), psychological (P < 0.001), level of independence (P < 0.001), social relationships (P = 0.047), environment (P < 0.001), and spirituality domain (P < 0.001). Significant difference in mean quality of life score was observed with respect to level of depression in physical (P = 0.003), psychological (P = 0.036), level of independence (P = 0.017), social relationships (P = 0.019), and spirituality (P = 0.001). Friend support was positively associated with HRQOL in physical (P < 0.001), psychological (P < 0.001), level of independence (P = 0.013), social relationships (P < 0.001), environment (0.001), and spirituality domain (0.026). Family support was positively associated with HRQOL in physical (P = 0.001), psychological (P = 0.001), level of independence (P = 0.040), social relationships (P = 0.008), environment (0.001), and spirituality domain (0.026). A significant difference was observed with respect to affiliation to social organization in social relationships domain (P = 0.044). CONCLUSIONS: Psychosocial challenges including anxiety, depression, and social support impact upon all domains of HRQOL of PLHA. PMID- 24627749 TI - The Effects of 8-week Nigella sativa Supplementation and Aerobic Training on Lipid Profile and VO2 max in Sedentary Overweight Females. AB - BACKGROUND: Regular moderate intensity physical activity and lipid lowering effects of Nigella sativa (N. sativa) supplementation may be appropriate management for sedentary overweight females. Therefore, the aim of the present study was to examine the effects of long-term N. sativa supplementation and aerobic training on lipid profile and maximal oxygen consumption (VO2 max) in sedentary overweight females. METHODS: In this randomized, double-blind, controlled trial, which was conducted in Kerman city (Iran), 20 sedentary overweight females were divided into two groups and assigned to N. sativa supplementation (N. sativa capsules) or a placebo for the 8 weeks, both groups participated in an aerobic training program (3 times/week). Each N. sativa capsule contained 500 +/- 10 mg N. sativa crushed seeds and subjects had to take 2 g N. sativa per day for 8 weeks. Blood lipids and VO2 max were determined at baseline and at the end of 8 weeks. RESULTS: N. sativa supplementation lowered total cholesterol (TC) (P < 0.01), triglyceride (P < 0.001), low-density lipoprotein (LDL) (P < 0.001) and body mass index (P < 0.01) and increased high density lipoprotein (HDL) and VO2 max (P < 0.01). Aerobic training program lowered TC (P < 0.001) and LDL (P < 0.01) and increased VO2 max (P < 0.01). Furthermore, we observed a significant effect of aerobic training program and N. sativa supplementation lowered LDL and HDL (P < 0.05). CONCLUSIONS: The present study demonstrates that 8-week aerobic training plus N. sativa supplementation have a synergistic effect in improve profile lipid parameters. PMID- 24627750 TI - Seeking comfort: women mental health process in I. R. Iran: a grounded theory study. AB - BACKGROUND: Psychosocial factor is considered as intermediate social determinant of health, because it has powerful effects on health especially in women. Hence deeper understanding of the mental-health process needed for its promotion. The aim of this study was to explore women's experience of the mental-health problem and related action-interactions activities to design the appropriate interventions. METHODS: In-depth interviews with women 18-65 years were analyzed according to the grounded theory method. The selection of Participants was based on purposeful and theoretical sampling. RESULTS: In this study, a substantive theory was generated; explaining how female with the mental-health problem handled their main concern, which was identified as their effort to achieve comfort (core variable). The other six categories are elements in this process. Daily stress as a trigger, satisfaction is the end point, marriage is the key point and action - interaction activities in this process are strengthening human essence, Developing life skills and help seeking. CONCLUSIONS: Better understanding the mental-health process might be useful to design the interventional program among women with mental-health problems. PMID- 24627751 TI - A Nationwide Survey on the Daily Screen Time of Iranian Children and Adolescents: The CASPIAN - IV Study. AB - BACKGROUND: Leisure time activity is an important life-style habit. This study aims to determine the screen time of a nationally representative sample of Iranian children and adolescents. METHODS: This nationwide cross-sectional study was conducted as part of the fourth survey of a surveillance system. The participants consisted of 14880 students, with aged range from 6 to 18 years, living in 30 provinces in Iran. Screen time, i.e. the time spent on watching television (TV)/video and computer games during leisure time, was assessed by using the questionnaire of the Globasl Student Health Survey of the World Health Organization. RESULTS: The study participants were 13486 school students (participation rate of 90.6%) with a mean age of 12. 47 (3.36) years. Overall, 75.6% of students were from urban and 24.4% from rural areas and 50.8% were boys respectively. Overall, 33.4% and 53% of students watched TV/video more than 2 h a day in their leisure time during school days and holidays, respectively. Likewise, 6.3% and 10.9% of students used computer more than 2 h a day in their leisure time during the school days and holidays, respectively. Overall, 47.1% of urban students and 24.2% of rural students used personal computer in their leisure time during the school days. The corresponding figures were 50.8% and 27.2% in weekends and holidays, respectively. CONCLUSIONS: The time spent on screen activities is long in a considerably high number of Iranian children and adolescents. It should be reduced by increasing the public awareness and by providing facilities for regular daily physic activity for students' leisure times. PMID- 24627752 TI - Primary germ cell tumor of the mediastinum - presenting as a huge mass. AB - Germ cell tumors compromise 15-20% of all anterior mediastinal masses; 50-60% of these are benign mediastinal teratoma. There may be mature, immature, and rarely with malignant component within the tumor mass. There are more chances of malignancy with immature type. We are reporting a case in 20-year young male diagnosed as giant benign cystic teratoma which was adherent to superior vena cava. The patient underwent surgical excision. In follow up of 2 years, the patient is not having any complaints. PMID- 24627753 TI - Characteristics associated with suboptimal bowel preparation prior to colonoscopy: results of a national survey. AB - BACKGROUND: Inadequate bowel preparation prior to colonoscopy compromises the medical value of the procedure. The aim of this study is to explore the factors associated with pre-colonoscopy sub-optimal bowel preparation from the perspective of the physician. METHODS: Using a cross-sectional study design, we examined the role of various factors thought to be associated with sub-optimal bowel preparation as reported by a sample of practicing Gastroenterologists across the United States. We conducted a survey among active members of the American College of Gastroenterology to assess Gastroenterologists' perceptions about barriers faced by the patients in the bowel preparation process. Descriptions of factors associated with sub-optimal bowel preparation prior to screening colonoscopy were identified and described, including health conditions, patient cognitive/behavioral characteristics and medication use. RESULTS: Health conditions (including constipation and diabetes) and particular patient characteristics (including older age) were the most common perceived determinants of sub-optimal bowel preparation. Although some barriers to colonoscopy preparation (e.g., older age), cannot be modified, many are amenable to change through education. CONCLUSIONS: This study indicates the potential value of a personalized approach to bowel preparation, which addresses the specific needs of an individual patient like chronic constipation and diabetes and those with poor literacy skills or poor fluency in English. Development and evaluation of educational interventions to address these factors warrants investment. PMID- 24627754 TI - Role of Angiotensin Type 2 Receptor on Nitric Oxide Production Response to Angiotensin II Administration in Ovariectomised Rats Treated with Estradiol. AB - BACKGROUND: Renin-angiotensin system activity is gender related. The vasodilatory response of angiotensin II (AngII) angiotensin type 2 receptor (AT2R) may involve nitric oxide (NO) production. We attempted to find the role of AT2R on NO formation response to AngII administration in ovariectomised rats treated with estradiol (OVE). METHODS: A total of 33 female Wistar rats were divided into 3 groups; intact animals, ovariectomised treated with placebo (OVX) and OVE. At 2 weeks later, all animals were subjected to anesthetize and catheterize and each group was divided into two subgroups that received AT2R antagonist (PD123319) or vehicle. Each animal was subjected to 1 h continuous infusion of AngII (~20 MUg/kg/h) and the level of NO metabolite (nitrite) was measured before and after AngII infusion. RESULTS: At the presence of AT2R, the serum level of nitrite in response to AngII administration in OVE groups increased significantly (P < 0.05). CONCLUSIONS: However, this increase was abolished by AT2R antagonist. It seems that AT2R involves nitrite production response to AngII in OVE. PMID- 24627755 TI - Deadly rural road traffic injury: a rising public health concern in I.R. Iran. AB - BACKGROUND: The 5(th) Iran National Development Plan, 2011-2015, has emphasized on expansion of rural asphalt roads. This article aims to illustrate the trend of deaths caused by rural road traffic crashes (RTCs) and its association with length of the rural roads in Iran. METHODS: We carried out a retrospective analysis on secondary data for the period from 2005 to 2010. The Iranian Forensic Medicine Organization, High Commission for Road Safety and Iran's Statistical Center were the sources for the number of RTC death, length of the road and population data, respectively. RESULTS: Number of RTC deaths in rural roads increased from 1,672 in 2005 to 2,206 in 2010. This was associated with expansion of the rural asphalt roads (P = 0.04). The construction of urban asphalt roads was also on an increasing trend, but the number of traffic deaths in these roads decreased from 26,083 in 2005 to 21,043 in 2010. Adjusted for 100,000 populations, the number of traffic deaths in urban roads showed a decrease from 37.0 to 28.0, while this number increased from 2.4 to 2.9 in rural roads during the study period. CONCLUSIONS: Although expansion of rural roads would contribute to economic development in rural areas, it exposes people to risk of severe RTCs if effective preventive actions are not taken. To prevent this threat, the Iranian policy makers need to take the followings into consideration: Public awareness, improving the safety of roads and vehicles, law enforcement, increasing coverage of police and Emergency Medical Services. PMID- 24627756 TI - Re: Protective Role of Silymarin and Deferoxamine against Iron Dextran - Induced Renal Iron Deposition in Male Rats. PMID- 24627757 TI - Considerations for clinical read alignment and mutational profiling using next generation sequencing. AB - Next-generation sequencing technologies are increasingly being applied in clinical settings, however the data are characterized by a range of platform specific artifacts making downstream analysis problematic and error prone. One major application of NGS is in the profiling of clinically relevant mutations whereby sequences are aligned to a reference genome and potential mutations assessed and scored. Accurate sequence alignment is pivotal in reliable assessment of potential mutations however selection of appropriate alignment tools is a non-trivial task complicated by the availability of multiple solutions each with its own performance characteristics. Using BRCA1 as an example, we have simulated and mutated a test dataset based on Illumina sequencing technology. Our findings reveal key differences in the performances of a range of common commercial and open source tools and will be of importance to anyone using NGS to profile mutations in clinical or basic research. PMID- 24627758 TI - Low budget analysis of Direct-To-Consumer genomic testing familial data. AB - Direct-to-consumer (DTC) genetic testing is a recent commercial endeavor that allows the general public to access personal genomic data. The growing availability of personal genomic data has in turn stimulated the development of non-commercial tools for DTC data analysis. Despite this new wealth of public resources, no systematic research has been carried out to assess these tools for interpretation of DTC data. Here, we provide an initial analysis benchmark in the context of a whole family, using single nucleotide polymorphism (SNP) data. Five blood-related DTC SNP chip data tests were analyzed in conjunction with one whole exome sequence. We report findings related to genomic similarity between individuals, genetic risks and an overall assessment of data quality; thus providing an evaluation of the current potential of public domain analysis tools for personal genomics. We envisage that as the use of personal genome tests spreads to the general population, publicly available tools will have a more prominent role in the interpretation of genomic data in the context of health risks and ancestry. PMID- 24627759 TI - Sirenomelia in a Cameroonian woman: a case report and review of the literature. AB - Sirenomelia is a rare congenital malformative disorder characterized by fusion of the lower limbs giving a characteristic mermaid-like appearance to the affected foetus. We report a case of sirenomelia occurring in a 19 year old Cameroonian woman following premature rupture of membranes and associated cord prolapse. This is the first documented case in this country. We highlight some of the cultural myths associated with this disorder and discuss our findings relative to the present literature and related controversies on its etiopathogenesis. PMID- 24627760 TI - Murine Tim-1 is excluded from the immunological synapse. AB - The interaction between T cells and APCs bearing cognate antigen results in the formation of an immunological synapse (IS). During this process, many receptors and signaling proteins segregate to regions proximal to the synapse. This protein movement is thought to influence T cell function. However, some proteins are transported away from the IS, which is controlled in part by ERM family proteins. Tim-1 is a transmembrane protein with co-stimulatory functions that is found on many immune cells, including T cells. However, the expression pattern of Tim-1 on T cells upon activation by APCs has not been explored. Interestingly, in this study we demonstrate that the majority of Tim-1 on activated T cells is excluded from the IS. Tim-1 predominantly resides outside of the IS, and structure/function studies indicate that the cytoplasmic tail influences Tim-1 polarization. Specifically, a putative ERM binding motif (KRK 244-246) in the Tim 1 cytoplasmic tail appears necessary for proper Tim-1 localization. Furthermore, mutation of the KRK motif results in enhanced Tim1-mediated early tyrosine phosphorylation downstream of TCR/CD28 stimulation. Paradoxically however, the KRK motif is necessary for Tim-1 induced NFAT/AP-1 activation and co-stimulation of cytokine production. This work reveals unexpected complexity underlying Tim-1 localization and suggests potentially novel mechanisms by which Tim-1 modulates T cell activity. PMID- 24627761 TI - A rare variation of hydranencephaly: case report. AB - Hydranencephaly is a rare severe abnormality characterized by replacement of cerebral hemisphere with fluid covered by leptomeninges such that absent cerebral cortex. We present the Ultrasonographic diagnosis of a case of fetal Hydranencephaly at 38 weeks of gestation. Sonography revealed the absence of cerebral cortex, thalami and basal ganglia with disrupted falx and preserved posterior fossa structures. This was the first reported case of Hydranencephaly with absence thalami and basal ganglia along with midbrain. Confirmation of diagnosis was made with postnatal computed tomography. Even though it was diagnosed in the late third trimester, it allowed prompt and finest obstetric management which reduced the risk for both fetus and mother. Furthermore it allowed arrangement of optimal conditions for birth at a unit with accessible specialized pediatric facilities. PMID- 24627762 TI - Female circumcision: Limiting the harm: (Previously titled: Female Genital Cutting is a Harmful Practice. Where is the Evidence?). AB - OBJECTIVE: To review the strength of evidence that links many health hazards to female genital cutting. MATERIAL AND METHODS: Literature search in Medline/Pubmed and Google scholar. RESULTS: Female genital cutting is still practiced secretly in both underdeveloped and developed countries due to prevailing strong traditional beliefs. There is insufficient evidence to support the claims that genital cutting is a harmful procedure if performed by experienced personnel in a suitable theatre with facilities for pain control and anesthesia. Cutting, however, is advised not to go beyond type I. CONCLUSION: Law makers around the globe are invited to review the legal situation in relation to female genital cutting. Proper counseling of parents about possible risks is a must in order to make informed decision about circumcising their daughters. The procedure should be offered to parents who insist on it; otherwise, they will do it illegally, exposing their daughters to possible complications. PMID- 24627763 TI - Longhorned beetle (Coleoptera: Cerambycidae) diversity in a fragmented temperate forest landscape. AB - LONGHORNED BEETLES (COLEOPTERA: Cerambycidae) are an important component of temperate forest ecosystems. We trapped longhorned beetles in forests in northwest Ohio during 2008 to test the hypothesis that larger forests have greater species diversity than smaller forests. Large forests had a significantly greater cerambycid species richness than small forests (t = 3.16. P = 0.02), and there was a significant relationship between forest size and cerambycid species richness. PMID- 24627764 TI - ALS-linked SOD1 in glial cells enhances beta-N-Methylamino L-Alanine (BMAA) induced toxicity in Drosophila. AB - Environmental factors have been implicated in the etiology of a number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of environmental agents in ALS remains poorly understood. To this end, we used transgenic fruit flies (Drosophila melanogaster) to explore the interaction between mutant superoxide dismutase 1 (SOD1) and chemicals such as beta-N-methylamino L-alanine (BMAA), the herbicide agent paraquat, and superoxide species. We expressed ALS-linked human SOD1 (hSOD1A4V, and hSOD1G85R), hSOD1wt as well as the Drosophila native SOD1 (dSOD1) in motoneurons (MNs) or in glial cells alone and simultaneously in both types of cells. We then examined the effect of BMAA (3 mM), paraquat (20 mM), and hydrogen peroxide (H2O2, 1%) on the lifespan of SOD1-expressing flies. Our data show that glial expression of mutant and wild type hSOD1s reduces the ability of flies to climb. Further, we show that while all three chemicals significantly shorten the lifespan of flies, mutant SOD1 does not have a significant additional effect on the lifespan of flies fed on paraquat, but further shortens the lifespan of flies fed on H2O2. Finally, we show that BMAA shows a dramatic cell-type specific effect with mutant SOD1. Flies with expression of mutant hSOD1 in MNs survived longer on BMAA compared to control flies. In contrast, BMAA significantly shortened the lifespan of flies expressing mutant hSOD1 in glia. Consistent with a neuronal protection role, flies expressing these mutant hSOD1s in both MNs and glia also lived longer. Hence, our studies reveal a synergistic effect of mutant SOD1 with H2O2 and novel roles for mutant hSOD1s in neurons to reduce BMAA toxicity and in glia to enhance the toxicity of BMAA in flies. PMID- 24627765 TI - Kyasanur forest disease virus: viremia and challenge studies in monkeys with evidence of cross-protection by Langat virus infection. AB - Kyasanur Forest Disease Virus (KFDV), discovered in 1957, is a member of the tick borne encephalitis virus (TBEV) complex. Diseases caused by members of the TBEV complex occur in many parts of the world. KFDV produces a hemorrhagic fever in humans in South India and fatal illnesses in both species of monkeys in the area, the black faced langur (Presbytis entellus) and the bonnet macaque (Macaca radiata). Experimental infection of the langur and the bonnet macaque with early mouse passage KFDV strain P9605 resulted in a viremia of up to 11 days duration, peak viremia titers as high as 10 (9), and death in 82 = 100% of the animals. Prolonged passage of the KFDV strain P9605 in monkey kidney tissue culture resulted in a markedly reduced virulence of the virus for both species; peak viremia titers in monkeys decreased by 2.5 to 4.0 log LD 50 (p= 0.001), and the mortality decreased to 10% (p= 0.001). In challenge experiments, monkeys previously infected with tissue-culture-adapted KFDV, or with the related Langat virus from Malaysia, were fully protected against virulent KFDV. These studies in non-human primates lend support to the idea that a live virus vaccine from a member of the TBEV complex may be broadly protective against infections by other members of the TBEV complex. PMID- 24627766 TI - The novel Arabidopsis thaliana svt2 suppressor of the ascorbic acid-deficient mutant vtc1-1 exhibits phenotypic and genotypic instability. AB - Ascorbic acid is a potent antioxidant that detoxifies reactive oxygen species when plants are exposed to unfavorable environmental conditions. In addition to its antioxidant properties, ascorbic acid and its biosynthetic precursors fulfill a variety of other physiological and molecular functions. A mutation in the ascorbic acid biosynthesis gene VTC1, which encodes GDP-mannose pyrophosphorylase, results in conditional root growth inhibition in the presence of ammonium. To isolate suppressors of vtc1-1, which is in the Arabidopsis Columbia-0 background, seeds of the mutant were subjected to ethyl methanesulfonate mutagenesis. A suppressor mutant of vtc1-1 2, svt2, with wild type levels of ascorbic acid and root growth similar to the wild type in the presence of ammonium was isolated. Interestingly, svt2 has Arabidopsis Landsberg erecta features, although svt2 is delayed in flowering and has an enlarged morphology. Moreover, the svt2 genotype shares similarities with L er polymorphism markers and sequences, despite the fact that the mutant derived from mutagenesis of Col-0 vtc1-1 seed. We provide evidence that svt2 is not an artifact of the experiment, a contamination of L er seed, or a result of outcrossing of the svt2 mutant with L er pollen. Instead, our results show that svt2 exhibits transgenerational genotypic and phenotypic instability, which is manifested in a fraction of svt2 progeny, producing revertants that have Col-like phenotypic and genotypic characteristics. Some of those Col-like revertants then revert back to svt2-like plants in the subsequent generation. Our findings have important implications for undiscovered phenomena in transmitting genetic information in addition to the Mendelian laws of inheritance. Our results suggest that stress can trigger a genome restoration mechanism that could be advantageous for plants to survive environmental changes for which the ancestral genes were better adapted. PMID- 24627768 TI - A flexible user-interface for audiovisual presentation and interactive control in neurobehavioral experiments. AB - A major problem facing behavioral neuroscientists is a lack of unified, vendor distributed data acquisition systems that allow stimulus presentation and behavioral monitoring while recording neural activity. Numerous systems perform one of these tasks well independently, but to our knowledge, a useful package with a straightforward user interface does not exist. Here we describe the development of a flexible, script-based user interface that enables customization for real-time stimulus presentation, behavioral monitoring and data acquisition. The experimental design can also incorporate neural microstimulation paradigms. We used this interface to deliver multimodal, auditory and visual (images or video) stimuli to a nonhuman primate and acquire single-unit data. Our design is cost-effective and works well with commercially available hardware and software. Our design incorporates a script, providing high-level control of data acquisition via a sequencer running on a digital signal processor to enable behaviorally triggered control of the presentation of visual and auditory stimuli. Our experiments were conducted in combination with eye-tracking hardware. The script, however, is designed to be broadly useful to neuroscientists who may want to deliver stimuli of different modalities using any animal model. PMID- 24627767 TI - I. Embryonal vasculature formation recapitulated in transgenic mammary tumor spheroids implanted pseudo-orthotopicly into mouse dorsal skin fold: the organoblasts concept. AB - Inadequate understanding of cancer biology is a problem. This work focused on cellular mechanisms of tumor vascularization. According to earlier studies, the tumor vasculature derives from host endothelial cells (angiogenesis) or their precursors of bone marrow origin circulating in the blood (neo-vasculogenesis) unlike in embryos. In this study, we observed the neo-vasculature form in multiple ways from local precursor cells. Recapitulation of primitive as well as advanced embryonal stages of vasculature formation followed co-implantation of avascular ( in vitro cultured) N202 breast tumor spheroids and homologous tissue grafts into mouse dorsal skin chambers. Ultrastructural and immunocytochemical analysis of tissue sections exposed the interactions between the tumor and the graft tissue stem cells. It revealed details of vasculature morphogenesis not seen before in either tumors or embryos. A gradual increase in complexity of the vascular morphogenesis at the tumor site reflected a range of steps in ontogenic evolution of the differentiating cells. Malignant- and surgical injury repair related tissue growth prompted local cells to initiate extramedullar erythropoiesis and vascular patterning. The new findings included: interdependence between the extramedullar hematopoiesis and assembly of new vessels (both from the locally differentiating precursors); nucleo-cytoplasmic conversion (karyolysis) as the mechanism of erythroblast enucleation; the role of megakaryocytes and platelets in vascular pattern formation before emergence of endothelial cells; lineage relationships between hematopoietic and endothelial cells; the role of extracellular calmyrin in tissue morphogenesis; and calmyrite, a new ultrastructural entity associated with anaerobic energy metabolism. The central role of the extramedullar erythropoiesis in the formation of new vasculature (blood and vessels) emerged here as part of the tissue building process including the lymphatic system and nerves, and suggests a cellular mechanism for instigating variable properties of endothelial surfaces in different organs. Those findings are consistent with the organoblasts concept, previously discussed in a study on childhood tumors, and have implications for tissue definition. PMID- 24627769 TI - Mutation detection in cholestatic patients using microarray resequencing of ATP8B1 and ABCB11. AB - Background : Neonatal cholestasis is a common presentation of childhood liver diseases and can be a feature of various conditions including disorders of bile acid biogenesis and transport, various inborn errors of metabolism and perinatal infections. Some inherited metabolic diseases can be easily screened using biochemical assays, however many can only be accurately diagnosed by DNA sequencing. Fluorescent capillary Sanger sequencing (FS) is the gold standard method used by clinical laboratories for genetic diagnosis of many inherited conditions; however, it does have limitations. Recently microarray resequencing (MR) has been introduced into research and clinical practice as an alternative method for genetic diagnosis of heterogeneous conditions. In this report we compared the accuracy of mutation detection for MR with FS in a group of patients with 'low-normal' gamma glutamyl transpeptidase (gGT) cholestasis without known molecular diagnoses. Methods : 29 patient DNA samples were tested for mutations in the ATP8B1 and ABCB11 genes using both FS and MR. Other known causes of "low gGT cholestasis" such as ARC syndrome and bile acid biosynthesis disorders were excluded. Results : Mutations were identified in 13/29 samples. In 3/29 samples FS and MR gave discordant results: MR had a false positive rate of 3.4% and a false negative rate of 7%. Conclusions : The major advantage of MR over FS is that multiple genes can be screened in one experiment, allowing rapid and cost effective diagnoses. However, we have demonstrated that MR technology is limited in sensitivity. We therefore recommend that MR be used as an initial evaluation, with FS deployed when genetic and clinical or histopathological findings are discordant. PMID- 24627770 TI - Verbal and novel multisensory associative learning in adults. AB - To date, few studies have focused on the behavioural differences between the learning of multisensory auditory-visual and intra-modal associations. More specifically, the relative benefits of novel auditory-visual and verbal-visual associations for learning have not been directly compared. In Experiment 1, 20 adult volunteers completed three paired associate learning tasks: non-verbal novel auditory-visual (novel-AV), verbal-visual (verbal-AV; using pseudowords), and visual-visual (shape-VV). Participants were directed to make a motor response to matching novel and arbitrarily related stimulus pairs. Feedback was provided to facilitate trial and error learning. The results of Signal Detection Theory analyses suggested a multisensory enhancement of learning, with significantly higher discriminability measures (d-prime) in both the novel-AV and verbal-AV tasks than the shape-VV task. Motor reaction times were also significantly faster during the verbal-AV task than during the non-verbal learning tasks. Experiment 2 (n = 12) used a forced-choice discrimination paradigm to assess whether a difference in unisensory stimulus discriminability could account for the learning trends in Experiment 1. Participants were significantly slower at discriminating unisensory pseudowords than the novel sounds and visual shapes, which was notable given that these stimuli produced superior learning. Together the findings suggest that verbal information has an added enhancing effect on multisensory associative learning in adults. PMID- 24627771 TI - Selection and validation of reference genes for quantitative gene expression studies in Erythroxylum coca. AB - Real-time quantitative PCR is a powerful technique for the investigation of comparative gene expression, but its accuracy and reliability depend on the reference genes used as internal standards. Only genes that show a high level of expression stability are suitable for use as reference genes, and these must be identified on a case-by-case basis. Erythroxylum coca produces and accumulates high amounts of the pharmacologically active tropane alkaloid cocaine (especially in the leaves), and is an emerging model for the investigation of tropane alkaloid biosynthesis. The identification of stable internal reference genes for this species is important for its development as a model species, and would enable comparative analysis of candidate biosynthetic genes in the different tissues of the coca plant. In this study, we evaluated the expression stability of nine candidate reference genes in E. coca ( Ec6409, Ec10131, Ec11142, Actin, APT2, EF1alpha, TPB1, Pex4, Pp2aa3). The expression of these genes was measured in seven tissues (flowers, stems, roots and four developmental leaf stages) and the stability of expression was assessed using three algorithms (geNorm, NormFinder and BestKeeper). From our results we conclude that Ec10131 and TPB1 are the most appropriate internal reference genes in leaves (where the majority of cocaine is produced), while Ec10131 and Ec6409 are the most suitable internal reference genes across all of the tissues tested. PMID- 24627772 TI - Prostitution use has non sexual functions - case report of a depressed psychiatric out-patient. AB - CASE: A shy, depressed 30 year old male discussed his frequent ego-syntonic indoor prostitution consumption in small peer groups. Several distinctive non sexual functions of this paid sex habit were identified. DESIGN AND METHOD: The patient had 40 hourly psychiatric sessions in the private practice setting over 14 months. The Arizona Sexual Experience Scale was applied to compare the subjective appraisal of both paid sex and sex in a relationship. RESULTS: The paid sex consumption functioned as a proud male life style choice to reinforce the patients fragile identity. The effect on self esteem was a release similar to his favorite past-time of kick-boxing. With paid sex asserted as a group ritual, it was practiced even with frequent erectile dysfunction and when sex with a stable romantic partner was more enjoyable and satisfying. The therapeutic attitude of the female psychiatrist, with her own ethical values, is put in to context with two opposing theories about prostitution: the 'Sex-Work-model' and the 'Oppression-model'. The therapist's reaction to the patients' information was seen as a starting point to understanding the intrapsychic function of paid sex as a coping mechanism against depressive feelings. CONCLUSIONS: Exploring and understanding prostitution consumption patterns in young men can benefit the treatment of psychiatric disorders in the private practice setting. It is the psychiatrists task to investigate the patients hidden motives behind paid sex use to help patients achieve a greater inner and relational freedom. PMID- 24627773 TI - Casanovas are liars: behavioral syndromes, sperm competition risk, and the evolution of deceptive male mating behavior in live-bearing fishes. AB - Mate choice in many species is sensitive to social cues from neighboring individuals; for example, animals can copy mate choice decisions. If males copy other males' choices, sperm of two or more males can compete for fertilization of the female's ova. In the internally fertilizing fish Poecilia mexicana, males respond to the presence of rivals with reduced expression of mating preferences (audience effect), thereby lowering the risk of by-standing rivals copying their mate choice. Also, males interact initially more with a non-preferred female when observed by a rival, which has been interpreted in previous studies as a strategy to mislead rivals, again reducing sperm competition risk (SCR). Using a comparative approach, we tested the hypothesis that SCR is indeed a driving force explaining the occurrence of audience-induced changes in poeciliid male mate choice behavior. If this were true, then males of species with higher overall sexual activity - and, thus, higher potential for multiple mating - should show stronger audience effects. We investigated ten poeciliid species (in two cases including multiple populations) and found support for our hypothesis as mean sexual activity correlated positively with the occurrence of potentially deceptive behavior. An alternative explanation for audience effects would be that males attempt to avoid aggressive encounters, which would predict stronger audience effects in more aggressive species, and so we also characterized the examined species for aggressiveness using staged contests of size-matched males. We demonstrate a positive correlation between mean aggressiveness and sexual activity (suggesting a hormonal link as a mechanistic explanation), but we detected no correlation between aggressiveness and audience effects. Suites of correlated behavioral tendencies are termed behavioral syndromes, and our present study provides correlational evidence for the evolutionary significance of SCR in shaping a behavioral syndrome at the species level across poeciliid taxa. PMID- 24627774 TI - Anacardic acid, a histone acetyltransferase inhibitor, modulates LPS-induced IL-8 expression in a human alveolar epithelial cell line A549. AB - OBJECTIVE AND DESIGN: The histone acetylation processes, which are believed to play a critical role in the regulation of many inflammatory genes, are reversible and regulated by histone acetyltransferases (HATs), which promote acetylation, and histone deacetylases (HDACs), which promote deacetylation. We studied the effects of lipopolysaccharide (LPS) on histone acetylation and its role in the regulation of interleukin (IL)-8 expression. MATERIAL: A human alveolar epithelial cell line A549 was used in vitro. METHODS: Histone H4 acetylation at the IL-8 promoter region was assessed by a chromatin immunoprecipitation (ChIP) assay. The expression and production of IL-8 were evaluated by quantitative polymerase chain reaction and specific immunoassay. Effects of a HDAC inhibitor, trichostatin A (TSA), and a HAT inhibitor, anacardic acid, were assessed. RESULTS: Escherichia coli-derived LPS showed a dose- and time-dependent stimulatory effect on IL-8 protein production and mRNA expression in A549 cells in vitro. LPS showed a significant stimulatory effect on histone H4 acetylation at the IL-8 promoter region by ChIP assay. Pretreatment with TSA showed a dose dependent stimulatory effect on IL-8 release from A549 cells as compared to LPS alone. Conversely, pretreatment with anacardic acid inhibited IL-8 production and expression in A549 cells. CONCLUSION: These data suggest that LPS-mediated proinflammatory responses in the lungs might be modulated via changing chromatin remodeling by HAT inhibition. PMID- 24627775 TI - Delayed ejaculation and alexithymia: what is the relationship? AB - Delayed Ejaculation (DE) is probably the least studied and understood of the male sexual dysfunctions (MSD). There is still little unanimity concerning its psychological/interpersonal aetiology. Previous studies found that MSD are strongly related with alexithymia, a multifaceted personality construct that describes a disturbance in the regulation of emotions.The aim of this study was to investigate the presence of alexithymia in men with DE and correlate alexithymia levels with DE severity. According to specific features of the symptoms, we hypothesized that alexithymia would not be correlated with this specific sexual disorder. 54 outpatients with a diagnosis of DE assessed at the Institute of Clinical Sexology and the Urology Department of Sapienza, University in Rome were enrolled in the study. DE was diagnosed after a specialist examination and according to Diagnostic and Statistical Manual of Mental Disorders -IV-TR criteria. Participants were provided with the Toronto Alexithymia Scale (20 items; TAS-20), a self-measure of the Intravaginal Ejaculation Latency Time and an ad hoc questionnaire to collect anamnestic data. 9.3% of patients could be categorized as alexithymics, 9.3% of them as borderline, while 81.4% of the sample was found to be non-alexithymic. The overall average TAS-20 score was 45.46. Results show that alexithymia is correlated neither with the presence of DE nor with its severity, in contrast to other MSDs, where this condition was found in about 30% of patients. The data presented suggest that DE, although not correlated to alexithymia, is probably related to other psychogenic features such as hypercontrol configuration. This paper can contribute to the understanding of DE, by excluding one of the possible etiological factors, previously found to be important in the onset and the maintenance of the other MSDs. More studies are needed in order to better understand DE and provide recommendations about treatment. PMID- 24627776 TI - Nigerian secondary school adolescents' perspective on abstinence-only sexual education as an effective tool for promotion of sexual health. AB - The success of any type of sexual education programme depends on the knowledge and preparedness for practice by adolescents. A recent study has found that an 'abstinence-only' sexual education programme is effective in reducing sexual activity among adolescents. Knowledge of abstinence-only sexual education and preparedness for practice as an effective tool for promotion of sexual health among Nigerian secondary school adolescents was studied. An analytic descriptive survey design was used for the study. The research population comprised of all public secondary schools in three southern geopolitical zones of the Niger Delta Region of Nigeria. A multistage sampling technique was used to select 2020 senior secondary school (SS1-SS3) students as sample for the study. A partially self designed and partially adapted questionnaire from an 'abstinence-only versus comprehensive sex education' debate, from debatepedia (http://wiki.idebate.org/), entitled 'Questionnaire on Nigerian Secondary School Adolescents' Perspective on Abstinence-Only Sexual Education (QNSSAPAOSE)' was used in eliciting information from respondents. Hypotheses were formulated and tested. Frequency counts, percentage and Pearson Product Moment Correlation were used in analysing data. A greater proportion of secondary school adolescents in this study lacked knowledge of sexual education. About 80% of the respondents could not define sexual education. The general perspective on abstinence-only sexual education was negative, as revealed by the larger number of respondents who demonstrated unwillingness to practice abstinence-only sexual education. Specifically, of those who responded in favour of abstinence-only sexual education, the youngest group of adolescents (11-13 years) and the male respondents were more likely to accept this type of education than the other groups. Poor knowledge of sexual education could be responsible for unwillingness to practice abstinence-only sexual education. Sexual education should, therefore, be introduced into the secondary school curriculum and taught by well-prepared teachers to enable an informed decision on practice. PMID- 24627777 TI - Paging Doctor Google! Heuristics vs. technology. AB - The most dramatic development in medical decision-making technology has been the advent of the Internet. This has had an impact not only on clinicians, but has also become an important resource for patients who often approach their doctors with medical information they have obtained from the Internet. Increasingly, medical students, residents and attending physicians have been using the Internet as a tool for diagnosing and treating disease. Internet-based resources that are available take various forms, including informational websites, online journals and textbooks, and social media. Search engines such as Google have been increasingly used to help in making diagnoses of disease entities. Do these search methods fare better than experienced heuristic methods? In a small study, we examined the comparative role of heuristics versus the 'Google' mode of thinking. Internal medicine residents were asked to "google" key words to come up with a diagnosis. Their results were compared to experienced nephrology faculty and fellows in training using heuristics and no additional help of internet. Overall, with the aid of Google, the novices (internal medicine residents) correctly diagnosed renal diseases less often than the experts (the attendings) but with the same frequency as the intermediates (nephrology fellows). However, in a subgroup analysis of both common diseases and rare diseases, the novices correctly diagnosed renal diseases less often than the experts but more often than the intermediates in each analysis. The novices correctly diagnosed renal diseases with the same frequency as nephrology fellows in training. PMID- 24627778 TI - Over 30 million psychedelic users in the United States. AB - We estimated lifetime prevalence of psychedelic use (lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), mescaline, and peyote) by age category using data from a 2010 US population survey of 57,873 individuals aged 12 years and older. There were approximately 32 million lifetime psychedelic users in the US in 2010; including 17% of people aged 21 to 64 years (22% of males and 12% of females). Rate of lifetime psychedelic use was greatest among people aged 30 to 34 (total 20%, including 26% of males and 15% of females). PMID- 24627779 TI - Global identification of genes and pathways regulated by Akt during activation of T helper cells. AB - We previously demonstrated that Akt differentially modulated a subset of NF-kB target genes during T cell activation. In the current study, we further explored the broader effects of Akt inhibition on T cell gene induction. Global microarray analysis was used to characterize T helper cell transcriptional responses following antigen receptor stimulation in the absence or presence of Akti1/2 (an allosteric inhibitor which targets Akt1 and Akt2), to identify novel targets dependent upon Akt and obtain a more comprehensive view of Akt-sensitive genes in T helper cells. Pathway analysis of microarray data from a CD4 (+) T cell line revealed effects on gene networks involving ribosomal and T cell receptor signaling pathways associated with Akti1/2 treatment. Using real-time PCR analysis, we validated differential regulation of several genes in these pathways, including Ier3, Il13, Klf6, Egr1, Ccl1 and Ccl4, among others. Additionally, transcription factor target gene (TFactS) analysis revealed that NF kB and Myc were the most significantly enriched transcription factors among Akt dependent genes after T cell receptor and CD28 stimulation. Akt activation elicited increases in the enrichment of NF-kB- and Myc-targeted genes. The present study has identified a diverse set of genes, and possible mechanisms for their regulation, that are dependent on Akt during T cell activation. PMID- 24627780 TI - Association between digital dermatoglyphics and handedness among Sinhalese in Sri Lanka. AB - Background The relationship between handedness and digital dermatoglyphic patterns has never been investigated in the Sinhalese population. The goal of this study is to establish the above mentioned relationship, which would positively aid personal identification. Findings One hundred Sinhalese students (50 right-handed and 50 left-handed) were studied for their digital dermatoglyphic pattern distribution. The results show that a statistically significant correlation exists for digit 3 (P=0.002, Fisher's exact test) of the right hand and digit 1 (P=0.002, Fisher's exact test) and digit 2 (P=0.021, Fisher's exact test) of the left hand. Further, whorl patterns are more common in right-handed than left-handed Sinhalese students. Conclusions Statistically significant differences in handedness and digital dermatoglyphic patterns were evident among Sinhalese people. Further study with a larger sample size is recommended. PMID- 24627781 TI - Variation in candidate genes CLOCK and ADCYAP1 does not consistently predict differences in migratory behavior in the songbird genus Junco. AB - Recent studies exploring the molecular genetic basis for migratory variation in animals have identified polymorphisms in two genes ( CLOCK and ADCYAP1) that are linked to circadian rhythms and correlate with migratory propensity and phenology among individuals and populations. Results from these initial studies are mixed, however, and additional data are needed to assess the generality and diversity of the molecular mechanisms that regulate the biology of migration. We sequenced CLOCK and ADCYAP1 in 15 populations across the two species of the avian genus Junco, a North American lineage in which multiple recently diverged subspecies and populations range from sedentary to long-distance migrants. We found no consistent associations between allele length and migratory status across the genus for either CLOCK or ADCYAP1. However, within two subspecies groups, populations that migrate longer distances have longer CLOCK alleles on average. Additionally, there was a positive relationship between ADCYAP1 allele length and migratory restlessness (zugunruhe) among individuals within one of two captive populations studied-a result similar to those reported previously within captive blackcaps ( Sylvia atricapilla). We conclude that, while both ADCYAP1 and CLOCK may correlate with migratory propensity within or among certain populations or species, previously identified relationships between migratory behavior and sequence variants cannot be easily generalized across taxa. PMID- 24627782 TI - Microbiopsy engineered for minimally invasive and suture-free sub-millimetre skin sampling. AB - We describe the development of a sub-millimetre skin punch biopsy device for painless and suture-free skin sampling for molecular diagnosis and research. Conventional skin punch biopsies range from 2-4 mm in diameter. Local anaesthesia is required and sutures are usually used to close the wound. Our microbiopsy is 0.50 mm wide and 0.20 mm thick. The microbiopsy device is fabricated from three stacked medical grade stainless steel plates tapered to a point and contains a chamber within the centre plate to collect the skin sample. We observed that the application of this device resulted in a 0.21 +/- 0.04 mm wide puncture site in volunteer skin using reflectance confocal microscopy. Histological sections from microbiopsied skin revealed 0.22 +/- 0.12 mm wide and 0.26 +/- 0.09 mm deep puncture sites. Longitudinal observation in microbiopsied volunteers showed that the wound closed within 1 day and was not visible after 7 days. Reflectance confocal microscope images from these same sites showed the formation of a tiny crust that resolved by 3 weeks and was completely undetectable by the naked eye. The design parameters of the device were optimised for molecular analysis using sampled DNA mass as the primary end point in volunteer studies. Finally, total RNA was characterized. The optimised device extracted 5.9 +/- 3.4 ng DNA and 9.0 +/- 10.1 ng RNA. We foresee that minimally invasive molecular sampling will play an increasingly significant role in diagnostic dermatology and skin research. PMID- 24627784 TI - Using computation to enhance diagnosis and therapy: a novel mutation operator for real-coded adaptive genetic algorithms. AB - The fields of molecular biology and neurobiology have advanced rapidly over the last two decades. These advances have resulted in the development of large proteomic and genetic databases that need to be searched for the prediction, early detection and treatment of neuropathologies and other genetic disorders. This need, in turn, has pushed the development of novel computational algorithms that are critical for searching genetic databases. One successful approach has been to use artificial intelligence and pattern recognition algorithms, such as neural networks and optimization algorithms (e.g. genetic algorithms). The focus of this paper is on optimizing the design of genetic algorithms by using an adaptive mutation rate based on the fitness function of passing generations. We propose a novel pseudo-derivative based mutation rate operator designed to allow a genetic algorithm to escape local optima and successfully continue to the global optimum. Once proven successful, this algorithm can be implemented to solve real problems in neurology and bioinformatics. As a first step towards this goal, we tested our algorithm on two 3-dimensional surfaces with multiple local optima, but only one global optimum, as well as on the N-queens problem, an applied problem in which the function that maps the curve is implicit. For all tests, the adaptive mutation rate allowed the genetic algorithm to find the global optimal solution, performing significantly better than other search methods, including genetic algorithms that implement fixed mutation rates. PMID- 24627783 TI - Clinical applications of microRNAs. AB - MicroRNAs represent a class of small RNAs derived from polymerase II controlled transcriptional regions. The primary transcript forms one or several bulging double stranded hairpins which are processed by Drosha and Dicer into hetero duplexes. The targeting microRNA strand of the duplex is incorporated into the RNA Induced Silencing Complex from where it silences up to hundreds of mRNA transcript by inducing mRNA degradation or blocking protein translation. Apart from involvement in a variety of biological processes, microRNAs were early recognized for their potential in disease diagnostics and therapeutics. Due to their stability, microRNAs could be used as biomarkers. Currently, there are microRNA panels helping physicians determining the origins of cancer in disseminated tumors. The development of microRNA therapeutics has proved more challenging mainly due to delivery issues. However, one drug is already in clinical trials and several more await entering clinical phases. This review summarizes what has been recognized pre-clinically and clinically on diagnostic microRNAs. In addition, it highlights individual microRNA drugs in running platforms driven by four leading microRNA-therapeutic companies. PMID- 24627785 TI - Identification and molecular characterization of a Chlamydomonas reinhardtii mutant that shows a light intensity dependent progressive chlorophyll deficiency. AB - The green micro-alga Chlamydomonas reinhardtii is an elegant model organism to study all aspects of oxygenic photosynthesis. Chlorophyll (Chl) and heme are major tetrapyrroles that play an essential role in energy metabolism in photosynthetic organisms. These tetrapyrroles are synthesized via a common branched pathway that involves mainly nuclear encoded enzymes. One of the enzymes in the pathway is Mg chelatase (MgChel) which inserts Mg (2+) into protoporphyrin IX (PPIX, proto) to form Magnesium-protoporphyrin IX (MgPPIX, Mgproto), the first biosynthetic intermediate in the Chl branch. The GUN4 (genomes uncoupled 4) protein is not essential for the MgChel activity but has been shown to significantly stimulate its activity. We have isolated a light sensitive mutant, 6F14, by random DNA insertional mutagenesis. 6F14 cannot tolerate light intensities higher than 90-100 MUmol photons m (-2) s (-1). It shows a light intensity dependent progressive photo-bleaching. 6F14 is incapable of photo autotrophic growth under light intensity higher than 100 MUmol photons m (-2) s ( 1). PCR based analyses show that in 6F14 the insertion of the plasmid outside the GUN4 locus has resulted in a genetic rearrangement of the GUN4 gene and possible deletions in the genomic region flanking the GUN4 gene. Our gun4 mutant has a Chl content very similar to that in the wild type in the dark and is very sensitive to fluctuations in the light intensity in the environment unlike the earlier identified Chlamydomonas gun4 mutant. Complementation with a functional copy of the GUN4 gene restored light tolerance, Chl biosynthesis and photo-autotrophic growth under high light intensities in 6F14. 6F14 is the second gun4 mutant to be identified in C. reinhardtii. Additionally, we show that our two gun4 complements over-express the GUN4 protein and show a higher Chl content per cell compared to that in the wild type strain. PMID- 24627786 TI - A fragmented alignment method detects a phosphorylation site and a new BRC repeat in the Drosophila melanogaster BRCA2 protein, and a new HAT repeat in Utp6 from yeast. AB - Mutations in the BRCA2 tumor suppressor protein leave individuals susceptible to breast, ovarian and other cancers. The BRCA2 protein is a critical component of the DNA repair pathways in eukaryotes, and also plays an integral role in fostering genomic variability through meiotic recombination. Although present in many eukaryotes, as a whole the BRCA2 gene is weakly conserved. Conserved fragments of 30 amino acids (BRC repeats), which mediate interactions with the recombinase RAD51, helped detect orthologs of this protein in other organisms. The carboxy-terminal of the human BRCA2 has been shown to be phosphorylated by checkpoint kinases (Chk1/Chk2) at T3387, which regulate the sequestration of RAD51 on DNA damage. However, apart from three BRC repeats, the Drosophila melanogaster gene has not been annotated and associated with other functionally relevant sequence fragments in human BRCA2. In the current work, the carboxy terminal phosphorylation threonine site (E=9.1e-4) and a new BRC repeat (E=17e-4) in D. melanogaster has been identified, using a fragmented alignment methodology (FRAGAL). In a similar study, FRAGAL has also identified a novel half-a- tetratricopeptide (HAT) motif (E=11e-4), a helical repeat motif implicated in various aspects of RNA metabolism, in Utp6 from yeast. The characteristic three aromatic residues with conserved spacing are observed in this new HAT repeat, further strengthening my claim. The reference and target sequences are sliced into overlapping fragments of equal parameterized lengths. All pairs of fragments in the reference and target proteins are aligned, and the gap penalties are adjusted to discourage gaps in the middle of the alignment. The results of the best matches are sorted based on differing criteria to aid the detection of known and putative sequences. The source code for FRAGAL results on these sequences is available at https://github.com/sanchak/FragalCode, while the database can be accessed at www.sanchak.com/fragal.html. PMID- 24627787 TI - A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease. AB - BACKGROUND: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson disease (PD). While clozapine is an effective treatment, the need for blood monitoring has limited its first-line use. OBJECTIVE: Since olanzapine shows similar receptor affinity to clozapine, we hypothesized that it might be an effective alternative to clozapine for treatment of drug-induced psychosis (DIP) in PD, and that lower doses than usual might make it tolerable. METHODS: In 1998-2003 we conducted a four-week, double-blind, placebo-controlled, parallel group, fixed-dose trial of olanzapine (0, 2.5mg, or 5mg) in 23 PD patients with DIP while allowing for clinically realistic dose adjustments of dopaminomimetic mid-study. The primary outcome measures were Brief Psychiatric Rating Scale (BPRS) ratings scored from videotaped interviews after study termination by an observer blinded to dose assignment and to interview timing, and CGI (Clinical Global Impression). The Unified Parkinson's Disease Rating Scale motor subscale (UPDRS) was the primary measure of tolerability. RESULTS: Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo subjects reported mild side effects (p<0.04), many citing motor worsening. Fourteen patients completed the study (seven on placebo, two on 2.5mg olanzapine, five on 5mg olanzapine). In study completers, analysis by repeated measures ANOVA revealed no significant difference between olanzapine and placebo groups in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, PDQ-39, Schwab-England ADL assessment, and sleep scores). CONCLUSION: This study adds to other evidence that olanzapine is ineffective in treating medication-induced psychosis in Parkinson disease. PMID- 24627788 TI - Long term delivery of pulsed magnetic fields does not improve learning or alter dendritic spine density in the mouse hippocampus. AB - Repetitive transcranial magnetic stimulation (rTMS) is thought to facilitate brain plasticity. However, few studies address anatomical changes following rTMS in relation to behaviour. We delivered 5 weeks of daily pulsed rTMS stimulation to ephrin-A2 (-/-) and wildtype mice (n=10 per genotype) undergoing a visual learning task and analysed learning performance, as well as spine density, in the dentate gyrus molecular and CA1 pyramidal cell layers in Golgi-stained brain sections. We found that neither learning behaviour, nor hippocampal spine density was affected by long term rTMS. Our negative results highlight the lack of deleterious side effects in normal subjects and are consistent with previous studies suggesting that rTMS has a bigger effect on abnormal or injured brain substrates than on normal/control structures. PMID- 24627789 TI - Depth-dependent mortality of reef corals following a severe bleaching event: implications for thermal refuges and population recovery. AB - Coral bleaching caused by rising sea temperature is a primary cause of coral reef degradation. However, bleaching patterns often show significant spatial variability, therefore identifying locations where local conditions may provide thermal refuges is a high conservation priority. Coral bleaching mortality often diminishes with increasing depth, but clear depth zonation of coral communities and putative limited overlap in species composition between deep and shallow reef habitats has led to the conclusion that deeper reef habitats will provide limited refuge from bleaching for most species. Here, we show that coral mortality following a severe bleaching event diminished sharply with depth. Bleaching induced mortality of Acropora was approximately 90% at 0-2m, 60% at 3-4 m, yet at 6-8m there was negligible mortality. Importantly, at least two-thirds of the shallow-water (2-3 m) Acropora assemblage had a depth range that straddled the transition from high to low mortality. Cold-water upwelling may have contributed to the lower mortality observed in all but the shallowest depths. Our results demonstrate that, in this instance, depth provided a refuge for individuals from a high proportion of species in this Acropora-dominated assemblage. The persistence of deeper populations may provide a critical source of propagules to assist recovery of adjacent shallow-water reefs. PMID- 24627790 TI - MethylExtract: High-Quality methylation maps and SNV calling from whole genome bisulfite sequencing data. AB - Whole genome methylation profiling at a single cytosine resolution is now feasible due to the advent of high-throughput sequencing techniques together with bisulfite treatment of the DNA. To obtain the methylation value of each individual cytosine, the bisulfite-treated sequence reads are first aligned to a reference genome, and then the profiling of the methylation levels is done from the alignments. A huge effort has been made to quickly and correctly align the reads and many different algorithms and programs to do this have been created. However, the second step is just as crucial and non-trivial, but much less attention has been paid to the final inference of the methylation states. Important error sources do exist, such as sequencing errors, bisulfite failure, clonal reads, and single nucleotide variants. We developed MethylExtract, a user friendly tool to: i) generate high quality, whole genome methylation maps and ii) detect sequence variation within the same sample preparation. The program is implemented into a single script and takes into account all major error sources. MethylExtract detects variation (SNVs - Single Nucleotide Variants) in a similar way to VarScan, a very sensitive method extensively used in SNV and genotype calling based on non-bisulfite-treated reads. The usefulness of MethylExtract is shown by means of extensive benchmarking based on artificial bisulfite-treated reads and a comparison to a recently published method, called Bis-SNP. MethylExtract is able to detect SNVs within High-Throughput Sequencing experiments of bisulfite treated DNA at the same time as it generates high quality methylation maps. This simultaneous detection of DNA methylation and sequence variation is crucial for many downstream analyses, for example when deciphering the impact of SNVs on differential methylation. An exclusive feature of MethylExtract, in comparison with existing software, is the possibility to assess the bisulfite failure in a statistical way. The source code, tutorial and artificial bisulfite datasets are available at http://bioinfo2.ugr.es/MethylExtract/ and http://sourceforge.net/projects/methylextract/, and also permanently accessible from 10.5281/zenodo.7144. PMID- 24627791 TI - Excess CD40L does not rescue anti-DNA B cells from clonal anergy. AB - CD40L, a member of the tumor necrosis factor (TNF) ligand family, is overexpressed in patients with systemic lupus erythematosus and in lupus mouse models. Previously, we demonstrated that B cells producing pathogenic anti-Sm/RNP antibodies are deleted in the splenic marginal zone (MZ), and that MZ deletion of these self-reactive B cells is reversed by excess CD40L, leading to autoantibody production. To address whether excess CD40L also perturbs clonal anergy, another self-tolerance mechanism of B cells whereby B cells are functionally inactivated and excluded from follicles in the peripheral lymphoid tissue, we crossed CD40L transgenic mice with the anti-DNA H chain transgenic mouse line 3H9, in which Ig lambda1+ anti-DNA B cells are anergized. However, the percentage and localization of Ig lambda1+ B cells in CD40L/3H9 double transgenic mice were no different from those in 3H9 mice. This result indicates that excess CD40L does not perturb clonal anergy, including follicular exclusion. Thus, MZ deletion is distinct from clonal anergy, and is more liable to tolerance break. PMID- 24627792 TI - Bispectral index detects intraoperative cerebral ischaemia during balloon assisted cerebral aneurysm coiling. AB - Bispectral index (BIS) is a monitoring modality designed and used for monitoring depth of anaesthesia. We wish to report a case where BIS monitoring may have alerted us to a potential adverse neurological event during angiographic coiling of a cerebral aneurysm. PMID- 24627793 TI - Study protocol for examining job strain as a risk factor for severe unipolar depression in an individual participant meta-analysis of 14 European cohorts. AB - BACKGROUND: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted "job strain") are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta analysis from 2008 indicated publication bias in the field. METHODS: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers. The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis. DISCUSSION: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied. PMID- 24627795 TI - StatsDB: platform-agnostic storage and understanding of next generation sequencing run metrics. AB - Modern sequencing platforms generate enormous quantities of data in ever decreasing amounts of time. Additionally, techniques such as multiplex sequencing allow one run to contain hundreds of different samples. With such data comes a significant challenge to understand its quality and to understand how the quality and yield are changing across instruments and over time. As well as the desire to understand historical data, sequencing centres often have a duty to provide clear summaries of individual run performance to collaborators or customers. We present StatsDB, an open-source software package for storage and analysis of next generation sequencing run metrics. The system has been designed for incorporation into a primary analysis pipeline, either at the programmatic level or via integration into existing user interfaces. Statistics are stored in an SQL database and APIs provide the ability to store and access the data while abstracting the underlying database design. This abstraction allows simpler, wider querying across multiple fields than is possible by the manual steps and calculation required to dissect individual reports, e.g. "provide metrics about nucleotide bias in libraries using adaptor barcode X, across all runs on sequencer A, within the last month". The software is supplied with modules for storage of statistics from FastQC, a commonly used tool for analysis of sequence reads, but the open nature of the database schema means it can be easily adapted to other tools. Currently at The Genome Analysis Centre (TGAC), reports are accessed through our LIMS system or through a standalone GUI tool, but the API and supplied examples make it easy to develop custom reports and to interface with other packages. PMID- 24627794 TI - From zebrafish heart jogging genes to mouse and human orthologs: using Gene Ontology to investigate mammalian heart development. AB - For the majority of organs in developing vertebrate embryos, left-right asymmetry is controlled by a ciliated region; the left-right organizer node in the mouse and human, and the Kuppfer's vesicle in the zebrafish. In the zebrafish, laterality cues from the Kuppfer's vesicle determine asymmetry in the developing heart, the direction of 'heart jogging' and the direction of 'heart looping'. 'Heart jogging' is the term given to the process by which the symmetrical zebrafish heart tube is displaced relative to the dorsal midline, with a leftward 'jog'. Heart jogging is not considered to occur in mammals, although a leftward shift of the developing mouse caudal heart does occur prior to looping, which may be analogous to zebrafish heart jogging. Previous studies have characterized 30 genes involved in zebrafish heart jogging, the majority of which have well defined orthologs in mouse and human and many of these orthologs have been associated with early mammalian heart development. We undertook manual curation of a specific set of genes associated with heart development and we describe the use of Gene Ontology term enrichment analyses to examine the cellular processes associated with heart jogging. We found that the human, mouse and zebrafish 'heart jogging orthologs' are involved in similar organ developmental processes across the three species, such as heart, kidney and nervous system development, as well as more specific cellular processes such as cilium development and function. The results of these analyses are consistent with a role for cilia in the determination of left-right asymmetry of many internal organs, in addition to their known role in zebrafish heart jogging. This study highlights the importance of model organisms in the study of human heart development, and emphasises both the conservation and divergence of developmental processes across vertebrates, as well as the limitations of this approach. PMID- 24627797 TI - Common sense ideas to increase the percentage of filled seats in nephrology fellowships. AB - Interest in nephrology has been decreasing for the last decade. In this opinion piece, the author provides four unconventional, outside-the-box strategies to increase the percentage of filled nephrology training positions. PMID- 24627796 TI - Neurocognitive endophenotypes in CGG KI and Fmr1 KO mouse models of Fragile X Associated disorders: an analysis of the state of the field. AB - It has become increasingly important that the field of behavioral genetics identifies not only the gross behavioral phenotypes associated with a given mutation, but also the behavioral endophenotypes that scale with the dosage of the particular mutation being studied. Over the past few years, studies evaluating the effects of the polymorphic CGG trinucleotide repeat on the FMR1 gene underlying Fragile X-Associated Disorders have reported preliminary evidence for a behavioral endophenotype in human Fragile X Premutation carrier populations as well as the CGG knock-in (KI) mouse model. More recently, the behavioral experiments used to test the CGG KI mouse model have been extended to the Fmr1 knock-out (KO) mouse model. When combined, these data provide compelling evidence for a clear neurocognitive endophenotype in the mouse models of Fragile X Associated Disorders such that behavioral deficits scale predictably with genetic dosage. Similarly, it appears that the CGG KI mouse effectively models the histopathology in Fragile X-Associated Disorders across CGG repeats well into the full mutation range, resulting in a reliable histopathological endophenotype. These endophenotypes may influence future research directions into treatment strategies for not only Fragile X Syndrome, but also the Fragile X Premutation and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). PMID- 24627798 TI - Postoperative visual loss following cerebral arteriovenous malformation surgery: a case report. AB - We report the case of a 46 year-old woman presenting with postoperative visual loss in the right eye after craniotomy for excision of an arteriovenous malformation. The intraoperative course was uneventful with hemodynamic stability and maintenance of blood pressure within 10% of the preoperative value. Blood loss was 300 ml; postoperative hemoglobin was 12.4 g/dl. In the recovery room, the ophthalmologic examination revealed decreased visual acuity, color vision, and visual field in the right eye. Assessment of the retina was normal, but the patient showed a relative afferent pupillary defect consistent with the clinical diagnosis of ischemic optic neuropathy. Anesthesiologists should be aware that this condition may follow uncomplicated intracranial surgeries in the supine position, and should obtain prompt ophthalmologic consultation when patients develop postoperative visual loss. PMID- 24627799 TI - Findings from a survey of wildlife reintroduction practitioners. AB - Wildlife reintroduction programs are a type of conservation initiative that seek to re-establish viable populations of a species in areas from which they have been extirpated or become extinct. Past efforts to improve the outcomes of reintroduction have focused heavily on overcoming ecological challenges, with little attention paid to the potential influence of leadership, management, and other aspects of reintroduction. This 2009 survey of reintroduction practitioners identified several key areas of leadership and management that may deserve further study, including: (i) the potential value of reintroduction partnerships for improving programmatic outcomes; (ii) the potential management value of autonomy vs. hierarchy in organizational structure; (iii) gaps in perceptions of success in reintroduction; and (iv) the need for improved evaluations of reintroduction programs and outcomes. PMID- 24627800 TI - Pancreatico-pericardial fistula as a complication of chronic pancreatitis. AB - Pancreatico-pericardial fistula is an extremely rare complication of chronic pancreatitis. We present a case of a 58-year-old man who presented with syncope. Transthoracic echocardiogram revealed a pericardial effusion with tamponade physiology. Pericardiocentesis and pericardial fluid analysis demonstrated a lipase level of 2321 U/L. Subsequently, an endoscopic retrograde cholangiopancreatography (ERCP) was performed, confirming the presence of a pancreatico-pericardial fistula (PPF) from the distal body of the pancreas. A pancreatic duct stent was placed across the duct disruption on two separate occasions; however, despite stent placement, the patient continued to re accumulate pericardial fluid and deteriorated. While rare, PPFs may complicate chronic pancreatitis, may not respond to pancreatic duct stenting and may portend a poor prognosis. PMID- 24627801 TI - Papular granuloma annulare of palms and soles: case report of a rare presentation. AB - We report the case of a 44-year-old Indian male patient who presented with mildly tender isolated papular lesions confined to the palms of the hands and soles of the feet. The histopathology was characteristic of granuloma annulare. There was an excellent response with 4-week treatment with a potent topical steroid ointment and no recurrence was reported at the follow-up one year later. This report is interesting because of the rare presentation of a common disease. PMID- 24627802 TI - Matched molecular pair-based data sets for computer-aided medicinal chemistry. AB - Matched molecular pairs (MMPs) are widely used in medicinal chemistry to study changes in compound properties including biological activity, which are associated with well-defined structural modifications. Herein we describe up-to date versions of three MMP-based data sets that have originated from in-house research projects. These data sets include activity cliffs, structure-activity relationship (SAR) transfer series, and second generation MMPs based upon retrosynthetic rules. The data sets have in common that they have been derived from compounds included in the latest release of the ChEMBL database for which high-confidence activity data are available. Thus, the activity data associated with MMP-based activity cliffs, SAR transfer series, and retrosynthetic MMPs cover the entire spectrum of current pharmaceutical targets. Our data sets are made freely available to the scientific community. PMID- 24627803 TI - Cerebral venous thrombosis in post-lumbar puncture intracranial hypotension: case report and review of literature. AB - The spectrum of presentation of intracranial hypotension is clinically perplexing. We report a case of 31-year-old post-partum woman who underwent an uneventful caesarean section under spinal anesthesia. From the second day of surgery she developed postural headache, the headache lost its postural character after few days. She then developed seizures and ataxic hemiparesis. Magnetic resonance imaging showed features of severe intracranial hypotension in the brain and the spinal cord, and magnetic resonance venography showed cortical vein and partial superior sagittal sinus thrombosis. Prothrombotic (etiological) work-up showed Protein C and S deficiency. She responded to anticoagulation therapy and recovered completely. On review of literature two distinct groups could be identified obstetric and non-obstetric. The non-obstetric group included patients who underwent diagnostic lumbar puncture, intrathecal injection of medications and epidural anesthesia for non-obstetric surgeries. Poor outcome and mortality was noted in non-obstetric group, while obstetric group had an excellent recovery. PMID- 24627804 TI - BioJS DAGViewer: A reusable JavaScript component for displaying directed graphs. AB - SUMMARY: The DAGViewer BioJS component is a reusable JavaScript component made available as part of the BioJS project and intended to be used to display graphs of structured data, with a particular emphasis on Directed Acyclic Graphs (DAGs). It enables users to embed representations of graphs of data, such as ontologies or phylogenetic trees, in hyper-text documents (HTML). This component is generic, since it is capable (given the appropriate configuration) of displaying any kind of data that is organised as a graph. The features of this component which are useful for examining and filtering large and complex graphs are described. AVAILABILITY: http://github.com/alexkalderimis/dag-viewer-biojs; http://github.com/biojs/biojs; http://dx.doi.org/10.5281/zenodo.8303. PMID- 24627805 TI - Epilepsy surgery series: a study of 502 consecutive patients from a developing country. AB - Purpose. To review the postoperative seizure outcomes of patients that underwent surgery for epilepsy at King Faisal Specialist Hospital & Research Centre (KFSHRC). Methods. A descriptive retrospective study for 502 patients operated on for medically intractable epilepsy between 1998 and 2012. The surgical outcome was measured using the ILAE criteria. Results. The epilepsy surgery outcome for temporal lobe epilepsy surgery (ILAE classes 1, 2, and 3) at 12, 36, and 60 months is 79.6%, 74.2%, and 67%, respectively. The favorable 12- and 36-month outcomes for frontal lobe epilepsy surgery are 62% and 52%, respectively. For both parietal and occipital epilepsy lobe surgeries the 12- and 36-month outcomes are 67%. For multilobar epilepsy surgery, the 12- and 36-month outcomes are 65% and 50%, respectively. The 12- and 36-month outcomes for functional hemispherectomy epilepsy surgery are 64.2% and 63%, respectively. According to histopathology diagnosis, mesiotemporal sclerosis (MTS) and benign CNS tumors had the best favorable outcome after surgery at 1 year (77.27% and 84.3%, resp.,) and 3 years (76% and 75%, resp.,). The least favorable seizure-free outcome after 3 years occurred in cases with dual pathology (66.6%). Thirty-four epilepsy patients with normal magnetic resonance imaging (MRI) brain scans were surgically treated. The first- and third-year epilepsy surgery outcome of 17 temporal lobe surgeries were (53%) and (47%) seizure-free, respectively. The first- and third year epilepsy surgery outcomes of 15 extratemporal epilepsy surgeries were (47%) and (33%) seizure-free. Conclusion. The best outcomes are achieved with temporal epilepsy surgery, mesial temporal sclerosis, and benign CNS tumor. The worst outcomes are from multilobar surgery, dual pathology, and normal MRI. PMID- 24627806 TI - The modified atkins diet in refractory epilepsy. AB - The modified Atkins diet is a less restrictive variation of the ketogenic diet. This diet is started on an outpatient basis without a fast, allows unlimited protein and fat, and does not restrict calories or fluids. Recent studies have shown good efficacy and tolerability of this diet in refractory epilepsy. In this review, we discuss the use of the modified Atkins diet in refractory epilepsy. PMID- 24627807 TI - Long-term survival and outcome in children admitted to kilifi district hospital with convulsive status epilepticus. AB - Objectives. The incidence of convulsive status epilepticus (CSE) is high in Africa but the long-term outcome is unknown. We examined the neurocognitive outcome and survival of children treated for CSE in a Kenyan hospital 3 to 4 years after discharge. Methods. The frequency and nature of neurological deficits among this group of children were determined and compared to a control group. The children were screened with the Ten Questions Questionnaire for neurodevelopmental impairment if alive and those that screened positive were invited for further assessment to determine the pattern and extent of their impairment. A verbal autopsy was performed to determine the cause of death in those that died. Results. In the 119 cases followed-up, 9 (8%) died after discharge, with the majority having seizures during their fatal illness. The 110 survivors (median age 5 years) had significantly more neurological impairments on the screening compared to 282 controls (34/110 (30.9%) versus 11/282 (3.9%), OR = 11.0, 95% CI 5.3-22.8). Fifteen percent of the cases had active epilepsy. Conclusions. This study demonstrates the considerable burden of CSE in African children. Strategies to manage children with CSE that are acceptable to the community need to be explored to improve the longer-term outcome. PMID- 24627808 TI - Urgent and nonurgent presentations to a psychiatric emergency service in Nigeria: pattern and correlates. AB - Psychiatric emergencies are acute mental health disturbances that require immediate intervention. However, the emergency department is increasingly being utilised for nonurgent mental health problems, thereby compromising the quality of care available for patients with urgent problems. This study assessed the level and correlates of urgency of mental health problems among patients presenting to an emergency department in Nigeria. The Crisis Triage Rating Scale, Clinical Global Impression Scale and a supplementary questionnaire were administered to 700 attendees at the emergency department of the Federal Neuro Psychiatric Hospital Yaba, Lagos. Only 29.1% of the presentations constituted an "emergency" 10.9% were "urgent," while 60% were "nonurgent." The most common reason for nonurgent presentations was the need for medication refill. On regression analysis, level of urgency of presentations was independently associated with employment status, need for medication refill, substance abuse, suicidality, routine clinic attendance, and use of physical restraint before presentation. The majority of visits to the emergency department are for apparently "nonurgent problems." However in a resource-poor setting, the emergency department may be the only safety net for the attendees. Our findings point to a need for education of service users and policy shifts in mental health care financing and organisation. PMID- 24627809 TI - Recent advances of hemorrhage management in severe trauma. AB - Trauma is one of the most common causes of mortality worldwide with a substantial percentage of deaths resulting secondary to haemorrhages, which are preventable and treatable when adequately managed. This paper offers a review of the current literature on how to successfully resuscitate patients with major haemorrhage. PMID- 24627810 TI - Characterization of the Merkel Cell Carcinoma miRNome. AB - MicroRNAs have been implicated in various skin cancers, including melanoma, squamous cell carcinoma, and basal cell carcinoma; however, the expression of microRNAs and their role in Merkel cell carcinoma (MCC) have yet to be explored in depth. To identify microRNAs specific to MCC (MCC-miRs), next-generation sequencing (NGS) of small RNA libraries was performed on different tissue samples including MCCs, other cutaneous tumors, and normal skin. Comparison of the profiles identified several microRNAs upregulated and downregulated in MCC. For validation, their expression was measured via qRT-PCR in a larger group of MCC and in a comparison group of non-MCC cutaneous tumors and normal skin. Eight microRNAs were upregulated in MCC: miR-502-3p, miR-9, miR-7, miR-340, miR-182, miR-190b, miR-873, and miR-183. Three microRNAs were downregulated: miR-3170, miR 125b, and miR-374c. Many of these MCC-miRs, the miR-183/182/96a cistron in particular, have connections to tumorigenic pathways implicated in MCC pathogenesis. In situ hybridization confirmed that the highly expressed MCC-miR, miR-182, is localized within tumor cells. Furthermore, NGS and qRT-PCR reveal that several of these MCC-miRs are highly expressed in the patient-derived MCC cell line, MS-1. These data indicate that we have identified a set of MCC-miRs with important implications for MCC research. PMID- 24627811 TI - Warfarin Dosing in a Patient with CYP2C9(*)3(*)3 and VKORC1-1639 AA Genotypes. AB - Genetic factors most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR). Patients receiving warfarin who possess one or more genetic variations in CYP2C9 and VKORC1 are at increased risk of adverse drug events and require significant dose reductions to achieve a therapeutic international normalized ratio (INR). A 74-year-old white female with atrial fibrillation was initiated on a warfarin dose of 2 mg PO daily, which resulted in multiple elevated INR measurements and three clinically significant hemorrhagic events and four vitamin K antidote treatments over a period of less than two weeks. Genetic analysis later revealed that she had the homozygous variant genotypes of CYP2C9*3*3 and VKORC1-1639 AA. Warfarin dosing was subsequently restarted and stabilized at 0.5 mg PO daily with therapeutic INRs. This is the first case report of a white female with these genotypes stabilized on warfarin, and it highlights the value of pharmacogenetic testing prior to the initiation of warfarin therapy to maximize efficacy and minimize the risk of adverse drug events. PMID- 24627812 TI - Health avatar: an informatics platform for personal and private big data. PMID- 24627813 TI - Health Informatics in Developing Countries: Going beyond Pilot Practices to Sustainable Implementations: A Review of the Current Challenges. AB - OBJECTIVES: Information technology is an essential tool to improve patient safety and the quality of care, and to reduce healthcare costs. There is a scarcity of large sustainable implementations in developing countries. The objective of this paper is to review the challenges faced by developing countries to achieve sustainable implementations in health informatics and possible ways to address them. METHODS: In this non-systematic review of the literature, articles were searched using the keywords medical informatics, developing countries, implementation, and challenges in PubMed, LILACS, CINAHL, Scopus, and EMBASE. The authors, after reading the literature, reached a consensus to classify the challenges into six broad categories. RESULTS: The authors describe the problems faced by developing countries arising from the lack of adequate infrastructure and the ways these can be bypassed; the fundamental need to develop nationwide e Health agendas to achieve sustainable implementations; ways to overcome public uncertainty with respect to privacy and security; the difficulties shared with developed countries in achieving interoperability; the need for a trained workforce in health informatics and existing initiatives for its development; and strategies to achieve regional integration. CONCLUSIONS: Central to the success of any implementation in health informatics is knowledge of the challenges to be faced. This is even more important in developing countries, where uncertainty and instability are common. The authors hope this article will assist policy makers, healthcare managers, and project leaders to successfully plan their implementations and make them sustainable, avoiding unexpected barriers and making better use of their resources. PMID- 24627814 TI - Free/Libre open source software in health care: a review. AB - OBJECTIVES: To assess the current state of the art and the contribution of Free/Libre Open Source Software in health care (FLOSS-HC). METHODS: The review is based on a narrative review of the scientific literature as well as sources in the context of FLOSS-HC available through the Internet. All relevant available sources have been integrated into the MedFLOSS database and are freely available to the community. RESULTS: The literature review reveals that publications about FLOSS-HC are scarce. The largest part of information about FLOSS-HC is available on dedicated websites and not in the academic literature. There are currently FLOSS alternatives available for nearly every specialty in health care. Maturity and quality varies considerably and there is little information available on the percentage of systems that are actually used in health care delivery. CONCLUSIONS: The global impact of FLOSS-HC is still very limited and no figures on the penetration and usage of FLOSS-HC are available. However, there has been a considerable growth in the last 5 to 10 years. While there where only few systems available a decade ago, in the meantime many systems got available (e.g., more than 300 in the MedFLOSS database). While FLOSS concepts play an important role in most IT related sectors (e.g., telecommunications, embedded devices) the healthcare industry is lagging behind this trend. PMID- 24627815 TI - Analysis of the information quality of korean obesity-management smartphone applications. AB - OBJECTIVES: This study analyzed smartphone obesity-management applications developed in Korea and the quality of the information that they provide. METHODS: Obesity-management smartphone applications were searched using the keywords 'obesity + management,' 'weight + management,' 'weight + loss,' 'weight + exercise,' 'weight + diet,' 'weight + calories,' and 'diet,' with a search application programming interface (provided by Apple) between September 23 and September 27, 2013. These applications were then classified according to their main purpose, type of interventions used, price, type of developer, and user ratings. The information quality of the applications was analyzed using the Silberg scale. RESULTS: In total, 148 smartphone applications for obesity management were found. The main purpose of most of these applications (70.95%) was to provide information regarding weight control. The most frequently used intervention (34.62%) was to provide information on exercise management. More than half of the applications (58.78%) were free of charge. The mean of users' rating of these applications was 3.68 out of 5. The quality of information provided by these applications was evaluated as 4.55 out of 9: specifically, 1.79 out of 3 for authorship, 0.22 out of 2 for attribution, 1.29 out of 2 for disclosure, and 1.25 out of 2 for currency. Only three of the applications (2.88%) had a score on the Silberg scale greater than or equal to 7 points. CONCLUSIONS: The findings of this study suggest that the quality of information provided by smartphone applications in the healthcare domain urgently need to be evaluated to prevent users being misinformed by these applications. PMID- 24627816 TI - Knowledge Discovery in a Community Data Set: Malnutrition among the Elderly. AB - OBJECTIVES: The purpose of this study was to design a prediction model that explains the characteristics of elderly adults at risk of malnutrition. METHODS: Data were obtained from a large data set, 2008 Korean Elderly Survey, in which the data of 15,146 subjects were entered. With nutritional status a target variable, the input variables included the demographic and socioeconomic status of participants. The data were analyzed by using the SPSS Clementine 12.0 program's feature selection node to select meaningful variables. RESULTS: Among the C5.0, C&R Tree, QUEST, and CHAID models, the highest predictability was reported by C&R Tree with the accuracy rate of 77.1%. The presence of more than two comorbidities, living alone status, having severe difficulty in daily activities, and lower perceived economic status were identified as risk factors of malnutrition in elderly. CONCLUSIONS: A reliable decision support model was designed to provide accurate information regarding the characteristics of elderly individuals with malnutrition. The findings demonstrated the good feasibility of data mining when used for a large community data set and its value in assisting health professionals and local decision makers to come up with effective strategies for achieving public health goals. PMID- 24627817 TI - CCR+: Metadata Based Extended Personal Health Record Data Model Interoperable with the ASTM CCR Standard. AB - OBJECTIVES: Extension of the standard model while retaining compliance with it is a challenging issue because there is currently no method for semantically or syntactically verifying an extended data model. A metadata-based extended model, named CCR+, was designed and implemented to achieve interoperability between standard and extended models. METHODS: Furthermore, a multilayered validation method was devised to validate the standard and extended models. The American Society for Testing and Materials (ASTM) Community Care Record (CCR) standard was selected to evaluate the CCR+ model; two CCR and one CCR+ XML files were evaluated. RESULTS: In total, 188 metadata were extracted from the ASTM CCR standard; these metadata are semantically interconnected and registered in the metadata registry. An extended-data-model-specific validation file was generated from these metadata. This file can be used in a smartphone application (Health Avatar CCR+) as a part of a multilayered validation. The new CCR+ model was successfully evaluated via a patient-centric exchange scenario involving multiple hospitals, with the results supporting both syntactic and semantic interoperability between the standard CCR and extended, CCR+, model. CONCLUSIONS: A feasible method for delivering an extended model that complies with the standard model is presented herein. There is a great need to extend static standard models such as the ASTM CCR in various domains: the methods presented here represent an important reference for achieving interoperability between standard and extended models. PMID- 24627818 TI - Study on user interface of pathology picture archiving and communication system. AB - OBJECTIVES: It is necessary to improve the pathology workflow. A workflow task analysis was performed using a pathology picture archiving and communication system (pathology PACS) in order to propose a user interface for the Pathology PACS considering user experience. METHODS: An interface analysis of the Pathology PACS in Seoul National University Hospital and a task analysis of the pathology workflow were performed by observing recorded video. Based on obtained results, a user interface for the Pathology PACS was proposed. RESULTS: Hierarchical task analysis of Pathology PACS was classified into 17 tasks including 1) pre operation, 2) text, 3) images, 4) medical record viewer, 5) screen transition, 6) pathology identification number input, 7) admission date input, 8) diagnosis doctor, 9) diagnosis code, 10) diagnosis, 11) pathology identification number check box, 12) presence or absence of images, 13) search, 14) clear, 15) Excel save, 16) search results, and 17) re-search. And frequently used menu items were identified and schematized. CONCLUSIONS: A user interface for the Pathology PACS considering user experience could be proposed as a preliminary step, and this study may contribute to the development of medical information systems based on user experience and usability. PMID- 24627820 TI - Online Learning for Classification of Alzheimer Disease based on Cortical Thickness and Hippocampal Shape Analysis. AB - OBJECTIVES: Mobile healthcare applications are becoming a growing trend. Also, the prevalence of dementia in modern society is showing a steady growing trend. Among degenerative brain diseases that cause dementia, Alzheimer disease (AD) is the most common. The purpose of this study was to identify AD patients using magnetic resonance imaging in the mobile environment. METHODS: We propose an incremental classification for mobile healthcare systems. Our classification method is based on incremental learning for AD diagnosis and AD prediction using the cortical thickness data and hippocampus shape. We constructed a classifier based on principal component analysis and linear discriminant analysis. We performed initial learning and mobile subject classification. Initial learning is the group learning part in our server. Our smartphone agent implements the mobile classification and shows various results. RESULTS: With use of cortical thickness data analysis alone, the discrimination accuracy was 87.33% (sensitivity 96.49% and specificity 64.33%). When cortical thickness data and hippocampal shape were analyzed together, the achieved accuracy was 87.52% (sensitivity 96.79% and specificity 63.24%). CONCLUSIONS: In this paper, we presented a classification method based on online learning for AD diagnosis by employing both cortical thickness data and hippocampal shape analysis data. Our method was implemented on smartphone devices and discriminated AD patients for normal group. PMID- 24627819 TI - Drug similarity search based on combined signatures in gene expression profiles. AB - OBJECTIVES: Recently, comparison of drug responses on gene expression has been a major approach to identifying the functional similarity of drugs. Previous studies have mostly focused on a single feature, the expression differences of individual genes. We provide a more robust and accurate method to compare the functional similarity of drugs by diversifying the features of comparison in gene expression and considering the sample dependent variations. METHODS: For differentially expressed gene measurement, we modified the conventional t-test to normalize variations in diverse experimental conditions of individual samples. To extract significant differentially co-expressed gene modules, we searched maximal cliques among the co-expressed gene network. Finally, we calculated a combined similarity score by averaging the two scaled scores from the above two measurements. RESULTS: This method shows significant performance improvement in comparison to other approaches in the test with Connectivity Map data. In the test to find the drugs based on their own expression profiles with leave-one-out cross validation, the proposed method showed an area under the curve (AUC) score of 0.99, which is much higher than scores obtained with previous methods, ranging from 0.71 to 0.93. In the drug networks, we could find well clustered drugs having the same target proteins and novel relations among drugs implying the possibility of drug repurposing. CONCLUSIONS: Inclusion of the features of a co expressed module provides more implications to infer drug action. We propose that this method be used to find collaborative cellular mechanisms associated with drug action and to simply identify drugs having similar responses. PMID- 24627821 TI - Lifelog agent for human activity pattern analysis on health avatar platform. AB - OBJECTIVES: To provide accurate personalized medical care, it is necessary to gather individual-related data or contextual information regarding the target person. Nowadays a large number of people possess smartphones, which enables sensors in the smartphones to be used for lifelogging. The objective of the study is to analyze human activity pattern by using lifelog agent cooperating with the Health Avatar platform. METHODS: Using the lifelog measured by accelerometer and gyroscope in a smartphone at a 50 Hz rate, the agent reveals how long the user walks, runs, sits, stands, and lies down, and this information is summarized by hours. The summaries are sent to the Health Avatar platform and finally are written in the Continuity of Care Record (CCR) format. RESULTS: The lifelog agent is successfully operated with the Health Avatar platform. In addition, we implement an application that displays the user's activity patterns in a graph and calculates the metabolic equivalent of task based calorie burned by hour or by day using the lifelog of the CCR form to show that the lifelog can be used as medical records. CONCLUSIONS: The agent shows how lifelogs are analyzed and summarized to help activity recognition. We believe that our agent demonstrates a way of incorporating lifelogs into medical care and a way of exploiting lifelogs in a medical format. PMID- 24627822 TI - Gestational diabetes mellitus in korean women: similarities and differences from other racial/ethnic groups. AB - Gestational diabetes mellitus (GDM) reflects defects in insulin secretion in response to the metabolic demands of pregnancy. While GDM is increasingly common worldwide due in large part to the obesity epidemic, its frequency is relatively low in Korean women. In this report, the prevalence and risk factors for GDM, perinatal outcomes, and postpartum course are compared in non-Korean and Korean women. While Koreans and non-Koreans with GDM share pathophysiology and complications, there may be differences in the role of obesity and thus the effectiveness of interventions targeting obesity in GDM women. Further investigations of the effectiveness of weight loss interventions and pharmacotherapy specifically among Korean women are needed. Dietary and other lifestyle data from Korean populations could inform prevention and treatment strategies in other countries which suffer from significantly higher prevalences of GDM. PMID- 24627824 TI - Current status of diabetic peripheral neuropathy in Korea: report of a hospital based study of type 2 diabetic patients in Korea by the diabetic neuropathy study group of the korean diabetes association. AB - Diabetic peripheral neuropathy (DPN) is the most common complication associated with diabetes. DPN can present as a loss of sensation, may lead to neuropathic ulcers, and is a leading cause of amputation. Reported estimates of the prevalence of DPN vary due to differences in study populations and diagnostic criteria. Furthermore, the epidemiology and clinical characteristics of DPN in Korean patients with type 2 diabetes mellitus (T2DM) are not as well understood as those of other complications of diabetes such as retinal and renal disease. Recently, the Diabetic Neuropathy Study Group of the Korean Diabetes Association (KDA) conducted a study investigating the impact of DPN on disease burden and quality of life in patients with T2DM and has published some data that are representative of the nation. This review investigated the prevalence and associated clinical implications of DPN in Korean patients with diabetes based on the KDA study. PMID- 24627825 TI - Statin for the primary prevention of cardiovascular disease in patients with diabetes mellitus. PMID- 24627823 TI - The hijacking of cellular signaling and the diabetes epidemic: mechanisms of environmental disruption of insulin action and glucose homeostasis. AB - The burgeoning epidemic of metabolic disease causes significant societal and individual morbidity and threatens the stability of health care systems around the globe. Efforts to understand the factors that contribute to metabolic derangements are critical for reversing these troubling trends. While excess caloric consumption and physical inactivity superimposed on a susceptible genetic background are central drivers of this crisis, these factors alone fail to fully account for the magnitude and rapidity with which metabolic diseases have increased in prevalence worldwide. Recent epidemiological evidence implicates endocrine disrupting chemicals in the pathogenesis of metabolic diseases. These compounds represent a diverse array of chemicals to which humans are exposed via multiple routes in adulthood and during development. Furthermore, a growing ensemble of animal- and cell-based studies provides preclinical evidence supporting the hypothesis that environmental contaminants contribute to the development of metabolic diseases, including diabetes. Herein are reviewed studies linking specific endocrine disruptors to impairments in glucose homeostasis as well as tying these compounds to disturbances in insulin secretion and impairments in insulin signal transduction. While the data remains somewhat incomplete, the current body of evidence supports the hypothesis that our chemically polluted environment may play a contributing role in the current metabolic crisis. PMID- 24627826 TI - Prevalence, awareness, and management of obesity in Korea: data from the Korea national health and nutrition examination survey (1998-2011). AB - BACKGROUND: Obesity is a risk factor for diabetes and several cardiovascular diseases. This study was to investigate the trends in the prevalence, awareness, and management status of obesity among the Korean population for recent 13 years. METHODS: The prevalence, subjective awareness, and management of obesity were investigated in adults aged >=19 years by using the data from the Korea National Health and Nutrition Examination Surveys (KNHANES) 1998 to 2011. RESULTS: The number of participants was 8,117, 5,826, 5,500, 3,025, 6,756, 7,506, 6,255, and 6,155 in the KNHANES in years 1998, 2001, 2005, 2007, 2008, 2009, 2010, and 2011, respectively. The prevalence of obesity was 26.9%, 29.2%, 32.9%, 32.5%, 32.0%, 32.6%, 32.0%, and 32.0% in 1998, 2001, 2005, 2007, 2008, 2009, 2010, and 2011, respectively, while the overall prevalence of obesity and abdominal obesity increased by 1.19-fold and 1.24-fold respectively in 2011 compared against 2001. In general, a gradual increase in the prevalence of severe obesity has been observed as years go by. Furthermore, trends of improvements in obesity awareness and management rates were visible over the period of surveys. CONCLUSION: Although the management status of obesity has improved during the recent years, more effective strategy to control obesity is needed. PMID- 24627827 TI - Plasma glucose regulation and mortality in Korea: a pooled analysis of three community-based cohort studies. AB - BACKGROUND: Although diabetes is a well-known risk factor for death, its impact on cancer death is not clearly understood. Furthermore, it remains controversial whether impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are associated with increased risk of mortality. We investigated the impact of diabetes or glucose tolerance categories on all cause and cause-specific mortality. METHODS: Mortality analysis was conducted in three population-based cohort studies of 3,801 participants, divided according to fasting plasma glucose (FPG) (normal; stage 1 IFG [5.6<=FPG<6.1 mmol/L]; stage 2 IFG [6.1<=FPG<7.0 mmol/L]; diabetes mellitus [DM]-FPG); or 2-hour glucose after 75 g glucose loading (2hPG) (normal; IGT; DM-2hPG), or a combination of FPG and 2hPG criteria. RESULTS: During a median follow-up of 11.0 years, 474 subjects died from all causes. Hazard ratios (HRs) for all cause death were higher in those with diabetes as defined by either FPG or 2hPG criteria than their normal counterparts (HR, 2.2, 95% confidence interval [CI], 1.6 to 2.9 for DM-FPG; HR, 2.0, 95% CI, 1.5 to 2.7 for DM-2hPG). Similarly, diabetes defined by either FPG or 2hPG was associated with cancer death (HR, 2.9, 95% CI, 1.7 to 5.0; and HR, 2.1, 95% CI, 1.2 to 3.9, respectively). Although neither IFG nor IGT conferred higher risk for death, when combining stage 2 IFG and/or IGT, the risk of all cause death was higher than in subjects with normal glucose regulation (HR, 1.3; 95% CI, 1.0 to 1.6). CONCLUSION: Diabetes is associated with higher risk of death from all causes and cancer. In subjects without diabetes, stage 2 IFG and/or IGT confers increased risk for mortality. PMID- 24627828 TI - Higher prevalence and awareness, but lower control rate of hypertension in patients with diabetes than general population: the fifth korean national health and nutrition examination survey in 2011. AB - BACKGROUND: We investigated the prevalence, awareness, treatment, and control rate of hypertension in Korean adults with diabetes using nationally representative data. METHODS: Using data of 5,105 adults from the fifth Korea National Health and Nutrition Examination Survey in 2011 (4,389 nondiabetes mellitus [non-DM]), 242 newly diagnosed with DM (new-DM), and 474 previously diagnosed with DM (known-DM), we analyzed the prevalence of hypertension (mean systolic blood pressure >=140 mm Hg, diastolic blood pressure >=90 mm Hg, or use of antihypertensive medication) and control rate of hypertension (blood pressure [BP] <130/80 mm Hg). RESULTS: The prevalence of hypertension in diabetic adults was 54.6% (44.4% in new-DM and 62.6% in known-DM, P<0.0001 and P<0.0001, respectively) compared with non-DM adults (26.2%). Compared to non-DM, awareness (85.7%, P<0.001) and treatment (97.0%, P=0.020) rates were higher in known-DM, whereas no differences were found between new-DM and non-DM. Control rate among all hypertensive subjects was lower in new-DM (14.9%), compared to non-DM (35.1%, P<0.001) and known-DM (33.3%, P=0.004). Control rate among treated subjects was also lower in new-DM (25.2%), compared to non-DM (68.4%, P<0.0001) and known-DM (39.9%, P<0.0001). CONCLUSION: Higher prevalence and low control rate of hypertension in adults with diabetes suggest that stringent efforts are needed to control BP in patients with diabetes, particularly in newly diagnosed diabetic patients. PMID- 24627829 TI - Assessment of the Association between Mean Hemoglobin A1c Levels for 5 Years and Coronary Artery Disease by Coronary Angiography in Nondiabetic Patients. AB - BACKGROUND: The effects of glucose on cardiovascular events or mortality in nondiabetic patients has been recently reported. However, since atherosclerosis can be formed over a long period of time, it is necessary to devote several years to unveil the relationship between the two factors. Here, we attempted to find out the relationship between the mean hemoglobin A1c (HbA1c) level and HbA1c variability for 5 years and coronary artery disease (CAD) by using coronary angiography (CAG) to assess nondiabetic patients. METHODS: We reviewed patients who performed CAG who were followed up for at least 5 years after the initial diagnosis. The fasting blood test was performed annually for glucose and HbA1c level. CAD was defined as more than 50% of luminal narrowing. The severity of CAD was divided into two groups depending on whether no vessels were involved or one more vessel were involved (CAD(-) or CAD(+), respectively). RESULTS: The patients in CAD(+) group had higher mean HbA1c level for 5 years than CAD(-) group (5.71+/ 0.40 vs. 5.86+/-0.68; P=0.04). Mean HbA1c was a significant predictor for CAD in multiple regression (odds ratio, 2.224; P=0.028). The percentage of patients with CAD was significantly higher in patients with >6.2% of mean HbA1c levels compared to patients with <6.2% of mean HbA1c levels (P<0.019). CONCLUSION: When the mean HbA1c levels were above 6.2%, the risk of CAD was higher. Also this study shows that HbA1c level can be one of the predictors for CAD even if the patients do not have diabetes. PMID- 24627830 TI - Statin Discontinuation after Achieving a Target Low Density Lipoprotein Cholesterol Level in Type 2 Diabetic Patients without Cardiovascular Disease: A Randomized Controlled Study. AB - BACKGROUND: This study investigated the rate of relapse of dyslipidemia and the factors which could predict relapse following a short-term statin discontinuation after achieving a target low density lipoprotein cholesterol (LDL-C) level in type 2 diabetic patients without cardiovascular disease (CVD). METHODS: Ninety nine subjects on rosuvastatin treatment and whose LDL-C level was lower than 100 mg/dL were randomly assigned to discontinue or maintain statin treatment at a 2:1 ratio. The subjects were followed-up after 10 weeks. A relapse of dyslipidemia was defined as a reascent of LDL-C level to greater than 100 mg/dL. RESULTS: The statin discontinuation group had a significant rate of relapse compared to the maintenance group (79% vs. 3%, respectively). Pretreatment and baseline lipid levels, their ratios, and hemoglobin A1c level were significantly different between the relapse and nonrelapse groups. The pretreatment and baseline lipid profiles and their ratios were independently associated with relapse. The pretreatment LDL-C level was the most useful parameter for predicting a relapse, with a cutoff of 123 mg/dL. During the follow-up period, no CVD event was noted. CONCLUSION: The relapse rate of dyslipidemia was high when statins were discontinued in type 2 diabetic patients without CVD. Statin discontinuation should be considered carefully based on the pretreatment lipid profiles of patients. PMID- 24627831 TI - Women are diagnosed with type 2 diabetes at higher body mass indices and older ages than men: Korea national health and nutrition examination survey 2007-2010. AB - BACKGROUND: Many epidemiologic studies have shown that women with type 2 diabetes have an increased risk of developing cardiovascular disease compared with men with diabetes. The aim of this study is to elucidate whether disparities of adiposity, age and insulin resistance (IR) at the time of diabetes diagnosis exist between women and men in the adult Korean population. METHODS: Data from The Korea National Health and Nutrition Examination Survey, performed in Korea from 2007 to 2010, were used. In the survey, anthropometric data and blood samples were obtained during a fasting state. IR and beta-cell function were calculated using the homeostasis model assessment (HOMA-IR and HOMA-beta, respectvely). RESULTS: The mean age of diabetes diagnosis was 58.5 years in women and was 55.1 years in men (P=0.015). The mean body mass index (BMI) of newly diagnosed diabetes subjects was 26.1 kg/m(2) in women and 25.0 kg/m(2) in men (P=0.001). The BMI was inversely related to age in both genders, and the higher BMI in women than men was consistent throughout all age groups divided by decade. The HOMA-IR in women with diabetes is higher than in men with diabetes (7.25+/ 0.77 vs. 5.20+/-0.32; P=0.012). CONCLUSION: Korean adult women are diagnosed with type 2 diabetes at higher BMI and older age than men and are more insulin resistant at the time of diabetes diagnosis. This may help explain why women with diabetes have an increased risk of developing cardiovascular disease after the diagnosis of diabetes, compared to men. PMID- 24627832 TI - Response: predicting mortality of critically ill patients by blood glucose levels (diabetes metab j 2013;37:385-90). PMID- 24627833 TI - Letter: subclinical hypothyroidism is independently associated with microalbuminuria in a cohort of prediabetic egyptian adults (diabetes metab j 2013;37:450-7). PMID- 24627834 TI - Response: subclinical hypothyroidism is independently associated with microalbuminuria in a cohort of prediabetic egyptian adults (diabetes metab j 2013;37:450-7). PMID- 24627835 TI - Type of intractable temporomandibular disorder and treatment protocols. PMID- 24627836 TI - Controlled release of nerve growth factor from heparin-conjugated fibrin gel within the nerve growth factor-delivering implant. AB - OBJECTIVES: Although nerve growth factor (NGF) could promote the functional regeneration of an injured peripheral nerve, it is very difficult for NGF to sustain the therapeutic dose in the defect due to its short half-life. In this study, we loaded the NGF-bound heparin-conjugated fibrin (HCF) gel in the NGF delivering implants and analyzed the time-dependent release of NGF and its bioactivity to evaluate the clinical effectiveness. MATERIALS AND METHODS: NGF solution was made of 1.0 mg of NGF and 1.0 mL of phosphate buffered saline (PBS). Experimental group A consisted of three implants, in which 0.25 uL of NGF solution, 0.75 uL of HCF, 1.0 uL of fibrinogen and 2.0 uL of thrombin was injected via apex hole with micropipette and gelated, were put into the centrifuge tube. Three implants of experimental group B were prepared with the mixture of 0.5 uL of NGF solution, 0.5 uL HCF, 1.0 uL of fibrinogen and 2.0 uL of thrombin. These six centrifuge tubes were filled with 1.0 mL of PBS and stirred in the water-filled beaker at 50 rpm. At 1, 3, 5, 7, 10, and 14 days, 1.0 mL of solution in each tubes was collected and preserved at -20C with adding same amount of fresh PBS. Enzyme-linked immunosorbent assay (ELISA) was done to determine in vitro release profile of NGF and its bioactivity was evaluated with neural differentiation of pheochromocytoma (PC12) cells. RESULTS: The average concentration of released NGF in the group A and B increased for the first 5 days and then gradually decreased. Almost all of NGF was released during 10 days. Released NGF from two groups could promote neural differentiation and neurite outgrowth of PC12 cells and these bioactivity was maintained over 14 days. CONCLUSION: Controlled release system using NGF-HCF gel via NGF-delivering implant could be an another vehicle of delivering NGF to promote the nerve regeneration of dental implant related nerve damage. PMID- 24627837 TI - Three-dimensional evaluation of lingual split line after bilateral sagittal split osteotomy in asymmetric prognathism. AB - OBJECTIVES: The aim of this study was to evaluate the pattern of lingual split line when performing a bilateral sagittal split osteotomy (BSSO) for asymmetric prognathism. This was accomplished with the use of cone-beam computed tomography (CBCT) and three-dimensional (3D) software program. MATERIALS AND METHODS: The study group was comprised of 40 patients (20 males and 20 females) with asymmetric prognathism, who underwent BSSO (80 splits; n=80) from January 2012 through June 2013. We observed the pattern of lingual split line using CBCT data and image analysis program. The deviated side was compared to the contralateral side in each patient. To analyze the contributing factors to the split pattern, we observed the position of the lateral cortical bone cut end and measured the thickness of the ramus that surrounds the mandibular lingula. RESULTS: The lingual split patterns were classified into. The true "Hunsuck" line was 60.00% (n=48), and the bad split was 7.50% (n=6). Ramal thickness surrounding the lingual was 5.55+/-1.07 mm (deviated) and 5.66+/-1.34 mm (contralateral) (P=0.409). The position of the lateral cortical bone cut end was classified into three types: A, lingual; B, inferior; C, buccal. Type A comprised 66.25% (n=53), Type B comprised 22.50% (n=18), and Type C comprised 11.25% (n=9). CONCLUSION: In asymmetric prognathism patients, there were no differences in the ramal thickness between the deviated side and the contralateral side. Furthermore, no differences were found in the lingual split pattern. The lingual split pattern correlated with the position of the lateral cortical bone cut end. In addition, the 3D-CT reformation was a useful tool for evaluating the surgical results of BSSO of the mandible. PMID- 24627838 TI - Survival rate of Astra Tech implants with maxillary sinus lift. AB - OBJECTIVES: The aim of this study was to retrospectively evaluate the clinical survival rate of Astra Tech implants in the maxillary molar region performed with sinus lift and bone graft. MATERIALS AND METHODS: Ninety-nine Astra Tech implants (Osseospeed) placed in the maxillary molar region using sinus lift from September 2009 to February 2012 were selected with a minimum follow-up period of 1 year. The height of alveolar bone, sinus approach technique, bone material and implant survival rate were evaluated. RESULTS: Of the 99 implants, the survival rate was 90.9%; 8 implants failed within 1 year after implant placement, and 1 implant failed 1 year after implant loading. All failed implants were placed with sinus lift simultaneously. The average height of alveolar bone before implant placement was 6.9 mm, while the height of alveolar bone of failed implants was 2.1 mm, on average. CONCLUSION: Astra Tech implants placed in the maxillary molar region had generally good survival rates, but the relationship between reduced pre-implant alveolar bone height and implant failure requires further attention. PMID- 24627839 TI - Retrospective clinical study of mandible fractures. AB - OBJECTIVES: The purpose of this article is to analyze the incidence, demographic distribution, type, and etiology of mandible fractures that were treated by the Department of Oral and Maxillofacial Surgery in Kyung Hee University Dental Hospital from January 2002 to December 2012. MATERIALS AND METHODS: This was a descriptive and analytic retrospective study that evaluated 735 patients that were treated for mandible fracture. RESULTS: This study included 1,172 fractures in 735 patients. The ratio of male to female patients was 5.45 : 1; the maximum value was in patients between 20 and 29 years (38.1%) and the minimum in patients over 70 years old. The monthly distribution of facial fractures peaked in the fall and was lower during winter. No specific correlation was identified based on the annual fracture distribution. Among the 735 fracture patients, 1.59 fracture lines were observed per patient. The most frequent site was the symphysis, which accounted for a total of 431 fractures, followed by the angle (348), condyle (279), and body (95). The symphysis with angle was the most common site identified in combination with fracture and accounted for 22.4%, followed by symphysis with condyle (19.8%). The angle was the most frequent site of single fractures (20.8%). The major cause of injury was accidental trauma (43.4%), which was followed by other causes such as violence (33.9%), sports-related accidents (10.5%), and traffic accidents (10.1%). Fracture incidents correlated with alcohol consumption were reported between 10.0%-26.9% annually. CONCLUSION: Although mandible fracture pattern is similar to the previous researches, there is some changes in the etiologic factors. PMID- 24627840 TI - Esthetic neck dissection using an endoscope via retroauricular incision: a report of two cases. AB - Various surgical techniques, such as endoscopic surgery and robotic surgery, are developed to optimize the esthetic outcome even in operations for malignancy. A modified face-lift or retroauricular approach are used to minimize postoperative scarring. Recently, robot-assisted surgery is being done in various fields and considered as favorable treatment method by many surgeons. However its high cost is a nonnegligible fraction for many patients. On the other hand, endoscopic surgery, which is cheaper than robotic surgery, is minimally invasive with contentable neck dissection. Although it is a difficult technique for a beginner surgeon due to its limited operation view, we suppose it as an alternative method for robotic surgery. Herein, we report two cases of endoscopic neck dissection via retroauricular incision with a discussion regarding the pros and cons of endoscopic neck dissection. PMID- 24627841 TI - Unilateral intraoral vertical ramus osteotomy based on preoperative three dimensional simulation surgery in a patient with facial asymmetry. AB - Preoperative surgical simulation in orthognathic surgery has progressed in recent years; the movement of the mandible can be anticipated through three-dimensional (3D) simulation surgery before the actual procedure. In this case report, the mandible was moved to the intended postoperative occlusion through preoperative surgical 3D simulation. Right-side condylar movement change was very slight in the surgical simulation, suggesting the possibility of mandibular surgery that included only left-side ramal osteotomy. This case report describes a patient with a mild asymmetric facial profile in which the mandibular menton had been deviated to the right and the lips canted down to the left. Before surgery, three dimensional surgical simulation was used to evaluate and confirm a position for the condyle as well as the symmetrical postoperative state of the face. Facial asymmetry was resolved with minimal surgical treatment through unilateral intraoral vertical ramus osteotomy on the left side of the mandible. It would be a valuable complement for the reduction of the surgical treatment if one could decide with good predictability when an isolated intraoral vertical ramus osteotomy can be done without a compensatory osteotomy on the contralateral side. PMID- 24627842 TI - Familial tooth bone graft for ridge and sinus augmentation: a report of two cases. AB - Recently, clinical application of autogenous tooth bone-graft materials has been reported. Autogenous tooth bone graft has been used in implant surgery. Familial tooth bone graft is a more advanced procedure than autogenous teeth bone graft in that extracted teeth can be used for bone graft materials of implant and teeth donation between siblings is possible. We used autogenous tooth and familial tooth bone-graft materials for ridge augmentation and sinus bone graft and obtained satisfactory results. The cases are presented herein. PMID- 24627843 TI - Eagle's syndrome: a case report. AB - Eagle's syndrome is a disease caused by an elongated styloid process or calcified stylohyoid ligament. Eagle defined the disorder in 1937 by describing clinical findings related to an elongated styloid process, which is one of the numerous causes of pain in the craniofacial and cervical region. The prevalence of individuals with this anatomic abnormality in the adult population is estimated to be 4% with 0.16% of these individuals reported to be symptomatic. Eagle's syndrome is usually characterized by neck, throat, or ear pain; pharyngeal foreign body sensation; dysphagia; pain upon head movement; and headache. The diagnosis of Eagle's syndrome must be made in association with data from the clinical history, physical examination, and imaging studies. Patients with increased symptom severity require surgical excision of the styloid process, which can be performed through an intraoral or an extraoral approach. Here, we report a rare case of stylohyoid ligament bilaterally elongated to more than 60 mm in a 51-year-old female. We did a surgery by extraoral approach and patient's symptom was improved. PMID- 24627844 TI - Prevalence of genitalia malformation in Iranian children: findings of a nationwide screening survey at school entry. AB - BACKGROUND: Ambiguous genitalia is a hereditary disorder that usually requires early attention and detection. The discovery of ambiguous genitalia in a neonate is situation that could be difficult to manage, not only because of complications such as salt-losing, but also due to the importance of sex determination before psychological gender could be established. Awareness of the prevalence of ambiguous genitalia can affect the attitude and consideration of physicians and related medical personnel about disease in different communities. So in this study, the prevalence of ambiguous genitalia and undescended testes (UDT) in Iran was reported. MATERIALS AND METHODS: This national study was conducted in 2009 2010 as part of the routine screening examinations at school entry in Iran. The physical examinations were performed for students at entry to three school levels by physicians and medical personnel. Execution and conduction of this program was the duty of the University of Medical Sciences in each province. RESULTS: On average, the prevalence of ambiguous genitalia was 0.04% at national level (0.03%, 0.05%, and 0.03% at 6, 12, and 15 year olds, respectively). The prevalence of ambiguous genitalia was not significantly different according to age group and living area. The average of UDT) prevalence in the whole country was 0.13%. The prevalence of UDT was higher at elementary school level than in the other two levels. CONCLUSION: Although the prevalence of genitalia abnormalities was not high in the school students in Iran, given the importance of the issue and in order to find the ambiguous genitalia or UDT, medical examinations and parental notification should be taken seriously at an earlier age. PMID- 24627845 TI - Comparative evaluation of hemodynamic and respiratory parameters during mechanical ventilation with two tidal volumes calculated by demi-span based height and measured height in normal lungs. AB - BACKGROUND: Appropriate determination of tidal volume (VT) is important for preventing ventilation induced lung injury. We compared hemodynamic and respiratory parameters in two conditions of receiving VTs calculated by using body weight (BW), which was estimated by measured height (HBW) or demi-span based body weight (DBW). MATERIALS AND METHODS: This controlled-trial was conducted in St. Alzahra Hospital in 2009 on American Society of Anesthesiologists (ASA) I and II, 18-65-years-old patients. Standing height and weight were measured and then height was calculated using demi-span method. BW and VT were calculated with acute respiratory distress syndrome-net formula. Patients were randomized and then crossed to receive ventilation with both calculated VTs for 20 min. Hemodynamic and respiratory parameters were analyzed with SPSS version 20.0 using univariate and multivariate analyses. RESULTS: Forty nine patients were studied. Demi-span based body weight and thus VT (DTV) were lower than Height based body weight and VT (HTV) (P = 0.028), in male patients (P = 0.005). Difference was observed in peak airway pressure (PAP) and airway resistance (AR) changes with higher PAP and AR at 20 min after receiving HTV compared with DTV. CONCLUSIONS: Estimated VT based on measured height is higher than that based on demi-span and this difference exists only in females, and this higher VT results higher airway pressures during mechanical ventilation. PMID- 24627846 TI - Cytotoxicity of different extracts of arial parts of Ziziphus spina-christi on Hela and MDA-MB-468 tumor cells. AB - BACKGROUND: It has been shown that plants from the family Rhamnaceae possess anticancer activity. In this study, we sought to determine if Ziziphus spina christi, a species from this family, has cytotoxic effect on cancer cell lines. MATERIALS AND METHODS: Using maceration method, different extracts of leaves of Z. spina-christi were prepared. Hexane, chloroform, chloroform-methanol (9:1), methanol-water (7:1) methanol, butanol and water were used for extraction, after preliminary phytochemical analyses were done. The cytotoxic activity of the extracts against Hela and MDA-MB-468 tumor cells was evaluated by MTT assay. Briefly, cells were seeded in microplates and different concentrations of extracts were added. After incubation of cells for 72 h, their viability was evaluated by addition of tetrazolium salt solution. After 3 h medium was aspirated, dimethyl sulfoxide was added and absorbance was determined at 540 nm with an ELISA plate reader. Extracts were considered cytotoxic when more than 50% reduction on cell survival was observed. RESULTS: Hexane, chloroform, chloroform methanol, butanol, methanol-water and aqueous extracts of Z. spina-christi significantly and concentration-dependently reduced viability of Hela and MAD-MB 468 cells. In the both cell lines, chloroform-methanol extract of Z. spina christi was more potent than the other extracts. RESULTS: From the finding of this study it can be concluded that Z. spina-christi is a good candidate for further study for new cytotoxic agents. PMID- 24627847 TI - A case of sine scleroderma with parenchymal lung disease. AB - Systemic sclerosis sine scleroderma is a subtype of scleroderma, which is characterized by involvement of visceral organs, but no characteristic skin alteration. The involved organs could be kidneys, heart, gastrointestinal system, and lungs. Interstitial lung disease (ILD) is one of the pulmonary manifestations of sine scleroderma. We report a 38-year-old woman presenting with chill, fever, generalized malaise, dyspnea on exertion, and dry cough with a history of Raynaud's phenomenon, who was evaluated by physical examination, spirometry, and computed tomography scan, that all lead to the diagnosis of ILD. Combination of high-titer positive anti-nuclear antibody, high erythrocyte sedimentation rate, positive C-reactive protein, and ILD could be explained by sine scleroderma. PMID- 24627848 TI - The evaluation of toxicity of carbon nanotubes on the human adipose-derived-stem cells in-vitro. AB - BACKGROUND: Carbon nanotubes (CNTs) have a large variety of applications in tissue engineering and biomedical devices. The biocompatibility and cytotoxicity of CNTs have been studied widely, however, up until now; there was uncertainty on how nanosized materials behave in the human body and stem cells. The current study describes the functionalized carbon nanotubes on adipose-derived stem cells (ADSCs) for viability and proliferation purposes in vitro. MATERIALS AND METHODS: After chemical modification of the CNTs, the ADSCs were cultured in Dulbecco's Modified Eagle's. Medium (DMEM) having doses of 0.1, 1, 10, 20, 50, and 100 MUg/ml of CNTs. On the third and seventh days of the experiment, the cellular viability, proliferation, and stemness were determined, using the MTT, trypan Blue, and flow cytometry assays in variable CNTs dosage. RESULTS: In doses of 0.1 and 1 MUg/ml, the expression of the surface markers were similar to the control groups on day three, but decreased in higher dosages on day seven. The viability of both groups was the same on day three, but in comparison to the control groups, was found to decrease in the higher dosages on day seven. CONCLUSION: The effect of CNTs on the viability and proliferation of ADSCs is a function of time and the doses used. Through further investigation by using these particles, we expect that we should be able to increase the viability and proliferation of ADSCs. PMID- 24627849 TI - In silico study of ligand binding site of toll-like receptor 5. AB - BACKGROUND: Toll-like receptor-5 (TLR-5) is a member of TLRs family and responsible for bacterial flagellin recognition. The activation of TLR-5 with flagellin leads to initiation of signaling cascades, which in turn results in transcription of pro-inflammatory cytokines. Regarding the critical role of TLR-5 agonists and antagonists in activation of innate immune responses, an increasing number of studies have focused on their therapeutic applications in drug and vaccine design. In this study, to identify the most critical region and residues of TLR-5 for interaction with flagellin, different truncated forms of TLR-5 were designed and subjected to protein-protein interaction studies. MATERIALS AND METHODS: The interactions of the full native TLR-5 and its truncated forms with bacterial flagellin (FliC) were evaluated using Hex docking server and molecular interaction analysis was performed using Dimplot analysis. RESULTS: According to our in silico results, truncated form C (an amino acid sequence containing residues 174-401 of TLR-5) has the most suitable interaction with FliC and seven amino acids within this region were found to be crucial for the interaction with flagellin. CONCLUSIONS: These results provide new insights in to potential drug target sites of TLR-5, which may guide future TLR-5 targeting studies. PMID- 24627851 TI - Study of the association between blood types and breast cancer among Isfahanian women with breast cancer. AB - BACKGROUND: Previous studies suggest a possible association between ABO blood group and the risk of breast cancer. The aim of this study is to investigate the presence of a possible association between breast cancer and blood groups ABO and Rh. MATERIALS AND METHODS: 549 women including 173 cases and 376 controls were selected. The case group included patients with breast cancer and the cancer diagnosis was confirmed for all of them. The control group included women with no reports of breast cancer. Blood group sampling of all cases was performed. The obtained information regarding presence or absence of cancer, blood type, age group and type of cancer were analyzed. RESULTS: There is no significant association between blood types ABO (Rh) and the breast cancer. (P > 0.05) It has been found that the prevalence of invasive intraductal carcinoma was 85% among the cases. About 5% of the total diagnosed cancers in the case group were allocated to modularly carcinoma, invasive lobular carcinoma and Paget's disease. There was no relative frequency in specific blood group for these three types of cancer. The blood types ABO (Rh) and breast cancer type showed no significant relation (P = 0.2). CONCLUSION: According to the obtained results from this study, there was no relative frequency in specific blood group for these three types of cancer and the blood type could not be influenced as a risk factor in breast cancer. PMID- 24627850 TI - The effect of vitamin E on neuronal apoptosis in hippocampal dentate gyrus in rabbits fed with high-cholesterol diets. AB - BACKGROUND: Hypercholesterolemia that can increase stress oxidative has destructive effects on brain functions. Vitamin E is a powerful antioxidant and its effects on decrement of oxidative stress in the diseases such as Alzheimer's and hypercholesterolemia are demonstrated. The aim of this study was evaluation of the effects of vitamin E on the level of neuronal apoptosis in granular layer of dentate gyrus in the rabbits that fed with high-cholesterol diet. MATERIALS AND METHODS: Male New Zealand white rabbits were divided into the control, the Vitamin E (50 mg/kg; gavage), the high-cholesterol diet (containing 2% cholesterol), and the high-cholesterol diet-vitamin E groups. Serum levels of cholesterol, LDL, and HDL, before and after the regimen for 6 weeks, were measured. Then, the rabbits for immunohistochemical staining (TUNEL Test) and evaluation of neuronal apoptosis in dentate gyrus of hippocampal formation were anesthetized and brains were dissected. RESULTS: Results showed that after the regimens, serum levels of cholesterol, LDL, and HDL in the cholesterol receiving groups were increased significantly (P < 0.05). Histological results demonstrated that neuronal apoptosis in the dentate gyrus of the high-cholesterol diet group was increased significantly (P < 0.05) comparing to the control group; however, vitamin E decreased apoptosis as there wasn't any significant differences between the high-cholesterol diet-vitamin E and control groups. CONCLUSIONS: Present results showed that consumption of high-cholesterol diets through hypercholesterolemia and its complication can induce neuronal death in hippocampus and probable resulting cognition disorders; however, vitamin E has neuroprotective effects and prevents neuronal apoptosis significantly. PMID- 24627852 TI - Correlation between workplace and occupational burnout syndrome in nurses. AB - BACKGROUND: This study was conducted to determine the effect of nurses' workplace on burnout syndrome among nurses working in Isfahan's Alzahra Hospital as a reference and typical university affiliated hospital, in 2010. MATERIALS AND METHODS: In this cross-sectional study, 100 nurses were randomly selected among those working in emergency, orthopedic, dialysis wards and intensive care unit (ICU). Required data on determination of occupational burnout rate among the nurses of these wards were collected using Maslach Burnout Inventory (MBI) standard and validated questionnaire. Nurses were selected using simple random sampling. RESULTS: The multivariate ANOVA analysis showed that occupational burnout mean values of nurses working in orthopedic and dialysis wards were significantly less than those of nurses working in emergency ward and ICU (P = 0.01). There was also no significant difference between occupational burnout mean values of nurses working in emergency ward and ICU (P > 0.05). t-test showed that there was a difference between occupational burnout values of men and women, as these values for women were higher than those of men (P = 0.001). CONCLUSION: Results showed that occupational burnout mean values of nurses working in emergency ward and ICU were significantly more than those of nurses working in orthopedic and dialysis wards. PMID- 24627853 TI - Adding metoclopramide to lidocaine for intravenous regional anesthesia in trauma patients. AB - BACKGROUND: Metoclopromide have local anesthetic properties. The main object of performing the present study was to evaluate the analgesic effect of metoclopromide 10 mg when added to lidocaine for intravenous regional anesthesia (IVRA) of upper extremities in trauma patients. MATERIALS AND METHODS: Ninety patients undergoing upper limb producer were randomly allocated to the three groups to receive 3 mg/kg 2% lidocaine diluted with saline to a total dose of 40 ml (Group L, n = 30) or 10 mg metoclopromide plus 3 mg/kg 2% lidocaine diluted with saline to a total dose of 40 ml (group LM, n = 30) or 3 mg/kg 2% lidocaine diluted with saline to a total dose of 40 ml plus 10 mg metoclopromide intravenously (Group IM, n = 30). RESULTS: Our study showed that the onset times for sensory and motor block were significantly shorter in Group LM compared with Group L and Group IM (4.5 +/- 0.7 vs. 5.0 +/- 0.7 and 5.0 +/- 0.6, respectively, P = 0.006 for sensory block; 6.3 +/- 0.7 vs. 5.1 +/- 0.9 and 5.9 +/- 0.6 respectively, P = 0.000 for motor block). The postoperative VAS scores were significantly less at 1, 5, 10, 15, and 30 minutes after tourniquet release in Group LM compared with Group L and Group IM (P < 0.05). CONCLUSION: The results of our study showed that adding 10 mg metoclopromide to lidocaine for IVRG in trauma patients reduced intraoperative and postoperative analgesic use till 24 hours and improve quality of anesthesia. PMID- 24627854 TI - Supraglottic paraganglioma originated from superior laryngeal nerve. AB - Neurogenic tumors, especially paraganglioma of larynx, are rare. In this article, we present a 64-year-old woman who complained of intermittent dysphagia to solid foods. Further evaluation revealed a supraglottic paraganglioma and she was treated successfully by total excision of tumor. PMID- 24627855 TI - Glycemic index, glycemic load and childhood obesity: A systematic review. AB - BACKGROUND: Several evidences have been reported so far in terms of the relationship between obesity and glycemic index and glycemic load in children. However, the number of review studies that have dealt with recent findings is quite low. The purpose of present study is to review the existing evidences in this regard. MATERIALS AND METHODS: FIRST OF ALL, THE PHRASES: "Glycaemic index", "Glycaemic load", "Glycemic index" OR "Glycemic load" accompanied by one of the words: "Adolescent", "Young", "Youth" "Children" OR "Child" were searched in texts of articles existing in ISI and PUBMED databases which were obtained out of 1001 articles. Among these, some articles, which reviewed the relationship of obesity with glycemic index and glycemic load, were selected. Finally, 20 articles were studied in current review study. RESULTS: The majority of cross sectional studies have found children's obesity directly linked with glycemic index and glycemic load; however, cohort studies found controversial results. Also, the intervention studies indicate the negative effect of glycemic index and glycemic load on obesity in children. CONCLUSION: Published evidences reported inconsistent results. It seems that existing studies are not sufficient and more studies are needed in this regard. PMID- 24627857 TI - Risks of concomitant trauma to the knee in lower limb long bone shaft fractures: A retrospective analysis from a prospective study population. AB - BACKGROUND: Numerous associated injuries (bony and/or soft tissue lesions) occur commonly in conjunction with fractures of the femoral shaft in young patients after high-energy injuries. Knee ligamentous injuries, historically called as the internal derangements of the knee or IDK, are mostly not visible in plain radiographs taken in the emergency and these injuries are likely to be overlooked by clinicians because first attention always goes to open wounds and radiologically visible injuries of the limb whenever a patient is received in a trauma unit. MATERIALS AND METHODS: A total of 93 cases of lower limb long bone fractures were retrospectively analyzed from materials of a prospective study conducted on consecutive patients having high-velocity injuries to lower limb long bones with a view to confirm or rule out concomitant ipsilateral IDK in cases of femoral and tibial shaft fractures, that already employed a policy of focused clinical examination followed by arthroscopy of the ipsilateral knee, immediately after operative fracture fixation under the same anesthesia. The goal was to determine the incidence of concomitant internal derangement of the ipsilateral knee and to understand any value of adding arthroscopy to detect concomitant IDK in lower limb long bone fractures besides careful intraoperative examination to propose a recommendation thereof. RESULTS: Concomitant knee injury was found in 14 femoral fractures and 1 tibial fracture. Fifteen out of 93 (16%) such cases had concomitant knee ligamentous or meniscal injures. A total of 13 anterior cruciate and 4 posterior cruciate tears, 11 collateral ligament tears, and 10 meniscal injuries were confirmed in these 15 knees. Femoral shaft fractures were associated with a high incidence of serious ligamentous, meniscal, and chondral injury. Twelve out of 41 femoral fractures had chondral injuries (contusion), especially of the patello-femoral articulation, identifiable during arthroscopy. CONCLUSION: One should have high index of suspicion about internal knee injuries and capsule-ligamentous injuries while dealing with femoral shaft fractures in particular. Arthroscopy of knee may safely enhance the diagnosis of simultaneous IDK. We propose that when MR imaging is not possible and when contraindication for arthroscopy does not exist, a careful clinical examination followed by arthroscopy of the knee may be considered a useful adjunct in femoral shaft fractures as it can readily confirm IDK by its ability to objectively look, probe, and distinguish fragile tissue from a normal one. Further study in larger number of subjects is needed to validate our findings. PMID- 24627856 TI - Prevalence of Helicobacter pylori vacA different genotypes in Isfahan, Iran. AB - BACKGROUND: It is believed that the Helicobacter pylori (H. pylori) vacA gene, as a major virulence determinant (One of the major virulence determinant, not major), may be a risk factor for the development of gastroduodenal diseases. The frequency of vacA genotypes varies in different human populations. This study evaluated the prevalence of vacA alleles/genotypes among dyspeptic patients in Isfahan. MATERIALS AND METHODS: One-hundred H. pylori-positive adult patients were examined in this study. After culture of gastric biopsies and DNA extraction from individual H. pylori isolates, the (all H. pylori strains harbor vacA alleles, please replace "presence" with "genotypes") of the vacA s and m alleles were determined using polymerase chain reaction (PCR). RESULTS: There were four vacA mosaicisms, including 28 for s1a/m1 (28%), 23 for s1b/m1 (23%), 26 for s1a/m2 (26%) and 23 for s1b/m2 (23%). The s2 allele was not found. The predominant vacA genotype in patients with non-ulcer dyspepsia and duodenal ulcer was s1a/m2, whereas in patients with adenocarcinoma was s1a/m1. CONCLUSION: The results showed there was no significant correlation between different genotypes of the vacA and the clinical outcomes and appears to vacA genotypes were not useful determinants for gastrointestinal diseases in our area. PMID- 24627858 TI - Medical academia clinical experiences of Ward Round Teaching curriculum. AB - BACKGROUND: Medical students spend most of their time in hospital wards and it is necessary to study clinical educational opportunities. This study was aimed to explore faculty members' experience on Ward Round Teaching content. METHODS AND MATERIALS: This qualitative study was conducted by purposive sampling with the maximum variation of major clinical departments faculty members in Isfahan University of Medical Sciences (n = 9). Data gathering was based on deep and semi structured interviews. Data gathering continued till data saturation. Data was analyzed through the Collaizzi method and validated. Strategies to ensure trustworthiness of data (credibility, dependability, conformability, transferability) were employed (Guba and Lincoln). RESULTS: Basic codes extracted from the analyzed data were categorized into two main themes and related subthemes, including (1) tangible teachings (analytic intelligence, technical intelligence, legal duties) and (2) implied teachings (professionalism, professional discipline, professional difficulties). CONCLUSION: Ward round teaching is a valuable opportunity for learners to learn not only patient care aspects but also ethical values. By appropriate planning, opportunities can be used to teach capabilities that are expected of general practitioners. PMID- 24627859 TI - Some anatomical variation of paranasal sinuses using sinus endoscopic approach on "cadaver" in Isfahan, Iran. AB - BACKGROUND: Due to the anatomical variations of the paranasal sinuses and its great importance in sinus surgery, as this area is in very close proximity to vital structures including the optic nerve, carotid artery, and skull base, anatomical knowledge of this area is of high importance. The purpose of this study is defining a full and clear impression of paranasal sinus anatomy and its variations as a model for the human population of the country. MATERIALS AND METHODS: This study was conducted on 45 cadavers in Isfahan forensic Medicine center during 2010 to 2011. Nasal and paranasal sinuses endoscopic dissection was done with (zero and 30 degrees ) lenses (Olympus). The methods of performed dissection were via the Stamberger technique. RESULTS: This study showed that 88.9% (40 cases) of middle turbinates were in a typical form, while 6.7% (3 cases) were in medial and only 4.4% (2 cases) were in the lateral form. We also observed 88.9% (40 cases) with Agger nasi cells, 37.8% (17 cases) with Onodi cells, 28.9% cases with accessory Ostia of maxillary sinus (13 cases), and 15.6% of the cases (7 cases) with concha bullosa. The position of the maxillary sinus ostium was as follows. The inferior 1/3 of hiatus semilunaris in 38 (84.5%), superior 1/3 of hiatus semilunaris in 4 (4.4%), middle 1/3 of hiatus semilunaris in 5 (11.1%). The sphenoid ostia in 53.3% (24 cases) were slit shape, 28.9% (13 cases) oval, and 17.8% (18 cases) were round shape. CONCLUSION: Our survey showed that the distance between anterior nasal spine and anterior wall of the sphenoid sinus was within 7.6 +/- 0.2 cm SD. PMID- 24627860 TI - The comparison between proton pump inhibitors and sucralfate in incidence of ventilator associated pneumonia in critically ill patients. AB - BACKGROUND: Ventilator associated pneumonia (VAP) are one of the most common nosocomial infections in intensive care unit (ICU). The ICU patients are at risk of stress ulcer and gastrointestinal bleeding for different reasons. In order to prevent this complication, anti acids are used for patients. This study compared pantoprazole with sucralfate in incidence of ventilator associated pneumonia. MATERIALS AND METHODS: This randomized clinical trial was carried out on ICU patients with mechanical ventilation in Alzahra university hospital in Isfahan from 2010 to 2011. One hundred forty eight ventilated patients were randomly allocated in two groups. The first group was treated with sucralfate and the second group was treated with pantoprazole for stress ulcer prophylaxis and followed up during hospitalization in ICU for nosocomial pneumonia. Data analyzed by SPSS software. RESULTS: One hundred thirty seven patients were selected for study. During the study period, 34 cases (24.8%) acquired pneumonia, of which 10 were in the sucralfate group and 24 were in the pantoprazole group (14.1% vs. 36.4%). According to Chi-square test, rate of pneumonia was significantly lower in patients receiving sucralfate than the pantoprazole group (P < 0.001). CONCLUSION: On the basis of the results, there is a significant relationship between the kind of drug used for stress ulcer and ventilator associated pneumonia. According to this article, rate of pneumonia was significantly lower in patients receiving sucralfate than the pantoprazole group. PMID- 24627861 TI - The evaluations of frequency distribution heparin resistance during coronary artery bypass graft. AB - BACKGROUND: Heparin is one of the most important medication that is used in coronary artery bypass graft (CABG) operations, but some patients demonstrate heparin resistance (HR) during CABG. Heparin resistance was defined as at least one activated clothing time <400 seconds after heparinization and/or the need for purified antithrombin III (AT-III) administration. The goal of this study was the investigation of HR prevalence in our country and relation between HR and post operative CABG complications. MATERIALS AND METHODS: One hundred patients that candidate for CABG were selected and surveyed for HR and complications. The data entered to computer and analyzed by SPSS soft ware. The Chi-square and student t tests were used for data analysis. RESULTS: The prevalence of heparin resistance in our study was 3%. There was no relation among bleeding, cardiac arrest and HR. Bleeding happened in 13 patients of which 1 person was in HR group (33.3%) and 12 in non HR group (12.4%) (P = 0.34). Cardiac arrest happened in 8 patients, 1 person was in HR group (33.3%) and 7 in non HR group (7.2%) (P = 0.22). According our data there were no relation among HR and gender and ventilator dependency time. CONCLUSIONS: HR is a nearly prevalent complication among patients that undergone CABG that may led to some complications such as bleeding and cardiac arrest. In our study, we did not find significant relation among them, but in frequency these complications were higher in HR group. PMID- 24627862 TI - Assessment of TGF-beta3 on production of aggrecan by human articular chondrocytes in pellet culture system. AB - BACKGROUND: The Autologous Chondrocytes Transplantation (ACT) method is being studied for repair of cartilage diseases. As the chondrocytes dedifferentiated during monolayer culture, three-dimensional cultures are suggested to redifferentiate them. The aim of this study was investigation of the effect of TGF-beta3 growth factor on chondrocytes in pellet culture system. MATERIALS AND METHODS: The chondrocytes were isolated from three human articular cartilages by enzymatic digestion. The cells of the second passage were transferred to pellet culture system. We determined the chondrogenic medium with TGF-beta3 as the experimental group and without it as the control group. After 2 weeks, the aggrecan production was investigated using histological and immunohistochemical (IHC) methods. RESULTS: The presence of glycosaminoglycans was proved through Toluiden blue staining. Comparison of IHC results using MATLAB software showed that aggrecan in the experimental group was significantly higher than in the control group (P <= 0.05). CONCLUSION: The presence of TGF-beta3 in the chondrogenic medium could lead to the production of more aggrecan in chondrocytes cultivated in pellet culture system. PMID- 24627863 TI - Gestational throphoblastic diseases in North East of Iran: 10 years (2001-2010) prospective epidemiological and clinicopathological study. AB - BACKGROUND: Many aspects of epidemiological and clinicopathological features of gestational trophoblastic disease (GTD), one of the important subject in gynecology oncology, needs to be defined so as to recommend the best approach and management toward it. In the present study, we evaluated 10-years incidence of throphoblastic diseases in north east of Iran in prospective epidemiological and clinicopathological study. MATERIALS AND METHODS: We reviewed the registered histopathology database archive (120 records) related to throphoblastic diseases of the Ghaem Hospital, Mashhad University of Medical Sciences from 2001 to 2010. RESULTS: Evaluation of the pathological reports revealed 5 (4.2%) choriocarcinom and 115 (95.8%) of hydatidiform mole (HM), with complete and partial HM diagnosis in 29 (25.2%) and 86 (74.8%) patients, respectively. The pregnancy rate of HM patients (2.72 +/- 1.86) and choriocarcinoma patients (3.56 +/- 2.8) was not significantly different (P = 0.61). There was no statistical significant difference between the number of pregnancies in HM (2.90 +/- 3.13) and choriocarcinoma (3.84 +/- 3.80) patients (P = 0.46). The ratio of complete to partial mole increased with age, although this correlation was not significant. Most patients in both the groups had no history of abortion. O positive was the predominant blood group among the studied patients. CONCLUSION: Throphoblastic diseases occur during the fertility age mostly, and there is an increased risk with more previous pregnancies; ultrasound sonography is a useful method for primary diagnosis of this disease. Further pathological studies are needed to define the mole type. PMID- 24627864 TI - Comparison of tympanic membrane grafting medial or lateral to malleus handle. AB - BACKGROUND: To compare two methods of tympanic membrane (TM) grafting when graft materials medial or lateral to malleus, this study have been done. MATERIALS AND METHODS: In this clinical trial which was conducted in Alzahra and Kashani hospitals, between June 2010 and February 2012, 56 patients with chronic otitis media and perforated TM entered the study in two groups. The inclusion criteria consisted of patients who were at least 15-years-old without history of smoking, diabetes mellitus or autoimmune disease. Exclusion criteria of the study: No compliance for follow up, post-surgical ear trauma or any infective pathology that directly affects the ear. In Group A patients, the graft material is pierced in near central part of the graft and they lodged so that the malleus handle projects through the graft perforation. Group B had grafting in the lateral side of the malleus. Three month after surgery both groups examined and tested by audiometry. Success of surgery is defined as complete repair of TM, without lateralization, atelectasis, blunting or retraction pocket. RESULTS: This study contained 28 patients in Group A and 28 in Group B. Overall success rate was 94.64% that was 96.42% in Group A, and 92.85% in Group B. Differences of air-bone gap in each group before and after surgery was 16.10 (+/-4.89) in Group A, and 15.78 (+/-3.40) in Group B. Improvement of hearing level was not significant between two surgical methods (P = 0.442). CONCLUSIONS: Both techniques (medial and lateral to malleus handle) of TM grafting are effective with success rates 96.42% and 92.85% respectively. PMID- 24627865 TI - Identification and cloning of putative water clarification genes of Moringa peregrina (Forssk.) Fiori in E. coli Xl1 blue cells. AB - BACKGROUND: Water purification processes include the use of chemical compounds despite the concern that they may induce diseases. An ecological solution to this dilemma can come from the use of plant seeds for this purpose. Moringa peregrina (Forssk.) Fiori seeds have water clarification ability. Therefore, the aim of this work was to look for certain water clarification genes in M. peregrina. MATERIALS AND METHODS: After preparation of M. peregrina callus, mRNA was extracted from these cells. After application of reverse transcriptase, the obtained cDNA (s) were used for PCR amplification of the desired genes using primers based on MO2.1 gene of Moringa oleifera. DNA amplification products were cloned in E. coli Xl1 blue cells and DNA sequences were compared with Mo1,2 gene in M. oleifera. RESULTS: We obtained 3 PCR products (approximately 200, 300, and 400 bps). CONCLUSION: After comparison of the sequences of 300bp band obtained from M. peregrina with Mo1,2 gene in M. oleifera, it seems that 300bp band is a good candidate to investigate regarding its potential flocculent activity. PMID- 24627866 TI - Nutritional status in patients with ulcerative colitis in Isfahan, Iran. AB - BACKGROUND: Malnutrition is common among patients with inflammatory bowel disease. The present study aimed to investigate the nutritional status of ulcerative colitis (UC) patients in Isfahan, Iran. MATERIALS AND METHODS: In this descriptive analytical cross-sectional study, between Dec 2011 and Jun 2012, 99 patients with UC were randomly selected and evaluated. Age, sex, duration of disease, body mass index (BMI) and laboratory parameters recorded for all patients. Nutritional risk index (NRI) was calculated and its association with patients' variables was assessed with regard to UC disease severity. RESULTS: Twelve patients out of 99 patients had mild UC and 87 patients had moderate to severe UC. Based on the NRI, 90.9% were not malnourished and 9.1% were at moderate to severe risk for malnutrition. Among laboratory parameters only, serum potassium level in patients with moderate to severe UC was significantly higher than those with mild UC (P = 0.017). Other laboratory parameters were similar between patients stratified by US status. Patients age s significantly correlate with serum vitamin D, immunoglobulin a (IgA) and potassium level (P > 0.05), also duration of disease was significantly correlate with Phosphorus (P = 0.024) among laboratory parameters. CONCLUSION: In studied UC patients, malnutrition risk was based on degree of disease severity. Patients with moderate to severe UC were more at risk for malnutrition compared to the patients with mild UC. Furthermore, among laboratory parameters only serum potassium level was higher among patients with moderate to severe UC compared to others. PMID- 24627867 TI - Prevalence of hippocampal morphologic variants between healthy elderly subjects and patients with Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with atrophic changes in the temporal lobe. Enlargement of cerebrospinal fluid (CSF) spaces, hippocampal sulcus (HS) enlargement, or an increase in the number or size of hippocampal cavities (HCs) could be associated with medial temporal lobe atrophy (MTA). In this study, we assessed the relation of these CSF spaces with AD. MATERIALS AND METHODS: A total 36 demented patients with diagnosis of Alzheimer (Mini-Mental State Examination (MMSE) <=25) and 36 non-demented elderly individuals were referred for basic magnetic resonance imaging (MRI) before initiating anti-dementia therapy in the demented group. Two observers assessed the maximal HS width, as well as the occurrence, number, and size of HCs, and the visual rating score of MTA on magnified coronal high-resolution T1-weighted MR images. RESULTS: The findings of our study indicate that the presence of hippocampal cavity (HC) (especially in the left side) and medial temporal lobe atrophy in demented patients was significantly higher in comparison with non demented elderly subjects (P <= 0.05). There was a significant relationship between MTA and HS width (P = 0.003, r = 0.00323), and it also had a trend to be significant with size of HCs (P = 0.08, r = 0.00314). A correlation between MTA and number of HCs was not detected. CONCLUSION: HS width is associated with MTA in patients with AD. It may serve as a measure to evaluate MTA for identifying individuals at particularly high risk for Alzheimer progression, and could be employed for selecting subjects for clinical trials or for treatment decisions. PMID- 24627868 TI - Factors influencing left ventricular hypertrophy in children and adolescents with or without family history of premature myocardial infarction. AB - BACKGROUND: Cardiovascular diseases are the highest ranking cause of mortality. The prevalence of cardiovascular diseases is increasing among people in developed and developing countries. Since left ventricular hypertrophy is one of the risk factors leading to extremely dangerous heart diseases and even sudden death at early ages, investigating its contributing factors can be beneficial. The purpose of this study was to determine factors contributing to left ventricular hypertrophy in students aged 7-18 years in Isfahan. Statistical population of this case-control study was the 7-18 year old students in Isfahan, who were studied in two groups of children with premature myocardial infarction in their parents and the control group. MATERIALS AND METHODS: After determining the sample size of 138 people, a two-part questionnaire was designed and demographic characteristics and anthropometric measures were recorded in students' profiles. The obtained information was analyzed using SPSS15 software and logistic regression model and the results were reported at P < 0.05. RESULT: The results showed that among the studied variables, gender, age, body mass index, and blood pressure were associated with the left ventricular hypertrophy. CONCLUSION: Considering the results and previous studies in this field, it was observed that left ventricular hypertrophy exists at early ages, which is very dangerous and can lead to heart diseases at early ages. Factors such as being overweight, having high blood pressure, and being male cause left ventricular hypertrophy and lead to undiagnosable heart diseases. PMID- 24627869 TI - Inhibition of microRNA miR-92a induces apoptosis and necrosis in human acute promyelocytic leukemia. AB - BACKGROUND: MicroRNAs (miRNAs) are endogenous non-coding RNAs, 19-25 nucleotides in length, involved in post-transcriptional regulation of gene expression in a considerable majority of mRNAs. Different aspects of cellular activities like cell growth, proliferation, and differentiation are regulated by miRNAs through their regulatory effects on particular RNA species. In many tumors, up- or down regulation of different miRNAs has been reported. In acute myeloid leukemia, up regulation of miR-92a has been reported in human in-vitro studies. MATERIALS AND METHODS: We performed inhibition of miR-92a in an acute promyelocytic leukemia cell line (HL-60), using locked nucleic acid (LNA) Antagomir. At different time points after LNA-anti-miR92a transfection, qRT-Real-Time-polymerase chain reaction (PCR) and Annexin-V/Propidium Iodide staining were performed and the data was analyzed using the Kruskal-Wallis and Mann-Whitney tests. RESULTS: The assessment of the apoptosis and necrosis indicates that miR-92a inhibition can decrease the viable HL-60 cells and this is at least partially due to induction of apoptosis. CONCLUSION: These findings suggest the inhibition of miR-92a as a novel approach for treatment of Acute Promyelocytic Leukemia (APL). PMID- 24627870 TI - Ewing's sarcoma in mandibular similar to dental abscess. AB - Ewing's sarcoma is a rare malignant neoplasm that comprises approximately 4-6% of primary bone tumors. In most cases, femur and pelvis are affected, and less commonly the head and neck areas (in the jaws, usually the mandible). These tumors have been reported more frequently in males, mostly aged 5-20 years old. Systemic symptoms and signs such as fever, weight loss, anemia, leukocytosis, and elevated erythrocyte sedimentation rate (ESR) may be the first signs in oral Ewing's sarcoma. Such signs and symptoms are also seen in odontogenic infections and abscess. In one case, the patient went to a dentist with pain, swelling, and abscess similar to odontogenic infection and patient's tooth was pulled due to misdiagnosis. This tumor has an aggressive clinical behavior and is identified with rapid growth and high probability of metastasis at diagnosis. Thus, it is necessary to differentiate it from a dental abscess. As for the treatment of Ewing's sarcoma, first the tumor must undergo chemotherapy to reduce its size and, eventually, it undergoes extensive surgery. This case report deals with a 16 year-old patient wrongly diagnosed with odontogenic infection and abscess, and hospitalized. As the symptoms did not remit, biopsy was carried out and the patient was operated on with Ewing's sarcoma diagnosis. PMID- 24627871 TI - Helicobacter pylori in humans: Where are we now? AB - Helicobacter pylori has been associated with colonization of gastro duodenal mucosa of humans from millions of years. The main burden of the disese is in the developing countries, due to overcrowding and poor hygiene. If left untreated it leads to lot of sequlae from minor to sinister diseases over a period of time. The main challenges that remain are prevention of H. pylori-related diseases by effective treatment and screening procedures and development of a vaccine, which can address all these issues including beneficial aspects of H. pylori. The literature pertaining to different aspects of H. pylori were scrutinized from Pubmed. Material on clinical behavior, complications of chronic gastric involvement, and prevention besides role of H. pylori in nongastric diseases and the latest trends of management was collected for research and review. We continue to face many challenges. The prevention of cancer of the stomach, a worst sequlae of H. pylori continues to be a big challenge despite population screening and prevention surveys being underway in many countries. On the other hand continued scientific work has now unfolded involvement of H. pylori in extragastric diseases like cerebrovascular, cardiovascular, idiopathic thrombocytopenia, sideroblastic anemia, mental diseases, and collagen vascular diseases. In contrast, the beneficial effects of H. pylori with respect to allergic diseases and obesity are now clear. Moreover, problem of drug resistance for eradication of H. pylori has arisen for which novel treatments are being tried. Lactobacillus reuteri having anti H. pylori action is emerging as one of the promising treatment. PMID- 24627872 TI - Premedication with oral tramadol reduces severity of postoperative shivering after general anesthesia. AB - BACKGROUND: Postanesthetic shivering (PAS) is an accompanying part of general anesthesia with different unpleasant and stressful complications. Considering the importance of proper prevention of PAS in order to reduce its related adverse complications in patients undergoing surgery, in this study, we investigated the effect of orally administrated tramadol in the prevention of this common complication of general anesthesia. MATERIALS AND METHODS: In this prospective randomized double-blind clinical trial, 80 ASA I and II patients aged 15-70 years, scheduled for elective surgery under general anesthesia, were randomized to intervention (oral tramadol 50 mg) and placebo groups. PAS was evaluated during surgery and in the recovery room, and compared in the two study groups. RESULTS: PAS was seen in 5 patients (12.5%) in the intervention group and 10 patients (25%) in the placebo group (P = 0.12). The prevalence of grade III and IV shivering was 7.5% (3/40) and 25% (10/40) in tramadol and placebo groups, respectively (P = 0.03). CONCLUSION: The overall prevalence of PAS was not significantly different in the two study groups, but the higher grades of shivering which needed treatment were significantly lower in the tramadol group than in the placebo, and those patients who received tramadol experienced milder form of shivering. It is suggested that higher doses of tramadol would have better anti-shivering as well as analgesic effects. Studying different doses of tramadol would be helpful in this regard. PMID- 24627873 TI - Polymerase chain reaction amplification of a GC rich region by adding 1,2 propanediol. AB - BACKGROUND: Apolipoprotein E (ApoE) is one of the most important carriers of lipids in mammalians. The gene for this lipoprotein (ApoE) is located on chromosome 19 which is related with the pathogenesis of some nervous system disease. ApoE gene is identified as a high guanine-cytosine (GC) content fragment. Detection and amplification of these templates are extensively laborious and baffling. The aim of this study was to find a practical and feasible method for the amplification of the number of GC rich genes such as ApoE. MATERIALS AND METHODS: We experimented with simple polymerase chain reaction (PCR), nested PCR and PCR with 1-2 propanediol, dimethylsulfoxide (DMSO), and ethyleneglicol as additive substances to enhance the amplification ApoE gene and used the 40 samples of the human whole blood were collected in test tubes with a pre-treatment of ethylene diaminetetraacetic acid. RESULTS: According to our observations, presence of 1-2 propanediol, DMSO, and ethyleneglicol as additive substances resulted to enhanced amplification of ApoE gene. Addition of 1-2 propanediol showed the best results, caused optimization and revealed more specific and sharp bands. CONCLUSION: According to our findings 1-2 propanediol are the best organic reagent for improving the amplification of ApoE gene. Optimization procedure for each GC rich sequence is recommended to be performed separately in order to identify which of the additive agent is more efficient and applicable for a particular target. PMID- 24627874 TI - Urine and serum neutrophil gelatinase-associated lipocalin cut-off point for the prediction of acute kidney injury. AB - BACKGROUND: The aim of the present study was to determine the optimum cut-off point of urine and serum neutrophil gelatinase-associated lipocalin (NGAL) for the predictive diagnosis of acute kidney injury (AKI). MATERIALS AND METHODS: This study was a prospective observational study which was performed at Alzahra hospital and Emam Hussein Hospital, Isfahan, Iran. During a period of 4 months, from February 2012 to May 2012, consecutive patients admitted to pediatric intensive care unit (PICU) aged between 1 month and 15 years with glomerular filtration rate (GFR) more than 90 ml/min were enrolled in the study. In all the patients who were enrolled in the study, blood and urine samples were attained on the first, third, and fifth day of admission. Serum and urine NGAL were assessed and compared between patients who developed AKI and who didn't. RESULTS: Of 25 patients who enrolled in the study, 13 developed AKI. For the serum NGAL, the most accurate cut-off point was the fifth day cut-off point which was 163 375 pg/ml (sensitivity: 61.5%, specificity: 94.6%, AUC: 0.76) and urine NGAL cut-off point was 86 040 pg/ml (sensitivity: 50%, specificity: 92.5%, AUC: 0.73). CONCLUSIONS: In conclusion, we deduced that serum NGAL level significantly elevates in critically ill patients admitted in PICU who develop AKI. Serum and urine NGAL on the fifth day are the best predictors for the AKI with cut-off points 163 375 and 86 040. PMID- 24627875 TI - Biosensors in clinical chemistry: An overview. AB - Biosensors are small devices that employ biological/biochemical reactions for detecting target analytes. Basically, the device consists of a biocatalyst and a transducer. The biocatalyst may be a cell, tissue, enzyme or even an oligonucleotide. The transducers are mainly amperometric, potentiometric or optical. The classification of biosensors is based on (a) the nature of the recognition event or (b) the intimacy between the biocatalyst and the transducer. Bioaffinity and biocatalytic devices are examples for the former and the first, whereas second and third generation instruments are examples for the latter. Cell based biosensors utilizing immobilized cells, tissues as also enzyme immunosensors and DNA biosensors find variegated uses in diagnostics. Enzyme nanoparticle-based biosensors make use of small particles in the nanometer scale and are currently making a mark in laboratory medicine. Nanotechnology can help in optimizing the diagnostic biochips, which would facilitate sensitive, rapid, accurate and precise bedside monitoring. Biosensors render themselves as capable diagnostic tools as they meet most of the above-mentioned criteria. PMID- 24627876 TI - Galactomannan antigen assay from bronchoalveolar lavage fluid in diagnosis of invasive pulmonary aspergillosis in intensive care units patients. AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) is an important infection in critically ill patients including patients of intensive care units (ICU). Different diagnostic tools are available and since its mortality is high, it is vital to start the antifungal therapy as soon as possible. Knowing the epidemiology of this disease in each ICU and area will help to better and more rapid management of such patients. The aim of this study is to determine the frequency of IPA based on the level of galactomannan in bronchoalveolar lavage fluid in ICU of Al-Zahra hospital, Isfahan, Iran. MATERIALS AND METHODS: This was a cross sectional study, which was conducted in Al-Zahra hospital, Isfahan, Iran, between 2010 to 2011. The study population was all the patients admitted to ICU and were suspected to have invasive Aspergillus spp pneumonia. The level of galactomannan in bronchoalveolar lavage was measured and demographic data were gathered by the questionnaire. RESULTS: The frequency of IPA in this study was calculated as 2.43% while galactomannan level in bronchoalveolar lavage fluid of this patient (2.50) was significantly higher than others (0.03 +/- 0.02). CONCLUSION: Larger studies are required to determine the exact frequency of IPA and the best antifungal therapy for it. PMID- 24627877 TI - New look at about nature, structure and function of Trietz ligament. AB - BACKGROUND: Trietz ligament connects the duodeno-jejunal flexure to the right crus of the diaphragm. There are various opinions regarding the existence of the smooth muscle fibers in the ligament. We want to resolve this complexity with microscopic study of this part in cadavers. MATERIALS AND METHODS: This study done on three cadavers in the medical faculty of Isfahan University of Medical Sciences. Three samples of histological specimens were collected from the upper, the central, and the lower parts of Trietz ligament and were stained by H and E staining and Mallory's trichrome stain. Three samples were collected from the regions of exact connection of the main mesentery to the body wall, the intestine, and the region between these two connected regions, and these specimens were stained. RESULTS: In the microscopic survey, no collagen bundles were observed in the collected samples of the Trietz ligament after the dense muscular tissues. In the samples which were collected to work on collagen tissues stretching from the Trietz ligament to the main mesentery of intestine, no collagen bundles were observed. CONCLUSION: Trietz ligament is connected to the right crus of the diaphragm from the third and the fourth parts of the duodenum. Number of researchers state that there are smooth and striated muscular tissues and some others, with regard to observations of histological phases made from the samples of Trietz muscles, conclude that it can probably be noted that muscular bundles or the dense connective tissue bundles of collagen cannot be observed in the way we imagine. PMID- 24627878 TI - Extraction of total RNA in the developing chicken forebrain. AB - BACKGROUND: Gene expression of Gama-Aminobutyric acid (GABAA) receptor subunits may change during development. Procedures in molecular biology are required to understand the gene expression profile GABAA R in chicken. The outcome of the results depends on good-quality high-molecular-weight RNA. Several procedures can be used to isolate RNA from the brain of chicken; however, most of them are time consuming and require disruption of cells or freeze and thaw in the presence of RNase inhibitors. The aim of this experiment was isolation of RNA from chicken embryonic brain tissues using appropriate RNA extraction kit. MATERIALS AND METHODS: Fertilized eggs from Ross breed (Gallus gallus) were incubated at 38 degrees C and 60% relative humidity in a forced-draft incubator and were turned every 3 h. After 3, 7, 14 and 20 days of incubation, eggs were cooled on ice to induce deep anesthesia. Then whole brains were dissected out. As brains could not be excised in a reproducible way from earlier embryos (embryonic days 4 and 6), whole heads were collected. Chicken embryos between day 7 to 20 and 1 day after birth were decapitated, and their brains removed. Samples were immediately inserted into lysis buffer and stored at -70 degrees C. Total RNA was isolated and a contaminating genomic deoxyribonucleic acid (DNA) was digested. RNA quality was checked using gel electrophoresis. RESULTS: We obtained 52 mg/ml to 745 mg/ml with A260/280 1.7-2.2. Only high-quality RNA, with no signs of degradation, was used for further experiments. CONCLUSION: In conclusion, protocol was found to be suitable for the isolation of total RNA from embryonic chicken cells. PMID- 24627879 TI - Intraoperative diagnosis by frozen section study would prevent unnecessary surgery in ovarian Burkitt's lymphoma. PMID- 24627880 TI - Evaluation of multiplex ligation-dependent probe amplification analysis versus multiplex polymerase chain reaction assays in the detection of dystrophin gene rearrangements in an Iranian population subset. AB - BACKGROUND: The Duchenne muscular dystrophy (DMD) gene is located in the short arm of the X chromosome (Xp21). It spans 2.4 Mb of the human genomic DNA and is composed of 79 exons. Mutations in the Dystrophin gene result in DMD and Becker muscular dystrophy. In this study, the efficiency of multiplex ligation-dependent probe amplification (MLPA) over multiplex polymerase chain reaction (PCR) assays in an Iranian population was investigated. MATERIALS AND METHODS: Multiplex PCR assays and MLPA analysis were carried out in 74 patients affected with DMD. RESULTS: Multiplex PCR detected deletions in 51% of the patients with DMD. MLPA analysis could determine all the deletions detected by the multiplex PCR. Additionally, MLPA was able to identify one more deletion and duplication in patients without detectable mutations by multiplex PCR. Moreover, MLPA precisely determined the exact size of the deletions. CONCLUSION: Although MLPA analysis is more sensitive for detection of deletions and duplications in the dystrophin gene, multiplex PCR might be used for the initial analysis of the boys affected with DMD in the Iranian population as it was able to detect 95% of the rearrangements in patients with DMD. PMID- 24627881 TI - Prevalence and risk factors of hepatitis B and C viruses among hemodialysis patients in Isfahan, Iran. AB - BACKGROUND: The aim of this study was to assess the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) and their associated risk factors among hemodialysis patients in Isfahan, Iran in 2011. MATERIALS AND METHODS: In this cross-sectional study, a total of 499 chronic hemodialysis patients from eight governmental hemodialysis centers were tested. Demographic information, time duration on hemodialysis, history of blood transfusion, and the number of transfused blood units as risk factors to HBV and HCV infections were calculated. The status of HBsAg and anti-HCV was assessed by serological testing. RESULTS: The overall prevalence of HBV-positive and HCV-positive among study population was 1.2% and 5.2%, respectively. Age, sex, and time duration on hemodialysis were not statistically significant in HBV- and HCV-patients compared with other hemodialysis patients (P > 0.05). History of blood transfusion and the number of transfused blood units in HBV infected patients were similar to other patients (P > 0.05). The main risk factors in hemodialysis patients infected by HCV were history of blood transfusion and the number of transfused blood units (P < 0.0001). CONCLUSION: In conclusion, the prevalence of HBV and HCV infections in hemodialysis centers in Isfahan is lower than in some other cities of Iran. History of blood transfusion and the number of blood units transfused might be a risk factor for HCV gaining. However, further studies are needed to assess the role of other demographic and clinical risk factors in these patients. PMID- 24627882 TI - Genotype-phenotype correlation of survival motor neuron and neuronal apoptosis inhibitory protein genes in spinal muscular atrophy patients from Iran. AB - BACKGROUND: Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by symmetrical proximal muscle weakness and atrophy. According to the severity of the disease and the age of onset, SMA can be divided into three groups. The survival motor neuron (SMN) gene that is located on 5q13 is identified as the disease determining gene. Another gene in this region is neuronal apoptosis inhibitory protein (NAIP), and its functional role in the pathogenesis of SMA has not been fully elucidated. Here, we investigated the correlation between deletions in SMN and NAIP genes with clinical features of SMA patients. MATERIALS AND METHODS: In the current study, 71 unrelated Iranian patients were investigated for the detection of deletions in SMN1 and NAIP genes. Polymerase chain reaction (PCR) was used to detect the deletions of exon 4 and 5 of the NAIP gene. Deletions in exon 7 and 8 of SMN1 gene were detected by RFLP-PCR with DraI and DdeI, respectively. RESULTS: Our results showed that 51 patients have homozygous deletions in SMN1 and/or NAIP genes. Among these 51 patients, deletion in NAIP gene were found in 35 patients (65.7% of type I, 22.5% type II and 11.42% type III). CONCLUSION: Defect in SMN1 gene plays a major role in manifesting of the disease and NAIP (4 and 5) gene acts as a modifying factor in severity of symptoms. Correlation between NAIP gene defect and severity of the disease is confirmed. However, the exact role of NAIP gene in SMA has yet to be fully clarified. PMID- 24627883 TI - Prevalence of human papilloma virus among women with breast cancer since 2005 2009 in Isfahan. AB - BACKGROUND: Human papilloma virus (HPV) DNA has been detected in breast carcinoma by different laboratorial techniques, suggesting that the virus could play a role in the pathogenesis of this tumor. MATERIALS AND METHODS: It was a descriptive study. Systematic random sampling was used for selecting 55 cases of breast cancer and 51 controls of benign breast lesions from the file of Seyedshohada hospital of Isfahan since 2005-2009. A total of 106 paraffin-embedded specimens were selected and HPV DNA was analyzed by polymerase chain reaction and sequenced for different types of HPV in case of positivity for HPV DNA. Data analysis was performed by SPSS 16 software using descriptive statistic, Chi-square, and Fisher's exact tests. RESULTS: Out of 55 malignant and 51 benign breast specimens, 18.2% (10) and 13.7% (7) were positive to HPV DNA, respectively (P = 0.53); 70% (7) malignant and 43% (3) benign breast specimens were positive to high-risk HPV genotypes. In malignant specimens, the most common high- and low risk genotypes were HPV-16 (3.6%) and HPV-11 (3.6%), respectively. In benign specimens, the most common high- and low-risk genotypes were HPV-31 (3.9%) and HPV-43 (3.9%), respectively. Among malignant and benign specimens, ductal carcinoma and fibro adenoma were the most common lesions positive to different types of HPV, respectively. CONCLUSION: This study demonstrated the presence of HPV genome in both malignant and benign tumor tissues in women with breast lesions in Isfahan; therefore, further larger epidemiologic studies need to be analyzed to establish the exact role of this virus in the pathogenesis of breast cancer. PMID- 24627885 TI - Training and validation of standardized patients for evaluation of general practitioners' performance in management of obesity and overweight. AB - BACKGROUND: Standardized patient (SP) can serve as a valuable tool to measure the physician performance in actual clinical settings, but it has not been validated for obesity/overweight disorders. This study has been conducted to describe the process of creating reliable and valid SPs for evaluation of general practitioners' management of obesity/overweight in Iran. MATERIALS AND METHODS: A total of 6 obese/overweight volunteers (potential SPs) took part in training. Three scenarios, along with corresponding checklists including 102 items representing different aspects of diagnosis and treatment of obesity/overweight, were developed by an expert group. The SPs were trained using role playing method. During this part, one of the SPs failed. The SPs' portrayal of their respective scenario was online watched in another room and the checklist filled independently by the physician, research assistant and other SPs. The reliability of the checklist to be used by the SPs was assessed by Cronbach's alpha. The overall inter-rater agreement was calculated by the intraclass correlation coefficient statistic for total scores. RESULTS: The 5 eligible SPs were all women between 20 years and 39 years of age. Inter-rater agreement between the SPs' total scores was 0.899, value (95% confidence intervals) were 11.8 (0.68 0.98) and P value was <0.001. The Cronbach's alpha for reliability of completed checklists was 0.91. CONCLUSION: SP could be a powerful instrument for evaluating medical performance of general practitioners in the field of obesity/overweight management. Further research is needed to find the more aspects of training and validation of unannounced SPs in this field. PMID- 24627884 TI - Effect of low-frequency electromagnetic field exposure on oocyte differentiation and follicular development. AB - BACKGROUND: The effect of electromagnetic field (EMF) as an environmental factor on different organs including female reproductive system is of critical concern. The aim of the present study is to evaluate the effect of low-frequency (LF)-EMF on oocyte differentiation and follicular development. MATERIALS AND METHODS: The experiment was carried out in animal lab of Faculty of Medicine Tabriz University of Medical Sciences. For this purpose, the BALB/c mice were divided into control and experimental group in animal lab. The pregnant mice in the experimental group were exposed to 3 mT EMF field, 4 h/day during the pregnancy period. The LF-EMF was produced by a system using 50 Hz alternative current, in the control group the pregnant mice were kept in a similar condition without exposure to EMF. The neonatal mice from both groups were sacrificed immediately after birth and their ovary was dissected apart and prepared for light and electron microscopy. RESULT: Microscopy revealed that in the experimental group, in comparison to control group, oocyte nests were mostly broken and irregularly arranged. The primordial follicles were less developed and nuclei of oocytes with an electron microscope appeared heterochromatic, shrunken and had vacuolated cytoplasm. CONCLUSION: It is concluded that exposure to EMF during the developmental period could affect both oocyte differentiation and folliculogenesis and may result in reduced fertility, by decreasing ovarian reservoir. PMID- 24627886 TI - Preparation of a core-shell magnetic ion-imprinted polymer via a sol-gel process for selective extraction of Cu(II) from herbal medicines. AB - A novel magnetic surface ion-imprinted polymer (c-MMWCNTs-SiO2-IIP) was synthesized for the first time using magnetic CNTs/Fe3O4 composites (c-MMWCNTs) as the core, 3-ammonium propyltriethoxysilane (APTES) as the functional monomer, tetraethylorthosilicate (TEOS) as the cross-linker and Cu(II) as the template. c MMWCNTs-SiO2-IIP was evaluated for selective extraction of Cu(II) from herbal medicines via a magnetic solid phase extraction (M-SPE) procedure. One factor affecting the separation and preconcentration of the target heavy metal was pH. Under the optimized experimental conditions, the adsorption kinetics and adsorption capacity of c-MMWCNTs-SiO2-IIP toward Cu(II) were estimated. The results indicated that the adsorption mechanism corresponds to a pseudo-second order adsorption process, with a correlation coefficient (R(2)) of 0.985 and a maximum adsorption capacity of 42.2 mg g(-1). The relative selectivity factor (beta) values of Cu(II)/Zn(II) and Cu(II)/Pb(II) were 38.5 and 34.5, respectively. c-MMWCNTs-SiO2-IIP, combined with flame atomic absorption spectrometry, was successfully applied in the extraction and detection of Cu(II) in herbal medicine, with high recoveries ranging from 95.6% to 108.4%. PMID- 24627887 TI - DNA-embedded Au-Ag core-shell nanoparticles assembled on silicon slides as a reliable SERS substrate. AB - This study aimed at developing a sensitive and reliable SERS substrate by assembling DNA-embedded Au-Ag core-shell nanoparticles (NPs) on silicon slides. First, a monolayer of well separated DNA-functionalized Au NPs (40 nm) was decorated on (3-aminopropyl)triethoxysilane modified silicon slides. The DNA embedded Au-Ag core-shell NPs were assembled on the 40 nm Au-DNA NPs to form a core-satellite structure through DNA hybridization. Using 4-MBA as a Raman dye, the SERS performance of the substrates was evaluated after being cleaned by low oxygen and argon plasma. The Raman intensity of the assembly using DNA-embedded Au-Ag core-shell NPs was 8-10 times higher than the intensity of the assembly using Au NPs as satellites. In addition, the signal-to-noise ratio of the assembly was 2.6 times higher than that of a commercial substrate (KlariteTM) when a 785 nm laser was used. The SERS enhancements of the assembled substrates were 2.2 to 2.8 times higher than the Klarite when an acquisition time of 5 s was used at an excitation wavelength of 633 nm. The assembled substrates also show a good spot-to-spot and substrate-to-substrate reproducibility at the excitation wavelengths of 633 and 785 nm. These results demonstrate that the fabrication process is simple and cost-effective for assembling DNA-embedded Au-Ag core-shell NPs on silicon slides that can be used as a reliable SERS substrate. PMID- 24627888 TI - One-pot synthesis of beta-N-glycosyl imidazole analogues via a palladium catalysed decarboxylative allylation. AB - A concise and highly efficient strategy for the synthesis of N-glycosyl imidazole analogues is reported. This reaction is based on a palladium catalysed decarboxylative allylation and three steps, namely, carbamation, decarboxylation and allylation are involved. All the substrates can afford the desired products with excellent yields and selectivities. PMID- 24627889 TI - Hierarchical self-assembly of a discrete hexagonal metallacycle into the ordered nanofibers and stimuli-responsive supramolecular gels. AB - A discrete hexagonal metallacycle decorated with multiple amide groups and long hydrophobic alkyl chains was constructed via [3+3] coordination-driven self assembly, from which the ordered nanofibers and stimuli-responsive supramolecular gels were successfully obtained via hierarchical self-assembly. PMID- 24627890 TI - MOF membrane synthesis in the confined space of a vertically aligned LDH network. AB - MOF membranes have gained widespread attention due to their unprecedented gas separation performance. Relying on physical interactions, we successfully deposited MOF seeds on a substrate modified with a network of vertically aligned LDH walls before secondary growth of the MOF layer. ZIF-8 membranes thus prepared show considerable H2 permeance with high H2-CH4 selectivity. This approach is in general suitable for the deposition of nanoparticles on solid surface and their subsequent growth into a dense layer. PMID- 24627891 TI - Foundations for lung nodule management for nurse navigators. PMID- 24627892 TI - The author responds. PMID- 24627893 TI - Abstracts of the VII National Congress of the Romanian Society of Endoscopic Surgery, November 23, 2013, Bucharest, Romania. PMID- 24627894 TI - Chern band insulators in a magnetic field. AB - The effect of a magnetic field on a two-dimensional Chern band insulator is discussed. It is shown that, unlike the trivial insulator, an anomalous Hall insulator with Chern number C becomes a metal when a magnetic field is applied at constant particle density, for any C > 0. For a time-reversal invariant topological insulator with a spin Chern resolved number, C? = -C? = C, the magnetic field induces a spin polarized spin Hall insulator. We consider also the effect of a superlattice potential and extend previous results for the quantization of the Hall conductance of filled Hofstadter bands to this problem. PMID- 24627895 TI - Surface correlation effects in two-band strongly correlated slabs. AB - Using an extension of the Gutzwiller approximation for an inhomogeneous system, we study the two-band Hubbard model with unequal band widths for a slab geometry. The aim is to investigate the mutual effect of individual bands on the spatial distribution of quasi-particle weight and charge density, especially near the surface of the slab. The main effect of the difference in band width is the presence of two different length scales corresponding to the quasi-particle profile of each band. This is enhanced in the vicinity of the critical interaction of the narrow band where an orbitally selective Mott transition occurs and a surface dead layer forms for the narrow band. For the doped case, two different regimes of charge transfer between the surface and the bulk of the slab are revealed. The charge transfer from surface/center to center/surface depends on both the doping level and the average relative charge accumulated in each band. Such effects could also be of importance when describing the accumulation of charges at the interface between structures made of multi-band strongly correlated materials. PMID- 24627896 TI - Adenosquamous carcinoma of the parotid gland. PMID- 24627897 TI - Conflicting results of genetic studies looking at SPINK 1 mutations. PMID- 24627898 TI - Evaluation of the oral fludrocortisone suppression test for diagnosing primary hyperaldosteronism in cats. AB - BACKGROUND: Primary hyperaldosteronism (PHA) in cats is suggested by clinical signs and an elevated plasma aldosterone-to-renin ratio (ARR), but a test to confirm the diagnosis is lacking. HYPOTHESIS: Fludrocortisone does not suppress urinary aldosterone excretion in cats with PHA, but does so in cats with arterial hypertension because of other causes. ANIMALS: Nineteen client-owned cats with arterial hypertension because of PHA (n = 9) or other causes (n = 10). METHODS: Prospective clinical study. The urinary aldosterone-to-creatinine ratio (UACR) was determined in morning urine before, during, and after 4 days of oral fludrocortisone administration in a dose of 0.05 mg/kg q12h. Arterial blood pressure and plasma potassium concentration were measured before and after fludrocortisone administration. RESULTS: A basal UACR above 46.5 * 10(-9), the upper limit of the reference range, was found in 3 cats with PHA. All PHA cats had basal UACRs >7.5 * 10(-9). In all non-PHA cats with a basal UACR >7.5 * 10( 9), fludrocortisone administration induced >50% suppression. In contrast, fludrocortisone administration resulted in <50% suppression in 6 of the 9 PHA cats. Neither basal UACR, nor UACR after suppression testing, correlated with the etiology of PHA (adenoma, adenocarcinoma, or suspected bilateral hyperplasia of the zona glomerulosa). Fludrocortisone induced hypokalemia in 7 cats, but did not induce or exacerbate arterial hypertension. CONCLUSIONS AND CLINICAL IMPORTANCE: Measuring the UACR before and after 4 days of administering fludrocortisone is a practical method of confirming most cases of PHA in cats, and of substantiating the absence of PHA in cats having an ARR within the reference range. PMID- 24627899 TI - Treatment of idiopathic headshaking in horses with pulsed high-dose dexamethasone. AB - BACKGROUND: Treatment of idiopathic headshaking in horses is complicated by an incomplete understanding of underlying pathophysiology and partially effective treatments. If an inflammatory etiology exists, corticosteroids could be beneficial. HYPOTHESIS: An anti-inflammatory dose of dexamethasone reduces the signs of idiopathic headshaking in a field setting. ANIMALS: Convenience sample of 20 adult horses with idiopathic headshaking syndrome. Cases were recruited from the general population and diagnosed by attending veterinarians. METHODS: Prospective, blinded clinical trial. Pulsed dosing was with oral dexamethasone (60 mg PO Q24h * 4 days, q3 weeks for 4 months) or placebo (inert paste). Owners were blinded and asked to score the headshaking from 0 to 4 (4 = most severe) 3 days per week. The change in headshaking scores (HS) over each treatment pulse was compared between groups by ordinal logistic regression. RESULTS: Twelve horses completed the trial. There was no significant difference between treated or placebo horses (P = .987). Sun (P <= .001), wind (P = .028), and exercise (P <= .045) significantly increased HS. CONCLUSIONS AND CLINICAL IMPORTANCE: No benefit of dexamethasone treatment was detected for idiopathic headshaking. The results confirmed previous reports of common triggers for headshaking behavior PMID- 24627900 TI - Genetic diagnosis through whole-exome sequencing. PMID- 24627901 TI - Transfer of the virulence-associated protein a-bearing plasmid between field strains of virulent and avirulent Rhodococcus equi. AB - BACKGROUND: Virulent and avirulent isolates of Rhodococcus equi coexist in equine feces and the environment and are a source of infection for foals. The extent to which plasmid transfer occurs among field strains is ill-defined and this information is important for understanding the epidemiology of R. equi infections of foals. OBJECTIVES: To estimate the frequency of transfer of the virulence plasmid between virulent and avirulent strains of R. equi derived from foals and their environment. ANIMALS: None. METHODS: In vitro study; 5 rifampin susceptible, virulent R. equi isolates obtained from clinically affected foals or air samples from a farm with a history of recurrent R. equi foal pneumonia were each mixed with 5 rifampin-resistant, avirulent isolates derived from soil samples, using solid medium, at a ratio of 10 donor cells (virulent) per recipient cell. Presumed transconjugates were detected by plating on media with rifampin and colony immunoblotting to detect the presence of the virulence associated protein A. RESULTS: Three presumed transconjugates were detected among 2,037 recipient colonies, indicating an overall estimated transfer frequency of 0.15% (95% CI, 0.03-0.43%). All 3 transconjugates were associated with a single donor and 2 recipient strains. Genotyping and multiplex PCR of presumed transconjugates demonstrated transfer of the virulence-associated protein A bearing plasmid between virulent and avirulent R. equi. CONCLUSIONS AND CLINICAL IMPORTANCE: Transfer of the virulence plasmid occurs with relatively high frequency. These findings could impact strategies to control or prevent R. equi through environmental management. PMID- 24627902 TI - Laccase activity could contribute to cell-wall reconstitution in regenerating protoplasts. AB - Laccase (EC 1.10.3.1) activity was measured in regenerating and non-regenerating protoplasts isolated from tobacco (Nicotiana tabacum, L.) leaves. Laccase activity diminished soon after isolation: thereafter,it steadily increased in regenerating protoplasts during a 6-day culture period, whereas it was undetectable in non-regenerating protoplasts. A different pattern of isoforms was expressed in protoplasts by comparison with the donor tissue. Polyphenol oxidizing activity was detected also in the spent medium but it was not possible to definitely determine if it was due to laccase or to peroxidase (POX, EC 1.11.1.7) activity. New isoPOXs were quickly expressed soon after protoplast isolation as well, but POX activity remained negligible during the first day in culture. Leaf wounding induced an immediate stimulation of laccase activity whereas POX activity increased very slowly and peaked only after 4 days. Therefore, laccase could be the only effective polymerizing enzyme during the first day of protoplast culture and could contribute in the first steps of healing in wounded leaves, substituting for POX activity in cell wall reconstitution when hydrogen peroxide is not yet available. PMID- 24627904 TI - Preliminary investigation of cardiac troponin I concentration in cows with common production diseases. AB - BACKGROUND: Increased cTnI concentrations are associated with adverse outcomes in humans and animals. Limited information is available on the prognostic value of cTnI in cows. OBJECTIVE: To measure cTnI in cows with noncardiac diseases and evaluate the association of cTnI concentration with adverse outcomes such as death or early removal from the herd. ANIMALS: Thirty control and 53 diseased cows. METHODS: Serum cTnI concentrations were determined with a point-of-care immunoassay. Cows were diagnosed ante- or postmortem with metritis (n = 6), mastitis (n = 4), peritonitis (n = 6), LDA (n = 14), LDA and metritis (n = 4), pneumonia (n = 6), dystocia requiring cesarean section (n = 5), and downer cow syndrome (n = 8). Animal survival was determined for up to 2 months after presentation. RESULTS: The immunoassay showed reliability for the detection of bovine cTnI. Cows with LDA and metritis (P < .05), peritonitis (P < .05), LDA (P < .001), dystocia requiring cesarean section (P < .01), and downer cow syndrome (P < .001) had higher cTnI concentrations than control cows. The odds of a negative outcome (death or culling) for cows with cTnI concentrations of >= 0.05, >= 0.1, >= 0.2, and >= 0.5 ng/mL were 2.4, 2.9, 4.8, and 6.2, respectively. CONCLUSION: Cows with noncardiac diseases may have some degree of myocardial injury. The magnitude of cTnI increased may assist clinicians in evaluating the risk of an adverse outcome and help guide decision-making regarding treatment and prognosis. PMID- 24627905 TI - 2013 San Antonio Breast Cancer Symposium. PMID- 24627906 TI - Case mix and patient experiences of cancer care. PMID- 24627907 TI - Palliative care in India suffers due to cumbersome rules. PMID- 24627908 TI - Colorado: a first in the USA for legal sale of marijuana. PMID- 24627909 TI - Epigenetic modification boosts ovarian cancer vaccination. PMID- 24627910 TI - A New York bill for regulation of electronic cigarettes. PMID- 24627911 TI - Chemoimmunotherapy improves survival in CLL. PMID- 24627912 TI - Waking up to the merits of mindfulness. PMID- 24627913 TI - Preoperative MRI fails to reduce breast cancer recurrence. PMID- 24627914 TI - Geoscience: Fracking fundamentals. PMID- 24627915 TI - Don't hide the decline. PMID- 24627916 TI - An elegant chaos. PMID- 24627918 TI - History: A medieval multiverse. PMID- 24627917 TI - Share alike. PMID- 24627919 TI - Policy: The art of science advice to government. PMID- 24627920 TI - The authors reply. PMID- 24627921 TI - Restricted intravenous fluid regimen reduces fluid redistribution of patients operated for abdominal malignancy. AB - BACKGROUND/AIMS: Recent studies indicate that perioperative fluid restriction leads to better preserved clinical data as well as reduced complication rates. This study aimed to determine the probable mechanism of fluid restriction influence on the complication rate of patients undergoing gastrointestinal surgery for malignancy. METHODOLOGY: Patients (n = 174) undergoing restricted fluid regimen (R group) or standard fluid regimen (S group) were included in this prospective, randomized trial over 16 months. Fluid distribution was determined by Bioelectrical Impedance Analyzer (BIA) and the difference between two groups was compared regarding complications and the relationship between complications and fluid distribution changes. RESULTS: The restricted intravenous fluid regimen significantly reduced perioperative intravenous fluid volume. Weight gained in S group and was not significantly changed in R group after surgery, especially in POD2 (media; R vs. S; 61.17 vs. 65.40 kg, p = 0.017). The number of patients with postoperative complications was reduced in R group compared with in S group (34.5% vs. 47.8%, p = 0.076). Systemic complications were significantly reduced in R group (t = -5.895, p = 0.000). Patients with complications had an average of 1.6 complications in R group vs. 2.0 in S group (t = -1.345, p = 0.183). The multivariate analysis suggested that perioperative fluid distribution changes were associated with the development of postoperative complications. CONCLUSIONS: Perioperative fluid restriction could effect on fluid distribution and reduce tissue and cellular edema, and further, could reduce postoperative complication rates. PMID- 24627922 TI - The clinicopathological impact of gross classification on solitary small hepatocellular carcinoma. AB - BACKGROUND/AIMS: The aim of this retrospective study was to determine the effect of gross classification on the outcome of hepatic resection for small solitary hepatocellular carcinoma (HCC). METHODOLOGY: This study consisted of 179 consecutive primary HCC patients who were not preoperatively diagnosed with vascular invasion or intrahepatic metastasis. The clinicopathological impact of gross classification was compared. Patients were classified into four groups, vaguely nodular (VN) type, single nodular (SN) type, single nodular type with extranodular growth (SNEG), and confluent multinodular (CMN) type, according to the gross classification of resected specimens. RESULTS: The SNEG and CMN types showed a significantly higher rate of MVI and intrahepatic metastasis than VN and SN type. Multivariate analysis showed SNEG and CMN type is independent predictor of MVI. The survival rates and the disease free survival rates of four groups were equal after curative hepatectomy. CONCLUSIONS: This study demonstrated that the gross classifications were correlated significantly with the prevalence of MVI or intrahepatic metastasis, and that aggressive tumor spread in the SNEG type and in the CMN type was observed even in patients with small solitary HCC. PMID- 24627923 TI - Reducing the gastroesophageal reflux with lip-type reinforcement technique during intrathoracic esophagogastrostomy. AB - BACKGROUND/AIMS: Gastroesophageal reflux is a significant problem after esophagogastrostomy, and impact considerably upon the quality of patients' lives. Aims of this study were to evaluate the operative effects in prevention of reflux with lip-type reinforcement during intrathoracic esophagogastric anastomosis. METHODOLOGY: From January 2005 to December 2009, 216 patients received circular stapled esophagogastrostomy with lip-type reinforcement (LR group), and 69 patients with standard reinforcement (SR group) at our hospital. Major observation parameters were symptoms of reflux and dysphagia. RESULTS: No differences in clinicopathologic characteristics between two groups, in addition to the incidence of anastomotic leakage was less in LR group (p = 0.039). Grade of dysphagia and anastomotic stricture also were not different between two groups (p >0.05). Symptoms of reflux were better controlled in patients with lip-type reinforcement than standard reinforcement (p <0.001). In LR group, 71.3% were asymptomatic with respect to reflux compared to 29.7% in SR group (p <0.001). The incidence of reflux esophagitis was 23.5% in LR group and 58.3% in SR group (p <0.001). There was a significant correlation between reflux symptoms and endoscopic findings of reflux esophagitis (p = 0.001). CONCLUSIONS: Lip-type reinforcement is simple to perform, and effective in controlling gastroesophageal reflux and decreasing anastomotic leakage in majority of patients after esophagogastrostomy. PMID- 24627924 TI - Clinical pathology and recent follow-up study on gastric intraepithelial neoplasia and gastric mucosal lesions. AB - BACKGROUND/AIMS: To explore the correlations between endoscopic gastric mucosal lesions and pathological gastric intraepithelial neoplasia (GIN), and to investigate outcomes of gastric intraepithelial neoplasia after treatments. METHODOLOGY: Biopsies of 18,566 Chinese patients undergoing diagnostic gastroscopy were included. Among them, 130 patients were given various treatments, including medication, endoscopic treatment and surgery. RESULTS: There were 433 patients with GIN by initial pathological diagnosis. Among them, 367 low-grade GIN and 66 high-grade GIN, 348 cases accompanied with chronic gastritis, and 85 cases accompanied with localized foci. Eighty cases of Hp positive patients with low-grade GIN were given anti-Hp therapy. Our results showed that 45 cases of intraepithelial neoplasia disappeared when chronic inflammation left, and 33 cases were given the original diagnoses and two cases developed into high-grade GIN. Surgery was then performed, after which one case was confirmed to have early gastric carcinoma, and the other was diagnosed as advanced gastric carcinoma. Pathological examinations were carried out undergoing EMR or ESD treatment for 18 patients with localized foci accompanied with low grade GIN. Results showed four cases of chronic inflammation, 11 cases with original diagnoses maintained, and three cases of high-grade GIN. CONCLUSIONS: GIN occurred frequently in patients with more severe pathological inflammations under endoscope, which also had certain correlations with intestinal metaplasia. After treatment, parts of low-grade GIN could be reserved. The effect of endoscopic resection on localized foci accompanied with low-grade GIN was affirmative. However, the limitation of endoscopic biopsy should be fully understood. PMID- 24627925 TI - Re-evaluation of cases with gastroenteropancreatic neuroendocrine tumors between 2004 and 2012 according to the 2010 criteria. AB - BACKGROUND/AIMS: We re-evaluated the clinical, histopathological and immunohistochemical features of neuroendocrine tumors (NETs) diagnosed in our pathology laboratory between 2004 and 2012 and re-classified them according to the WHO-2000 and WHO-2010 criteria. METHODOLOGY: The study included NET samples of 106 patients having gastroenteropancreatic and hepatobiliary tumors. The histopathological findings were re-assessed. The cases were re-appraised based on the WHO-2000 and WHO-2010 criteria. The association between survival and Ki-67 index was analysed. RESULTS: The most frequent localization was the stomach. The average tumor size was 3.0+/-4.1 cm. Differentiation was poor in 17 cases (16.0%). Lymphovascular invasion was detected in 16.1% (n = 17) and necrosis was identified in 15.1% (n = 16). The average number of Ki-67 was 9.1+/-19.9. Ki-67 measurements were significantly higher in patients who died compared to those who survived (p <0.01). In ROC analysis, the cut-off point for Ki-67 was 5. CONCLUSIONS: Our study is a single-center study comprising patients from Turkey for a period of 8 years. We found that the most frequent localization is the stomach. This ratio is associated with common use of endoscopy in our center. The specimens were re-evaluated according to the WHO-2000 and WHO-2010 classification systems the data and terminology have been updated. PMID- 24627927 TI - The thin end of the wedge: how the Newman government's changes to legislation will affect you. PMID- 24627928 TI - Medication management: RNs and AINs. PMID- 24627926 TI - Drug induced hypersensitivity syndrome by triple therapy of peginterferon alpha2b, ribavirin and telaprevir in patient with double positive for HBV and HCV. AB - Sixty year-old male positive for both HCV-RNA and HBsAg was treated by triple therapy of peginterferon alpha2b, ribavirin and telaprevir. Eight weeks after the beginning of the therapy, the patient developed drug induced hypersensitivity syndrome (DIHS) with general erythema multiforme and 64 times anti-HHV6 antibody elevation. Sixty milligram of prednisolone was administered with gradual dose reduction and the skin lesion was improved. HBV-DNA and transaminase elevated one week after the steroid induction and entecavir improved them. DIHS itself and the aggravation of hepatitis B by corticosteroid should be kept in mind in cases with dual infection of HBV and HCV treated by antivirals including telaprevir. PMID- 24627929 TI - Metro South HHS torpedoes continuity of care model at Logan Hospital. PMID- 24627930 TI - Are ethics and private detention centres compatible? PMID- 24627931 TI - Lives at risk as federal government dumps Mae Tao Clinic funding. PMID- 24627933 TI - Patient education: Why do breasts get attention? PMID- 24627932 TI - The responsibility and rewards of being a carer. PMID- 24627934 TI - Medication errors and how to avoid them. It may be as simple as charting your daily medications and learning their names. PMID- 24627935 TI - T-DNA of a crown gall teratoma is covalently joined to host plant DNA. AB - Agrobacterium tumefaciens strains containing tumour-inducing (Ti) plasmids incite cancerous growths called crown galls when inoculated into wounded dicotyledonous plants. Tumour tissue can be cultured axenically in vitro, and exhibits a transformed phenotype in the absence of the inciting bacterium. Transformed cells grow autonomously, are auxin and cytokinin autotrophic in vitro and synthesize opines, novel amino acid derivatives dictated by Ti plasmid genetic information. A small segment of the Ti plasmid, termed T-DNA is maintained in axenic tumour cells. Mitochondrial and chloroplast DNA from a crown gall teratoma are free from T-DNA, whereas nuclear DNA contains T-DNA in amounts similar to that in total tumour cell DNA. T-DNA appears to be attached to what is presumably plant DNA in the crown gall tumour cell: Southern blot analysis of tumour DNA digested with restriction endonucleases reveals T-DNA fragments that are not fully homologous to Ti plasmid DNA. We report here the isolation by molecular cloning of a 'border fragment' T-DNA and flanking plant DNA from the crown gall teratoma BT37 and show that T-DNA is covalently joined to a repeated DNA element of the tobacco nuclear genome. PMID- 24627936 TI - [Distinguishing normal women from those with schizophrenia by means of MRI]. PMID- 24627937 TI - [Effect of menopause on morphological changes of the brain in schizophrenia]. PMID- 24627938 TI - [Latest diagnostic techniques in areas outside of oto-rhino-laryngology- chromosomal and genetic diagnosis of malignant lymphoma]. PMID- 24627939 TI - [Recent progress in computer-supported surgery--technology to apply navigation surgery to the otological field]. PMID- 24627940 TI - [Responses to protracted coughing]. PMID- 24627941 TI - [Basic method and the concept of endoscopic nasal and paranasal sinuses]. PMID- 24627942 TI - [EBM of sudden hearing loss]. PMID- 24627943 TI - [Diagnosis and treatment of vertigo due to sleep disturbances]. PMID- 24627944 TI - Expression of Defense Genes in Strawberry Fruits Treated with Different Resistance Inducers. AB - The expression of 18 defense genes in strawberry fruit treated with elicitors: chitosan, BTH, and COA, at 0.5, 6, 24, and 48 h post-treatment was analyzed. The genes were up-regulated differentially, according to the elicitor. Chitosan and COA treatments promoted the expression of key phenylpropanoid pathway genes, for synthesis of lignin and flavonoids; only those associated with flavonoid metabolism were up-regulated by BTH. The calcium-dependent protein kinase, endo beta 1,4-glucanase, ascorbate peroxidase, and glutathione-S-transferase genes were up-regulated by BTH. The K+ channel, polygalacturonase, polygalacturonase inhibiting protein, and beta-1,3-glucanase, increased in response to all tested elicitors. The enzyme activities of phenylalanine ammonia lyase, beta-1,3 glucanase, Chitinase, and guaiacol peroxidase supported the gene expression results. Similarity of gene expression was >72% between chitosan and COA treatments, while BTH showed lower similarity (38%) with the other elicitors. This study suggests the relationship between the composition of the elicitors and a specific pattern of induced defense genes. PMID- 24627945 TI - Computational prediction of circular dichroism spectra and quantification of helicity loss upon peptide adsorption on silica. AB - Circular dichroism (CD) spectroscopy is one of the few experimental techniques sensitive to the structural changes that peptides undergo when they adsorb on inorganic material surfaces, a problem of deep significance in medicine, biotechnology, and materials science. Although the theoretical calculation of the CD spectrum of a molecule in a given conformation can be routinely performed, the inverse problem of extracting atomistic structural details from a measured spectrum is not uniquely determined. Especially complicated is the case of oligopeptides, whose folding/unfolding energy landscapes are often very broad and shallow. This means that the CD spectra measured for either dissolved or adsorbed peptides arise from a multitude of different structures, each present with a probability dictated by their relative free-energy variations, according to Boltzmann statistics. Here we present a modeling method based on replica exchange with solute tempering in combination with metadynamics, which allows us to predict both the helicity loss of a small peptide upon interaction with silica colloids in water and to compute the full CD spectra of the adsorbed and dissolved states, in quantitative agreement with experimental measurements. In our method, the CD ellipticity Theta for any given wavelength lambda is calculated as an external collective variable by means of reweighting the biased trajectory obtained using the peptide-SiO2 surface distance and the structural helicity as two independent, internal collective variables. Our results also provide support for the often-employed hypothesis that the Theta intensity at lambda = 222 nm is linearly correlated with the peptides' fractional helicity. PMID- 24627946 TI - A general strategy for label-free sensitive DNA detection based on quantum dot doping. AB - Development of rapid, sensitive, and cost-effective DNA detection is of great significance to meet the growing demand of disease diagnostics. Herein, we report a new general strategy for label-free sensitive in-solution DNA detection using quantum dot (QD) doping-induced photoluminescence as a fluorogenic reporter system. The dopant mercury (Hg(II)) ions are initially sequestered in the hairpin structured probe through T-Hg(2+)-T mismatch formation. Upon hybridization with the DNA target, the hairpin is disrupted and Hg(2+) ions are released and incorporated into ZnSe QDs, leading to a dopant-specific emission peak at 560 nm for DNA detection. Unlike the other methods, this method does not require any chemical modification of the DNA probe. It could provide high signal-to-noise ratio, robust single-base mismatch discrimination capability, and 3 orders of magnitude lower limit of detection (LOD) than the traditional molecular beacon (MB)-based fluorescence spectroscopy without any type of amplification. The method could be used for the detection of a variety of clinical significant DNA targets containing single mutations. To the best of our knowledge, this is the first study on applying chemical transformation of inorganic nanostructures to sensitive DNA detection. PMID- 24627947 TI - How to adjust media recommendations on reporting suicidal behavior to new media developments. AB - This study examines the inclusion of preventive factors and new media developments in media recommendations on suicide reporting. Of the 193 member states of the United Nations screened for media recommendations, information was available for 74 countries. Similarities and differences in their contents were analyzed by cluster analysis. Results indicate that of these 74 countries, 38% have national suicide prevention programs, 38% have media recommendations, and 25% have press codes including suicide reporting. Less than 25% of the media recommendations advise against mentioning online forums, suicide notes, pacts, clusters, hotspots, details of the person, and positive consequences. No more than 15% refer to self-help groups, fictional and online reporting. We conclude that media recommendations need to be revised by adding these preventive factors and by including sections on new media reporting. PMID- 24627948 TI - Distribution, prevalence and intensity of Anguillicola crassus (Nematoda) infection in Anguilla anguilla in the Republic of Ireland. AB - This study is the first comprehensive documentation of the geographical range of Anguillicola crassus in its host, the European eel Anguilla anguilla, in the Republic of Ireland. The prevalence and intensity of infections across 234 sites and 93 river basins in Ireland comprising rivers, lakes and transitional waters (estuaries) were analysed. While only 32% of the river basins were affected by this nematode, they correspond to 74% of the total wetted area. Significant differences in infection levels among water body types were found with lakes and transitional waters yielding the highest values, which can be attributed to the proportions of juvenile (total length, L(T) < 300 mm) A. anguilla caught. There were no significant differences in infection levels between water body types for adult A. anguilla or between sexes for any water body type. Prevalence was significantly lower in juvenile compared with adult A. anguilla captured in rivers and a positive correlation between infection levels and host size-classes was found. Future efforts should focus on monitoring the spread of A. crassus infections and assessing the swimbladder health of A. anguilla in Ireland. PMID- 24627949 TI - Three new triterpene saponins from roots of Eryngium planum. AB - Saponin composition of the roots of Eryngium planum L. was investigated. Triterpene saponins found in E. planum and also present in Eryngium maritimum were different from those described previously in Eryngium campestre L. Three primary saponins were isolated and their tentative identifications, based on the electrospray MS/MS fragmentation patterns, were subsequently confirmed by 1D and 2D NMR analyses. Their structures were established as 3-O-beta-D-glucopyranosyl (1 -> 2)-beta-D-glucuronopyranosyl-21-O-acetyl-22-O-angeloyl-R1-barrigenol (1) and 3-O-beta-D-glucopyranosyl-(1 -> 2)-beta-D-glucuronopyranosyl-22-O-angeloyl-A1 barrigenol (2) and 3-O-beta-D-glucopyranosyl-(1 -> 2)-beta-D-glucuronopyranosyl 22-O-angeloyl-R1-barrigenol (3). Concentrations of the newly identified compounds in aerial parts and roots of both species were estimated using the liquid chromatography-mass spectrometry method. PMID- 24627950 TI - A critical assessment of approaches to outpatient monitoring. PMID- 24627951 TI - The safety and efficacy of chloral hydrate sedation for pediatric ophthalmic procedures: a retrospective review. AB - PURPOSE: To determine the safety and efficacy of high-dose oral chloral hydrate for pediatric ophthalmic procedures. METHODS: This study is a retrospective review of a quality audit of pediatric sedation for ophthalmic evaluation and imaging performed at King Khaled Eye Specialist Hospital between January 1 and December 31, 2011, in children aged 1 month to 6 years. RESULTS: Three hundred fifty-eight of 380 (94.2%) sedation procedures were successful after a single dose of chloral hydrate, with 356 of 380 (93.7%) children sedated within 45 minutes of the first dose. The total success rate of the sedation procedure increased to 97.9% (372 of 380) when a second dose was administered. Children adequately sedated after a single dose of chloral hydrate were on average younger and weighed less than children who required additional doses. No major adverse events were documented. CONCLUSIONS: The use of chloral hydrate sedation for ophthalmic evaluation and imaging was safe and effective in this patient population with a high rate of procedure completion. PMID- 24627952 TI - The efficacy and safety of topical 5% 5-fluorouracil in renal transplant recipients for the treatment of actinic keratoses. AB - Actinic keratoses (AK) occur more commonly and behave more aggressively in renal transplant recipients (RTR). Topical 5% 5-fluorouracil (5-FU) cream is a commonly used agent whose efficacy and safety have never been exclusively studied in the RTR population before. Eight RTR were enrolled and 5% 5-FU cream applied to AK lesions on their face twice daily for 3 weeks. They were reviewed at 2 and 8 weeks, and 12 months post-commencement of treatment. Their AK were counted and their cumulative surface areas measured. Patients completed surveys monitoring adverse effects and tolerability. Complete (100%) and partial clearance (>= 75%) rates were measured, as well as mean percentages of the reduction in AK surface area. Patients had complete clearance rates of 63 and 0% at 8 weeks and 12 months, respectively. All (100%) patients had partial clearance at week 8 and 71% had partial clearance at 12 months. Patients had on average 15 AK at week 0 and 1 and 3 at 8 weeks and 12 months, respectively. The mean AK clearance rate was 98% at week 8 and 79% at 12 months. Common side-effects were erythema, itch and flaking or scaling, mostly mild in severity. 5-FU appears to be an efficacious and safe treatment for AK in RTR. PMID- 24627953 TI - Intercalation of bovine serum albumin coated gold clusters between phospholipid bilayers: temperature-dependent behavior of lipid-AuQC@BSA assemblies with red emission and superlattice structure. AB - A method has been developed to encapsulate bovine serum albumin (BSA)-coated gold quantum clusters (AuQC@BSA) in a multilamellar system of dipalmitoylphosphatidylcholine (DPPC). Results have shown that intercalation of AuQC@BSA particles into lipid bilayers occurs in the presence of CaCl2. Intense red photoluminescence emission was observed after encapsulation of the clusters. A well-defined structure was found with periodic distances drastically larger than that in the pure DPPC/water system. Although Ca(2+) ions can change the dipole characteristics of the lipid bilayer surface, leading to unbinding between the bilayers of multilamellar DPPC/water system, the repulsion is shielded in the presence of AuQC@BSA particles. A coherent superlattice structure evolves due to mixed Ca(2+)-DPPC and Ca(2+)-AuQC@BSA interactions. Studies at different temperatures have suggested a correlation between the luminescence properties of the clusters and phase transition of the lipid layers. The temperature-dependent behavior assumes the connection between the coating and the lipid bilayer surface. Temperature-dependent features of lipid intercalated Au clusters provide new opportunities in their application. PMID- 24627954 TI - Detecting the presence of bacterial DNA by PCR can be useful in diagnosing culture-negative cases of infection, especially in patients with suspected infection and antibiotic therapy. AB - Failing in bacteria isolation in a significant number of infections might be due to the involvement of microorganisms nonrecoverable in culture media. The presence cannot be ruled out of nondividing cells or even bacterial products still capable of promoting a host immunological response. Antibiotic therapy, for example, might induce a block of bacterial division and the impossibility of recovering cells in culture media. In these cases, a molecular method targeting DNA should be used. In this study, 230 clinical samples with a culture-negative report obtained from 182 patients were examined with a protocol of PCR targeting the bacterial 16S rRNA gene to evaluate the usefulness of molecular methods in differencing culture-negative infections from other pathologies. Amplicons were obtained in 14% of the samples, although this percentage increased (27%) in a subgroup of patients with presumptive diagnosis of infection and ongoing antibiotic therapy. By multiplex PCR, it was shown that detected DNA belonged mostly to Enterobacteriaceae and enterococcal species. Multiple culture-negative, PCR-positive samples and isolation of the same bacterial species in culture in additional samples from the same patient support the clinical significance of the data obtained and highlight the complementary role and usefulness of applying molecular methods in diagnostic microbiology. PMID- 24627955 TI - Virus-encapsulated DNA origami nanostructures for cellular delivery. AB - DNA origami structures can be programmed into arbitrary shapes with nanometer scale precision, which opens up numerous attractive opportunities to engineer novel functional materials. One intriguing possibility is to use DNA origamis for fully tunable, targeted, and triggered drug delivery. In this work, we demonstrate the coating of DNA origami nanostructures with virus capsid proteins for enhancing cellular delivery. Our approach utilizes purified cowpea chlorotic mottle virus capsid proteins that can bind and self-assemble on the origami surface through electrostatic interactions and further pack the origami nanostructures inside the viral capsid. Confocal microscopy imaging and transfection studies with a human HEK293 cell line indicate that protein coating improves cellular attachment and delivery of origamis into the cells by 13-fold compared to bare DNA origamis. The presented method could readily find applications not only in sophisticated drug delivery applications but also in organizing intracellular reactions by origami-based templates. PMID- 24627956 TI - Reactivity of an iron-oxygen oxidant generated upon oxidative decarboxylation of biomimetic iron(II) alpha-hydroxy acid complexes. AB - Three biomimetic iron(II) alpha-hydroxy acid complexes, [(Tp(Ph2))Fe(II)(mandelate)(H2O)] (1), [(Tp(Ph2))Fe(II)(benzilate)] (2), and [(Tp(Ph2))Fe(II)(HMP)] (3), together with two iron(II) alpha-methoxy acid complexes, [(Tp(Ph2))Fe(II)(MPA)] (4) and [(Tp(Ph2))Fe(II)(MMP)] (5) (where HMP = 2-hydroxy-2-methylpropanoate, MPA = 2-methoxy-2-phenylacetate, and MMP = 2 methoxy-2-methylpropanoate), of a facial tridentate ligand Tp(Ph2) [where Tp(Ph2) = hydrotris(3,5-diphenylpyrazole-1-yl)borate] were isolated and characterized to study the mechanism of dioxygen activation at the iron(II) centers. Single crystal X-ray structural analyses of 1, 2, and 5 were performed to assess the binding mode of an alpha-hydroxy/methoxy acid anion to the iron(II) center. While the iron(II) alpha-methoxy acid complexes are unreactive toward dioxygen, the iron(II) alpha-hydroxy acid complexes undergo oxidative decarboxylation, implying the importance of the hydroxyl group in the activation of dioxygen. In the reaction with dioxygen, the iron(II) alpha-hydroxy acid complexes form iron(III) phenolate complexes of a modified ligand (Tp(Ph2)*), where the ortho position of one of the phenyl rings of Tp(Ph2) gets hydroxylated. The iron(II) mandelate complex (1), upon decarboxylation of mandelate, affords a mixture of benzaldehyde (67%), benzoic acid (20%), and benzyl alcohol (10%). On the other hand, complexes 2 and 3 react with dioxygen to form benzophenone and acetone, respectively. The intramolecular ligand hydroxylation gets inhibited in the presence of external intercepting agents. Reactions of 1 and 2 with dioxygen in the presence of an excess amount of alkenes result in the formation of the corresponding cis-diols in good yield. The incorporation of both oxygen atoms of dioxygen into the diol products is confirmed by (18)O-labeling studies. On the basis of reactivity and mechanistic studies, the generation of a nucleophilic iron-oxygen intermediate upon decarboxylation of the coordinated alpha-hydroxy acids is proposed as the active oxidant. The novel iron-oxygen intermediate oxidizes various substrates like sulfide, fluorene, toluene, ethylbenzene, and benzaldehyde. The oxidant oxidizes benzaldehyde to benzoic acid and also participates in the Cannizzaro reaction. PMID- 24627957 TI - Iron lanthanide phosphonate clusters: {Fe6Ln6P6} Wells-Dawson-like structures with D3d symmetry. AB - Reaction of [Fe3(MU3-O)(O2C(t)Bu)6(HO2C(t)Bu)3](O2C(t)Bu) and [Ln2(O2C(t)Bu)6(HO2C(t)Bu)6] (Ln = lanthanide) with three different phosphonic acids produce a family of highly symmetrical {Fe6Ln6P6} clusters with general formula [Fe6Ln6(MU3-O)2(CO3)(O3PR)6(O2C(t)Bu)18], where R = methyl 1, phenyl 2, or n-hexyl 3. All the clusters present an analogous metal frame to the previously reported {Ni6Ln6P6} both being related to the well-known Wells-Dawson ion from polyoxometallate chemistry. These highly symmetrical clusters have, or approximate very closely to, D3d point symmetry. Both Fe(III) and Gd(III) ions are magnetically isotropic and could thus exhibit promising magnetocaloric properties; hence we investigated the {Fe6Gd6P6} compounds accordingly. Modeling the magnetic data of [Fe6Gd6(MU3-O)2(CO3)(O3PPh)6(O2C(t)Bu)18] by the finite temperature Lanczos method gave a strong antiferromagnetic Fe...Fe interaction (J(Fe-Fe) = -30 cm(-1)) and very weak Gd...Gd and Gd...Fe exchange interactions (|J| < 0.1 cm(-1)). The strong antiferromagnetic Fe...Fe interaction could account for the relatively smaller -DeltaSm value observed, compared against the {Ni6Gd6P6} analogues. PMID- 24627958 TI - Addition of mesalazine for subclinical post-surgical endoscopic recurrence of Crohn's disease despite preventive thiopurine therapy: A case-control study. AB - BACKGROUND AND AIM: Thiopurines prevent Crohn's disease (CD) endoscopic recurrence (ER) at least in 50% of patients 1 year after surgery. This study aimed to evaluate the value of adding mesalazine in patients with subclinical ER despite preventive thiopurine therapy. METHODS: Crohn's disease patients with ileocecal resection treated with thiopurines for postsurgical recurrence prevention in whom mesalazine was added (cases) to treat ER without clinical recurrence (CR) were identified and compared with those in whom no treatment was added to thiopurines (controls). All patients were followed up for at least 1 year from the index endoscopy. Development of CR as well as evolution of mucosal lesions was evaluated. RESULTS: Thirty-seven patients were included (19 cases and 18 controls). Initial Rutgeerts' score was i2 in 16 patients (9 cases and 7 controls), and i3 in 21 patients (10 cases and 11 controls). After a median clinical follow-up of 59 months (interquartile range 22-100) from the index endoscopy, six cases (32%) and two controls (11%) developed CR (P = 0.2). After a median time to last endoscopic follow-up of 23 months (interquartile range 17 71), 18 patients (49%) showed improvement in Rutgeerts' score, 11 patients (30%) demonstrated progression of mucosal lesions, and 8 (22%) had no changes, with no differences between study groups. CONCLUSIONS: The addition of mesalazine seems to be of no benefit in patients with subclinical endoscopic recurrence while on thiopurine prevention. Moderate endoscopic postsurgical recurrence while on thiopurines may even revert with no additional therapy in some patients. PMID- 24627959 TI - Nobiletin restores impaired hippocampal mitochondrial bioenergetics in hypothyroidism through activation of matrix substrate-level phosphorylation. AB - OBJECTIVE: Evaluation of the effect of citrus flavonoid - nobiletin on the bioenergetics of synaptic and non-synaptic mitochondria in the hippocampus of hypothyroid rats. METHODS: Male Wistar rats were divided into hypothyroid (methimazole-treated), nobiletin supplemented hypothyroid, thyroxine-treated hypothyroid, and euthyroid (control) groups. Synaptic and non-synaptic (cell) mitochondria were isolated from hippocampus. Oligomycin-sensitive, oligomycin insensitive, alpha-ketoglutarate dehydrogenase-dependent synthesis of adenosine triphosphate (ATP), succinate dehydrogenase, and hexokinase activities were determined luminometrically and spectrophotometrically, respectively. RESULTS: Decreased synthesis of oligomycin-sensitive and oligomycin-insensitive ATP in hypothyroid rat hippocampus was observed in synaptic and non-synaptic mitochondria. Supplementation of hypothyroid rats with nobiletin increases oligomycin-insensitive and alpha-ketoglutarate-dependent production of ATP in both types of mitochondria. The activity of succinate dehydrogenase in non synaptic mitochondria and the activities of hexokinase in both types of mitochondria were normalized in nobiletin-treated hypothyroid rats. DISCUSSION: Nobiletin restores reduced mitochondrial metabolism in hypothyroid rat hippocampus through acceleration of matrix substrate-level phosphorylation that may be important for the prevention of hypometabolic complications in neurological disorders. PMID- 24627960 TI - Cognitive model and cognitive behavior therapy for schizophrenia: an overview. AB - BACKGROUND: Schizophrenia causes great suffering for patients and families. Today, patients are treated with medications, but unfortunately many still have persistent symptoms and an impaired quality of life. During the last 20 years of research in cognitive behavioral therapy (CBT) for schizophrenia, evidence has been found that the treatment is good for patients but it is not satisfactory enough, and more studies are being carried out hopefully to achieve further improvement. PURPOSE: Clinical trials and meta-analyses are being used to try to prove the efficacy of CBT. In this article, we summarize recent research using the cognitive model for people with schizophrenia. METHODS: A systematic search was carried out in PubMed (Medline). Relevant articles were selected if they contained a description of cognitive models for schizophrenia or psychotic disorders. RESULTS: There is now evidence that positive and negative symptoms exist in a continuum, from normality (mild form and few symptoms) to fully developed disease (intensive form with many symptoms). Delusional patients have reasoning bias such as jumping to conclusions, and those with hallucination have impaired self-monitoring and experience their own thoughts as voices. Patients with negative symptoms have negative beliefs such as low expectations regarding pleasure and success. In the entire patient group, it is common to have low self esteem. CONCLUSIONS: The cognitive model integrates very well with the aberrant salience model. It takes into account neurobiology, cognitive, emotional and social processes. The therapist uses this knowledge when he or she chooses techniques for treatment of patients. PMID- 24627961 TI - Development of a Swedish Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for adult patients with attention-deficit hyperactivity disorder (ADHD). AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) in adults is a phenomenon that attracts a lot of attention in society today. Advances in research have made it clear that many conditions that make people seek medical and psychiatric care may have pervasive deficits in attention, motor control and impulsivity at their roots. Since ADHD in adults is a relatively new and very versatile concept, there is a great need for systemized classification of the ramifications of the deficit that extends into every aspect of these patients' lives. AIMS: To develop a Swedish Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for adult patients with ADHD. METHODS: A national expert survey was conducted using the Delphi technique and a formal consensus conference. Forty-two experts from different professions and organizations, including psychiatrists and physicians, psychologists, occupational therapists, a counsellor, a specialist nurse, representatives from a patient organization and representatives from the Swedish Social Insurance Agency, participated in the Delphi process and 28 participants from the expert group attended the consensus conference. RESULTS: At the formal consensus conference, 66 categories from the ICF were identified and included in the national Comprehensive Core Set for ADHD: 21 categories from the component body functions, 26 categories from the component activities and participation, and 19 categories from the component environmental factors. CONCLUSION: The Comprehensive Core Set for ADHD should be regarded as national and preliminary, and should be further tested and evaluated by experts in ADHD in clinical settings in Sweden. PMID- 24627962 TI - Finnish Prenatal Study of Bipolar Disorders (FIPS-B): overview, design and description of the sample. AB - BACKGROUND: Bipolar disorders (BPD) are chronic mental illnesses, the development of which involves genetic factors and environmental influences. AIMS: The aim of this paper is to provide an overall description of the Finnish Prenatal Study of Bipolar Disorders (FIPS-B), including the study design, national registers and linkage of the registers. METHODS: FIPS-B is a population-based prenatal epidemiological study of BPD with a nested case-control study design using several national registers. The registers used are: the Finnish Medical Birth Register (FMBR), the Finnish Hospital Discharge Register (FHDR), the Population Central Register and the Finnish Maternity Cohort (FMC), which are linked using the unique personal identity code (PIC). FIPS-B includes all children born from January 1, 1983 to December 31, 1998 and diagnosed with BPD in Finland by December 31, 2008. RESULTS: The total number of cases included in the FIPS-B is 1887. The age at first diagnosis ranged from 4 to 25 years. Half (50.4%) of the cases utilized only outpatient services, 12.7% only inpatient services and the rest (36.9%) utilized both services. Offspring of mothers with the lowest educational level had an increased odds of BPD (OR = 1.46, 95% CI 1.13-1.88). The cumulative incidence of BPD in the population aged 25 years or younger was 11.6/10,000 in 2008. CONCLUSIONS: FIPS-B has all the strengths of a register based prenatal epidemiological study, along with the availability of maternal biomarkers, enabling it to examine several prenatal, perinatal and familial risk factors for BPD. PMID- 24627963 TI - Pseudo-hypoproteinemia in a hyperbilirubinemic dog with immune-mediated hemolytic anemia. AB - A 10-year-old spayed female Miniature Poodle was presented to the University of Georgia veterinary teaching hospital for evaluation of lethargy, vomiting and anorexia of 4 days' duration. Physical examination, history and a minimum database led to a diagnosis of immune-mediated hemolytic anemia accompanied by marked hyperbilirubinemia. Refractometric protein determination was within the reference interval, whereas the biuret method indicated hypoproteinemia. This discrepancy was attributed to interference of bilirubin and biliverdin with the spectrophotometric read-out of the biuret total protein assay. The albumin concentration, determined by bromcresol green, and refractometric total protein were less affected by this interference. PMID- 24627964 TI - Characterization of OsLCT1, a cadmium transporter from indica rice (Oryza sativa). AB - Molecular understanding of cadmium (Cd) transport in indica rice (Oryza sativa) is still insufficient, although indica rice generally has a potential to accumulate higher Cd in shoots and grains than japonica rice. We have previously demonstrated that OsLCT1 is a Cd transporter gene responsible for grain Cd accumulation in the japonica model cultivar Nipponbare. In this study, we isolated OsLCT1 cDNA from Kasalath, a model indica (aus subgroup) cultivar and conducted cation transport activity assays in yeast and mRNA expression analysis in plants. The deduced amino acid sequence of Kasalath OsLCT1 is 91.2% identical and 93.8% similar to that of Nipponbare OsLCT1. We established the yeast heterologous system expressing the Kasalath allele of OsLCT1. Elemental profiling of the yeast cells suggested an efflux activity of Kasalath OsLCT1 for Cd, K, Mg, Ca and Mn, but not for Fe, Zn, Cu and Na. This substrate specificity was identical to that of the Nipponbare version. Quantitative real time-polymerase chain reaction (RT-PCR) showed that expression of OsLCT1 in Kasalath was higher in reproductive stage than in vegetative stage. The expression level of OsLCT1 was significantly higher in Kasalath than in Nipponbare. Phylogenetic analysis found several LCT1-like genes only in grass plants. OsLCT1 is the sole copy in the rice genome and is conserved among each rice subgroup. These newly found low affinity cation transporter (LCT) homologs will provide a basis for further understanding of LCT-mediated Cd transport. PMID- 24627966 TI - Polyglycine hydrolases secreted by Pleosporineae fungi that target the linker region of plant class IV chitinases. AB - Cmps (chitinase-modifying proteins) are fungal proteases that truncate plant class IV chitinases by cleaving near their N-termini. We previously described Fv cmp, a fungalysin protease that cleaves a conserved glycine-cysteine bond within the hevein domain. In the present paper we describe a new type of cmp, polyglycine hydrolases, as proteases that selectively cleave glycine-glycine peptide bonds within the polyglycine linker of plant class IV chitinases. Polyglycine hydrolases were purified from Cochliobolus carbonum (syn. Bipolaris zeicola; Bz-cmp) and Epicoccum sorghi (syn. Phoma sorghina; Es-cmp) and were shown to cleave three different maize class IV chitinase substrates. The proteolytic cleavage sites were assessed by SDS/PAGE and MALDI-TOF-MS and indicated the cleavage of multiple peptide bonds within the polyglycine linker regions. Site-directed mutagenesis was used to produce mutants of maize ChitB chitinase in which two serine residues in its linker were systematically modified to glycine. Serine to glycine changes in the ChitB linker resulted in higher susceptibility to truncation by Bz-cmp and altered substrate specificity for Bz cmp and Es-cmp, such that different glycine-glycine peptide bonds were cleaved. Removal of the hevein domain led to loss of Es-cmp activity, indicating that interactions outside of the active site are important for recognition. Our findings demonstrate that plant class IV chitinases with polyglycine linkers are targeted for truncation by selective polyglycine hydrolases that are secreted by plant pathogenic fungi. This novel proteolysis of polyglycine motifs is previously unreported, but the specificity is similar to that of bacterial lysostaphin proteases, which cleave pentaglycine cross-links from peptidoglycan. PMID- 24627965 TI - Directing group-controlled regioselectivity in an enzymatic C-H bond oxygenation. AB - Highly regioselective remote hydroxylation of a natural product scaffold is demonstrated by exploiting the anchoring mechanism of the biosynthetic P450 monooxygenase PikCD50N-RhFRED. Previous studies have revealed structural and biochemical evidence for the role of a salt bridge between the desosamine N,N dimethylamino functionality of the natural substrate YC-17 and carboxylate residues within the active site of the enzyme, and selectivity in subsequent C-H bond functionalization. In the present study, a substrate-engineering approach was conducted that involves replacing desosamine with varied synthetic N,N dimethylamino anchoring groups. We then determined their ability to mediate enzymatic total turnover numbers approaching or exceeding that of the natural sugar, while enabling ready introduction and removal of these amino anchoring groups from the substrate. The data establish that the size, stereochemistry, and rigidity of the anchoring group influence the regioselectivity of enzymatic hydroxylation. The natural anchoring group desosamine affords a 1:1 mixture of regioisomers, while synthetic anchors shift YC-17 analogue C-10/C-12 hydroxylation from 20:1 to 1:4. The work demonstrates the utility of substrate engineering as an orthogonal approach to protein engineering for modulation of regioselective C-H functionalization in biocatalysis. PMID- 24627967 TI - Discontinuation of dual antiplatelet therapy over 12 months after acute coronary syndromes increases risk for adverse events in patients treated with percutaneous coronary intervention: systematic review and meta-analysis. AB - INTRODUCTION: Duration of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) hospitalization remains to be defined, both for patients treated medically and for those undergoing percutaneous transluminal coronary angioplasty (PTCA). METHODS: PubMed, Cochrane, and Google Scholar were systematically searched for studies including patients presenting with ACS, and treated either with DAPT longer than or shorter than 12 months. Multivariable adjusted risk estimates for death and recurrent ACS with stopping DAPT after 12 months (odds ratios [OR] 95% confidence intervals [CI]) were pooled after logarithmic transformation according to random-effect models with inverse variance weighting. RESULTS: Five studies with 49,586 patients were included. Median age was 66 (64-67) years, with 67% (65-75) males. Myocardial infarction (MI) represented the admission diagnosis for 88% (60-100) of the patients, and 66% (50-74) were treated with stenting. After a follow-up of 2.1 years (1.5-2.7), 40% (35-46) still on DAPT after 12 months and the rates of death or recurrent ACS were 16.6 (14.5-17.0). Risk of adverse events for patients stopping DAPT after 1 year was significantly increased (OR = 1.19 [1.07-1.32]) for those receiving stents, but not for patients managed medically (OR = 1.13 [0.95-1.35]). The increased risk did not vary according to age, gender, myocardial infarction as admission diagnosis, and kind of stent. CONCLUSIONS: Interruption of DAPT over 12 months after ACS increases the risk of adverse events for patients treated with PTCA, but not for those managed conservatively, independently from baseline features and admission diagnosis. This hypothesis-generating finding should be tested in randomized controlled trials. PMID- 24627969 TI - Effectiveness of ProTaper Universal retreatment instruments used with rotary or reciprocating adaptive motion in the removal of root canal filling material. AB - AIM: To compare the effectiveness of ProTaper Universal retreatment instruments with continuous rotation and adaptive motion (AM; a modified reciprocating motion that combines rotational and reciprocating motion) in the removal of filling material. METHODOLOGY: Mesiobuccal root canals in 36 mandibular first molars were instrumented up to size F2 with the ProTaper Universal instrument (Dentsply Maillefer, Ballaigues, Switzerland) and filled using sealer and ProTaper Universal F2 gutta-percha cones. Gutta-percha was then down-packed and the root canal backfilled using the extruder hand-piece of the Elements Obturation System (SybronEndo, Orange, CA, USA). The teeth were assigned to two groups (n = 18), and removal of the root fillings was performed using one of the following techniques: group 1) ProTaper Universal retreatment files used with rotational motion (RM) and group 2) ProTaper Universal retreatment files used with adaptive motion (AM) (600 degrees clockwise/0 degrees counter-clockwise to 370 degrees clockwise/50 degrees counter-clockwise). The teeth were sectioned, and both halves were analysed at 8 * magnification. The percentage of remaining filling material was recorded. The data were analysed statistically using the Student's t test at a 95% confidence level (P < 0.05). RESULTS: There was no significant difference between the groups with respect to the total time required for retreatment (P = 0.481). The AM technique left significantly less filling material than the RM method (P = 0.013). CONCLUSION: The use of ProTaper Universal retreatment files with adaptive motion removed more filling materials from root canals than the rotational movement. PMID- 24627968 TI - Reactive oxygen species induce MMP12-dependent degradation of collagen 5 and fibronectin to promote the motility of human umbilical cord-derived mesenchymal stem cells. AB - BACKGROUND AND PURPOSE: Reactive oxygen species (ROS) are potent regulators of stem cell behaviour; however, their physiological significance as regards MMP mediated regulation of the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) has not been characterized. In the present study, we investigated the role of hydrogen peroxide (H2O2 ) and associated signalling pathways in promoting UCB-MSCs motility. EXPERIMENTAL APPROACH: The regulatory effects of H2O2 on the activation of PKC, MAPKs, NF-kappaB and beta catenin were determined. The expressions of MMP and extracellular matrix proteins were examined. Pharmacological inhibitors and gene-specific siRNA were used to identify the signalling pathways of H2O2 that affect UCB-MSCs motility. An experimental skin wound-healing model was used to confirm the functional role of UCB-MSCs treated with H2O2 in ICR mice. KEY RESULTS: H2O2 increased the motility of UCB-MSCs by activating PKCalpha via a calcium influx mechanism. H2O2 activated ERK and p38 MAPK, which are responsible for the distinct activation of transcription factors NF-kappaB and beta-catenin. UCB-MSCs expressed eight MMP genes, but only MMP12 expression was uniquely regulated by NF-kappaB and beta catenin activation. H2O2 increased the MMP12-dependent degradation of collagen 5 (COL-5) and fibronectin (FN) associated with UCB-MSCs motility. Finally, topical transplantation of UCB-MSCs treated with H2O2 enhanced skin wound healing in mice. CONCLUSIONS AND IMPLICATIONS: H2O2 stimulated UCB-MSCs motility by increasing MMP12-dependent degradation of COL-5 and FN through the activation of NF-kappaB and glycogen synthase kinase-3beta/beta-catenin, which is critical for providing a suitable microenvironment for MSCs transplantation and re epithelialization of skin wounds in mice. PMID- 24627970 TI - Marker assisted selection of low phytic acid trait in maize (Zea mays L.). AB - Maize is the third important major food crop. Breeding for low phytate maize genotypes is an effective strategy for decreasing the content of kernel phytic acid (a chelator of cations such as Ca(2+) and Fe(3+) ) and thereby increasing the bioavailability of nutritive minerals in human diet and animal feed. Previous studies have established that a mutant plant with a lpa2-2 allele accumulates less phytic acid in seeds. Therefore, the marker assisted backcross breeding (MABB), which involves introgression of lpa2-2 recessive allele (which confer low phytate trait) from a lpa2-2 mutant line into a well-adapted line using backcrosses and selection of lines possessing lpa2-2 allele in each backcross population using molecular markers, is an effective strategy for developing low phytate maize. So far, no studies have developed any lpa2-2 allele specific molecular markers for this purpose. Here, using backcross and selfed progenies, obtained by crossing low phytate mutant line 'EC 659418' (i.e. donor of lpa2-2 allele) into agronomically superior line 'UMI395', we have validated that a SSR marker 'umc2230', located 0.4 cM downstream of lpa2-2, cosegregate, in a Mendelian fashion, with low phytic acid trait. Therefore umc2230 can be dependably used in MABB for the development of low phytate maize. PMID- 24627972 TI - The excess mortality related to cardiovascular diseases and cancer among adults pharmacologically treated for diabetes--the 2001-2006 ENTRED cohort. AB - AIMS: To compare the 5-year mortality (overall and cause-specific) of a cohort of adults pharmacologically treated for diabetes with that of the rest of the French adult population. METHODS: In 2001, 10 000 adults treated for diabetes were randomly selected from the major French National Health Insurance System database. Vital status and causes of death were successfully extracted from the national registry for 9101 persons. We computed standardized mortality ratios. RESULTS: Over 5 years, 1388 adults pharmacologically treated for diabetes died (15% of the cohort, 32.4/1000 person-years). An excess mortality, which decreased with age, was found for both genders [standardized mortality ratio 1.45 (1.37 1.52)]. Excess mortality was related to: hypertensive disease [2.90 (2.50-3.33)], ischaemic heart disease [2.19 (1.93-2.48)], cerebrovascular disease [1.76 (1.52 2.03)], renal failure [2.14 (1.77-2.56)], hepatic failure [2.17 (1.52-3.00)] in both genders and septicaemia among men [1.56 (1.15-2.09)]. An association was also found with cancer-related mortality: liver cancer in men [3.00 (2.10-4.15)]; pancreatic cancer in women [3.22 (1.94-5.03)]; colon/rectum cancer in both genders [1.66 (1.28-2.12)]. Excess mortality was not observed for breast, lung or stomach cancers. CONCLUSIONS: Adults pharmacologically treated for diabetes had a 45% increased risk of mortality at 5 years, mostly related to cardiovascular complications, emphasizing the need for further prevention. The increased risk of mortality from cancer raises questions about the relationship between cancer and diabetes and prompts the need for improved cancer screening in people with diabetes. PMID- 24627973 TI - Isolation and HPLC method development of azafrin from Alectra parasitica var. chitrakutensis. AB - This study was undertaken to isolate and quantify azafrin in Alectra parasitica (Scrophulariaceae) rhizomes. A simple method for the isolation of carotenoid, azafrin, involves solvent extraction of the dried rhizome powder using a single solvent and further purification by recrystallisation. The structure of the compound was elucidated and confirmed by thin-layer chromatography, infrared spectroscopy, mass spectroscopy and nuclear magnetic resonance spectral analysis. A specific and rapid reversed-phase high-performance liquid chromatography (HPLC) method was developed for the analysis of azafrin. The method was validated for accuracy, precision, linearity and specificity. Validation revealed that the method is specific, accurate, precise, reliable and reproducible. The proposed HPLC method can be used for the identification and quantitative analysis of azafrin in A. parasitica rhizomes. PMID- 24627971 TI - Detecting cryptic indirect genetic effects. AB - Indirect genetic effects (IGEs) occur when genes expressed in one individual alter the phenotype of an interacting partner. IGEs can dramatically affect the expression and evolution of social traits. However, the interacting phenotype(s) through which they are transmitted are often unknown, or cryptic, and their detection would enhance our ability to accurately predict evolutionary change. To illustrate this challenge and possible solutions to it, we assayed male leg tapping behavior using inbred lines of Drosophila melanogaster paired with a common focal male strain. The expression of tapping in focal males was dependent on the genotype of their interacting partner, but this strong IGE was cryptic. Using a multiple-regression approach, we identified male startle response as a candidate interacting phenotype: the longer it took interacting males to settle after being startled, the less focal males tapped them. A genome-wide association analysis identified approximately a dozen candidate protein-coding genes potentially underlying the IGE, of which the most significant was slowpoke. Our methodological framework provides information about candidate phenotypes and candidate single-nucleotide polymorphisms that underpin a strong yet cryptic IGE. We discuss how this approach can facilitate the detection of cryptic IGEs contributing to unusual evolutionary dynamics in other study systems. PMID- 24627974 TI - Systematic evidence synthesis of treatments for ADHD in children and adolescents: indirect treatment comparisons of lisdexamfetamine with methylphenidate and atomoxetine. AB - OBJECTIVE: Systematically review and synthesize the clinical evidence of treatments for attention deficit hyperactivity disorder (ADHD) by indirectly comparing established treatments in the UK with a drug recently approved in Europe (lisdexamfetamine [LDX]). RESEARCH DESIGN AND METHODS: POPULATION: children and adolescents. SETTING: Europe. Comparators: methylphenidate (MPH), atomoxetine (ATX), and dexamphetamine (DEX). Electronic databases and relevant conference proceedings were searched for randomized, controlled clinical trials evaluating efficacy and safety of at least one of the comparators and LDX. Quality assessments for each included trial were performed using criteria recommended by the Centre for Reviews and Dissemination. Network meta-analysis methods for dichotomous outcomes were employed to evaluate treatment efficacy. MAIN OUTCOME MEASURES: Response, as defined by either a reduction from baseline of at least 25% in the ADHD Rating Scale [ADHD-RS] total score or, separately, as assessed on the Clinical Global Impression-Improvement [CGI-I] scale, and safety (all-cause withdrawals and withdrawal due to adverse events). RESULTS: The systematic review found 32 trials for the meta-analysis, including data on LDX, ATX, and different formulations of MPH. No trials for DEX meeting the inclusion criteria were found. Sufficient data were identified for each outcome: ADHD-RS, 16 trials; CGI-I, 20 trials; all-cause withdrawals, 28 trials; and withdrawals due to adverse events, 27 trials. The relative probability of treatment response for CGI-I (95% confidence intervals [CI]) for ATX versus LDX was 0.65 (0.53 0.78); for long-acting MPH versus LDX, 0.82 (0.69-0.97); for intermediate release MPH versus LDX, 0.51 (0.40-0.65); and for short-acting MPH versus LDX, 0.62 (0.51 0.76). The relative probabilities of ADHD-RS treatment response also favored LDX. CONCLUSIONS: For the treatment of ADHD, the synthesis of efficacy data showed statistically significant better probabilities of response with LDX than for formulations of MPH or ATX. The analysis of safety data proved inconclusive due to low event rates. These results may be limited by the studies included, which only investigated the short-term efficacy of medications in patients without comorbid disorders. PMID- 24627975 TI - Derivation of an oral reference dose (RfD) for the nonphthalate alternative plasticizer 1,2-cyclohexane dicarboxylic acid, di-isononyl ester (DINCH). AB - 1,2-Cyclohexanedicarboxylic acid, 1,2-diisononylester (DINCH), a polyvinyl chloride plasticizer, has food, beverage, and medical device applications that may result in general population exposure. Although no apparent toxicity information in humans was identified, there is a substantial data set in lab animals to serve as the basis of hazard identification for DINCH. Target tissues associated with repeated dietary DINCH exposure in lab animals included liver, kidney, and thyroid and mammary glands. In contrast to some phthalate ester plasticizers, DINCH did not show evidence of hepatic peroxisomal proliferation, testicular toxicity, or liver tumors in rats. Liver and thyroid effects associated with DINCH exposure were attributed to compensatory thyroid stimulation secondary to prolonged metabolic enzyme induction. The toxicological significance of mammary fibroadenomas in female rats is unclear, given that this common benign and spontaneously occurring tumor type is unique to rats. The weight of evidence suggests DINCH is not genotoxic and the proposed mode of action (MOA) for thyroid gland lesions was considered to have a threshold. No adverse reproductive effects were seen in a two-generation study. An oral reference dose (RfD) of 0.7 mg/kg-d was derived from a human equivalent BMDL10 of 21 mg/kg-d for thyroid hypertrophy/hyperplasia seen in adult F1 rats also exposed in utero. The total uncertainty factor of 30x was comprised of intraspecies (10*) and database (3*) factors. An interspecies extrapolation factor was not applied since rodents are more sensitive than humans with respect to the proposed indirect MOA for thyroid gland lesions. PMID- 24627976 TI - Toxicogenetic profile and cancer risk in Lebanese. AB - An increasing number of genetic polymorphisms in drug-metabolizing enzymes (DME) were identified among different ethnic groups. Some of these polymorphisms are associated with an increased cancer risk, while others remain equivocal. However, there is sufficient evidence that these associations become significant in populations overexposed to environmental carcinogens. Hence, genetic differences in expression activity of both Phase I and Phase II enzymes may affect cancer risk in exposed populations. In Lebanon, there has been a marked rise in reported cancer incidence since the 1990s. There are also indicators of exposure to unusually high levels of environmental pollutants and carcinogens in the country. This review considers this high cancer incidence by exploring a potential gene environment model based on available DME polymorphism prevalence, and their impact on bladder, colorectal, prostate, breast, and lung cancer in the Lebanese population. The examined DME include glutathione S-transferases (GST), N acetyltransferases (NAT), and cytochromes P-450 (CYP). Data suggest that these DME influence bladder cancer risk in the Lebanese population. Evidence indicates that identification of a gene-environment interaction model may help in defining future research priorities and preventive cancer control strategies in this country, particularly for breast and lung cancer. PMID- 24627977 TI - Association between mood and diet quality in subjects with metabolic syndrome participating in a behavioural weight-loss programme: a cross-sectional assessment. AB - BACKGROUND/OBJECTIVE: The interplay between individual's mood fluctuations and nutrition has important health implications. However, little information is available on the relationship between dietary intake and mood state in a population with metabolic syndrome (MetS). The aim of the present study was to evaluate the association between dietary intake and mood state in subjects with MetS. METHODS: This cross-sectional study was based on the baseline data of 84 volunteers (mean age 49 +/- 1 years) recruited into the Metabolic Syndrome Reduction in Navarra-Spain (RESMENA-S) study. Mood state was determined using a mood thermometer visual analogue scale. The dietary intake was assessed with a 48 hours weighted food record, from which a Healthy Eating Index (HEI) score was obtained. Anthropometrical measurements and biochemical parameters were also analysed. RESULTS: At baseline, a positive association between mood thermometer and HEI was observed. Among the 10 HEI components, vegetables, fruits, calories from lipids, saturated fatty acids, and dietary variety were related with higher mood. Moreover, those participants who consumed more water, fibre, vitamin B6, ascorbic acid, tryptophan, magnesium, and selenium have higher mood. DISCUSSION: In conclusion, an association between both the overall dietary pattern and isolated nutrients with mood state was observed. The analyses of both dietary patterns and specific nutrients are important to determine the association between mental disorders and dietary intake. PMID- 24627978 TI - Personality risk for alcohol consequences among college freshmen. AB - Drinking is pervasive in the lifestyle of many college students. This study investigated the relationship between drinking and students' impulsivity, sensation seeking, alcohol consequences, and expectancies. The study was based on the Acquired Preparedness Model, which posits that personality constructs like impulsivity and sensation seeking influence drinking through the formation of positive expectancies about the effects of drinking. Freshmen (N = 260) from a large public university volunteered for the study and were administered three surveys. Structural equation modeling was used to examine the study variables. The findings showed that the total effect of impulsivity was mediated by positive alcohol expectancies. The total effect of sensation seeking was mediated by alcohol expectancies. Freshmen who were more impulsive and sensation seeking had more positive alcohol expectancies and experienced more negative consequences related to alcohol use. These findings suggest that the risk of alcohol consequences was associated with personality constructs and alcohol expectancies. PMID- 24627979 TI - Characterization of the pharmaceutical effect of drugs on atherosclerotic lesions in vivo using integrated fluorescence imaging and Raman spectral measurements. AB - Direct assessment of the vascular lesions of model animals in vivo is important for the development of new antiatherosclerotic drugs. Nevertheless, biochemical analysis of the lipid profile in blood in vitro remains the most common way to evaluate the therapeutic effect of drugs targeting atherosclerosis because of an inherent difficulty to access the vascular wall. Using hypercholesterolemic zebrafish, we present an orchestrated application of Raman spectral measurements and confocal fluorescence imaging to interrogate the pharmacological response of atherosclerotic lesions in situ and in vivo. For demonstration, we investigated two commonly prescribed antihyperlipidemic drugs, ezetimibe and atorvastatin. The treatment of ezetimibe or atorvastatin alone decreased effectively the deposition of lipids in the vascular wall, and a combined dose showed a synergistic effect. Atorvastatin exerted a profound antioxidative effect on vascular fatty lesions. Analysis of individual lesions shows further that these lesions exhibited a heterogeneous response to the treatment of atorvastatin; a significant fraction of, but not all, the lesions became nonoxidized after the intervention. Beyond its efficacies in suppressing both the accumulation and oxidation of vascular lipids, atorvastatin expedited the clearance of vascular lipids. The possession of pleotropic (multiple) therapeutic effects on vascular fatty lesions of hypercholesterolemic zebrafish by atorvastatin is notably consistent with the known pharmaceutical effects of this drug on human beings. These results improve our understanding of the antiatherosclerotic effect of drugs. We envisage that our approach has the potential to become a platform to predict the pharmaceutical effects of new drugs aiming to cure human atherosclerotic diseases. PMID- 24627980 TI - [4.2](2,2')(2,2')Biphenylophanetriyne: a twisted biphenylophane with a highly distorted diacetylene bridge. AB - Biphenylophane 1 bridged by acetylene and diacetylene linkages was synthesized. X ray analysis revealed its highly deformed diacetylene unit with a bond angle of 160 degrees . Enantiomers of 1 resolved by chiral HPLC underwent facile racemization with an activation energy of 90.6 kJ mol(-1). Transannular cyclization of 1 was induced by heating to generate benzyne intermediate 8, which was intercepted by furan to give 9, and by treatment with bromine to give dibromodibenzopicene (10). PMID- 24627981 TI - Two-site adsolubilization model of incorporation of fluoromonomers into fluorosurfactants formed on cotton fabric. AB - The adsorption of surfactants and adsolubilization of organic compounds on knit cotton fabric are fundamentally important in admicellar polymerization to impart characteristics like water repellency, stain resistance, and flame retardancy. The main objective of this research is to study adsorption and adsolubilization of fluororsurfactants and fluoromonomers used to obtain water repellency characteristics. Adsorption of nonionic (fluoroaliphatic amine oxide) and cationic (fluoroaliphatic quaternary ammonium surfactant) fluororsurfactants at the interface of cotton is investigated with and without fluoroacrylate monomers. A two-site adsolubilization model was used to predict the aggregation number of fluorosurfactant. PMID- 24627982 TI - Supergelation via purely aromatic pi-pi driven self-assembly of pseudodiscotic oxadiazole mesogens. AB - A series of highly luminescent oxadiazole-based stilbene molecules (OXD4, OXD8, OXD10, and OXD12) exhibiting interesting enantiotropic liquid crystalline and gelation properties have been synthesized and characterized. The molecules possessing longer alkyl substituents, OXD10 and OXD12, possess a pseudodisc shape and are capable of behaving as supergelators in nonpolar solvents, forming self standing gels with very high thermal and mechanical stability. Notably the self assembly of these molecules, which do not possess any hydrogen-bonding motifs normally observed in most reported supergelators, is driven purely by pi-stacking interactions of the constituent molecules. The d-spacing ratios estimated from XRD analysis of OXD derivatives possessing longer alkyl chains show that the molecules are arranged in a columnar fashion in the mesogens and the self assembled nanofibers formed in the gelation process. PMID- 24627983 TI - 2D spectroscopy study of water-soluble chlorophyll-binding protein from Lepidium virginicum. AB - Water-soluble chlorophyll-binding proteins (WSCPs) are interesting model systems for the study of pigment-pigment and pigment-protein interactions. While class IIa WSCP has been extensively studied by spectroscopic and theoretical methods, a comprehensive spectroscopic study of class IIb WSCP was lacking so far despite the fact that its structure was determined by X-ray crystallography. In this paper, results of two-dimensional electronic spectroscopy applied to the class IIb WSCP from Lepidium virginicum are presented. Global analysis of 2D data allowed determination of energy levels and excitation energy transfer pathways in the system. Some additional pathways, not present in class IIa WSCP, were observed. The data were interpreted in terms of a model comprising two interacting chlorophyll dimers. In addition, oscillatory signals were observed and identified as coherent beatings of vibrational origin. PMID- 24627984 TI - Blending lecithin and gelatin improves the formation of thymol nanodispersions. AB - Delivery systems of lipophilic antimicrobials such as thymol prepared with generally recognized-as-safe ingredients are needed to enhance the microbiological safety of low-acid (pH > 4.6) foods. Nanodispersions with particle diameters below 100 nm are particularly demanded because of the low turbidity and physical stability. In this study, thymol dispersions were prepared by gelatin and soy lecithin on an individual basis or in combination. Dispersions prepared with the lecithin-gelatin blend were translucent and stable at pH 5.0 8.0, contrasting with turbid and unstable dispersions when the emulsifiers were used individually. The synergistic surface activity of gelatin and lecithin was due to complex formation that effectively prevented particle size change due to coalescence and Ostwald ripening. Electrostatic interactions were observed to be the colloidal force responsible for preventing particle aggregation. The studied generally recognized-as-safe nanodispersions have great potential to deliver lipophilic antimicrobials such as thymol in low-acid foods to enhance food safety. PMID- 24627985 TI - The non-muscle functions of actinins: an update. AB - alpha-Actinins are a major class of actin filament cross-linking proteins expressed in virtually all cells. In muscle, actinins cross-link thin filaments from adjacent sarcomeres. In non-muscle cells, different actinin isoforms play analogous roles in cross-linking actin filaments and anchoring them to structures such as cell-cell and cell-matrix junctions. Although actinins have long been known to play roles in cytokinesis, cell adhesion and cell migration, recent studies have provided further mechanistic insights into these functions. Roles for actinins in synaptic plasticity and membrane trafficking events have emerged more recently, as has a 'non-canonical' function for actinins in transcriptional regulation in the nucleus. In the present paper we review recent advances in our understanding of these diverse cell biological functions of actinins in non muscle cells, as well as their roles in cancer and in genetic disorders affecting platelet and kidney physiology. We also make two proposals with regard to the actinin nomenclature. First, we argue that naming actinin isoforms according to their expression patterns is problematic and we suggest a more precise nomenclature system. Secondly, we suggest that the alpha in alpha-actinin is superfluous and can be omitted. PMID- 24627986 TI - Mechanically interlocked DNA nanostructures for functional devices. AB - CONSPECTUS: Self-assembled functional DNA oligonucleotide based architectures represent highly promising candidates for the creation of nanoscale devices. The field of DNA nanotechnology has emerged to a high level of maturity and currently constitutes one of the most dynamic, creative, and exciting modern research areas. The transformation from structural DNA nanotechnology to functional DNA architectures is already taking place with tremendous pace. Particularly the advent of DNA origami technology has propelled DNA nanotechnology forward. DNA origami provided a versatile method for precisely aligning structural and functional DNA modules in two and three dimensions, thereby serving as a means for constructing scaffolds and chassis required for the precise orchestration of multiple functional DNA architectures. Key modules of these will contain interlocked nanomechanical components made of DNA. The mechanical interlocking allows for performing highly specific and controlled motion, by reducing the dimensionality of diffusion-controlled processes without restrictions in motional flexibility. Examples for nanoscale interlocked DNA architectures illustrate how elementary functional units of future nanomachines can be designed and realized, and show what role interlocked DNA architectures may play in this endeavor. Functional supramolecular systems, in general, and nanomachinery, in particular, self-organize into architectures that reflect different levels of complexity with respect to their function, their arrangement in the second and third dimension, their suitability for different purposes, and their functional interplay. Toward this goal, DNA nanotechnology and especially the DNA origami technology provide opportunities for nanomechanics, nanorobotics, and nanomachines. In this Account, we address approaches that apply to the construction of interlocked DNA nanostructures, drawing largely form our own contributions to interlocked architectures based on double-stranded (ds) circular geometries, and describe progress, opportunities, and challenges in rotaxanes and pseudorotaxanes made of dsDNA. Operating nanomechanical devices in a reliable and repetitive fashion requires methods for switching movable parts in DNA nanostructures from one state to another. An important issue is the orthogonality of switches that allow for operating different parts in parallel under spatiotemporal control. A variety of switching methods have been applied to switch individual components in interlocked DNA nanostructures like rotaxanes and catenanes. They are based on toehold, light, pseudocomplementary peptide nucleic acids (pcPNAs), and others. The key issues discussed here illustrate our perspective on the future prospects of interlocked DNA-based devices and the challenges that lay ahead. PMID- 24627987 TI - What is your diagnosis? Aspirate from a digit in a cat. PMID- 24627988 TI - Persistent occiput posterior: OUTcomes following digital rotation: a pilot randomised controlled trial. AB - AIM: To determine the feasibility of a multicentre randomised controlled trial (RCT) to investigate whether digital rotation of the fetal head from occiput posterior (OP) position in the second stage of labour reduces the risk of operative delivery (defined as caesarean section (CS) or instrumental delivery). METHODS: We conducted the study between December 2010 and December 2011 in a tertiary referral hospital in Australia. A transabdominal ultrasound was performed early in the second stage of labour on women with cephalic, singleton pregnancies to determine the fetal position. Those women with a fetus in the OP position were randomised to either a digital rotation or a sham procedure. In all other ways, participants received their usual intrapartum care. Data regarding demographics, mode of delivery, labour, post natal period and neonatal outcomes were collected. RESULTS: One thousand and four women were consented, 834 achieved full dilatation, and 30 were randomised. An additional portable ultrasound scan and a blinded 'sham' digital rotation were acceptable to women and staff. Operative delivery rates were 13/15 in the digital rotation (four CS and nine instrumental) and 12/15 in the sham (three CS and nine instrumental) groups, respectively. CONCLUSION: A large double-blinded multicentre RCT would be feasible and acceptable to women and staff. Strategies to improve recruitment such as consenting women with an effective epidural in active labour should be considered. This would be the first RCT to answer a clinically important question which could significantly affect the operative delivery rate in Australia and internationally. PMID- 24627989 TI - Diversity of pulsed-field gel electrophoresis patterns of cereulide-producing isolates of Bacillus cereus and Bacillus weihenstephanensis. AB - Bacillus cereus is an important foodborne pathogen causing diarrhoea, emesis and in, rare cases, lethal poisonings. The emetic syndrome is caused by cereulide, a heat-stable toxin. Originally considered as a rather homogenous group, the emetic strains have since been shown to display some diversity, including the existence of two clusters of mesophilic B. cereus and psychrotolerant B. weihenstephanensis. Using pulsed-field gel electrophoresis (PFGE) analysis, this research aimed to better understand the diversity and spatio-temporal occurrence of emetic strains originating from environmental or food niches vs. those isolated from foodborne cases. The diversity was evaluated using a set of 52 B. cereus and B. weihenstephanensis strains isolated between 2000 and 2011 in ten countries. PFGE analysis could discriminate 17 distinct profiles (pulsotypes). The most striking observations were as follows: (1) more than one emetic pulsotype can be observed in a single outbreak; (2) the number of distinct isolates involved in emetic intoxications is limited, and these potentially clonal strains frequently occurred in successive and independent food poisoning cases; (3) isolates from different countries displayed identical profiles; and (4) the cereulide-producing psychrotolerant B. weihenstephanensis were, so far, only isolated from environmental niches. PMID- 24627990 TI - Making good theory practical: five lessons for an Applied Social Identity Approach to challenges of organizational, health, and clinical psychology. AB - Social identity research was pioneered as a distinctive theoretical approach to the analysis of intergroup relations but over the last two decades it has increasingly been used to shed light on applied issues. One early application of insights from social identity and self-categorization theories was to the organizational domain (with a particular focus on leadership), but more recently there has been a surge of interest in applications to the realm of health and clinical topics. This article charts the development of this Applied Social Identity Approach, and abstracts five core lessons from the research that has taken this forward. (1) Groups and social identities matter because they have a critical role to play in organizational and health outcomes. (2) Self categorizations matter because it is people's self-understandings in a given context that shape their psychology and behaviour. (3) The power of groups is unlocked by working with social identities not across or against them. (4) Social identities need to be made to matter in deed not just in word. (5) Psychological intervention is always political because it always involves some form of social identity management. Programmes that seek to incorporate these principles are reviewed and important challenges and opportunities for the future are identified. PMID- 24627991 TI - To be respected and to respect: the challenge of mutual respect in intergroup relations. AB - Building on theorizing in social and political philosophy the article illuminates the phenomenology of respect and examines its role in intergroup relations. The particular focus is on members of the gay and lesbian community in Germany, their respect experiences, and how these experiences relate to their attitudes towards Muslims. We predicted and found that the experience of being respected in society primarily reflected perceived recognition of gays and lesbians as equal members of society. In addition, we predicted and found that perceived respect from the Muslim community was negatively related to anti-Muslim attitude among gays and lesbians. The same was true for perceived respect from society at large. More specifically, respondents who felt respected by the majority of society showed lower levels of anti-Muslim attitude and, in line with the dominant status of perceived equality recognition in the experience of being respected, this decrease was fully mediated via an increase in perceived equality recognition. PMID- 24627993 TI - Evolution of asexuality via different mechanisms in grass thrips (thysanoptera: Aptinothrips). AB - Asexual lineages can derive from sexual ancestors via different mechanisms and at variable rates, which affects the diversity of the asexual population and thereby its ecological success. We investigated the variation and evolution of reproductive systems in Aptinothrips, a genus of grass thrips comprising four species. Extensive population surveys and breeding experiments indicated sexual reproduction in A. elegans, asexuality in A. stylifer and A. karnyi, and both sexual and asexual lineages in A. rufus. Asexuality in A. stylifer and A. rufus coincides with a worldwide distribution, with sexual A. rufus lineages confined to a limited area. Inference of molecular phylogenies and antibiotic treatment revealed different causes of asexuality in different species. Asexuality in A. stylifer and A. karnyi has most likely genetic causes, while it is induced by endosymbionts in A. rufus. Endosymbiont-community characterization revealed presence of Wolbachia, and lack of other bacteria known to manipulate host reproduction. However, only 69% asexual A. rufus females are Wolbachia-infected, indicating that either an undescribed endosymbiont causes asexuality in this species or that Wolbachia was lost in several lineages that remained asexual. These results open new perspectives for studies on the maintenance of mixed sexual and asexual reproduction in natural populations. PMID- 24627994 TI - Molecular mechanisms regulating CD13-mediated adhesion. AB - CD13/Aminopeptidase N is a transmembrane metalloproteinase that is expressed in many tissues where it regulates various cellular functions. In inflammation, CD13 is expressed on myeloid cells, is up-regulated on endothelial cells at sites of inflammation and mediates monocyte/endothelial adhesion by homotypic interactions. In animal models the lack of CD13 alters the profiles of infiltrating inflammatory cells at sites of ischaemic injury. Here, we found that CD13 expression is enriched specifically on the pro-inflammatory subset of monocytes, suggesting that CD13 may regulate trafficking and function of specific subsets of immune cells. To further dissect the mechanisms regulating CD13 dependent trafficking we used the murine model of thioglycollate-induced sterile peritonitis. Peritoneal monocytes, macrophages and dendritic cells were significantly decreased in inflammatory exudates from global CD13(KO) animals when compared with wild-type controls. Furthermore, adoptive transfer of wild type and CD13(KO) primary myeloid cells, or wild-type myeloid cells pre-treated with CD13-blocking antibodies into thioglycollate-challenged wild-type recipients demonstrated fewer CD13(KO) or treated cells in the lavage, suggesting that CD13 expression confers a competitive advantage in trafficking. Similarly, both wild type and CD13(KO) cells were reduced in infiltrates in CD13(KO) recipients, confirming that both monocytic and endothelial CD13 contribute to trafficking. Finally, murine monocyte cell lines expressing mouse/human chimeric CD13 molecules demonstrated that the C-terminal domain of the protein mediates CD13 adhesion. Therefore, this work verifies that the altered inflammatory trafficking in CD13(KO) mice is the result of aberrant myeloid cell subset trafficking and further defines the molecular mechanisms underlying this regulation. PMID- 24627996 TI - Stable nitrogen isotopes of nestling tree swallows indicate exposure to different types of oil sands reclamation. AB - Tree swallows (Tachycineta bicolor) inhabiting reclaimed wetlands on the oil sands in northern Alberta are potentially exposed to elevated levels of oil sands constituents such as polycyclic aromatic compounds (PAC) through diet. While increased detoxification enzyme activity as measured using 7-ethoxyresorufin O deethylase in nestlings is a generally accepted indicator of exposure to oil sands constituents, there is no apparent method to detect dietary exposure specific to oil sands processed material (OSPM). In this study, stable C and N isotopes were analyzed from muscle and feathers of nestling tree swallows (15 d old) to distinguish dietary exposure of birds near reference and OSPM wetlands. High delta15N and low delta13C values in the nestling tissues differentiated those from the OSPM wetlands and reference sites. Lower delta15N values of nestlings compared to the delta15N values of larval chironomids from an earlier study suggested that the majority of the diet of the nestlings was derived from non-OSPM sources, despite residence near and on the OSPM wetlands. Our finding of limited utilization of OSPM resources by tree swallows indicates either low abundance or diversity of dietary items emerging from OSPM wetlands, or sensory avoidance of prey from those wetlands. Minimal consumption of OSPM-derived dietary sources may be attributed to published findings of limited adverse effects on tree swallow reproduction, or growth and development for these same nestlings. This study demonstrated that stable isotope analysis, particularly for N isotopes, may serve as a useful tool to trace dietary exposure to OSPM constituents as part of avian ecotoxicology assessments of reclaimed wetlands on the oil sands. PMID- 24627995 TI - S-Nitrosoglutathione improves haemodynamics in early-onset pre-eclampsia. AB - AIMS: To determine the effects of in vivo S-nitrosoglutathione (GSNO) infusion on cardiovascular function, platelet function, proteinuria and biomarker parameters in early-onset pre-eclampsia. METHODS: We performed an open-label dose-ranging study of GSNO in early-onset pre-eclampsia. Six women underwent GSNO infusion whilst receiving standard therapy. The dose of GSNO was increased incrementally to 100 MUg min(-1) whilst maintaining blood pressure of >140/80 mmHg. Aortic augmentation index, aortic pulse wave velocity, blood pressure and maternal-fetal Doppler parameters were measured at each dose. Platelet P-selectin, protein-to creatinine ratio and soluble anti-angiogenic factors were measured pre- and postinfusion. RESULTS: Augmentation index fell at 30 MUg min(-1) S nitrosoglutathione (-6%, 95% confidence interval 0.6 to 13%), a dose that did not affect blood pressure. Platelet P-selectin expression was reduced [mean (interquartile range), 6.3 (4.9-7.6) vs. 4.1 (3.1-5.7)% positive, P = 0.03]. Soluble endoglin levels showed borderline reduction (P = 0.06). There was a borderline significant change in pre-to-postinfusion protein-to-creatinine ratio [mean (interquartile range), 0.37 (0.09-0.82) vs. 0.23 (0.07-0.49) g mmol(-1) , P = 0.06]. Maternal uterine and fetal Doppler pulsatility indices were unchanged. CONCLUSIONS: In early-onset pre-eclampsia, GSNO reduces augmentation index, a biomarker of small vessel tone and pulse wave reflection, prior to affecting blood pressure. Proteinuria and platelet activation are improved at doses that affect blood pressure minimally. These effects of GSNO may be of therapeutic potential in pre-eclampsia, a condition for which no specific treatment exists. Clinical studies of GSNO in early-onset pre-eclampsia will determine whether these findings translate to improvement in maternal and/or fetal outcome. PMID- 24627997 TI - Reference values of lead in blood and related factors among blood donors in the Western Amazon, Brazil. AB - The aim of this study was to (1) determine the reference value of blood lead levels (BLL) in a sample of blood donors of Rio Branco, the capital city of Acre, in the Western Brazilian Amazon, and (2) explore factors influencing lead (Pb) exposure levels. Between 2010 and 2011, blood samples were collected from universal blood donors attending the Central Hemotherapic Unit in Rio Branco with a total number of 1196. Information on characteristics of 1183 donors was obtained through questionnaires. Blood Pb concentrations were determined by inductively coupled plasma-mass spectrometry with detection limit of 0.003 MUg/L. Association between BLL and participant characteristics was examined by linear regression analysis. Reference values of BLL were calculated as the upper limit of the 95% confidence interval of the 95th percentile. Reference values of BLL were 109.5 MUg/L for men, 70.7 MUg/L for women, 88.9 MUg/L for younger individuals (18-29 yr), 115.3 MUg/L for older ones (>=30 yr), 94.2 MUg/L for nonsmokers, and 164.5 MUg/L for smokers. Levels of BLL were significantly higher in males, subjects older than 29 yr, non-whites, smokers, regular consumers of manioc flour, and donors practicing any activity related to paints, ceramics, pottery, fishing, or firearms. Subjects with higher education, higher income, vitamin intake use, and drinkers of bottled water displayed lower BLL. In general, BLL in men and women from Rio Branco were higher than those described in other adult populations. Prevention of exposure of this population to local sources of Pb needs to be addressed. PMID- 24627998 TI - Cumulative PM(2.5) exposure and telomere length in workers exposed to welding fumes. AB - Telomeres are genomic structures that reflect both mitotic history and biochemical trauma to the genome. Metals inherent in fine particulate matter (PM(2.5)) were shown to be genotoxic via oxidative damage. However, few studies investigated the induction time of cumulative PM(2.5) exposure on telomere length in a longitudinal setting. Therefore, the purpose of this study was to assess the association between occupational PM(2.5) exposure in various time windows and telomere length. The study population consisted of 48 boilermakers and the follow up period was 8 yr. The main exposures were cumulative occupational PM(2.5) in the month, year, and career prior to each blood draw, assessed via work history questionnaires and area air measures. Repeated telomere length measurements from leukocytes were assessed via real-time qualitative polymerase chain reaction (qPCR). Analysis was performed using linear mixed models controlling for confounders and white blood cell differentials. Cumulative PM(2.5) exposure was treated continuously and categorized into quartiles, in separate analyses. At any follow-up time, for each milligram per cubic meter per hour increase in cumulative PM(2.5) exposure in the prior month, there was a statistically significant decrease in relative telomere length of -0.04 units. When categorizing the exposure into quartiles, there was a significant negative association between telomere length and highest quartile of cumulative PM(2.5) exposure in the prior month (-0.16). These findings suggest that genomic trauma to leukocyte telomeres was more consistent with recent occupational PM(2.5) exposure, as opposed to cumulative exposure extending into the distant past. PMID- 24627999 TI - In vivo evaluation of activities and expression of antioxidant enzymes in Wistar rats exposed for 90 days to a modified clay. AB - Although clays are wildly used in a range of applications, the toxicity assessment of these new materials is still scarce. In the present study, oxidative stress induced by Clay 1, a novel clay, was determined in rats after 90 d of oral exposure. The activities of antioxidant enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S transferase (GST), were examined. In addition, genetic expressions of SOD and CAT and relative protein abundance of CAT were also determined. Data showed that most of the biomarkers assayed remained unaltered. Only CAT activity, as well as its genetic and protein expressions, appeared enhanced in the kidney. Therefore, further studies are needed to clarify the relevance and consequences of these findings to ensure the safety of this clay. PMID- 24628000 TI - Short-term effect of fine particulate air pollution on daily mortality: a case crossover study in a tropical city, Kaohsiung, Taiwan. AB - Many studies have examined the short-term effects of air pollution on frequency of daily mortality over the past two decades. However, information on the relationship between levels of fine particles (PM(2.5)) and daily mortality is relatively sparse due to limited availability of monitoring data. Further the results are inconsistent. This study was undertaken to determine whether there was an association between PM(2.5) levels and daily mortality rate in Kaohsiung, Taiwan, a large industrial city with a tropical climate. Daily mortality rate, air pollution parameters, and weather data for Kaohsiung were obtained for the period from 2006 through 2008. The relative risk of daily mortality occurrence was estimated using a time-stratified case-crossover approach, controlling for (1) weather variables, (2) day of the week, (3) seasonality, and (4) long-term time trends. For the single-pollutant model (without adjustment for other pollutants), no significant effects were found between PM(2.5) and frequency of daily mortality on warm days (>=25 degrees C). On cool days, PM(2.5) showed significant correlation with increased risk of mortality rate for all causes and circulatory diseases in single-pollutant model. There was no indication of an association between PM(2.5) and deaths due to respiratory diseases. The relationship appeared to be stronger on cool days. This study provided evidence of associations between short-term exposure to PM(2.5) and elevated risk of death for all cause and circulatory diseases. PMID- 24628001 TI - Oxygen consumption and haematology of juvenile shortnose sturgeon Acipenser brevirostrum during an acute 24 h saltwater challenge. AB - This study focused on the acute physiological responses to saltwater exposure in juvenile shortnose sturgeon Acipenser brevirostrum. In two separate laboratory experiments, 2 year-old A. brevirostrum were exposed to either full (32) or half strength (16) seawater for up to 24 h. First, oxygen consumption rates were used to estimate the metabolic costs over 24 h. Secondly, blood and muscle samples were analysed at 6, 12 and 24 h for water loss, various measures of osmoregulatory status (plasma osmolality and ions) and other standard haematological variables. Juveniles exposed to full-strength seawater showed significant decreases in oxygen consumption rates during the 24 h exposure. Furthermore, seawater-exposed fish had significantly increased plasma osmolality, ions (Na(+) and Cl(-)) and a 17% decrease in total wet mass over the 24 h exposure period. To a lesser extent, increases in osmolality, ions and mass loss were observed in fish exposed to half-strength seawater but no changes to oxygen consumption. Cortisol was also significantly increased in fish exposed to full strength seawater. While plasma protein was elevated following 24 h in full strength seawater, haemoglobin, haematocrit and plasma glucose levels did not change with increased salinity. These results imply an inability of juvenile A. brevirostrum to regulate water and ions in full-strength seawater within 24 h. Nonetheless, no mortality occurred in any exposure, suggesting that juvenile A. brevirostrum can tolerate short periods in saline environments. PMID- 24628003 TI - Interleukin-6 levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. AB - OBJECTIVE: The aim of this study was to evaluate serum concentrations of interleukin-6 (IL-6) in relation with hormonal and metabolic profile in patients with and without polycystic ovary syndrome (PCOS). METHODS: A total of 40 women with PCOS and 40 age-matched controls were eligible for the study. Hirsutism scores, hormonal and metabolic profile as well as IL-6 levels were evaluated in each subject. RESULTS: Women with PCOS exhibited higher body mass index (BMI) and serum concentrations of IL-6 levels than controls (p < 0.05); however, levels of IL-6 were not significantly increased when compared with BMI-matched controls (p > 0.05). IL-6 levels were significantly correlated positively with BMI and triglyceride levels; however, negatively correlated with high-density lipoprotein levels. CONCLUSION: The data of this study suggested that serum IL-6 levels were found to be higher in women with PCOS as compared to controls; however, IL-6 levels might be dependent on nutritional status but not on PCOS per se. Raised serum IL-6 levels may be related to BMI and serum lipid levels and may be a predictor for cardiometabolic risks. PMID- 24628004 TI - Lipid guidelines - are we heading in the right direction? PMID- 24628002 TI - Hemoglobin combined with triglyceride and ferritin in predicting non-alcoholic fatty liver. AB - BACKGROUND AND AIM: The red blood cells (RBC) count is closely associated with insulin resistance (IR), which is origin of non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the correlation of RBC indices with NAFLD. METHODS: A total of 977 cases including 446 NAFLD patients and 531 controls were enrolled and examined for biochemical and metabolic indices. RBC, hematocrit (HCT), hemoglobin (HGB), insulin, and ferritin were detected. The IR indicator latest homeostasis model assessment-insulin resistance and fatty liver index were calculated. The correlation analysis was assessed by Spearman's rank test. Receiver operating characteristic was used to evaluate diagnostic performance. After quartile classification of RBC indices, logistic regression analysis was conducted to evaluate the odds ratios (OR) of NAFLD. RESULTS: RBC, HCT, and HGB levels were obviously higher in NAFLD group. RBC, HCT, and HGB showed significant positive correlation with homeostasis model assessment-insulin resistance and NAFLD. Multivariate analysis revealed HGB, ferritin, and triglyceride (TG) as independent parameters associated with NAFLD. The predictive value after combination of HGB with ferritin and TG was equal to fatty liver index. After adjustment for age,body mass index, systolic blood pressure, total cholesterol, TG, low-density lipoprotein, high-density lipoprotein and smoking, comparing the groups with the highest and lowest HGB, HCT, and RBC, the OR (95% confidence intervals) of NAFLD were 2.369 (1.279-4.368) (P < 0.05), 1.504 (0.819 2.713) (P > 0.05), and 2.332 (0.823-2.550) (P > 0.05) in men. In women, the OR were 2.541 (1.118-5.771), 3.578 (1.464-8.748), and 3.215 (1.387-7.455) (P < 0.05). CONCLUSIONS: Our data suggest that HGB combined with TG and ferritin may serve as the indicator of predicting NAFLD. PMID- 24628005 TI - Do women really take their osteoporosis therapy? PMID- 24628006 TI - Aldehyde dehydrogenase-bright cells correlated with the colony-forming unit granulocyte-macrophage assay of thawed cord blood units. AB - BACKGROUND: The number of aldehyde dehydrogenase-bright (ALDH(br) ) cells has been suggested as a viable marker of hematopoietic stem cell function. We evaluated the suitability of ALDH(br) cell analysis in the quality assessment of postthaw cord blood (CB) units. STUDY DESIGN AND METHODS: A total of 245 CB units were obtained for estimating the numbers of total nucleated cells (TNCs), CD34+ cells, ALDH(br) cells, ALDH(br) cells among CD34+ cells (CD34+ALDH(br) cells), CD34+ cells among ALDH(br) cells (ALDH(br) CD34+ cells), colony-forming unit (CFU)-granulocyte-macrophages (GMs), and CFU-granulocyte-erythrocyte-macrophage megakaryocytes (GEMMs). Simple linear regression analysis was performed to assess the correlation between the number of TNCs and CD34+ cells before and after crypreservation and CD34+ALDH(br) cells, ALDH(br) cells, and ALDH(br) CD34+ cells after cryopreservation and the number of CFU-GEMMS and CFU-GMs. RESULTS: The number of CFU-GMs was found to be significantly correlated with the number of CD34+ cells before and after cryopreservation (r = 0.418 and r = 0.359, respectively), CD34+ALDH(br) cells, ALDH(br) cells, and ALDH(br) CD34+ cells (r = 0.426, r = 0.455, and r = 0.469, respectively). The number of CFU-GEMMs was found to be significantly correlated with the number of TNCs and CD34+ cells before and after cryopreservation (TNCs, r = 0.251 and r = 0.250, respectively; CD34+ cells, r = 0.391 and r = 0.347, respectively), CD34+ALDH(br) cells, ALDH(br) cells, and ALDH(br) CD34+ cells (r = 0.297, r = 0.297, and r = 0.252, respectively). CONCLUSION: The high correlation found between ALDH activity and CFU-GM number supports the suitability of ALDH analysis in the quality assessment of postthaw CB units. PMID- 24628007 TI - Decreased plasma chemerin levels in women with gestational diabetes mellitus. AB - AIMS: To evaluate fasting and post-prandial serum chemerin levels in pregnant women with and without gestational diabetes, and again following delivery when normal glucose homeostasis is re-established. METHODS: Chemerin levels were measured in serum from nine women with gestational diabetes, and from eight age- and BMI-matched pregnant women with normal glucose tolerance during two meal tests: in the third trimester and 3-4 months post partum. All women with gestational diabetes re-established normal glucose tolerance after delivery. RESULTS: Meal intake did not affect serum chemerin levels. The group with gestational diabetes had lower mean serum chemerin levels during the third trimester compared with the group with normal glucose tolerance (28 +/- 1.3 vs. 88 +/- 3.5 ng/ml, P < 0.0001). In the group with normal glucose tolerance, mean serum chemerin levels decreased significantly post partum to 57 +/- 2.8 ng/ml (P = 0.0001), but remained significantly (P = 0.0003) higher than post-partum levels in the group with gestational diabetes (31 +/- 1.9 ng/ml), which did not differ significantly from third trimester levels (P = 0.31). CONCLUSIONS: Normal pregnancy is associated with increased circulating chemerin levels, which may act to reduce pregnancy-induced insulin resistance and prevent glucose intolerance. Women with gestational diabetes, however, have severely reduced chemerin levels that remain low after delivery, which may contribute to the insulin resistance, glucose intolerance and high type 2 diabetes risk associated with gestational diabetes. PMID- 24628008 TI - Immobilization of lambda exonuclease onto polymer micropillar arrays for the solid-phase digestion of dsDNAs. AB - The process of immobilizing enzymes onto solid supports for bioreactions has some compelling advantages compared to their solution-based counterpart including the facile separation of enzyme from products, elimination of enzyme autodigestion, and increased enzyme stability and activity. We report the immobilization of lambda-exonuclease onto poly(methylmethacrylate) (PMMA) micropillars populated within a microfluidic device for the on-chip digestion of double-stranded DNA. Enzyme immobilization was successfully accomplished using 3-(3 dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling to carboxylic acid functionalized PMMA micropillars. Our results suggest that the efficiency for the catalysis of dsDNA digestion using lambda-exonuclease, including its processivity and reaction rate, were higher when the enzyme was attached to a solid support compared to the free solution digestion. We obtained a clipping rate of 1.0 * 10(3) nucleotides s(-1) for the digestion of lambda-DNA (48.5 kbp) by lambda-exonuclease. The kinetic behavior of the solid-phase reactor could be described by a fractal Michaelis-Menten model with a catalytic efficiency nearly 17% better than the homogeneous solution-phase reaction. The results from this work will have important ramifications in new single-molecule DNA sequencing strategies that employ free mononucleotide identification. PMID- 24628009 TI - Behavioral interventions for office-based care: foreword. PMID- 24628010 TI - Behavioral interventions for office-based care: interventions in the family medicine setting. AB - The practice of family medicine includes the care of many patients with mental health or behavior change needs. Patients in mild to moderate distress may benefit from brief interventions performed in the family physician's office. Patients in more extreme distress may be helped by referral to behavioral health clinicians for short-term or open-ended therapies. Electronic therapy programs and bibliotherapy are also useful resources. The transition to the patient centered medical home model may allow for more widespread integration of behavioral health care clinicians into primary care, in person and through telemental health care. Integrated care holds the promise of improved access, greater effectiveness of behavioral health service provision, and enhanced efficiency of primary care for patients with behavioral health care needs. PMID- 24628012 TI - Behavioral interventions for office-based care: depressive disorders. AB - Depressive disorders commonly are diagnosed and managed in primary care settings, and many patients prefer a nonpharmacologic approach. Traditionally, symptom reduction through pharmacotherapy has been the primary focus of management, but there is a growing acknowledgment of the need to develop modalities that prevent subsequent relapse and recurrences. Psychotherapy, including cognitive behavioral and interpersonal therapies, can have enduring effects that reduce subsequent risk in ways that drugs cannot. Although most family physicians do not provide formal psychosocial interventions for depression, brief interventions and behavioral intervention technologies, such as those that deliver care via the Internet or mobile device, are key means of increasing access to psychotherapy. For children and adolescents with mild, uncomplicated depression, physician provided social support, encouragement, and reinforcement of adaptive behavior patterns can be as effective as cognitive behavioral therapy. In addition, a primary care physician's involvement in parent education and safety planning for suicide prevention holds promise for risk reduction. Evidence also supports the use of problem-solving therapy and components of cognitive behavioral therapy and interpersonal psychotherapy provided by primary care physicians for patients with depression. PMID- 24628011 TI - Behavioral interventions for office-based care: behavior change. AB - Family physicians play an important role in identifying and treating the behavioral etiologies of morbidity and mortality. Changing behavior is a challenging process that begins with identifying a patient's readiness to change. Interventions, such as motivational interviewing, are used to increase a patient's desire to change, and cognitive behavioral therapy can be initiated to increase a patient's likelihood of change, particularly if barriers are identified. After patients embark on change, family physicians are uniquely positioned to connect them to self-help programs, more intensive psychotherapy, and newer technology-based support programs, and to provide repeated, brief, positive reinforcement. Specific behavioral interventions that can be effective include computerized smoking cessation programs; electronic reminders and support delivered by family physicians or other clinicians for weight loss; linkage to community-based programs for seniors; increased length and demands of in-school programs to support exercise participation by children; and access reduction education to prevent firearm injury. PMID- 24628013 TI - Behavioral interventions for office-based care: stress and anxiety disorders. AB - Numerous behavioral therapies have been investigated in the management of anxiety and stress-related disorders. There is strong evidence to support cognitive behavioral therapy (CBT) in the management of generalized anxiety disorder (GAD), posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, and social phobias. Adjunctive behavioral sleep intervention may enhance results for GAD, and initiation of a selective serotonin reuptake inhibitor for GAD before CBT also may enhance response. Several randomized clinical trials showed benefit of Internet-based CBT for GAD, but additional studies are needed before conclusions can be drawn regarding its effectiveness for posttraumatic stress disorder. Although outcome data are limited, family physicians can offer patients screening for anxiety disorders, psychological first aid (ie, listening to and comforting patients, teaching about emotional and physiologic responses to traumatic incidents, and encouraging engagement with social supports and coping) after trauma, education about anxiety disorders, and referral to evidence-based self-help resources. Family physicians also can ensure linkage with behavioral health care physicians and encourage adherence to self-help protocols. PMID- 24628014 TI - The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients. AB - Everolimus (EVR) has inter-individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co-medications, and/or demographic variables accounted for inter individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T, CYP3A4*1B, CYP3A5*3, CYP2C8*2/*3/*4, and pregnane X receptor (NR1I2) c.44477T>C, c.63396C>T, c.69789A>G polymorphisms. The primary outcome was the difference in dose-adjusted EVR levels (EVR L/D) between ABCB1 diplotype groups (2 vs. 1 vs. 0 copies of the 1236C/2677G/3435C haplotype). Sixty-five LTxR were included. There was no significant difference in EVR L/D between ABCB1 CGC diplotype groups (CGC/CGC = 2.4 +/- 1.1 [n = 9] vs. CGC/XXX = 2.5 +/- 1.7 [n = 36] vs. XXX/XXX = 2.7 +/- 1.7 ng/mL per mg/d [n = 20]; p = 0.9). CYP3A5*3, CYP3A4*1B, CYP2C8*3/*4, and NR1I2 polymorphisms were not associated with EVR L/D. EVR L/D was 3.4 +/- 1.7 in LTxR receiving diltiazem (DILT) vs. 1.8 +/- 1.1 ng/mL per mg/d in LTxR not receiving DILT (p <0.001). Demographic variables, including cystic fibrosis, were not associated with EVR PK. DILT use increased EVR L/D, but selected polymorphisms in ABCB1, CYP3A5, CYP3A4, CYP2C8, and NR1I2 did not affect EVR L/D in LTxR. Genotyping LTxR for these polymorphisms is unlikely to aid clinicians in optimizing EVR therapy. PMID- 24628015 TI - Regulation of ACh release from guinea pig bladder urothelial cells: potential role in bladder filling sensations. AB - BACKGROUND AND PURPOSE: The aim of this study was to quantify and characterize the mechanism of non-neuronal ACh release from bladder urothelial cells and to determine if urothelial cells could be a site of action of anti-muscarinic drugs. EXPERIMENTAL APPROACH: A novel technique was developed whereby ACh could be measured from freshly isolated guinea pig urothelial cells in suspension following mechanical stimulation. Various agents were used to manipulate possible ACh release pathways in turn and to study the effects of muscarinic receptor activation and inhibition on urothelial ATP release. KEY RESULTS: Minimal mechanical stimulus achieved full ACh release, indicating a small dynamic range and possible all-or-none signal. ACh release involved a mechanism dependent on the anion channel CFTR and intracellular calcium concentration, but was independent of extracellular calcium, vesicular trafficking, connexins or pannexins, organic cation transporters and was not affected by botulinum-A toxin. Stimulating ACh receptors increased ATP production and antagonizing them reduced ATP release, suggesting a link between ACh and ATP release. CONCLUSIONS AND IMPLICATIONS: These results suggest that release of non-neuronal ACh from the urothelium is large enough and well located to act as a modulator of ATP release. It is hypothesized that this pathway may contribute to the actions of anti muscarinic drugs in reducing the symptoms of lower urinary tract syndromes. Additionally the involvement of CFTR in ACh release suggests an exciting new direction for the treatment of these conditions. PMID- 24628016 TI - Cross-coupling hydrogen evolution reaction in homogeneous solution without noble metals. AB - A highly efficient noble-metal-free homogeneous system for a cross-coupling hydrogen evolution (CCHE) reaction is developed. With cheap, earth-abundant eosin Y and molecular catalyst Co(dmgH)2Cl2, good to excellent yields for coupling reactions with a variety of isoquinolines and indole substrates and H2 have been achieved without any sacrificial oxidants. Mechanistic insights provide rich information on the effective, clean, and economic CCHE reaction. PMID- 24628017 TI - Portuguese nurses' knowledge of and attitudes toward hospitalized older adults. AB - Portugal is impacted by the rapid growth of the aging population, which has significant implications for its health care system. However, nurses have received little education focusing on the unique and complex care needs of older adults. This gap in the nurses' education has an enormous impact in their knowledge and attitudes and affects the quality of nursing care provided to older adults. A cross-sectional study was conducted among 1068 Portuguese nurses in five hospitals (northern and central region) with the following purposes: (i) explore the knowledge and attitudes of nurses about four common geriatric syndromes (pressure ulcer, incontinence, restraint use and sleep disturbance) in Portuguese hospitals; and (ii) evaluate the influence of demographic, professional and nurses' perception about hospital educational support, geriatric knowledge, and burden of caring for older adults upon geriatric nursing knowledge and attitudes. The mean knowledge and attitudes scores were 0.41 +/- 0.15 and 0.40 +/- 0.21, respectively (the maximum score was 1). Knowledge of nurses in Portuguese hospitals about the four geriatric syndromes (pressure ulcers, sleep disturbance, urinary incontinence and restraint use) was found inadequate. The nurses' attitudes towards caring for hospitalized older adults were generally negative. Nurses who work in academic hospitals demonstrated significantly more knowledge than nurses in hospital centers. The attitudes of nurses were significantly associated with the hospital and unit type, region, hospital educational support, staff knowledge, and perceived burden of caring for older adults. The study findings support the need for improving nurses' knowledge and attitudes towards hospitalized older adults and implementing evidence-based guidelines in their practice. PMID- 24628019 TI - Investigating water interactions with collagen using 2H multiple quantum filtered NMR spectroscopy to provide insights into the source of double quantum filtered signal in tissue. AB - In an effort to provide insight into the molecular origins of the (2)H double quantum filtered (DQF) NMR signal observed in connective tissue, specifically spinal disc tissue, (2)H multiple quantum filtered (MQF) NMR spectroscopy is used to study the structure and dynamics of D2O in collagen as a function of hydration. Residual quadrupolar coupling constants are measured and decrease from 3500 to 20 Hz while T2 relaxation times increase from 0.65 to 20 ms as hydration increases. Analysis of the data indicates that the quadrupolar coupling and T2 relaxation arises when water molecules spend time in restricted environments. The residual quadrupolar coupling is influenced almost exclusively by the most restricted water sites, the clefts of the triple helices not exposed on the surface of the fibrils, while the T2 relaxation has secondary contributions from less restricted water environments. The magnitudes of the measured values are consistent with results from DQF NMR studies of spinal disc tissue, supporting the assertion that water binding to collagen is a major contributor to the DQF NMR signal observed in spinal disc tissue. PMID- 24628018 TI - Evaluation of peroxisome proliferator-activated receptor agonists on interleukin 5-induced eosinophil differentiation. AB - Peroxisome proliferator-activated receptor (PPAR) agonists have been suggested as novel therapeutics for the treatment of inflammatory lung disease, such as allergic asthma. Treatment with PPAR agonists has been shown to inhibit airway eosinophilia in murine models of allergic asthma, which can occur through several mechanisms including attenuated generation of chemoattractants (e.g. eotaxin) and decreased eosinophil migrational responses. In addition, studies report that PPAR agonists can inhibit the differentiation of several cell types. To date, no studies have examined the effects of PPAR agonists on interleukin-5 (IL-5) induced eosinophil differentiation from haemopoietic progenitor cells. Non adherent mononuclear cells or CD34(+) cells isolated from the peripheral blood of allergic subjects were grown for 2 weeks in Methocult((r)) cultures with IL-5 (10 ng/ml) and IL-3 (25 ng/ml) in the presence of 1-1000 nm PPARalpha agonist (GW9578), PPARbeta/delta agonist (GW501516), PPARgamma agonist (rosiglitazone) or diluent. The number of eosinophil/basophil colony-forming units (Eo/B CFU) was quantified by light microscopy. The signalling mechanism involved was assessed by phosphoflow. Blood-extracted CD34(+) cells cultured with IL-5 or IL-5 + IL-3 formed Eo/B CFU, which were significantly inhibited by rosiglitazone (100 nm, P < 0.01) but not GW9578 or GW501516. In addition, rosglitazone significantly inhibited IL-5-induced phosphorylation of extracellular signal-regulated kinase 1/2. We observed an inhibitory effect of rosiglitazone on eosinophil differentiation in vitro, mediated by attenuation of the extracellular signal regulated kinase 1/2 signalling pathway. These findings indicate that the PPARgamma agonist can attenuate tissue eosinophilia by interfering with local differentiative responses. PMID- 24628020 TI - The association of diet with quality of life, disability, and relapse rate in an international sample of people with multiple sclerosis. AB - OBJECTIVES: To explore the association between dietary factors including fat, fruit and vegetable intake, dairy and meat consumption, and health-related quality of life (HRQOL), disability and relapse rate in a large international sample of people with multiple sclerosis (MS). METHODS: Participants with MS were recruited to the study via Web 2.0 platforms and completed a comprehensive survey measuring demographic and clinical characteristics, HRQOL, disability, relapse rate, and the Diet Habits Questionnaire (DHQ). RESULTS: Of 2469 participants with confirmed MS, 2087 (84.5%) provided complete data on their dietary habits (DHQ total score). Multivariate regression models demonstrated that every 10-point increase on the DHQ total score was associated with nearly a six-point and five point increase in physical and mental HRQOL, respectively, and 30.0% reduced likelihood of a higher level of disability. After controlling for age and gender, and the other dietary covariates, 'healthy' consumption of fruit and vegetables and dietary fat predicted better quality of life and less likelihood of higher disability when compared to respondents with a 'poor' diet. For those with relapsing-remitting MS, the DHQ total significantly predicted a lower relapse rate and reduced odds of increasing disease activity, but the model fit was poor and the predicted change only marginal. DISCUSSION: This study supports significant associations of healthy dietary habits with better physical and mental HRQOL and a lower level of disability. Further research is urgently required to explore these associations including randomized controlled trials of dietary modification for people with MS. PMID- 24628021 TI - Enantioselective radiosynthesis of positron emission tomography (PET) tracers containing [18F]fluorohydrins. AB - Herein, we describe an operationally straightforward radiosynthesis of a chiral transition metal fluoride catalyst, [(18)F](salen)CoF, and its use for late-stage enantioselective aliphatic radiofluorination. We demonstrate the utility of the method by preparing single enantiomer experimental and clinically validated PET tracers that contain base-sensitive functional groups, epimerizable stereocenters, and nitrogen-rich motifs. Unlike the conventional radiosyntheses of these targets with [(18)F]KF, labeling with (salen)CoF is possible in the last step and under exceptionally mild conditions. These results constitute a rare example of a nucleophilic radiofluorination using a transition metal fluoride and highlight the potential of such reagents to enhance traditional methods for labeling aliphatic hydrocarbons. PMID- 24628022 TI - Microcones and nanograss: toward mechanically robust superhydrophobic surfaces. AB - We describe the generation of mechanically robust superhydrophobic surfaces, which carry a hierarchical roughness that is composed of silicon microcones and silicon nanograss. Both micro and nanostructures were fabricated using mask-free dry etching processes. The microcones were obtained utilizing a cryogenic deep reactive ion etching (DRIE) process run in the overpassivation regime. By varying process parameters, surfaces with different microcones geometries and densities were achieved. The nanograss was fabricated using a modified DRIE process with alternating etching and passivation cycles ('BOSCH process'). All surfaces were covered with a layer of a fluorinated film so that superhydrophobic structures resulted. Depending on microcone geometry and density, the advancing contact angle ranged between 170 degrees and 180 degrees , and roll-off angles of 10 MUL drops between 30' (0.5 degrees ) and 6 degrees were observed. The samples were exposed to varying shear loads, and the changes in the morphology were recorded by using electron microscopy. The wetting angles of the mechanically challenged surfaces were recorded and correlated with the mechanical properties of the samples. PMID- 24628024 TI - Complex mechanism of relaxation in solid chloroxylenol (antibacterial/antifungal agent) studied by 1H NMR spectroscopy and density functional theory calculations. AB - Molecular relaxation in antibacterial/antifungal agent: chloroxylenol (4-chloro 3,5-dimethylphenol, PCMX) in the solid state was studied by the (1)H NMR and quantum chemistry calculations. The temperature dependencies of the proton spin lattice relaxation time (T1) in the ranges 15-273 K (at 24.667 MHz), 77-295 K (at 15 MHz), and 112-291 K at 90 MHz and the second moment (M2) of (1)H NMR resonant line in the range 106-380 K were measured. The two minima in the temperature dependence of T1 revealed two activation processes, whereas the M2 dependence in the studied range was quite flat and revealed the only significant reduction at 380 K. The low temperature part of T1(T) dependence indicated the occurrence of two processes characteristic of methyl bearing solids; the quantum mechanics governed incoherent tunneling (responsible for the low temperature flattening of T1) and the classical Arrhenius dependence governed hindered rotation (related to the wide low temperature minimum of 0.066 s at 57 K, 24.667 MHz). The 2D potential energy surface obtained using DFT/B3LYP/6-311++G(2d,p) calculations revealed the inequivalence of methyl groups and the lack of their interplay/coupling. The activation energies of classical hindered rotation are 3.35 and 2.5 kJ/mol, whereas temperatures at which the proton tunneling T(tun) finally ceases are 52 and 63 K, for inequivalent methyl groups. C(p)(T) required for the estimation of T(tun) was calculated purely theoretically on the basis of the Einstein and Debye models of specific heat and 51 modes of atomic vibrations, 4 internal rotations, and 3 torsions calculated by DFT. The -CH3 motion (tunneling and classical) results in the reduction in the (1)H NMR line second moment from 17.3 G(2) (rigid) to approximately 11.05 G(2). The pointed high temperature minimum T1(T) of 0.109 s at 89 K, 24.667 MHz, which shifts with frequency, was assigned to small-angle libration jumps, by the Theta2 = +/-15 degrees between two positions of equilibrium. The activation energy of this motion estimated on the basis of the fit of the theoretical model to the experimental points is 10.5 kJ/mol. The reduction in the (1)H NMR line second moment assigned to this motion is much lower (due to order parameter s = 0.64) and equal to 1.6 G(2). The high temperature reduction from 9.6 G(2) to 0.9 G(2) at 380 K is a result of the phase transition connected with melting (385-389 K). PMID- 24628025 TI - Broadening the examination of sociocultural constructs relevant to African American colorectal cancer screening. AB - The importance of sociocultural constructs as influences on cancer attitudes and screening has been established in the literature. This paper reports on the efforts to explore alternatives to sociocultural constructs previously associated with African-American cancer screening, but with low acceptance among community members or incomplete measurement (empowerment and collectivism) and develop a measure for a recently identified construct of interest (privacy). We report preliminary psychometric data on these sociocultural scales and their associations with cancer attitudes. African-Americans (N = 1021), 50-75 years of age participated in this study. Participants were identified via a listed sample and completed a telephone survey administered via call center. Sociocultural attitudes were assessed using items identified through computerized database searches, reviewed by advisory panels, edited and tested using cognitive response strategies. Cancer screening pros and cons, cancer worry, perceived cancer risk, colorectal cancer (CRC) screening subjective norms, and perceived self-efficacy for colorectal cancer screening (CRCS) were also assessed. Confirmatory factor analyses and multivariate analyses were conducted to provide support for the validity of the constructs and to understand the associations among the selected sociocultural constructs (empowerment, collectivism, and privacy) and cancer beliefs and attitudes (CRC perceived benefits and barriers, perceived risks, subjective norms, and perceived behavioral control/self-efficacy). Consistent with the literature, the factor analytic model (RMSEA for the model was .062; 90% CI: .060-.065) provided support for the empowerment, collectivism, and privacy constructs. The modified collectivism and privacy scales had acceptable reliability. The privacy scale demonstrated the strongest associations with measures of cancer beliefs and attitudes. The implication of the findings and need for further scale development activities is discussed. PMID- 24628026 TI - Assortative social learning and its implications for human (and animal?) societies. AB - Choosing from whom to learn is an important element of social learning. It affects learner success and the profile of behaviors in the population. Because individuals often differ in their traits and capabilities, their benefits from different behaviors may also vary. Homophily, or assortment, the tendency of individuals to interact with other individuals with similar traits, is known to affect the spread of behaviors in humans. We introduce models to study the evolution of assortative social learning (ASL), where assorting on a trait acts as an individual-specific mechanism for filtering relevant models from which to learn when that trait varies. We show that when the trait is polymorphic, ASL may maintain a stable behavioral polymorphism within a population (independently of coexistence with individual learning in a population). We explore the evolution of ASL when assortment is based on a nonheritable or partially heritable trait, and when ASL competes with different non-ASL strategies: oblique (learning from the parental generation) and vertical (learning from the parent). We suggest that the tendency to assort may be advantageous in the context of social learning, and that ASL might be an important concept for the evolutionary theory of social learning. PMID- 24628027 TI - Acetylcholinesterase inhibitors with photoswitchable inhibition of beta-amyloid aggregation. AB - Photochromic cholinesterase inhibitors were obtained from cis-1,2-alpha dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved "photoswitchable". The AChE-induced beta-amyloid (Abeta) aggregation assay gave further experimental support to this finding: Abeta1-40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays. PMID- 24628028 TI - Clinical presentations of patients from different age cohorts with biliary tract stone diseases. AB - BACKGROUND AND AIM: The role of clinical symptoms, transabdominal ultrasound scan (USS), and liver function tests (LFTs) in evaluating common bile duct (CBD) stones in patients suspected to have pancreatobiliary disease has been studied. However, it is unclear whether these predictive models are useful in different age cohorts. The aim of this study is to investigate the clinical presentations from different age cohorts with and without CBD stones. METHODS: Four hundred and forty-three patients with pancreatobiliary diseases were divided into cohorts according to decades as follows: young (Y, 18-64 years old, n = 143), young-old (YO, 65-74 years old, n = 168), old-old (OO, 75-84 years old, n = 97), and very old (VO, >= 85 years old, n = 35). The clinical symptoms, LFTs, and USS findings were demonstrated and compared among patients. RESULTS: Y- and YO-group patients were more likely to develop symptoms such as biliary colic in the presence of CBD stones. The proportion of abnormal serum aspartate aminotransferase and alanine aminotransferase were significantly greater in Y-, YO-, and OO-group patients with than in those without CBD stones. Sensitivity of USS for CBD stones in Y: 0.15; YO: 0.45; OO: 0.57; and VO: 0.68. Accuracy of USS for detected CBD stone in Y: 48%; YO: 62.5%; OO: 70.1%; and VO: 71.4%. CONCLUSION: Combined evaluation of clinical symptoms, biochemical and USS findings may help predict the presence of CBD stones. In Y, YO, and OO patients with CBD stones, the incidences of abnormal LFTs were higher. The sensitivity and accuracy of USS in detecting CBD stones were increased according to age. PMID- 24628029 TI - Athletes' perceptions of National Collegiate Athletic Association-mandated sickle cell trait screening: insight for academic institutions and college health professionals. AB - OBJECTIVE: The study objective was to explore athletes' perspectives of National Collegiate Athletic Association (NCAA)-mandated sickle cell trait (SCT)-screening policy by examining race- and gender-related differences in athletes' perceptions regarding risk of having SCT and concern about loss of playing time. PARTICIPANTS: Participants were 259 athletes at a southeastern United States campus during April-August of 2010. METHODS: Athletes completed a 21-question survey. RESULTS: The majority of athletes (81.7%) perceived that they would have a high level of concern if found to carry the SCT. African Americans were 9.07 times more likely than Caucasians to perceive risk of having the SCT. The majority of athletes disagreed (38.4%) or did not know (50.8%) if they would lose playing time related to carrying the SCT. CONCLUSION: Campus health professionals must be aware of athletes' perspectives on NCAA's SCT screening so that athletes are not unnecessarily subjected to stress or harm. PMID- 24628030 TI - Trophic flexibility by roach Rutilus rutilus in novel habitats facilitates rapid growth and invasion success. AB - Stable isotope and gut content analyses, in conjunction with backcalculated length-at-age estimates of growth, were employed to examine the relationship between trophic ecology and growth rate of a successful invader, Rutilus rutilus, in eight lakes in Ireland. The data revealed that R. rutilus was a trophic generalist in Irish lakes. It utilized a greater proportion of pelagic resources in mesotrophic lakes than in eutrophic lakes, potentially due to a greater density of benthic macroinvertebrates in eutrophic systems. The species was characterized by a large dietary and isotopic niche width and high temporal and spatial variations in diet. Growth rates were typical of those found in the native range of the species and were unrelated to either lake productivity or fish's diet. A generalist trophic ecology confers significant advantages on an invasive species, allowing it to exploit a variety of novel resources and fluctuations in prey availability. PMID- 24628031 TI - Health knowledge and iodine intake in pregnancy. AB - BACKGROUND: Pregnant women have much higher iodine requirements as compared to all other population groups. The National Health and Medical Research Council (NHMRC) recommends pregnant women take a daily iodine supplement of 150 MUg to meet their high iodine requirements. AIM: To investigate iodine supplement use and health knowledge among pregnant women. METHOD: A cross-sectional sample of 200 pregnant women aged 18 years or older, in their third trimester based in Gippsland (Victoria, Australia) undertook a self-administered questionnaire from August 2011-May 2012. The women were recruited from antenatal classes and clinics from all birthing hospitals across Gippsland. Data were analysed using descriptive statistics and logistic regression. RESULTS: A total of 46% of participants did not follow the NHMRC recommendation of 150 MUg/day iodine supplement. The participants lacked knowledge about iodine and the need for supplementation. Only 18.5% of pregnant women believed they needed an iodine supplement. The majority of participants (83.5%) indicated their medical practitioners were the main source of health information, yet only 34.5% indicated being made aware of the importance of increasing iodine intake during pregnancy by their medical practitioner. The predictors of iodine supplementation are general supplementation use and knowledge of the importance of iodine. CONCLUSIONS: Despite NHMRC guidelines for iodine supplementation during pregnancy, many women were not taking a sufficient iodine supplement. Pregnant women may be inclined to take an iodine supplement if they had greater knowledge of their increased iodine needs during pregnancy. Medical practitioners are best placed to provide this information to pregnant women. PMID- 24628032 TI - How we incorporate molecular typing of donors and patients into our hospital transfusion service. PMID- 24628034 TI - Fibronectin-binding proteins are required for biofilm formation by community associated methicillin-resistant Staphylococcus aureus strain LAC. AB - Community-associated methicillin-resistant Staphylococcus aureus of the USA300 lineage is emerging as an important cause of medical device-related infection. However, few factors required for biofilm accumulation by USA300 strains have been identified, and the processes involved are poorly understood. Here, we identify S. aureus proteins required for the USA300 isolate LAC to form biofilm. A mutant with a deletion of the fnbA and fnbB genes did not express the fibronectin-binding proteins FnBPA and FnBPB and lacked the ability to adhere to fibronectin or to form biofilm. Biofilm formation by the mutant LAC?fnbAfnbB could be restored by expression of FnBPA or FnBPB from a plasmid demonstrating that both of these proteins can mediate biofilm formation when expressed by LAC. Expression of FnBPA and FnBPB increased bacterial aggregation suggesting that fibronectin-binding proteins can promote the accumulation phase of biofilm. Loss of fibronectin-binding proteins reduced the initial adherence of bacteria, indicating that these proteins are also involved in primary attachment. In summary, these findings improve our understanding of biofilm formation by the USA300 strain LAC by demonstrating that the fibronectin-binding proteins are required. PMID- 24628037 TI - A computational method for automated characterization of genetic components. AB - The ability to design and construct synthetic biological systems with predictable behavior could enable significant advances in medical treatment, agricultural sustainability, and bioenergy production. However, to reach a stage where such systems can be reliably designed from biological components, integrated experimental and computational techniques that enable robust component characterization are needed. In this paper we present a computational method for the automated characterization of genetic components. Our method exploits a recently developed multichannel experimental protocol and integrates bacterial growth modeling, Bayesian parameter estimation, and model selection, together with data processing steps that are amenable to automation. We implement the method within the Genetic Engineering of Cells modeling and design environment, which enables both characterization and design to be integrated within a common software framework. To demonstrate the application of the method, we quantitatively characterize a synthetic receiver device that responds to the 3 oxohexanoyl-homoserine lactone signal, across a range of experimental conditions. PMID- 24628035 TI - Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. AB - AIMS: Two double-blind, randomized studies were conducted to assess the tolerability, pharmacokinetics and pharmacodynamics of oral TA-8995, a new cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. METHODS: Study 1: Subjects received single doses of TA-8995 or placebo (fasted). Doses were 5, 10, 25, 50 (fed/fasted), 100 and 150 mg (Caucasian males, 18-55 years), 25 mg (Caucasian males, > 65 years and Caucasian females, 18-55 years), 25, 50, 100 and 150 mg (Japanese males, 18-55 years). Study 2: Caucasian males (18-55 years) received 1, 2.5, 10 or 25 mg once daily TA-8995 or placebo for 21 28 days. Blood and urine for pharmacokinetics and/or pharmacodynamics were collected. Tolerability was assessed by adverse events, vital signs, electrocardiograms and laboratory safety tests. RESULTS: Peak TA-8995 concentrations occurred approximately 4 h post-dose. Mean half-lives ranged from 81 to 166 h, without an obvious dose relationship. Exposure increased less than proportionally to dose. TA-8995 was not excreted in urine. Following 2.5 to 25 mg once daily dosing, TA-8995 demonstrated nearly complete inhibition of CETP activity (92-99%), increased high density lipoprotein-cholesterol (HDL-C) by 96 to 140% and decreased low density liporotein-cholesterol (LDL-C) by 40% to 53%. There were dose-related increases in apolipoproteins A-1 and E, HDL2-C and HDL3 C, and decreases in apolipoprotein B and lipoprotein A. There was no evidence of significant effects of age, gender, ethnicity or food on pharmacokinetics or pharmacodynamics. All doses were well tolerated. CONCLUSIONS: TA-8995 is a potent CETP inhibitor and warrants further investigation. PMID- 24628039 TI - Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-kappabeta. AB - Melatonin is an indoleamine that is synthesised from tryptophan under the control of the enzymes arylalkylamine N-acetyltransferase (AA-NAT) and acetylserotonin methyltransferase (ASMT). Melatonin inhibits colon cancer growth in both in vivo and in vitro models; however, a precise mechanism responsible for inhibiting tumour growth has not been clearly described. Endothelin-1 (ET-1) is a peptide that acts as a survival factor in colon cancer, inducing cell proliferation, protecting carcinoma cells from apoptosis and promoting angiogenesis. The data presented show that melatonin inhibits edn-1 mRNA expression (the first step in ET-1 synthesis), ECE-1 protein expression and the release of ET-1 from colorectal cancer cells in vitro. ET-1 levels in cultured media present a similar inhibition pattern to that of edn-1 mRNA expression despite the inhibition of ECE-1 protein after melatonin treatment, which suggests that an endopeptidase other than ECE-1 could be mainly responsible for ET-1 synthesis. The inhibition of edn-1 expression is due to an inactivation of FoxO1 and NF-kappabeta transcription factors. FoxO1 inactivation is associated with an increased Src phosphorylation, due to elevated cAMP content and PKA activity, whereas NF-kappabeta inactivation is associated with the blockade of Akt and ERK phosphorylation due to the inhibition of PKC activity after melatonin treatment. Melatonin also inhibits edn 1 promoter activity regulated by FoxO1 and NF-kappabeta. Finally, a significant correlation was observed between AA-NAT and edn-1 expression downregulation in human colorectal cancer tissues. In conclusion, melatonin may be useful in treating colon carcinoma in which the activation of ET-1 plays a role in tumour growth and progression. PMID- 24628040 TI - Multiple scale dynamics in proteins probed at multiple time scales through fluctuations of NMR chemical shifts. AB - Fluctuations of NMR resonance frequency shifts and their relation with protein exchanging conformations are usually analyzed in terms of simple two-site jump processes. However, this description is unable to account for the presence of multiple time scale dynamics. In this work, we present an alternative model for the interpretation of the stochastic processes underlying these fluctuations of resonance frequencies. Time correlation functions of (15)N amide chemical shifts computed from molecular dynamics simulations (MD) were analyzed in terms of a transiently fractional diffusion process. The analysis of MD trajectories spanning dramatically different time scales (~ 200 ns and 1 ms [ Shaw, D. E.; Science 2010, 330, 341 - 346]) allowed us to show that our model could capture the multiple scale structure of chemical shift fluctuations. Moreover, the predicted exchange contribution Rex to the NMR transverse relaxation rate is in qualitative agreement with experimental results. These observations suggest that the proposed fractional diffusion model may provide significative improvement to the analysis of NMR dispersion experiments. PMID- 24628038 TI - A study of the molecular mechanism of binding kinetics and long residence times of human CCR5 receptor small molecule allosteric ligands. AB - BACKGROUND AND PURPOSE: The human CCR5 receptor is a co-receptor for HIV-1 infection and a target for anti-viral therapy. A greater understanding of the binding kinetics of small molecule allosteric ligand interactions with CCR5 will lead to a better understanding of the binding process and may help discover new molecules that avoid resistance. EXPERIMENTAL APPROACH: Using [(3) H] maraviroc as a radioligand, a number of different binding protocols were employed in conjunction with simulations to determine rate constants, kinetic mechanism and mutant kinetic fingerprints for wild-type and mutant human CCR5 with maraviroc, aplaviroc and vicriviroc. KEY RESULTS: Kinetic characterization of maraviroc binding to the wild-type CCR5 was consistent with a two-step kinetic mechanism that involved an initial receptor-ligand complex (RA), which transitioned to a more stable complex, R'A, with at least a 13-fold increase in affinity. The dissociation rate from R'A, k-2 , was 1.2 * 10(-3) min(-1) . The maraviroc time dependent transition was influenced by F85L, W86A, Y108A, I198A and Y251A mutations of CCR5. CONCLUSIONS AND IMPLICATIONS: The interaction between maraviroc and CCR5 proceeded according to a multi-step kinetic mechanism, whereby initial mass action binding and later reorganizations of the initial maraviroc receptor complex lead to a complex with longer residence time. Site-directed mutagenesis identified a kinetic fingerprint of residues that affected the binding kinetics, leading to the conclusion that allosteric ligand binding to CCR5 involved the rearrangement of the binding site in a manner specific to each allosteric ligand. PMID- 24628041 TI - A mild method for the synthesis of carbamate-protected guanidines using the Burgess reagent. AB - A simple method for the synthesis of carbamate-protected guanidines from primary amines is described. A variety of thioureas derived from primary amines and isothiocyanates react with the Burgess reagent to give the corresponding guanidines via either a stepwise or one-pot procedure. By tuning the carbamoyl units of isothiocyanates and the Burgess reagent, differentially N,N'-diprotected guanidines can be obtained. Selective deprotection of the products affords N monoprotected guanidines. PMID- 24628043 TI - A bibliometric study of scientific literature on the dietary therapies for epilepsy in Scopus. AB - OBJECTIVES: The aim of this study was to provide a descriptive overview of the impact and production of literature on dietary therapies for epilepsy and perform a citation analysis of the related research articles. METHODS: We searched for 'ketogenic OR low-glycemic OR medium chain OR modified Atkins in TITLE AND epilep*' in Title/Abstract/Keyword in Scopus database. RESULTS: A total of 661 references were retrieved, 80% had been published after 2000s, 87% were published in English, and 39% of the publications were published in nine journals. The majority (76.3%) of research articles describe the clinical application of the dietary therapies regarding the classical ketogenic diet (80%), followed by the modified Atkins diet (11.5%), medium chain triglyceride diet (6.4%), and low glycemic index treatment (2.0%); the remaining are basic science studies on the mechanisms of action. The citation analysis revealed that the latter have the highest percentage variation in citation per publication across the years. Concerning the article cohorts, the greatest number of citations per publication was in 1998. DISCUSSION: The overview of the literature on the dietary therapy of epilepsy evidences a growing interest in the field with a striking prevalence of clinical over basic science studies. The most cited clinical studies have validated the efficacy of the dietary therapies; the few studies on the mechanisms of action received a great number of citations. Bibliometric analysis measuring the trends and the impact of the scientific literature would help researchers to a best knowledge of this specific topic. PMID- 24628042 TI - Safety and efficacy of intensive intraoperative glycaemic control in cardiopulmonary bypass surgery: a randomised trial. AB - BACKGROUND: This study aimed to determine the safety and efficacy of intraoperative intensive glycaemic treatment with modified glucose-insulin potassium solution by hyperinsulinemic normoglycaemic clamp in cardiopulmonary bypass surgery patients. We hypothesised that the treatment would reduce infection rates in this group of patients. METHODS: A prospective, randomised, double-blind trial was conducted in cardiopulmonary bypass surgery patients. A total of 199 adult patients (out of a planned 400) were randomly allocated to intensive or conventional treatment with target glucose levels of 4.4-8.3 mmol/l and < 13.8 mmol/l, respectively. The primary outcomes were clinical infection and cytokine levels, including interleukin (IL)-6 and IL-10. The secondary outcomes were morbidity and mortality. RESULTS: The study was terminated early because of safety concerns (hypoglycaemia). The clinical post-operative infection rate was 17% in the intensive group and 13% in the conventional group (P = 0.53). The proportion of patients with hypoglycaemia was significantly higher in the intensive group (23%) compared with the conventional group (3%) (P < 0.001). Morbidity and mortality rates were similar for both groups. Anaesthetic duration > 2 h (vs. <= 2 h), pre-operative IL-6 level > 15 pg/ml (vs. <= 15 pg/ml) and post-operative IL-6 level 56-110 pg/ml (vs. <= 55 pg/ml) were independent predictors for post-operative infection. CONCLUSIONS: Intraoperative intensive glycaemic treatment significantly increased the risk of hypoglycaemia, but its effect on post-operative infection by clinical assessment could not be determined. Anaesthetic duration, pre-operative and post-operative IL-6 levels can independently predict post-operative infection. PMID- 24628044 TI - Global quantitative structure-activity relationship models vs selected local models as predictors of off-target activities for project compounds. AB - In the pharmaceutical industry, it is common for large numbers of compounds to be tested for off-target activities. Given a compound synthesized for an on-target project P, what is the best way to predict its off-target activity X? Is it better to use a global quantitative structure-activity relationship (QSAR) model calibrated against all compounds tested for X, or is it better to use a local model for X calibrated against only the set of compounds in project P? The literature is not consistent on this topic, and strong claims have been made for either. One particular idea is that local models will be superior to global models in prospective prediction if one generates many local models and chooses the type of local model that best predicts recent data. We tested this idea via simulated prospective prediction using in-house data involving compounds in 11 projects tested for 9 off-target activities. In our hands, the local model that best predicts the recent past is seldom the local model that is best at predicting the immediate future. Also, the local model that best predicts the recent past is not systematically better than the global model. This means the complexity of having project- or series-specific models for X can be avoided; a single global model for X is sufficient. We suggest that the relative predictivity of global vs local models may depend on the type of chemical descriptor used. Finally, we speculate why, contrary to observation, intuition suggests local models should be superior to global models. PMID- 24628045 TI - Oral melatonin supplementation improves oocyte and embryo quality in women undergoing in vitro fertilization-embryo transfer. AB - The aim of this study was to evaluate the efficacy of oral melatonin supplementation on oocyte and embryo quality in patients in an assisted reproductive technologies program. All patients were treated for at least 2 weeks with melatonin (3 mg/day). To evaluate the cumulative effect of melatonin supplementation, we compared cycle outcomes between the first (no supplementation) and second cycles (melatonin supplementation) of patients who completed two treatment cycles. There were no significant differences in maturation rates (p = 0.50), blastocyst rates (p = 0.75), and the rate of good quality blastocysts (p = 0.59) between the first and second cycles. The fertilization rate of ICSI was higher in the second cycle than that in the first cycle (69.3 versus 77.5%). Being limited to patients with a low fertilization rate in the first cycle (<60%), the fertilization rate dramatically increased after melatonin treatment (35.1 versus 68.2%). The rate of good quality embryos also increased (48.0 versus 65.6%). An important finding in our study was that oral melatonin supplementation can have a beneficial effect on the improvement of fertilization and embryo quality and this may have occurred due to a reduction in oxidative damage. PMID- 24628046 TI - Adsorption process of CO2 on silicalite-1 zeolite using single-crystal X-ray method. AB - The process of CO2 adsorption on silicalite-1 zeolite (MFI-type) is revealed using a single-crystal X-ray method. The structure of CO2-silicalite-1 with a small amount of CO2 in the pore is determined, wherein most of CO2 molecules are located in the straight channel. It indicates the straight channel is the most stable sorption site based on the van der Waals interactions between the CO2 and the framework, and the CO2 molecules initially adsorb in the straight channel in the adsorption process. This is the first report to describe the structure of MFI type zeolites with the adsorbate molecules occupying only the straight channel. PMID- 24628047 TI - Vitamin D deficiency, parathyroid hormone levels, and bone disease among patients with end-stage liver disease and normal serum creatinine awaiting liver transplantation. AB - Vitamin D deficiency is common among patients with end-stage liver disease (ESLD). The primary aim of our study was to assess the prevalence of vitamin D deficiency, secondary hyperparathyroidism, and bone disease in patients with ESLD awaiting LT. METHODS: We retrospectively studied 190 patients at our center. Serum total 25-hydroxyvitamin D (25-OH D), parathyroid hormone (PTH), calcium, and bone mineral analysis (BMA) were recorded. Standard World Health Organization (WHO) criteria were used to diagnose osteopenia/osteoporosis. Only patients with normal serum creatinine were analyzed. RESULTS: Thirty-two of 190 patients were excluded from the final analysis (missing serum total 25-OH D levels in three patients and elevated serum creatinine, 29 patients). 105 of 158 (66.4%) evaluable patients had 25-OH D levels <25 ng/mL. Patients included in the analysis (n = 158) were divided according to serum total 25-OH D levels: 0-10 ng/mL (n = 23), 11-20 ng/mL (n = 64), and >20 ng/mL (n = 71). There were no significant differences in mean serum PTH and corrected calcium levels among the three subgroups. Only three patients had elevated serum PTH. Patients with total 25-OH D <= 10 ng/mL had higher model for end-stage liver disease (MELD) scores vs. those with 25-OH D > 20 ng/mL (13.3 +/- 3, range 8-21, vs. 11.9 +/- 3.4, range 6-29, p = 0.004). Irrespective of vitamin D status, bone disease was present in 64.6% of patients. CONCLUSION: Low vitamin D levels and bone disease are common among patients with ESLD awaiting LT. Despite a high prevalence of low serum total 25-OH D, our cohort maintained normal corrected calcium levels and did not develop secondary hyperparathyroidism. We propose that free serum 25-OH D and vitamin D-binding protein may be necessary to accurately establish the diagnosis of vitamin D deficiency in the setting of ESLD. Additional studies are needed to further define mechanisms of bone disease in patients with ESLD. PMID- 24628048 TI - Measuring health literacy - the Swedish Functional Health Literacy scale. AB - BACKGROUND: The benefits of health promotion efforts vary due to a complexity of reasons. One possible reason for an absence of effects is the level of functional health literacy among the individuals that participate in the interventions. Thus, valid and reliable instruments that capture these kinds of skills are needed. The aim of this study was to develop a Swedish Functional Health Literacy scale to use in health promotion and health prevention by translating the Japanese Functional Health Literacy scale into Swedish and testing some aspects of its validity and test-retest reliability. METHODS: The research project comprised six phases including translation and back translation, validity tests of the two first versions of the instrument based on interviews with professionals and representatives for the target group of the instrument, and a test-retest of the first version among target groups. RESULTS: The items in the first two versions were experienced as unclear, which led to improvements of the next version. The final version of the translated instrument (the Swedish Functional Literacy scale) showed evidence of content validity, and the test retest confirmed that the instrument had stability over time with a percentage agreement for the items ranging from 63% to 92% (M = 77.2%). CONCLUSION: The items in the Swedish version of the scale are equivalent to the original Japanese scale in terms of language and contents and cover the major aspects of functional health literacy as it is defined in the literature. The translated instrument shows stability over time, that is, reliability, at least for a part of the Swedish population. More validity tests of the Swedish Functional Health Literacy scale based on a broader population are needed. PMID- 24628050 TI - Undertaking and writing research that is important, targeted, and the best you can do. AB - Conducting and writing research is a privilege. It is a privilege because researchers can change lives through their findings and can influence public knowledge and debate. It is also a privilege because researchers are reliant on the time and goodwill of participants (and colleagues), and research is often underpinned by funding raised by the public, either through taxes or philanthropic donations. This privilege comes with responsibility. Researchers have a responsibility to undertake research that is important, targeted, and of high quality. This editorial aims to inspire, challenge, and bolster the research efforts of individuals and teams. PMID- 24628049 TI - Disruption of HLA class II antigen presentation in Burkitt lymphoma: implication of a 47,000 MW acid labile protein in CD4+ T-cell recognition. AB - While Burkitt lymphoma (BL) has a well-known defect in HLA class I-mediated antigen presentation, the exact role of BL-associated HLA class II in generating a poor CD4(+) T-cell response remains unresolved. Here, we found that BL cells are deficient in their ability to optimally stimulate CD4(+) T cells via the HLA class II pathway. This defect in CD4(+) T-cell recognition was not associated with low levels of co-stimulatory molecules on BL cells, as addition of external co-stimulation failed to elicit CD4(+) T-cell activation by BL. Further, the defect was not caused by faulty antigen/class II interaction, because antigenic peptides bound with measurable affinity to BL-associated class II molecules. Interestingly, functional class II-peptide complexes were formed at acidic pH 5.5, which restored immune recognition. Acidic buffer (pH 5.5) eluate from BL cells contained molecules that impaired class II-mediated antigen presentation and CD4(+) T-cell recognition. Biochemical analysis showed that these molecules were greater than 30,000 molecular weight in size, and proteinaceous in nature. In addition, BL was found to have decreased expression of a 47,000 molecular weight enolase-like molecule that enhances class II-mediated antigen presentation in B cells, macrophages and dendritic cells, but not in BL cells. These findings demonstrate that BL likely has multiple defects in HLA class II-mediated antigen presentation and immune recognition, which may be exploited for future immunotherapies. PMID- 24628051 TI - A zero-fluoroscopy approach to cavotricuspid isthmus catheter ablation: comparative analysis of two electroanatomical mapping systems. AB - BACKGROUND: Electroanatomical mapping systems have reduced the amount of fluoroscopy required to ablate the cavotricuspid isthmus. The aims of this study are to evaluate the feasibility and safety of a zero-fluoroscopy approach to cavotricuspid isthmus catheter ablation using the Carto(r)3 system (Biosense Webster, Diamond Bar, CA, USA) and to compare the results of this approach with those of the zero-fluoroscopy approach using the Ensite-NavXTM system (St. Jude Medical, St. Paul, MN, USA). METHODS: Twenty consecutive procedures guided by the Carto(r)3 system (Group A) were compared with two case-control groups matched from 146 procedures guided with the Ensite-NavXTM system. Group B consisted of 20 matched procedures from the first 50 procedures performed in the electrophysiology unit, and Group C consisted of 20 matched procedures from the last 50 procedures. Acute success (bidirectional block), complications, and recurrences were analyzed. The procedure times were also compared. RESULTS: There were no differences in the rates of acute success (95%, 100%, and 100%, respectively), complications (0%, 5%, and 0%), and recurrences (5.2%, 0%, and 5%) in the three groups. A zero-fluoroscopy approach was attempted in all procedures, and electroanatomical mapping made it possible to successfully avoid fluoroscopy in 90% of the procedures in Group A, 85% in B, and 95% in C. The total procedure time was shorter in Group C. The fluoroscopy and radiofrequency times were not different. CONCLUSIONS: A zero-fluoroscopy approach to cavotricuspid isthmus catheter ablation using the Carto(r)3 system is feasible in most procedures. This approach has similar results to the zero-fluoroscopy approach using the Ensite NavXTM system. PMID- 24628052 TI - The evolution of bipedalism in jerboas (rodentia: Dipodoidea): origin in humid and forested environments. AB - Mammalian bipedalism has long been thought to have arisen in response to arid and open environments. Here, we tested whether bipedalism coevolved with environmental changes using molecular and paleontological data from the rodent superfamily Dipodoidea and statistical methods for reconstructing ancestral characteristics and past climates. Our results show that the post-Late Miocene aridification exerted selective pressures on tooth shape, but not on leg length of bipedal jerboas. Cheek tooth crown height has increased since the Late Miocene, but the hind limb/head-body length ratios remained stable and high despite the environmental change from humid and forested to arid and open conditions, rather than increasing from low to high as predicted by the arid bipedalism hypothesis. The decoupling of locomotor and dental character evolution indicates that bipedalism evolved under selective pressure different from that of dental hypsodonty in jerboas. We reconstructed the habitats of early jerboas using floral and faunal data, and the results show that the environments in which bipedalism evolved were forested. Our results suggest that bipedalism evolved as an adaptation to humid woodlands or forests for vertical jumping. Running at high speeds is likely a by-product of selection for jumping, which became advantageous in open environments later on. PMID- 24628053 TI - Antimicrobial metallopolymers and their bioconjugates with conventional antibiotics against multidrug-resistant bacteria. AB - Bacteria are now becoming more resistant to most conventional antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), a complex of multidrug resistant Gram-positive bacterial strains, has proven especially problematic in both hospital and community settings by deactivating conventional beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, through various mechanisms, resulting in increased mortality rates and hospitalization costs. Here we introduce a class of charged metallopolymers that exhibit synergistic effects against MRSA by efficiently inhibiting activity of beta lactamase and effectively lysing bacterial cells. Various conventional beta lactam antibiotics, including penicillin-G, amoxicillin, ampicillin, and cefazolin, are protected from beta-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic cobaltocenium moieties. These discoveries could provide a new pathway for designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug-resistant bacteria and superbugs. PMID- 24628054 TI - Metallic stent with high axial force as a risk factor for cholecystitis in distal malignant biliary obstruction. AB - BACKGROUND AND AIM: Tumor involvement to the orifice of cystic duct (OCD) is a risk factor for cholecystitis after self-expandable metallic stent (SEMS) placement, but its prevention is still difficult. We conducted this multicenter analysis to clarify a type of SEMS or a method to place SEMS which would decrease the incidence of cholecystitis after SEMS placement. METHODS: The incidence of cholecystitis was studied in consecutive patients receiving SEMS for distal malignant biliary obstruction in five tertiary care centers. Multiple logistic regression analysis was performed to evaluate risk factors for cholecystitis. RESULTS: A total of 376 patients who received SEMS placement for distal malignant biliary obstruction were analyzed. Tumor involvement to OCD was diagnosed in 25.3%. Overall incidence of cholecystitis was 6.9%. Cholecystitis was observed in 8.0% of 300 patients with covered SEMS, 16.8% of 95 patients with tumor involvement to OCD, 10.8% of 234 patients with SEMS of high axial force (AF), and 12.0% of 158 patients with SEMS length <= 60 mm. In the multivariate analysis, tumor involvement to OCD (odds ratio [OR] 5.40, P < 0.001), SEMSs with high AF (OR 5.33, P = 0.002), and SEMS length <= 60 mm (OR 3.19, P = 0.010) are risk factors. Among patients with tumor involvement to OCD, the incidence of cholecystitis in SEMS with high and low AF was 25.0% and 5.0%, respectively. CONCLUSION: This study with an expanded cohort reconfirmed tumor involvement to OCD as a risk factor for cholecystitis after SEMS placement. SEMS with low AF might decrease cholecystitis. PMID- 24628056 TI - Editor-in-chief's introduction to the issue: The Architecture of action's perceptual basis: theory and issues. Introduction. PMID- 24628057 TI - The medium of haptic perception: a tensegrity hypothesis. AB - For any given animal, the sources of mechanical disturbances inducing tissue deformation define environment from the perspective of the animal's haptic perceptual system. The system's achievements include perceiving the body, attachments to the body, and the surfaces and substances adjacent to the body. Among the perceptual systems, it stands alone in having no defined medium. There is no articulated functional equivalent to air and water, the media that make possible the energy transmissions and diffusions underpinning the other perceptual systems. To identify the haptic system's medium the authors focus on connective tissue and the conjunction of muscular, connective tissue net, and skeletal (MCS) as the body's proper characterization. The challenge is a biophysical formulation of MCS as a continuum that, similar to air and water, is homogeneous and isotropic. The authors hypothesized a multifractal tensegrity (MFT) with the shape and stability of the constituents of each scale, from individual cell to whole body, derivative of continuous tension and discontinuous compression. Each component tensegrity of MFT is an adjustive-receptive unit, and the array of tensions in MFT is information about MCS. The authors extend the MFT hypothesis to body-brain linkages, and to limb perception phenomena attendant to amputation, vibration, anesthesia, neuropathy, and microgravity. PMID- 24628058 TI - The media for haptic perception and for force transmission in movement are the same of course. PMID- 24628059 TI - The bodywide fascial network as a sensory organ for haptic perception. PMID- 24628060 TI - Our internal universe. PMID- 24628061 TI - The stresses and strains of tensegrity. PMID- 24628062 TI - Proprioception, tensegrity, and motor control. PMID- 24628063 TI - The relationships between the use of self-regulated learning strategies and depression among medical students: an accelerated prospective cohort study. AB - We conducted this study to determine the relationships between the use of self regulated learning strategies (SRL) and depression scores among medical students. An accelerated prospective cohort study among 623 students at a public medical university in Vietnam was carried out during the academic year 2012-2013. The Depression, Anxiety and Stress Scales (21 items) was used to measure depression scores as the primary research outcome, and to measure anxiety and stress scores as the confounding variables. Fourteen SRL subscales including intrinsic/extrinsic goal orientation, task value, self-efficacy for learning, control of learning beliefs, rehearsal, elaboration, organization, critical thinking, meta-cognitive strategies, time and study environment, effort regulation, peer learning, and help seeking were measured using the Motivated Strategies for Learning Questionnaire. Data were collected at two points in time (once each semester). There were 744 responses at the first time (95.88%) and 623 at time two (drop-out rate of 16.26%). The generalized estimating equation was applied to identify any relationships between the use of each SRL subscale and depression scores at time 2, adjusting for the effects of depression at time 1, anxiety, stress, within cluster correlation, and potential demographic covariates. Separate multivariate GEE analysis indicated that all SRL subscales were significantly negatively associated with depression scores, except for extrinsic goal orientation and peer learning. Whereas full multivariate GEE analysis revealed that self-efficacyT1, help-seekingT1, time and study environmentT2 were found to be significantly negatively associated with depressionT2, adjusting for the effects of depressionT1, anxiety, stress, and demographic covariates. The results should be used to provide appropriate support for medical students to reduce depression. PMID- 24628065 TI - PAS-positive extracellular deposits within germinal centers of hyperplastic follicles during SIV infection in a rhesus macaque. AB - BACKGROUND: Lymphoid tissue remodeling is characteristic of chronic simian immunodeficiency virus infection. METHODS: A rhesus macaque infected with SIVmac239 was necropsied and its lymphoid tissues subjected to histopathology characterization. RESULTS: Germinal centers in spleen and lymph nodes contained PAS-positive, non-amyloid extracellular deposits, decreased T follicular helper cells, and normal density of Ki67(+) B cells. CONCLUSIONS: A possible mechanism for PAS-positive deposits includes exaggerated involution of SIV-induced follicular hyperplasia secondary to virus-associated immune reaction. PMID- 24628068 TI - Atopic dermatitis. PMID- 24628066 TI - Cardiac responses to beta-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity. AB - BACKGROUND AND PURPOSE: Despite the importance of mitochondrial Ca(2+) to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca(2+) entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca(2+) uniporter in an isolated heart model, at baseline and during increased workload following beta adrenoceptor stimulation. EXPERIMENTAL APPROACH: Cardiac contractility, oxygen consumption and intracellular Ca(2+) transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca(2+) uniporter activity. Changes in mitochondrial Ca(2+) content and energetic phosphate metabolite levels were determined. KEY RESULTS: The addition of Ru360 , a selective inhibitor of the mitochondrial Ca(2+) uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 MUM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360 . Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca(2+) -dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca(2+) content (2.5-fold). However, in Ru360 -treated hearts, this parameter was attenuated. In addition, beta-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca(2+) handling, PKA or Ca(2+) /calmodulin-dependent PK signalling. CONCLUSIONS AND IMPLICATIONS: Inhibition of the mitochondrial Ca(2+) uniporter decreases beta-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca(2+) uniporter activity. PMID- 24628067 TI - Modeling and testing for joint association using a genetic random field model. AB - Substantial progress has been made in identifying single genetic variants predisposing to common complex diseases. Nonetheless, the genetic etiology of human diseases remains largely unknown. Human complex diseases are likely influenced by the joint effect of a large number of genetic variants instead of a single variant. The joint analysis of multiple genetic variants considering linkage disequilibrium (LD) and potential interactions can further enhance the discovery process, leading to the identification of new disease-susceptibility genetic variants. Motivated by development in spatial statistics, we propose a new statistical model based on the random field theory, referred to as a genetic random field model (GenRF), for joint association analysis with the consideration of possible gene-gene interactions and LD. Using a pseudo-likelihood approach, a GenRF test for the joint association of multiple genetic variants is developed, which has the following advantages: (1) accommodating complex interactions for improved performance; (2) natural dimension reduction; (3) boosting power in the presence of LD; and (4) computationally efficient. Simulation studies are conducted under various scenarios. The development has been focused on quantitative traits and robustness of the GenRF test to other traits, for example, binary traits, is also discussed. Compared with a commonly adopted kernel machine approach, SKAT, as well as other more standard methods, GenRF shows overall comparable performance and better performance in the presence of complex interactions. The method is further illustrated by an application to the Dallas Heart Study. PMID- 24628069 TI - Epidemiology of atopic dermatitis in Japan. AB - Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic and eczematous skin disease. AD is the second most frequently observed skin disease in dermatology clinics in Japan. Prevalence of childhood AD is 12 13% in mainland Japan; however, it is only half that (~6%) in children from Ishigaki Island, Okinawa. Here, we summarize the prevalence, incidence and spontaneous regression of AD and the relation of AD to other allergic diseases from previous reports. We also refer to our recent findings from a population cohort study on Ishigaki Island, Okinawa. PMID- 24628070 TI - Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications. AB - Nerve density in the epidermis is partly involved in itch sensitization in pruritic skin diseases, such as atopic dermatitis (AD). Epidermal innervation is thought to be regulated by the balance between nerve elongation factors (e.g. nerve growth factor) and nerve repulsion factors (e.g. semaphorin 3A). Semaphorin 3A (Sema3A) has been shown to inhibit nerve growth factor (NGF)-induced sprouting of sensory nerves, and epidermal Sema3A levels are lower in AD patients, concomitant with an increase in epidermal nerve density. In addition, treatment with anti-NGF, Sema3A replacement, and several existing treatments, such as ultraviolet-based therapies, normalized the hyperinnervation in AD, resulting in suppression of itching. This review expands knowledge regarding potential therapeutic strategies for ameliorating intractable pruritus in AD. PMID- 24628071 TI - Genome-wide association studies of atopic dermatitis. AB - Atopic dermatitis is a common inflammatory disease caused by a combination of genetic and environmental factors. Genome-wide association study (GWAS) is a comprehensive and unbiased approach to identify the genetic components of human diseases and to discover the cellular pathways underlying them. GWAS and recent immunochip analysis of atopic dermatitis have identified a total of 19 associated loci with a genome-wide level of significance (P < 5 * 10(-8) ). The candidate genes identified by GWAS suggest a role for epidermal barrier functions, innate adaptive immunity, interleukin-1 family signaling, regulatory T cells, the vitamin D pathway and the nerve growth factor pathway in the pathogenesis of atopic dermatitis. Combinations of these genetic factors may influence a wide range of phenotypes of atopic dermatitis among individuals. Although a more complete collection of associated genes and pathways is needed, genetic components revealed by GWAS provide valuable insights into the pathophysiology of atopic dermatitis. PMID- 24628072 TI - Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis. AB - Thymus and activation-regulated chemokine (TARC/CCL17) is a member of the T helper 2 chemokine family. In Japan, serum TARC level has been commercially measured since 2008. After years of experience, we realized that TARC is an extremely useful clinical biomarker for atopic dermatitis (AD) treatment. Usually, physicians conduct a visual examination to determine whether their treatment has been successful; however, the visual examination results may not always be accurate; in such cases, serum TARC levels should be measured to eliminate any ambiguity regarding the treatment outcome. When the waning and waxing of eczema and fluctuations in the serum TARC levels were considered, we frequently found that AD does not follow a natural course but follows non regulated inflammatory floating caused by insufficient intermittent topical treatment. Serum TARC is a promising biomarker for remission and can be used for accurately monitoring proactive treatment for long-term control. Abnormally high serum TARC levels indicate accelerated pathogenesis of cutaneous inflammation. Rapid normalization and maintaining normal serum TARC levels using appropriate topical treatment is a reasonable strategy for alleviating inflammation without upregulating cytokine expression. Observing serum TARC levels during early intervention for severe infantile AD is worthwhile to determine initial disease activity and evaluate treatment efficacy. Appropriate control of severe early onset infantile AD is important for improving prognosis of eczema and for preventing food allergies. Additionally, this biomarker is useful for improving patient adherence. Dermatologists will be able to make great progress in treating AD by adopting biomarkers such as TARC for accurately assessing non-visible subclinical disorders. PMID- 24628073 TI - Effect of anti-CCR4 monoclonal antibody (mogamulizumab) on adult T-cell leukemia lymphoma: cutaneous adverse reactions may predict the prognosis. AB - Adult T-cell leukemia-lymphoma (ATL) is one of the most malignant lymphomas with poor prognosis. ATL cells express CC chemokine receptor 4 (CCR4) and mogamulizumab, a monoclonal antibody against CCR4 that exhibits very strong cytotoxicity for ATL cells via antibody-dependent cellular cytotoxicity. Although its effect is dramatic in ATL, serious adverse reactions such as Stevens-Johnson syndrome have been reported. However, these eruptions can appear as therapeutic signs of mogamulizumab. We evaluated the effectiveness of mogamulizumab in five acute-type ATL patients. Peripheral blood (PB) and lymph nodes (LN) were affected in three and four patients, respectively. In PB, complete response (CR) was obtained in all three patients and partial response (PR) was recorded in LN of one patient. In skin lesions, four of five patients manifested CR; in two, the lesions worsened after the start of mogamulizumab treatment and subsequently improved. In these lesions, CD4(+) 8(-) 25(+) ATL cells were replaced by CD3(+) 8(+) cytotoxic T cells. Cutaneous adverse reactions (CAR) developed in two patients with CR; they did not show a relapse of ATL over the course of 9 months. Our findings suggest that mogamulizumab should be continued and surface marker evaluation should be performed even in patients whose skin lesions show aggravation, and that CAR may be a marker for a favorable prognosis. PMID- 24628074 TI - Cutaneous Langerhans cell histiocytosis in elderly with chronic myelomonocytic leukemia. AB - Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm characterized by clonal proliferation of Langerhans cells in multi-organ systems including skin, bone, pituitary gland, liver and spleen. Skin-limited involvement of LCH usually indicates an indolent clinical course; however, in rare cases, LCH is accompanied by other myeloproliferative disorders, which may determine the prognosis. An 82-year old Japanese man presented with numerous asymptomatic facial papules clinically simulating rhinophyma. Although findings of histopathology and general examination including bone marrow biopsy led to the diagnosis of cutaneous LCH, he died from chronic myelomonocytic leukemia, which emerged 10 months after the initial diagnosis of LCH. The previously reported cases of LCH concomitant with other hematological disorders are also summarized and described compared with the present case. PMID- 24628075 TI - Small molecule regulation of self-association and catalytic activity in a supramolecular coordination complex. AB - Herein, we report the synthesis and characterization of the first weak-link approach (WLA) supramolecular construct that employs the small molecule regulation of intermolecular hydrogen bonding interactions for the in situ control of catalytic activity. A biaryl urea group, prone to self-aggregation, was functionalized with a phosphinoalkyl thioether (P,S) hemilabile moiety and incorporated into a homoligated Pt(II) tweezer WLA complex. This urea-containing construct, which has been characterized by a single crystal X-ray diffraction study, can be switched in situ from a rigid fully closed state to a flexible semiopen state via Cl(-) induced changes in the coordination mode at the Pt(II) structural node. FT-IR and (1)H NMR spectroscopy studies were used to demonstrate that while extensive urea self-association persists in the flexible semiopen complex, these interactions are deterred in the rigid, fully closed complex because of geometric and steric restraints. Consequently, the urea moieties in the fully closed complex are able to catalyze a Diels-Alder reaction between cyclopentadiene and methyl vinyl ketone to generate 2-acetyl-5-norbornene. The free urea ligand and the semiopen complex show no such activity. The successful incorporation and regulation of a hydrogen bond donating catalyst in a WLA construct open the doors to a vast and rapidly growing catalogue of allosteric catalysts for applications in the detection and amplification of organic analytes. PMID- 24628076 TI - Intrathecal fentanyl decreases the optimal effect site concentration of propofol during spinal anaesthesia. AB - BACKGROUND: The aim of this study was to assess the possible difference in the optimal effect site concentration of propofol for conscious sedation during spinal anaesthesia with or without intrathecal fentanyl in patients undergoing urologic surgery. The hypothesis was that intrathecal fentanyl would decrease the effect site concentration of propofol needed for conscious sedation. METHODS: Among 43 patients, 23 patients received fentanyl 25 mcg and 20 patients received normal saline in addition to hyperbaric bupivacaine 10 mg during spinal anaesthesia. Propofol was infused at a dose determined by a modified Dixon's up and-down method. The Cerebral State Index was recorded once target effect site concentration was reached to determine the effect of the successfulness of the conscious sedation. RESULTS: The half maximal effective concentration (EC50) of the effect-site concentration of propofol for sedation was 1.67 +/- 0.28 mcg/ml in the control group and 0.87 +/- 0.15 mcg/ml in the fentanyl group (P = 0.02). The propofol dose for conscious sedation during spinal anaesthesia was decreased by 48% when intrathecal fentanyl 25 mcg was added to local anaesthetics. CONCLUSION: The EC50 of the effect-site concentration of propofol for sedation decreased from 1.67 +/- 0.28 mcg/ml to 0.87 +/- 0.15 mcg/ml with the addition of 25 mcg fentanyl to a spinal anaesthetic in patients undergoing urologic surgery. PMID- 24628077 TI - A review of metal-catalyzed molecular damage: protection by melatonin. AB - Metal exposure is associated with several toxic effects; herein, we review the toxicity mechanisms of cadmium, mercury, arsenic, lead, aluminum, chromium, iron, copper, nickel, cobalt, vanadium, and molybdenum as these processes relate to free radical generation. Free radicals can be generated in cells due to a wide variety of exogenous and endogenous processes, causing modifications in DNA bases, enhancing lipid peroxidation, and altering calcium and sulfhydryl homeostasis. Melatonin, an ubiquitous and pleiotropic molecule, exerts efficient protection against oxidative stress and ameliorates oxidative/nitrosative damage by a variety of mechanisms. Also, melatonin has a chelating property which may contribute in reducing metal-induced toxicity as we postulate here. The aim of this review was to highlight the protective role of melatonin in counteracting metal-induced free radical generation. Understanding the physicochemical insights of melatonin related to the free radical scavenging activity and the stimulation of antioxidative enzymes is of critical importance for the development of novel therapeutic strategies against the toxic action of these metals. PMID- 24628078 TI - Safety and performance of liver biopsies in liver transplant recipients. AB - BACKGROUND: Liver biopsy in patients after liver transplantation (OLT) serves as a diagnostic tool to establish the cause of liver pathology. However, liver biopsy may cause life-threatening complications. Very limited information is available about complications and success rates of liver biopsies in patients after OLT. Our aim was to investigate biopsy-related complications and quality of specimen obtained by liver biopsy after OLT and to evaluate risks and benefits of this procedure. METHODS: Retrospective analysis of patients after OLT presenting for liver biopsy between January 2000 and October 2012. All patients were observed for 24 h after intervention. Twelve or more portal tracts were required for liver biopsy specimens to be considered as adequate. RESULTS: Of 703 liver biopsies were performed in 409 patients. Thirteen (1.9%) liver biopsies did not have an adequate number of portal tracts. Only 10 (1.4%) liver biopsies caused complications. Five patients suffered from pain, three patients developed post procedural fever, and three patients had subcapsular/intercostal bleeding. One patient suffered from a vasovagal reaction. Pain was treated by analgesics; none of the patients required blood transfusion or surgery. CONCLUSIONS: Liver biopsy is a safe and adequate diagnostic tool in patients after OLT. PMID- 24628079 TI - Diagnostic criteria for acute pericarditis need closer attention. PMID- 24628080 TI - Characterization of the chemical composition of polyisobutylene-based oil-soluble dispersants by fluorescence. AB - A novel methodology based on fluorescence quenching measurements is introduced to determine quantitatively the amine content of polyisobutylene succinimide (PIBSI) dispersants used as engine oil-additives. To this end, a series of five PIBSI dispersants were prepared by reacting 2 mol equiv of polyisobutylene succinic anhydride (PIBSA) with 1 mol equiv of hexamethylenediamine (HMDA), diethylenetriamine, triethylenetetramine, tetraethylenepentamine, and pentaethylenehexamine to yield the corresponding b-PIBSI dispersants. After having demonstrated that the presence of hydrogen bonds between the polyamine linker and the succinimide carbonyls of the dispersants prevents the quantitative analysis of the (1)H NMR and FTIR spectra of the dispersants to determine their chemical composition, alternative procedures based on gel permeation chromatography (GPC) and fluorescence quenching were implemented to estimate the amine content of the b-PIBSI dispersants. Taking advantage of the doubling in size that occurs when 2 mol of PIBSA are reacted with 1 mol of HMDA, a combination of GPC and FTIR was employed to follow how the chemical composition and molecular weight distribution of the polymers produced evolved with the reaction of PIBSA and HMDA mixed at different molar ratios. These experiments provided the PIBSA-to-HMDA molar ratio yielding the largest b-PIBSI dispersants and this molar ratio was then selected to prepare the four other dispersants. Having prepared five b-PIBSI dispersants with well-defined secondary amine content, the fluorescence of the succinimide groups was found to decrease with increasing number of secondary amines present in the polyamine linker. This result suggests that fluorescence quenching provides a valid method to determine the chemical composition of b-PIBSI dispersants which is otherwise difficult to characterize by standard (1)H NMR and FTIR spectroscopies. PMID- 24628081 TI - Copper-catalyzed direct amination of quinoline N-oxides via C-H bond activation under mild conditions. AB - A highly efficient and concise one-pot strategy for the direct amination of quinoline N-oxides via copper-catalyzed dehydrogenative C-N coupling has been developed. The desired products were obtained in good to excellent yields for 22 examples starting from the parent aliphatic amines. This methodology provides a practical pathway to 2-aminoquinolines and features a simple system, high efficiency, environmental friendliness, low reaction temperature, and ligand, additives, base, and external oxidant free conditions. PMID- 24628082 TI - Endocrine disruptome--an open source prediction tool for assessing endocrine disruption potential through nuclear receptor binding. AB - Predicting the endocrine disruption potential of compounds is a daunting but essential task. Here we report a new tool for this purpose that we have termed Endocrine Disruptome. It is a free and simple-to-use Web service that runs on an open source platform called Docking interface for Target Systems (DoTS). The molecular docking is handled via AutoDock Vina. Compounds are docked to 18 integrated and well-validated crystal structures of 14 different human nuclear receptors: androgen receptor; estrogen receptors alpha and beta; glucocorticoid receptor; liver X receptors alpha and beta; mineralocorticoid receptor; peroxisome proliferator activated receptors alpha, beta/delta, and gamma; progesterone receptor; retinoid X receptor alpha; and thyroid receptors alpha and beta. Endocrine Disruptome is free of charge and available at http://endocrinedisruptome.ki.si. PMID- 24628083 TI - Lack of transglutaminase 2 diminished T-cell responses in mice. AB - Transglutaminase 2 (TG2) has been reported to play a role in dendritic cell activation and B-cell differentiation after immunization. Its presence and role in T cells, however, has not been explored. In the present study, we determined the expression of TG2 on mouse T cells, and evaluated its role by comparing the behaviours of wild-type and TG2(-/-) T cells after activation. In our results, naive T cells minimally expressed TG2, expression of which was increased after activation. T-cell proliferation, expression of activation markers such as CD69 and CD25, and secretions of interleukin-2 and interferon-gamma were suppressed in the absence of TG2, presumably due, in part, to diminished nuclear factor-kappaB activation. These effects on T cells seemed to be reflected in the in vivo immune response, the contact hypersensitivity reaction elicited by 2,4-dinitro-1 fluorobenzene, with lowered peak responses in the TG2(-/-) mice. When splenic T cells from mice immunized with tumour lysate-loaded wild-type dendritic cells were re-challenged ex vivo with the same antigen, the profile of surface markers including CD44, CD62L, and CD127 strongly indicated lesser generation of memory CD8(+) T cells in TG2(-/-) mice. In the TG2(-/-) CD8(+) T cells, moreover, Eomes expression was markedly decreased. These results indicate possible roles of TG2 in CD8(+) T-cell activation and CD8(+) memory T-cell generation. PMID- 24628084 TI - Intensity and pleasantness of sucrose taste in patients with winter depression. AB - OBJECTIVES: Increased consumption of carbohydrates and craving for sweets are considered core features of winter depression. Unfortunately, little is known about neural and behavioral correlates of these symptoms. The primary aim of the present study was to evaluate taste responses to sucrose solutions in depressed patients with seasonal affective disorder (SAD). METHODS: Intensity and pleasantness ratings of sucrose solutions, electrogustometric thresholds, and taste identification abilities were assessed in depressed patients with SAD and non-seasonal affective disorder (non-SAD), and in non-depressed controls. RESULTS: Electrogustometric thresholds and identification abilities did not differ between the study groups. There were no differences between the groups in intensity or pleasantness ratings of sucrose solutions (1-30%). The proportion of 'sweet likers', i.e. subjects rating the highest sucrose concentration as most pleasant, was similar in the controls, SAD, and non-SAD patients. DISCUSSION: The present results suggest that: (i) winter depression is not associated with major alterations in gustatory function; and (ii) sweet craving and increased consumption of carbohydrates in patients with winter depression is not secondary to altered responses to sweet tastants. More studies are needed to characterize hedonic responses of patients with SAD to other sweet and non-sweet foods. PMID- 24628085 TI - Effect of the intermolecular excitation in the vibrational predissociation dynamics of van der Waals complexes and the implications for control. AB - The effect of intermolecular excitation on the vibrational predissociation lifetime is investigated systematically for different vdW complexes Rg-X2(B, v') (Rg = rare gas atom, X = halogen atom) by means of wave packet simulations. The lifetime as a function of intermolecular excitation displays a pattern of maxima and minima, with a similar shape for the different Rg-X2(B, v') complexes. The pattern is consistent with previous experimental findings involving lifetimes of intermolecular excitations in similar systems. The structure of the lifetime pattern is found to be determined by the shape of the resonance wave functions in the two van der Waals degrees of freedom, and more specifically by the magnitude of the overlap between the wave function and the coupling responsible for predissociation. Lifetime maxima and minima are associated with minima and maxima of this overlap, respectively. Implications for control of the complex lifetime are discussed. PMID- 24628086 TI - Editorial: New frontiers for family therapy-family centered practice and neuroscience. PMID- 24628087 TI - Stepparents and parenting stress: the roles of gender, marital quality, and views about gender roles. AB - Previous research suggests that stepparenting can be stressful, although the mechanisms that contribute to the experience of parenting stress in stepfamilies are less clear. This study examines gender, marital quality, and views about gendered family roles as correlates of parenting stress among 310 stepmothers, stepfathers, and biological mothers and fathers. Findings suggest that stepparents, and especially stepmothers, experience higher levels of parenting stress than biological parents. Findings also suggest that less traditional views about gendered family roles and higher dyadic adjustment are associated with lower parenting stress for stepparents, particularly in combination. Stepparents reporting both of these protective factors were indistinguishable in terms of parenting stress from biological parents. These findings indicate potential pathways to mitigate the stress associated with stepparenting. PMID- 24628088 TI - Inhibiting Interference--a grounded theory of health professionals' pattern of behaviour related to the relatives of older patients in fast-track treatment programmes. AB - AIM: To generate a grounded theory explaining health professionals' pattern of behaviour and experience related to the relatives of older patients in fast-track treatment programmes during total joint replacement. BACKGROUND: Health professionals uphold standardised care for patients, and effect on quality is seen when relatives support patients during total joint replacement. Since health professionals often have problematic relationships with relatives, knowledge is needed of the health professionals' pattern of behaviour in relation to relatives of older patients in fast-track treatment programme. DESIGN: Grounded theory according to Glaser's methodology was used to generate substantive theory of health professionals' pattern of behaviour. METHODS: Data were collected from 2010 to 2011 by 44 health professionals in orthopaedic wards at two Danish hospitals. Data from nonparticipant observations, formal interviews, group interviews, informal interviews and written information material were collected, coded and analysed through the constant comparative method. FINDINGS: Inhibiting Interference emerged as health professionals' pattern of behaviour through which they resolved their main concern, striving for maintenance of the fast-track treatment programme and principles. Their main concern was resolved by a main strategy: Focusing on Principles, by striving for patients' full compliance during the trajectory, followed by two strategies of social control: Accepting Compliant Motivators, by involving well-informed relatives, and Avoiding Disobedient Doubters, by excluding relatives who do not comply with programme principles. CONCLUSION: In the health professionals' strive to maintain programme principles, relatives were perceived as interferences, if noncompliant with trajectory rules, resulting in exclusion with consequences for their potential of being resources for patients. PMID- 24628090 TI - Micellar structures in nanoparticle-multiblock copolymer complexes. AB - Brownian dynamics simulation is employed to examine the structure changes of complexes composed of a hydrophobic nanoparticle and a multiblock copolymer molecule (MCP). The dependence of the structure transitions on the radius of the nanoparticle, on the interactions between the hydrophobic segments of the MCP, and on the interactions between the hydrophobic segments and hydrophobic nanoparticle is examined. It is shown that the multiblock copolymer adsorbed on a nanoparticle can acquire the structure of a micelle.To better characterize the micelle generated and the structure changes in the nanoparticle-MCP complex, the mass dipole moment of the complex [the distance between the center of mass of MCP and the center of the nanoparticle minus the radius of the nanoparticle (DCC)], the density profiles of MCP segments around its center of mass and around the nanoparticle, the radius of gyration of the MCP, and the thickness of the micelle around the nanoparticle are determined. It was found that, when structural transition of the complex occurs, the above quantities change dramatically. The present simulation may provide new insights regarding the drug-loaded micelle interacting with a virus represented by a nanoparticle. PMID- 24628089 TI - Pregnancy and Infants' Outcome: Nutritional and Metabolic Implications. AB - Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy. PMID- 24628091 TI - Core competencies for health professionals' training in pediatric behavioral sleep care: a Delphi study. AB - The need to train non-sleep-specialist health professionals in evidence-based pediatric behavioral sleep care is well established. The objective of the present study was to develop a list of core competencies for training health professionals in assisting families of 1- to 10-year old children with behavioral insomnia of childhood. A modified Delphi methodology was employed, involving iterative rounds of surveys that were administered to 46 experts to obtain consensus on a core competency list. The final list captured areas relevant to the identification and treatment of pediatric behavioral sleep problems. This work has the potential to contribute to the development of training materials to prepare non-sleep-specialist health professionals to identify and treat pediatric behavioral sleep problems, ideally within stepped-care frameworks. PMID- 24628092 TI - Ulinastatin activates the renin-angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis. AB - BACKGROUND AND AIM: Ulinastatin is a drug used effectively to alleviate symptoms and improve the pathophysiology of various types of pancreatitis. However, the molecular mechanism responsible for its action remains unknown. Therefore, we further explore the therapeutic effects of ulinastatin and investigate possible molecular pathways modulated by this drug in the development of severe acute pancreatitis (SAP). METHODS: SAP mouse model was created by administering intraperitoneal injections of cerulein and lipopolysaccharide. Pancreatic injury was assessed by performing biochemical and histological assays and by measuring the inflammatory response of the pancreas. Specifically, we examined changes in the expression of components of the rennin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-angiotensin type 1 receptor (AT-1R), and ACE2-Ang-(1-7)-Mas receptor. RESULTS: When SAP mouse models were treated with ulinastatin at a dosage of 50,000 U/kg body weight, we found, through biochemical and histopathological analyses, that the pancreatic injury was significantly ameliorated. Administration of ulinastatin to SAP mice led to increased expression of ACE2, Ang-(1-7), and Mas receptor, decreased expression of serum Ang II and pancreatic AT-1R, and no alterations in the expression of pancreatic ACE and Ang II when compared to cerulein-treated control group that did not receive ulinastatin. CONCLUSIONS: This study shows that ulinastatin has differential effects on the two axes of the RAS during SAP. Our results further suggest that upregulation of components of the ACE2-Ang-(1-7)-Mas pathway might be an important mechanism contributing to the therapeutic role of ulinastatin in alleviating pancreatitis-associated symptoms. PMID- 24628093 TI - BDNF blood levels after electroconvulsive therapy in patients with mood disorders: a systematic review and meta-analysis. AB - OBJECTIVES: To evaluate whether electroconvulsive therapy (ECT), a very effective non-pharmacological treatment for mood disorders, induces neurotrophic effects, indexed by the measurement of peripheral brain-derived neurotrophic factor (BDNF) levels. METHODS: Systematic review and meta-analysis of clinical trials published in PubMed/Medline from the first date available to October 2013. We included studies measuring pre- and post-BDNF blood levels under ECT in patients with mood disorders in the acute depressive episode. RESULTS: Eleven studies (n = 221 subjects) were eligible. These studies enrolled subjects with unipolar, bipolar and psychotic depression and varied regarding electrode placement (unipolar vs. bipolar) and previous use of pharmacotherapy. Nonetheless, BDNF significantly increased after ECT (Hedges' g pooled, random-effects model of 0.354; 95% CI = 0.162-0.546). The results were robust according to sensitivity analysis and Begg's funnel plot did not suggest publication bias. Meta-regression results did not show association of the outcome with any clinical and demographic variable, including depression improvement. CONCLUSIONS: Our meta-analysis indicates that, similar to pharmacological interventions, peripheral BDNF increases after ECT treatment. The lack of correlation between BDNF increasing and depression improvement suggests that ECT induces neurotrophic effects regardless of clinical response in depression. PMID- 24628095 TI - Microbial metabolism and community structure in response to bioelectrochemically enhanced remediation of petroleum hydrocarbon-contaminated soil. AB - This study demonstrates that electrodes in a bioelectrochemical system (BES) can potentially serve as a nonexhaustible electron acceptor for in situ bioremediation of hydrocarbon contaminated soil. The deployment of BES not only eliminates aeration or supplement of electron acceptors as in contemporary bioremediation but also significantly shortens the remediation period and produces sustainable electricity. More interestingly, the study reveals that microbial metabolism and community structure distinctively respond to the bioelectrochemically enhanced remediation. Tubular BESs with carbon cloth anode (CCA) or biochar anode (BCA) were inserted into raw water saturated soils containing petroleum hydrocarbons for enhancing in situ remediation. Results show that total petroleum hydrocarbon (TPH) removal rate almost doubled in soils close to the anode (63.5-78.7%) than that in the open circuit positive controls (37.6 43.4%) during a period of 64 days. The maximum current density from the BESs ranged from 73 to 86 mA/m(2). Comprehensive microbial and chemical characterizations and statistical analyses show that the residual TPH has a strongly positive correlation with hydrocarbon-degrading microorganisms (HDM) numbers, dehydrogenase activity, and lipase activity and a negative correlation with soil pH, conductivity, and catalase activity. Distinctive microbial communities were identified at the anode, in soil with electrodes, and soil without electrodes. Uncommon electrochemically active bacteria capable of hydrocarbon degradation such as Comamonas testosteroni, Pseudomonas putida, and Ochrobactrum anthropi were selectively enriched on the anode, while hydrocarbon oxidizing bacteria were dominant in soil samples. Results from genus or phylum level characterizations well agree with the data from cluster analysis. Data from this study suggests that a unique constitution of microbial communities may play a key role in BES enhancement of petroleum hydrocarbons biodegradation in soils. PMID- 24628096 TI - Guttate psoriasis is associated with an intermediate phenotype of impaired Langerhans cell migration. AB - BACKGROUND: An episode of guttate psoriasis can be an isolated event, can recur as guttate episodes, or develop into chronic plaque psoriasis (CPP). A previous study revealed that early-onset (before age 40 years) CPP is associated with inhibition of epidermal Langerhans cell (LC) migration. OBJECTIVES: To determine whether guttate psoriasis is also associated with abnormal LC mobilization. METHODS: Three groups of patients were recruited: current guttate episode (n = 5); guttate psoriasis progressed to CPP (n = 6); and resolved guttate psoriasis (n = 2). Biopsies were taken from uninvolved skin and LC migration was measured ex vivo using an epidermal explant model. RESULTS: Patients with a current episode of guttate psoriasis displayed epidermal LC migration, although the extent was significantly lower than in skin from healthy controls (P < 0.05). In contrast, in those patients in whom guttate psoriasis developed into CPP there was no mobilization of LC. Finally, in patients in whom guttate psoriasis had resolved, LC migration was normal. CONCLUSIONS: We have shown that guttate psoriasis is associated with an abnormality of LC mobilization, but a less marked inhibition compared with that seen in CPP. In resolved guttate psoriasis LC function returns to normal. These data provide further evidence that the pathogenesis of psoriasis is characterized by significant changes in epidermal LC function. PMID- 24628099 TI - Assessing quality of life in Alopecia areata patients in China. AB - Alopecia areata (AA) is a common chronic hair condition that has negative impact on both patients and their families. The aim of this article is to assess the impact of AA on patients' quality of life (QoL) using the dermatology life quality index (DLQI) questionnaire, and assess its feasibility and internal consistency. A cross-sectional survey was conducted among 831 patients with AA between January 2010 and July 2012. The Chinese version of DLQI questionnaire was used to assess the QoL of AA patients more than 16 years old. About 698 patients (84%) completed the questionnaire. The scores ranged from 0 to 29 with a mean of 5.8 +/- 5.6. Patients' QoL was affected moderately to extremely by AA. Questions 2 (embarrassment), 5(social or entertainment), and 3 (shopping or housework) had the most impact on patients. Mean score of younger patients was higher compared to older ones (6.2 vs. 4.8, P < .05). Patients with alopecia totalis/alopecia universalis, longer duration, local symptoms, and recurrent disease exhibited higher scores (P < .001). Among our patients with AA, Cronbach's alpha was .881, indicating high internal reliability of DLQI questionnaire. In conclusion, AA moderately affected the QoL of the patients. These individuals had to be treated early, and required psychological support in addition to prescription drugs. PMID- 24628098 TI - Subdural hygroma accompanied by parenchymal and subarachnoid haemorrhage after epidural analgesia in an obstetric patient. AB - BACKGROUND: Anaesthetists need to know the different causes of persistent headache or a change in level of consciousness following epidural analgesia for labour. Failure to recognise these neurological complications can lead to delayed diagnoses, with subsequent serious implications. METHODS: We present a patient who was re-admitted for postural headache resulting from an unrecognised dural puncture during an epidural for pain relief while in labour. During the interview, the patient confirmed drug use (cocaine), so she was evaluated by a psychiatrist with possible post-partum psychosis or drug withdrawal syndrome. Afterwards, the patient deteriorated neurologically, showing impaired consciousness and seizures. RESULTS: The cranial computed tomography showed bilateral frontoparietal subdural collections with intraparenchymal and subarachnoid haemorrhaging. She improved by burr hole drainage of subdural hygroma and a blood patch. CONCLUSIONS: Neurological signs should alert the clinician to the possibility of subdural collection and other possible complications such as sinking of the brain in order not to delay the request for imaging tests for diagnoses and effective treatments. PMID- 24628100 TI - Persistent pruritic papules and plaques associated with adult-onset Still's disease: report of six cases. AB - Typical skin rash, which appears and disappears along with respective rise and fall of fever, is well-known, and included as one of the major criteria of adult onset Still's disease (AOSD) (Yamaguchi's criteria). In addition, various skin lesions are occasionally observed in association with AOSD. Persistent pruritic eruptions present with some clinical features, such as urticarial erythema, flagellate erythema, erythematous, slightly scaly or crusted papules, and/or plaques on the trunk and extremities. These lesions show unique histological features such as dyskeratosis with a peculiar, distinctive distribution in the upper epidermis and cornified layers with focal hyperkeratosis. We describe herein six cases of AOSD, which presented with skin lesions of persistent pruritic papules and plaques. All six cases were female, and three of them were elderly women. The patients presented with linear erythematous streaks, scaly erythema, keratotic papules, infiltrative plaques and irregular coalesced erythemas. By contrast, histological features were characteristic, and dyskeratotic cells were found in the horny layers as well as in the upper layers of the epidermis. Persistent pruritic eruption is an important cutaneous sign for the diagnosis of AOSD. PMID- 24628103 TI - The association between caesarean section and asthma or allergic disease continues to challenge. PMID- 24628104 TI - Are some clinicians missing a trick when it comes to gender at birth? (Case presentation). PMID- 24628105 TI - Are some clinicians missing a trick when it comes to gender at birth? (Discussion and diagnosis). PMID- 24628106 TI - Orthogonal reactivity of acyl azides in C-H activation: dichotomy between C-C and C-N amidations based on catalyst systems. AB - The dual reactivity of acyl azides was utilized successfully in C-H activation by the choice of catalyst systems: while selective C-C amidation was achieved under thermal Rh catalysis, a Ru catalyst was found to mediate direct C-N amidation also highly selectively. Investigations of the mechanistic dichotomy between two catalytic systems are also presented. PMID- 24628107 TI - End-of-life care for children enrolled in a community-based pediatric palliative care program. AB - BACKGROUND: Despite recent strides in pediatric palliative care (PPC), there are few published data on community-based care of dying children. OBJECTIVE: Our aim was to describe end-of-life care during the last 6 months of life for children on a community-based PPC program. METHODS: We conducted a retrospective review of children <21 years old who died while enrolled in a community-based PPC program (CompassionNet) from December 2004 through May 2008. Data were extracted on the last 6 months of life from hospital records (University of Rochester) and records of CompassionNet and its home-nursing team. RESULTS: Thirty-six children died while enrolled in the CompassionNet program; diagnoses included cancer 20 (56%), genetic/neurologic disorders 7 (19%), cardiac anomalies 6 (17%), and other 3 (8%). In the last 6 months of life, there were a median of 2 emergency room visits (range 0-12) and 2 unplanned hospitalizations (range 0-6). Home visits by CompassionNet (case manager, physician, nurse) ranged from 1 to 121 (median 24). A "goals of care" discussion was documented for 29 children (81%), occurring a median of 16 days before death (range 0-118). Sixteen children died at home (44%); 20 died in the hospital (56%). Of the 16 families with a documented preference for location of death, 14 children died in this location (88%). Thirty two families (89%) had bereavement support through CompassionNet. CONCLUSIONS: Children who die of complex chronic conditions spend the majority of their last 6 months of life at home. Community-based PPC can contribute substantially to their care and comfort. PMID- 24628109 TI - Cultural influences on children's understanding of the human body and the concept of life. AB - This study aimed to identify the age by which children begin to demonstrate a biological understanding of the human body and the idea that the purpose of body functioning is to maintain life. The study also explored the influence of education, culturally specific experiences and religion on knowledge acquisition in this domain. Children aged between 4 and 7 years from three different cultural backgrounds (White British, British Muslim, and Pakistani Muslim) were interviewed about the human body and its functioning. At least half of the 4- to 5-year-olds in each cultural group, and almost all 6- to 7-year-olds, referred to the maintenance of life when explaining organs' functions and so were classified as 'life theorizers'. Pakistani Muslim children gave fewer biological responses to questions about organs' functions and the purpose of eating and breathing, but referred to life more than their British counterparts. Irrespective of cultural group, older children understood organ location and function better than younger children. These findings support Jaakkola and Slaughter's (2002, Br. J. Dev. Psychol., 20, 325) view that children's understanding of the body as a 'life machine' emerges around the ages of 4-5 years. They also suggest that, despite many similarities in children's ideas cross-culturally, different educational input and culturally specific experiences influence aspects of their biological understanding. PMID- 24628108 TI - Visual and quantitative screening of alpha1-adrenoceptor antagonists in living cells using quantum dots. AB - The performance of alpha1-adrenoceptor antagonists in living cells was assessed using quantum dots conjugated to a derivative of the alpha1-adrenoceptor antagonist prazosin. The optimum receptor binding condition and apparent Kd of prazosin-conjugated quantum dots was first determined, followed by application of these structures to drug screening. Total internal reflection fluorescence microscopy and flow cytometry were used to visually and quantitatively measure the affinity of five candidate drugs. The observed affinity order and the affinity coefficient Ki were consistent with previously reported values. These results suggest that this method is suitable for specific drug screening in living cells and is able to realize the displacement assay over the large ranges of dissociation constants. PMID- 24628110 TI - The development of insomnia or the plasticity of good sleep? A preliminary study of acute changes in sleep and insomnia resulting from an analogue trauma. AB - The present preliminary study aimed to shed light on the mechanisms underlying the development of insomnia. An analogue stressor (i.e., trauma video) was used to prevent presleep cognitive de-arousal. Subsequent changes in nocturnal sleep and sleep-related attentional processing were examined. Thirty-four participants were randomly assigned to either a cognitive arousal (trauma video; age: M = 22.9, SD = 4.3, 6 male, 11 female) or control (pleasant video; age: M = 23.8, SD = 5.8, 7 male, 10 female) condition. Although no significant differences were found for presleep cognitive de-arousal (p = .39), the cognitive arousal group experienced a significant worsening in sleep latency (p = .048, partial eta(2) = .12) and an increase in sleep-related attentional bias (p = .032, d = 0.51) following the manipulation. However, changes in sleep and attentional bias were not maintained. Vulnerability to stress did not significantly account for any change in attentional bias, arousal, or sleep. These findings challenge current conceptualizations of the development of insomnia, yet also supporting the notion that good sleep is a default state that protects individuals from sleep disturbance. PMID- 24628111 TI - Melting of DNA nonoriented fibers: a wide-angle X-ray diffraction study. AB - The melting transition of A- and B-DNA has been investigated by wide-angle X-ray diffraction. A significant crystalline phase is present in both the systems, even if the fibers have not been artificially aligned. The behavior of the intramolecular Bragg peaks of both A- and B-DNA as a function of the temperature clearly reveals the unfolding structural transition of the double helix. This transition occurs at the same temperature as the melting of the crystalline phase. The trends of the intramolecular correlations and the index of crystallinity are nicely described by the Peyrard-Bishop-Dauxois model for DNA melting. A description of the processes taking place at a microscopic level, i.e., double-helix deformation, crystalline dilation, and collapse, on approaching and during thermal melting is proposed. PMID- 24628113 TI - Evaluation of the contribution of theatre attendance to medical undergraduate neuroscience teaching--a pilot study. AB - INTRODUCTION: Medical students often attend the neurosurgical theatre during their clinical neurosciences attachment. However, few studies have been performed to objectively assess the value of this theatre-based learning experience. The main aim of this study was to explore student perceptions on the contribution of neurosurgical theatre attendance to clinical neuroscience teaching. MATERIALS AND METHODS: Third-year medical students undergoing their 2-week clinical neurosciences rotation at the Royal Hospitals Belfast were invited to participate in this study. A multi-method strategy was employed using a survey questionnaire comprising of closed and open-ended questions followed by semi-structured interviews to gain a greater 'in-depth' analysis of the potential contribution of neurosurgical theatre attendance to neuroscience teaching. RESULTS: Based on the completed survey responses of 22 students, the overall experience of neurosurgical theatre-based learning was a positive one. 'In-depth' analysis from semi-structured interviews indicated that students felt that some aspects of their neurosurgical theatre attendance could be improved. Better preparation such as reading up on the case in hand and an introduction to simple theatre etiquette to put the student at ease (in particular, for students who had never attended theatre previously), would improve the learning experience. In addition, having an expectation of what students are expected to learn in theatre making it more learning outcomes-based would probably make it feel a more positive experience by the student. CONCLUSIONS: The vast majority of students acknowledged the positive learning outcomes of neurosurgical theatre attendance and felt that it should be made a mandatory component of the curriculum. PMID- 24628115 TI - Hospital social work in Australia: emerging trends or more of the same? AB - Social work in health care has been established for more than 100 years and is one of the largest areas of practice for social workers. Over time, demographic changes and growth in the aging population, increased longevity rates, an explosion in rates of chronic illness together with rapidly increasing cost of health care have created serious challenges for acute hospitals and health social workers. This article reviews the Australian health care system and policies with particular emphasis on the public hospital system. It then examines current hospital social work roles, including the continued role in discharge planning and expanding responsibility for emerging client problems, such as patient complexity, legal, and carer issues. The article concludes with a discussion of evolving issues and challenges facing health social work to ensure that social work remain relevant within this practice context. PMID- 24628114 TI - Interactions of antagonists with subtypes of inositol 1,4,5-trisphosphate (IP3) receptor. AB - BACKGROUND AND PURPOSE: Inositol 1,4,5-trisphosphate receptors (IP3 Rs) are intracellular Ca(2+) channels. Interactions of the commonly used antagonists of IP3Rs with IP3R subtypes are poorly understood. EXPERIMENTAL APPROACH: IP3-evoked Ca(2+) release from permeabilized DT40 cells stably expressing single subtypes of mammalian IP3R was measured using a luminal Ca(2+) indicator. The effects of commonly used antagonists on IP3-evoked Ca(2+) release and (3) H-IP3 binding were characterized. KEY RESULTS: Functional analyses showed that heparin was a competitive antagonist of all IP3R subtypes with different affinities for each (IP3R3 > IP3R1 >= IP3R2). This sequence did not match the affinities for heparin binding to the isolated N-terminal from each IP3R subtype. 2-aminoethoxydiphenyl borate (2-APB) and high concentrations of caffeine selectively inhibited IP3R1 without affecting IP3 binding. Neither Xestospongin C nor Xestospongin D effectively inhibited IP3-evoked Ca(2+) release via any IP3R subtype. CONCLUSIONS AND IMPLICATIONS: Heparin competes with IP3, but its access to the IP3-binding core is substantially hindered by additional IP3R residues. These interactions may contribute to its modest selectivity for IP3R3. Practicable concentrations of caffeine and 2-APB inhibit only IP3R1. Xestospongins do not appear to be effective antagonists of IP3Rs. PMID- 24628116 TI - Social support sources, types, and generativity: a focus group study of cancer survivors and their caregivers. AB - Various research studies have identified the sources and types of support that people with cancer receive; however, few have focused on identifying the specific characteristics of emotional, instrumental, and informational support. In this study, focus groups consisting of Gilda's Club members explored the types of support that people with cancer and their caregivers experienced and valued. Results showed that although men and women with cancer and caregivers identify similar sources of support, they experience different types of support. Results also indicated a desire among participants to help and support others, a concept referred to as generativity. Implications for social workers and health care providers are explored. PMID- 24628117 TI - Transition-age children with mental illness: hearing the voices of mothers. AB - Members of a local NAMI organization were surveyed in order to explore the perspectives of mothers of transitional age (18-25) children diagnosed with mental illness. Social workers in a diversity of mental health care settings can use this information to improve competence with this population. Results indicate a dynamic shift in the mothering role during this time period. Findings also suggest mothers and their transition-age children need emotional and practical support from social workers and other mental health professionals. PMID- 24628118 TI - Antecedents and consequences of workplace aggression in the allied health context. AB - Workplace aggression research has typically focused on groups in the health care industry considered to be high risk (e.g., nursing); however, aggression also occurs among other health care professional groups, such as those in allied health. This study aimed to investigate the antecedents and consequences of workplace aggression among allied health professionals. Allied health professionals working for an Australian health care organization were surveyed, with 134 (49%) responding. The largest group of allied health professionals surveyed were social workers (49%). Job demands, job control, and social support were linked to different types of aggression. Different sources of aggression were linked to various employee outcomes. The importance of considering stressors surrounding employee work conditions is highlighted. PMID- 24628119 TI - Pre-screening age African-American males: what do they know about prostate cancer screening, knowledge, and risk perceptions? AB - Prostate cancer is the most commonly diagnosed cancer among men and the second most common cause of cancer mortality among men in America. African-American men have a mortality rate from prostate cancer twice that of Caucasian men. Although prostate screening remains controversial, it provides an opportunity for the cancer to be detected early when treatment is most effective. Limited research has been conducted regarding prostate cancer awareness and knowledge among African-American men under 50. This article highlights a pilot study assessing the knowledge, attitudes, risk perceptions, and reasons for participating in prostate cancer screening among African-American males between the ages of 30-45. Study findings suggest these participants recognized an awareness of risk factors associated with the disease, yet underestimated their risk of developing the disease. Additionally they present uneven knowledge of the prostate and its function and possess positive perceptions of their general health beliefs and practices. Practice implications and directions for future research regarding prostate cancer among this population are highlighted. PMID- 24628120 TI - Family caregivers of cancer patients: perceived burden and symptoms during the early phases of cancer treatment. AB - This study investigated levels of symptoms, caregiver burden, and changes over time in 278 family caregivers (FC) of cancer patients. FCs experienced high levels of depressive symptoms and sleep disturbance, low levels of fatigue, and low to moderate levels of caregiver burden, yet these symptoms remained relatively stable over time. Being female and not being employed were factors associated with an increased risk of symptoms and caregiver burden. The understanding evolving from this study can enhance social- and health care professionals' awareness of FCs' challenging situation and the potential impact this has on the FCs' ability to provide care to the patient. PMID- 24628122 TI - An analysis platform for multiscale hydrogeologic modeling with emphasis on hybrid multiscale methods. AB - One of the most significant challenges faced by hydrogeologic modelers is the disparity between the spatial and temporal scales at which fundamental flow, transport, and reaction processes can best be understood and quantified (e.g., microscopic to pore scales and seconds to days) and at which practical model predictions are needed (e.g., plume to aquifer scales and years to centuries). While the multiscale nature of hydrogeologic problems is widely recognized, technological limitations in computation and characterization restrict most practical modeling efforts to fairly coarse representations of heterogeneous properties and processes. For some modern problems, the necessary level of simplification is such that model parameters may lose physical meaning and model predictive ability is questionable for any conditions other than those to which the model was calibrated. Recently, there has been broad interest across a wide range of scientific and engineering disciplines in simulation approaches that more rigorously account for the multiscale nature of systems of interest. In this article, we review a number of such approaches and propose a classification scheme for defining different types of multiscale simulation methods and those classes of problems to which they are most applicable. Our classification scheme is presented in terms of a flowchart (Multiscale Analysis Platform), and defines several different motifs of multiscale simulation. Within each motif, the member methods are reviewed and example applications are discussed. We focus attention on hybrid multiscale methods, in which two or more models with different physics described at fundamentally different scales are directly coupled within a single simulation. Very recently these methods have begun to be applied to groundwater flow and transport simulations, and we discuss these applications in the context of our classification scheme. As computational and characterization capabilities continue to improve, we envision that hybrid multiscale modeling will become more common and also a viable alternative to conventional single-scale models in the near future. PMID- 24628121 TI - Platelet-activating factor enhances tumour metastasis via the reactive oxygen species-dependent protein kinase casein kinase 2-mediated nuclear factor-kappaB activation. AB - Platelet-activating factor (PAF) promotes tumour metastasis via activation of the transcription factor nuclear factor-kappaB (NF-kappaB). We here investigated the role of the protein kinase CK2 (formerly Casein Kinase 2 or II) in PAF-induced NF kappaB activation and tumour metastasis, given that PAF has been reported to increase CK2 activity, and that CK2 plays a key role in NF-kappaB activation. PAF increased CK2 activity, phosphorylation and protein expression in vivo as well as in vitro. CK2 inhibitors inhibited the PAF-mediated NF-kappaB activation and expression of NF-kappaB-dependent pro-inflammatory cytokines and anti-apoptotic factors. Pre-treatment with the antioxidant N-Acetyl-L-Cysteine (NAC) resulted in a significant inhibition in PAF-induced enhancement of CK2 activity, phosphorylation and protein expression in vivo as well as in vitro. H2 O2 and known reactive oxygen species inducers, lipopolysaccharide (LPS) and tumour necrosis factor-alpha (TNF-alpha) enhanced CK2 activity, phosphorylation and protein expression, which was again inhibited by antioxidant. PAF, LPS and TNF alpha induced increased CK2 activity, phosphorylationand protein expression, which were inhibited by p38 inhibitor. PAF, LPS or TNF-alpha increased pulmonary metastasis of B16F10, which was inhibited by antioxidants, CK2 inhibitor and p38 inhibitor. Our data suggest that (i) reactive oxygen species activate CK2 via p38, which, in turn, induces NF-kappaB activation, and (ii) PAF, LPS and TNF alpha increase pulmonary tumour metastasis via the induction of the reactive oxygen species (ROS)/p38/CK2/NF-kappaB pathway. PMID- 24628124 TI - Is CANDLE the best nomenclature? PMID- 24628123 TI - Novel mycosin protease MycP1 inhibitors identified by virtual screening and 4D fingerprints. AB - The rise of drug-resistant Mycobacterium tuberculosis lends urgency to the need for new drugs for the treatment of tuberculosis (TB). The identification of a serine protease, mycosin protease-1 (MycP1), as the crucial agent in hydrolyzing the virulence factor, ESX-secretion-associated protein B (EspB), potentially opens the door to new tuberculosis treatment options. Using the crystal structure of mycobacterial MycP1 in the apo form, we performed an iterative ligand- and structure-based virtual screening (VS) strategy to identify novel, nonpeptide, small-molecule inhibitors against MycP1 protease. Screening of ~485,000 ligands from databases at the Genomics Research Institute (GRI) at the University of Cincinnati and the National Cancer Institute (NCI) using our VS approach, which integrated a pharmacophore model and consensus molecular shape patterns of active ligands (4D fingerprints), identified 81 putative inhibitors, and in vitro testing subsequently confirmed two of them as active inhibitors. Thereafter, the lead structures of each VS round were used to generate a new 4D fingerprint that enabled virtual rescreening of the chemical libraries. Finally, the iterative process identified a number of diverse scaffolds as lead compounds that were tested and found to have micromolar IC50 values against the MycP1 target. This study validated the efficiency of the SABRE 4D fingerprints as a means of identifying novel lead compounds in each screening round of the databases. Together, these results underscored the value of using a combination of in silico iterative ligand- and structure-based virtual screening of chemical libraries with experimental validation for the identification of promising structural scaffolds, such as the MycP1 inhibitors. PMID- 24628126 TI - Simplified one-orifice venoplasty for middle hepatic vein reconstruction in adult living donor liver transplantation using right lobe grafts. AB - Middle hepatic vein (MHV) reconstruction is often essential to avoid hepatic congestion and serious graft dysfunction in living donor liver transplantation (LDLT). The aim of this report was to introduce evolution of our MHV reconstruction technique and excellent outcomes of simplified one-orifice venoplasty. We compared clinical outcomes with two reconstruction techniques through retrospective review of 95 recipients who underwent LDLT using right lobe grafts at our institution from January 2008 to April 2012; group 1 received separate outflow reconstruction and group 2 received new one-orifice technique. The early patency rates of MHV in group 2 were higher than those in group 1; 98.4% vs. 88.2% on postoperative day 7 (p = 0.054) and 96.7% vs. 82.4% on postoperative day 14, respectively (p = 0.023). Right hepatic vein (RHV) stenosis developed in three cases in group 1, but no RHV stenosis developed because we adopted one-orifice technique (p = 0.043). The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in group 2 were significantly lower than those in group 1 during the early post-transplant period. In conclusion, our simplified one-orifice venoplasty technique could secure venous outflow and improve graft function during right lobe LDLT. PMID- 24628125 TI - Comparison of indirect and direct blood pressure measurements in baboons during ketamine anaesthesia. AB - BACKGROUND: The aim of this study was to assess agreement between different methods of blood pressure measurement in anaesthetised baboons. METHODS: Systolic and diastolic blood pressure (SBP and DBP) were measured in anaesthetised baboons using intra-arterial radiotelemetry, automated oscillometry and mercury sphygmomanometry. Correlation between the different methods was assessed. RESULTS: The correlation between intra-arterial radiotelemetry and automated oscillometry was 0.9 (P < 0.001) for SBP and 0.9 (P < 0.001) for DBP. Between method differences were -4.4 +/- 7.2 mm Hg for SBP and -3.4 +/- 7.1 mm Hg for DBP. For automated oscillometry vs. mercury sphygmomanometry, correlation was 0.4 for both SBP (P < 0.001) and DBP (P < 0.001). Between-method differences were 7.9 +/- 12.7 mm Hg for SBP and 7.3 +/- 12.6 mm Hg for DBP. CONCLUSIONS: Our study demonstrates that automated oscillometry may be an appropriate alternative to telemetry for measuring blood pressure in anaesthetised baboons. PMID- 24628127 TI - Syntheses and characterization of nearly monodispersed, size-tunable silver nanoparticles over a wide size range of 7-200 nm by tannic acid reduction. AB - Nearly monodispersed spherical silver nanoparticles (Ag NPs) were synthesized by using tannic acid (TA) as both reductant and stabilizer in a 30 degrees C water bath. The size of the as-prepared Ag NPs could be tuned in a range of 7-66 nm by changing the molar ratio of TA to silver nitrate and pH of the reaction solutions. UV-vis spectra, TEM observations, and temporal evolution of the monomer concentrations for the reactions carried out at different experimental conditions showed that the improved size distribution and size tunability of the Ag NPs were mainly attributed to the use of TA, which could promote the balance of nucleation and growth processes of the NPs effectively. The size of the Ag NPs was extendable up to 200 nm in one-pot fashion by the multi-injection approach. The size-dependent surface-enhanced Raman scattering (SERS) activity of the as prepared Ag NPs was evaluated, and the NPs with size around 100 nm were identified to show a maximum enhanced factor of 3.6 * 10(5). Moreover, the as prepared TA-coated Ag NPs presented excellent colloidal stability compared to the conventional citrate-coated ones. PMID- 24628128 TI - Transsacral axial interbody fusion. PMID- 24628129 TI - Management of sagittal balance in adult spinal deformity with minimally invasive anterolateral lumbar interbody fusion: a preliminary radiographic study. AB - OBJECT: Minimally invasive (MI) fusion and instrumentation techniques are playing a new role in the treatment of adult spinal deformity. The open pedicle subtraction osteotomy (PSO) and Smith-Petersen osteotomy (SPO) are proven segmental methods for improving regional lordosis and global sagittal parameters. Recently the MI anterior column release (ACR) was introduced as a segmental method for treating sagittal imbalance. There is a paucity of data in the literature evaluating the alternatives to PSO and SPO for sagittal balance correction. Thus, the authors conducted a preliminary retrospective radiographic review of prospectively collected data from 2009 to 2012 at a single institution. The objectives of this study were to: 1) investigate the radiographic effect of MI-ACR on spinopelvic parameters, 2) compare the radiographic effect of MI-ACR with PSO and SPO for treatment of adult spinal deformity, and 3) investigate the radiographic effect of percutaneous posterior spinal instrumentation on spinopelvic parameters when combined with MI transpsoas lateral interbody fusion (LIF) for adult spinal deformity. METHODS: Patient demographics and radiographic data were collected for 36 patients (9 patients who underwent MI-ACR and 27 patients who did not undergo MI-ACR). Patients included in the study were those who had undergone at least a 2-level MI-LIF procedure; adequate preoperative and postoperative 36-inch radiographs of the scoliotic curvature; a separate second stage procedure for the placement of posterior spinal instrumentation; and a diagnosis of degenerative scoliosis (coronal Cobb angle > 10 degrees and/or sagittal vertebral axis > 5 cm). Statistical analysis was performed for normality and significance testing. RESULTS: Percutaneous transpedicular spinal instrumentation did not significantly alter any of the spinopelvic parameters in either the ACR group or the non-ACR group. Lateral MI-LIF alone significantly improved coronal Cobb angle by 16 degrees , and the fractional curve significantly improved in a subgroup treated with L5-S1 transforaminal lumbar interbody fusion. Fifteen ACRs were performed in 9 patients and resulted in significant coronal Cobb angle correction, lumbar lordosis correction of 16.5 degrees , and sagittal vertebral axis correction of 4.8 cm per patient. Segmental analysis revealed a 12 degrees gain in segmental lumbar lordosis and a 3.1-cm correction of the sagittal vertebral axis per ACR level treated. CONCLUSIONS: The lateral MI-LIF with ACR has the ability to powerfully restore lumbar lordosis and correct sagittal imbalance. This segmental MI surgical technique boasts equivalence to SPO correction of these global radiographic parameters while simultaneously creating additional disc height and correcting coronal imbalance. Addition of posterior percutaneous instrumentation without in situ manipulation or overcorrection does not alter radiographic parameters when combined with the lateral MI-LIF. PMID- 24628130 TI - Local cooling for traumatic spinal cord injury: outcomes in 20 patients and review of the literature. AB - OBJECT: In this prospective study, the authors offered protocol-selected patients a combination of parenteral steroids, decompression surgery, and localized cooling to preserve viable spinal cord tissue and enhance functional recovery. METHODS: After acquiring informed consent, the authors offered this regimen with localized deep cord cooling (dural temperature 6 degrees C) to 20 patients with a neurologically complete spinal cord injury to begin within 8 hours of injury. After decompression, the cord was locally cooled through the intact dura using a suspended extradural saddle at the site of injury for up to 4 hours, during which time spinal fusion was performed. Sensation and motor function were evaluated directly after the injury and again over a year later. The patients were evaluated using the 2011 amendment to the American Spinal Injury Association (ASIA) Impairment Scale. RESULTS: Eighty percent of the 20 patients (12 with cervical and 4 thoracic injuries) with an initial neurologically complete cord injury had some recovery of sensory or motor function. All patients initially had ASIA Grade A impairment. Of 14 patients with quadriplegia, 5 remained ASIA Grade A, 5 improved to ASIA Grade B, 3 to ASIA Grade C, and 1 to ASIA Grade D. The remaining 6 patients had suffered a thoracic spinal cord injury, and of these 2 remained ASIA Grade A, 1 recovered to ASIA Grade B, 2 to ASIA Grade C, and 1 ASIA Grade D. All considered, of 20 patients, 35% remained ASIA Grade A, 30% improved to ASIA Grade B, and 25% to ASIA Grade C. Impairment in 2 (10%) of 20 patients improved to ASIA Grade D. The mean improvement in neurological level of injury in all patients was 1.05, the mean improvement in motor level was 1.7, and the mean improvement in sensory level was 2.8. Two patients recovered the ability to walk, 2 could extend their legs, 5 could sense bladder fullness, and 3 had partial ability to void voluntarily. Four males recovered subnormal ability to have voluntary erection sufficient for limited sexual activity. CONCLUSIONS: The authors present here results of 20 patients with neurologically complete spinal cord injury treated with a combination of surgical decompression, glucocorticoid administration, and regional hypothermia. These patients experienced a better recovery than might have been expected had traditional forms of treatment been used. The benefit of steroid treatment for cord injury has been debated in the last decade, but the authors feel that research into the effects of cord cooling should be expanded. Given that the optimal neuroprotective temperature after acute trauma has not yet been defined, and may well be below that which is considered safely approachable through systemic cooling, methods that allow for the early attainment of such a temperature locally should be further explored. The results are encouraging enough to suggest the undertaking of controlled clinical trials of treatment using localized spinal cord cooling, where such treatment can be instituted within hours following injury. PMID- 24628131 TI - Sagittal balance. PMID- 24628132 TI - Use of the low-dose buprenorphine patch: a response. PMID- 24628133 TI - Genetic and clinical risk factors for fluid overload following open-heart surgery. AB - BACKGROUND: Post-operative fluid overload following cardiac surgery is associated with increased morbidity and mortality. We hypothesised that genetic variations and pre-operative clinical factors predispose some patients to post-operative fluid overload. METHODS: Perioperative variables were collected prospectively for 1026 consecutive adults undergoing open-heart surgery at St. Olavs University Hospital, Norway from 2008-2010. Post-operative fluid overload was defined as a post-operative fluid balance/kg >= the 90th percentile of the study population. Genotyping was performed for 31 single-nucleotide polymorphisms related to inflammatory/vascular responses or previously associated with complications following open-heart surgery. Data were analysed using logistic regression modelling, and the findings were internally validated by bootstrapping (n = 100). RESULTS: Homozygous carriers of the common G allele of rs12917707 in the UMOD gene had a 2.2 times greater risk of post-operative fluid overload (P = 0.005) after adjustment for significant clinical variables (age, duration of cardiopulmonary bypass, and intraoperative red cell transfusion). A genetic risk score including 14 single-nucleotide polymorphisms was independently associated with post-operative fluid overload (P = 0.001). The number of risk alleles was linearly associated with the frequency of fluid overload (odds ratio per risk allele 1.153, 95 % confidence interval 1.056-1.258). Nagelkerke's R(2) increased with 7.5% to a total of 25% for the combined clinical and genetic model. Hemofiltration did not reduce the risk. CONCLUSION: A common variation in the UMOD gene previously shown to be related to renal function was associated with increased risk of post-operative fluid overload following cardiac surgery. Our findings support a genetic susceptibility to disturbed fluid handling following cardiac surgery. PMID- 24628134 TI - An elderly patient with chronic active Epstein-Barr virus infection with severe hydroa vacciniforme-like eruptions associated with alphabetaT-cell proliferation. PMID- 24628135 TI - A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3 iodobicyclo[1.1.1]pentane. AB - From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor. PMID- 24628136 TI - Ultrafast chemical reactions in shocked nitromethane probed with dynamic ellipsometry and transient absorption spectroscopy. AB - Initiation of the shock driven chemical reactions and detonation of nitromethane (NM) can be sensitized by the addition of a weak base; however, the chemical mechanism by which sensitization occurs remains unclear. We investigated the shock driven chemical reaction in NM and in NM sensitized with diethylenetriamine (DETA), using a sustained 300 ps shock driven by a chirped Ti:sapphire laser. We measured the solutions' visible transient absorption spectra and measured interface particle and shock velocities of the nitromethane solutions using ultrafast dynamic ellipsometry. We found there to be a volume-increasing reaction that takes place around interface particle velocity up = 2.4 km/s and up = 2.2 km/s for neat NM and NM with 5% DETA, respectively. The rate at which transient absorption increases is similar in all mixtures, but with decreasing induction times for solutions with increasing DETA concentrations. This result supports the hypothesis that the chemical reaction mechanisms for shocked NM and NM with DETA are the same. Data from shocked NM are compared to literature experimental and theoretical data. PMID- 24628137 TI - Editor's introduction. PMID- 24628139 TI - Honoring the path. PMID- 24628140 TI - Relationship between pain and chronic illness among seriously ill older adults: expanding role for palliative social work. AB - Confronting the issue of pain among chronically ill older adults merits serious attention in light of mounting evidence that pain in this population is often undertreated or not treated at all (Institute of Medicine, 2011 ). The relationship between pain and chronic illness among adults age 50 and over was examined in this study through the use of longitudinal data from the University of Michigan Health and Retirement Study, sponsored by the National Institute on Aging and the Social Security Administration. Findings suggested positive associations between pain and chronic disease, pain and multimorbidity, as well as an inverse association between pain and education. Policy implications for workforce development and public health are many, and amplification of palliative social work roles to relieve pain and suffering among seriously ill older adults at all stages of the chronic illness trajectory is needed. PMID- 24628141 TI - End of life, chronic illness, and trans-identities. AB - In this study, the experiences and needs of a sample of 1,963 current, global, English-speaking, transgender-identified adults responding to the Transgender MetLife Survey (TMLS) as related to a number of later-life and end-of-life (EOL) preparations and concerns were examined. EOL concerns are integrated with concerns and challenges around chronic illness and disability. Overall, this population was significantly ill-prepared for the major legalities and events that occur in the later to EOL time periods. The population was found to harbor significant fears around the future. Drawing on the author's decades of survey research in transgender aging and case data along with current scientific and online literature, illustrative quotations and case examples are provided. PMID- 24628142 TI - A conceptual model of family surrogate end-of-life decision-making process in the nursing home setting: goals of care as guiding stars. AB - An increasing proportion of dying is occurring in America's nursing homes (NH). Family members are involved in (and affected by) medical decision-making on behalf of NH residents approaching the end of life, especially when the resident is cognitively impaired. This article proposes an empirically derived conceptual model of the key factors NH family surrogate decision-makers consider when establishing or changing goals of care and the iterative process as applied to the NH setting. This model also establishes the importance of family social role expectations toward their loved one as well as the concept, "stance toward dying," as key in establishing or changing the main goal of care. NH staff and physicians can use the model as a framework for providing information and support to family members. Research is needed to better understand how to prepare staff and settings to support family surrogate decision-makers, in particular around setting goals of care. The model can be generalized beyond nursing homes. PMID- 24628143 TI - The grief experience of prison inmate hospice volunteer caregivers. AB - Correctional institutions are obligated to provide end-of-life care to a population with complex medical needs. Prison hospices are increasingly being formed to address this demand. Few empirical studies have examined the impact of caring for dying inmates on the hospice inmate volunteers, who, in several prison health care systems, provide direct care. In this study, experiences of the inmate hospice volunteers with death were investigated to illuminate their grief processes. Understanding the bereavement needs of hospice volunteers and how prison hospice volunteers navigate grief and remain committed to providing excellent hospice care can inform the grief processes and practices of hospice care professionals. PMID- 24628144 TI - Suicide prevention training program for gatekeepers working in community hospice settings. AB - Gatekeepers in community hospice settings encounter patients and caregivers struggling with suicidal thoughts. Limited guidance is available for training staff on the prevention of suicide in hospice care. This study evaluated one promising, evidence-based, suicide prevention program with a behavioral rehearsal practice session. A pre- and post-, one group design, was utilized to measure the training impact and educational needs of staff working in community hospice settings (N =39). Training increased awareness of the risk factors for suicide, as reported by nearly 80% of participants. Self-efficacy scores showed a statistically significant Increase, t(df=35), -9.59, p=.00 (two-tailed), from pretraining (n=36, M=2.21, SD=.65) to posttraining (n=36, M=3.03, SD=.56). Satisfaction and the need for additional devoted time for suicide prevention training were highly rated. Suicide prevention training programs can enhance self efficacy, knowledge, and skills for gatekeepers working in community hospice settings. PMID- 24628146 TI - Effective electron displacements: a tool for time-dependent density functional theory computational spectroscopy. AB - We extend our previous definition of the metric Deltar for electronic excitations in the framework of the time-dependent density functional theory [C. A. Guido, P. Cortona, B. Mennucci, and C. Adamo, J. Chem. Theory Comput. 9, 3118 (2013)], by including a measure of the difference of electronic position variances in passing from occupied to virtual orbitals. This new definition, called Gamma, permits applications in those situations where the Deltar-index is not helpful: transitions in centrosymmetric systems and Rydberg excitations. The Gamma-metric is then extended by using the Natural Transition Orbitals, thus providing an intuitive picture of how locally the electron density changes during the electronic transitions. Furthermore, the Gamma values give insight about the functional performances in reproducing different type of transitions, and allow one to define a "confidence radius" for GGA and hybrid functionals. PMID- 24628145 TI - Communication: Coordination structure of bromide ions associated with hexyltrimethylammonium cations at liquid/liquid interfaces under potentiostatic control as studied by total-reflection X-ray absorption fine structure. AB - Total-reflection X-ray absorption fine structure (TR-XAFS) technique was applied for the first time to an interface between two immiscible electrolyte solutions under potentiostatic control. The hydration structure of bromide ions was investigated at polarized 2-octanone/water interfaces. TR-XAFS spectra at Br K edge measured in the presence of hexyltrimethylammonium bromide (C6TAB) were slightly modified depending on the Galvani potential difference (Delta(o)(w)phi). The extended X-ray absorption fine structure analysis exposed hydration structure changes of bromide ions at the polarized interface. The coordination structure of bromide ions at the interface could be analyzed as compared with bromide ions dissolved in aqueous solution and Br(-)-exchanged resin having quaternary ammonium groups. The results indicated that bromide ions were associated with C6TA(+) at the polarized interface. The relative contribution of ion association form of bromide ions with quaternary ammonium groups was enhanced at a potential close to the ion transfer of C6TA(+), where the interfacial concentration of C6TA(+) is increased as a function of Delta(o)(w)phi. PMID- 24628147 TI - Electrostatics of proteins in dielectric solvent continua. I. An accurate and efficient reaction field description. AB - We present a reaction field (RF) method which accurately solves the Poisson equation for proteins embedded in dielectric solvent continua at a computational effort comparable to that of an electrostatics calculation with polarizable molecular mechanics (MM) force fields. The method combines an approach originally suggested by Egwolf and Tavan [J. Chem. Phys. 118, 2039 (2003)] with concepts generalizing the Born solution [Z. Phys. 1, 45 (1920)] for a solvated ion. First, we derive an exact representation according to which the sources of the RF potential and energy are inducible atomic anti-polarization densities and atomic shielding charge distributions. Modeling these atomic densities by Gaussians leads to an approximate representation. Here, the strengths of the Gaussian shielding charge distributions are directly given in terms of the static partial charges as defined, e.g., by standard MM force fields for the various atom types, whereas the strengths of the Gaussian anti-polarization densities are calculated by a self-consistency iteration. The atomic volumes are also described by Gaussians. To account for covalently overlapping atoms, their effective volumes are calculated by another self-consistency procedure, which guarantees that the dielectric function epsilon(r) is close to one everywhere inside the protein. The Gaussian widths sigma(i) of the atoms i are parameters of the RF approximation. The remarkable accuracy of the method is demonstrated by comparison with Kirkwood's analytical solution for a spherical protein [J. Chem. Phys. 2, 351 (1934)] and with computationally expensive grid-based numerical solutions for simple model systems in dielectric continua including a di-peptide (Ac-Ala-NHMe) as modeled by a standard MM force field. The latter example shows how weakly the RF conformational free energy landscape depends on the parameters sigma(i). A summarizing discussion highlights the achievements of the new theory and of its approximate solution particularly by comparison with so-called generalized Born methods. A follow-up paper describes how the method enables Hamiltonian, efficient, and accurate MM molecular dynamics simulations of proteins in dielectric solvent continua. PMID- 24628148 TI - Electrostatics of proteins in dielectric solvent continua. II. Hamiltonian reaction field dynamics. AB - In Paper I of this work [S. Bauer, G. Mathias, and P. Tavan, J. Chem. Phys. 140, 104102 (2014)] we have presented a reaction field (RF) method, which accurately solves the Poisson equation for proteins embedded in dielectric solvent continua at a computational effort comparable to that of polarizable molecular mechanics (MM) force fields. Building upon these results, here we suggest a method for linearly scaling Hamiltonian RF/MM molecular dynamics (MD) simulations, which we call "Hamiltonian dielectric solvent" (HADES). First, we derive analytical expressions for the RF forces acting on the solute atoms. These forces properly account for all those conditions, which have to be self-consistently fulfilled by RF quantities introduced in Paper I. Next we provide details on the implementation, i.e., we show how our RF approach is combined with a fast multipole method and how the self-consistency iterations are accelerated by the use of the so-called direct inversion in the iterative subspace. Finally we demonstrate that the method and its implementation enable Hamiltonian, i.e., energy and momentum conserving HADES-MD, and compare in a sample application on Ac-Ala-NHMe the HADES-MD free energy landscape at 300 K with that obtained in Paper I by scanning of configurations and with one obtained from an explicit solvent simulation. PMID- 24628149 TI - Multi-scale coarse-graining of non-conservative interactions in molecular liquids. AB - A new bottom-up procedure for constructing non-conservative (dissipative and stochastic) interactions for dissipative particle dynamics (DPD) models is described and applied to perform hierarchical coarse-graining of a polar molecular liquid (nitromethane). The distant-dependent radial and shear frictions in functional-free form are derived consistently with a chosen form for conservative interactions by matching two-body force-velocity and three-body velocity-velocity correlations along the microscopic trajectories of the centroids of Voronoi cells (clusters), which represent the dissipative particles within the DPD description. The Voronoi tessellation is achieved by application of the K-means clustering algorithm at regular time intervals. Consistently with a notion of many-body DPD, the conservative interactions are determined through the multi-scale coarse-graining (MS-CG) method, which naturally implements a pairwise decomposition of the microscopic free energy. A hierarchy of MS-CG/DPD models starting with one molecule per Voronoi cell and up to 64 molecules per cell is derived. The radial contribution to the friction appears to be dominant for all models. As the Voronoi cell sizes increase, the dissipative forces rapidly become confined to the first coordination shell. For Voronoi cells of two and more molecules the time dependence of the velocity autocorrelation function becomes monotonic and well reproduced by the respective MS-CG/DPD models. A comparative analysis of force and velocity correlations in the atomistic and CG ensembles indicates Markovian behavior with as low as two molecules per dissipative particle. The models with one and two molecules per Voronoi cell yield transport properties (diffusion and shear viscosity) that are in good agreement with the atomistic data. The coarser models produce slower dynamics that can be appreciably attributed to unaccounted dissipation introduced by regular Voronoi re-partitioning as well as by larger numerical errors in mapping out the dissipative forces. The framework presented herein can be used to develop computational models of real liquids which are capable of bridging the atomistic and mesoscopic scales. PMID- 24628150 TI - Electronic couplings for molecular charge transfer: benchmarking CDFT, FODFT, and FODFTB against high-level ab initio calculations. AB - We introduce a database (HAB11) of electronic coupling matrix elements (H(ab)) for electron transfer in 11 pi-conjugated organic homo-dimer cations. High-level ab inito calculations at the multireference configuration interaction MRCI+Q level of theory, n-electron valence state perturbation theory NEVPT2, and (spin component scaled) approximate coupled cluster model (SCS)-CC2 are reported for this database to assess the performance of three DFT methods of decreasing computational cost, including constrained density functional theory (CDFT), fragment-orbital DFT (FODFT), and self-consistent charge density functional tight binding (FODFTB). We find that the CDFT approach in combination with a modified PBE functional containing 50% Hartree-Fock exchange gives best results for absolute H(ab) values (mean relative unsigned error = 5.3%) and exponential distance decay constants beta (4.3%). CDFT in combination with pure PBE overestimates couplings by 38.7% due to a too diffuse excess charge distribution, whereas the economic FODFT and highly cost-effective FODFTB methods underestimate couplings by 37.6% and 42.4%, respectively, due to neglect of interaction between donor and acceptor. The errors are systematic, however, and can be significantly reduced by applying a uniform scaling factor for each method. Applications to dimers outside the database, specifically rotated thiophene dimers and larger acenes up to pentacene, suggests that the same scaling procedure significantly improves the FODFT and FODFTB results for larger pi-conjugated systems relevant to organic semiconductors and DNA. PMID- 24628151 TI - Inter-layer potential for hexagonal boron nitride. AB - A new interlayer force-field for layered hexagonal boron nitride (h-BN) based structures is presented. The force-field contains three terms representing the interlayer attraction due to dispersive interactions, repulsion due to anisotropic overlaps of electron clouds, and monopolar electrostatic interactions. With appropriate parameterization, the potential is able to simultaneously capture well the binding and lateral sliding energies of planar h BN based dimer systems as well as the interlayer telescoping and rotation of double walled boron-nitride nanotubes of different crystallographic orientations. The new potential thus allows for the accurate and efficient modeling and simulation of large-scale h-BN based layered structures. PMID- 24628152 TI - Calculation of nuclear spin-spin coupling constants using frozen density embedding. AB - We present a method for a subsystem-based calculation of indirect nuclear spin spin coupling tensors within the framework of current-spin-density-functional theory. Our approach is based on the frozen-density embedding scheme within density-functional theory and extends a previously reported subsystem-based approach for the calculation of nuclear magnetic resonance shielding tensors to magnetic fields which couple not only to orbital but also spin degrees of freedom. This leads to a formulation in which the electron density, the induced paramagnetic current, and the induced spin-magnetization density are calculated separately for the individual subsystems. This is particularly useful for the inclusion of environmental effects in the calculation of nuclear spin-spin coupling constants. Neglecting the induced paramagnetic current and spin magnetization density in the environment due to the magnetic moments of the coupled nuclei leads to a very efficient method in which the computationally expensive response calculation has to be performed only for the subsystem of interest. We show that this approach leads to very good results for the calculation of solvent-induced shifts of nuclear spin-spin coupling constants in hydrogen-bonded systems. Also for systems with stronger interactions, frozen density embedding performs remarkably well, given the approximate nature of currently available functionals for the non-additive kinetic energy. As an example we show results for methylmercury halides which exhibit an exceptionally large shift of the one-bond coupling constants between (199)Hg and (13)C upon coordination of dimethylsulfoxide solvent molecules. PMID- 24628153 TI - Free energy calculations from adaptive molecular dynamics simulations with adiabatic reweighting. AB - We propose an adiabatic reweighting algorithm for computing the free energy along an external parameter from adaptive molecular dynamics simulations. The adaptive bias is estimated using Bayes identity and information from all the sampled configurations. We apply the algorithm to a structural transition in a cluster and to the migration of a crystalline defect along a reaction coordinate. Compared to standard adaptive molecular dynamics, we observe an acceleration of convergence. With the aid of the algorithm, it is also possible to iteratively construct the free energy along the reaction coordinate without having to differentiate the gradient of the reaction coordinate or any biasing potential. PMID- 24628154 TI - Evaluation of the grand-canonical partition function using expanded Wang-Landau simulations. III. Impact of combining rules on mixtures properties. AB - Combining rules, such as the Lorentz-Berthelot rules, are routinely used to calculate the thermodynamic properties of mixtures using molecular simulations. Here we extend the expanded Wang-Landau simulation approach to determine the impact of the combining rules on the value of the partition function of binary systems, and, in turn, on the phase coexistence and thermodynamics of these mixtures. We study various types of mixtures, ranging from systems of rare gases to biologically and technologically relevant mixtures, such as water-urea and water-carbon dioxide. Comparing the simulation results to the experimental data on mixtures of rare gases allows us to rank the performance of combining rules. We find that the widely used Lorentz-Berthelot rules exhibit the largest deviations from the experimental data, both for the bulk and at coexistence, while the Kong and Waldman-Hagler provide much better alternatives. In particular, in the case of aqueous solutions of urea, we show that the use of the Lorentz-Berthelot rules has a strong impact on the Gibbs free energy of the solute, overshooting the value predicted by the Waldman-Hagler rules by 7%. This result emphasizes the importance of the combining rule for the determination of hydration free energies using molecular simulations. PMID- 24628155 TI - A quasi-classical mapping approach to vibrationally coupled electron transport in molecular junctions. AB - We develop a classical mapping approach suitable to describe vibrationally coupled charge transport in molecular junctions based on the Cartesian mapping for many-electron systems [B. Li and W. H. Miller, J. Chem. Phys. 137, 154107 (2012)]. To properly describe vibrational quantum effects in the transport characteristics, we introduce a simple transformation rewriting the Hamiltonian in terms of occupation numbers and use a binning function to facilitate quantization. The approach provides accurate results for the nonequilibrium Holstein model for a range of bias voltages, vibrational frequencies, and temperatures. It also captures the hallmarks of vibrational quantum effects apparent in step-like structure in the current-voltage characteristics at low temperatures as well as the phenomenon of Franck-Condon blockade. PMID- 24628156 TI - Calculation of excitation energies from the CC2 linear response theory using Cholesky decomposition. AB - A new implementation of the approximate coupled cluster singles and doubles CC2 linear response model is reported. It employs a Cholesky decomposition of the two electron integrals that significantly reduces the computational cost and the storage requirements of the method compared to standard implementations. Our algorithm also exploits a partitioning form of the CC2 equations which reduces the dimension of the problem and avoids the storage of doubles amplitudes. We present calculation of excitation energies of benzene using a hierarchy of basis sets and compare the results with conventional CC2 calculations. The reduction of the scaling is evaluated as well as the effect of the Cholesky decomposition parameter on the quality of the results. The new algorithm is used to perform an extrapolation to complete basis set investigation on the spectroscopically interesting benzylallene conformers. A set of calculations on medium-sized molecules is carried out to check the dependence of the accuracy of the results on the decomposition thresholds. Moreover, CC2 singlet excitation energies of the free base porphin are also presented. PMID- 24628158 TI - Exciton dissociation in the presence of phonons: a reduced hierarchy equations of motion approach. AB - Combining the reduced hierarchy equations of motion (HEOM) approach with the Wigner-function formalism, we investigate nonperturbatively exciton dissociation under the influence of a phonon bath in an organic heterojunction. The exciton is modeled by an electron-hole pair with the electron moving in the presence of both an external electric field and the Coulomb attraction potential from the hole. In the absence of a phonon bath, calculated HEOM results reproduce those from the Onsager-Braun theory in weak electric fields. In the presence of a phonon bath, substantial deviations from the Onsager-Braun theory are found, signaling phonon induced quantum effects. Furthermore, time evolution of the spatial current distribution is examined, and an initial spike followed by a polarity change of the transient photocurrent have been recovered. PMID- 24628157 TI - Spectroscopic accuracy directly from quantum chemistry: application to ground and excited states of beryllium dimer. AB - We combine explicit correlation via the canonical transcorrelation approach with the density matrix renormalization group and initiator full configuration interaction quantum Monte Carlo methods to compute a near-exact beryllium dimer curve, without the use of composite methods. In particular, our direct density matrix renormalization group calculations produce a well-depth of D(e) = 931.2 cm(-1) which agrees very well with recent experimentally derived estimates D(e) = 929.7+/-2 cm(-1) [J. M. Merritt, V. E. Bondybey, and M. C. Heaven, Science 324, 1548 (2009)] and D(e) = 934.6 cm(-1) [K. Patkowski, V. Spirko, and K. Szalewicz, Science 326, 1382 (2009)], as well the best composite theoretical estimates, D(e) = 938+/-15 cm(-1) [K. Patkowski, R. Podeszwa, and K. Szalewicz, J. Phys. Chem. A 111, 12822 (2007)] and D(e) = 935.1+/-10 cm(-1) [J. Koput, Phys. Chem. Chem. Phys. 13, 20311 (2011)]. Our results suggest possible inaccuracies in the functional form of the potential used at shorter bond lengths to fit the experimental data [J. M. Merritt, V. E. Bondybey, and M. C. Heaven, Science 324, 1548 (2009)]. With the density matrix renormalization group we also compute near exact vertical excitation energies at the equilibrium geometry. These provide non trivial benchmarks for quantum chemical methods for excited states, and illustrate the surprisingly large error that remains for 1 1Sigma(g)- state with approximate multi-reference configuration interaction and equation-of-motion coupled cluster methods. Overall, we demonstrate that explicitly correlated density matrix renormalization group and initiator full configuration interaction quantum Monte Carlo methods allow us to fully converge to the basis set and correlation limit of the non-relativistic Schrodinger equation in small molecules. PMID- 24628159 TI - Exploring the topography of the stress-modified energy landscapes of mechanosensitive molecules. AB - We propose a method for computing the activation barrier for chemical reactions involving molecules subjected to mechanical stress. The method avoids reactant and transition-state saddle optimizations at every force by, instead, solving the differential equations governing the force dependence of the critical points (i.e., minima and saddles) on the system's potential energy surface (PES). As a result, only zero-force geometry optimization (or, more generally, optimization performed at a single force value) is required by the method. In many cases, minima and transition-state saddles only exist within a range of forces and disappear beyond a certain critical point. Our method identifies such force induced instabilities as points at which one of the Hessian eigenvalues vanishes. We elucidate the nature of those instabilities as fold and cusp catastrophes, where two or three critical points on the force-modified PES coalesce, and provide a classification of various physically distinct instability scenarios, each illustrated with a concrete chemical example. PMID- 24628160 TI - Charge asymmetry in the rovibrationally excited HD molecule. AB - The recently developed method for performing all-particle non-Born-Oppenheimer variational calculations on diatomic molecular systems excited to the first excited rotational state and simultaneously vibrationally excited is employed to study the charge asymmetry and the level lifetimes of the HD molecule. The method uses all-particle explicitly correlated Gaussian functions. The nonlinear parameters of the Gaussians are optimized with the aid of the analytical energy gradient determined with respect to these parameters. PMID- 24628161 TI - Getting a grip on the transverse motion in a Zeeman decelerator. AB - Zeeman deceleration is an experimental technique in which inhomogeneous, time dependent magnetic fields generated inside an array of solenoid coils are used to manipulate the velocity of a supersonic beam. A 12-stage Zeeman decelerator has been built and characterized using hydrogen atoms as a test system. The instrument has several original features including the possibility to replace each deceleration coil individually. In this article, we give a detailed description of the experimental setup, and illustrate its performance. We demonstrate that the overall acceptance in a Zeeman decelerator can be significantly increased with only minor changes to the setup itself. This is achieved by applying a rather low, anti-parallel magnetic field in one of the solenoid coils that forms a temporally varying quadrupole field, and improves particle confinement in the transverse direction. The results are reproduced by three-dimensional numerical particle trajectory simulations thus allowing for a rigorous analysis of the experimental data. The findings suggest the use of a modified coil configuration to improve transverse focusing during the deceleration process. PMID- 24628162 TI - Novel two-step laser ablation and ionization mass spectrometry (2S-LAIMS) of actor-spectator ice layers: probing chemical composition of D2O ice beneath a H2O ice layer. AB - In this work, we report for the first time successful analysis of organic aromatic analytes imbedded in D2O ices by novel infrared (IR) laser ablation of a layered non-absorbing D2O ice (spectator) containing the analytes and an ablation active IR-absorbing H2O ice layer (actor) without the analyte. With these studies we have opened up a new method for the in situ analysis of solids containing analytes when covered with an IR laser-absorbing layer that can be resonantly ablated. This soft ejection method takes advantage of the tenability of two-step infrared laser ablation and ultraviolet laser ionization mass spectrometry, previously demonstrated in this lab to study chemical reactions of polycyclic aromatic hydrocarbons (PAHs) in cryogenic ices. The IR laser pulse tuned to resonantly excite only the upper H2O ice layer (actor) generates a shockwave upon impact. This shockwave penetrates the lower analyte-containing D2O ice layer (spectator, a non-absorbing ice that cannot be ablated directly with the wavelength of the IR laser employed) and is reflected back, ejecting the contents of the D2O layer into the vacuum where they are intersected by a UV laser for ionization and detection by a time-of-flight mass spectrometer. Thus, energy is transmitted from the laser-absorbing actor layer into the non-absorbing spectator layer resulting its ablation. We found that isotope cross-contamination between layers was negligible. We also did not see any evidence for thermal or collisional chemistry of PAH molecules with H2O molecules in the shockwave. We call this "shockwave mediated surface resonance enhanced subsurface ablation" technique as "two-step laser ablation and ionization mass spectrometry of actor spectator ice layers." This method has its roots in the well-established MALDI (matrix assisted laser desorption and ionization) method. Our method offers more flexibility to optimize both the processes--ablation and ionization. This new technique can thus be potentially employed to undertake in situ analysis of materials imbedded in diverse media, such as cryogenic ices, biological samples, tissues, minerals, etc., by covered with an IR-absorbing laser ablation medium and study the chemical composition and reaction pathways of the analyte in its natural surroundings. PMID- 24628163 TI - Electron correlations and two-photon states in polycyclic aromatic hydrocarbon molecules: a peculiar role of geometry. AB - We present numerical studies of one- and two-photon excited states ordering in a number of polycyclic aromatic hydrocarbon molecules: coronene, hexa-peri hexabenzocoronene, and circumcoronene, all possessing D(6h) point group symmetry versus ovalene with D(2h) symmetry, within the Pariser-Parr-Pople model of interacting pi-electrons. The calculated energies of the two-photon states as well as their relative two-photon absorption cross-sections within the interacting model are qualitatively different from single-particle descriptions. More remarkably, a peculiar role of molecular geometry is found. The consequence of electron correlations is far stronger for ovalene, where the lowest spin singlet two-photon state is a quantum superposition of pairs of lowest spin triplet states, as in the linear polyenes. The same is not true for D(6h) group hydrocarbons. Our work indicates significant covalent character, in valence bond language, of the ground state, the lowest spin triplet state and a few of the lowest two-photon states in D(2h) ovalene but not in those with D(6h) symmetry. PMID- 24628164 TI - D(3h) [A-CE3-A]- (E = Al and Ga, A = Si, Ge, Sn, and Pb): a new class of hexatomic mono-anionic species with trigonal bipyramidal carbon. AB - The non-classical trigonal bipyramidal carbon (TBPC) arrangement generally exists as transition states (TSs) in nucleophilic bimolecular substitution (S(N)2) reactions. Nevertheless, chemists have been curious about whether such a carbon bonding could be stable in equilibrium structures for decades. As the TBPC arrangement was normally realized as cationic species theoretically and experimentally, only one anionic example ([At-C(CN)3-At](-)) was computationally devised. Herein, we report the design of a new class of anionic TBPC species by using the strategy similar to that for stabilizing the non-classical planar hypercoordinate carbon. When electron deficient Al and Ga were used as the equatorial ligands, eight D(3h) [A-CE3-A](-) (E = Al and Ga, A = Si, Ge, Sn, and Pb) TBPC structures were found to be the energy minima rather than TSs at both the B3LYP and MP2 levels. Remarkably, the energetic results at the CCSD(T) optimization level further identify [Ge-CAl3-Ge](-) and [Sn-CGa3-Sn](-) even to be the global minima and [Si-CAl3-Si](-) and [Ge-CGa3-Ge](-) to be the local minima, only slightly higher than their global minima. The electronic structure analyses reveal that the substantial ionic C-E bonding, the peripheral E-A covalent bonding, and the axial mc-2e (multi center-two electrons) bonding play roles in stabilizing these TBPC structures. The structural simplicity and the high thermodynamic stability suggest that some of these species may be generated and captured in the gas phase. Furthermore, as mono-anionic species, their first vertical detachment energies are differentiable from those of their nearest isomers, which would facilitate their characterization via experiments such as the negative ion photoelectron spectroscopy. PMID- 24628165 TI - Determination of the binding energies of the np Rydberg states of H2, HD, and D2 from high-resolution spectroscopic data by multichannel quantum-defect theory. AB - Multichannel quantum-defect theory (MQDT) is used to calculate the electron binding energies of np Rydberg states of H2, HD, and D2 around n = 60 at an accuracy of better than 0.5 MHz. The theory includes the effects of rovibronic channel interactions and the hyperfine structure, and has been extended to the calculation of the asymmetric hyperfine structure of Rydberg states of a heteronuclear diatomic molecule (HD). Starting values for the eigenquantum-defect parameters of MQDT were extracted from ab initio potential-energy functions for the low-lying p Rydberg states of molecular hydrogen and subsequently refined in a global weighted fit to available experimental data on the singlet and triplet Rydberg states of H2 and D2. The electron binding energies of high-np Rydberg states derived in this work represent important quantities for future determinations of the adiabatic ionization energies of H2, HD, and D2 at sub-MHz accuracy. PMID- 24628166 TI - Two dimensional symmetric correlation functions of the S operator and two dimensional Fourier transforms: considering the line coupling for P and R lines of linear molecules. AB - The refinement of the Robert-Bonamy (RB) formalism by considering the line coupling for isotropic Raman Q lines of linear molecules developed in our previous study [Q. Ma, C. Boulet, and R. H. Tipping, J. Chem. Phys. 139, 034305 (2013)] has been extended to infrared P and R lines. In these calculations, the main task is to derive diagonal and off-diagonal matrix elements of the Liouville operator iS1 - S2 introduced in the formalism. When one considers the line coupling for isotropic Raman Q lines where their initial and final rotational quantum numbers are identical, the derivations of off-diagonal elements do not require extra correlation functions of the S operator and their Fourier transforms except for those used in deriving diagonal elements. In contrast, the derivations for infrared P and R lines become more difficult because they require a lot of new correlation functions and their Fourier transforms. By introducing two dimensional correlation functions labeled by two tensor ranks and making variable changes to become even functions, the derivations only require the latters' two dimensional Fourier transforms evaluated at two modulation frequencies characterizing the averaged energy gap and the frequency detuning between the two coupled transitions. With the coordinate representation, it is easy to accurately derive these two dimensional correlation functions. Meanwhile, by using the sampling theory one is able to effectively evaluate their two dimensional Fourier transforms. Thus, the obstacles in considering the line coupling for P and R lines have been overcome. Numerical calculations have been carried out for the half-widths of both the isotropic Raman Q lines and the infrared P and R lines of C2H2 broadened by N2. In comparison with values derived from the RB formalism, new calculated values are significantly reduced and become closer to measurements. PMID- 24628167 TI - Rovibronic structure in slow photoelectron velocity-map imaging spectroscopy of CH2CN- and CD2CN-. AB - We report high-resolution anion photoelectron spectra of the cryogenically cooled cyanomethide anion, CH2CN(-), and its isotopologue, CD2CN(-), using slow photoelectron velocity-map imaging (SEVI) spectroscopy. Electron affinities of 12 468(2) cm(-1) for CH2CN and 12 402(2) cm(-1) for CD2CN are obtained, demonstrating greater precision than previous experiments. New vibrational structure is resolved for both neutral species, especially activity of the nu5 hydrogen umbrella modes. The nu6 out-of-plane bending mode fundamental frequency is measured for the first time in both systems and found to be 420(10) cm(-1) for CH2CN and 389(8) cm(-1) for CD2CN. Some rotational structure is resolved, allowing for accurate extraction of vibrational frequencies. Temperature dependent SEVI spectra show marked effects ascribed to controlled population of low-lying anion vibrational levels. We directly measure the inversion splitting between the first two vibrational levels of the anion nu5 umbrella mode in both species, finding a splitting of 130(20) cm(-1) for CH2CN(-) and 81(20) cm(-1) for CD2CN(-). Franck-Condon forbidden activity is observed and attributed to mode specific vibrational autodetachment from the CH2CN(-) and CD2CN(-) dipole bound excited states. We also refine the binding energy of the anion dipole bound states to 39 and 42 cm(-1), respectively, for CH2CN(-) and CD2CN(-). PMID- 24628168 TI - Electronic properties of linear carbon chains: resolving the controversy. AB - Literature values for the energy gap of long one-dimensional carbon chains vary from as little as 0.2 eV to more than 4 eV. To resolve this discrepancy, we use the GW many-body approach to calculate the band gap E(g) of an infinite carbon chain. We also compute the energy dependence of the attenuation coefficient beta governing the decay with chain length of the electrical conductance of long chains and compare this with recent experimental measurements of the single molecule conductance of end-capped carbon chains. For long chains, we find E(g) = 2.16 eV and an upper bound for beta of 0.21 A(-1). PMID- 24628169 TI - Complex quantum Hamilton-Jacobi equation with Bohmian trajectories: application to the photodissociation dynamics of NOCl. AB - The complex quantum Hamilton-Jacobi equation-Bohmian trajectories (CQHJE-BT) method is introduced as a synthetic trajectory method for integrating the complex quantum Hamilton-Jacobi equation for the complex action function by propagating an ensemble of real-valued correlated Bohmian trajectories. Substituting the wave function expressed in exponential form in terms of the complex action into the time-dependent Schrodinger equation yields the complex quantum Hamilton-Jacobi equation. We transform this equation into the arbitrary Lagrangian-Eulerian version with the grid velocity matching the flow velocity of the probability fluid. The resulting equation describing the rate of change in the complex action transported along Bohmian trajectories is simultaneously integrated with the guidance equation for Bohmian trajectories, and the time-dependent wave function is readily synthesized. The spatial derivatives of the complex action required for the integration scheme are obtained by solving one moving least squares matrix equation. In addition, the method is applied to the photodissociation of NOCl. The photodissociation dynamics of NOCl can be accurately described by propagating a small ensemble of trajectories. This study demonstrates that the CQHJE-BT method combines the considerable advantages of both the real and the complex quantum trajectory methods previously developed for wave packet dynamics. PMID- 24628170 TI - Aromatic molecules as spintronic devices. AB - In this paper, we study the spin-dependent electron transport through aromatic molecular chains attached to two semi-infinite leads. We model this system taking into account different geometrical configurations which are all characterized by a tight binding Hamiltonian. Based on the Green's function approach with a Landauer formalism, we find spin-dependent transport in short aromatic molecules by applying external magnetic fields. Additionally, we find that the magnetoresistance of aromatic molecules can reach different values, which are dependent on the variations in the applied magnetic field, length of the molecules, and the interactions between the contacts and the aromatic molecule. PMID- 24628171 TI - Far-infrared amplified spontaneous emission and collisional energy transfer between the E 0(g)+ (3P2) and D 0(u)+ (3P2) ion-pair states of I2. AB - We report direct observation of far-infrared amplified spontaneous emission from the E 0(g)+ ((3)P2) (v(E) = 0 - 3) ion-pair state of I2 by using an optical optical double resonance technique with the B (3)Piu (0(u)+) (v(B) = 19) valence state as the intermediate state. The directional far-infrared emission detected in the wavelength range from 19 to 28 MUm was assigned to the vibronic transitions from the E 0(g)+ ((3)P2) ion-pair state to the D 0(u)+ ((3)P2) ion pair state. The subsequent UV fluorescence from the D 0(u)+ ((3)P2) state was also observed, which consists not only from the vibrational levels populated by the amplified spontaneous emission but also from those populated by collisional energy transfer. Analyses of the vibrational distribution in the D 0(u)+ ((3)P2) state revealed that the population transfer through the amplified spontaneous emission was dominant under our experimental conditions. PMID- 24628172 TI - Fourier-transform microwave spectroscopy and determination of the three dimensional potential energy surface for Ar-CS. AB - Pure rotational transitions of the Ar-CS van der Waals complex have been observed by Fourier Transform Microwave (FTMW) and FTMW-millimeter wave double resonance spectroscopy. Rotational transitions of v(s) = 0, 1, and 2 were able to be observed for normal CS, together with those of C(34)S in v(s) = 0, where vs stands for the quantum number of the CS stretching vibration. The observed transition frequencies were analyzed by a free rotor model Hamiltonian, where rovibrational energies were calculated as dynamical motions of the three nuclei on a three-dimensional potential energy surface, expressed by analytical functions with 57 parameters. Initial values for the potential parameters were obtained by high-level ab initio calculations. Fifteen parameters were adjusted among the 57 parameters to reproduce all the observed transition frequencies with the standard deviation of the fit to be 0.028 MHz. PMID- 24628173 TI - Radiative cooling of C7-. AB - The spontaneous and photo-induced neutralization of C7- produced in a laser ablation source was measured in an electrostatic storage ring. The measurements provide three independent determinations of the radiative cooling of the ions, based on the short time spontaneous decay and on the integrated amplitude and the shape of the photo-induced neutralization signal. The amplitude of the photo induced signal was measured between 0.5 ms and 35 ms and found to depend on photon wavelength and ion storage time. All three signals can be reproduced with identical thermal IR radiative cooling rates with oscillator strengths equal to theoretical predictions. In addition, the measurements provide the excitation energy distribution. PMID- 24628174 TI - Phase behavior of the 38-atom Lennard-Jones cluster. AB - We have developed a coarse-grained description of the phase behavior of the isolated 38-atom Lennard-Jones cluster (LJ38). The model captures both the solid solid polymorphic transitions at low temperatures and the complex cluster breakup and melting transitions at higher temperatures. For this coarse model development, we employ the manifold learning technique of diffusion mapping. The outcome of the diffusion mapping analysis over a broad temperature range indicates that two order parameters are sufficient to describe the cluster's phase behavior; we have chosen two such appropriate order parameters that are metrics of condensation and overall crystallinity. In this well-justified coarse variable space, we calculate the cluster's free energy landscape (FEL) as a function of temperature, employing Monte Carlo umbrella sampling. These FELs are used to quantify the phase behavior and onsets of phase transitions of the LJ38 cluster. PMID- 24628175 TI - Oxidation of ligand-protected aluminum clusters: an ab initio molecular dynamics study. AB - We report Car-Parrinello molecular dynamics simulations of the oxidation of ligand-protected aluminum clusters that form a prototypical cluster-assembled material. These clusters contain a small aluminum core surrounded by a monolayer of organic ligand. The aromatic cyclopentadienyl ligands form a strong bond with surface Al atoms, giving rise to an organometallic cluster that crystallizes into a low-symmetry solid and is briefly stable in air before oxidizing. Our calculations of isolated aluminum/cyclopentadienyl clusters reacting with oxygen show minimal reaction between the ligand and O2 molecules at simulation temperatures of 500 and 1000 K. In all cases, the reaction pathway involves O2 diffusing through the ligand barrier, splitting into atomic oxygen upon contact with the aluminum, and forming an oxide cluster with aluminum/ligand bonds still largely intact. Loss of individual aluminum-ligand units, as expected from unimolecular decomposition calculations, is not observed except following significant oxidation. These calculations highlight the role of the ligand in providing a steric barrier against oxidizers and in maintaining the large aluminum surface area of the solid-state cluster material. PMID- 24628176 TI - Molecular dynamics simulation of diffusion coefficients and structural properties of some alkylbenzenes in supercritical carbon dioxide at infinite dilution. AB - The binary infinite dilute diffusion coefficients, D12(infinity), of some alkylbenzenes (Ph-C(n), from Ph-H to Ph-C12) from 313 K to 333 K at 15 MPa in supercritical carbon dioxide (scCO2) have been studied by molecular dynamics (MD) simulation. The MD values agree well with the experimental ones, which indicate MD simulation technique is a powerful way to predict and obtain diffusion coefficients of solutes in supercritical fluids. Besides, the local structures of Ph-C(n)/CO2 fluids are further investigated by calculating radial distribution functions and coordination numbers. It qualitatively convinces that the first solvation shell of Ph-C(n) in scCO2 is significantly influenced by the structure of Ph-C(n) solute. Meanwhile, the mean end-to-end distance, the mean radius of gyration and dihedral angle distribution are calculated to gain an insight into the structural properties of Ph-C(n) in scCO2. The abnormal trends of radial distribution functions and coordination numbers can be reasonably explained in term of molecular flexibility. Moreover, the computed results of dihedral angle clarify that flexibility of long-chain Ph-C(n) is the result of internal rotation of C-C single bond (sigma(c-c)) in alkyl chain. It is interesting that compared with n-alkane, because of the existence of benzene ring, the flexibility of alkyl chain in Ph-C(n) with same carbon atom number is significantly reduced, as a result, the carbon chain dependence of diffusion behaviors for long-chain n alkane (n >= 5) and long-chain Ph-C(n) (n >= 4) in scCO2 are different. PMID- 24628177 TI - Two-state thermodynamics of the ST2 model for supercooled water. AB - Thermodynamic properties of the ST2 model for supercooled liquid water exhibit anomalies similar to those observed in real water. A possible explanation of these anomalies is the existence of a metastable, liquid-liquid transition terminated by a critical point. This phenomenon, whose possible existence in real water is the subject of much current experimental work, has been unambiguously demonstrated for this particular model by most recent simulations. In this work, we reproduce the anomalies of two versions of the ST2 model with an equation of state describing water as a non-ideal "mixture" of two different types of local molecular order. We show that the liquid-liquid transition in the ST2 water is energy-driven. This is in contrast to another popular model, mW, in which non ideality in mixing of two alternative local molecular orders is entropy-driven, and is not sufficiently strong to induce a liquid-liquid transition. PMID- 24628178 TI - Defect-mediated relaxation in the random tiling phase of a binary mixture: birth, death and mobility of an atomic zipper. AB - This paper describes the mechanism of defect-mediated relaxation in a dodecagonal square-triangle random tiling phase exhibited by a simulated binary mixture of soft discs in 2D. We examine the internal transitions within the elementary mobile defect (christened the "zipper") that allow it to move, as well as the mechanisms by which the zipper is created and annihilated. The structural relaxation of the random tiling phase is quantified and we show that this relaxation is well described by a model based on the distribution of waiting times for each atom to be visited by the diffusing zipper. This system, representing one of the few instances where a well defined mobile defect is capable of structural relaxation, can provide a valuable test case for general theories of relaxation in complex and disordered materials. PMID- 24628179 TI - How distributed charge reduces the melting points of model ionic salts. AB - Using coarse grain model ions and NPT molecular dynamics simulations, we determine melting point trends across a set of salts beginning with a system closely akin to the restricted primitive model. Redistributing the cation charge in salts with size-symmetric, monovalent, spherical ions can reduce the melting temperature by up to 50% compared to the charge-centered case. Displacing the charge from the ion center reduces the enthalpy of the liquid more than that of the solid resulting in a lower melting point. Upon cooling from the liquid phase, the model salts considered either crystallize as orientationally-disordered CsCl solids, or become trapped in glassy states, depending on the amount and extent of the cation charge redistribution. For the latter case, we find an orientationally ordered crystal structure with space group 111 (P(42m)) underlying the glassy states. The structural and dynamical properties of both the solid and liquid phases of the model salts are discussed in some detail. PMID- 24628180 TI - Thermodynamic properties and diffusion of water + methane binary mixtures. AB - Thermodynamic and diffusion properties of water + methane mixtures in a single liquid phase are studied using NVT molecular dynamics. An extensive comparison is reported for the thermal pressure coefficient, compressibilities, expansion coefficients, heat capacities, Joule-Thomson coefficient, zero frequency speed of sound, and diffusion coefficient at methane concentrations up to 15% in the temperature range of 298-650 K. The simulations reveal a complex concentration dependence of the thermodynamic properties of water + methane mixtures. The compressibilities, heat capacities, and diffusion coefficients decrease with increasing methane concentration, whereas values of the thermal expansion coefficients and speed of sound increase. Increasing methane concentration considerably retards the self-diffusion of both water and methane in the mixture. These effects are caused by changes in hydrogen bond network, solvation shell structure, and dynamics of water molecules induced by the solvation of methane at constant volume conditions. PMID- 24628181 TI - Structural quantities of quasi-two-dimensional fluids. AB - Quasi-two-dimensional fluids can be generated by confining a fluid between two parallel walls with narrow separation. Such fluids exhibit an inhomogeneous structure perpendicular to the walls due to the loss of translational symmetry. Taking the transversal degrees of freedom as a perturbation to an appropriate 2D reference fluid we provide a systematic expansion of the m-particle density for arbitrary m. To leading order in the slit width this density factorizes into the densities of the transversal and lateral degrees of freedom. Explicit expressions for the next-to-leading order terms are elaborated analytically quantifying the onset of inhomogeneity. The case m = 1 yields the density profile with a curvature given by an integral over the pair-distribution function of the corresponding 2D reference fluid, which reduces to its 2D contact value in the case of pure excluded-volume interactions. Interestingly, we find that the 2D limit is subtle and requires stringent conditions on the fluid-wall interactions. We quantify the rapidity of convergence for various structural quantities to their 2D counterparts. PMID- 24628182 TI - Experimental tests of free-volume tracer diffusion in water and other solvents. AB - Using forced Rayleigh scattering, the tracer diffusion of methyl red through water and eight other solvents at different temperatures is investigated and the results are compared to the Cohen-Turnbull theory of free-volume diffusion. In seven solvents the effective non-Arrhenius activation energy measured experimentally agrees with the Cohen-Turnbull energy. In water, however, the diffusion can be described mathematically by the free volume model but there is a disagreement of more than an order of magnitude between these energies. We propose that the unique "zero point" free volume forced onto water by the strong hydrogen bonding requires a different mechanism for tracer motion. PMID- 24628183 TI - Calculation of anharmonic couplings and THz linewidths in crystalline PETN. AB - We have developed a method for calculating the cubic anharmonic couplings in molecular crystals for normal modes with the zero wave vector in the framework of classical mechanics, and have applied it, combined with perturbation theory, to obtain the linewidths of all infrared absorption lines of crystalline pentaerythritol tetranitrate in the terahertz region (<100 cm(-1)). Contributions of the up- and down-conversion processes to the total linewidth were calculated. The computed linewidths are in qualitative agreement with experimental data and the results of molecular dynamics simulations. Quantum corrections to the linewidths in the terahertz region are shown to be negligible. PMID- 24628184 TI - A finite-temperature Monte Carlo algorithm for network forming materials. AB - Computer simulations of structure formation in network forming materials (such as amorphous semiconductors, glasses, or fluids containing hydrogen bonds) are challenging. The problem is that large structural changes in the network topology are rare events, making it very difficult to equilibrate these systems. To overcome this problem, Wooten, Winer, and Weaire [Phys. Rev. Lett. 54, 1392 (1985)] proposed a Monte Carlo bond-switch move, constructed to alter the network topology at every step. The resulting algorithm is well suited to study networks at zero temperature. However, since thermal fluctuations are ignored, it cannot be used to probe the phase behavior at finite temperature. In this paper, a modification of the original bond-switch move is proposed, in which detailed balance and ergodicity are both obeyed, thereby facilitating a correct sampling of the Boltzmann distribution for these systems at any finite temperature. The merits of the modified algorithm are demonstrated in a detailed investigation of the melting transition in a two-dimensional 3-fold coordinated network. PMID- 24628185 TI - Observation of the slow, Debye-like relaxation in hydrogen-bonded liquids by dynamic light scattering. AB - The slow, Debye-like relaxation in hydrogen-bonded liquids has largely remained a dielectric phenomenon and has thus far eluded observation by other experimental techniques. Here we report the first observation of a slow, Debye-like relaxation by both depolarized dynamic light scattering (DLS) and dielectric spectroscopy in a model hydrogen-bonded liquid, 2-ethyl-4-methylimidazole (2E4MIm). The relaxation times obtained by these two techniques are in good agreement and can be well explained by the Debye model of rotational diffusion. On the one hand, 2E4MIm is analogous to the widely studied monohydroxy alcohols in which transient chain-like supramolecular structure can be formed by hydrogen bonding. On the other hand, the hydrogen-bonded backbone of 2E4MIm is much more optically polarizable, making it possible to apply light scattering to study the dynamics of the supramolecular structure. These findings provide the missing evidence of the slow, Debye-like relaxation in DLS and open the venue for the application of dynamic light scattering to the study of supramolecular structures in hydrogen bonded liquids. PMID- 24628186 TI - Theoretical characterization of the "ridge" in the supercritical region in the fluid phase diagram of water. AB - The density fluctuation of water in the supercritical region was investigated theoretically using the reference interaction site model theory combined with the Kovalenko-Hirata closure relation, the so-called RISM-KH theory. The density fluctuation was evaluated by the numerical differentiation of density with respect to pressure at constant temperature. The density fluctuations plotted against density show finite maxima along a line slightly off from the critical isochore, in accordance with experimental results. The microscopic structures of water on both regions that were separated by the line were investigated by analyzing the site-site radial distribution functions. The analysis clearly indicates that the structure is determined by the two effects featuring liquid states: the packing or volume exclusion effect and the screening of the Coulomb interaction or the hydrogen bond, both becoming more important at higher densities. An interplay of the two effects creates maxima of the density fluctuation in the supercritical region of water. PMID- 24628187 TI - Polymorphism of triphenyl phosphite. AB - The glass-forming liquid triphenyl phosphite (TPP) has recently attracted much attention due to the possible existence of a polyamorphism, i.e., the existence of two or more amorphous phases. In the present work we provide experimental evidence of the existence of a polymorphism in TPP. In addition to the already known conventional crystalline phase, which melts at 299.1 K, it has been found that TPP can crystallize in another polymorphic phase. The new polymorph can be obtained from the liquid phase due to direct cooling from the room temperature up to 245 K where it is held for 15 min and then heated up to 270 K. At 270 K crystallization of the new polymorph occurs, which melts at 291.6 K. PMID- 24628188 TI - Dependence of crystal nucleation on prior liquid overheating by differential fast scanning calorimeter. AB - The degree of overheating of a melt often plays an important role in the response of the melt to subsequent undercooling, it determines the nucleation and growth behavior and the properties of the final crystalline products. However, the dependence of accessible undercooling of different bulk melt samples on prior liquid overheating has been reported to exhibit a variety of specific features which could not be given a satisfactory explanation so far. In order to determine uniquely the dependence of accessible undercooling on prior overheating and the possible factors affecting it, the solidification of a pure Sn single micro-sized droplet was studied by differential fast scanning calorimeter with cooling rates in the range from 500 to 10,000 K/s. It is observed experimentally that (i) the degree of undercooling increases first gradually with increase of prior overheating; (ii) if the degree of prior superheating exceeds a certain limiting value, then the accessible undercooling increases always with increasing cooling rate; in the alternative case of moderate initial overheating, the degree of undercooling reaches an undercooling plateau; and (iii) in latter case, the accessible undercooling increases initially with increasing cooling rate. However, at a certain limiting value of the cooling rate this kind of response is qualitatively changed and the accessible undercooling decreases strongly with a further increase of cooling rate. The observed rate dependent behavior is consistent with a kinetic model involving cavity induced heterogeneous nucleation and cavity size dependent growth. This mechanism is believed to be relevant also for other similar rapid solidification nucleation processes. PMID- 24628189 TI - Interaction and dynamics of (alkylamide + electrolyte) deep eutectics: dependence on alkyl chain-length, temperature, and anion identity. AB - Here we investigate the solute-medium interaction and solute-centered dynamics in (RCONH2 + LiX) deep eutectics (DEs) via carrying out time-resolved fluorescence measurements and all-atom molecular dynamics simulations at various temperatures. Alkylamides (RCONH2) considered are acetamide (CH3CONH2), propionamide (CH3CH2CONH2), and butyramide (CH3CH2CH2CONH2); the electrolytes (LiX) are lithium perchlorate (LiClO4), lithium bromide (LiBr), and lithium nitrate (LiNO3). Differential scanning calorimetric measurements reveal glass transition temperatures (T(g)) of these DEs are ~195 K and show a very weak dependence on alkyl chain-length and electrolyte identity. Time-resolved and steady state fluorescence measurements with these DEs have been carried out at six-to-nine different temperatures that are ~100-150 K above their individual T(g)s. Four different solute probes providing a good spread of fluorescence lifetimes have been employed in steady state measurements, revealing strong excitation wavelength dependence of probe fluorescence emission peak frequencies. Extent of this dependence, which shows sensitivity to anion identity, has been found to increase with increase of amide chain-length and decrease of probe lifetime. Time resolved measurements reveal strong fractional power dependence of average rates for solute solvation and rotation with fraction power being relatively smaller (stronger viscosity decoupling) for DEs containing longer amide and larger (weaker decoupling) for DEs containing perchlorate anion. Representative all-atom molecular dynamics simulations of (CH3CONH2 + LiX) DEs at different temperatures reveal strongly stretched exponential relaxation of wavevector dependent acetamide self dynamic structure factor with time constants dependent both on ion identity and temperature, providing justification for explaining the fluorescence results in terms of temporal heterogeneity and amide clustering in these multi component melts. PMID- 24628190 TI - Hydrogenation of O and OH on Pt(111): a comparison between the reaction rates of the first and the second hydrogen addition steps. AB - The formation of water through hydrogenation of oxygen on platinum occurs at a surprisingly low reaction rate. The reaction rate limited process for this catalytic reaction is, however, yet to be settled. In the present work, the reaction rates of the first and the second hydrogen addition steps are compared when hydrogen is obtained through intense synchrotron radiation that induces proton production in a water overlayer on top of the adsorbed oxygen species. A substantial amount of the produced hydrogen diffuses to the platinum surface and promotes water formation at the two starting conditions O/Pt(111) and (H2O+OH)/Pt(111). The comparison shows no significant difference in the reaction rate between the first and the second hydrogen addition steps, which indicates that the rate determining process of the water formation from oxygen on Pt(111) is neither the first nor the second H addition step or, alternatively, that both H addition steps exert rate control. PMID- 24628192 TI - Surface tension of isotropic-nematic interfaces: fundamental measure theory for hard spherocylinders. AB - A fluid constituted of hard spherocylinders is studied using a density functional theory for non-spherical hard particles, which can be written as a function of weighted densities. This is based on an extended deconvolution of the Mayer f function for arbitrarily shaped convex hard bodies in tensorial weight functions, which depend each only on the shape and orientation of a single particle. In the course of an examination of the isotropic-nematic interface at coexistence the functional is applied to anisotropic and inhomogeneous problems for the first time. We find good qualitative agreement with other theoretical predictions and also with Monte Carlo simulations. PMID- 24628193 TI - Porous carbon nanotubes: molecular absorption, transport, and separation. AB - We use classical molecular dynamics simulations to study nanofluidic properties of porous carbon nanotubes. We show that saturated water vapor condenses on the porous nanotubes, can be absorbed by them and transported in their interior. When these nanotubes are charged and placed in ionic solutions, they can selectively absorb ions in their interior and transport them. Porous carbon nanotubes can also be used as selective molecular sieves, as illustrated on a room temperature separation of benzene and ethanol. PMID- 24628191 TI - Theoretical study of sum-frequency vibrational spectroscopy on limonene surface. AB - By combining molecule dynamics (MD) simulation and quantum chemistry computation, we calculate the surface sum-frequency vibrational spectroscopy (SFVS) of R limonene molecules at the gas-liquid interface for SSP, PPP, and SPS polarization combinations. The distributions of the Euler angles are obtained using MD simulation, the psi-distribution is between isotropic and Gaussian. Instead of the MD distributions, different analytical distributions such as the delta function, Gaussian and isotropic distributions are applied to simulate surface SFVS. We find that different distributions significantly affect the absolute SFVS intensity and also influence on relative SFVS intensity, and the delta-function distribution should be used with caution when the orientation distribution is broad. Furthermore, the reason that the SPS signal is weak in reflected arrangement is discussed. PMID- 24628194 TI - Contribution of the entropy on the thermodynamic equilibrium of vacancies in nickel. AB - The equilibrium vacancy concentration in nickel was determined from ab initio calculations performed with both generalized gradient approximation and local density approximation up to the melting point. We focus the study on the vacancy formation entropy expressed as a sum of a vibration and an electronic contribution, which were determined from the vibration modes and the electronic densities of states. Applying a method based on the quasi-harmonic approximation, the temperature dependence of the defect formation energy and entropy were calculated. We show that the vibrations of the first shell of atoms around the defect are predominant to the vibration formation entropy. On the other hand, the electronic formation entropy is very sensitive to the exchange-correlation potential used for the calculations. Finally, the vacancy concentration is computed at finite temperature with the calculated values for the defect formation energy and entropy. In order to reconcile point-defects concentration obtained with our calculations and experimental data, we conducted complementary calorimetric measurements of the vacancy concentration in the 1073-1273 K temperature range. Close agreement between theory and experiments at high temperature is achieved if the calculations are performed with the generalized gradient approximation and both vibration and electronic contributions to the formation entropy are taken into account. PMID- 24628195 TI - The effect of Coulomb interactions on thermoelectric properties of quantum dots. AB - Thermoelectric effects in a quantum dot coupled to the source and drain charge reservoirs are explored using a nonequilibrium Green's functions formalism beyond the Hartree-Fock approximation. Thermal transport is analyzed within a linear response regime. A transition from Coulomb blockade regime to Kondo regime in thermoelectric transport through a single-level quantum dot is traced using unified approximations for the relevant Green's functions. PMID- 24628196 TI - Assessing electronic structure approaches for gas-ligand interactions in metal organic frameworks: the CO2-benzene complex. AB - Adsorption of gas molecules in metal-organic frameworks is governed by many factors, the most dominant of which are the interaction of the gas with open metal sites, and the interaction of the gas with the ligands. Herein, we examine the latter class of interaction in the context of CO2 binding to benzene. We begin by clarifying the geometry of the CO2-benzene complex. We then generate a benchmark binding curve using a coupled-cluster approach with single, double, and perturbative triple excitations [CCSD(T)] at the complete basis set (CBS) limit. Against this DeltaCCSD(T)/CBS standard, we evaluate a plethora of electronic structure approximations: Hartree-Fock, second-order Moller-Plesset perturbation theory (MP2) with the resolution-of-the-identity approximation, attenuated MP2, and a number of density functionals with and without different empirical and nonempirical van der Waals corrections. We find that finite-basis MP2 significantly overbinds the complex. On the other hand, even the simplest empirical correction to standard density functionals is sufficient to bring the binding energies to well within 1 kJ/mol of the benchmark, corresponding to an error of less than 10%; PBE-D in particular performs well. Methods that explicitly include nonlocal correlation kernels, such as VV10, vdW-DF2, and omegaB97X-V, perform with similar accuracy for this system, as do omegaB97X and M06-L. PMID- 24628197 TI - Curvature dependence of the interfacial heat and mass transfer coefficients. AB - Nucleation is often accompanied by heat transfer between the surroundings and a nucleus of a new phase. The interface between two phases gives an additional resistance to this transfer. For small nuclei the interfacial curvature is high, which affects not only equilibrium quantities such as surface tension, but also the transport properties. In particular, high curvature affects the interfacial resistance to heat and mass transfer. We develop a framework for determining the curvature dependence of the interfacial heat and mass transfer resistances. We determine the interfacial resistances as a function of a curvature. The analysis is performed for a bubble of a one-component fluid and may be extended to various nuclei of multicomponent systems. The curvature dependence of the interfacial resistances is important in modeling transport processes in multiphase systems. PMID- 24628198 TI - Anisotropic surface phonon dispersion of the hydrogen-terminated Si(110)-(1*1) surface: one-dimensional phonons propagating along the glide planes. AB - We have measured the surface phonon dispersion curves on the hydrogen-terminated Si(110)-(1*1) surface with the two-dimensional space group of p2mg along the two highly symmetric and rectangular directions of GammaX and GammaX' using high resolution electron-energy-loss spectroscopy. All the essential energy-loss peaks on H:Si(110) were assigned to the vibrational phonon modes by using the selection rules of inelastic electron scattering including the glide-plane symmetry. Actually, the surface phonon modes of even-symmetry to the glide plane (along GammaX) were observed in the first Brillouin zone, and those of odd-symmetry to the glide plane were in the second Brillouin zone. The detailed assignment was made by referring to theoretical phonon dispersion curves of Graschus et al. [Phys. Rev. B 56, 6482 (1997)]. We found that the H-Si stretching and bending modes, which exhibit highly anisotropic dispersion, propagate along GammaX direction as a one-dimensional phonon. Judging from the surface structure as well as our classical and quantum mechanical estimations, the H-Si stretching phonon propagates by a direct repulsive interaction between the nearest neighbor H atoms facing each other along GammaX, whereas the H-Si bending phonon propagates by indirect interaction through the substrate Si atomic linkage. PMID- 24628199 TI - Diffusion and spectroscopy of water and lipids in fully hydrated dimyristoylphosphatidylcholine bilayer membranes. AB - Microscopic structure and dynamics of water and lipids in a fully hydrated dimyristoylphosphatidylcholine phospholipid lipid bilayer membrane in the liquid crystalline phase have been analyzed with all-atom molecular dynamics simulations based on the recently parameterized CHARMM36 force field. The diffusive dynamics of the membrane lipids and of its hydration water, their reorientational motions as well as their corresponding spectral densities, related to the absorption of radiation, have been considered for the first time using the present force field. In addition, structural properties such as density and pressure profiles, a deuterium-order parameter, surface tension, and the extent of water penetration in the membrane have been analyzed. Molecular self-diffusion, reorientational motions, and spectral densities of atomic species reveal a variety of time scales playing a role in membrane dynamics. The mechanisms of lipid motion strongly depend on the time scale considered, from fast ballistic translation at the scale of picoseconds (effective diffusion coefficients of the order of 10(-5) cm(2)/s) to diffusive flow of a few lipids forming nanodomains at the scale of hundreds of nanoseconds (diffusion coefficients of the order of 10(-8) cm(2)/s). In the intermediate regime of sub-diffusion, collisions with nearest neighbors prevent the lipids to achieve full diffusion. Lipid reorientations along selected directions agree well with reported nuclear magnetic resonance data and indicate two different time scales, one about 1 ns and a second one in the range of 2-8 ns. We associated the two time scales of reorientational motions with angular distributions of selected vectors. Calculated spectral densities corresponding to lipid and water reveal an overall good qualitative agreement with Fourier transform infrared spectroscopy experiments. Our simulations indicate a blue shift of the low frequency spectral bands of hydration water as a result of its interaction with lipids. We have thoroughly analyzed the physical meaning of all spectral features from lipid atomic sites and correlated them with experimental data. Our findings include a "wagging of the tails" frequency around 30 cm(-1), which essentially corresponds to motions of the tail-group along the instantaneous plane formed by the two lipid tails, i.e., in-plane oscillations are clearly of bigger importance than those along the normal-to-the plane direction. PMID- 24628200 TI - Study on the polymer diffusion in a media with periodically distributed nano sized fillers. AB - The effect of nano-sized fillers on the equilibrium and dynamical properties of a linear polymer is studied by using off-lattice Monte Carlo simulation. Fillers are arranged periodically in the system with period d and Lennard-Jones interaction between polymer and fillers is considered. Results show that the statistical dimension and dynamical diffusion of the polymer are dependent on the polymer-filler interaction strength E(pf) and the relative size between R(G0) and d, here R(G0) is the radius of gyration of polymer in dilute solution. Normal diffusion of polymer is always observed in the regime 2R(G0) > d. And the diffusion coefficient D is scaled with chain length N as D ~ N(-alpha), where the exponent alpha increases with E(pf). Whereas in the regime 2R(G0) < d ? Nl0 with l0 the mean bond length of polymer, normal diffusion is observed only at E(pf) < 2, but the polymer will be adsorbed on the fillers and cannot diffuse at E(pf) > 2. In addition, we find that there is a critical interaction strength E*(pf) = 2 in our model system. PMID- 24628201 TI - Mesoscale modeling of shear-thinning polymer solutions. AB - We simulate the linear and nonlinear rheology of two different viscoelastic polymer solutions, a polyisobutylene solution in pristane and an aqueous solution of hydroxypropylcellulose, using a highly coarse-grained approach known as Responsive Particle Dynamics (RaPiD) model. In RaPiD, each polymer has originally been depicted as a spherical particle with the effects of the eliminated degrees of freedom accounted for by an appropriate free energy and transient pairwise forces. Motivated by the inability of this spherical particle representation to entirely capture the nonlinear rheology of both fluids, we extended the RaPiD model by introducing a deformable particle capable of elongation. A Finite Extensible Non-Linear Elastic potential provides a free energy penalty for particle elongation. Upon disentangling, this deformability allows more time for particles to re-entangle with neighbouring particles. We show this process to be integral towards recovering the experimental nonlinear rheology, obtaining excellent agreement. We show that the nonlinear rheology is crucially dependent upon the maximum elongation and less so on the elasticity of the particles. In addition, the description of the linear rheology has been retained in the process. PMID- 24628202 TI - A two-dimensional nematic phase of magnetic nanorods. AB - We report a hybrid mesophase consisting of magnetic nanorods confined between the non-ionic surfactant bilayers of a lamellar phase. The magnetic field-induced ordering of the nanorods was measured experimentally and modeled by a two dimensional Onsager theory including the third virial coefficient. The nanorods are strongly confined in layers, with no orientational coupling from one layer to the next. At high volume concentration they exhibit spontaneous in-plane orientational ordering and form a stack of independent two-dimensional nematic systems. This isotropic-nematic transition is first-order. PMID- 24628203 TI - Micellar morphological transformations for a series of linear diblock model surfactants. AB - The concentration induced shape transitions of linear model surfactants, H(x)T(y), on a lattice have been studied using Monte Carlo simulation. It has been found that a sphere to cylinder shape transition is generally found on shortening the hydrophilic part of the surfactant and anticipates an eventual phase transition. Asymmetric surfactants with longer heads than tails (x > y) prefer to form only spherical micelles independent of total surfactant concentration while asymmetric surfactants with longer tails than heads (x < y) form spherical micelles at lower concentration and undergo a shape transition to cylindrical micelles on increasing the total concentration. Finally, in the case of symmetric surfactants with x = y, only the shortest surfactants H1T1 and H2T2 undergo a sphere to cylinder shape transition on increasing surfactant concentration. Longer symmetric surfactants are always found to prefer to form spherical micelles. PMID- 24628204 TI - Measurements of dispersion forces between colloidal latex particles with the atomic force microscope and comparison with Lifshitz theory. AB - Interaction forces between carboxylate colloidal latex particles of about 2 MUm in diameter immersed in aqueous solutions of monovalent salts were measured with the colloidal probe technique, which is based on the atomic force microscope. We have systematically varied the ionic strength, the type of salt, and also the surface charge densities of the particles through changes in the solution pH. Based on these measurements, we have accurately measured the dispersion forces acting between the particles and estimated the apparent Hamaker constant to be (2.0 +/- 0.5) * 10(-21) J at a separation distance of about 10 nm. This value is basically independent of the salt concentration and the type of salt. Good agreement with Lifshitz theory is found when roughness effects are taken into account. The combination of retardation and roughness effects reduces the value of the apparent Hamaker constant and its ionic strength dependence with respect to the case of ideally smooth surfaces. PMID- 24628205 TI - The effect of boundary adaptivity on hexagonal ordering and bistability in circularly confined quasi hard discs. AB - The behaviour of materials under spatial confinement is sensitively dependent on the nature of the confining boundaries. In two dimensions, confinement within a hard circular boundary inhibits the hexagonal ordering observed in bulk systems at high density. Using colloidal experiments and Monte Carlo simulations, we investigate two model systems of quasi hard discs under circularly symmetric confinement. The first system employs an adaptive circular boundary, defined experimentally using holographic optical tweezers. We show that deformation of this boundary allows, and indeed is required for, hexagonal ordering in the confined system. The second system employs a circularly symmetric optical potential to confine particles without a physical boundary. We show that, in the absence of a curved wall, near perfect hexagonal ordering is possible. We propose that the degree to which hexagonal ordering is suppressed by a curved boundary is determined by the "strictness" of that wall. PMID- 24628206 TI - Studies of nanocomposites of carbon nanotubes and a negative dielectric anisotropy liquid crystal. AB - It has been widely recognized that the combination of carbon nanotube (CNT) and liquid crystals (LCs) not only provides a useful way to align CNTs, but also dramatically enhances the order in the LC phases, which is especially useful in liquid crystal display (LCD) technology. As the measure of this phase behavior, the complex specific heat is presented over a wide temperature range for a negative dielectric anisotropy alkoxyphenylbenzoate liquid crystal (9OO4) and CNT composites as a function of CNT concentration. The calorimetric scans were performed under near-equilibrium conditions between 25 and 95 degrees C, first cooling and then followed by heating for CNT weight percent ranging from phi(w) = 0 to 0.2. All 9OO4/CNT mesophases have transition temperatures ~1 K higher and a crystallization temperature 4 K higher than that of the pure 9OO4. The crystal phase superheats until a strongly first-order specific heat feature is observed, 0.5 K higher than in the pure 9OO4. The transition enthalpy for the nanocomposite mesophases is 10% lower than that observed in the pure 9OO4. The strongly first order crystallization and melting transition enthalpies are essentially constant over this range of phi(w). Complementary electroclinic measurement on a 0.05 wt. % sample, cooling towards the smectic-C phase from the smectic-A, indicates that the SmA-SmC transition remains mean-field-like in the presence of the CNTs. Given the homogeneous and random distribution of CNTs in these nanocomposites, we interpret these results as arising from the LC-CNT surface interaction pinning the orientational order uniformly along the CNT, without pinning the position of the 9OO4 molecule, leading to a net ordering effect for all phases. These effects of incorporating CNTs into LCs are likely due to "anisotropic orientational" coupling between CNT and LC, the change in the elastic properties of composites and thermal anisotropic properties of the CNTs. PMID- 24628207 TI - Evidence of entropically driven C60 fullerene aggregation in aqueous solution. AB - In the present work, we report the first experimental evidence of entropically driven C60 fullerene aggregation in aqueous solution, occurring with nearly zero enthalpy change. PMID- 24628208 TI - Peptide dynamics by molecular dynamics simulation and diffusion theory method with improved basis sets. AB - Improved basis sets for the study of polymer dynamics by means of the diffusion theory, and tests on a melt of cis-1,4-polyisoprene decamers, and a toluene solution of a 71-mer syndiotactic trans-1,2-polypentadiene were presented recently [R. Gaspari and A. Rapallo, J. Chem. Phys. 128, 244109 (2008)]. The proposed hybrid basis approach (HBA) combined two techniques, the long time sorting procedure and the maximum correlation approximation. The HBA takes advantage of the strength of these two techniques, and its basis sets proved to be very effective and computationally convenient in describing both local and global dynamics in cases of flexible synthetic polymers where the repeating unit is a unique type of monomer. The question then arises if the same efficacy continues when the HBA is applied to polymers of different monomers, variable local stiffness along the chain and with longer persistence length, which have different local and global dynamical properties against the above-mentioned systems. Important examples of this kind of molecular chains are the proteins, so that a fragment of the protein transthyretin is chosen as the system of the present study. This peptide corresponds to a sequence that is structured in beta sheets of the protein and is located on the surface of the channel with thyroxin. The protein transthyretin forms amyloid fibrils in vivo, whereas the peptide fragment has been shown [C. P. Jaroniec, C. E. MacPhee, N. S. Astrof, C. M. Dobson, and R. G. Griffin, Proc. Natl. Acad. Sci. U.S.A. 99, 16748 (2002)] to form amyloid fibrils in vitro in extended beta-sheet conformations. For these reasons the latter is given considerable attention in the literature and studied also as an isolated fragment in water solution where both experimental and theoretical efforts have indicated the propensity of the system to form beta turns or alpha helices, but is otherwise predominantly unstructured. Differing from previous computational studies that employed implicit solvent, we performed in this work the classical molecular dynamics simulation on a realistic model solution with the peptide embedded in an explicit water environment, and calculated its dynamic properties both as an outcome of the simulations, and by the diffusion theory in reduced statistical-mechanical approach within HBA on the premise that the mode-coupling approach to the diffusion theory can give both the long-range and local dynamics starting from equilibrium averages which were obtained from detailed atomistic simulations. PMID- 24628209 TI - Molecular dynamics simulations of polyelectrolyte brushes under poor solvent conditions: origins of bundle formation. AB - Molecular dynamics simulations are applied to investigate salt-free planar polyelectrolyte brushes under poor solvent conditions. Starting above the Theta point with a homogeneous brush and then gradually reducing the temperature, the polymers initially display a lateral structure formation, forming vertical bundles of chains. A further reduction of the temperature (or solvent quality) leads to a vertical collapse of the brush. By varying the size and selectivity of the counterions, we show that lateral structure formation persists and therefore demonstrate that the entropy of counterions being the dominant factor for the formation of the bundle phase. By applying an external compression force on the brush we calculate the minimal work done on the polymer phase only and prove that the entropy gain of counterions in the bundle state, as compared to the homogeneously collapsed state at the same temperature, is responsible for the lateral microphase segregation. As a consequence, the observed lateral structure formation has to be regarded universal for osmotic polymer brushes below the Theta-point. PMID- 24628210 TI - A model study of sequential enzyme reactions and electrostatic channeling. AB - We study models of two sequential enzyme-catalyzed reactions as a basic functional building block for coupled biochemical networks. We investigate the influence of enzyme distributions and long-range molecular interactions on reaction kinetics, which have been exploited in biological systems to maximize metabolic efficiency and signaling effects. Specifically, we examine how the maximal rate of product generation in a series of sequential reactions is dependent on the enzyme distribution and the electrostatic composition of its participant enzymes and substrates. We find that close proximity between enzymes does not guarantee optimal reaction rates, as the benefit of decreasing enzyme separation is countered by the volume excluded by adjacent enzymes. We further quantify the extent to which the electrostatic potential increases the efficiency of transferring substrate between enzymes, which supports the existence of electrostatic channeling in nature. Here, a major finding is that the role of attractive electrostatic interactions in confining intermediate substrates in the vicinity of the enzymes can contribute more to net reactive throughput than the directional properties of the electrostatic fields. These findings shed light on the interplay of long-range interactions and enzyme distributions in coupled enzyme-catalyzed reactions, and their influence on signaling in biological systems. PMID- 24628211 TI - UV-tunable laser induced phototransformations of matrix isolated anethole. AB - A matrix isolation study of the infrared spectra and structure of anethole (1 methoxy-4-(1-propenyl)benzene) has been carried out, showing the presence of two E conformers (AE1, AE2) of the molecule in the as-deposited matrices. Irradiation using ultraviolet-tunable laser light at 308-307 nm induced conformationally selective phototransformations of these forms into two less stable Z conformers (AZ1, AZ2). The back reactions were also detected upon irradiation at 301 nm. On the whole, the obtained results allow for full assignment of the infrared spectra of all the four experimentally observed anethole isomers and showed that the narrowband UV-induced E-Z photoisomerization is an efficient and selective way to interconvert the two isomers of anethole into each other, with conformational discrimination. Photolysis of anethole was observed as well, with initial methoxyl O-C bond cleavage and formation of CH3 and p-propenylphenoxy (AR) radicals, followed by radical recombination to form 2-methyl-4-propenyl-2,4 cyclohexadienone, which subsequently undergoes ring-opening generating several conformers of long-chain conjugated ketenes. Interpretation of the experimental observations was supported by density functional theory (B3LYP and B2PLYD) calculations. PMID- 24628213 TI - Welcome to the second edition of the year. PMID- 24628212 TI - Folding and self-assembly of a small heterotetramer. AB - Designed miniproteins offer a possibility to study folding and association of protein complexes, both experimentally and in silico. Using replica exchange molecular dynamics and the coarse-grain UNRES force field, we have simulated the folding and self-assembly of the heterotetramer BBAThet1, comparing it with that of the homotetramer BBAT1 which has the same size and betabetaalpha-fold. For both proteins, association of the tetramer precedes and facilitates folding of the individual chains. PMID- 24628215 TI - Clinical value of a self-designed training model for pinpointing and puncturing trigeminal ganglion. AB - OBJECTIVES. A training model was designed for learners and young physicians to polish their skills in clinical practices of pinpointing and puncturing trigeminal ganglion. METHODS. A head model, on both cheeks of which the deep soft tissue was replaced by stuffed organosilicone and sponge while the superficial soft tissue, skin and the trigeminal ganglion were made of organic silicon rubber for an appearance of real human being, was made from a dried skull specimen and epoxy resin. Two physicians who had experiences in puncturing foramen ovale and trigeminal ganglion were selected to test the model, mainly for its appearance, X ray permeability, handling of the puncture, and closure of the puncture sites. Four inexperienced physicians were selected afterwards to be trained combining Hartel's anterior facial approach with the new method of real-time observation on foramen ovale studied by us. RESULTS. Both appearance and texture of the model were extremely close to those of a real human. The fact that the skin, superficial soft tissue, deep muscles of the cheeks, and the trigeminal ganglion made of organic silicon rubber all had great elasticity resulted in quick closure and sealing of the puncture sites. The head model made of epoxy resin had similar X-ray permeability to a human skull specimen under fluoroscopy. The soft tissue was made of radiolucent material so that the training can be conducted with X-ray guidance. After repeated training, all the four young physicians were able to smoothly and successfully accomplish the puncture. CONCLUSION. This self-made model can substitute for cadaver specimen in training learners and young physicians on foramen ovale and trigeminal ganglion puncture. It is very helpful for fast learning and mastering this interventional operation skill, and the puncture accuracy can be improved significantly with our new method of real-time observation on foramen ovale. PMID- 24628216 TI - Super-sub-ultra-specialisation--this far and no further? PMID- 24628217 TI - Urgent revision required of NICE guidance relating to prevention of spread of vCJD through neurosurgical instruments. AB - In 2006, NICE brought out guidance relating to prevention of vCJD through contaminated surgical instruments. This was with the aim of protecting patients born after 1997 who did not have any risk of developing vCJD through eating beef contaminated with BSE through the food chain. Many adult neurosurgical units did not pay much attention to this until 2013 when they were suddenly faced with these children who were now 16 and being admitted to the adult neurosurgical service rather than pediatric. The NICE guidance requires that most patients born after 1997 be operated on using a separate set of neurosurgical instruments than those born before this. This is proving to be a huge financial, as well as logistical, challenge and also a clinical risk as attention is being diverted to searching for the right kit when it should be spent on saving lives. It is now clear in 2013 that the risks that NICE feared were perhaps overstated as there is nowhere near the number of deaths from vCJD that NICE had feared would happen. Worldwide there have been only five cases whereby CJD was transmitted through contaminated neurosurgical instruments and the last case was in 1976. There have been no cases of vCJD transmission attributed to use of contaminated neurosurgical instruments. NICE should revisit this guidance urgently in view of these circumstances. PMID- 24628218 TI - Comment on: Urgent revision required of NICE guidance relating to the prevention of spread of vCJD through neurosurgical instruments. PMID- 24628219 TI - Notice of retraction. AB - The author of the following article has requested that it be retracted from publication in British Journal of Neurosurgery : Sri D. The management of spinal dural fistulas: a 13-year retrospective analysis. British Journal of Neurosurgery 2013;27(4):471 - 4. The retraction has been requested on the grounds that the study leaders had not participated in or agreed to the submitted article. The retraction is not made on the basis of any concerns with the data or findings of the study. D. Sri sincerely apologises for the inconvenience caused. PMID- 24628221 TI - From switch-words to stitch-words. AB - During the course of treatment with some patients a word or phrase reappears that functions to connect layers of fantasies and to identify a history of conflicts and defenses. These stitch-words are compared to the switch-words proposed by Freud as points of condensation in dreams, as well as to other forms of idiolectic evidence (e.g. metaphors) that inform therapeutic listening. Stitch words expand on Freud's concept by taking into account syntactic aspects of language that function to hold together layers of unconscious fantasies. A description of the grammatical type of words (syncategorematic) best suited to function as stitch-words is presented and illustrated by their use in two clinical examples ('normal', 'fair'). The therapeutic value of listening to, as well as through, the surface of patients' language is discussed. PMID- 24628222 TI - Attention deficit hyperactivity disorder (ADHD): an affect-processing and thought disorder? AB - In the literature on child and adolescent psychoanalysis attention deficit hyperactivity disorder (ADHD) is described as complex syndrome with wide-ranging psychodynamic features. Broadly speaking, the disorder is divided into three categories: 1. a disorder in early object relations leading to the development of a maniform defence organization in which object-loss anxieties and depressed affects are not worked through via symbolization but are organized in a body-near manner; 2. a triangulation disorder in which the cathexis of the paternal position is not stable; structures providing little support alternate with excessive arousal, affect regulation is restricted; 3. current emotional stress or a traumatic experience. I suggest taking a fresh look at ADHD from a psychoanalytic vantage point. With respect to the phenomenology of the disorder, the conflict-dynamic approach should be supplemented by a perspective regarding deficits in alpha-function as constitutive for ADHD. These deficits cause affect processing and thought disorders compensated for (though not fully) by the symptomatology. At a secondary level, a vicious circle develops through the mutual reinforcement of defective processing of sense data and affects into potential thought content, on the one hand, and secondary, largely narcissistic defence processes on the other. These considerations have major relevance for the improved understanding of ADHD and for psychoanalytic technique. PMID- 24628223 TI - Analytic discourse, analytic intercourse: birth and death in a psychoanalysis the case of Ellen. PMID- 24628225 TI - Introduction to Paul-Claude Racamier's paper 'On narcissistic perversion'. PMID- 24628226 TI - Racamier's 'on narcissistic perversion'. PMID- 24628227 TI - On: psychoanalysis in South Africa. PMID- 24628228 TI - On: reply to Solms. PMID- 24628229 TI - "We need to talk about Kevin": an unusual, unconventional film Some reflections on 'bad boys', between transgenerational projections and socio-cultural influences. PMID- 24628230 TI - Trigeminal autonomic headaches caused by a multinodular goiter--a case report. AB - BACKGROUND: Though thyroid growths are considered to be a frequent cause of Horner's syndrome, concurrent headache attacks are not commonly seen. CASE: A 63 year-old woman presented with severe, daily occurring, unilateral headache attacks with ipsilateral Horner's syndrome. Magnetic resonance imaging arteriography showed a multinodular goiter displacing the left common carotid artery. CONCLUSION: This case exemplifies the combination of headache attacks and Horner's syndrome due to mechanical pressure of an enlarged thyroid, mimicking the symptoms both of carotid dissection as well as trigeminal autonomic cephalgias like paroxysmal hemicrania. PMID- 24628231 TI - Editorial: Antitumor alkylphospholipid analogs: a promising and growing family of synthetic cell membrane-targeting molecules for cancer treatment). PMID- 24628232 TI - 1-O-octadecyl-2-O-methylglycero-3-phosphocholine (Edelfosine) and cancer cell invasion: a short review. AB - 1-O-octadecyl-2-O-methylglycero-3-phosphocholine (ET-18-OMe) is an analogue of the naturally occurring 2- lysophosphatidylcholine belonging to the class of alkyllysophospholipids (ALPs). ALPs accumulate in cell membranes and can modulate phospholipid metabolism as well as signal transduction pathways, often inducing apoptosis. This review describes the effect of ET-18- OMe on cancer cell invasion. Interestingly, ET-18-OMe may inhibit invasion of cancer cells but can also stimulate invasive behavior of cancer cells. We discuss the biochemical alterations that are induced by ET-18-OMe under these circumstances and conclude that ET-18- OMe is an interesting tool to study mechanisms of tumor cell invasion since it has pointed to yet unknown aspects of these mechanisms. PMID- 24628233 TI - Glycosylated antitumor ether lipids: activity and mechanism of action. AB - Glycosylated antitumor ether lipids (GAELs) are distinguished from the alkyllysophospholipids or alkylphosphocholines classes of antitumor ether lipids (AEL) by the presence of a sugar moiety. Non-phosphorus GAELs, the subject of this review, have a sugar moiety in place of the phosphobase found in alkyllysophospholipids. Analogues of non-phosphorus GAELs with glucose, maltose, arabinose, or disaccharide moieties have been synthesized. Non-phosphorus GAELs with monosaccharides have cytotoxic and antiproliferative effects against cancer cells derived from a wide range of tissues, including drug resistant cell lines. The most active compound of this group to date is 1-O-hexadecyl-2-O-methyl-3-O (2'-amino-2'-deoxy-beta-D-glucopyranosyl)-sn-glycerol (11), which displays in vitro activity similar to or greater than that of ET-18-OCH3, the AEL "gold" standard. While the detailed molecular mechanism of action of non-phosphorus GAELs is not known, the data indicate that non-phosphorus GAELs are taken up by endocytosis and incorporated into early endosomes. The presence of non-phosphorus GAELs perturbs the maturation of the endocytic vesicles, resulting in the formation of large acidic vacuoles. Cell death appears to be the result of the release of cathepsins from the vacuoles into the cytosol and subsequent activation of a death pathway that is independent of the mitochondria and independent of apoptosis. The ability of these GAELs to kill cells via an apoptosis-independent mechanism makes them prime candidates for development of effective compounds against chemo-resistant tumors and cancer stem cells. The disaccharide-linked GAELs do not have cytotoxic activity but rather inhibit cancer cell motility due to the ability of the compounds to block specific calcium-activated potassium channels in cells. The antitumor activities displayed by these experimental compounds augurs well for their eventual development into clinically useful agents for cancer treatment. PMID- 24628234 TI - Edelfosine in membrane environment - the Langmuir monolayer studies. AB - The Langmuir monolayer technique is one of the methods used to build models of cellular membranes and enables to investigate the interactions of membrane components with other biomolecules. This method has been applied to study the effect of edelfosine - a synthetic alkyl-lysophospholipid analog - on model lipid membranes in order to get insight into its mode of action and selectivity. Edelfosine is mainly known for its anticancer properties, although it is also applied in the treatment of other diseases, like autoimmune, anti-HIV and antiparasitic. In this review we focus on its antitumor activity (although some other aspects of its therapeutic effects are also indicated) and summarize the results obtained so far with use of the monolayer technique. The application of this method evidenced for a key role of cholesterol and membrane rafts in the mechanism of anticancer activity of edelfosine. As regards the selectivity of this drug, the obtained results proved that the difference in fluidity of tumor versus normal cell membrane is important but probably not the only factor determining an easier incorporation of edelfosine into cancer cells. Further studies show that edelfosine is of strong affinity to gangliosides, which may be considered as molecules targeting edelfosine into cancer cell membrane. PMID- 24628235 TI - Apoptosis induction by erucylphosphohomocholine via the 18 kDa mitochondrial translocator protein: implications for cancer treatment. AB - Many types of cancer, for example glioblastoma, show resistance against current anti-cancer treatments. One reason is that they are not capable to effectively activate their intracellular cell death pathways. Novel treatments designed to overcome these deficiencies in cancer cells present promising concepts to eradicate chemotherapy-resistant cancer cells. One of these approaches includes the membrane seeking compound erucylphosphohomocholine (ErPC3) which is part of the latest generation of alkylphospholipid analogs developed over the last two and-a-half decades. ErPC3 exerts potent antineoplastic effects in animal models and against established cancer cell lines including, for example, glioblastoma and different types of leukemia, while sparing their normal counterparts. Starting with a historical survey, we report here on the anticancer activity of ErPC3 and on ErPC3's established mechanisms of action. We cover the current knowledge on the induction of mitochondrial apoptosis by ErPC3, including its interaction with the 18 kDa translocator protein (TSPO). In addition we discuss other signaling pathways modulated by ErPC3. Interaction with the TSPO leads to activation of the mitochondrial apoptosis cascade. This includes cardiolipin oxidation at mitochondrial levels, collapse of the mitochondrial membrane potential, and release of cytochrome c, the initiating steps of the mitochondrial apoptosis cascade. Other pathways modulated by ErPC3 include different kinases for the PI3K/Akt/mTOR and the MAP kinase pathways. Furthermore, ErPC3's cytotoxic actions may include its effects on phosphatidylcholine synthesis to inhibit the endoplasmic reticulum enzyme CTP:phosphocholine cytidyltransferase. These basic research data hopefully will lead to effective approaches toward exploitation of ErPC3 for the treatment of cancer. PMID- 24628236 TI - Current view on the mechanism of action of perifosine in cancer. AB - Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid rafts. However, the molecular response can vary between different tumor entities and the contribution of each target pathway to the activity of Perifosine might be distinct depending on the tumor entity or the agent combined with Perifosine. In this review we discuss the current view on the mechanism of action of perifosine in cancer and the contribution of the molecular targets of Perifosine to its activity. PMID- 24628237 TI - Antitumoral alkylphospholipids alter cell lipid metabolism. AB - Alkylphospholipid (APL) analogues are promising candidates in the search for treatments for cancer. In contrast to standard chemotherapeutic drugs, these lipophilic agents target the cell membrane without interacting directly with DNA. A variety of mechanisms have been suggested to explain the actions of these compounds, which can induce apoptosis and/or cell growth arrest. In this review, we focus on recent advances in our understanding of the actions of clinically relevant APLs, such as hexadecylphosphocholine (HePC), edelfosine, erucylphosphocholine (ErPC) and perifosine on the human hepatoma HepG2 cell line, which is commonly used for lipid metabolism studies with a special emphasis on cholesterol metabolism. One consistent finding is that HePC and other APLs cause a reduction in the biosynthesis of phosphatidylcholine (PC) by inhibiting the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CT). Our research group has been at the forefront in demonstrating that exposure to APLs affects cholesterol homeostasis in mammalian cells. Treatment with HePC, for example, causes a marked enhancement in cholesterol synthesis, which has been related to an impairment in the arrival of cholesterol at the endoplasmic reticulum (ER). In a similar way to HePC, edelfosine, ErPC and perifosine increase the de novo synthesis and uptake of cholesterol and also inhibit the arrival of plasma membrane cholesterol at the ER, which induces a significant cholesterogenic response in these cells, involving an increase in gene expression and higher levels of several proteins related to the biosynthetic pathway and receptor mediated uptake of cholesterol. It is generally accepted nowadays that the maintenance of a tightly controlled free-cholesterol/PC ratio is crucial to optimum cell behaviour and that alterations to this ratio may lead to necrosis and/or apoptosis. Our results have considerable bearing on this idea because an increase in cholesterol biosynthesis associated with a decrease in the synthesis of choline-containing phospholipids and cholesterol esterification leads to a modification in the free-cholesterol/PC ratio in cells exposed to APLs. It is well accepted that cholesterol is critical for the formation of lipid rafts and therefore drugs that alter cell cholesterol content should modify the properties of these membrane domains and consequently the signal-transduction pathways, which depends upon lipid-raft integrity. Results on the whole show that APLs share a common active mechanism consisting of disrupting PC and sphingomyelin (SM) biosyntheses and cholesterol homeostasis, all of which leads to a disturbance in the native membrane structure, thus affecting signaling processes vital to cell survival and growth. PMID- 24628238 TI - Combining anti-tumor alkyl-phospholipid analogs and radiotherapy: rationale and clinical outlook. AB - Our improved understanding of the molecular processes that determine cellular sensitivity to ionizing radiation has accelerated the identification of new targets for intervention. Indeed, novel agents have become available for combined clinical use to overcome radioresistance and increase the therapeutic ratio of radiotherapy. Synthetic alkyl-phospholipid analogs (APLs), such as edelfosine, ilmofosine, miltefosine, perifosine and erucylphosphocholine, are a novel class of anti-tumor agents that target cell membranes to induce growth arrest and apoptosis. In addition, APLs strongly enhance the cytotoxic effect of radiation in preclinical models making these compounds attractive candidates as clinical radiosensitizers. In this review, we will discuss mechanisms of action underlying the rationale to combine APLs with radiotherapy and highlight the clinical perspective of this novel combined modality treatment. PMID- 24628239 TI - A fluorescent alkyllysophospholipid analog exhibits selective cytotoxicity against the hormone-insensitive prostate cancer cell line PC3. AB - A fluorescent analog of ET-18-OCH3, 1-O-(7'-N,N-dimethylamino-3'-pentadecanoyl-1' naphthyl)-2-O-methyl-sn-glycerophosphocholine (1), was synthesized and its bioactivity was screened against 12 human cancer cell lines. The bioactivity of 1 was found to differ markedly from that of ET-18-OCH3. Growth of two prostate cell lines (PC3 and DU145) and a glioma cell line (U251) was significantly affected by 1, with IC50 values of 2, 6, and 12 uM, respectively. Compound 1 was cytotoxic to PC3 cells by caspasedependent apoptosis. The subcellular distribution of 1 differed from that reported for a phenyl-polyene analog of ET-18-OCH3; 1 was found to be localized in the endoplasmic reticulum, mitochondria, and lysosomes but not in the plasma membrane or nucleus of PC3 cells. However, no differences in accumulation of 1 were found between PC3 and cells that were not affected by the compound, implying that the selective PC3 cytotoxicity is a consequence of specific molecular components of PC3 cells. PMID- 24628240 TI - Glycosidated phospholipids - a promising group of anti-tumour lipids. AB - Synthetic alkylphospholipids (APLs), exhibit similarity to the platelet activating factor (PAF). These compounds have antiproliferative effects on tumour cells and can therefore be regarded as a new class of drugs. Unlike classic cytostatic agents, synthetic alkylphospholipids do not interfere with the DNA or the mitotic spindle apparatus. Instead, due to their aliphatic character, alkylphospholipids accumulate in cell membranes, where they have an impact on lipid metabolism and lipid-dependent signalling pathways which leads to inhibition of proliferation and induction of apoptosis in malignant cells. Normal cells remain unaffected by these compounds. Glycosidated phospholipids, are a novel class of alkylphospholipids, in which carbohydrates or carbohydrate-related molecules are introduced in the chemical lead of PAF. These hybrid alkylphospholipids also exhibit anti-proliferative capacity. Furthermore, members of this subfamily also modulate cell adhesion, differentiation, apoptosis and migration of tumour cells. Among the members of this group, Inositol-C2-platelet activating factor (Ino-C2-PAF) is the most effective compound developed so far. Recently, we also showed that Ino-C2-PAF exhibited the strongest impact on the gene expression levels of immortalised keratinocytes in comparison to edelfosine and another glycosidated alkylphospholipid, Glucose-platelet-activating factor (Glc-PAF). Furthermore, Ino-C2-PAF reduced the expression of genes encoding proteins associated with inflammation and the innate and acquired immune responses. PMID- 24628241 TI - Lipid rafts, endoplasmic reticulum and mitochondria in the antitumor action of the alkylphospholipid analog edelfosine. AB - The so-called alkylphospholipid analogs (APLs) constitute a family of synthetic antitumor compounds that target cell membranes. The ether phospholipid edelfosine has been considered the long-standing prototype of these antitumor agents and promotes apoptosis in tumor cells by a rather selective way, while sparing normal cells. Increasing evidence suggests that edelfosine-induced apoptosis involves a number of subcellular structures in tumor cells, including plasma membrane lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine has been shown to accumulate in plasma membrane lipid rafts, ER and mitochondria in different tumor cells in a cell type-dependent way. Edelfosine induces apoptosis in several hematopoietic cancer cells by recruiting death receptor and downstream apoptotic signaling molecules into lipid rafts and displacing survival signaling molecules from these membrane domains. However, in vitro and in vivo evidences suggest that edelfosine-induced apoptosis in solid tumor cells is mediated through an ER stress response. Both raft- and ER-mediated proapoptotic responses require a mitochondrial-related step to eventually promote cell death, and overexpression of Bcl-2 or Bcl-xL prevents edelfosine-induced apoptosis. Edelfosine can also interact with mitochondria leading to an increase in mitochondrial membrane permeability and loss of mitochondrial membrane potential. Edelfosine treatment also induced a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. The involvement of lipid rafts, ER and mitochondria in the apoptotic response induced by edelfosine may provide new avenues for targeting cancer cells as well as new opportunities for cancer therapy. PMID- 24628242 TI - Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single-center experience. AB - To examine risk factors for Stenotrophomonas maltophilia (S. maltophilia) infection during allogeneic hematopoietic stem cell transplantation (allo-HSCT), we retrospectively analyzed 259 patients who underwent allo-HSCT. Not only S. maltophilia infection but also S. maltophilia colonization was associated with mortality during allo-HSCT. Among 52 episodes in 39 patients in whom S. maltophilia was detected, documented infection developed in 33 episodes (25 patients). The onset of S. maltophilia infection in the period from the conditioning regimen to engraftment was associated with a high mortality rate. Breakthrough S. maltophilia infection developed in 24% of the patients during prophylactic administration of fluoroquinolones, to which S. maltophilia is sensitive. Reinsertion of a central venous catheter (CVC) immediately after removal was suggested to be a risk for persistent S. maltophilia infection in the period of neutropenia. Our results indicated that (i) onset of S. maltophilia infection in the period from the conditioning therapy to engraftment and (ii) removal and immediate reinsertion of a CVC as treatment after the onset of S. maltophilia infection are possible risk factors for S. maltophilia-related mortality during allo-HSCT. PMID- 24628243 TI - Effects of arginine 10 to lysine substitution on omega-conotoxin CVIE and CVIF block of Cav2.2 channels. AB - BACKGROUND AND PURPOSE: omega-Conotoxins CVIE and CVIF (CVIE&F) selectively inhibit Cav2.2 channels and are lead molecules in the development of novel analgesics. At physiological membrane potentials, CVIE&F block of Cav2.2 channels is weakly reversible. To improve reversibility, we designed and synthesized arginine CVIE&F analogues in which arginine was substituted for lysine at position 10 ([R10K]CVIE&F), and investigated their serum stability and pharmacological actions on voltage-gated calcium channels (VGCCs). EXPERIMENTAL APPROACH: Changes in peptide structure due to R10K substitution were assessed by NMR. Peptide stability in human serum was analysed by reversed-phase HPLC and MS over a 24 h period. Two-electrode voltage-clamp and whole-cell patch clamp techniques were used to study [R10K]CVIE&F effects on VGCC currents in Xenopus oocytes and rat dorsal root ganglion neurons respectively. KEY RESULTS: R10K substitution did not change the conserved omega-conotoxin backbone conformations of CVIE&F nor the omega-conotoxin selectivity for recombinant or native Cav2.2 channels, although the inhibitory potency of [R10K]CVIF was better than that of CVIF. At -80 mV, the R10K chemical modification significantly affected omega conotoxin-channel interaction, resulting in faster onset kinetics than those of CVIE&F. Heterologous and native Cav2.2 channels recovered better from [R10K]CVIE&F block than CVIE&F. In human serum, the omega-conotoxin half-lives were 6-10 h. CVIE&F and [R10K]CVIE&F were more stable than CVID. CONCLUSIONS AND IMPLICATIONS: R10K substitution in CVIE&F significantly alters the kinetics of omega-conotoxin action and improves reversibility without diminishing conotoxin potency and specificity for the Cav2.2 channel and without diminishing the serum stability. These results may help generate omega-conotoxins with optimized kinetic profiles for target binding. PMID- 24628244 TI - MTHFR C677T variant reduces risk of sporadic Parkinson's disease in ethnic Chinese. AB - BACKGROUND: Genetic variability of methylenetetrahydrofolate reductase (MTHFR) may be associated with Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. Our study aimed to investigate whether MTHFR C677T variation was linked to PD risk in a Han Chinese population from mainland China. METHODS: To investigate the association with the risk of PD, we analyzed the single-nucleotide polymorphism C677T in MTHFR gene using a case-control methodology. A total of 1482 subjects included 765 patients with idiopathic PD, and 717 age- and sex-matched controls were recruited in this study. RESULTS: The T allele of MTHFR C677T was associated with a decreased risk of PD (OR = 0.80, 95% CI: 0.688-0.926, P = 0.003). Patients with CT + TT genotypes have a decreased risk of PD compared with those with CC genotypes (OR = 0.66, 95%CI: 0.532-0.813, P = 0.000). CT + TT subjects cannot be differentiated from CC subjects based on their clinical features. CONCLUSION: We showed that the C677T polymorphism in MTHFR gene was associated with decreased PD susceptibility in a Han Chinese population from mainland China. Efforts to fully elucidate the pathophysiologic role of the variant in PD should be necessary. PMID- 24628246 TI - Warfarin and palliative care #278. PMID- 24628245 TI - Polydopamine-based simple and versatile surface modification of polymeric nano drug carriers. AB - The surface of a polymeric nanoparticle (NP) is often functionalized with cell interactive ligands and/or additional polymeric layers to control NP interaction with cells and proteins. However, such modification is not always straightforward when the surface is not chemically reactive. For this reason, most NP functionalization processes employ reactive linkers or coupling agents or involve prefunctionalization of the polymer, which are complicated and inefficient. Moreover, prefunctionalized polymers can lose the ability to encapsulate and retain a drug if the added ligands change the chemical properties of the polymer. To overcome this challenge, we use dopamine polymerization as a way of functionalizing NP surfaces. This method includes brief incubation of the preformed NPs in a weak alkaline solution of dopamine, followed by secondary incubation with desired ligands. Using this method, we have functionalized poly(lactic-co-glycolic acid) (PLGA) NPs with three representative surface modifiers: a small molecule (folate), a peptide (Arg-Gly-Asp), and a polymer [poly(carboxybetaine methacrylate)]. We confirmed that the modified NPs showed the expected cellular interactions with no cytotoxicity or residual bioactivity of dopamine. The dopamine polymerization method is a simple and versatile surface modification method, applicable to a variety of NP drug carriers irrespective of their chemical reactivity and the types of ligands. PMID- 24628247 TI - Thiophene-based compounds as fluorescent tags to study mesenchymal stem cell uptake and release of taxanes. AB - Human mesenchymal stem cells (hMSC) are multipotent cells that display the unique ability to home and engraft in tumor stroma. This remarkable tumor tropic property has generated a great deal of interest in many clinical settings. Recently, we showed that hMSC represent an excellent base for cell-mediated anticancer therapy since they are able to internalize paclitaxel (PTX) and to release it in an amount sufficient to inhibit tumor cell proliferation. In order to shed light on the dynamics of drug uptake and release, in the present paper we describe the synthesis of two novel thiophene-based fluorophore-paclitaxel conjugates, namely PTX-F32 and PTX-F35, as tools for in vitro drug tracking. We aimed to study the ability of these novel derivatives to be efficiently internalized by hMSC and, in a properly engineered coculture assay, to be released in the medium and taken up by tumor cells. In order to ensure better stability of the conjugates toward enzymatic hydrolysis, the selected oligothiophenes were connected to the taxol core at the C7 position through a carbamate linkage between PTX and the diamino linker. Antiproliferative experiments on both tumor cells and stromal cells clearly indicate that, in good correlation with the parent compound, cells are sensitive to nanomolar concentrations of the fluorescent conjugates. Moreover, in the coculture assay we were able to monitor, by fluorescence microscopy, PTX-F32 trafficking from hMSC toward glioblastoma U87 tumor cells. Our work paves the way for novel possibilities to perform extensive and high quality fluorescence-based analysis in order to better understand the cellular mechanisms involved in drug trafficking, such as microvescicle/exosome mediated release, in hMSC vehicle cells. PMID- 24628248 TI - Response to letter to editor regarding "Serum biochemical markers of central nerve system damage in children with acute elemental mercury intoxication" in Clinical Toxicology 2014: (doi: 10.3109/15563650.2013.860986). PMID- 24628249 TI - Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes. AB - Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked to abnormal glucose metabolism and increased diabetes risk. Well controlled laboratory studies have provided insights regarding the underlying mechanisms. Several large prospective studies suggest that these sleep disturbances are associated with an increased risk of incident diabetes. Obstructive sleep apnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistance and possibly diabetes. Whether glycemic control in type 2 diabetes patients can be improved by treating sleep apnea remains controversial. Recently, sleep disturbances during pregnancy and their relationship to gestational diabetes and hyperglycemia have received considerable attention owing to potential adverse effects on maternal and fetal health. Additionally, evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes. The purpose of this review is to provide an update on the current state of knowledge linking sleep disturbances, circadian dysfunction, and glucose metabolism. Experimental, prospective, and interventional studies are discussed. PMID- 24628250 TI - Differentiation of the four major species of cinnamons (C. burmannii, C. verum, C. cassia, and C. loureiroi) using a flow injection mass spectrometric (FIMS) fingerprinting method. AB - A simple and efficient flow injection mass spectrometric (FIMS) method was developed to differentiate cinnamon (Cinnamomum) bark (CB) samples of the four major species (C. burmannii, C. verum, C. aromaticum, and C. loureiroi) of cinnamon. Fifty cinnamon samples collected from China, Vietnam, Indonesia, and Sri Lanka were studied using the developed FIMS fingerprinting method. The FIMS fingerprints of the cinnamon samples were analyzed using principal component analysis (PCA). The FIMS technique required only 1 min of analysis time per sample. The representative samples from each of the four major species of cinnamon were further examined using an ultrahigh-performance liquid chromatography-high-resolution mass spectrometry system, and the chemical differences between the four species were profiled. The results showed that the 1 min FIMS fingerprinting method successfully differentiated the four cinnamon species studied. PMID- 24628251 TI - Carotid dosimetry for T1 glottic cancer radiotherapy. AB - OBJECTIVE: Radiotherapy for T1 glottic cancer is commonly delivered using a lateral parallel opposed pair of megavoltage photon fields. There is increasing reported evidence of cerebrovascular events due to radiation-induced carotid stenosis. An alternative field arrangement is to use an anterior oblique technique. This study compares the carotid dosimetry between the two techniques and reviews the evidence for the risk of radiation-induced vascular events. METHODS: The radiotherapy plans of 10 patients with T1 glottic cancer treated with an anterior oblique technique were examined for carotid dose. Alternative plans were then created using a parallel opposed pair of fields and the dose to the carotids compared. All patients received 50 Gy in 16 fractions treating once daily, for 5 days in a week. RESULTS: The average of the mean dose to the carotids with the anterior oblique technique was 21 Gy compared with 37 Gy using the lateral parallel opposed pair arrangement (p < 0.0001). CONCLUSION: An anterior oblique field arrangement for the treatment of T1 glottic cancer results in a significantly lower radiation dose to the carotid arteries, which may be clinically important in terms of reducing the risk of cerebrovascular events in long-term survivors. ADVANCES IN KNOWLEDGE: Although the anterior oblique technique for treating early glottic cancers is well described, and it is predictable that the dose received by the carotid arteries should be lower with this technique, to our knowledge this is the first study to quantify that reduction in dose with a series of patients. PMID- 24628252 TI - Pharmacokinetic-pharmacodynamic model of the antihypertensive interaction between telmisartan and hydrochlorothiazide in spontaneously hypertensive rats. AB - OBJECTIVES: The goal of this study was to establish an integrated indirect response pharmacokinetic-pharmacodynamic model between telmisartan and hydrochlorothiazide to describe the antihypertensive interaction of these two drugs in spontaneously hypertensive rats. METHODS: The blood pressure and plasma concentrations were measured by the tail-cuff test and high performance liquid chromatography-mass spectrometry, respectively, in spontaneously hypertensive rats. The current pharmacokinetic-pharmacodynamic model was based on the non competitive pharmacodynamic interaction of two drugs acting on different physiological processes. KEY FINDINGS: This model was able to acquire the temporal changes in drug concentration and blood pressure after administration of telmisartan or hydrochlorothiazide. The noncompetitive pharmacodynamic interaction assumed that the decreased blood pressure was attributed to the inhibitory function of telmisartan and stimulatory function of hydrochlorothiazide after administration of these two drugs. There was no significant pharmacokinetic change of telmisartan and hydrochlorothiazide in the different groups tested. The model predicted a synergistic pharmacodynamic interaction when telmisartan was administered in combination with hydrochlorothiazide, which was notably stronger than if the effects were additive. CONCLUSION: The results showed that the presented pharmacokinetic pharmacodynamic model was suitable for describing the antihypertensive interaction between telmisartan and hydrochlorothiazide. PMID- 24628253 TI - Case of giant basal cell carcinoma around the base of the penis in an elderly patient. AB - We report a case of an 85-year-old man with a doughnut-shaped basal cell carcinoma around the base of the penis invading the cavernosum urethra. In cases in which curative resection is planned, the penis is resected, cystostomy is performed, and postoperative self-management is required. In line with the patient's wishes and the fact that he was an elderly person living alone without family support, we decided to perform penis-conserving surgery. Relapse occurred once, for which additional resection was conducted. Two years after the resection, there was no evidence of tumor recurrence. The therapeutic plan for elderly patients should be modified after considering the patient's social background, wishes, activity and life expectancy. PMID- 24628255 TI - Size-focusing synthesis of gold nanoclusters with p-mercaptobenzoic acid. AB - Etching or size-focusing methods are now widespread for preparation of atomically monodisperse thiolate-protected gold nanoparticles. Size-focusing methods are not widespread, however, in the production of water-soluble gold nanoparticles. Reported here is a new method for size-focusing of large gold nanoparticles utilizing p-mercaptobenzoic acid. We observe preferential formation of three large gold nanoparticles with approximate masses of 23, 51, and 88 kDa. On the basis of the stability of these masses against further etching or growth, they appear to be especially stable sizes. These sizes are not prominent after etching challenges with organosoluble ligands, and the 51 and 88 kDa sizes appear to be novel stable thiolate-protected gold cluster sizes. The overall trend in particle size distribution over time is also unusual, with larger sizes dominating at longer time points. PMID- 24628254 TI - Distinguishing between the permeability relationships with absorption and metabolism to improve BCS and BDDCS predictions in early drug discovery. AB - The biopharmaceutics classification system (BCS) and biopharmaceutics drug distribution classification system (BDDCS) are complementary classification systems that can improve, simplify, and accelerate drug discovery, development, and regulatory processes. Drug permeability has been widely accepted as a screening tool for determining intestinal absorption via the BCS during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for industry and regulatory agencies. The BDDCS, a modification of BCS that utilizes drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug-drug interactions in the intestine, the liver, and most recently the brain. Although correlations between BCS and BDDCS have been observed with drug permeability rates, discrepancies have been noted in drug classifications between the two systems utilizing different permeability models, which are accepted as surrogate models for demonstrating human intestinal permeability by the FDA. Here, we recommend the most applicable permeability models for improving the prediction of BCS and BDDCS classifications. We demonstrate that the passive transcellular permeability rate, characterized by means of permeability models that are deficient in transporter expression and paracellular junctions (e.g., PAMPA and Caco-2), will most accurately predict BDDCS metabolism. These systems will inaccurately predict BCS classifications for drugs that particularly are substrates of highly expressed intestinal transporters. Moreover, in this latter case, a system more representative of complete human intestinal permeability is needed to accurately predict BCS absorption. PMID- 24628256 TI - In silico thermodynamics stability change analysis involved in BH4 responsive mutations in phenylalanine hydroxylase: QM/MM and MD simulations analysis. AB - The mammalian tetrahydrobiopterin (BH4)-dependent phenylalanine hydroxylases (PAH), involved in important metabolic pathways of phenylalanine, belong to non heme iron-containing aromatic acid hydroxylases' enzyme (AAH) family. AAHs utilize BH4 as protein co-factor and thus promote hydroxylation reactions of their substrates. Any alterations in BH4 -mediated AAH's pathway or mutations in these enzymes are responsible for various disorders, and thus highlights the importance of mutational analysis to assess the effect on their biosynthetic pathways. Our present studies are aimed at single-site mutations in PAH that lead to thermodynamic stability change upon folding and further validation of designed non-reduced BH2 designed co-factors. We have presented single-site mutational analysis of PAH where single-site mutations have been identified from known literature. Further, in silico studies with the PAH, in silico mutant PAH, and crystallized known mutant A313T forms, involved QM/MM and Molecular Dynamics (MD) simulations analysis. The modified co-factor A showed high affinity with PAH and all mutant PAH with high G-score of -14.851. The best pose high affinity co factor A subjected to QM/MM optimization which leads to square-pyramidal coordination of non-heme active site. The structural and energetic information obtained from the production phase of 20 ns MD simulation of co-factor metalloprotein complex results helped to understand the binding mode and involvement of three molecules throughout the reaction pathways' catalysis of PAH. The free energies of binding (dG) of A were found to be -68.181 kcal/mol and -72.249 for 1DMW and 1TDW for A313T mutant. Binding of Co-factor A do not perturb the coordination environment of iron at the active site which resides in 2 Histdine and 1-Glutamate triad, and may enhance the percentage response towards co-factor-mediated therapy. PMID- 24628257 TI - Nucleostemin knocking-down causes cell cycle arrest and apoptosis in human T-cell acute lymphoblastic leukemia MOLT-4 cells via p53 and p21Waf1/Cip1 up-regulation. AB - OBJECTIVES: Nucleostemin (NS), a recently discovered nucleolar protein, is essential for maintaining self-renewal and proliferation of embryonic and adult stem cells as well as cancerous cells. The aim of this study was to determine biological function of NS in MOLT-4 cells as a human T-cell acute lymphocytic leukemia (T-ALL) model. METHODS: Efficacy of a specific small interference RNA on NS depletion was studied by quantitative polymerase chain reaction and western blotting. The growth rate and viability were analyzed by trypan blue exclusion test. Fluorescent microscopy was used for detecting apoptosis. Cell cycle and apoptosis were mechanistically studied by flow cytometry and western blotting. RESULTS: Knockdown of NS inhibited proliferation, arrested the cell cycle, and induced apoptosis through p53 and p21(Waf1/Cip1) pathways in MOLT-4 cells. DISCUSSION: These findings demonstrate critical roles of NS in MOLT-4 cells and may implicate on its therapeutic potential in this human T-ALL model. PMID- 24628258 TI - Hand eczema in The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis (TOACS): prevalence, incidence and risk factors from adolescence to adulthood. AB - BACKGROUND: Several studies have evaluated the incidence and prevalence of hand eczema in unselected adults. However, no studies have followed unselected adolescents from primary school into adult life to evaluate the course and risk factors for hand eczema. OBJECTIVES: To estimate the incidence of hand eczema from adolescence to adulthood and the prevalence of hand eczema in young adults, together with risk factors for hand eczema. METHODS: A cohort of 1501 unselected eighth-grade schoolchildren (mean age 14 years) was established in 1995. In 2010, 1206 young adults from the cohort were asked to complete a questionnaire and participate in a clinical examination, including patch testing. RESULTS: The incidence of hand eczema was 8.8 per 1000 person-years. The 1-year-period prevalence of hand eczema in the young adults was 14.3% (127 of 891) and the point prevalence 7.1% (63 of 891), with significantly higher prevalence in females. At the clinical examination 6.4% (30 of 469) had hand eczema. Factors in childhood of importance for adult hand eczema were atopic dermatitis and hand eczema. Wet work in adulthood was a risk factor, as was taking care of small children at home. Interestingly, hand eczema among unselected young adults was associated with sick leave/pension/rehabilitation, indicating possible severe social consequences. Only 39.0% of patients participated in the clinical examination, while 75.0% answered the questionnaire. CONCLUSIONS: A high incidence and prevalence of hand eczema were found in 28-30-year-old adults, and were highly associated with childhood hand eczema and atopic dermatitis, along with wet work and taking care of small children in adulthood. There was no association with smoking, education level or nickel allergy in childhood. PMID- 24628259 TI - Mechanism of brain tumor headache. AB - BACKGROUND: Headaches occur commonly in all patients, including those who have brain tumors. Using the search terms "headache and brain tumors," "intracranial neoplasms and headache," "facial pain and brain tumors," "brain neoplasms/pathology," and "headache/etiology," we reviewed the literature from the past 78 years on the proposed mechanisms of brain tumor headache, beginning with the work of Penfield. FINDINGS: Most of what we know about the mechanisms of brain tumor associated headache come from neurosurgical observations from intra operative dural and blood vessel stimulation as well as intra-operative observations and anecdotal information about resolution of headache symptoms with various tumor-directed therapies. CONCLUSION: There is an increasing overlap between the primary and secondary headaches and they may actually share a similar biological mechanism. While there can be some criticism that the experimental work with dural and arterial stimulation produced head pain and not actual headache, when considered with the clinical observations about headache type, coupled with improvement after treatment of the primary tumor, we believe that traction on these structures, coupled with increased intracranial pressure, is clearly part of the genesis of brain tumor headache and may also involve peripheral sensitization with neurogenic inflammation as well as a component of central sensitization through trigeminovascular afferents on the meninges and cranial vessels. PMID- 24628260 TI - Wilhelm Reich's self-censorship after his arrest as an enemy alien: the chilling effect of an illegal imprisonment. AB - After discussing Wilhelm Reich's place in psychoanalysis, the article explores his arrest as an 'enemy alien' in December 1941. Reich's emotional responses to his imprisonment (which was illegal and which lasted nearly a month) are explored. A number of scholars have suggested that many European radical psychoanalysts refrained from sharing their former political ideas once they emigrated to the United States. Following a brief discussion of this pattern of 'silencing,' it is argued that Reich's withholding certain documents from publication was due to a self-imposed censorship, motivated in part by the fear of further governmental interference with his life and work. This fear, however, did not extend to his discussion of his newly developed theory of orgone energy. PMID- 24628262 TI - Impacts of MR spectroscopic imaging on glioma patient management. AB - Magnetic resonance (MR) modalities are routine imaging tools in the diagnosis and management of gliomas. MR spectroscopic imaging (MRSI), which relies on the metabolic characteristics of tissues, has been developed to accelerate the understanding of gliomas and to aid in effective clinical decision making and development of targeted therapies. In this review, the potentials and practical challenges to frequently use this technique in clinical management of gliomas are discussed. The applications of new biomarkers detectable by MRSI in differential glioma diagnosis, pre- and post-treatment evaluations, and neurosurgery are also addressed. PMID- 24628261 TI - Activation of the delta-opioid receptor promotes cutaneous wound healing by affecting keratinocyte intercellular adhesion and migration. AB - BACKGROUND AND PURPOSE: In addition to its analgesic functions, the peripheral opioid receptor system affects skin homeostasis by influencing cell differentiation, migration and adhesion; also, wound healing is altered in delta opioid receptor knockout mice (DOPr(-/-) ). Hence, we investigated delta-opioid receptor effects on the expression of several proteins of the desmosomal junction complex and on the migratory behaviour of keratinocytes. EXPERIMENTAL APPROACH: Expression levels of desmosomal cadherins in wild-type and DOPr(-/-) mice, and the morphology of intercellular adhesion in human keratinocytes were analysed by immunofluorescence. To investigate the delta-opioid receptor activation pathway, protein expression was studied using Western blot and its effect on cellular migration determined by in vitro live cell migration recordings from human keratinocytes. KEY RESULTS: Expression of the desmosomal cadherins, desmogleins 1 and 4, was up-regulated in skin from DOPr(-/-) mice, and down-regulated in delta opioid receptor-overexpressing human keratinocytes. The localization of desmoplakin expression was rearranged from linear arrays emanating from cell borders to puncta in cell periphery, resulting in less stable intercellular adhesion. Migration and wound recovery were enhanced in human keratinocyte monolayers overexpressing delta-opioid receptors in vitro. These delta-opioid receptor effects were antagonized by specific PKCalpha/beta inhibition indicating they were mediated through the PKC signalling pathway. Finally, cells overexpressing delta-opioid receptors developed characteristically long but undirected protrusions containing filamentous actin and delta-opioid receptors, indicating an enhanced migratory phenotype. CONCLUSION AND IMPLICATIONS: Opioid receptors affect intercellular adhesion and wound healing mechanisms, underlining the importance of a cutaneous neuroendocrine system in wound healing and skin homeostasis. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. PMID- 24628263 TI - The validity and reliability of the 'Cancer Caregiving Tasks, Consequences and Needs Questionnaire' (CaTCoN). AB - BACKGROUND: Caregivers are often involved in and affected by the patient's disease. The questionnaire 'Cancer Caregiving Tasks, Consequences and Needs Questionnaire' (CaTCoN) was developed to measure caregivers' experiences. The aim of this study is to evaluate the construct validity and reliability of the multi item scales in the CaTCoN using psychometric analyses as well as tests of convergent and discriminant validity with the existing instruments FAMCARE and Family Inventory of Needs (FIN). MATERIAL AND METHODS: Based on theoretical considerations, a subscale structure in the CaTCoN was hypothesized, and the subscales were tested by item-item correlations, followed by factor analysis, calculation of internal consistency by Cronbach's alpha, and multitrait-scaling analysis. Further, theoretically based hypotheses about convergence and divergence between CaTCoN and FAMCARE/FIN (sub)scales were formulated and tested. RESULTS: Analyses were based on 590 caregivers' responses. Initially, 11 CaTCoN subscales were hypothesized. The item-item correlations and factor analysis lead to some revisions, but the analyses confirmed the hypothesized subscales to a large extent, resulting in nine CaTCoN subscales (Cronbach's alpha range 0.65 0.95). The hypothesized convergent CaTCoN and FAMCARE/FIN subscales correlated 0.59-0.74, and hypothesized divergent CaTCoN and FAMCARE/FIN subscales correlated -0.11-0.25, thus confirming the hypotheses concerning convergent and discriminant validity between CaTCoN and the existing questionnaires FAMCARE and FIN. CONCLUSION: Taken together the psychometric analyses and tests of convergent and discriminant validity indicate that the validity and reliability of the CaTCoN are satisfactory. PMID- 24628264 TI - The role of mammalian target of rapamycin inhibitors in the management of post transplant malignancy. AB - Post-transplant malignancies, which occur either de novo or as cancer recurrences, are due to chronic exposure to immunosuppressive agents and are often more aggressive than those that develop in the non-transplant setting. Mammalian target of rapamycin (mTOR) inhibitors have antitumor and immunosuppressive effects. The dual effects of this class of agents may provide adequate immunosuppression to prevent organ rejection while simultaneously reducing the risk of post-transplant malignancy. mTOR inhibitors have become established approved agents for treating renal cell carcinoma and other cancers and, as reviewed herein, accumulating experience among organ transplant recipients collectively points toward a potential to prevent the development of de novo malignancies of various types in the post-transplant period. To date, most research efforts surrounding mTOR inhibitors and cancer control in the transplant population have been in the area of skin cancer prevention, but there have also been interesting observations regarding regression of post-transplant Kaposi's sarcoma and post-transplantation lymphoproliferative disorder that warrant further study. PMID- 24628265 TI - The membrane-targeted alkylphosphocholine erufosine interferes with survival signals from the extracellular matrix. AB - Integrin-dependent adhesion of tumor cells to extracellular matrix proteins provides anchorage-dependent protection from cell death. In the present investigation we aimed to understand whether and how the paradigmatic membrane targeted synthetic phospholipid analog erufosine is relevant for tumor cell adhesion to extracellular matrix proteins, cell survival and migration. The antineoplastic action of erufosine was analyzed with glioblastoma and prostate cancer cells adhering to fibronectin or collagen I using proliferation, adhesion and migration assays. The composition of adhesion contacts containing activated beta1 integrins was studied using immunofluorescence. The importance of beta1 integrins for the observed effects was analyzed in fibroblasts proficient or deficient in beta1 integrin expression. Adhesion to collagen I and fibronectin increased the death threshold in serum-deprived tumor cells. Moreover, beta1 integrin-deficient cells were more sensitive to erufosine-treatment compared to beta1 integrin proficient cells suggesting a role of beta1 integrins for matrix mediated death resistance. Most importantly, erufosine disturbed the maturation of the cell adhesion complexes containing paxillin, activated beta1 integrins and phosphorylated FAK, leading to a reduction of survival signals and inhibition of tumor cell adhesion and migration. These findings suggest that membrane-targeted synthetic phospholipids analogs may be of value for counteracting matrix-mediated treatment resistance in combined treatment approaches with radiotherapy or chemotherapy. PMID- 24628266 TI - alpha-Methylene-gamma-lactones as a novel class of anti-leukemic agents. AB - Natural products are important leads in drug discovery. In recent years, the anti leukemic properties of natural compounds isolated from plants, containing an alpha-Methylene-gamma-lactones skeleton, have attracted a lot of attention. Extensive research has been carried out to characterize their molecular mechanisms of action and potential chemotherapeutic application in different types of cancer, including leukemias. Sesquiterpene lactones, a group of alpha Methylene-gamma-lactones are plant-derived compounds, mostly of the Compositae family, used in traditional medicine especially for the treatment of inflammation. However, they exhibit a broad spectrum of other biological effects, including cytotoxic, anti-bacterial, anti-helminthic, and anti-tumor activity. Recently, a sesquiterpene lactone, parthenolide, and several other compounds containing an alpha-methylene-gamma-lactone skeleton have become topics of interest as potential antileukemic agents. The recent research emphasizes their selective activity against leukemia cells while the normal hematopoietic cells remain unaffected. In this review, we give a brief description of natural alpha Methylene-gamma-lactones isolated from plants and their derivates with minor chemical modifications that possess anti-leukemic activity. We also discuss molecular mechanisms of action of these compounds, in particular, their selectivity against leukemia cells. PMID- 24628267 TI - The actin binding affinity of the utrophin tandem calponin-homology domain is primarily determined by its N-terminal domain. AB - The structural determinants of the actin binding function of tandem calponin homology (CH) domains are poorly understood, particularly the role of individual domains. We determined the actin binding affinity of isolated CH domains from human utrophin and compared them with the affinity of the full-length tandem CH domain. Traditional cosedimentation assays indicate that the C-terminal CH2 domain binds to F-actin much weaker than the full-length tandem CH domain. The N terminal CH1 domain is less stable and undergoes severe protein aggregation; therefore, traditional actin cosedimentation assays could not be used. To address this, we have developed a folding-upon-binding method. We refolded the CH1 domain from its unfolded state in the presence of F-actin. This results in a competition between actin binding and aggregation. A differential centrifugation technique was used to distinguish actin binding from aggregation. Low-speed centrifugation pelleted CH1 aggregates, but not F-actin or its bound protein. Subsequent high speed centrifugation resulted in the cosedimentation of bound CH1 along with F actin. The CH1 domain binds to F-actin with an affinity similar to that of the full-length tandem CH domain, unlike the CH2 domain. The actin binding cooperativity between the two domains was quantitatively calculated from the association constants of the full-length tandem CH domain and its CH domains, and found to be much smaller than the association constant of the CH1 domain alone. These results indicate that the actin binding affinity of the utrophin tandem CH domain is primarily determined by its CH1 domain, when compared to that of its CH2 domain or the cooperativity between the two CH domains. PMID- 24628268 TI - Au25(SEt)18, a nearly naked thiolate-protected Au25 cluster: structural analysis by single crystal X-ray crystallography and electron nuclear double resonance. AB - X-ray crystallography has been fundamental in discovering fine structural features of ultrasmall gold clusters capped by thiolated ligands. For still unknown structures, however, new tools capable of providing relevant structural information are sought. We prepared a 25-gold atom nanocluster protected by the smallest ligand ever used, ethanethiol. This cluster displays the electrochemistry, mass spectrometry, and UV-vis absorption spectroscopy features of similar Au25 clusters protected by 18 thiolated ligands. The anionic and the neutral form of Au25(SEt)18 were fully characterized by (1)H and (13)C NMR spectroscopy, which confirmed the monolayer's properties and the paramagnetism of neutral Au25(SEt)18(0). X-ray crystallography analysis of the latter provided the first known structure of a gold cluster protected by a simple, linear alkanethiolate. Here, we also report the direct observation by electron nuclear double resonance (ENDOR) of hyperfine interactions between a surface-delocalized unpaired electron and the gold atoms of a nanocluster. The advantages of knowing the exact molecular structure and having used such a small ligand allowed us to compare the experimental values of hyperfine couplings with DFT calculations unaffected by structure's approximations or omissions. PMID- 24628270 TI - A review of bacterial cellulose-based drug delivery systems: their biochemistry, current approaches and future prospects. AB - OBJECTIVES: The field of pharmaceutical technology is expanding rapidly because of the increasing number of drug delivery options. Successful drug delivery is influenced by multiple factors, one of which is the appropriate identification of materials for research and engineering of new drug delivery systems. Bacterial cellulose (BC) is one such biopolymer that fulfils the criteria for consideration as a drug delivery material. KEY FINDINGS: BC showed versatility in terms of its potential for in-situ modulation, chemical modification after synthesis and application in the biomedical field, thus expanding the current, more limited view of BC and facilitating the investigation of its potential for application in drug delivery. SUMMARY: Cellulose, which is widely available in nature, has numerous applications. One of the applications is that of BC in the pharmaceutical and biomedical fields, where it has been primarily applied for transdermal formulations to improve clinical outcomes. This review takes a multidisciplinary approach to consideration of the feasibility and potential benefits of BC in the development of other drug delivery systems for various routes of administration. PMID- 24628269 TI - Adaptive radiotherapy in lung cancer: dosimetric benefits and clinical outcome. AB - OBJECTIVE: Anatomical changes during radiotherapy (RT) might introduce discrepancies between planned and delivered doses. This study evaluates the need for adaptive treatment in lung cancer RT. METHODS: 15 patients with non-small cell lung cancer, undergoing radical RT with or without concurrent chemotherapy, consecutively underwent planning CT scans at baseline and after 44-46 Gy. Target volumes were delineated on both scans. Phase I delivered 44-46 Gy to the initial planning target volume (PTV). Two Phase II plans for 16-20 Gy were developed on initial and mid-treatment scans, the treatment being delivered with the mid treatment plan. The second CT structure set was fused with the initial scan data set using dose wash. Volumetric and dosimetric changes in target volumes and critical structures were assessed. RESULTS: There was significant reduction in primary gross tumour volume (34.00%; p = 0.02) and PTV (34.70%; p < 0.01) in the second scan. In Plan 2, delivering the same dose to the initial PTV would have resulted in a significantly higher dose to the lung PTV (V20, 52.18%; V5, 21.76%; mean, 23.93%), contralateral lung (mean, 29.43%), heart (V10, 81.47%; V5, 56.62%; mean, 35.21%) and spinal cord (maximum dose, 37.53%). CONCLUSION: Treatment replanning can account for anatomical changes during RT and thereby enable better normal tissue sparing, while allowing radical target doses with the possibility of maximizing local control. ADVANCES IN KNOWLEDGE: This study supports the sparse dosimetric data regarding the quantitative tumour volume reduction, re emphasizing the need for adaptive replanning for minimizing normal tissue toxicity without compromising local control, and adds to the existing body of literature. PMID- 24628271 TI - Synthetic curcumin analog UBS109 inhibits the growth of head and neck squamous cell carcinoma xenografts. AB - The natural compound curcumin has been investigated as an anticancer agent in many cellular systems, in animal models and in the clinic. The overriding negative characteristics of curcumin are its low solubility, weak potency and poor bioavailability. We have examined the efficacy and mechanism of action of a synthetic curcumin analog, UBS109, in head and neck squamous cell carcinoma. By nephelometry, this analog exhibits considerably greater solubility than curcumin. Pharmacokinetic studies of a single oral dose of UBS109 in mice revealed that peak plasma concentrations were reached at 0.5 hours post-dose (Tmax) with average plasma concentrations (Cmax) of 131 and 248 ng/mL for oral doses of 50 and 150 mg/kg, respectively. The terminal elimination half-lives (T1/2) for these doses averaged 3.7 and 4.5 hours, respectively. In both in vitro and in vivo studies, we found that UBS109 decreased the levels of phosphorylated IKKbeta and phosphorylated p65 and, unexpectedly, increased the levels of phosphorylated IkappaBalpha by Western blot analysis. These observations may suggest that UBS109 suppresses tumor growth through, in part, inhibition of NF-kappaB p65 phosphorylation by PKAc and not through IkappaBalpha. Finally, we demonstrate that UBS109 is efficacious in retarding the growth of Tu212 (head and neck) squamous cell carcinoma (SCC) xenograft tumors in mice and may be useful for treating head and neck SCC tumors. PMID- 24628272 TI - Antibacterial resistance in sub-Saharan Africa: an underestimated emergency. AB - Antibacterial resistance-associated infections are known to increase morbidity, mortality, and cost of treatment, and to potentially put others in the community at higher risk of infections. In high-income countries, where the burden of infectious diseases is relatively modest, resistance to first-line antibacterial agents is usually overcome by use of second- and third-line agents. However, in developing countries where the burden of infectious diseases is high, patients with antibacterial-resistant infections may be unable to obtain or afford effective second-line treatments. In sub-Saharan Africa (SSA), the situation is aggravated by poor hygiene, unreliable water supplies, civil conflicts, and increasing numbers of immunocompromised people, such as those with HIV, which facilitate both the evolution of resistant pathogens and their rapid spread in the community. Because of limited capacity for disease detection and surveillance, the burden of illnesses due to treatable bacterial infections, their specific etiologies, and the awareness of antibacterial resistance are less well established in most of SSA, and therefore the ability to mitigate their consequences is significantly limited. PMID- 24628273 TI - Paediatric celiac patients carrying the HLA-DR7-DQ2 and HLA-DR3-DQ2 haplotypes display small clinical differences. AB - AIM: The aim of this study was to determine the relevance of HLA-DR7-DQ2 typing in a prospective cohort of paediatric coeliac disease patients from Southern Europe. METHODS: This cross-sectional study tested 249 paediatric patients with coeliac disease. HLA-DR3-DQ2 was typed in combination with HLA-DR7-DQ2 to screen for the HLA-DQ2 haplotype. The histological, analytical and clinical characteristics of the subjects were recorded. RESULTS: A total of 91 coeliac patients were diagnosed: 96.7% carried HLA-DQ2 and 4.4% carried HLA-DQ8. In percentage terms, 80.2% of patients carried HLA-DR3-DQ2 and 34.1% carried HLA-DR7 DQ2. We did not find significant differences between HLA-DR7-DQ2 and HLA-DR3-DQ2 paediatric patients with respect to histological damage and clinical characteristics, except for irritability and weight loss. These characteristics were more frequent in HLA-DQ2trans than in HLA-DQ2cis (22.2% vs. 0.0% [p = 0.035] and 55.6% vs. 21.4% [p = 0.017], respectively). Coeliac-specific autoantibody levels were higher in HLA-DQ2cis than one half of HLA-DQ2trans patients (105.5 vs. 19.2 U/mL, p = 0.014). CONCLUSION: Small clinical differences were found between paediatric coeliac patients carrying HLA-DR7-DQ2 and HLA-DR3-DQ2. For a correct screening of HLA-DQ2, at least in our geographical population, the HLA DR7-DQ2 haplotype should be typed due to its frequency and clinical presentation. PMID- 24628274 TI - Genetic predisposition to Parkinson's disease and cancer. AB - Parkinson's disease (PD) and cancer are often thought of as two sides of the same coin. At first glance, cancer and PD appear to have little in common. PD is caused by the degeneration of dopaminergic neurons, whereas cancer results from the uninhibited growth of tumor cells. Increasing numbers of genetic studies suggest that the pathogenesis of PD and cancer may involve similar genes, pathways, and mechanisms. The differences in the pathological and cellular mechanisms, and the associated genetic mutations, may result in two such divergent diseases. In this article, we highlight some molecular mechanisms and key biomarkers which might cause those two diseases from misfolding and degradation of proteins, mitochondrial damage, oxidative stress response, cell cycle control and DNA repair, and the PI3K/AKT/ mTOR pathway, in order to provide help to the understanding and treatment of these two diseases. PMID- 24628275 TI - Hepatic artery complications following liver transplantation. Does preoperative chemoembolization impact the postoperative course? AB - BACKGROUND: Transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) may cause damage to the hepatic artery (HA) and impact the postoperative course of the liver transplantation (LT). We aim to describe the relationship between preoperative TACE and the occurrence of histological and radiological hepatic artery complications (HAC). METHODS: All cirrhotic patients with HCC undergoing LT between January 2009 and October 2012 were included and divided in two groups: TACE (group 1) and No TACE (group 2). HA histological complications were reviewed and compared. RESULTS: Sixty-seven patients were reviewed, 32 in group 1 and 35 in group 2. Both groups were similar in gender, age, cirrhosis origin, and American Society of Anesthesiology (ASA) score. After a mean follow-up of 17 months, 10 radiological HAC occurred: seven in group 1 and three in group 2 (p = 0.02). There was one thrombosis in each group: six non-thrombotic complications in group 1 and two in group 2. Histological screening showed 12 HA injuries in group 1 (three HA wall edemas, five fibrosis, one edema + fibrosis, one hemorragic necrosis + thrombosis, two thrombosis) and three in group 2 (two HA wall edemas, one fibrosis) (p = 0.01). All these injuries were found at the proper HA and at the right/left HA bifurcation level. CONCLUSIONS: Despite the limits of our study, we found a higher incidence of radiological and histological injury in patients underwent TACE. PMID- 24628276 TI - Immunocompetent 3D model of human upper airway for disease modeling and in vitro drug evaluation. AB - The development of more complex in vitro models for the assessment of novel drugs and chemicals is needed because of the limited biological relevance of animal models to humans as well as ethical considerations. Although some human-cell based assays exist, they are usually 2D, consist of single cell type, and have limited cellular and functional representation of the native tissue. In this study, we have used biomimetic porous electrospun scaffolds to develop an immunocompetent 3D model of the human respiratory tract comprised of three key cell types present in upper airway epithelium. The three cell types, namely, epithelial cells (providing a physical barrier), fibroblasts (extracellular matrix production), and dendritic cells (immune sensing), were initially grown on individual scaffolds and then assembled into the 3D multicell tissue model. The epithelial layer was cultured at the air-liquid interface for up to four weeks, leading to formation of a functional barrier as evidenced by an increase in transepithelial electrical resistance (TEER) and tight junction formation. The response of epithelial cells to allergen exposure was monitored by quantifying changes in TEER readings and by assessment of cellular tight junctions using immunostaining. It was found that epithelial cells cocultured with fibroblasts formed a functional epithelial barrier at a quicker rate than single cultures of epithelial cells and that the recovery from allergen exposure was also more rapid. Also, our data show that dendritic cells within this model remain viable and responsive to external stimulation as evidenced by their migration within the 3D construct in response to allergen challenge. This model provides an easy to assemble and physiologically relevant 3D model of human airway epithelium that can be used for studies aiming at better understanding lung biology, the cross talk between immune cells, and airborne allergens and pathogens as well as drug delivery. PMID- 24628278 TI - Relationship between serum VEGF level and radiosensitivity of patients with nonsmall cell lung cancer among asians: a meta-analysis. AB - This meta-analysis aims to evaluate the relationships between serum vascular endothelial growth factor (VEGF) level and radiosensitivity in patients with nonsmall cell lung cancer (NSCLC) among Asians. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from their inception through October 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Fourteen clinical studies were included in this meta analysis, including five case-control studies and nine cohort studies. Our meta analysis results revealed that levels of serum VEGF in NSCLC patients were higher than that of healthy controls. There was a significant difference in serum VEGF levels between before and after radiotherapy in NSCLC patients. Further, we found significant differences in serum VEGF levels between effective and noneffective clinical response groups pre- and postradiotherapy. Serum VEGF levels showed no significant associations with tumor-node-metastasis (TNM) stage and histologic grade in NSCLC patients. NSCLC patients with positive VEGF expression had shorter overall survival than those with negative VEGF expression. Our meta-analysis suggests that serum VEGF level may be a useful biomarker in predicting radiosensitivity and prognosis of NSCLC patients among Asians. PMID- 24628277 TI - Thermoresponsive nanofabricated substratum for the engineering of three dimensional tissues with layer-by-layer architectural control. AB - Current tissue engineering methods lack the ability to properly recreate scaffold free, cell-dense tissues with physiological structures. Recent studies have shown that the use of nanoscale cues allows for precise control over large-area 2D tissue structures without restricting cell growth or cell density. In this study, we developed a simple and versatile platform combining a thermoresponsive nanofabricated substratum (TNFS) incorporating nanotopographical cues and the gel casting method for the fabrication of scaffold-free 3D tissues. Our TNFS allows for the structural control of aligned cell monolayers which can be spontaneously detached via a change in culture temperature. Utilizing our gel casting method, viable, aligned cell sheets can be transferred without loss of anisotropy or stacked with control over individual layer orientations. Transferred cell sheets and individual cell layers within multilayered tissues robustly retain structural anisotropy, allowing for the fabrication of scaffold-free, 3D tissues with hierarchical control of overall tissue structure. PMID- 24628279 TI - High throughput screening of perfumery raw materials for antimicrobial properties. AB - A microdilution protocol was developed and automated using a liquid handling station, allowing the determination of minimum inhibitory concentrations (MIC) of hydrophobic raw materials commonly used in the perfume industry (essential oils and synthetic chemicals). Tests were performed in 96-well microtiter plates against standard bacterial test strains and skin isolates involved in underarm malodor. The comparison with data previously reported in the literature indicated that the protocol was suitable, yielding MIC values that were in general agreement with those derived from manual test methods. For the majority of active test compounds, results showed a pronounced difference in susceptibility pattern between the Gram-positive and Gram-negative test strains used in this study. For a group of acyclic aliphatic aldehydes, a structure-activity relationship depending on the chain length was found. PMID- 24628280 TI - A convenient synthesis of 2-imino-1,3-thiazine-4-one derivatives from the reaction of primary amines and phenyl isothiocyanate in the presence of acryloyl chloride. AB - An efficient, one-pot and three-component synthesis of biologically important heterocyclic compounds is described from the reaction of primary amines and phenyl isothiocyanate in the presence of acryloyl chloride at room temperature without the need to use any catalyst. PMID- 24628282 TI - Structures and electronic properties of transition metal-containing ionic liquids: insights from ion pairs. AB - Transition metal-containing ionic liquids (TM-ILs) have attracted a great deal of attention in recent years, due to their unique physical and chemical properties. In this work, several representative TM-ILs, such as the cations consisting of silver(I) center coordinated by two n-alkylimidazole ligands ([(C(n)(im))Ag(mim)](+)) and the anions involving mercury(II) (HgCl3(-)), zinc(II) (ZnCl3(-)), and rhenium(VII) (ReO4(-)), were investigated using density functional theory calculations. First, the structural and energetic properties of the ion pairs for these TM-ILs have been examined in detail and compared with properties for conventional ILs. It was found that the interactions between the cations and anions, including hydrogen bonds and electrostatic interactions, in TM-ILs become weaker in strength than those in traditional ILs. In particular, the calculated geometric and energetic features compare fairly well with the experimental results, such as melting points and X-ray crystal structures of these TM-ILs. Then, the structures and energetics of ion-pair dimers for three ILs containing HgCl3(-), ZnCl3(-), and ReO4(-) were also explored, to gain a deeper understanding of the properties of TM-ILs. Finally, a survey of the Cambridge Structural Database (CSD) was undertaken to provide some crystallographic implications of TM-ILs. PMID- 24628281 TI - Novel lead structures and activation mechanisms for CO-releasing molecules (CORMs). AB - Carbon monoxide (CO) is an endogenous small signalling molecule in the human body, produced by the action of haem oxygenase on haem. Since it is very difficult to apply safely as a gas, solid storage and delivery forms for CO are now explored. Most of these CO-releasing molecules (CORMs) are based on the inactivation of the CO by coordinating it to a transition metal centre in a prodrug approach. After a brief look at the potential cellular target structures of CO, an overview of the design principles and activation mechanisms for CO release from a metal coordination sphere is given. Endogenous and exogenous triggers discussed include ligand exchange reactions with medium, enzymatically induced CO release and photoactivated liberation of CO. Furthermore, the attachment of CORMs to hard and soft nanomaterials to confer additional target specificity to such systems is critically assessed. A survey of analytical methods for the study of the stoichiometry and kinetics of CO release, as well as the tracking of CO in living systems by using fluorescent probes, concludes this review. CORMs are very valuable tools for studying CO bioactivity and might lead to new drug candidates; however, in the design of future generations of CORMs, particular attention has to be paid to their drug-likeness and the tuning of the peripheral 'drug sphere' for specific biomedical applications. Further progress in this field will thus critically depend on a close interaction between synthetic chemists and researchers exploring the physiological effects and therapeutic applications of CO. PMID- 24628283 TI - Reversible cerebral vasoconstriction syndrome after blood transfusion. AB - OBJECTIVES: To report 2 cases of reversible cerebral vasoconstriction syndrome (RCVS) with posterior reversible encephalopathy syndrome (PRES) after blood transfusion for severe anemia. BACKGROUND: RCVS is presented with recurrent thunderclap headache and reversible constriction of cerebral arteries. PRES is a known complication of RCVS. Blood transfusion for severe anemia could be a cause for PRES in few cases; however, it is seldom mentioned as an etiology for RCVS. METHODS: We report a case series. RESULTS: We report 2 women presented with RCVS with PRES after blood transfusion for anemia, and reviewed another 4 similar cases reported in the literature. Our 2 patients were middle-aged women, with severe chronic anemia (average hemoglobin: 1.45 g/dL), and received multiple blood transfusions (average: 3250 mL) over a period of 5-7 days. They developed thunderclap headache and other symptoms about 1 week after the last blood transfusion. Cerebral vasoconstrictions were demonstrated by magnetic resonance angiography and transcranial color-coded sonography. PRES was found in both of them using magnetic resonance imaging, and one of them also had cytotoxic edema on diffusion weighted image. CONCLUSIONS: RCVS with PRES is one complication of blood transfusion in patients under chronic severe anemia (especially when hemoglobin level increased for more than 5 g/dL), particularly in Asian women with menorrhagia. Blood pressure surge and the occurrence of severe headaches or other neurological symptoms should be aggressively monitored within 10 days after the last blood transfusion. PMID- 24628284 TI - Increased expression of epidermal thymic stromal lymphopoietin in inflammatory peeling skin syndrome. PMID- 24628286 TI - Testing advances in molecular discrimination among Chinook salmon life histories: evidence from a blind test. AB - The application of DNA-based markers toward the task of discriminating among alternate salmon runs has evolved in accordance with ongoing genomic developments and increasingly has enabled resolution of which genetic markers associate with important life-history differences. Accurate and efficient identification of the most likely origin for salmon encountered during ocean fisheries, or at salvage from fresh water diversion and monitoring facilities, has far-reaching consequences for improving measures for management, restoration and conservation. Near-real-time provision of high-resolution identity information enables prompt response to changes in encounter rates. We thus continue to develop new tools to provide the greatest statistical power for run identification. As a proof of concept for genetic identification improvements, we conducted simulation and blind tests for 623 known-origin Chinook salmon (Oncorhynchus tshawytscha) to compare and contrast the accuracy of different population sampling baselines and microsatellite loci panels. This test included 35 microsatellite loci (1266 alleles), some known to be associated with specific coding regions of functional significance, such as the circadian rhythm cryptochrome genes, and others not known to be associated with any functional importance. The identification of fall run with unprecedented accuracy was demonstrated. Overall, the top performing panel and baseline (HMSC21) were predicted to have a success rate of 98%, but the blind-test success rate was 84%. Findings for bias or non-bias are discussed to target primary areas for further research and resolution. PMID- 24628285 TI - C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. AB - RATIONALE: C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. OBJECTIVES: To determine if CXCL13 is associated with IPF progression. METHODS: CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA. MEASUREMENTS AND MAIN RESULTS: CXCL13 mRNA was threefold and eightfold greater in IPF lungs (n = 92) compared with chronic obstructive pulmonary disease (COPD) (n = 191) and normal (n = 108) specimens, respectively (P < 0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 patients with IPF (94 +/- 8) than in 128 subjects with COPD (53 +/- 9) and 57 normal subjects (35 +/- 3) (P < 0.0001). Circulating CXCL13 levels were highest in patients with IPF with pulmonary artery hypertension (P = 0.01) or acute exacerbations (P = 0.002). Six-month survival of patients with IPF in the highest quartile of plasma CXCL13 was 65 +/- 10% versus 93 +/- 10% in the others (hazard ratio, 5.5; 95% confidence interval, 1.8-16.9; P = 0.0008). CXCL13 increases by more than 50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (hazard ratio, 7.2; 95% confidence interval, 1.3-40.0; P = 0.008). In contrast, CXCL13 clinical associations in subjects with COPD were limited to modest correlations with FEV1 (P = 0.05) and progression of radiographic emphysema (P = 0.05). CONCLUSIONS: CXCL13 is increased and is a prognostic biomarker in patients with IPF, and more so than in patients with COPD. This contrast indicates CXCL13 overexpressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B cells in IPF pathogenesis, and support considerations for trials of specific B cell-targeted therapies in patients with this intractable disease. PMID- 24628287 TI - Lanthionine synthetase component C-like protein 2: a new drug target for inflammatory diseases and diabetes. AB - Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the LANCL protein family, which is broadly expressed throughout the body. LANCL2 is the molecular target of abscisic acid (ABA), a compound with insulin-sensitizing and immune modulatory actions. LANCL2 is required for membrane binding and signaling of ABA in immune cells. Direct binding of ABA to LANCL2 was predicted in silico using molecular modeling approaches and validated experimentally using ligand-binding assays and kinetic surface plasmon resonance studies. The therapeutic potential of the LANCL2 pathway ranges from increasing cellular sensitivity to anticancer drugs, insulin-sensitizing effects and modulating immune and inflammatory responses in the context of immune-mediated and infectious diseases. A case for LANCL2-based drug discovery and development is also illustrated by the anti-inflammatory activity of novel LANCL2 ligands such as NSC61610 against inflammatory bowel disease and influenza-driven inflammation in mice. This review discusses the value of LANCL2 as a novel therapeutic target for the discovery and development of new classes of orally active drugs against chronic metabolic, immune-mediated and infectious diseases. PMID- 24628288 TI - Effectiveness of cigarette warning labels: examining the impact of graphics, message framing, and temporal framing. AB - This study examines the effectiveness of cigarette warning labels, with a specific focus on the impact of graphics, message framing (gain vs. loss), and temporal framing (present-oriented vs. future-oriented) among nonsmokers in the United States. A controlled experiment (N = 253) revealed that graphic warning labels were perceived as more effective, stronger in argument strength, and were generally liked more compared to text-only labels. In addition, loss-framed labels, compared to their gain-framed counterparts, were rated higher in perceived effectiveness, argument strength, and liking. No significant difference was observed between the present- and future-oriented frames on any of the dependent variables. Implications of the findings for antismoking communication efforts are discussed. PMID- 24628289 TI - Sifting through the sands of time: mourning and melancholia revisited via the documentary Nostalgia for the Light (2011). PMID- 24628291 TI - Under-recognition of acral peeling skin syndrome: 59 new cases with 15 novel mutations. AB - BACKGROUND: Acral peeling skin syndrome (APSS) is a rare skin fragility disorder usually caused by mutations in the transglutaminase 5 gene (TGM5). METHODS: We investigated the mutation spectrum of APSS in the U.K., Germany and Poland. RESULTS: We identified 59 children with APSS from 52 families. The phenotype was readily recognizable, with some variation in severity both within and between families. Most cases had been misdiagnosed as the localized form of epidermolysis bullosa simplex (EBS-loc). Eighteen different TGM5 mutations were identified, 15 of which were novel. Eight mutations were unique to a single family, nine each occurred in two families, while the common p.Gly113Cys mutation linked to a second missense variant p.Thr109Met occurred in 47 of the 52 families and was homozygous in 28. Most patients were of nonconsanguineous white European origin. CONCLUSIONS: We propose that APSS is under-reported and widely misdiagnosed as EBS-loc, with significant counselling implications as APSS is autosomal recessive while EBS-loc is dominant. We recommend screening for TGM5 mutations when EBS-loc is suspected but not confirmed by mutations in KRT5 or KRT14. Our report trebles the number of known TGM5 mutations. It provides further evidence that p.Gly113Cys is a founder mutation in the European population. This is consistent with the striking ethnic distribution of APSS in U.K., where the majority of patients are of nonconsanguineous white European origin, in contrast to the pattern of other recessive skin disorders. PMID- 24628290 TI - Positron emission tomography for measurement of copper fluxes in live organisms. AB - Copper is an essential nutrient for the physiology of live organisms, but excessive copper can be harmful. Copper radioisotopes are used for measurement of copper fluxes in live organisms using a radioactivity assay of body fluids or whole-body positron emission tomography (PET). Hybrid positron emission tomography-computed tomography (PET/CT) is a versatile tool for real-time measurement of copper fluxes combining the high sensitivity and quantification capability of PET and the superior spatial resolution of CT for anatomic localization of radioactive tracer activity. Kinetic analysis of copper metabolism in the liver and extrahepatic tissues of Atp7b(-/-) knockout mice, a mouse model of Wilson's disease, demonstrated the feasibility of measuring copper fluxes in live organisms with PET/CT using copper-64 chloride ((64) CuCl2 ) as a radioactive tracer ((64) CuCl2 -PET/CT). (64) CuCl2 -PET/CT holds potential as a useful tool for the diagnosis of inherited and acquired human copper metabolism disorders and for monitoring the effects of copper-modulating therapy. PMID- 24628292 TI - A Novel Investigation of the Formation of Titanium Oxide Nanotubes on Thermally Formed Oxide of Ti-6Al-4V. AB - Traditionally, titanium oxide (TiO2) nanotubes (TNTs) are anodized on Ti-6Al-4V alloy (Ti-V) surfaces with native TiO2 (amorphous TiO2); subsequent heat treatment of anodized surfaces has been observed to enhance cellular response. As is bulk Ti-V, however, is often subjected to heat treatment, such as thermal oxidation (TO), to improve its mechanical properties. Thermal oxidation treatment of Ti-V at temperatures greater than 200 degrees C and 400 degrees C initiates the formation of anatase and rutile TiO2, respectively, which can affect TNT formation. This study aims at understanding the TNT formation mechanism on Ti-V surfaces with TO-formed TiO2 compared with that on as-is Ti-V surfaces with native oxide. Thermal oxidation-formed TiO2 can affect TNT formation and surface wettability because TO-formed TiO2 is expected to be part of the TNT structure. Surface characterization was carried out with field emission scanning electron microscopy, energy dispersive x-ray spectroscopy, water contact angle measurements, and white light interferometry. The TNTs were formed on control and 300 degrees C and 600 degrees C TO-treated Ti-V samples, and significant differences in TNT lengths and surface morphology were observed. No difference in elemental composition was found. Thermal oxidation and TO/anodization treatments produced hydrophilic surfaces, while hydrophobic behavior was observed over time (aging) for all samples. Reduced hydrophobic behavior was observed for TO/anodized samples when compared with control, control/anodized, and TO-treated samples. A method for improved surface wettability and TNT morphology is therefore discussed for possible applications in effective osseointegration of dental and orthopedic implants. PMID- 24628293 TI - The effect of calcium channel blockers on the outcome of acute myeloid leukemia. AB - The effect of calcium channel blockers (CCBs), beta blockers and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) on the prognosis of patients with acute myeloid leukemia (AML) is largely unknown. We collected data on the use of these medications in 1043 patients with AML, excluding promyelocytic leukemia, diagnosed and treated at M. D. Anderson Cancer Center between 2000 and 2012. Treatment with either amlodipine or diltiazem predicted a worse overall survival (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.22-2.06, p < 0.0001). There was no difference in survival depending on whether patients were taking beta blockers, ACE inhibitors or ARBs. The effect of CCBs on survival was independent from the National Comprehensive Cancer Network risk classification, age, performance status, response to treatment, year of diagnosis and CD34 levels, assessed by flow cytometry (HR 1.39, 95% CI 1.05-1.80, p = 0.02). Treatment with either amlodipine or diltiazem predicts worse survival in patients with AML independent of known prognostic factors. PMID- 24628294 TI - Treatment of high-risk aggressive B-cell non-Hodgkin lymphomas with rituximab, intensive induction and high-dose consolidation: long-term analysis of the R MegaCHOP-ESHAP-BEAM Trial. AB - We have studied the feasibility and efficacy of intensified R-MegaCHOP-ESHAP-BEAM therapy in high-risk aggressive B-cell lymphomas. Altogether 105 patients (19-64 years) with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL) or follicular lymphoma grade 3 (FL3) with an age-adjusted International Prognostic Index of 2-3 were recruited. Treatment consisted of three cycles of high-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), followed by three cycles of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) and high-dose consolidation with BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem cell transplant. The 5-year progression-free survival (PFS) was 72% (DLBCL 60%, PMBL 89%) and overall survival (OS) was 74% (DLBCL 61%, PMBL 89%) after a median follow-up of 85 months. However, an independent prognostic factor was age only, with patients <= 45 years having 5-year PFS 90% and patients > 45 years having PFS 54%. PMBL had better prognosis than DLBCL/FL3 in patients > 45 years (PFS, 88% vs. 48%), but not in younger patients (PFS, 91% vs. 94%). PMID- 24628295 TI - Prospective single-center study of chronic myeloid leukemia in chronic phase: switching from branded imatinib to a copy drug and back. AB - Imatinib (Glivec((r))/Gleevec((r))) has shown long-term efficacy and safety in randomized trials. No large-scale studies have prospectively assessed the benefit risk profile of an imatinib copy drug. We prospectively evaluated the response of patients with chronic myeloid leukemia in chronic phase in one institution. Patients with a complete hematologic response (n = 126) switched from branded imatinib to an imatinib copy drug. Subsequently, all patients switched back to the branded imatinib. Many patients in this study had a loss of hematologic response and tolerability issues with the imatinib copy drug. Hematologic response and tolerability improved upon retreatment with branded Glivec. PMID- 24628297 TI - A 5-day outpatient regimen of azacitidine is effective and well tolerated in patients with acute myeloid leukemia unsuitable for intensive chemotherapy. PMID- 24628296 TI - A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies. PMID- 24628298 TI - Comparative proteomic analysis of histone post-translational modifications upon ischemia/reperfusion-induced retinal injury. AB - We present a detailed quantitative map of single and coexisting histone post translational modifications (PTMs) in rat retinas affected by ischemia and reperfusion (I/R) injury. Retinal I/R injury contributes to serious ocular diseases, which can lead to vision loss and blindness. We applied linear ion trap orbitrap hybrid tandem mass spectrometry (MS/MS) to quantify 131 single histone marks and 143 combinations of multiple histone marks in noninjured and injured retinas. We observed 34 histone PTMs that exhibited significantly (p < 0.05) different abundance between healthy and I/R injured eyes, of which we confirmed three H4 histone marks by Western blotting. H4K20me2 was up to 4-fold change up regulated after the injury and is associated with the response to DNA damage as demonstrated by an increase in the phosphorylation of p53 and Chk1. This study demonstrates that quantitative MS provides a sensitive and accurate way to dissect the changes in the histone code after retinal injury. Specifically, DNA damage associated histone PTMs may contribute to neurovascular degeneration during the process of ischemia/reperfusion injury. PMID- 24628299 TI - Does suicide cause suicide headache? PMID- 24628300 TI - KIT and melanoma predisposition in pigs: sequence variants and association analysis. AB - KIT mutations have been detected in different cancer subtypes, including melanoma. The gene also has been extensively studied in farm animals for its prominent role in coat color. The present work aimed at detecting KIT variants in a porcine model of cutaneous melanoma, the melanoblastoma-bearing Libechov Minipig (MeLiM). By sequencing exons and intron borders, 36 SNPs and one indel were identified. Of 10 coding SNPs, three were non-synonymous mutations, likely to affect the protein conformation. A promising variant, located in exon 19 (p.Val870Ala), was genotyped in a MeLiM * Duroc cross, and an association analysis was conducted on several melanoma-related traits. This variant showed a significant association with melanoma development, tumor ulceration and cutaneous invasion. In conclusion, although the KIT gene would not be a major causal gene for melanoma development in pig, its genetic variation could be influencing this trait. PMID- 24628301 TI - Less is more: long-term in vitro exposure to low levels of silver nanoparticles provides new insights for nanomaterial evaluation. AB - In view of the vast number of new nanomaterials (NMs) that require testing and the constraints associated with animal models, the majority of studies to elucidate nanotoxicological effects have occurred in vitro, with limited correlation and applicability to in vivo systems and realistic, occupational exposure scenarios. In this study, we developed and implemented a chronic in vitro model coupled with lower, regulatory dosages in order to provide a more realistic assessment of NM-dependent consequences and illuminate the implications of long-term NM exposure. When keratinocytes were exposed to 50 nm silver nanoparticles (Ag-NPs), we determined that chronically dosed cells operated under augmented stress and modified functionality in comparison to their acute counterparts. Specifically, Ag-NP exposure through a chronic mechanism increased p38 activation, actin disorganization, heightened ki67 expression, and extensive gene modification. Additionally, chronic Ag-NP exposure altered the way in which cells perceived and responded to epidermal growth factor stimulation, indicating a transformation of cell functionality. Most importantly, this study demonstrated that chronic exposure in the pg/mL range to Ag-NPs did not induce a cytotoxic response, but instead activated sustained stress and signaling responses, suggesting that cells are able to cope with prolonged, low levels of Ag-NP exposure. In summary, we demonstrated that through implementation of a chronic dosimetry paradigm, which more closely resembles realistic NM exposure scenarios, it is possible to illuminate long-term cellular consequences, which greatly differ from previously obtained acute assessments. PMID- 24628302 TI - A case of Mycobacterium abscessus infection presenting as a cystic lesion in an insulin injection site in a diabetic patient. PMID- 24628303 TI - Lansoprazole enhances the antidiabetic effect of sitagliptin in mice with diet induced obesity and healthy human subjects. AB - OBJECTIVES: Proton pump inhibitors as adjunctive therapy would improve diabetes control and could enhance the hypoglycaemic activity of DPP-4 inhibitors. The aim of the study was to investigate the short-term effects of lansoprazole (LPZ), sitagliptin (SITA) and their combination therapy on glucose regulation and gut peptide secretion. METHODS: Glucose and gut peptide were determined and compared after short-term administration of LPZ or SITA, or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects (n = 16) in a 75 g oral glucose tolerance test (OGTT) by a crossover design. KEY FINDINGS: In DIO mice, LPZ significantly improve glucose metabolism, increase plasma C-peptide and insulin compared with vehicle treatment. Furthermore, the combination of LPZ and SITA improved glucose tolerance additively, with higher plasma insulin and C peptide levels compared with SITA-treated mice. Similarly, in human in the OGTT, the combination showed significant improvement in glucose-lowering and insulin increase vs SITA-treated group. However, no significant differences in area under curve (AUC) of insulin, glucose and C-peptide between the LPZ-treated group and baseline, except that mean AUCgastrin was significantly increased by LPZ. CONCLUSIONS: LPZ and SITA combination therapy appears to have complementary mechanisms of action and additive antidiabetic effect. PMID- 24628304 TI - Dynamic, nonsink method for the simultaneous determination of drug permeability and binding coefficients in liposomes. AB - Drug release from liposomal formulations is governed by a complex interplay of kinetic (i.e., drug permeability) and thermodynamic factors (i.e., drug partitioning to the bilayer surface). Release studies under sink conditions that attempt to mimic physiological conditions are insufficient to decipher these separate contributions. The present study explores release studies performed under nonsink conditions coupled with appropriate mathematical models to describe both the release kinetics and the conditions in which equilibrium is established. Liposomal release profiles for a model anticancer agent, topotecan, under nonsink conditions provided values for both the first-order rate constant for drug release and the bilayer/water partition coefficient. These findings were validated by conducting release studies under sink conditions via dynamic dialysis at the same temperature and buffer pH. A nearly identical rate constant for drug release could be obtained from dynamic dialysis data when appropriate volume corrections were applied and a mechanism-based mathematical model was employed to account for lipid bilayer binding and dialysis membrane transport. The usefulness of the nonsink method combined with mathematical modeling was further explored by demonstrating the effects of topotecan dimerization and bilayer surface charge potential on the bilayer/water partition coefficient at varying suspension concentrations of lipid and drug. PMID- 24628306 TI - Development of an SI-Traceable HPLC-Isotope Dilution Mass Spectrometry Method To Quantify beta-Lactoglobulin in Milk Powders. AB - beta-Lactoglobulin (beta-LG) is one of the major allergenic proteins in milk. There is an urgent demand for an accurate and traceable method to develop beta-LG certified reference material (CRM). In this work, beta-LG was enzymatically digested and a specific peptide was chosen for quantitation by isotope-dilution mass spectrometry (IDMS). With amino acid CRMs as standards, the results could be traced to SI unit. By the proposed method, the recovery ranged from 86.0% to 118.3% with CVs <9.0%. The LOD and LOQ were 4.8 * 10-5 g/g and 1.6 * 10-4 g/g of beta-LG in milk powder, respectively. Ten samples from domestic market were analyzed with CVs <5.6%, and the relative expanded uncertainties ranged from 4.2% to 5.9% (k = 2). With the CRMs, it is expected that the comparability of beta-LG quantitation results will be improved among different laboratories. PMID- 24628305 TI - Structure of Class B GPCRs: new horizons for drug discovery. AB - Class B GPCRs of the secretin family are important drug targets in many human diseases including diabetes, neurodegeneration, cardiovascular disease and psychiatric disorders. X-ray crystal structures for the glucagon receptor and corticotropin-releasing factor receptor 1 have now been published. In this review, we analyse the new structures and how they compare with each other and with Class A and F receptors. We also consider the differences in druggability and possible similarity in the activation mechanisms. Finally, we discuss the potential for the design of small-molecule modulators for these important targets in drug discovery. This new structural insight allows, for the first time, structure-based drug design methods to be applied to Class B GPCRs. PMID- 24628307 TI - Severe asthma: pragmatic clinical lumping and time for investigational splitting. PMID- 24628308 TI - Magnetic resonance imaging of inflammation in subjects with allergic asthma. PMID- 24628309 TI - Of delirium and sedation. PMID- 24628310 TI - beta2-agonists and acute respiratory distress syndrome. PMID- 24628311 TI - The lymphatic system in malignant pleural effusion. Drain or immune switch? PMID- 24628313 TI - Consequences of a thoracoabdominal aortic graft infection. PMID- 24628312 TI - An official American Thoracic Society clinical practice guideline: diagnosis, risk stratification, and management of pulmonary hypertension of sickle cell disease. AB - BACKGROUND: In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. METHODS: A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians who take care of patients with SCD. RESULTS: Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy. CONCLUSIONS: Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating. PMID- 24628315 TI - Cystic fibrosis and bone disease: defective osteoblast maturation with the F508del mutation in cystic fibrosis transmembrane conductance regulator. PMID- 24628314 TI - Redox imaging of inflammation in asthma. PMID- 24628316 TI - Increased cellular activity in thoracic lymph nodes in early human latent tuberculosis infection. PMID- 24628317 TI - Novel mutation in ABCA3 resulting in fatal congenital surfactant deficiency in two siblings. PMID- 24628318 TI - Perspective on coccidioidomycosis and histoplasmosis. PMID- 24628319 TI - Is telomeropathy the explanation for combined pulmonary fibrosis and emphysema syndrome?: report of a family with TERT mutation. PMID- 24628320 TI - Reply: telomerase makes connections between pulmonary fibrosis and emphysema. PMID- 24628321 TI - Cognitive decline in patients with pneumonia: a role for IL-2? PMID- 24628322 TI - Isolation of drug-resistant pathogens does not always require use of broad spectrum antibiotics in pneumonia. PMID- 24628323 TI - Reply: isolation of drug-resistant pathogens does not always require use of broad spectrum antibiotics in pneumonia. PMID- 24628324 TI - Pulmonary artery dissection and rupture in a patient with idiopathic pulmonary artery hypertension. PMID- 24628325 TI - Exacerbation of COPD. PMID- 24628326 TI - Preoperative Cylex assay predicts rejection risk in patients with kidney transplant. AB - INTRODUCTION AND OBJECTIVES: The ImmuKnow assay measures cell-mediated immunity by quantifying ATP release from CD4+ T-cells in peripheral blood. Herein, we hypothesized that this assay could predict complications associated with over /under-immunosuppression in patients with kidney transplant (KT). METHODS: Sixty seven patients undergoing KT were recruited prospectively and had ATP levels measured preoperatively, and at specified intervals over two months. Clinicians were blinded to ATP levels. Clinical events including rejection and infection/cancer were documented with a median follow-up of 21 months. Parameters including absolute ATP levels and changes in ATP patterns (slopes, delta) were analyzed. Association between ATP parameters and clinical outcomes was compared using the likelihood-ratio test and Kaplan-Meier curves. RESULTS: Absolute ATP values postoperatively had poor predictive value with regard to rejection or infection/malignancy. As well, changes in ATP values were poorly associated with complications. Importantly, patients with pre-transplant ATP values <300 ng/mL had significantly less rejection episodes vs. those with ATP values >300 ng/mL (p < 0.0001). CONCLUSIONS: For the first time, we have evidence that a preoperative ImmuKnow level can stratify patients with KT into low/high risk groups for rejection. Future studies used to assess the utility of this assay to design individualized immunosuppressive regimens are required. PMID- 24628327 TI - Relativistic small-core pseudopotentials for actinium, thorium, and protactinium. AB - Small-core pseudopotentials for actinium, thorium, and protactinium have been energy-adjusted to multiconfiguration Dirac-Hartree-Fock reference data based on the Dirac-Coulomb-Breit Hamiltonian and the Fermi nucleus model. Corresponding optimized valence basis sets of polarized valence quadruple-zeta quality are presented. Atomic test calculations for the first four ionization potentials show satisfactory results at both the Hartree-Fock and the multireference averaged coupled-pair functional level. Highly correlated Fock-space coupled cluster calculations demonstrate that the new pseudopotentials yield ionization potentials, which are in excellent agreement with corresponding all-electron results and experimental data. The pseudopotentials and basis sets supplement a similar set previously published for uranium. PMID- 24628329 TI - Epithelial-mesenchymal transition during invasion of cutaneous squamous cell carcinoma is paralleled by AKT activation. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is required for tumour invasion and dissemination to occur. OBJECTIVES: To investigate EMT during invasion of cutaneous squamous cell carcinoma (cSCC) and the involvement of AKT. METHODS: Using a tissue microarray, we measured expression of EMT-markers and AKT activation in 140 samples from patients with skin cancer and matched samples of normal skin adjacent to cSCC in cSCC in situ (cSCCIS) and in invasive cSCC. We investigated EMT using functional assays and the expression of EMT markers in an isogenic skin cancer progression model using cell lines derived from dysplastic forehead skin (PM1), primary invasive cSCC (MET1) and its lymph node metastasis (MET4). This model was used to investigate AKT-specific inhibition of the EMT process. RESULTS: In comparison with normal skin, and normal skin plus cSCCIS, the invasive cSCCs show significantly increased vimentin expression, decreased E cadherin expression and increased expression of the active form of AKT. In the cell culture model, the primary MET1 cells display the lowest adhesion potential, the highest migratory and invasive ability through a Matrigel-coated porous membrane, the highest expression of EMT markers vimentin and Slug and the lowest expression of the epithelial marker E-cadherin. Pharmacological AKT inhibition in this model suppressed EMT mechanisms. CONCLUSIONS: AKT may serve as a therapeutic target to avoid dissemination of cSCC cells. PMID- 24628330 TI - David Barker (1938-2013)--a giant in reproductive epidemiology. PMID- 24628328 TI - The dynamic lives of macrophage and dendritic cell subsets in atherosclerosis. AB - Atherosclerosis, the major pathological process through which arterial plaques are formed, is a dynamic chronic inflammatory disease of large- and medium-sized arteries in which the vasculature, lipid metabolism, and the immune system all play integral roles. Both the innate and adaptive immune systems are involved in the development and progression of atherosclerosis but myeloid cells represent the major component of the burgeoning atherosclerotic plaque. Various myeloid cells, including monocytes, macrophages (MPhis), and dendritic cells (DCs) can be found within the healthy and atherosclerotic arterial wall, where they can contribute to or regulate inflammation. However, the precise behaviors and functions of these cells in situ are still active areas of investigation that continue to yield exciting and surprising new data. Here, we review recent progress in understanding of the complex biology of MPhis and DCs, focusing particularly on the dynamic regulation of these subsets in the arterial wall and novel, emerging functions of these cells during atherogenesis. PMID- 24628331 TI - Abundance-ratio-based semiquantitative analysis of site-specific N-linked glycopeptides present in the plasma of hepatocellular carcinoma patients. AB - Aberrant structures of site-specific N-linked glycans are closely associated with the tumorigenesis of hepatocellular carcinoma (HCC), one of the most common fatal cancers worldwide. Vitronectin (VTN) is considered a candidate glycobiomarker of HCC. In this study, we describe a reliable and simple quantification strategy based on abundance ratios of site-specific N-linked glycopeptides of VTN to screen for potential biomarkers. A total of 14 unique N-linked glycans corresponding to 27 unique N-linked glycopeptides were characterized at three N linked sites (Asn-86, -169, and -242) present in VTN. These glycans could be good candidate markers for HCC. Among these glycans, the abundance ratio of two representative glycoforms (fucosyl vs non-fucosyl) was significantly increased in HCC plasma relative to normal plasma. This strategy was also successfully applied to another potential HCC biomarker, haptoglobin. Furthermore, we demonstrate that our approach employing tandem mass tag (TMT) and target N-linked glycopeptides of VTN is a useful tool for quantifying specific glycans in HCC plasma relative to normal plasma. Our strategy represents a simple and potentially useful screening platform for the discovery of cancer-specific glycobiomarkers. PMID- 24628332 TI - Acute headache originating from a bleeding convexity meningioma. PMID- 24628333 TI - Audiovestibular findings in patients with Vogt-Koyanagi-Harada disease. AB - CONCLUSION: The long-term follow-up study revealed a good audiovestibular prognosis in our patients with Vogt-Koyanagi-Harada disease (VKH) after adequate treatment. OBJECTIVES: To evaluate the audiovestibular findings and long-term prognosis of patients with VKH. METHODS: A total of 82 ears in 41 patients (9 males and 32 females, aged 18-78 years) with VKH were examined in the audiovestibular study. Of the 41 patients, 16 patients with follow-up periods of more than 12 months (13-158 months) were included in the long-term follow-up study. Audiovestibular examinations included pure-tone audiometry; positional, positioning, and spontaneous nystagmus tests; and a caloric test. RESULTS: Among the 41 patients, 28 (68%) complained of auditory symptoms at the initial visit and 28 (68%) showed sensorineural hearing loss (SNHL). Of the 24 patients who underwent nystagmus tests, only 3 (13%) presented with vestibular symptoms whereas 11 (46%) had nystagmus. Among 32 ears in 16 patients enrolled in the long term follow-up study, 19 ears showed SNHL at the initial visit. The SNHL returned to normal in 14 ears (74%) and remained minimal in severity in the other 5 ears (26%) at the last visit. None of the patients showed persistent or repetitive vestibular symptoms. PMID- 24628334 TI - Magnetically driven middle ear ossicles with laser vibrometry as a new diagnostic tool to quantify ossicular fixation. AB - CONCLUSION: Information on the degree of incus fixation can be gathered by measuring the ratio of incus to umbo long process velocity through the ear canal. OBJECTIVES: To test a new method of quantifying partial ossicular fixation in an ear with an elevated tympanic membrane. METHODS: Measurements were made on four fresh-frozen human temporal bones. After elevating the tympanic membrane a small magnet was attached to the manubrium and an electromagnetic excitation coil was used to vibrate the ossicles. The vibration response of the tip of the incus long process and the umbo were measured before and after artificially fixating the incus to the lateral attic wall. RESULTS: Partial incus fixation resulted in a decrease in both the incus and umbo velocities, with the incus velocity being more severely reduced. The decreased ratio of their vibrations is a clear indicator of the degree of incus fixation. PMID- 24628335 TI - Effect of omalizumab on biomarkers in middle ear effusion in patients with eosinophilic otitis media. AB - CONCLUSIONS: Eosinophil cationic protein (ECP) concentrations in middle ear effusion (MEE) in patients with eosinophilic otitis media (EOM) were significantly decreased at 3 months after the administration of omalizumab from the baseline level (p < 0.05). This study provides new evidence that omalizumab reduces eosinophilic inflammation in the middle ear and that the reduction of ECP may not be caused by suppression of interleukin (IL)-5 production in the middle ear mucosa. OBJECTIVE: EOM is an intractable otitis media characterized by a highly viscous effusion containing eosinophils. We recently reported that anti IgE therapy using omalizumab was efficacious in the treatment of EOM. To clarify the underlying mechanism, we determined changes in biomarkers in MEE related to eosinophilic inflammation after therapy. METHODS: Nine patients with EOM received the anti-IgE agent omalizumab for 3 months. Among them, five patients continued anti-IgE therapy for longer than 1 year. Eight EOM patients without administration of omalizumab were also included in the study as controls. The concentrations of eosinophilic inflammatory markers such as ECP, IgE, IL-4, and IL-5 in MEE were measured before and after the administration of omalizumab. RESULTS: After 3 months of omalizumab therapy, the ECP concentration in MEE was significantly reduced from the baseline level (p < 0.05), while no significant change of ECP in the serum was observed. The concentrations of IL-4 and IL-5 in MEE showed no significant change before and after the therapy in EOM patients treated with omalizumab. PMID- 24628336 TI - High-risk human papillomavirus and lymph node size in patients with single node metastasis of oral and oropharyngeal cancer. AB - CONCLUSION: High-risk human papillomavirus (HPV) infection was significantly related to lymph node size in patients with single node metastasis of oral and oropharyngeal cancer. OBJECTIVE: The purpose of this study was to examine the relationship between high-risk HPV infection and lymph node size in patients with single node metastasis of oral and oropharyngeal carcinoma. METHODS: This study included 48 patients with oral and oropharyngeal carcinoma. Pathologic lymph node stages comprised 36 N1 and 12 N2a. RESULTS: High-risk HPV in situ hybridization was positive in 29% of patients (14/48). Of those patients with high-risk HPV, there was a significant difference (p = 0.008) between oral (9.5%) and oropharyngeal (44.4%) cancers. Average lymph node diameter was 20.7 +/- 12.6 mm (range 5-54 mm). We found a positive correlation between high-risk HPV status and lymph node size (p = 0.018). Mean lymph node diameter in high-risk HPV-positive cases was 27.3 +/- 13.1 mm and 18.0 +/- 11.5 mm in high-risk HPV-negative cases. Extracapsular spread (p = 0.030) and cystic nodal metastases (p = 0.019) were also significantly related to lymph node size. High-risk HPV negative status (p = 0.043), advanced tumor stage (p = 0.009), and extracapsular spread (p = 0.038) all had significant adverse effects on 5-year disease-specific survival. PMID- 24628337 TI - Clinicobiological progression and prognosis of oral squamous cell carcinoma in relation to the tumor invasive front: impact on prognosis. AB - CONCLUSION: There are several factors that influence the final outcome when treating oral squamous cell carcinoma (OSCC). Invasive front phenomena and more importantly their clinicopathological translation can have a direct impact on survival, and subsequently on the decision for an adjuvant treatment. OBJECTIVES: In recent years, the concept of tumor-host interaction has been the subject of substantial efforts in cancer research. Tumoral behavior may be better understood when studying the changes occurring at the tumor-host interface. This study evaluated the influence of several clinicopathological features on the outcome of OSCCs. METHODS: The clinical records and pathology specimens of 54 patients with OSCC treated by primary resection were reviewed retrospectively. The pathologic features reviewed were: invasive front grading (IFG), stromal reaction, lymphovascular invasion (LVI), perineural invasion (PNI), margin status, and depth of invasion. RESULTS: High IFGs had a significant relationship with pT status and pN status. High IFGs were strongly correlated with nodal metastases (odds ratio (OR) = 4.77; confidence interaval (CI) = 1.37-16.64). Concerning survival, IFG had a strong impact on disease-free survival in patients treated unimodally, as did the depth of invasion in the same group. Lymphovascular involvement was found to have a negative impact on overall survival in patients treated multimodally. PMID- 24628338 TI - Nuclear magnetic resonance structure of the cytoplasmic tail of heparin binding EGF-like growth factor (proHB-EGF-CT) complexed with the ubiquitin homology domain of Bcl-2-associated athanogene 1 from Mus musculus (mBAG-1-UBH). AB - The membrane form of heparin binding EGF-like growth factor (proHB-EGF) yields secreted HB-EGF and a membrane-anchored cytoplasmic tail (proHB-EGF-CT), which may be targeted to the nuclear membrane after a shedding stimulus. Bcl-2 associated athanogene 1 (BAG-1) accumulates in the nuclei and inhibits apoptosis in adenoma-derived cell lines. The maintenance of high levels of nuclear BAG-1 enhances cell survival. However, the ubiquitin homology domain of BAG-1 from Mus musculus (mBAG-1-UBH) is proposed to interact with proHB-EGF-CT, and this interaction may enhance the cytoprotection against the apoptosis inducer. The mechanism of the synergistic anti-apoptosis function of proHB-EGF-CT and mBAG-1 UBH is still unknown. We offer a hypothesis that proHB-EGF-CT can maintain high levels of nuclear BAG-1. In this study, we first report the three-dimensional nuclear magnetic resonance structure of proHB-EGF-CT complexed with mBAG-1-UBH. In the structure of the complex, the residues in the C-terminus and one turn between beta-strands beta1 and beta2 of mBAG-1-UBH bind to two terminals of proHB EGF-CT, which folds into a loop with end-to-end contact. This end-to-end folding of proHB-EGF-CT causes the basic amino acids to colocalize and form a positively charged groove. The dominant forces in the binding interface between proHB-EGF-CT and mBAG-1-UBH are charge-charge interactions. On the basis of our mutagenesis results, the basic amino acid cluster in the N-terminus of proHB-EGF-CT is the crucial binding site for mBAG-1-UBH, whereas another basic amino acid in the C terminus facilitates this interaction. Interestingly, the mBAG-1-UBH binding region on the proHB-EGF-CT peptide is also involved in the region found to be important for nuclear envelope targeting, supporting the hypothesis that proHB EGF-CT is most likely able to trigger the nuclear translocation of BAG-1 in keeping its level high. PMID- 24628343 TI - Novel Y-chromosome polymorphisms in Chinese domestic yak. AB - Y-chromosome-specific haplotypes (Y-haplotypes) constructed using single nucleotide polymorphisms (Y-SNPs) in the MSY (male-specific region of the Y chromosome) are valuable in population genetic studies. But sequence variants in the yak MSY region have been poorly characterized so far. In this study, we screened a total of 16 Y-chromosome-specific gene segments from the ZFY, SRY, UTY, USP9Y, AMELY and OFD1Y genes to identify Y-SNPs in domestic yaks. Six novel Y-SNPs distributed in the USP9Y (g.223C>T), UTY19 (g.158A>C and g.169C>T), AMELY2 (g.261C>T), OFD1Y9 (g.165A>G) and SRY4 (g.104G>A) loci, which can define three Y haplotypes (YH1, YH2 and YH3) in yaks, were discovered. YH1 was the dominant and presumably most ancient haplotype based on the comparison of UTY19 locus with other bovid species. Interestingly, we found informative UTY19 markers (g.158A>C and g.169C>T) that can effectively distinguish the three yak Y-haplotypes. The nucleotide diversity was 1.7 * 10(-4) +/- 0.3 * 10(-4) , indicating rich Y chromosome diversity in yaks. We identified two highly divergent lineages (YH1 and YH2 vs. YH3) that share similar frequencies (YH1 + YH2: 0.82-0.89, YH3: 0.11 0.18) among all three populations. In agreement with previous mtDNA studies, we supported the hypothesis that the two highly divergent lineages (YH1 and YH2 vs. YH3) derived from a single gene pool, which can be explained by the reunion of at least two paternal populations with the divergent lineages already accumulated before domestication. We estimated a divergence time of 408 110 years between the two divergent lineages, which is consistent with the data from mitochondrial DNA in yaks. PMID- 24628344 TI - Contact and photocontact allergy to octocrylene: a review. AB - Octocrylene is an ultraviolet (UV)B and UVAII absorber that was introduced some 15 years ago, and is now widely used in sunscreen agents and skin care cosmetics. Since 2003, several studies, notably from France, Belgium, Spain, and Italy, have reported an increasing number of patients with photocontact allergy to octocrylene. This reaction is seen mainly in adult patients who have previously used topical products containing the non-steroidal anti-inflammatory drug ketoprofen. Photosensitization to ketoprofen leads, in many cases, to photocontact allergy to octocrylene; the mechanism of this reaction is unknown. Contact allergy to octocrylene also occurs, but is far less frequent, and is seen, in most cases, in children, resulting from the use of octocrylene containing sunscreen products. In this article, (photo)contact allergy to octocrylene is fully reviewed. PMID- 24628345 TI - p-Phenylenediamine and other allergens in hair dye products in the United States: a consumer exposure study. AB - BACKGROUND: Hair dye products constitute an important source of allergen exposure, and contribute importantly to allergic contact dermatitis in consumers and hairdressers. OBJECTIVES: To evaluate the presence of potent contact sensitizers in oxidative hair dye products intended for home use on the US market. METHODS: Ingredient labels of 107 hair dyes from 10 major brands were examined and used to assess the prevalence of hair dye substances known to be potent contact sensitizers. RESULTS: One hundred and six of 107 (99%) products contained at least one potent sensitizer, and the average product contained six (range 0-11). p-Phenylenediamine (PPD) was found in 83 products (78%), but resorcinol (89%), m-aminophenol (75%), p-aminophenol (60%) and toluene-2,5 diamine (21%) were also frequently identified. CONCLUSIONS: Potent contact sensitizers were almost universally included in the hair dyes investigated in the United States. Although PPD is a common allergen, resorcinol and m-aminophenol were found more frequently. In total, 30 potent sensitizers were found. Clinicians should consider other allergens in addition to PPD when evaluating patients with suspected hair dye allergy. PMID- 24628346 TI - The rise in prevalence of contact allergy to methylisothiazolinone in the British Isles. PMID- 24628347 TI - Can methylisothiazolinone be patch tested in petrolatum? PMID- 24628348 TI - Methylisothiazolinone: second 'epidemic' of isothiazolinone sensitization. PMID- 24628349 TI - Repeated open application test with methylisothiazolinone in individuals sensitive to methylchloroisothiazolinone/methylisothiazolinone. PMID- 24628350 TI - Further evidence of the methylisothiazolinone epidemic. PMID- 24628351 TI - Palpebral eczematous dermatitis caused by nickel in an eye pencil. PMID- 24628352 TI - Natural rubber gloves might not protect against skin penetration of methylisothiazolinone. PMID- 24628353 TI - Contact allergy to Tinosorb(r) M: recommendations for diagnostic improvement. PMID- 24628354 TI - Allergic contact eczema caused by exotic wood material in sauna interior decoration. PMID- 24628355 TI - Bullous allergic reaction caused by colophonium in medical adhesives. PMID- 24628356 TI - Hidden exposure to formaldehyde in a swab caused allergic contact dermatitis. PMID- 24628357 TI - Late-onset Brooke-Spiegler syndrome with family histories of various cancers. PMID- 24628358 TI - Temperature-dependent deliquescence relative humidities and water activities using humidity controlled thermogravimetric analysis with application to malonic acid. AB - We utilize a new experimental technique, humidity-controlled thermogravimetric analysis (HTGA), to determine temperature-dependent deliquescence relative humidities (DRH) and to determine the equilibrium concentration of a solution at a given temperature and relative humidity. To that end, we have investigated the malonic acid/water system determining the DRH and concentration/RH relationship in the temperature range 303-278 K. Excellent agreement is found with literature values for the DRH of malonic acid as a function of temperature and for the concentration/RH relationship at several temperatures. Thus, we extend the DRH and concentration/RH relationship to a broader temperature range and are using the HTGA experiments to investigate other organic acids. PMID- 24628359 TI - Ex vivo localization and permeation of cisplatin from novel topical formulations through excised pig, goat, and mice skin and in vitro characterization for effective management of skin-cited malignancies. AB - CONTEXT: It would be advantageous to administer cisplatin topically for treatment of cutaneous malignancies. OBJECTIVES: Present work focuses on ex vivo and in vitro characterization of proultraflexible topical formulations. MATERIALS AND METHODS: Permeation of cisplatin through the excised pig, goat, and mice skin was quantitatively determined. RESULTS: Data indicate that protransfersome carbopol gel (pcg) formulation clearly delayed drug permeation through skin. Permeation of cisplatin from protransfersome system (ps) formulation was enhanced by approximately 1.5 fold compared with pcg for pig and goat skin. DISCUSSION: Localization of drug from pcg was higher and showed less permeation. CONCLUSION: Cisplatin-loaded pcg formulation is better to treat cutaneous malignancies. PMID- 24628361 TI - A rapid method for differentiating four species of the Engraulidae (anchovy) family. AB - The four species of the Engraulidae family: European anchovy (Engraulis encrasicolus), Californian anchovy (Engraulis mordax), Peruvian anchoveta (Engraulis ringens), and Japanese anchovy (Engraulis japonicus) studied in this work are very similar morphologically, and it is very difficult to distinguish between them, especially when frozen or processed. We have used the 5S rDNA as a molecular marker to discriminate these four species and used specific primers designed for each species in the nontranscribed spacers (NTS) of these genes. Multiplex PCR was performed with three pairs of primers, and three different sizes were obtained: 597 bp E. encrasicolus, 598 bp E. japonicus, 380 bp E. mordax, and 250 bp E. ringens. For the species E. encrasicolus and E. japonicus, PCR-RFLP was used as an additional technique to distinguish between them because their NTS sequences showed considerable similarity. PMID- 24628360 TI - Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens. AB - BACKGROUND AND PURPOSE: Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via alpha4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline's effects on ethanol consumption. EXPERIMENTAL APPROACH: Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV). KEY RESULTS: Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. CONCLUSION AND IMPLICATIONS: Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline's effects on ethanol consumption. PMID- 24628362 TI - Evaluation of efficacy, pharmacokinetics and tolerability of peptidomimetic aspartic proteinase inhibitors as cream formulation in experimental vaginal candidiasis. AB - OBJECTIVES: It has been previously shown that the treatment with the two protease inhibitors APG12 and APG19 confers protection in a rat model of mucosal candidiasis; in this study, we examined whether these peptidomimetic inhibitors are also effective as a cream formulation in reducing Candida albicans vaginal infection. METHODS: These efficacy studies were performed in a rat model of estrogen-dependent rat vaginitis by C. albicans on both azole-susceptible and azole-resistant C. albicans, and on both caspofungin-susceptible and caspofungin resistant C. albicans strains. In vivo studies were also conducted in female albino rats and rabbits to obtain information about the safety, local tolerability and principal pharmacokinetics parameters of the two compounds. KEY FINDINGS AND CONCLUSIONS: Both hit compounds showed remarkable results within the 48-h range as effective inhibitors of the infection, particularly causing rapid decay of vaginal C. albicans burden. Importantly, the two compounds showed marked acceleration of fungus clearance in the rats challenged with the fluconazole resistant as well as with the capsofungin-resistant strain of C. albicans. Both compounds showed fast elimination rates when given by the intravenous route, and poor systemic absorption after intravaginal cream administration. Test drugs were also well tolerated in 7-day local tolerability experiments in the rabbit. PMID- 24628363 TI - Dietary patterns and gastric cancer risk in Mexico. AB - Multiple epidemiological studies have evaluated the relationship between diet and gastric cancer (GC), focusing on individual foods and nutrients. However, some studies have estimated the association between dietary patterns and GC risk. To identify the dietary patterns of residents of Mexico City and to assess the association of these patterns with GC, a population-based case-control study with 248 histologically confirmed GC cases and 478 controls paired by age and sex was carried out. The dietary patterns were characterized from 22 food groups through factorial analysis. Three major dietary patterns were identified. Pattern 1 was characterized by the consumption of vegetables, fruits, and white meat; subjects in the highest quintile of this pattern had a lower GC risk than those in the lowest quintile [odds ratio (OR(Q5 vs. Q1)) = 0.43; 95% confidence interval (95%CI): 0.24-0.77; P trend = 0.010]. A comparison between the extreme quintiles of the third pattern (which included major consumption of refined grains and desserts), resulted in the following: OR(Q5 vs. Q1) = 4.80; 95%CI: 2.56-8.98; P trend < 0.001). Additionally, we found no significant association between the second pattern (characterized by high consumption of Mexican food) and GC risk. This is the first study of associations between dietary patterns and GC in Mexico to confirm that GC risk is lower in individuals with healthy dietary patterns. PMID- 24628364 TI - Effects of alpha-lipoic acid supplementation on sexual difference of growth performance, heat exposure-induced metabolic response and lipid peroxidation of raw meat in broiler chickens. AB - 1. The effects of alpha-lipoic acid administration on sexual differences in growth performance, heat exposure-induced metabolic response and lipid peroxidation of raw meat in broiler chickens were studied. 2. Two-week-old male and female broiler chicks were divided into two groups each, as a 2 * 2 factorial arrangement. Half the birds were fed on a diet supplemented with alpha-lipoic acid (100 mg/kg) and half on a control diet. All groups were reared to 6 weeks of age at 25 degrees C and, thereafter, exposed to 33 degrees C for 8 h per day for 3 d. 3. Under thermo-neutral conditions, alpha-lipoic acid decreased feed consumption and body weight gain of male chickens. However, the feed conversion rate and tissue mass of breast muscle and abdominal fat were unchanged. 4. In plasma metabolites, alpha-lipoic acid increased the molar ratio of non-esterified fatty acids to free glycerol, regardless of sex and heat exposure. A decrease in beta-hydroxybutyrate was observed in the alpha-lipoic acid-fed male chickens. In the heat-exposed chickens, alpha-lipoic acid lowered the molar ratio of plasma lactate to pyruvate in relation to the enhanced concentrations of plasma pyruvate. However, no sexual difference was observed. 5. The value of thiobarbituric acid reactive substances in breast meat of heat-stressed chickens that was refrigerated for 3 or 7 d was higher in males than in females. An antioxidative effect of alpha-lipoic acid was observed in the meat of male chickens. 6. The present study suggests that the alpha-lipoic acid-inducing fatty acid metabolism and antioxidative effect persisted during the heat stress, even though a sexual difference in the responsiveness was seen in broiler chickens. PMID- 24628365 TI - Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults. AB - OBJECTIVE: Redox status and inflammation are important in the pathophysiology of numerous chronic diseases. Epidemiological studies have linked vitamin D status to a number of chronic diseases. We aimed to examine the relationships between serum 25-hydroxyvitamin D [25(OH)D] and circulating thiol/disulphide redox status and biomarkers of inflammation. DESIGN: This was a cross-sectional study of N = 693 adults (449 females, 244 males) in an apparently healthy, working cohort in Atlanta, GA. Plasma glutathione (GSH), cysteine (Cys) and their associated disulphides were determined with high-performance liquid chromatography, and their redox potentials (Eh GSSG and Eh CySS) were calculated using the Nernst equation. Serum inflammatory markers included interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha, assayed on a multiplex platform, and C reactive protein (CRP), assayed commercially. Relationships were assessed with multiple linear regression analyses. RESULTS: Serum 25(OH)D was positively associated with plasma GSH (beta +/- SE: 0.002 +/- 0.0004) and negatively associated with plasma Eh GSSG (beta +/- SE: -0.06 +/- 0.01) and Cys (beta +/- SE: -0.01 +/- 0.003) (P < 0.001 for all); statistical significance remained after adjusting for age, gender, race, percentage body fat and traditional cardiovascular risk factors (P = 0.01-0.02). The inverse relationship between serum 25(OH)D and CRP was confounded by percentage body fat, and full adjustment for covariates attenuated serum 25(OH)D relationships with other inflammatory markers to nonstatistical significance. CONCLUSIONS: Serum 25(OH)D concentrations were independently associated with major plasma thiol/disulphide redox systems, suggesting that vitamin D status may be involved in redox-mediated pathophysiology. PMID- 24628366 TI - Breaking the vicious circle of illegal logging in Indonesia. AB - The government of Indonesia, which presides over 10% of the world's tropical forests, has set ambitious targets to cut its high deforestation rates through an REDD+ scheme (Reducing Emissions from Deforestation and forest Degradation). This will require strong law enforcement to succeed. Yet, strategies that have accomplished this are rare and, along with past failures, tend not to be documented. We evaluated a multistakeholder approach that seeks to tackle illegal logging in the carbon-rich province of Aceh, Sumatra. From 2008 to 2009, Fauna & Flora International established and supported a community-based informant network for the 738,000 ha Ulu Masen ecosystem. The network reported 190 forest offenses to local law enforcement agencies, which responded with 86 field operations that confiscated illicit vehicles, equipment, and timber, and arrested 138 illegal logging suspects. From 45 cases subsequently monitored, 64.4% proceeded to court, from which 90.0% of defendants received a prison sentence or a verbal warning for a first offense. Spatial analyses of illegal logging and timber storage incidents predicted that illegal activities would be more effectively deterred by law enforcement operations that targeted the storage sites. Although numerous clusters of incidents were identified, they were still widespread reflecting the ubiquity of illegal activities. The multistakeholder results were promising, but illegal logging still persisted at apparently similar levels at the project's end, indicating that efforts need to be further strengthened. Nevertheless, several actions contributed to the law enforcement achievements: strong political will; strong stakeholder support; and funding that could be promptly accessed. These factors are highlighted as prerequisites for achieving Indonesia's ambitious REDD+ goals. PMID- 24628367 TI - Responses to: 'Legitimacy in legacy: a discussion paper of historical scholarship published in the Journal of Advanced Nursing, 1976-2011' by Fealy G., Kelly J. & Watson R. (2013) Journal of Advanced Nursing 69(8), 1881-1894. PMID- 24628370 TI - Filaggrin loss-of-function mutations and incident cancer: a population-based study. AB - BACKGROUND: Loss-of-function mutations in the filaggrin gene (FLG) could have opposing effects on cancer risk, as mutations are associated with both 10% higher serum vitamin D levels, which may protect against cancer, and with impaired skin barrier function, which may lead to higher cancer susceptibility. OBJECTIVES: To investigate the association of the FLG genotype and cancer types in four population-based cohorts. METHODS: A total of 13,376 individuals were genotyped for FLG mutations. Information on cancer was obtained from the Danish Cancer Registry. Persons with a history of cancer at baseline were excluded from prospective analyses. RESULTS: There were 1339 incident cancers (median follow-up 11.4 years). The hazard ratios (HRs) and 95% confidence intervals (CIs) for FLG mutation carriers vs. wild types were: for any cancer (HR 0.95, 95% CI 0.78 1.16), any cancer excluding nonmelanoma skin cancer (NMSC) (HR 1.05, 95% CI 0.84 1.31), head and neck cancer (HR 1.72, 95% CI 0.71-4.15), colorectal cancer (HR 0.82, 95% CI 0.44-1.52), bronchus and lung cancer (HR 1.34, 95% CI 0.77-2.33), breast cancer (HR 0.58, 95% CI 0.30-1.14), uterine cancer (HR 0.42, 95% CI 0.06 3.10), prostate cancer (HR 1.09, 95% CI 0.61-1.94), urinary cancer (HR 1.30, 95% CI 0.51-3.29), malignant melanoma (HR 1.03, 95% CI 0.41-2.58) and NMSC (HR 0.70, 95% CI 0.47-1.05). Among participants aged over 60 years at baseline, we found statistically significant lower risks of all cancers and NMSC among FLG mutation carriers. CONCLUSIONS: The only significant associations between FLG loss-of function mutations and cancer were in subgroup analyses. PMID- 24628371 TI - Oral solid self-emulsifying formulations: a patent review. AB - Self-emulsifying compositions are lipidic drug delivery systems that provide a number of delivery advantages. A variety of excipients are available for designing of these drug delivery systems. These systems can be classified as Type I, II, III, and IV, and alternatively as solid, semi-solid, and liquid. Till date many patents have been published on self-emulsifying compositions, and a few commercial products have also been launched. The purpose of this review is to have insights into the patent literature capturing the developments in the area of oral solid self-emulsifying formulations. Though the main emphasis is on developments in solid self-emulsifying formulations, an overview of different manufacturing techniques has also been provided. These formulations can be grouped as conventional, granules, pellets, tablets, supersaturable, controlled release, eutectic-based, and positively charged. The components of self emulsifying formulations described in this review are not limited only to oils, surfactants, and cosurfactants but also include binders, polymers, diluents, alkalinizing agents, stabilizing agents, preservatives, and viscosity adjusting agents. The inventions highlighted in this article provide useful guidelines for enhancement of oral bioavailability of drugs through this drug delivery platform. PMID- 24628372 TI - 4',4''',7,7"-tetra-O-methylcupressuflavone inhibits seed germination of Lactuca sativa. AB - Biflavonoids have been isolated from a wide variety of plant species, but little is known about their native biological functions. Here we report a possible ecological role for biflavonoids by describing the isolation of the biflavonoid 4',4''',7,7"-tetra-O-methylcupressuflavone (1) from Araucaria columnaris and its inhibitory effect on seed germination. Compound 1 was isolated from needles of a single A. columnaris specimen and inhibited germination of Lactuca sativa seeds in a culture-dish assay; it was also detected in soil samples under the canopy where reduced germination was observed, but not in a location away from the canopy where germination was uninhibited. PMID- 24628373 TI - Fecal metabolomics of healthy breast-fed versus formula-fed infants before and during in vitro batch culture fermentation. AB - Nontargeted metabolomics analyses were used (1) to compare fecal metabolite profiles of healthy breast-fed (BF) and formula-fed (FF) infants before and during in vitro fermentation in batch culture and (2) to evaluate fecal metabolomics in assessing infant diet. Samples from healthy BF (n = 4) or FF (n = 4) infants were individually incubated at 37( degrees )C in anaerobic media containing 1% (wt/vol) galactooligosaccharides, 6'-sialyllactose, 2' fucosyllactose, lacto-N-neotetraose, inulin, and gum arabic for up to 6 h, and supernatants were analyzed using GC/MS and LC/MS/MS to assess changes in various compounds. Comparison of over 250 metabolites prior to incubation showed that BF samples contained higher relative concentrations (P <= 0.05) of 14 compounds including human milk oligosaccharides and other metabolites presumably transferred through breast feeding (linoelaidate, myo-inositol) (P <= 0.05). Conversely, feces from FF infants contained 41 identified metabolites at higher levels (P <= 0.05) with many indicative of carbon limitation and protein fermentation. Our data are consistent with the notion that carbon-limited cultures catabolize protein and amino acids to obtain energy, whereas the provision of fermentable carbohydrate creates anabolic conditions relying on amino acids for bacterial growth. Results also suggest that fecal metabolomics can be a useful tool for studying interactions among diet, microbes, and host. PMID- 24628374 TI - Copy number variation in Fayoumi and Leghorn chickens analyzed using array comparative genomic hybridization. AB - Copy number variation refers to regions along chromosomes that harbor a type of structural variation, such as duplications or deletions. Copy number variants (CNVs) play a role in many important traits as well as in genetic diversity. Previous analyses of chickens using array comparative genomic hybridizations or single-nucleotide polymorphism chip assays have been performed on various breeds and genetic lines to discover CNVs. In this study, we assessed individuals from two highly inbred (inbreeding coefficiency > 99.99%) lines, Leghorn G-B2 and Fayoumi M15.2, to discover novel CNVs in chickens. These lines have been previously studied for disease resistance, and to our knowledge, this represents the first global assessment of CNVs in the Fayoumi breed. Genomic DNA from individuals was examined using the Agilent chicken 244 K comparative genomic hybridization array and quantitative PCR. We identified a total of 273 CNVs overall, with 112 CNVs being novel and not previously reported. Quantitative PCR using the standard curve method validated a subset of our array data. Through enrichment analysis of genes within CNV regions, we observed multiple chromosomes, terms and pathways that were significantly enriched, largely dealing with the major histocompatibility complex and immune responsiveness. Using an additional round of computational and statistical analysis with a different bioinformatic pipeline, we identified 43 CNVs among these as high-confidence regions, 14 of which were found to be novel. We further compared and contrasted individuals of the two inbred lines to discover regions that have a significant difference in copy number between lines. A total of 40 regions had significant deletions or duplications between the lines. Gene Ontology analysis of genomic regions containing CNVs between lines also was performed. This between-line candidate CNV list will be useful in studies with these two unique genetic lines, which may harbor variations that underlie quantitative trait loci for disease resistance and other important traits. Through the global discovery of novel CNVs in chicken, these data also provide resources for further genetic and functional genomics studies. PMID- 24628375 TI - Characteristics of men and premenopausal women with burning mouth symptoms: a case-control study. AB - OBJECTIVES: To identify possible clinical differences between male, premenopausal, and postmenopausal female patients with burning mouth symptoms. BACKGROUND: Burning mouth symptoms are known to occur predominantly in postmenopausal women. In some rare cases, however, such symptoms may also appear in men and younger premenopausal women. There is no information on the characteristics of male and premenopausal female patients with burning mouth symptoms. METHODS: A total of 22 male patients (no age limit) and 19 relatively younger premenopausal female patients (age: <=45 years) with a burning sensation in the mouth without any visible signs of oral mucosal diseases were included in the experimental groups. Sixty burning mouth patients (postmenopausal females, age: >=50 years) without oral mucosal diseases were included as a typical older postmenopausal group for comparison. All individuals in the 3 groups were subjected to clinical evaluations including an interview, a comprehensive questionnaire, a simplified psychological evaluation (Symptom Checklist-90 Revision [SCL-90-R]), blood tests, and a measurement of salivary flow rate. RESULTS: The male group reported taste problems less commonly (40.9%, P = .009) and less severely (median visual analog scale [VAS] = 0.00, P = .004) than the postmenopausal group (73.3%, median VAS = 4.50). The younger premenopausal group complained of paresthesia more commonly (68.4%, P = .006) and more severely (median VAS = 0.50, P = .007) than the postmenopausal group (30.0%, median VAS = 0.00). The male group (81.8%) reported discomfort of the tongue less commonly than the postmenopausal group (100.0%, P = .004). The percentage of patients with a symptom triad of oral mucosal pain, dysguesia, and xerostomia was significantly higher in the premenopausal (73.7%, P = .005) and postmenopausal (60.0%, P = .012) groups than the male group (27.3%). The flow rate of unstimulated whole saliva was significantly higher in the premenopausal group (0.27 +/- 0.18 mL/min) than the postmenopausal group (0.17 +/- 0.16 mL/min, P = .006). None of the 9 symptom dimensions of the SCL-90-R were significantly different among the 3 groups. The percentage of patients with abnormal blood tests and taking medications due to comorbid diseases was the lowest in the premenopausal group. CONCLUSIONS: Male and premenopausal female patients with burning mouth symptoms showed different characteristics compared with typical postmenopausal female patients. PMID- 24628376 TI - Three-dimensional culture and transforming growth factor beta3 synergistically promote tenogenic differentiation of equine embryo-derived stem cells. AB - The natural reparative mechanisms triggered by tendon damage often lead to the formation of biomechanically inferior scar tissue that is prone to re-injury. Before the efficient application of stem cell-based regenerative therapies, the processes regulating tenocyte differentiation should first be better understood. Three-dimensional (3D) growth environments under strain and the exogenous addition of transforming growth factor beta3 (TGF-beta3) have separately been shown to promote tendon differentiation. The aim of this study was to determine the ability of both of these factors to induce tendon differentiation of equine embryo-derived stem cells (ESCs). ESCs seeded into 3D collagen constructs can contract the matrix to a similar degree to that of tenocyte-seeded constructs and histologically appear nearly identical, with no areas of cartilage or bone tissue deposition. Tendon-associated genes and proteins Tenascin-C, Collagen Type I, and COMP are significantly up-regulated in the 3D ESC constructs compared with tenogenic induction in monolayer ESC cultures. The addition of TGF-beta3 to the 3D cultures further up-regulates the expression of these genes and also induces the expression of mature tenocyte markers Tenomodulin and Thrombospondin-4. Our results show that when ESCs are exposed to the intrinsic forces exerted by a 3D culture environment, they express tendon-associated genes and proteins which are indicative of tenocyte lineage differentiation and that this effect is synergistically enhanced and accelerated by the addition of TGF-beta3. PMID- 24628377 TI - Identification of charge transfer transitions related to thiamin-bound intermediates on enzymes provides a plethora of signatures useful in mechanistic studies. AB - Identification of enzyme-bound intermediates via their spectroscopic signatures, which then allows direct monitoring of the kinetic fate of these intermediates, poses a continuing challenge. As an electrophilic covalent catalyst, the thiamin diphosphate (ThDP) coenzyme forms a number of noncovalent and covalent intermediates along its reaction pathways, and multiple UV-vis and circular dichroism (CD) bands have been identified at Rutgers pertinent to several among them. These electronic transitions fall into two classes: those for which the conjugated system provides a reasonable guide to the observed lambdamax and others in which there is no corresponding conjugated system and the observed CD bands are best ascribed to charge transfer (CT) transitions. Herein is reported the reaction of four ThDP enzymes with alternate substrates: (a) acetyl pyruvate, its methyl ester, and fluoropyruvate, these providing the shortest side chains attached at the thiazolium C2 atom and leading to CT bands with lambdamax values of >390 nm, not pertinent to any on-pathway conjugated systems (estimated lambdamax values of <330 nm), and (b) (E)-4-(4-chlorophenyl)-2-oxo-3-butenoic acid displaying both a conjugated enamine (430 nm) and a CT transition (480 nm). We suggest that the CT transitions result from an interaction of the pi bond on the ThDP C2 side chain as a donor, and the positively charged thiazolium ring as an acceptor, and correspond to covalent ThDP-bound intermediates. Time resolution of these bands allows the rate constants for individual steps to be determined. These CD methods can be applied to the entire ThDP superfamily of enzymes and should find applications with other enzymes. PMID- 24628378 TI - Recommendations for the allergy management in the primary care. AB - The majority of patients seeking medical advice for allergic diseases are first seen in a primary care setting. Correct diagnosis with identification of all offending allergens is an absolute prerequisite for appropriate management of allergic disease by the general practitioner. Allergy diagnostic tests recommended for use in primary care are critically reviewed in accordance with the significant workload in a primary care setting. Simplified pathways for recognition and diagnosis of allergic diseases are proposed, that should be further adapted to local (national) conditions. PMID- 24628379 TI - Minimally invasive surfactant therapy with a gastric tube is as effective as the intubation, surfactant, and extubation technique in preterm babies. AB - AIM: Preterm infants requiring surfactant replacement have been treated using the INSURE technique, which requires sedation and comprises tracheal intubation, surfactant instillation and extubation. However, minimally invasive surfactant therapy (MIST) does not require sedation, minimises airway injury and avoids placing positive pressure ventilation on an immature lung. This study compared the feasibility of the two techniques and the outcomes in preterm babies with respiratory distress syndrome (RDS). METHODS: Preterm infants with RDS prospectively received surfactant via a gastric tube placed in the trachea by direct laryngoscopy with no sedation. Technique-related complications and respiratory outcomes were analysed. RESULTS: We compared 44 patients who received MIST with a historic cohort of 31 patients who received INSURE. This showed no differences in the rate of intubation and mechanical ventilation in the first 72 h, or secondary respiratory outcomes and relevant morbidities, between the babies who received INSURE and those who received MIST. More babies in the MIST group (35%) needed a second dose of surfactant than the INSURE group (6.5%) (p < 0.0001). CONCLUSION: Surfactant administration using MIST, with no sedation, is feasible in preterm infants with RDS. No significant differences in secondary respiratory outcomes were found between the MIST and INSURE techniques. PMID- 24628380 TI - Women with greater pelvic floor muscle strength have better sexual function. AB - OBJECTIVE: To investigate the relation between pelvic floor muscle strength and sexual function among women with higher and lower pelvic floor muscle strength. DESIGN: A cross-sectional study was performed among employees and students of the University. SETTING: Urogynecology department, Federal University of Pampa, Brazil, carried out between January and July of 2012. POPULATION: Forty women, aged 20-28 years. METHODS: Forty-nine women were screened and nine were excluded. Baseline information of the participants was obtained. The Female Sexual Function Index questionnaire was applied and pelvic floor muscle strength was randomly measured by transvaginal palpation according to the Ortiz scale, and by perineometry. Women were allocated into two groups according to muscle strength. MAIN OUTCOME MEASURES: Index of sexual function and pelvic floor muscle strength RESULTS: Women with stronger pelvic floor muscles scored higher in the following domains: desire, excitement, orgasm and general score of the questionnaire (4.9 +/- 0.73 vs. 3.8 +/- 0.58; 5.0 +/- 0.35 vs. 4.3 +/- 0.82; 5.8 +/- 0.21 vs. 4.0 +/ 1.00 and 32.4 +/- 0.77 vs. 27.6 +/- 3.29, p < 0.001). There was a moderate correlation between pelvic floor muscle pressure and both sexual satisfaction (r = 0.47, p = 0.03) and lubrication (r = -0.69, p = 0.001) as well as the manual evaluation of pelvic floor muscle strength, graded by the Ortiz and perineometry, which were interrelated (r = 0.65, p = 0.001). CONCLUSION: Our findings suggest that women with stronger pelvic floor muscles have better sexual function. PMID- 24628381 TI - Palmoplantar pustulosis associated with necrobiosis lipoidica: a possible role of tumor necrosis factor-alpha and interleukin-17. PMID- 24628382 TI - Synthesis, photophysics, and reverse saturable absorption of bipyridyl platinum(II) bis(acetylide) complexes bearing aromatic electron-withdrawing substituents on the acetylide ligands. AB - Three platinum(II) bipyridyl bis((7-R-fluoren-2-yl)acetylide) complexes (R = benzoyl (Pt-1), 2-(N-phenylbenzimidazoly) (Pt-2), or 2-(3-phenylquinoxalinyl) (Pt 3)) are synthesized and characterized. Their photophysical properties and reverse saturable absorption are systematically investigated via UV-vis absorption, emission, transient absorption, and nonlinear transmission spectroscopy/technique. All three complexes possess ligand-centered (1)pi,pi* transitions below 400 nm, and a broad, featureless (1)MLCT/(1)LLCT absorption band in the region of 400-550 nm in CH2Cl2 solutions. They are emissive in a variety of fluid solutions at room temperature and at 77 K glassy matrix. On the basis of the emission lifetime, solvatochromic effect, and thermally induced Stokes shift, the emitting states are tentatively ascribed to (3)pi,pi*/(3)MLCT/(3)LLCT states for Pt-1, and predominantly (3)MLCT/(3)LLCT states for Pt-2 and Pt-3 in polar solvents like CH3CN. Pt-1-Pt-3 also exhibit broad triplet excited-state absorption, i.e., 425-800 nm for Pt-1 and Pt-3, and 425-725 nm for Pt-2, from the same excited states that emit. Strong reverse saturable absorption (RSA) occurs at 532 nm for ns laser pulses from all of the complexes due to the stronger triplet excited-state absorption at this wavelength, suggesting that the pi-conjugated aromatic electron-withdrawing substituents at the fluorenylacetylide ligands enhance the RSA of the Pt(II) diimine bis(acetylide) complexes. PMID- 24628383 TI - Seroprevalence rates of hepatitis C virus (HCV) antibody and hepatitis B virus surface antigen (HBsAG) in blood donors in a Southwestern Nigerian city. AB - Hepatitis B and C have been identified as major causes of Transfusion transmitted infections, in Nigeria. Our objective was to determine the prevalence of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) in prospective blood donors in Abeokuta, Nigeria. 305 blood donors were screened for the presence of Hepatitis B virus surface antigen (HBsAg) and HCV using a rapid immunochromatographic kit (DiaSpot(r)). Demographic information was also collected. Males constituted 96.4%, singles were the majority with 65%. Prevalence of HBsAg was 9.8%, HCV 1.3%, and dual positivity 0.3%. Prevalence of HBsAg and HCV among males was 10.2% and 1.4%, while females recorded 0.0% for HCV and HBsAg. Dual positivity was recorded in a male (0.33%). Analysis of the study variables revealed that only educational status was statistically associated with positivity of HBsAg [Formula: see text], HCV prevalence was highest in the illiterate group it was not statistically significant (P > 0.05). We report the prevalence rates of anti-HCV Ab and HBsAg in blood donors from Ogun State, Nigeria. Our results reveals higher rate of HBsAg and evidence of co-infection with both viruses, illiteracy was the only variable associated with HBV infection. We advocate for the inclusion of anti-HBc or HBeAg in donor screening in our environment. PMID- 24628384 TI - Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin induced hepatotoxicity in primary rat hepatocytes. AB - OBJECTIVES: As part of our efforts to isolate anti-hepatotoxic agents from marine natural products, we screened the ability of 14 edible varieties of Korean seaweed to protect against doxorubicin-induced hepatotoxicity in primary rat hepatocytes. METHODS: Among the crude extracts of two Chlorophyta (Codium fragile and Capsosiphon fulvescens), seven Phaeophyta (Undaria pinnatifida, Sargassum thunbergii, Pelvetia siliquosa, Ishige okamurae, Ecklonia cava, Ecklonia stolonifera and Eisenia bicyclis), five Rhodophyta (Chondrus ocellatus, Gelidium amansii, Gracilaria verrucosa, Symphycladia latiuscula and Porphyra tenera), and the extracts of Ecklonia stolonifera, Ecklonia cava, Eisenia bicyclis and Pelvetia siliquosa exhibited significant protective effects on doxorubicin induced hepatotoxicity, with half maximal effective concentration (EC50) values of 2.0, 2.5, 3.0 and 15.0 MUg/ml, respectively. KEY FINDINGS: Since Ecklonia stolonifera exhibits a significant protective potential and is frequently used as foodstuff, we isolated six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5) and triphloroethol-A (6). Phlorotannins 2 ~ 6 exhibited potential protective effects on doxorubicin-induced hepatotoxicity, with corresponding EC50 values of 3.4, 8.3, 4.4, 5.5 and 11.5 MUg/ml, respectively. CONCLUSION: The results clearly demonstrated that the anti-hepatotoxic effects of Ecklonia stolonifera and its isolated phlorotannins are useful for further exploration and development of therapeutic modalities for treatment of hepatotoxicity. PMID- 24628385 TI - Study on clinical application of nano-hydroxyapatite bone in bone defect repair. AB - OBJECTIVE: To study the clinical effect of bone defect treated with nano hydroxyapatite(Nano-HA) artificial bone. METHODS: From September 2009 to June 2012, 27 cases of bone defect were analyzed retrospectively. The position of bone defect included humerus, radius, ulna, femur, tibia and calcaneus. The range of bone defect was from 0.3 * 1.0 cm to 3 * 6.5 cm. Among them, there were 22 cases with fractures and 5 cases with tumors. All patients were treated with Nano-HA artificial bone. The ability of bone defect repair was evaluated by X-ray exams performed preoperatively and postoperatively. HSS scores were adopted for final evaluation at the latest follow-up. RESULTS: The patients were followed up from 11 to 26 months (average of 18.5 months). No general side effects occurred. X-ray photo showed an integrity interface between Nano-HA and bone. Primary healing was obtained in all cases without any complication. CONCLUSION: The Nano-HA artificial bone had a good biocompatibility and could be an ideal artificial bone in the reconstruction of bone defect. PMID- 24628386 TI - Airborne trifluoroacetic acid and its fraction from the degradation of HFC-134a in Beijing, China. AB - Trifluoroacetic acid (TFA) has been attracting increasing attention worldwide because of its increased environmental concentrations and high aquatic toxicity. Atmospheric deposition is the major source of aquatic TFA, but only a few studies have reported either air concentrations or deposition fluxes for TFA. This is the first study to report the atmospheric concentrations of TFA in China, where an annular denuder and filter pack collection system were deployed at a highly urbanized site in Beijing. In total, 144 air samples were collected over the course of 1 year (from May 2012 to April 2013) and analyzed directly using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) or following derivatization by gas chromatography-mass spectrometry (GC-MS). The annual mean atmospheric concentration of TFA was 1580 +/- 558 pg/m(3), higher than the previously reported annual mean levels in Germany and Canada. For the first time, it was demonstrated that maximum concentrations of TFA were frequently observed in the afternoon, following a diurnal cycle and suggesting that a major source of airborne TFA is likely degradation of volatile precursors. Using a deposition model, the annual TFA deposition flux was estimated to be 619 +/- 264 MUg m(-2) year(-1). Nevertheless, a box model estimated that the TFA deposition flux from the degradation of HFC-134a contributed only 14% (6-33%) to the total TFA deposition flux in Beijing. Source analysis is quite important for future TFA risk predictions; therefore, future research should focus on identifying additional sources. PMID- 24628387 TI - New subtype of Cryptosporidium cuniculus isolated from rabbits by sequencing the Gp60 gene. AB - Given the paucity of literature available on rabbits infected with Cryptosporidium in Sichuan Province (China), 290 fecal samples were collected from rabbits in the animal house of Sichuan Agricultural University, China and examined for Cryptosporidium oocysts using the Sheather's sucrose flotation technique and a modified acid-fast staining method. Three samples tested positive (prevalence = 1.03%). The positive isolates were genotyped by sequence analysis of the 18S rRNA, HSP70, COWP, and Cp135 genes and characterized by PCR restriction fragment length polymorphism (RFLP) analysis of the 18S rRNA gene. Phylogenetic analysis was established using the neighbor-joining (NJ) method. All the isolates were identified as Cryptosporidium cuniculus. Further subtyping of the positive isolates was performed by DNA sequencing of the 60-kDa glycoprotein (gp60) gene. Only 1 subtype family was detected, Va, which was proposed to be a new subtype, VaA31. This study is the first report about the prevalence, genetic identification, and Cp135 gene of C. cuniculus in rabbits in Sichuan Province, China. The obtained results indicate that the C. cuniculus subtype in rabbits in Sichuan Province is unique. PMID- 24628388 TI - Growth performance and meat quality of broiler chickens supplemented with Rhodopseudomonas palustris in drinking water. AB - 1. The effect of the bacterium, Rhodopseudomonas palustris, on the growth performance and meat quality of broiler chickens was investigated. 2. A total of 900-d-old Arbor Acres broilers were allocated to three experimental treatments for 6 weeks. Chicks were administered with R. palustris in drinking water as follows: (i) control group without R. palustris; (ii) treatment 1 (R1) with R. palustris of 8 * 10(9) cells per chick per day in drinking water; (iii) treatment 2 (R2) with R. palustris of 1.6 * 10(10) cells per chick per day in drinking water. 3. The results showed that, compared with that of control, both groups of R. palustris treatment increased daily weight gain and improved feed conversion ratio of broiler chickens significantly during the whole growing period of 6 weeks. 4. Both total and glutamic acid contents of chicken breast fillet in R. palustris treatment R2 were higher, while the fat content was lower, than those of the control group. Furthermore, R. palustris treatments also improved sensory attributes of chicken breast fillet. 5. As a probiotic providing rich nutrients and biological active substances, R. palustris administration in drinking water displayed a growth promoting effect and improved meat quality of broiler chickens. PMID- 24628389 TI - Advanced prostate cancer lowers serum calcium levels--implications for epidemiologic studies. PMID- 24628390 TI - The effects of folate supplementation on inflammatory factors and biomarkers of oxidative stress in overweight and obese women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled clinical trial. AB - OBJECTIVE: This study was conducted to determine the effects of folate supplementation on inflammatory factors and biomarkers of oxidative stress among women with polycystic ovary syndrome (PCOS). DESIGN, PATIENTS AND MEASUREMENTS: This randomized, double-blind, placebo-controlled clinical trial was conducted among 69 women diagnosed with PCOS and aged 18-40 year old. Participants were randomly assigned to three groups receiving the following: (1) folate-1: 1 mg/d folate supplements (N = 23); (2) folate-5: 5 mg/d folate supplements (N = 23) and (3) placebo (N = 23) for 8 weeks. Fasting blood samples were taken at the beginning of the study and after 8 weeks to measure homocysteine (Hcy), inflammatory factors including high-sensitivity C-reactive protein (hs-CRP), nitric oxide (NO), biomarkers of oxidative stress including total antioxidant capacity (TAC), glutathione (GSH), malondialdehyde (MDA) and homoeostatic model assessment-beta cell function (HOMA-B). RESULTS: Supplementation with 5 mg/d folate resulted in reduced plasma Hcy (-2.23 vs -1.86 and 1.16 MUm, respectively, P < 0.05), HOMA-B (-7.63 vs 1.43 and 13.66, respectively, P < 0.05), serum hs-CRP (-212.2 vs -262.4 and 729.8 MUg/l, respectively, P < 0.05) and plasma MDA concentrations (-0.48 vs -0.24 and 0.69 MUm, respectively, P < 0.01) compared with folate-1 and placebo groups. Furthermore, a significant rise in plasma TAC (0.64 vs -3.53 and -215.47 mm, respectively, P < 0.01) and GSH levels (162.1 vs 195.8 and -158.2 MUm, respectively, P < 0.01) was also observed following the administration of 5 mg/d folate supplements compared with folate-1 and placebo groups. CONCLUSIONS: In conclusion, folate supplementation (5 mg/d) in women with PCOS had beneficial effects on inflammatory factors and biomarkers of oxidative stress. PMID- 24628391 TI - Reach out to one and you reach out to many: social touch affects third-party observers. AB - Casual social touch influences emotional perceptions, attitudes, and behaviours of interaction partners. We asked whether these influences extend to third-party observers. To this end, we developed the Social Touch Picture Set comprising line drawings of dyadic interactions, half of which entailed publicly acceptable casual touch and half of which served as no-touch controls. In Experiment 1, participants provided basic image norms by rating how frequently they observed a displayed touch gesture in everyday life and how comfortable they were observing it. Results implied that some touch gestures were observed more frequently and with greater comfort than others (e.g., handshake vs. hug). All gestures, however, obtained rating scores suitable for inclusion in Experiments 2 and 3. In Experiment 2, participants rated perceived valence, arousal, and likeability of randomly presented touch and no-touch images without being explicitly informed about touch. Image characters seemed more positive, aroused, and likeable when they touched as compared to when they did not touch. Image characters seemed more negative and aroused, but were equally likeable, when they received touch as compared to when there was no physical contact. In Experiment 3, participants passively viewed touch and no-touch images while their eye movements were recorded. Differential gazing at touch as compared to no-touch images emerged within the first 500 ms following image exposure and was largely restricted to the characters' upper body. Gazing at the touching body parts (e.g., hands) was minimal and largely unaffected by touch, suggesting that touch processing occurred outside the focus of visual attention. Together, these findings establish touch as an important visual cue and provide novel insights into how this cue modulates socio-emotional processing in third-party observers. PMID- 24628392 TI - Modulation of Strawberry/Cranberry Phenolic Compounds Glucuronidation by Co Supplementation with Onion: Characterization of Phenolic Metabolites in Rat Plasma Using an Optimized MUSPE-UHPLC-MS/MS Method. AB - Plant phenolic compounds are suggested to exert pharmacological activities in regards to obesity and type-2 diabetes, but their mode of action is poorly understood due to a lack of information about their bioavailability. This work aimed to study the bioavailability of GlucoPhenol phenolic compounds, a strawberry-cranberry extracts blend, by characterizing plasma phenolic profile in obese rats. A comparison was performed by co-supplementation with an onion extract. Using an optimized MUSPE-UHPLC-MS/MS method, 21 phenolic metabolites were characterized, mostly conjugated metabolites and microbial degradation products of the native phenolic compounds. Their kinetic profiles revealed either an intestinal or hepatic formation. Among identified metabolites, isorhamnetin glucuronide sulfate was found in greater amount in plasma. Three glucuronidated conjugates of strawberry-cranberry phenolic compounds, p-hydroxybenzoic acid glucuronide, catechins glucuronide, and methyl catechins glucuronide were found in higher quantities when GlucoPhenol was ingested together with onion extract (+252%, +279%, and +118% respectively), suggesting a possible induction of glucuronidation processes by quercetin. This work allowed the characterization of actual phenolic metabolites generated in vivo following a phenolic intake, the analysis of their kinetics and suggested a possible synergistic activity of phenolic compounds for improving bioavailability. PMID- 24628393 TI - 'Pin-point precision' for wedge excision of the ear. PMID- 24628394 TI - Effects of wind energy development on nesting ecology of greater prairie-chickens in fragmented grasslands. AB - Wind energy is targeted to meet 20% of U.S. energy needs by 2030, but new sites for development of renewable energy may overlap with important habitats of declining populations of grassland birds. Greater Prairie-Chickens (Tympanuchus cupido) are an obligate grassland bird species predicted to respond negatively to energy development. We used a modified before-after control-impact design to test for impacts of a wind energy development on the reproductive ecology of prairie chickens in a 5-year study. We located 59 and 185 nests before and after development, respectively, of a 201 MW wind energy facility in Greater Prairie Chicken nesting habitat and assessed nest site selection and nest survival relative to proximity to wind energy infrastructure and habitat conditions. Proximity to turbines did not negatively affect nest site selection (beta = 0.03, 95% CI = -1.2-1.3) or nest survival (beta = -0.3, 95% CI = -0.6-0.1). Instead, nest site selection and survival were strongly related to vegetative cover and other local conditions determined by management for cattle production. Integration of our project results with previous reports of behavioral avoidance of oil and gas facilities by other species of prairie grouse suggests new avenues for research to mitigate impacts of energy development. PMID- 24628395 TI - A peer support programme for enhancing adherence to oral antipsychotic medication in consumers with schizophrenia. AB - AIMS: To assess if consumers with schizophrenia who were non-adherent to their oral antipsychotic medication had improved adherence and mental state, after participating in a problem-solving based peer support programme. BACKGROUND: Many people with schizophrenia are reluctant to take their antipsychotic medications. Peer support, combined with a problem-solving approach, could be used as a strategy to improve adherence outcomes. A peer is an individual with mental illness who offers support to others. DESIGN: A quasi-experimental time-series design was used to measure the effect of the problem-solving based peer support programme on adherence and mental state. METHOD: Consumers who were non-adherent to oral antipsychotic medication were recruited from February 2009-June 2010. Peers contacted consumers by a weekly 20-minute telephone call for 8 weeks. Mental state was measured using the Brief Psychiatric Rating Scale-E and medication adherence was measured by self-report at baseline, postintervention (week 8) and follow-up (week 14). Data were analysed using the Friedman's test and Wilcoxon Signed Rank test for pair-wise comparisons. RESULTS: The study included 22 consumers and six peers: 19 males, mean age 35.1 years. Improvements were identified in medication adherence, negative symptoms and overall mental state between baseline and week 8. These improvements were maintained at week 14. CONCLUSION: Medication adherence may be enhanced with the addition of a peer support intervention. A problem-solving based peer support programme could be implemented in the community setting for patients who are non-adherent with oral antipsychotic medication. PMID- 24628396 TI - Macular pigment and macular volume in eyes of patients with cystic fibrosis. AB - BACKGROUND: Because patients with cystic fibrosis (CF) are living longer, chronic malabsorption of carotenoids associated with CF resulting in decreased macular pigment (MP) may affect macular long-term health in later-life pathology. This study compared the macular pigment optical density (MPOD) and corresponding central macular volume (MV) of adult CF subjects and age-matched normal controls subjects to determine whether chronic malabsorption associated with CF could adversely affect macular photoreceptor anatomy. OBJECTIVE: Our aim was to compare MPOD with measurements of central MV in CF patients with age-matched controls. Design. In nine adult CF patients (ages: 29-46) without a history of carotenoid supplementation or known retinal or optic nerve disease MPOD and MV were measured by heterochromatic flicker photometry (HFP) and optical coherence tomography (OCT), respectively, and compared to results obtained from 14 age-matched controls. RESULTS: MPOD was significantly reduced at 15' and 30' eccentricities in CF subjects compared to normal subjects (mean difference -0.21 at 15', -0.25 at 30', p < 0.005). No significant difference, in MV noted at any of the eccentricities tested between CF and normal subjects (CF: normal MV ratios ranged from 0.94 to 1.1 for all eccentricities with p > 0.1 at all eccentricities). Best corrected vision acuity and fundus examination were normal in all subjects. CONCLUSIONS: Unsupplemented CF patients have markedly lower levels of macular carotenoids (e.g., lutein and zeaxanthin), but well-maintained visual function and no significant reductions in central MV primarily composed of macular photoreceptors. Future studies are needed to determine whether the lifelong decrease in protective central retinal carotenoids predisposes CF patients to later-life retinal pathology. PMID- 24628397 TI - Adaptive reorganization of 2D molecular nanoporous network induced by coadsorbed guest molecule. AB - The ordered array of nanovoids in nanoporous networks, such as honeycomb, Kagome, and square, provides a molecular template for the accommodation of "guest molecules". Compared with the commonly studied guest molecules featuring high symmetry evenly incorporated into the template, guest molecules featuring lower symmetry are rare to report. Herein, we report the formation of a distinct patterned superlattice of guest molecules by selective trapping of guest molecules into the honeycomb network of trimesic acid (TMA). Two distinct surface patterns have been achieved by the guest inclusion induced adaptive reconstruction of a 2D molecular nanoporous network. The honeycomb networks can synergetically tune the arrangement upon inclusion of the guest molecules with different core size but similar peripherals groups, resulting in a trihexagonal Kagome or triangular patterns. PMID- 24628399 TI - Design and assembly procedures for large-sized biohybrid scaffolds as patches for myocardial infarct. AB - OBJECTIVE: To assemble a biohybrid cardiac patch consisting of a large (5 * 5 cm) elastomer scaffold whose pores are filled with a self-assembling peptide (SAP) gel entrapping adipose stem cells, to be used as a novel implant in a big animal model (sheep) of myocardial infarction. The study focuses on the way to determine optimal procedures for incorporating the SAP solution and the cells in the patch to ensure cell colonization and a homogeneous cell distribution in the construct before implantation. The problems associated with the scale-up of the different procedures raised by the large size of the construct are discussed. MATERIALS AND METHODS: Experiments were performed to choose between different assembling alternatives: incorporation of the SAP gel before cell seeding or simultaneous SAP and cell loading of the scaffold; surface seeding of cells or cell injection into the scaffold pores; dissemination of the cells throughout the scaffold before incubation by gentle shaking or by centrifugation. Immunocytochemistry techniques and confocal and scanning electron microscopies were employed to assess and quantify cell colonization of the material and early cell distribution. Cell concentrations and the uniformity of cellular distribution throughout the scaffold were taken as the main criteria to decide between the different alternative procedures. RESULTS: The combination of peptide preloading, cell injection, and shaking before incubation yielded the best results in terms of greater cell density and the most uniform distribution after 24 h of culture compared with the other methods. These techniques could be scaled-up to obtain large biohybrid cardiac patches with success. CONCLUSIONS: The results obtained after the different seeding methods allowed us to establish an effective protocol for the assembly of large biohybrid patches for their subsequent implantation in the heart of a big animal model of myocardial infarct in the context of a preclinical study. PMID- 24628398 TI - Adjunct antibiotic combination therapy for steroid-refractory or -dependent ulcerative colitis: an open-label multicentre study. AB - BACKGROUND: We previously demonstrated that antibiotic combination therapy is effective for induction and maintenance of ulcerative colitis (UC) remission. AIM: To assess whether antibiotic combination therapy is effective for active UC refractory to or dependent on steroids in a multicentre, open-label trial. METHODS: We enrolled 30 patients with steroid-refractory and 64 with steroid dependent active UC. These patients received three-times-daily by mouth amoxicillin 500 mg, tetracycline 500 mg and metronidazole 250 mg, for two weeks, as well as conventional treatment. Symptom assessment and colonoscopic evaluation were performed before enrolment and at 3 and 12 months after treatment completion. Clinical response was defined as a Lichtiger symptom score decrease in >=3 points and clinical remission as a score <=4. RESULTS: Nineteen of the 30 steroid-refractory (63.3%) and 47 of the 64 steroid-dependent (73.4%) patients showed a clinical response within 2 weeks. At 3 and 12 months, 60% and 66.6% of steroid-refractory patients, and 56.3% and 51.6% of steroid-dependent patients, respectively, achieved clinical remission. In the steroid-dependent group, 39 of the 64 patients (60.9%) were able to stop steroid therapy and remained in remission for 3 months. Three (10%) steroid-refractory and four (6.3%) steroid dependent patients underwent colectomy. CONCLUSIONS: This multicentre, long-term follow-up study suggests 2 week antibiotic combination therapy to be effective and safe in patients with active UC refractory to or dependent on steroids. PMID- 24628402 TI - A review of pharmacokinetic parameters of metabolites and prodrugs. AB - In drug discovery and development, the kinetic study of active metabolites plays an important role, helping to define the time course of the drug in the body and its activity or toxicity. After a pharmacokinetics assessment of a drug and its metabolite or a prodrug and its parent-drug, several parameters can be calculated. In some cases, achieving the objective of the study does not require all possible parameters to be calculated. When parameters are calculated, it is essential that their denotations are widely accepted and used. However, some parameters undergo a certain variability of denotation, which may confuse some readers. Thus, this review summarizes the current published data for experimental pharmacokinetic parameters of metabolites and the calculations involved in simple metabolite pharmacokinetic studies. It also evaluates the most common pharmacokinetic parameters in the literature and suggests metabolite parameters that could be determined to help advance metabolite kinetic models. PMID- 24628401 TI - Raman spectroscopy provides a noninvasive approach for determining biochemical composition of the pregnant cervix in vivo. AB - The molecular changes that occur with cervical remodelling during pregnancy are not completely understood. This study reviews Raman spectroscopy, an optical technique for detecting changes in the pregnant cervix, and reports preliminary studies on cervical remodelling in mice that suggest that the technique provides advantages over other methods. CONCLUSION: Raman spectroscopy is sensitive to biochemical changes in the pregnant cervix and has high potential as a tool for detecting premature cervical remodelling in pregnant women. PMID- 24628400 TI - A structural basis for the regulation of an H-NOX-associated cyclic-di-GMP synthase/phosphodiesterase enzyme by nitric oxide-bound H-NOX. AB - Biofilms are surface-attached communities of bacteria enclosed in a polysaccharide matrix. Bacteria in a biofilm are extremely resistant to antibiotics. Several recent reports have linked the signaling molecule nitric oxide (NO) with biofilm dispersal. We have previously reported that an H-NOX (heme-nitric oxide/oxygen binding) protein in the biofilm-dwelling bacterium Shewanella woodyi mediates NO-induced biofilm dispersal. In S. woodyi, H-NOX (SwH NOX) is cocistronic with a gene encoding a dual-functioning diguanylate cyclase/phosphodiesterase enzyme, designated here as HaCE (H-NOX-associated cyclic-di-GMP processing enzyme). Enzymes such as these are responsible for regulating the intracellular concentrations of cyclic-di-GMP, a secondary signaling molecule essential to biofilm formation in bacteria. We have demonstrated that NO-bound SwH-NOX regulates both enzymatic activities of SwHaCE, resulting in decreased cellular cyclic-di-GMP levels and disruption of biofilm formation. Thus, H-NOX/HaCE represents a potential drug target for regulating biofilm formation. In this work, the SwH-NOX surface residues critical for the formation of a protein complex with SwHaCE are identified using nuclear magnetic resonance, fluorescence quenching, and cosedimentation. Enzyme assays confirm this protein-protein interface and its importance for H-NOX/HaCE function. PMID- 24628403 TI - Metabolite characterization of anti-cancer agent gefitinib in human hepatocytes. AB - Intensive Biotransformation studies on Gefitinib could play a significant role in designing and synthesizing new drugs around the core structure of Gefitinib. These studies may be useful in developing an entirely new drug by blocking the metabolic spots in Gefitinib. Gefitinib (Iressa) was the first oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Gefitinib shows toxicity to cancer cells and has the capability to inhibit the growth of cancer cells. Gefitinib is considered as one of the selective EGFR inhibitors to be available in clinical practice. In 2003, FDA had approved Gefitinib for metastatic non small-cell lung cancer therapy (NSCLC). However, it was observed that NSCLC Patients who responded to treatment developed resistance to Gefitinib. Hence, in the present study Gefitinib was incubated with hepatocytes to identify both phase I and Phase-II metabolites. Identified Phase -I metabolites were due to oxidative defluorination, N-dealkylation and loss of morpholine ring. One of the phase-II metabolites identified i.e. the glutathione adduct suggests the need to modify the structure of the drug for higher potency and safety. PMID- 24628404 TI - Culture duration-, donor-, and medium-dependent changes in OATP1B3-mediated telmisartan uptake in human hepatocytes. AB - Human hepatic organic anion-transporting polypeptides (OATPs), including OATP1B1, 1B3, and 2B1, are expressed at the basolateral membrane of hepatocytes and mediate the uptake of a variety of compounds from blood into hepatocytes. The liver-specific OATPs are increasingly recognized as playing important roles in the pharmacokinetic (PK) of many drugs and thus, involved in the clinically significant drug-drug interactions (DDIs). However, the evaluation of the specific roles of individual OATPs in hepatocytes is challenging because of the lack of selective inhibitors and probe substrates for each OATP member. In the present study, the uptake activity of OATP1B3 was examined in human hepatocytes cultured up to 14 days using an in vitro uptake assay. The results showed that OATP-mediated uptake of rosuvastatin, a substrate for OATPs declined substantially in cultured human hepatocytes. In contrast, the uptake of OATP1B3 selective substrate telmisartan was not measureable at earlier culture periods, but became detectable on Day 7 and showed culture duration-dependent changes from Day 7 to 14. Quantitative polymerase chain reaction (qPCR) analyses illustrated that the OATP functional change was not correlated with messenger ribonucleic acid (mRNA) expression alteration in hepatocytes cultured for 3 hours or 7 days. The OATP1B3-mediated telmisartan uptake was also culture medium- and donor dependent, and only observed in 3 of 5 lots of hepatocytes cultured in 2 of 3 media tested. These results show that using human hepatocytes cultured in certain conditions may provide an excellent addition to transfected cell lines as a way to distinguish OATP1B3 from other hepatic OATP family members, such as OATP1B1, to provide more understanding of OATP-mediated clinical DDI. PMID- 24628405 TI - A proposed screening paradigm for discovery of covalent inhibitor drugs. AB - The in vitro and in vivo preclinical ADME properties of 10 clinically late stage or marketed covalent inhibitors were evaluated in order to define advancement criteria for discovery of future drugs in this arena. Our studies revealed the following: After incubating with S9 fractions for 30 minutes, the rat and human in vitro stability for these compounds ranged from 1% to 100%. The blood stability ranged from 30% to 100%. There was a broad range of CYP inhibition with prevalence for time-dependent inhibition of at least one enzyme. The Caco-2 permeability (A->B) ranged from negligible (0.6 x 10(-6) cm/s) to highly permeable (31 x 10(-6) cm/s) and the efflux ratio also varied widely (0.2-30). Most of the compounds were highly protein bound in both rat and human with binding >= 90%. Rat plasma clearance for the 10 compounds ranged from slow (11 mL/min/kg) to very rapid (350 mL/min/kg). The Vss ranged from low (0.67 L/kg) to very high (115 L/kg). MRT's also ranged from short (0.5 hr) to long (7.4 hr). The oral exposures also showed a very broad range with CMax's ranging from 0.01-77 MUM and exposure levels ranging from 0.03-106 MUM.hr. In conclusion, the wide range in in vitro and in vivo ADME data makes these particular ADME assays non discriminatory in the selection of promising compounds. In our opinion, non traditional assays such as target mass modification, target confirmation by amino acid sequencing, cellular target occupancy, and target turnover rate data in combination with the pharmacokinetic profiles are the critical considerations for progression of irreversible compounds in early discovery. PMID- 24628406 TI - Thin, tough, pH-sensitive hydrogel films with rapid load recovery. AB - Stimuli-responsive hydrogels are used as the building blocks of actuators and sensors. Their application has been limited, however, by their lack of mechanical strength and recovery from loading. Here, we report the preparation of pH sensitive hydrogels as thin as 20 MUm. The hydrogels are made of a polyether based polyurethane and poly(acrylic acid). A simple method was employed to create hydrogels with thicknesses in the range of 20-570 MUm. The hydrogel films volume changed by a factor of ~2 when the pH was switched around the transition point (pH 4). Tensile extensibilities of up to ~350% were maintained at each pH, and the average Young's modulus and tensile strength were in the range of 580-910 and 715-1320 kPa, respectively, depending on the pH. Repeated tensile loading and unloading to 100% extension showed little permanent damage, unlike analogous double-network hydrogels, and with immediate recovery (up to 75-85% of the first loading cycle), unlike hybrid ionic-covalent interpenetrating network hydrogels. PMID- 24628407 TI - Cases with a spontaneous regression of an infiltrating non-crateriform keratoacanthoma and squamous cell carcinoma with a keratoacanthoma-like component. AB - We herein report the natural course of an early/proliferative stage keratoacanthoma (KA) with infiltrating islands of cytological malignancy (case 1) and a squamous cell carcinoma (SCC) with a KA-like component (case 2), which were observed until their complete regression. The presented case 1 suggests that one of the histopathological forms of KA includes this unusual, infiltrating, non crateriform architecture, and also indicates the possibility of complete remission in the KA associated with infiltrating islands of cytological malignancy. In the presented case 2, the peripherally-associated KA-like focus was histopathologically considered to be either a remnant of KA focus or verrucous keratosis (hyperplasia). Therefore, the complete spontaneous regression of case 2 suggests that SCC arising in KA still has the potential of spontaneous regression, or that an extremely rare event, namely, the spontaneous regression of (traditional) SCC occurred in the present case. PMID- 24628408 TI - Effects of face mask treatment with and without rapid maxillary expansion in young adult subjects. AB - OBJECTIVES: To investigate the skeletal, dental, and soft tissue effects of the face mask (FM) treatment with and without rapid maxillary expansion (RME) in young adult subjects with maxillary retrognathia. MATERIALS AND METHODS: Pretreatment and posttreatment cephalometric radiographs from 32 subjects who had a skeletal Class III malocclusion were analyzed. The subjects were divided into two groups: FM group (N = 17; 3 male and 14 female subjects; mean [SD] age 14.47 [0.89] years) was treated with FM only, while the RME+FM group (N = 15; 3 male and 12 female subjects; mean [SD] age 14.67 [1.28] years) was treated with both FM and RME. Ten cephalometric linear and nine angular variables were measured to assess dentofacial changes. Within-group and between-group comparisons were determined by a paired t-test and Student's t-test, respectively. RESULTS: Forward displacement of the maxilla and a clockwise rotation of the mandible occurred in both groups. The maxillary-mandibular relationship improved and soft tissue changes resulted in a more convex profile. The maxillary incisors were more proclined in the FM group than in the RME+FM group, the only difference between the two groups. Notably, the mandibular incisors moved backward in both groups. CONCLUSIONS: Forward movement of the maxilla can be obtained in young adults after face mask treatment. However, there was no difference in this phenomenon between the FM and RME+FM groups. PMID- 24628409 TI - Unusual congenital pulmonary anomaly with presumed left lung hypoplasia in a young dog. AB - A seven-month-old, entire, male miniature schnauzer dog was referred with acute vomiting, inappetence and depression primarily as a result of a gastric foreign body (pine cones). During investigations, thoracic radiographs revealed increased volume of the right lung lobes, deviated cardiomediastinal structures and elevation of the heart from the sternum. Thoracic computed tomography revealed left cranial lung lobe hypoplasia and extension of the right cranial lung parenchyma across the midline to the left hemithorax. Branches of the right pulmonary vessels and bronchi also crossed the midline and extended to the left caudal lung lobe. These findings suggested that the right and left lungs were fused. In humans this finding is consistent with horseshoe lung, which is an uncommon congenital malformation. To the authors' knowledge, this case represents the first report of such a pulmonary anomaly in a dog. PMID- 24628410 TI - Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation. AB - Robenacoxib and ketoprofen are acidic nonsteroidal anti-inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half-lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three period cross-over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX-1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX-2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX-1 and COX-2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half life = 1.13 h). Exudate elimination half-lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivo IC50 COX-1/IC50 COX-2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX-2 inhibition in exudate, despite short half-lives in blood. PMID- 24628411 TI - Cytotoxicity and apoptosis induced by alfalfa (Medicago sativa) leaf extracts in sensitive and multidrug-resistant tumor cells. AB - Alfalfa (Medicago sativa) has been used to cure a wide variety of ailments. However, only a few studies have reported its anticancer effects. In this study, extracts were obtained from alfalfa leaves and their cytotoxic effects were assessed on several sensitive and multidrug-resistant tumor cells lines. Using the mouse leukaemia P388 cell line and its doxorubicin-resistant counterpart (P388/DOX), we showed that the inhibition of cell growth induced by alfalfa leaf extracts was mediated through the induction of apoptosis, as evidenced by DNA fragmentation analysis. The execution of programmed cell death was achieved via the activation of caspase-3, leading to PARP cleavage. Fractionation of toluene extract (To-1), the most active extract obtained from crude extract, led to the identification of 3 terpene derivatives and 5 flavonoids. Among them, (-) medicarpin, (-)-melilotocarpan E, millepurpan, tricin, and chrysoeriol showed cytotoxic effects in P388 as well as P388/DOX cells. These results demonstrate that alfalfa leaf extract may have interesting potential in cancer chemoprevention and therapy. PMID- 24628412 TI - The intestinal microbiome in type 1 diabetes. AB - Few concepts in recent years have garnered more disease research attention than that of the intestinal (i.e. 'gut') microbiome. This emerging interest has included investigations of the microbiome's role in the pathogenesis of a variety of autoimmune disorders, including type 1 diabetes (T1D). Indeed, a growing number of recent studies of patients with T1D or at varying levels of risk for this disease, as well as in animal models of the disorder, lend increasing support to the notion that alterations in the microbiome precede T1D onset. Herein, we review these investigations, examining the mechanisms by which the microbiome may influence T1D development and explore how multi-disciplinary analysis of the microbiome and the host immune response may provide novel biomarkers and therapeutic options for prevention of T1D. PMID- 24628413 TI - Elevated levels of polychlorinated biphenyls in plants, air, and soils at an E waste site in Southern China and enantioselective biotransformation of chiral PCBs in plants. AB - E-waste that contains polychlorinated biphenyls (PCBs) is moved across national boundaries, often from industrialized countries in the northern hemisphere, where the items were formerly used, to subtropical and tropical regions in southeastern Asia and Africa. As a result, there is a high likelihood that PCBs will be released into the environment from a primary source due to the elevated temperatures encountered in these low-latitude regions. In the present study, PCBs and enantiomer fractions (EFs) of chiral PCBs (PCB 84, 95, 132, 136, 149, and 183) were analyzed in air, eucalyptus leaves, pine needles, and soil at an e waste site and a rural site in southern China. The concentrations of PCBs at the e-waste site ranged from 7825 to 76330 pg/m(3), 27.5 to 1993 ng/g, and 24.2 to 12045 ng/g in the air (gas plus particle), plant leaves, and soils, respectively. The atmospheric PCB composition profiles in the present study indicated relatively high abundances of penta- and hexa-PCBs, which were different from those previously observed in the air across China. The Clausius-Clapeyron regression analysis indicated that evaporation from local contaminated surfaces constitutes a primary emission source of PCBs in the air at the e-waste site. The chiral signatures of PCBs in the air at the e-waste site were essentially racemic (mean EFs = (0.484 +/- 0.022)-(0.499 +/- 0.004) in the gaseous phase) except for PCB 84 (0.420 +/- 0.050), indicating that racemic sources dominate the PCB emission in the air. PCB chiral signatures in the soils ((0.422 +/- 0.038)-(0.515 +/- 0.016)) were similar to those in the air except for PCB 95. However, the chiral PCBs in the plants (especially the eucalyptus leaves) had significantly nonracemic residues ((0.368 +/- 0.075)-(0.561 +/- 0.045)) compared to those in the air and soil. This finding suggests that enantioselective biotransformation of these atropisomeric PCBs was very likely to occur in the plant leaves, possibly due to metabolism by cytochrome P-450 enzymes in leaves. To our knowledge, this is the first report on the enantioselective metabolism of chiral PCBs in plants under field conditions. PMID- 24628415 TI - Camp-based immersion treatment for obese, low socioeconomic status, multi-ethnic adolescents. AB - BACKGROUND: Immersion treatment (IT) provided in a camp setting has been shown to promote short-term improvements in weight and health status in obese adolescents. However, evidence of IT's long-term efficacy and efficacy for multi-ethnic and lower socioeconomic status (SES) adolescents is limited. METHODS: This was a cohort study with a pre/post design and longitudinal follow-up. The intervention was a 19-day camp-based IT program comprising (1) a nutrition curriculum and ad lib access to a nutritious diet, (2) several hours of physical activity daily, (3) group therapy, and (4) cognitive-behavioral therapy (CBT). This analysis included 52 low-SES adolescents that participated in 2009 and 2010. A subgroup of 33 campers and their families was offered follow-up monthly for 10 months. Primary outcome measures were change in weight-related parameters immediately postcamp and after 10 months of follow-up. RESULTS: Campers had significant short term improvements in mean waist circumference (mean [M], 2.6; standard deviation [SD], 3.2 cm), weight (M, 2.6; SD, 1.9 kg), BMI (M, 1.1; SD, 0.9 kg/m2), BMI z score (M, 0.06; SD, 0.07), and percent overweight (M, 6.1; SD, 4.7). Campers offered follow-up had a modest increase in mean percent overweight (M, 2.0; SD, 8.4) during 10 months of follow-up. However, 33% experienced continuing decline in percent overweight during follow-up, and long-term follow-up was associated with significant overall (precamp vs. end of follow-up) improvements in percent overweight (M, 4.9; SD, 7.2). CONCLUSIONS: Camp-based IT with CBT is a promising intervention for improving short- and long-term weight status of low-SES adolescents. Additional research is needed to increase long-term efficacy. PMID- 24628416 TI - Cancer during pregnancy. AB - Cancer during pregnancy is a rare and complex problem involving many different health care professionals, which emphasizes the need for a multidisciplinary teamwork. Obstetricians are continuously involved from antenatal care to delivery and the puerperal period including lactation. Recent research indicates that most chemotherapy administered in the second and third trimester does not have serious impact on the health and development of the children and that most pregnant women with cancer treatment should go to term and aim for a vaginal delivery. However, continuous registration and follow-up of these women and their children is needed in an international setting to obtain sufficient numbers, and not least a multidisciplinary contribution to cover the different aspects of management and surveillance of pregnant women with cancer. PMID- 24628414 TI - Disparities in quality of care among publicly insured adults with schizophrenia in four large U.S. states, 2002-2008. AB - OBJECTIVE: To examine racial/ethnic disparities in quality of schizophrenia care and assess the size of observed disparities across states and over time. DATA SOURCES: Medicaid claims data from CA, FL, NY, and NC. STUDY DESIGN: Observational repeated cross-sectional panel cohort study of white, black, and Latino fee-for-service adult beneficiaries with schizophrenia. Main outcome was the relationship of race/ethnicity and year with a composite measure of quality of schizophrenia care derived from 14 evidence-based quality indicators. PRINCIPAL FINDINGS: Quality was assessed for 325,373 twelve-month person-episodes between 2002 and 2008, corresponding to 123,496 Medicaid beneficiaries. In 2002, quality was lowest for blacks in all states. With the exception of FL, quality was lower for Latinos than whites. In CA, blacks had about 43 percent of the individual indicators met compared to 58 percent for whites. Quality improved annually for all groups in CA, NY, and NC. While in CA the improvement was slightly larger for Latinos, in FL quality improved for blacks but declined for Latinos and whites. CONCLUSIONS: Quality of schizophrenia care is poor and racial/ethnic disparities exist among Medicaid beneficiaries from four states. The size of the disparities varied across the states, and most of the initial disparities were unchanged by 2008. PMID- 24628417 TI - Altered agonist sensitivity of a mutant v2 receptor suggests a novel therapeutic strategy for nephrogenic diabetes insipidus. AB - Loss-of-function mutations of the type 2 vasopressin receptor (V2R) in kidney can lead to nephrogenic diabetes insipidus (NDI). We studied a previously described, but uncharacterized, mutation of the V2R (N321K missense mutation) of a patient with NDI. The properties of the mutant receptor were evaluated. We constructed a highly sensitive Epac-based bioluminescence resonance energy transfer biosensor to perform real-time cAMP measurements after agonist stimulation of transiently transfected HEK293 cells with V2Rs. beta-Arrestin binding of the activated receptors was examined with luciferase-tagged beta-arrestin and mVenus-tagged V2Rs using the bioluminescence resonance energy transfer technique. Cell surface expression levels of hemagglutinin-tagged receptors were determined with flow cytometry using anti-hemagglutinin-Alexa 488 antibodies. Cellular localization examinations were implemented with fluorescent tagged receptors visualized with confocal laser scanning microscopy. The effect of various vasopressin analogs on the type 1 vasopressin receptor (V1R) was tested on mouse arteries by wire myography. The N321K mutant V2R showed normal cell surface expression, but the potency of arginine vasopressin for cAMP generation was low, whereas the clinically used desmopressin was not efficient. The beta-arrestin binding and internalization properties of the mutant receptor were also different than those for the wild type. The function of the mutant receptor can be rescued with administration of the V2R agonist Val(4)-desmopressin, which had no detectable side effects on V1R in the effective cAMP generating concentrations. Based on these findings we propose a therapeutic strategy for patients with NDI carrying the N321K mutation, as our in vivo experiments suggest that Val(4)-desmopressin could rescue the function of the N321K-V2R without significant side effects on the V1R. PMID- 24628419 TI - Directed branch growth in aligned nanowire arrays. AB - Branch growth is directed along two, three, or four in-plane directions in vertically aligned nanowire arrays using vapor-liquid-solid glancing angle deposition (VLS-GLAD) flux engineering. In this work, a dynamically controlled collimated vapor flux guides branch placement during the self-catalyzed epitaxial growth of branched indium tin oxide nanowire arrays. The flux is positioned to grow branches on select nanowire facets, enabling fabrication of aligned nanotree arrays with L-, T-, or X-branching. In addition, a flux motion algorithm is designed to selectively elongate branches along one in-plane axis. Nanotrees are found to be aligned across large areas by X-ray diffraction pole figure analysis and through branch length and orientation measurements collected over 140 MUm(2) from scanning electron microscopy images for each array. The pathway to guided assembly of nanowire architectures with controlled interconnectivity in three dimensions using VLS-GLAD is discussed. PMID- 24628418 TI - Thioredoxin-interacting protein stimulates its own expression via a positive feedback loop. AB - Thioredoxin-interacting protein (TXNIP) has emerged as a key regulator of important cellular processes including redox state, inflammation, and apoptosis and plays a particularly critical role in pancreatic beta-cell biology and diabetes development. High glucose and diabetes induce TXNIP expression, whereas inhibition of TXNIP expression or TXNIP deficiency protects against pancreatic beta-cell apoptosis and diabetes. We now have discovered that TXNIP stimulates its own expression by promoting dephosphorylation and nuclear translocation of its transcription factor, carbohydrate response element-binding protein (ChREBP), resulting in a positive feedback loop as well as regulation of other ChREBP target genes playing important roles in glucose and lipid metabolism. Considering the detrimental effects of elevated TXNIP in beta-cell biology, this novel pathway sheds new light onto the vicious cycle of increased TXNIP, leading to even more TXNIP expression, oxidative stress, inflammation, beta-cell apoptosis, and diabetes progression. Moreover, the results demonstrate, for the first time, that TXNIP modulates ChREBP activity and thereby uncover a previously unappreciated link between TXNIP signaling and cell metabolism. PMID- 24628420 TI - Increase in insulin-induced relaxation of consecutive arterial segments toward the periphery: Role of vascular oxidative state. AB - RATIONALE: The oxidative state has been implicated in the signaling of various vasomotor functions, yet its role regarding the vasomotor action of insulin is less known. OBJECTIVE: To investigate the insulin-evoked relaxations of consecutive arterial segments of different oxidative state and the role of extracellular signal-regulated kinase (ERK) pathway. METHODS AND RESULTS: The oxidative state, as assessed by the level of ortho-tyrosine, was higher in the thoracic aorta of rats than in the abdominal aorta, and was the lowest in the femoral artery. The vasomotor function of vessels of same origin was studied using a small-vessel myograph. Insulin-induced relaxations increased toward the periphery (i.e., thoracic < abdominal < femoral). Aortic banding and hydrogen peroxide/aminotriazole increased the oxidative state of the thoracic aorta that was accompanied by ERK activation and decreased relaxation to insulin, and vice versa, acutely lowered oxidative state by superoxide dismutase/catalase improved relaxation. In contrast, insulin-induced relaxation of the femoral artery could be enhanced with a higher oxidative state, and reduced with a lower state. CONCLUSIONS: Oxidative state of vessels modulates the magnitude of vasomotor responses to insulin, which appears to be mediated via the ERK signaling pathway. PMID- 24628421 TI - Inhibitory effects and analysis of RNA interference on thioredoxin glutathione reductase expression in Schistosoma japonicum. AB - Schistosomes infect around 280 million people worldwide. The worms survive in the veins of the final host, where thioredoxin glutathione reductase (TGR) activity helps the parasites to survive in the aerobic environment. In the present study, we synthesized 4 small interfering RNAs (siRNA S1, S2, S3, and S4) targeting the Schistosoma japonicum (Sj) TGR gene and used them to knockdown the TGR gene. The knockdown effects of the siRNAs on SjTGR, and the thioredoxin reductase (TrxR) activity of SjTGR, were evaluated in vitro. The results of transfection with the siRNAs via the soaking method in vitro were confirmed by flow cytometry. S2 siRNA at a final concentration of 200 nM partially inhibited the expression of SjTGR at both the transcript and protein levels in vitro. TrxR-activity was lower in worms in the S2 siRNA-treated group compared with the control groups. Further analysis revealed that purified recombinant SjTGR could remove oxygen free radicals but not H(2)O(2) directly, which may explain the incomplete effects of RNA interference on SjTGR. The results of this study indicate that SjTGR may play an important role in the clearance of oxygen free radicals and protection of S. japonicum parasites against oxidative damage. PMID- 24628422 TI - Effect of Cissampelos capensis rhizome extract on human spermatozoa in vitro. AB - Cissampelos capensis is commonly known by the Afrikaans name 'dawidjies' or 'dawidjieswortel'. C. capensis is the most important and best-known medicinal plant of the family Menispermaceae used by the Khoisan and other rural people in the western regions of South Africa. Among numerous other ailments, it is traditionally taken to treat male fertility problems. Yet, no studies have investigated the effects of this plant or its extracts on human spermatozoa. The aim of study was to investigate the effects of C. capensis extracts on sperm function. A total of 77 semen samples were collected. Spermatozoa were washed with HTF-BSA medium and incubated with different concentrations of C. capensis (0, 0.05, 0.5, 5, 50, 200 MUg ml(-1) ) for 1 h at 37 degrees C. Sperm motility, vitality, acrosome reaction, reactive oxygen species (ROS), capacitation, Annexin V binding, DNA fragmentation and mitochondrial membrane potential (Deltapsim ) were determined. While viability, Annexin V positivity and Deltapsim were not affected, the percentages of ROS-positive, TUNEL-positive, capacitated and hyperactivated spermatozoa increased significantly and dose-dependently. It is concluded that the alkaloids present in the extract of C. capansis rhizomes triggered sperm intrinsic superoxide production leading to sperm capacitation and DNA fragmentation. PMID- 24628423 TI - Age-related effects on the potency of human adipose-derived stem cells: creation and evaluation of superlots and implications for musculoskeletal tissue engineering applications. AB - Human adipose-derived stem cells (hASC) are now a prevalent source of adult stem cells for studies in tissue engineering and regenerative medicine. However, researchers utilizing hASC in their investigations often encounter high levels of donor-to-donor variability in hASC differentiation potential. Because of this, conducting studies with this primary cell type can require extensive resources to generate statistically significant data. We present a method to generate pooled donor cell populations, termed "superlots," containing cell populations derived from four to five age-clustered donors. The goal of generating these superlots was to 1) increase experimental throughput, 2) to utilize assay resources more efficiently, and 3) to begin to establish global hASC differentiation behaviors that may be associated with donor age. With our superlot approach, we have validated that pooled donor cell populations exhibit proliferative activity representing the combined behavior of each individual donor cell line. Further, the superlots also exhibit differentiation levels roughly approximating the average combined differentiation levels of each individual donor cell line. We established that high donor-to-donor variability exists between the pre-, peri-, and postmenopausal age groupings and that proliferation and differentiation characteristics can vary widely, independent of age. Interestingly, we did observe that cell lines derived from postmenopausal donors demonstrated a relatively high proclivity for osteogenic differentiation and a relatively lowered proclivity for adipogenic differentiation as compared with cells derived from pre- and perimenopausal donors. In general, superlots effectively represented the average differentiation behavior of each of their contributing cell populations and could provide a powerful tool for increasing experimental throughput to more efficiently utilize resources when studying hASC differentiation. PMID- 24628424 TI - Promotoras as facilitators of change: Latinas' perspectives after participating in a lifestyle behaviour intervention program. AB - AIM: To describe immigrant Latinas' perspectives of a lifestyle behaviour intervention, focusing on their interactions with and perceptions of the promotoras who delivered the program in the USA. BACKGROUND: Immigrant Latinas in the USA have high obesity rates, which contribute to increased risk for cardiovascular disease and other long-term diseases. Interventions using the promotora model appear to be effective in reducing cardiovascular disease risk by improving dietary habits, physical activity and selected clinical variables among Latinas. However, there has been very limited enquiry into what it is about these interventions and promotoras that facilitates behaviour change, from the perspective of participants. DESIGN: Grounded theory methodology guided the data collection and analysis. METHODS: This qualitative study was completed in 2012 in California, after the end of a lifestyle behaviour intervention. Four focus groups and seven one-on-one interviews were conducted with a total of 18 immigrant Latina intervention participants. RESULTS: Women described promotoras as helping them change by motivating them through three interconnected elements: tools, support and knowledge. Latinas viewed their ability to make lifestyle changes as connected with their emotional and psychological health and saw promotoras as counsellors who gave emotional and social support. In this respect, the intervention was emotionally therapeutic for this sample of Latinas, although this was not the original intention of the program. CONCLUSION: Promotoras gave the backbone of the intervention and were crucial in motivating Latinas to implement lifestyle changes. Future lifestyle behaviour interventions should include a strong component of mental and emotional well-being. PMID- 24628426 TI - Thermodynamic and phylogenetic insights into hnRNP A1 recognition of the HIV-1 exon splicing silencer 3 element. AB - Complete expression of the HIV-1 genome requires balanced usage of suboptimal splice sites. The 3' acceptor site A7 (ssA7) is negatively regulated in part by an interaction between the host hnRNP A1 protein and a viral splicing silencer (ESS3). Binding of hnRNP A1 to ESS3 and other upstream silencers is sufficient to occlude spliceosome assembly. Efforts to understand the splicing repressive properties of hnRNP A1 on ssA7 have revealed hnRNP A1 binds specific sites within the context of a highly folded RNA structure; however, biochemical models assert hnRNP A1 disrupts RNA structure through cooperative spreading. In an effort to improve our understanding of the ssA7 binding properties of hnRNP A1, herein we have performed a combined phylogenetic and biophysical study of the interaction of its UP1 domain with ESS3. Phylogenetic analyses of group M sequences (x = 2860) taken from the Los Alamos HIV database reveal the ESS3 stem loop (SL3(ESS3)) structure has been conserved throughout HIV-1 evolution, despite variations in primary sequence. Calorimetric titrations with UP1 clearly show the SL3(ESS3) structure is a critical binding determinant because deletion of the base-paired region reduces the affinity by ~150-fold (Kd values of 27.8 nM and 4.2 MUM). Cytosine substitutions of conserved apical loop nucleobases show UP1 preferentially binds purines over pyrimidines, where site-specific interactions were detected via saturation transfer difference nuclear magnetic resonance. Chemical shift mapping of the UP1-SL3(ESS3) interface by (1)H-(15)N heteronuclear single-quantum coherence spectroscopy titrations reveals a broad interaction surface on UP1 that encompasses both RRM domains and the inter-RRM linker. Collectively, our results describe a UP1 binding mechanism that is likely different from current models used to explain the alternative splicing properties of hnRNP A1. PMID- 24628427 TI - Use of multispecies occupancy models to evaluate the response of bird communities to forest degradation associated with logging. AB - Forest degradation is arguably the greatest threat to biodiversity, ecosystem services, and rural livelihoods. Therefore, increasing understanding of how organisms respond to degradation is essential for management and conservation planning. We were motivated by the need for rapid and practical analytical tools to assess the influence of management and degradation on biodiversity and system state in areas subject to rapid environmental change. We compared bird community composition and size in managed (ejido, i.e., communally owned lands) and unmanaged (national park) forests in the Sierra Tarahumara region, Mexico, using multispecies occupancy models and data from a 2-year breeding bird survey. Unmanaged sites had on average higher species occupancy and richness than managed sites. Most species were present in low numbers as indicated by lower values of detection and occupancy associated with logging-induced degradation. Less than 10% of species had occupancy probabilities >0.5, and degradation had no positive effects on occupancy. The estimated metacommunity size of 125 exceeded previous estimates for the region, and sites with mature trees and uneven-aged forest stand characteristics contained the highest species richness. Higher estimation uncertainty and decreases in richness and occupancy for all species, including habitat generalists, were associated with degraded young, even-aged stands. Our findings show that multispecies occupancy methods provide tractable measures of biodiversity and system state and valuable decision support for landholders and managers. These techniques can be used to rapidly address gaps in biodiversity information, threats to biodiversity, and vulnerabilities of species of interest on a landscape level, even in degraded or fast-changing environments. Moreover, such tools may be particularly relevant in the assessment of species richness and distribution in a wide array of habitats. PMID- 24628428 TI - Establishing IMMULITE(r) 2000 cut-off values for serum allergen-specific immunoglobulin and exploring their relationship to exhaled nitric oxide. AB - AIM: Paediatric cut-off values for serum allergen-specific IgE (sIgE) using the Siemens IMMULITE((r)) 2000 system to diagnose allergic rhinoconjunctivitis have not been established. We aimed to determine cut-off levels for sIgE for 10 common inhalant allergens and to study the relationship between sIgE, total IgE and fractional exhaled nitric oxide (FENO ). METHODS: We enrolled 243 schoolchildren, including 164 with allergic rhinoconjunctivitis. Parental interviews, skin prick tests, sIgE, total IgE, FENO measurements, spirometry and exercise tests were performed. RESULTS: Cut-off values with the best combined sensitivity and specificity were above the detection limit of the assay for seven of the ten allergens (0.23-1.1 kU/L). The overall accuracy of the IMMULITE((r)) in detecting allergic rhinoconjunctivitis was good. sIgE was superior to total IgE and FENO in predicting allergic rhinoconjunctivitis to timothy, birch, mugwort, cat, dog and house dust mite. FENO was elevated in children with allergic rhinoconjunctivitis, irrespective of asthma. CONCLUSION: Cut-off values for sIgE were dependent on the allergic phenotype and were above the IMMULITE((r)) detection limit for seven of ten inhalant allergens. Consequently, using the detection limit for sIgE as the decision point would result in over-diagnosing allergic rhinoconjunctivitis. When measuring elevated FENO in children, allergic rhinoconjunctivitis should be suspected. PMID- 24628429 TI - Congenital lymphangiomatosis and an enteric duplication cyst in a young dog. AB - A two-year-old female poodle with abdominal distention was diagnosed with concurrent enteric duplication cyst and lymphangiomatosis. Both lesions were shown as cystic structures, but some characteristic features of enteric duplication cyst were identified including a thick cyst wall and shared blood supply with the duodenum. Although it was challenging to discriminate between the types of cyst based on diagnostic imaging, this report describes the characteristics of each type of lesion using several different imaging modalities. PMID- 24628425 TI - Annual research review: Reaction time variability in ADHD and autism spectrum disorders: measurement and mechanisms of a proposed trans-diagnostic phenotype. AB - BACKGROUND: Intraindividual variability in reaction time (RT) has received extensive discussion as an indicator of cognitive performance, a putative intermediate phenotype of many clinical disorders, and a possible trans diagnostic phenotype that may elucidate shared risk factors for mechanisms of psychiatric illnesses. SCOPE AND METHODOLOGY: Using the examples of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), we discuss RT variability. We first present a new meta-analysis of RT variability in ASD with and without comorbid ADHD. We then discuss potential mechanisms that may account for RT variability and statistical models that disentangle the cognitive processes affecting RTs. We then report a second meta-analysis comparing ADHD and non-ADHD children on diffusion model parameters. We consider how findings inform the search for neural correlates of RT variability. FINDINGS: Results suggest that RT variability is increased in ASD only when children with comorbid ADHD are included in the sample. Furthermore, RT variability in ADHD is explained by moderate to large increases (d = 0.63-0.99) in the ex-Gaussian parameter tau and the diffusion parameter drift rate, as well as by smaller differences (d = 0.32) in the diffusion parameter of nondecision time. The former may suggest problems in state regulation or arousal and difficulty detecting signal from noise, whereas the latter may reflect contributions from deficits in motor organization or output. The neuroimaging literature converges with this multicomponent interpretation and also highlights the role of top-down control circuits. CONCLUSION: We underscore the importance of considering the interactions between top-down control, state regulation (e.g., arousal), and motor preparation when interpreting RT variability and conclude that decomposition of the RT signal provides superior interpretive power and suggests mechanisms convergent with those implicated using other cognitive paradigms. We conclude with specific recommendations for the field for next steps in the study of RT variability in neurodevelopmental disorders. PMID- 24628430 TI - The interaction of enolase-1 with caveolae-associated proteins regulates its subcellular localization. AB - Cell-surface-associated proteolysis plays a crucial role in embryonic development, monocyte/macrophage recruitment and tumour cell invasion. The glycolytic enzyme ENO-1 (enolase-1) is translocated from the cytoplasm to the cell surface, where it binds PLG (plasminogen) to enhance pericellular plasmin production and cell motility. In the present study, ENO-1 was found to localize to a specialized subset of lipid rafts called caveolae as demonstrated by fluorescence confocal microscopy and sucrose gradient ultracentrifugation. Co immunoprecipitation studies revealed that ENO-1 interacts with Cav-1 (caveolin 1), but not with Cav-2, via the CSD (Cav-scaffolding domain). Moreover, an evolutionarily conserved CBM (Cav-binding motif) F296DQDDWGAW304 was identified within ENO-1. The point mutation W301A within the ENO-1 CBM was, however, not sufficient to disrupt ENO-1-Cav-1 interaction, whereas the mutations F296A and W304A markedly affected ENO-1 protein expression. Furthermore, ENO-1 was found associated with Annx2 (annexin 2), representing another caveolar protein, and this interaction was dependent on Cav-1 expression. Knockdown of Cav-1 and Annx2 markedly decreased cell surface expression of ENO-1. ENO-1 overexpression increased cell migration and invasion in a Cav-1-dependent manner. Thus the differential association of ENO-1 with caveolar proteins regulates ENO-1 subcellular localization and, consequently, ENO-1-dependent cell migration and invasion. PMID- 24628431 TI - Photoreactivity of unfunctionalized single-wall carbon nanotubes involving hydroxyl radical: chiral dependency and surface coating effect. AB - Single-wall carbon nanotubes (SWCNTs) have a variety of potential and demonstrated applications, and their production rates are increasing rapidly. This increase in production has motivated research on their transport and potential transformation and their toxicity in the environment. In this work, we examined the direct and indirect photoreactivity of SWCNTs under sunlight conditions. We found that the direct photoreactivity of pristine SWCNTs is generally low; however, indirect photoreaction involving .OH may be significant in natural aquatic environments. Environmental photochemical reactions generating .OH lead to distinct changes in SWCNT fluorescence efficiency in the near infrared (NIR) region, Raman spectra, and light attenuation spectra in the UV, visible, and NIR regions, indicating that covalent functionalization of SWCNTs occurs. The reactivity of SWCNTs to .OH is dependent on the specific chiral structure of the SWCNTs and the surfactant associated with it. An operationally defined second-order rate constant (based on the decrease in NIR fluorescence signals) for all SWCNT chiral species reacting with .OH was estimated to be (2.91 +/- 1.30) * 10(10) M(-1 )s(-1). Our work suggests that photochemical reactions may be a significant transformation pathway of SWCNTs in aquatic systems. PMID- 24628432 TI - Nutritional and Antioxidant Potential of Lentil Sprouts Affected by Elicitation with Temperature Stress. AB - The influences of temperature stress on antioxidant potential and nutritional quality of lentil sprouts were studied. Temperature treatments (TC, 1 h at 4 degrees C; TH, 1 h at 40 degrees C) significantly improved the nutraceutical potential without any negative effect on nutritional quality. In comparison to control, elicited sprouts were characterized by elevated content of condensed tannins, flavonoids, and total phenolics. The highest content of total phenolics and flavonoids was determined for 6-day-old TH sprouts -23.7 +/- 0.87 and 2.50 +/ 0.07 mg/(g of dry weight (DW)), respectively. The general trend of antiradical, lipid preventing, and reducing properties in elicited sprouts indicates a significantly improvement of these activities. The highest reducing power was determined for 6-day-old sprouts induced at TH (0.43 +/- 0.02 mmol of Trolox/(g of DW)), while the lowest for 3-day-old sprouts elicited at TC (0.29 +/- 0.02 mmol of Trolox/(g of DW)). Both modifications effectively elevated the ability to prevent lipids against oxidation (in 3-day-old sprouts a 3.3- and 4-fold increase for TC and TH, respectively). PMID- 24628433 TI - Efficacious treatment of psoriasis with low-dose and intermittent cyclosporin microemulsion therapy. AB - Cyclosporin is used for moderate to severe psoriasis and improves not only the skin lesions but also quality of life of the patients. To improve its safe use, we evaluated a low-dose, intermittent regimen of cyclosporin in the treatment of psoriasis vulgaris. Seventy-three patients received approximately 2.5 mg/kg per day of cyclosporin microemulsion twice daily before breakfast and dinner for 2-12 weeks until 75% reduction was achieved in Psoriasis Area and Severity Index (PASI) score. When the skin lesions relapsed after cessation of cyclosporin and showed less than 50% reduction from baseline in PASI score, cyclosporin was restarted. This cessation and restart cycle was repeated if necessary. Treatment outcomes were assessed at 12, 48 and 96 weeks after initiation of the therapy. The initial dose of cyclosporin was 2.32 +/- 0.27 (standard deviation [SD]) mg/kg per day. At baseline, the mean PASI score was 11.3 +/- 5.3 (SD). An average of 49.8 +/- 23.8 (SD) days of the therapy achieved PASI 75% reduction. In 20 of 73 patients, the second course of cyclosporin was required. The mean interval between the first and second course was 94 days. An average of 60.8 +/- 26.9 days was required to achieve PASI 75% reduction in the second course, which was not significantly longer than that in the first course. Only six patients required cyclosporin for 96 weeks. The adverse effects included one case of hypertension. Our study suggests that low-dose, intermittent cyclosporin microemulsion is efficacious for the treatment of moderate to severe psoriasis. PMID- 24628434 TI - The use of proton pump inhibitors and the spectrum and number of biliary pathogens in patients with acute cholangitis. AB - BACKGROUND: Knowledge of the bacterial spectrum for acute cholangitis is essential for adequate empiric antibiotic treatment. AIM: To analyse the relation of proton pump inhibitors (PPI) with biliary pathogens in patients with acute cholangitis. METHODS: This retrospective study identified 278 patients with 318 acute cholangitis episodes using an endoscopic database. The relationship between PPI and microbiological outcomes was assessed by logistic and poisson regression analysis for binary and count data. RESULTS: In total, 882 pathogens were isolated, of which, 120 cholangitis episodes occurred with PPI; 198 cholangitis episodes without PPI. Multivariate poisson regression analysis showed that PPI use resulted in a 23% increase in the number of biliary pathogens [3.14 vs. 2.55 (Delta = 0.59), P < 0.01], whereas stent therapy, previous interventional procedures (endoscopic retrograde cholangiography/percutaneous transhepatic cholangiography), genesis, age and sex showed no significant association with the number of biliary pathogens. Significantly, more cholangitis episodes with more than one pathogen isolated occurred during PPI treatment [103/120 (86%) vs. 151/198 (76%), P = 0.04]. Analysis of intrinsic anti-microbial resistance patterns was performed: Anti-microbial combination therapies were significantly more required to cover all isolated pathogens in cholangitis episodes with PPI than in cholangitis episodes without PPI (44/120 vs. 46/198, P = 0.01). Additionally, PPI use was associated with a significantly higher incidence of oropharyngeal flora in the biliary tract (53/120 vs. 61/198, P = 0.02). CONCLUSIONS: Proton pump inhibitors seem to influence biliary pathogens by increasing the number and broadening the spectrum of biliary pathogens. However, the findings of this hypothesis-generating study need to be tested by confirmatory studies. PMID- 24628435 TI - Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens. AB - Butyrate, a commonly applied feed additive in poultry nutrition, can modify the expression of certain genes, including those encoding cytochrome P450 (CYP) enzymes. In comparative in vitro and in vivo experiments, the effect of butyrate on hepatic CYP genes was examined in primary cultures of chicken hepatocytes and in liver samples of chickens collected from animals that had been given butyrate as a feed additive. Moreover, the effect of butyrate on the biotransformation of erythromycin, a marker substance for the activity of enzymes of the CYP3A family, was investigated in vitro and in vivo. Butyrate increased the expression of the avian-specific CYP2H1 both in vitro and in vivo. In contrast, the avian CYP3A37 expression was decreased in hepatocytes following butyrate exposure, but not in the in vivo model. CYP1A was suppressed by butyrate in the in vitro experiments, and overexpressed in vivo in butyrate-fed animals. The concomitant incubation of hepatocytes with butyrate and erythromycin led to an increased CYP2H1 expression and a less pronounced inhibition of CYP3A37. In in vivo pharmacokinetic experiments, butyrate-fed animals given a single i.m. injection of erythromycin, a slower absorption phase (longer T(half-abs) and delayed T(max)) but a rapid elimination phase of this marker substrate was observed. Although these measurable differences were detected in the pharmacokinetics of erythromycin, it is unlikely that a concomitant application of sodium butyrate with erythromycin or other CYP substrates will cause clinically significant feed-drug interaction in chickens. PMID- 24628436 TI - Characterization of adverse events detected in a large health care delivery system using an enhanced global trigger tool over a five-year interval. AB - OBJECTIVE: To report 5 years of adverse events (AEs) identified using an enhanced Global Trigger Tool (GTT) in a large health care system. STUDY SETTING: Records from monthly random samples of adults admitted to eight acute care hospitals from 2007 to 2011 with lengths of stay >=3 days were reviewed. STUDY DESIGN: We examined AE incidence overall and by presence on admission, severity, stemming from care provided versus omitted, preventability, and category; and the overlap with commonly used AE-detection systems. DATA COLLECTION: Professional nurse reviewers abstracted 9,017 records using the enhanced GTT, recording triggers and AEs. Medical record/account numbers were matched to identify overlapping voluntary reports or AHRQ Patient Safety Indicators (PSIs). PRINCIPAL FINDINGS: Estimated AE rates were as follows: 61.4 AEs/1,000 patient-days, 38.1 AEs/100 discharges, and 32.1 percent of patients with >=1 AE. Of 1,300 present-on admission AEs (37.9 percent of total), 78.5 percent showed NCC-MERP level F harm and 87.6 percent were "preventable/possibly preventable." Of 2,129 hospital acquired AEs, 63.3 percent had level E harm, 70.8 percent were "preventable/possibly preventable"; the most common category was "surgical/procedural" (40.5 percent). Voluntary reports and PSIs captured <5 percent of encounters with hospital-acquired AEs. CONCLUSIONS: AEs are common and potentially amenable to prevention. GTT-identified AEs are seldom caught by commonly used AE-detection systems. PMID- 24628437 TI - Influence of intra-pocket anesthesia gel on treatment outcome in periodontal patients: a randomized controlled trial. AB - AIM: Compare the treatment outcome after scaling and root-planing using local anesthesia gel or injected local anesthesia. MATERIAL AND METHOD: Thirty-eight patients with periodontitis and good general health were included in a randomized, single-blind, split-mouth clinical trial. Probing depths and clinical attachment levels were recorded at baseline and 6 weeks after treatment. Performed treatment procedures were scaling and root planing using two types of local anesthesia for separate treatment appointments. Anesthetics used were intra pocket lidocaine and prilocaine gel (2.5% each) and injected articaine (1:100,000 adrenaline). Type of anesthesia for first appointment was randomized and switched for second appointment. Patients' pain perception and anesthesia acceptance were recorded on questionnaires. RESULTS: No influence of applied type of anesthesia could be detected for change of probing pocket depths and clinical attachment level (p > 0.05). These findings are valid even for deeper pockets. Gel-group had significant higher intra-operative pain perception. In retrospect 69% of patients favored gel. CONCLUSION: Treatment outcome is not compromised by use of anesthesia gel in comparison to injected anesthesia. The same beneficial results for probing pocket depths and clinical attachment gain could be detected. The majority of patients prefer local anesthesia gel despite a slightly greater procedural discomfort. PMID- 24628438 TI - Working memory training in young children with ADHD: a randomized placebo controlled trial. AB - BACKGROUND: Until now, working memory training has not reached sufficient evidence as effective treatment for ADHD core symptoms in children with ADHD; for young children with ADHD, no studies are available. To this end, a triple-blind, randomized, placebo-controlled study was designed to assess the efficacy of Cogmed Working Memory Training (CWMT) in young children with ADHD. METHODS: Fifty one children (5-7 years) with a DSM-IV-TR diagnosis of ADHD (without current psychotropic medication) were randomly assigned to the active (adaptive) or placebo (nonadaptive) training condition for 25 sessions during 5 weeks. The compliance criterion (>20 sessions) was met for 47 children. The primary outcome measure concerned the core behavioural symptoms of ADHD, measured with the ADHD Rating Scale IV (ADHD-RS). Secondary outcome measures were neurocognitive functioning, daily executive functioning, and global clinical functioning. The influence of the increase in difficulty level (Index-Improvement) for the treatment group was also analysed. Clinical trial registration information - 'Working Memory Training in Young ADHD Children'; www.clinicaltrials.gov; NCT00819611. RESULTS: A significant improvement in favour of the active condition was found on a verbal working memory task (p = .041; adapted Digit Span WISC-III, backward condition). However, it did not survive correction for multiple testing. No significant treatment effect on any of the primary or other secondary outcome measurements was found. The Index-Improvement significantly contributed to ADHD RS and the Behavior Rating Inventory of Executive Function, both rated by the teacher, but revealed no significant group difference. CONCLUSIONS: This study failed to find robust evidence for benefits of CMWT over the placebo training on behavioural symptoms, neurocognitive, daily executive, and global clinical functioning in young children with ADHD. PMID- 24628439 TI - Primary care of female adolescents with type 1 diabetes mellitus and disordered eating. AB - AIM: To identify the role of the nurse practitioner in caring for female adolescents with type 1 diabetes mellitus at risk for disordered eating behaviour and to formulate clinical recommendations for nurse practitioners in the primary care setting. BACKGROUND: Transition into adulthood can be difficult for female adolescents with type 1 diabetes mellitus. Challenges associated with management of this illness may place adolescent females at an increased risk for disordered eating. DESIGN: Discussion paper. DATA SOURCES: Sourced literature from 1991 2013, located through CINAHL, Health Source, Proquest, PubMed, PsychInfo, Web of Science and Medline databases. IMPLICATIONS FOR NURSING: Nurses involved in the primary care of female adolescents with type 1 diabetes mellitus need to be aware of the increased risk for disordered eating behaviours and develop the competencies to care for both the adolescent and her family to reduce the serious consequences of these behaviours. CONCLUSION: Awareness and acquisition of the skills required to intervene will enable nurse practitioners to recognize clients at risk for disordered eating, gain appreciation of the motivation of female adolescents with type 1 diabetes mellitus towards disordered eating behaviours and give optimal opportunity for education, counselling and recovery. Future direction for research includes exploration of the experiences of adolescents with type 1 diabetes mellitus; early interventions in the primary care setting; effective educational, preventative or supportive services for adolescents with this illness and their families; and outcomes to emerging technologies for insulin therapy on disordered eating occurrence. PMID- 24628440 TI - What is suppression of anti-adeno-associated virus capsid T-cells achieving? PMID- 24628442 TI - Vocal activity as a low cost and scalable index of seabird colony size. AB - Although wildlife conservation actions have increased globally in number and complexity, the lack of scalable, cost-effective monitoring methods limits adaptive management and the evaluation of conservation efficacy. Automated sensors and computer-aided analyses provide a scalable and increasingly cost effective tool for conservation monitoring. A key assumption of automated acoustic monitoring of birds is that measures of acoustic activity at colony sites are correlated with the relative abundance of nesting birds. We tested this assumption for nesting Forster's terns (Sterna forsteri) in San Francisco Bay for 2 breeding seasons. Sensors recorded ambient sound at 7 colonies that had 15-111 nests in 2009 and 2010. Colonies were spaced at least 250 m apart and ranged from 36 to 2,571 m(2) . We used spectrogram cross-correlation to automate the detection of tern calls from recordings. We calculated mean seasonal call rate and compared it with mean active nest count at each colony. Acoustic activity explained 71% of the variation in nest abundance between breeding sites and 88% of the change in colony size between years. These results validate a primary assumption of acoustic indices; that is, for terns, acoustic activity is correlated to relative abundance, a fundamental step toward designing rigorous and scalable acoustic monitoring programs to measure the effectiveness of conservation actions for colonial birds and other acoustically active wildlife. PMID- 24628443 TI - Organic dyes containing fluorene decorated with imidazole units for dye sensitized solar cells. AB - New organic dyes containing fluorene functionalized with two imidazole chromophores as donors and cyanoacrylic acid acceptors have been synthesized and successfully demonstrated as sensitizers in nanocrystalline TiO2-based dye sensitized solar cells (DSSCs). The monoimidazole analogues were also synthesized for comparison. The Sommelet reaction of bromomethylated 2-bromo-9,9-diethyl-9H fluorene produced the key precursor 7-bromo-9,9-diethyl-9H-fluorene-2,4 dicarbaldehyde required for the preparation of imidazole-functionalized fluorenes. Since the dyes possess weak donor segment, the electron-richness of the conjugation pathway dictated the optical, electrochemical, and photovoltaic properties of the dyes. The dyes served as sensitizers in DSSC and exhibited moderate efficiency up to 3.44%. The additional imidazole present on the fluorene has been found to retard the electron recombination due to the bulkier hydrophobic environment and led to high open-circuit voltage in the devices. PMID- 24628445 TI - Sciadopitysin alleviates methylglyoxal-mediated glycation in osteoblastic MC3T3 E1 cells by enhancing glyoxalase system and mitochondrial biogenesis. AB - Methylglyoxal (MG) is a precursor of advanced glycation end products, which contribute to diabetic complications, including bone defects. In the present study, the effect of sciadopitysin on MG-induced cytotoxicity was investigated using osteoblastic MC3T3-E1 cells. Pretreatment of MC3T3-E1 cells with sciadopitysin prevented the MG-induced cell death and protein adducts formation. Sciadopitysin restored the MG-induced change in glyoxalase activity almost to the control level and increased glutathione levels. In addition, sciadopitysin decreased MG-induced formation of intracellular reactive oxygen species (ROS), mitochondrial superoxide, and cardiolipin peroxidation. These findings suggest that sciadopitysin provides a protective action against MG-induced glycation by increasing MG detoxification system and by reducing oxidative stress. Pretreatment with sciadopitysin prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential (MMP) dissipation and adenosine triphosphate (ATP) loss. The nitric oxide (NO) level was decreased by MG treatment, but it was significantly increased by sciadopitysin, suggesting that sciadopitysin may induce NO-dependent mitochondrial biogenesis. Furthermore, sciadopitysin treatment increased the levels of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM). These findings indicate that sciadopitysin might exert its therapeutic effects via upregulation of mitochondrial biogenesis. Therefore, sciadopitysin may prevent the development of diabetic osteopathy. PMID- 24628446 TI - Highly stable skyrmion state in helimagnetic MnSi nanowires. AB - Topologically stable magnetic skyrmions realized in B20 metal silicide or germanide compounds with helimagnetic order are very promising for magnetic memory and logic devices. However, these applications are hindered because the skyrmions only survive in a small temperature-field (T-H) pocket near the critical temperature Tc in bulk materials. Here we demonstrate that the skyrmion state in helimagnetic MnSi nanowires with varied sizes from 400 to 250 nm can exist in a substantially extended T-H region. Magnetoresistance measurements under a moderate external magnetic field along the long axis of the nanowires (H?) show transitions corresponding to the skyrmion state from Tc ~32 K down to at least 3 K, the lowest temperature in our measurement. When the field is applied perpendicular to the wire axis (H?), the skyrmion state was not resolvable using the magnetoresistance measurements. Our analysis suggests that the shape-induced uniaxial anisotropy might be responsible for the stabilization of skyrmion state observed in nanowires. PMID- 24628444 TI - Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes. AB - Type 1 diabetes (T1DM) is a T cell-mediated autoimmune disease that selectively destroys pancreatic beta cells. The only possible cure for T1DM is to control autoimmunity against beta cell-specific antigens. We explored whether the natural compound curcumin, with anti-oxidant and anti-inflammatory activities, might down regulate the T cell response that destroys pancreatic beta cells to improve disease outcome in autoimmune diabetes. We employed two accelerated autoimmune diabetes models: (i) cyclophosphamide (CYP) administration to non-obese diabetic (NOD) mice and (ii) adoptive transfer of diabetogenic splenocytes into NODscid mice. Curcumin treatment led to significant delay of disease onset, and in some instances prevented autoimmune diabetes by inhibiting pancreatic leucocyte infiltration and preserving insulin-expressing cells. To investigate the mechanisms of protection we studied the effect of curcumin on key immune cell populations involved in the pathogenesis of the disease. Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-gamma production through modulation of T-box expressed in T cells (T-bet), a key transcription factor for proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Also, curcumin reduces nuclear factor (NF)-kappaB activation in T cell receptor (TCR)-stimulated NOD lymphocytes. In addition, curcumin impairs the T cell stimulatory function of dendritic cells with reduced secretion of proinflammatory cytokines and nitric oxide (NO) and low surface expression of co-stimulatory molecules, leading to an overall diminished antigen-presenting cell activity. These in-vitro effects correlated with ex-vivo analysis of cells obtained from curcumin-treated mice during the course of autoimmune diabetes. These findings reveal an effective therapeutic effect of curcumin in autoimmune diabetes by its actions on key immune cells responsible for beta cell death. PMID- 24628447 TI - Sexual assault: where are mid-life women in the research? AB - PURPOSE: There is extensive literature related to the experience of sexual assault of women with a majority focused on younger women, college-aged women, or older women. There is little research about the experience of sexual assault of mid-life women. DESIGN AND METHODS: This paper synthesizes the current literature associated with sexual assault by describing the increased number of single women in the population, defining terms associated with sexual assault, examining rape myths, characteristics of the victim, describing the relationship of victim to assailant, extent of victimization experienced by women, common physical injuries, age-related physiological changes, psychological considerations, and post-traumatic stress disorder specific to mid-life women. FINDINGS: The population of single women has increased across the life span. Current studies utilize varying definitions of sexual assault, examine results across variable age groups, and include the responses of single women with married women. Characteristics of victims demonstrate similarities by age group, relationship type, living conditions, and physical or mental capabilities that affect the occurrence of sexual assault. PRACTICE IMPLICATIONS: There are few studies that examine the sexual assault experiences of single mid-life women. Further research into the experiences of single mid-life women is warranted to provide direction for nursing education programs and clinical practice. PMID- 24628448 TI - Antifungal Activity of Citrus Essential Oils. AB - Citrus essential oils (CEOs) are a mixture of volatile compounds consisting mainly of monoterpene hydrocarbons and are widely used in the food and pharmaceutical industries because of their antifungal activities. To face the challenge of growing public awareness and concern about food and health safety, studies concerning natural biopreservatives have become the focus of multidisciplinary research efforts. In the past decades, a large amount of literature has been published on the antifungal activity of CEOs. This paper reviews the advances of research on CEOs and focuses on their in vitro and food antifungal activities, chemical compositions of CEOs, and the methods used in antifungal assessment. Furthermore, the antifungal bioactive components in CEOs and their potential mechanism of action are summarized. Finally, the applications of CEOs in the food industry are discussed in an attempt to provide new information for future utilization of CEOs in modern industries. PMID- 24628450 TI - Once more unto the breach. PMID- 24628451 TI - Mitigating overdiagnosis and overtreatment in breast cancer: what is the role of the pathologist? PMID- 24628449 TI - Physician practice participation in accountable care organizations: the emergence of the unicorn. AB - OBJECTIVE: To provide the first nationally based information on physician practice involvement in ACOs. DATA SOURCES/STUDY SETTING: Primary data from the third National Survey of Physician Organizations (January 2012-May 2013). STUDY DESIGN: We conducted a 40-minute phone survey in a sample of physician practices. A nationally representative sample of practices was surveyed in order to provide estimates of organizational characteristics, care management processes, ACO participation, and related variables for four major chronic illnesses. DATA COLLECTION/EXTRACTION METHODS: We evaluated the associations between ACO participation, organizational characteristics, and a 25-point index of patient centered medical home processes. PRINCIPAL FINDINGS: We found that 23.7 percent of physician practices (n = 280) reported joining an ACO; 15.7 percent (n = 186) were planning to become involved within the next 12 months and 60.6 percent (n = 717) reported no involvement and no plans to become involved. Larger practices, those receiving patients from an IPA and/or PHO, those that were physician-owned versus hospital/health system-owned, those located in New England, and those with greater patient-centered medical home (PCMH) care management processes were more likely to have joined an ACO. CONCLUSIONS: Physician practices that are currently participating in ACOs appear to be relatively large, or to be members of an IPA or PHO, are less likely to be hospital-owned and are more likely to use more care management processes than nonparticipating practices. PMID- 24628453 TI - Body composition in late preterm infants in the first 10 days of life and at full term. AB - AIM: To investigate changes in body weight, fat-free mass, fat mass and percentage of body fat during early life and at full-term postconceptional age (PCA) in preterm infants born after 32 gestational weeks and before 37. METHODS: Twenty-nine late preterm infants underwent growth and body composition assessment by air displacement plethysmography (ADP) at the age of 4 days and at full-term PCA. In 25 of these infants, body composition was assessed three times between days four and nine of life. The preterm infants were compared with 29 full-term infants, matched for gestational age, sex and body weight. RESULTS: There was a significant increase in birth weight and fat-free mass between days four and nine of life. Preterm infants had significantly more body fat 382 +/- 180 g vs 287 +/- 160 g than full-term infants at full-term PCA. Preterm infants showed poor linear growth between birth and full-term PCA. CONCLUSION: Weight gain after the initial postnatal weight loss consists of gain in fat-free mass. At full-term PCA, preterm infants were stunted. When compared with full-term new born infants matched for body weight and gestational age, preterm infants had more body fat and a higher percentage of body fat. PMID- 24628454 TI - The influence of a glucosyltransferase, encoded by gtfP, on biofilm formation by Streptococcus sanguinis in a dual-species model. AB - Streptococcus sanguinis is an early colonizer of tooth surfaces and forms biofilms with other species of microorganisms. In vitro, S. sanguinis produces water-soluble glucans from sucrose and releases them into the culture supernatant; however, the role played by these glucans in biofilm formation is unclear. The present study examined both the effect of glucans on biofilm formation by S. sanguinis and the proportion of this bacterial species within the biofilms. Inactivation of the gtfP gene, annotated as glucosyltransferase in the S. sanguinis genome database, caused a marked reduction in the amount of water soluble glucans in the culture supernatant, but not in the amount of water insoluble glucans expressed on the bacterial cell surface. Scanning electron microscopy revealed that wild-type S. sanguinis, but not the gtfP-deficient mutant, produced large amounts of sticky material in the presence of 1% (w/v) sucrose. In addition, biofilm production by wild-type bacteria was greater than that by the mutant strain. By contrast, co-culture of mutant bacteria with Streptococcus mutans, S. sobrinus, S. oralis, S. gordonii, S. anginosus, or S. salivarius showed that inactivating the gtfP gene had little effect on the amount of biofilm produced. Furthermore, inactivating the gtfP gene did not greatly alter the proportion of S. sanguinis in the biofilms formed by the co-cultures. Thus, despite the role of S. sanguinis glucosyltransferase in formation of water soluble glucans and biofilms in monoculture, the functional gene contributed little to biofilms in co-culture experiments. PMID- 24628452 TI - Theranostic unimolecular micelles based on brush-shaped amphiphilic block copolymers for tumor-targeted drug delivery and positron emission tomography imaging. AB - Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for (64)Cu labeling to generate multifunctional theranostic unimolecular micelles. The backbone of the brush-shaped amphiphilic block copolymer was poly(2-hydroxyethyl methacrylate) (PHEMA) and the side chains were poly(L-lactide)-poly(ethylene glycol) (PLLA-PEG). The doxorubicin (DOX)-loaded unimolecular micelles showed a pH-dependent drug release profile and a uniform size distribution. A significantly higher cellular uptake of TRC105-conjugated micelles was observed in CD105-positive human umbilical vein endothelial cells (HUVEC) than nontargeted micelles due to CD105-mediated endocytosis. In contrast, similar and extremely low cellular uptake of both targeted and nontargeted micelles was observed in MCF 7 human breast cancer cells (CD105-negative). The difference between the in vivo tumor accumulation of (64)Cu-labeled TRC105-conjugated micelles and that of nontargeted micelles was studied in 4T1 murine breast tumor-bearing mice, by serial positron emission tomography (PET) imaging and validated by biodistribution studies. These multifunctional unimolecular micelles offer pH responsive drug release, noninvasive PET imaging capability, together with both passive and active tumor-targeting abilities, thus making them a desirable nanoplatform for cancer theranostics. PMID- 24628455 TI - Diurnal variation of urinary markers of nucleic acid oxidation. AB - AIMS: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8 dihydroguanosine (8-oxoGuo) are biomarkers of oxidative stress with clinical potential in a variety of diseases. As part of their clinical validation, this study aimed to investigate whether the urinary excretion of 8-oxodG and 8-oxoGuo undergoes diurnal variation and to evaluate the validity of 6-hour sampling as well as creatinine corrected spot urine sampling. METHODS: A total of 23 healthy study subjects collecting their 24-h urine in four fractions covering 6 hours each. Urinary 8-oxodG and 8-oxoGuo levels were quantified using a modified version of UPLC-MS/MS. RESULTS: No significant difference in excretion levels between the 12-h diurnal and 12-h nocturnal state or between the four 6-h periods during the day was found for either biomarker. A strong linear relationship between the excretion levels in each of the 6-h periods and the 24-h excretion level was shown for both biomarkers. Creatinine correction of the 6-h levels reduced the biological variation of the excretion levels and weakened the linear relationship with the uncorrected 24-h excretion level for both biomarkers. The correlations were strengthened when the 24-h excretion level was expressed per kg body weight. CONCLUSION: The results showed that 8-oxodG and 8-oxoGuo did not undergo diurnal variation in the study population overall and hence that the time of sampling is not crucial. Furthermore, 6-h sampling can be used as a substitute for 24-h sampling, and creatinine corrected sampling may be rational due to the reduction in biological variation of the biomarkers and the reasonable correlation with body weight-adjusted 24-h levels. PMID- 24628456 TI - Abscess infections and malnutrition--a cross-sectional study of polydrug addicts in Oslo, Norway. AB - BACKGROUND: Injection drug use and malnutrition are widespread among polydrug addicts in Oslo, Norway, but little is known about the frequency of abscess infections and possible relations to malnutrition. OBJECTIVES: To assess the prevalence of abscess infections, and differences in nutritional status between drug addicts with or without abscess infections. DESIGN: A cross-sectional study of 195 polydrug addicts encompassing interview of demographics, dietary recall, anthropometric measurements and biochemical analyses. All respondents were under the influence of illicit drugs and were not participating in any drug treatment or rehabilitation program at the time of investigation. RESULTS: Abscess infections were reported by 25% of the respondents, 19% of the men and 33% of the women (p = 0.025). Underweight (BMI < 18.5 kg/m(2)) was significantly more prevalent in the abscess infected than in the non-abscess-infected group (p = 0.001). The abscess-infected addicts reported fewer meals, lower intakes of fruits and vegetables, lower energy percentage (E%) from protein and higher E% from sugar. They also had lower total intakes of vitamins D, B1, B6, B12, folic acid and vitamin C than the non-abscess-infected group. The two groups differed significantly with respect to S-C-peptide (p = 0.042) and B-HbA1c (p = 0.012), and the prevalence of hyperhomocysteinemia (P-tHCY > 15 MUmol/L) was 73% in the abscess-infected group and 41% in the non-abscess-infected group (p = 0.001). The concentrations of S-25-hydroxy-vitamin D3 was very low. CONCLUSION: The prevalence of abscess infections was 25% among the examined polydrug addicts. Dietary, anthropometric and biochemical assessment indicated a relation between abscess infections and malnutrition. PMID- 24628457 TI - The structure of lipid bilayers adsorbed on activated carboxy-terminated monolayers investigated by sum frequency generation spectroscopy. AB - The formation and structure of isotopically asymmetric supported bilayer membranes (SBMs) has been investigated using sum frequency generation (SFG) vibrational spectroscopy supplemented by reflection absorption infrared spectroscopy (RAIRS). The bilayers were composed of a proximal and distal leaflet of the phospholipid dipalmitoyl phosphatidylethanolamine (DPPE) supported on a gold surface. The proximal leaflet was chemically tethered to the gold via an 11 mercapto-undecanoic acid (MUA) self-assembled monolayer (SAM) that had been chemically modified to produce an activated succinimidyl ester headgroup using N hydroxysuccinimide (NHS) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). The activation of the MUA and the tethering of the DPPE were monitored and confirmed using SFG and RAIRS. The distal leaflet of the bilayer was added using either vesicle fusion (VF) or Langmuir-Blodgett (LB) deposition. To gain insight into the structure of each layer of the SBM perdeuterated DPPE (d-DPPE) and MUA (d-MUA) were used to create SBMs with a layer that was isotopically distinguishable from the rest. The polar orientation and conformational ordering of the lipids was determined using SFG. It was found that the tethering of the proximal lipid leaflet resulted in an increase in the conformational order of the MUA SAM. Furthermore, by careful analysis and comparison of spectra recorded in both the C-H (2800-3000 cm(-1)) and C-D (2000-2300 cm(-1)) stretching regions it was concluded that a better ordered and more biologically relevant lipid bilayer was formed when the distal leaflet was added using LB deposition. On the other hand the SFG spectra of the SBMs in which the distal leaflet was added by VF showed little evidence of conformational ordering on the time scale of minutes, suggesting the presence of an incomplete monolayer or of multilayer formation. PMID- 24628458 TI - Interactive effects of silver nanoparticles and phosphorus on phytoplankton growth in natural waters. AB - Increasing amounts of silver nanoparticles (AgNPs) are expected to enter the aquatic ecosystems where their effects on natural phytoplankton communities are poorly understood. We investigated the effects of AgNPs and its interactions with phosphorus (P) supply on the growth kinetics and stoichiometry of natural phytoplankton. Lake water was dosed with AgNPs (carboxy-functionalized capping agent; ~10-nm particle size; ~20% Ag w/w) at four different concentrations and five P concentrations and incubated in situ for 3 days. A treatment with ionic silver (AgNO3) was used as a positive control. We found that growth rates, calculated from changes in seston carbon and chlorophyll, responded significantly and interactively (p < 0.0001) to both AgNPs and P. AgNPs reduced the maximum phytoplankton growth rates by 11-85%. In the positive control, no or very little growth was observed. Inhibition of growth rates after exposure to Ag might be related to the reduction in chlorophyll and the inhibition of C and N acquisition rather than P uptake mechanisms. AgNPs, P supply and their interactions also significantly (p < 0.0001) reduced sestonic C:P and N:P ratios and increased C:N, C:Chl and cell-bound Ag stoichiometry. Our results indicate that fate and toxicity of AgNP will vary with phosphorus pollution level in aquatic ecosystems. PMID- 24628460 TI - miR-424 levels in hair shaft are increased in psoriatic patients. AB - Objective diagnostic markers have not been in clinical use for psoriasis. In this study, we investigated the levels of miR-424 in hair roots and hair shafts in psoriatic patients, and evaluated the possibility that miR-424 can be a biomarker of the disease. A single hair root and five pieces of hair shafts (~5 cm in length) were obtained from the non-lesional occiput of each individual of 26 psoriatic patients. Control hair samples were collected from nine normal subjects. Samples from 10 atopic dermatitis patients were also included as the disease control. miR-424 levels were determined by quantitative real-time polymerase chain reaction. Hair shaft miR-424 levels were significantly upregulated only in patients with psoriasis compared with normal controls and those with atopic dermatitis. By receiver-operator curve analysis of hair shaft miR-424 to distinguish psoriatic patients from normal subjects, the area under the curve was 0.77. However, relative miR-424 levels were not correlated with disease activity markers including disease duration, body surface area and Psoriasis Area and Severity Index. Hair root miR-424 was not useful for evaluating both diagnosis and severity of the disease. Our results indicated hair shaft miR-424 levels may be useful as a diagnostic marker of psoriasis. PMID- 24628459 TI - Depressive comorbidity in preschool anxiety disorder. AB - BACKGROUND: The threshold for clinical relevance of preschool anxiety has recently come under increasing scrutiny in view of large variations in prevalence estimates. We studied the impact of presence/absence of additional depressive comorbidity (symptoms and/or diagnosis) on preschoolers with anxiety disorders in relation to clinical phenomenology, family, and peer problems compared to healthy controls. METHOD: A population of 1738 preschoolers were screened and oversampled for internalizing symptoms from community sites, yielding a sample of 236 children. RESULTS: Using a multi-informant approach (mother, father, teacher, child), we found evidence that children with anxiety disorders and depressive comorbidity display a greater internalizing symptom-load, more peer problems and live in families with more psychosocial impairment (poor family functioning, family adversity, maternal mental health problems). The pure anxiety group was merely dissociable from controls with regard to internalizing symptoms and family adversity. CONCLUSION: The presence of depressive comorbidity in anxiety disorders may mark the transition to a more detrimental and impairing disorder at preschool age. PMID- 24628461 TI - Prospective memory in young and older adults: the effects of task importance and ongoing task load. AB - Remembering to perform an action in the future, called prospective memory, often shows age-related differences in favor of young adults when tested in the laboratory. Recently Smith, Horn, and Bayen (2012; Aging, Neuropsychology, and Cognition, 19, 495) embedded a PM task in an ongoing color-matching task and manipulated the difficulty of the ongoing task by varying the number of colors on each trial of the task. Smith et al. found that age-related differences in PM performance (lower PM performance for older adults relative to young adults) persisted even when older adults could perform the ongoing task as well or better than the young adults. The current study investigates a possible explanation for the pattern of results reported by Smith et al. by including a manipulation of task emphasis: for half of the participants the prospective memory task was emphasize, while for the other half the ongoing color-matching task was emphasized. Older adults performed a 4-color version of the ongoing color matching task, while young adults completed either the 4-color or a more difficult 6-color version of the ongoing task. Older adults failed to perform as well as the young adults on the prospective memory task regardless of task emphasis, even when older adults were performing as well or better than the young adults on the ongoing color-matching task. The current results indicate that the lack of an effect of ongoing task load on prospective memory task performance is not due to a perception that one or the other task is more important than the other. PMID- 24628462 TI - Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits. AB - Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n = 6/group) were given a single oral GaM dose (50 mg/kg). Serial blood samples were collected from 0 to 216 h post treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma-mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] alpha = 5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116 +/- 0.004 (SD) vs. 0.0171 +/ 0.0028 per hour; P = 0.03]; but half-life (59.4 +/- 24.0 vs. 39.4 +/- 10.8 h; P = 0.12); Cmax (0.50 +/- 0.21 vs. 0.59 +/- 0.42 MUg/mL; P = 0.45); tmax (1.75 +/- 0.41 vs. 0.9 +/- 0.37 h; P = 0.20); and oral clearance (6.743 +/- 1.887 vs. 7.208 +/- 2.565 L/h; P = 0.74) were not. IT's [Ga] and [Fe] were higher (P < 0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48 h GaM dosing interval is appropriate for multidose studies in EPE rabbits. PMID- 24628463 TI - Magnetic resonance imaging pattern of bone marrow involvement as a new predictive parameter of disease progression in newly diagnosed patients with multiple myeloma eligible for autologous stem cell transplantation. AB - We investigated the prognostic value of the magnetic resonance imaging (MRI) pattern of bone marrow involvement in patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). 126 patients with untreated MM indicated for ASCT underwent spine MRI and cytogenetic analysis at diagnosis. All patients received ASCT after induction therapy of VAD (vincristine, doxorubicin, dexamethasone; n = 55) or a thalidomide-based regimen (TCD; n = 71). Thalidomide maintenance therapy was performed in 68 patients. The MRI pattern was normal in 27, focal in 47, and diffuse/variegated in 52 patients. Patients with the diffuse/variegated pattern showed significantly higher stage (P = 0.038), higher beta-2 microglobulin level (P = 0.001) and severe anaemia (P = 0.015). However, the cytogenetics were not different among the MRI patterns (P = 0.890). Progression-free survival (PFS) was lower in the diffuse/variegated pattern (P = 0.002) than other patterns, but not overall survival (OS) (P = 0.058). Thalidomide maintenance therapy was correlated only with PFS (P = 0.001). High-risk cytogenetics were associated with both poorer PFS (P < 0.001) and OS (P = 0.003). In a multivariate analysis, the diffuse/variegated MRI pattern was an independent predictor of disease progression (Hazard Ratio, 1.922; 95% confidence interval, 1.185-3.118; P = 0.008). The diffuse/variegated MRI pattern is a novel prognostic factor for disease progression in MM patients eligible for ASCT. PMID- 24628465 TI - The effects of natural cigarette claims on adolescents' brand-related beliefs, attitudes, and intentions. AB - The marketing of natural cigarettes has been widely criticized by consumer advocates and public policymakers. The present research is designed to inform the ongoing policy debate by examining the effects of natural cigarette claims on adolescents' brand impressions. The authors report the results of an experiment in which high school students viewed images of cigarette packages for three different brands. Findings indicate that including natural claims on cigarette packages can weaken beliefs that the cigarettes cause diseases. Results also reveal that skepticism toward marketing claims may play an important role in undermining brand attitudes and trial intentions toward cigarette brands promoted with natural claims. Policy implications and suggestions for further research are provided. PMID- 24628464 TI - Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. AB - BACKGROUND: Safety of individual probiotic strains approved under Investigational New Drug (IND) policies in cirrhosis with minimal hepatic encephalopathy (MHE) is not clear. AIM: The primary aim of this phase I study was to evaluate the safety, tolerability of probiotic Lactobacillus GG (LGG) compared to placebo, while secondary ones were to explore its mechanism of action using cognitive, microbiome, metabolome and endotoxin analysis in MHE patients. METHODS: Cirrhotic patients with MHE patients were randomised 1:1 into LGG or placebo BID after being prescribed a standard diet and multi-vitamin regimen and were followed up for 8 weeks. Serum, urine and stool samples were collected at baseline and study end. Safety was assessed at Weeks 4 and 8. Endotoxin and systemic inflammation, microbiome using multi-tagged pyrosequencing, serum/urine metabolome were analysed between groups using correlation networks. RESULTS: Thirty MHE patients (14 LGG and 16 placebo) completed the study without any differences in serious adverse events. However, self-limited diarrhoea was more frequent in LGG patients. A standard diet was maintained and LGG batches were comparable throughout. Only in the LGG-randomised group, endotoxemia and TNF-alpha decreased, microbiome changed (reduced Enterobacteriaceae and increased Clostridiales Incertae Sedis XIV and Lachnospiraceae relative abundance) with changes in metabolite/microbiome correlations pertaining to amino acid, vitamin and secondary BA metabolism. No change in cognition was found. CONCLUSIONS: In this phase I study, Lactobacillus GG is safe and well-tolerated in cirrhosis and is associated with a reduction in endotoxemia and dysbiosis. PMID- 24628467 TI - A comparison of the orthotic effect of the Odstock Dropped Foot Stimulator and the Walkaide functional electrical stimulation systems on energy cost and speed of walking in Multiple Sclerosis. AB - Abstract Purpose: Functional electrical stimulation (FES), an assistive device used for foot drop, has been found to improve the speed and energy cost of walking in people with multiple sclerosis (pwMS). This study aims to compare the immediate orthotic effect on walking of two different devices; the Odstock Dropped Foot Stimulator (ODFS) and Walkaide (WA). Method: Twenty pwMS (10 female, 10 male, mean age 50.4 +/- 7.3 years) currently using ODFS were recruited. Participants walked for 5 min around an elliptical 9.5 m course at their preferred walking speed; once with ODFS, once with WA and once without FES on the same day of testing. Gait speed, distance and energy cost were measured. Results: There was a statistically significant increase in walking speed for the ODFS (p = 0.043) and a near to significant increase for the WA (p = 0.06) in comparison to without FES. There were no differences between the ODFS and WA in terms of either walking speed (p = 0.596) or energy cost (p = 0.205). Conclusions: This is the first pilot study to compare the effects of two different FES devices on walking. Further research recruiting a larger cohort of FES naive participants is needed. Implications for Rehabilitation Functional electrical stimulation (FES) used for foot drop in multiple sclerosis (MS) is effective in improving the speed of walking. The Odstock Dropped Foot Stimulator and the Walkaide have similar orthotic effects on the speed and energy cost of walking in people with MS. Further research is urgently needed to compare FES devices, recruiting treatment of naive participants for a fully powered RCT. PMID- 24628466 TI - Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddm rats over time compared to other congenic LEW strains. AB - The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes (T1D), which arose through a spontaneous mutation within the major histocompatibility complex (MHC)-congenic background strain LEW.1AR1. The LEW.1AR1-iddm rat is characterized by two phenotypes: diabetes development with a diabetes incidence of 60% and a variable T cell frequency in peripheral blood. In this study the immune cell repertoire of LEW.1AR1-iddm rats was analysed over time from days 30 to 90 of life and compared to the background strain LEW.1AR1 and the LEW rat strain as well as the LEW.1WR1 rat strain. The LEW.1AR1-iddm rats are characterized by a high variability of CD3(+), CD4(+) and CD8(+) T cell frequencies in peripheral blood over time, and the frequency is unique for each animal. The variability within the frequencies resulted in changes of the CD4(+) : CD8(+) T cell ratio. The other three rat strains studied were characterized by a stable but nevertheless strain-specific T cell frequency resulting in a specific CD4(+) : CD8(+) T cell ratio. The frequency of natural killer (NK) cells and B cells in LEW.1AR1-iddm rats was increased, with a higher variability compared to the other strains. Only monocytes showed no differences in frequency and variability between all strains studied. These variabilities of immune cell frequencies in the LEW.1AR1-iddm rats might lead to imbalances between autoreactive and regulatory T cells in peripheral blood as a prerequisite for diabetes development. PMID- 24628468 TI - Improving conservation outcomes with insights from local experts and bureaucracies. AB - We describe conservation built on local expertise such that it constitutes a hybrid form of traditional and bureaucratic knowledge. Researchers regularly ask how local knowledge might be applied to programs linked to protected areas. By examining the production of conservation knowledge in southern Mexico, we assert local expertise is already central to conservation. However, bureaucratic norms and social identity differences between lay experts and conservation practitioners prevent the public valuing of traditional knowledge. We make this point by contrasting 2 examples. The first is a master's thesis survey of local experts regarding the biology of the King Vulture (Sarcoramphus papa) in which data collection took place in communities adjacent to the Calakmul Biosphere Reserve. The second is a workshop sponsored by the same reserve that instructed farmers on how to monitor endangered species, including the King Vulture. In both examples, conservation knowledge would not have existed without traditional knowledge. In both examples, this traditional knowledge is absent from scientific reporting. On the basis of these findings, we suggest conservation outcomes may be improved by recognizing the knowledge contributions local experts already make to conservation programming. PMID- 24628469 TI - Anxiety across the transition to parenthood: change trajectories among low-risk parents. AB - BACKGROUND AND OBJECTIVES: A number of sources suggest changes in anxiety across the transition to parenthood may be experienced by parents in different ways, yet no studies have examined whether new parents experience changes in anxiety in distinct subgroups. DESIGN: We conducted a longitudinal study of 208 first-time parents (104 couples) from a low-risk population. Parents were interviewed from the third trimester of pregnancy to nine-months postpartum. METHODS: The current study utilized latent class growth analysis to explore subgroups of change in symptoms of anxiety. Based on stress and coping theory, we also examined a number of personal and social prenatal predictors of subgroup membership. RESULTS: We identified two distinct change trajectories: (1) moderate and stable and (2) low and declining. We also found prenatal depression, expected parenting efficacy, and relationship satisfaction were significantly associated with subgroup membership. CONCLUSIONS: Our results suggest a majority of new parents adjust well to parenthood in terms of anxiety, while a smaller subgroup of parents experience continually higher levels of anxiety months after the baby is born. PMID- 24628470 TI - Biotransformations of racemic 2,3-allenenitriles in biphasic systems: synthesis and transformations of enantioenriched axially chiral 2,3-allenoic acids and their derivatives. AB - Catalyzed by Rhodococcus erythropolis AJ270 whole cells in an aqueous phosphate buffer-n-hexane biphasic system, racemic axially chiral 2,3-allenenitriles underwent hydrolysis to afford enantioenriched (aR)-2,3-allenamides and (aS)-2,3 allenoic acids with ee's up to >99.5%. Overall biotransformations proceeded through the nitrile hydratase-catalyzed efficient but nonselective hydration of nitriles followed by the amide hydrolysis catalyzed by the substrate-dependent enantioselective amidase. The application of the method has been demonstrated by the transformations of the resulting allene products into highly functionalized heterocyclic compounds with axial chirality of reactants being entirely transferred into or expressed as point chirality of products. PMID- 24628472 TI - The entire issue is devoted to the memory of Professor Nick Turro who passed away a few months ago. PMID- 24628473 TI - Nicholas J. Turro, 1938-2012. AB - This volume of Photochemistry and Photobiology contains a memoriam to Nicholas J. Turro (1938-2012). It is a collection of review articles and papers, dedicated to his memory, authored by those who remember him as a teacher, mentor, colleague and friend. PMID- 24628471 TI - The association between long-term care setting and potentially preventable hospitalizations among older dual eligibles. AB - OBJECTIVE: To compare the probability of experiencing a potentially preventable hospitalization (PPH) between older dual eligible Medicaid home and community based service (HCBS) users and nursing home residents. DATA SOURCES: Three years of Medicaid and Medicare claims data (2003-2005) from seven states, linked to area characteristics from the Area Resource File. STUDY DESIGN: A primary diagnosis of an ambulatory care sensitive condition on the inpatient hospital claim was used to identify PPHs. We used inverse probability of treatment weighting to mitigate the potential selection of HCBS versus nursing home use. PRINCIPAL FINDINGS: The most frequent conditions accounting for PPHs were the same among the HCBS users and nursing home residents and included congestive heart failure, pneumonia, chronic obstructive pulmonary disease, urinary tract infection, and dehydration. Compared to nursing home residents, elderly HCBS users had an increased probability of experiencing both a PPH and a non-PPH. CONCLUSIONS: HCBS users' increased probability for potentially and non-PPHs suggests a need for more proactive integration of medical and long-term care. PMID- 24628475 TI - In Vitro Metabolism of Flucetosulfuron by Human Liver Microsomes. AB - To investigate herbicide metabolism, human liver microsomes were incubated with threo- and erythro-isomers of flucetosulfuron. Each isomer produced one metabolite; the metabolites were unambiguously identified as enzymatic hydrolysis products by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). These metabolites were synthesized, producing white solids characterized using LC MS/MS and nuclear magnetic resonance spectroscopy (1H and 13C). Using specific esterase inhibitors and activators, carboxylesterases and cholinesterases were demonstrated to be involved in flucetosulfuron metabolism. Under optimized metabolic conditions, the kinetic parameters for metabolite formation from threo flucetosulfuron and erythro-flucetosulfuron were: Vmax, 151.41 and 134.38 nmol/min/mg protein, respectively; Km, 2957.37 and 2798.53 MUM, respectively; and CLint, 51.20 and 48.02 MUL/min/mg microsomes respectively. No significant kinetic differences were observed between the two isomers. These results indicated that the primary metabolic pathway for both flucetosulfuron isomers in human liver microsomes involves hydrolysis, catalyzed by carboxylesterase and cholinesterase. PMID- 24628474 TI - Dark-field illumination on zero-mode waveguide/microfluidic hybrid chip reveals T4 replisomal protein interactions. AB - The ability of zero-mode waveguides (ZMWs) to guide light energy into subwavelength-diameter cylindrical nanoapertures has been exploited for single molecule fluorescence studies of biomolecules at micromolar concentrations, the typical dissociation constants for biomolecular interactions. Although epi fluorescence microscopy is now adopted for ZMW-based imaging as an alternative to the commercialized ZMW imaging platform, its suitability and performance awaits rigorous examination. Here, we present conical lens-based dark-field fluorescence microscopy in combination with a ZMW/microfluidic chip for single-molecule fluorescence imaging. We demonstrate that compared to epi-illumination, the dark field configuration displayed diminished background and noise and enhanced signal to-noise ratios. This signal-to-noise ratio for imaging using the dark-field setup remains essentially unperturbed by the presence of background fluorescent molecules at micromolar concentration. Our design allowed single-molecule FRET studies that revealed weak DNA-protein and protein-protein interactions found with T4 replisomal proteins. PMID- 24628476 TI - Decreased susceptibility to chlorhexidine and prevalence of disinfectant resistance genes among clinical isolates of Staphylococcus epidermidis. AB - Staphylococcus epidermidis is a versatile agent, being both a commensal and a nosocomial pathogen usually with an opportunistic role in association with implanted foreign body materials. Pre-operative antiseptic preparation is an important strategy for reducing the risk of complications such as surgical site infection (SSI). Currently, the most widely used antiseptics are alcohols, quaternary ammonium compounds (QACs), and the bisbiguanide chlorhexidine. Occurrence of resistance to the latter agent has drawn increasing attention. The aim of this study was to investigate if decreased susceptibility to chlorhexidine among S. epidermidis was present in our setting, a Swedish university hospital. Staphylococcus epidermidis (n = 143), retrospectively collected, were obtained from prosthetic joint infections (PJI) (n = 61), post-operative infections after cardiac surgery (n = 31), and the skin of the chest after routine disinfection prior to cardiac surgery (n = 27). In addition, 24 commensal isolates were included. Minimum inhibitory concentration (MIC) of chlorhexidine was determined on Mueller Hinton agar plates supplemented with serial dilutions of chlorhexidine. Five QAC resistance genes, qacA/B, smr, qacH, qacJ, and qacG, were detected using PCR. Decreased susceptibility to chlorhexidine was found in 54% of PJI isolates, 68% of cardiac isolates, 21% of commensal isolates, and 7% of skin isolates from cardiac patients, respectively. The qacA/B gene was present in 62/143 isolates (43%), smr in 8/143 (6%), and qacH in one isolate (0.7%). The qacA/B gene was found in 52% of PJI isolates, 61% of cardiac isolates, 25% of commensal isolates, and 19% of the skin isolates. In conclusion, decreased susceptibility to chlorhexidine, as well as QAC resistance genes, were prevalent among S. epidermidis isolates associated with deep SSIs. PMID- 24628478 TI - A network meta-analysis of the efficacy of belatacept, cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients. AB - Belatacept is a first in-class co-stimulation blocker developed for primary maintenance immunosuppression following renal transplantation. The objective of this study was to estimate the efficacy of belatacept relative to tacrolimus and cyclosporine among adults receiving a single kidney transplant. A systematic review was conducted of randomized clinical trials (RCTs) published between January 1990 and December 2013 using EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and unpublished study reports from two belatacept RCTs. Bayesian network meta-analysis (NMA) methods were used to compare the efficacy measures, mortality, graft loss, acute rejection and glomerular filtration rate (GFR). Heterogeneity was quantified using statistical metrics and potential sources were evaluated using meta-regression and subgroup analysis. A total of 28 RCTs comparing tacrolimus with cyclosporine, and three comparing belatacept with cyclosporine, were identified. All three agents provided comparable graft and patient survival, despite a higher risk of acute rejection associated with belatacept and cyclosporine. Belatacept was associated with significant improvement in GFR versus cyclosporine. Compared with tacrolimus, this difference was clinically meaningful yet statistically non-significant. The probability of being the best treatment was highest for belatacept for graft survival (68%), patient survival (97%) and renal function (89%), and highest for tacrolimus for acute rejection (99%).Variability in donor, recipient, and trial characteristics was present in the included RCTs; however, minimal statistical heterogeneity was detected in the analysis of acute rejection, graft or patient survival, and none of the characteristics were found to be significantly associated with relative effect. Although the direction of effect of immunosuppressants on GFR was consistent across RCTs, precise estimation of its magnitude was limited by a small number of RCTs and heterogeneity in relative effect sizes. Clinicians often seek an alternative to CNIs due to their nephrotoxic effects. The results of this indirect comparison indicate that belatacept is an effective immunosuppressive agent in renal transplantation among adults. PMID- 24628479 TI - Extreme carbon dioxide concentrations in acidic pit lakes provoked by water/rock interaction. AB - We quantify the gas pressure and concentration of a gas-charged acidic pit lake in SW Spain. We measured total dissolved gas pressure, carbon dioxide (CO2) concentration, major ion concentration, isotopic composition of dissolved inorganic carbon (delta(13)C(DIC)), and other physicochemical parameters. CO2 is the dominant dissolved gas in this lake and results mainly from carbonate dissolution during the interaction of acidic water with wall rocks, followed by diffusive and advective transport through the water column. The delta(13)C(DIC) values suggest that the biological contribution is comparatively small. Maximum CO2 concentrations higher than 0.1 M (~5000 mg/L) have been measured, which are only comparable to those found in volcanic crater lakes. The corresponding gas pressures of CO2 alone (pCO2 ~3.6 bar) imply 60% saturation relative to local pressure at 50 m depth. High CO2 concentrations have been observed in other pit lakes of the region. We recommend gas-specific monitoring in acidic pit lakes and, if necessary, the design of feasible degassing strategies. PMID- 24628480 TI - Effect of peroral endoscopic myotomy in achalasia patients with failure of prior pneumatic dilation: a prospective case-control study. AB - BACKGROUND AND AIM: To investigate the effectiveness of peroral endoscopic myotomy (POEM) surgery in achalasia patients with failure of prior pneumatic dilation (PD). METHODS: Twenty-one patients with a history of failed PD were prospectively recruited as the case group, and 30 patients with no history of prior treatment for achalasia were included as the control group. Outcome of POEM procedures was evaluated through esophageal manometry, timed barium esophagogram and short form 36 (SF-36) questionnaires, which were performed before surgery, at 5 days after surgery and at the last follow-up, respectively. Relief of patients' symptoms was considered as the primary outcome. Secondary outcomes included lower esophageal sphincter pressure, esophageal emptying, quality of life of the patient, and procedure-related complications. RESULTS: The two groups were matched in terms of age, gender, body mass index, and results of preoperative examinations. For patients with failed PD, it was observed that Eckardt score, lower esophageal sphincter pressure, and height of the barium column were significantly decreased after POEM surgery. Besides, the mean physical component summary and mental component summary of patients at the final follow were significantly higher than those before surgery. Complications that occurred during the surgery included three cases of subcutaneous emphysema (14.3%) and one case of pneumothorax (4.8%). Patients with failed PD were found to have the significantly longer operation time than the control group. There was no significant difference between the two groups in terms of surgical outcome at the final follow-up. CONCLUSIONS: POEM is a promising therapeutic modality for achalasia patients who have failed to respond to PD therapy. Previous dilation procedures might have no obvious influence on the efficacy of POEM surgery. PMID- 24628477 TI - NADPH oxidase-2: linking glucose, acidosis, and excitotoxicity in stroke. AB - SIGNIFICANCE: Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke. RECENT ADVANCES: Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase zeta/delta, casein kinase 2, phosphoinositide-3-kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury. CRITICAL ISSUES: Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria. FUTURE DIRECTIONS: It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade. PMID- 24628481 TI - Wetting dynamics on superhydrophilic surfaces prepared by photonic microfolding. AB - The wetting dynamic on microrough and perfectly wetting (superhydrophilic) acrylates was studied. These surfaces were achieved by coating polymer films made of poly(ethyleneterephthalate) (PET) with a hydrophilic acrylate based on hydroxypropylacrylate and polyethyleneglycolmonoacrylate, which was then cured and microroughened by photonic microfolding. The high transparency of the thin acrylate layers and polymer films allowed us to record the spreading of an applied water droplet through the film samples. Subsequently, the dynamic radius of the spreading pattern rc(t) was determined from the video recording. Various models for the wetting dynamics of superhydrophilic surfaces, namely, Tanner's law and a roughness-modified derivation published by McHale et al. in 2009, were then compared to the experimental results. Basically, the development of rc(t) in time was found to be in good agreement with McHale's model. Data analysis showed, however, that the initial phase of the spreading, that is, for t < 1 s, was not predicted well. This differing behavior relates well to a theory published by Cazabat and Cohen Stuart, who proposed that, on rough surfaces, spreading follows a power law in three time regimes. In this model, the (very) initial spreading is expected to be similar to the spreading on a smooth surface. PMID- 24628484 TI - Laryngeal tuberculosis in the United States of America: a forgotten disease. AB - Laryngeal tuberculosis (TB) was a common manifestation of TB in the early twentieth century, but now represents only 1% of all cases. Most modern case series of laryngeal TB originate outside the USA. We report a case of laryngeal TB from our institution and review other US cases published between 1970 and 2012. One hundred twenty-seven cases were identified. The mean patient age was 49 y and 28% were female. The mean duration of symptoms was 19 weeks. Dysphonia and weight loss were the most common manifestations, seen in 96% and 47% of cases, respectively. These symptoms were usually attributed to malignancy initially. Most cases involved the vocal cords. Eighty-six percent of cases had underlying pulmonary involvement. Mortality was 3%. In the USA, laryngeal TB is rarely suspected and often confused with malignancy. This infection should be considered in patients with unexplained dysphonia and weight loss. PMID- 24628483 TI - Patterns of dental services and factors that influence dental services among 64 65-year-old regular users of dental care in Denmark. AB - OBJECTIVES: To describe the pattern of dental services provided to 64-65-year-old Danes who are regular users of dental care over a 5-year period, to analyse whether this pattern is associated with socio-demographic and/or socioeconomic factors, and if different uses of dental services are related to dental status and caries experience. Finally, to discuss the future planning of dental services aimed at the increasing population of elderly citizens. [Correction made on 21 March 2014, after first online publication: The sentence 'Data on elderly's dental service are scarce, although increased use is seen and more teeth are present in this age group.' was removed.] METHODS: A cross-sectional study of all aged 64-65 (n = 37 234) who received a dental examination in 2009 was conducted. Clinical data comprised dental services received under the National Health Insurance reimbursement scheme, dental status and DMFT. Geographical, socio demographic and socioeconomic data derived from public registers. RESULTS: Almost all received restorations, while periodontal treatment was received by <50% during 5 years. Heavy use of dental services was dominated by periodontal services. Periodontal services were most prevalent in the capital and the most affluent areas. Relatively more extractions were related to low income and persons in least affluent areas. Total number of services was highest among women, persons with >=20 teeth, persons living in the capital, and where the ratio user per dentist was low. CONCLUSION: For future planning of dental care for elderly, dental status, geographical and social area-based factors and to some degree gender, income, and education must be taken into consideration as all these factors seem to influence the future demand for dental services. PMID- 24628486 TI - Editorial perspective: assessing developmental risk in cultural context: the case of 'left behind' children in rural China. PMID- 24628485 TI - Recurrent invasive pneumococcal disease in children: epidemiological, microbiological, and clinical aspects from a Danish 33-year nationwide survey (1980-2013). AB - BACKGROUND: Pneumococcal diseases play a major role in human morbidity and mortality. We present the results of a Danish nationwide study of recurrent paediatric invasive pneumococcal disease (rIPD) focusing on the epidemiological, microbiological, and clinical aspects. METHODS: All laboratory-confirmed cases of IPD in children aged 0-15 y were identified from the Neisseria and Streptococcus Reference Laboratory, Statens Serum Institut, Denmark for the period 1980-2013. rIPD was defined as isolation of Streptococcus pneumoniae from any normally sterile site >= 30 days after an initial positive culture. Clinical data were obtained for all children with rIPD. RESULTS: Of all children with IPD, 2.4% (59/2418) experienced at least 1 episode of rIPD, and an underlying condition was documented in 39 (66%). Immune deficiency due to transplantation (n = 9) was the most common disease; however, anatomic abnormalities (n = 8), complement C2 deficiency (n = 4), and congenital asplenia (n = 3) were all registered more than once. No underlying disease was detected in 18 children (31%). Based on the serotype distribution of S. pneumoniae isolates in rIPD among children aged 0-5 y (n = 41), 51%, 66%, and 78% of the cases would have been covered by the 7-, 10-, and 13-valent pneumococcal conjugate vaccines, respectively. CONCLUSIONS: Of children with an IPD episode, 2.4% experienced rIPD, and an underlying disease was documented in 66% of these children. Investigation of underlying conditions is essential in episodes of rIPD. PMID- 24628482 TI - Stem cells on the brain: modeling neurodevelopmental and neurodegenerative diseases using human induced pluripotent stem cells. AB - Seven years have passed since the initial report of the generation of induced pluripotent stem cells (iPSCs) from adult human somatic cells, and in the intervening time the field of neuroscience has developed numerous disease models using this technology. Here, we review progress in the field and describe both the advantages and potential pitfalls of modeling neurodegenerative and neurodevelopmental diseases using this technology. We include tables with information on neural differentiation protocols and studies that developed human iPSC lines to model neurological diseases. We also discuss how one can: investigate effects of genetic mutations with iPSCs, examine cell fate-specific phenotypes, best determine the specificity of a phenotype, and bring in vivo relevance to this in vitro technique. PMID- 24628487 TI - Productive failure in learning math. AB - When learning a new math concept, should learners be first taught the concept and its associated procedures and then solve problems, or solve problems first even if it leads to failure and then be taught the concept and the procedures? Two randomized-controlled studies found that both methods lead to high levels of procedural knowledge. However, students who engaged in problem solving before being taught demonstrated significantly greater conceptual understanding and ability to transfer to novel problems than those who were taught first. The second study further showed that when given an opportunity to learn from the failed problem-solving attempts of their peers, students outperformed those who were taught first, but not those who engaged in problem solving first. Process findings showed that the number of student-generated solutions significantly predicted learning outcomes. These results challenge the conventional practice of direct instruction to teach new math concepts and procedures, and propose the possibility of learning from one's own failed problem-solving attempts or those of others before receiving instruction as alternatives for better math learning. PMID- 24628488 TI - Understanding the effects of MTV's 16 and Pregnant on adolescent girls' beliefs, attitudes, and behavioral intentions toward teen pregnancy. AB - This article examines the impact of a popular documentary series about teen pregnancy, MTV's 16 and Pregnant, on adolescent girls' pregnancy-related attitudes, beliefs, and behavioral intentions. The results suggest that girls who watched 16 and Pregnant, compared with a control group, reported a lower perception of their own risk for pregnancy and a greater perception that the benefits of teen pregnancy outweigh the risks. The authors also examined the relationships between homophily and parasocial interaction with the teen moms featured in 16 and Pregnant and attitudes, beliefs, and behavioral intentions, finding that homophily predicted lower risk perceptions, greater acceptance of myths about teen pregnancy, and more favorable attitudes about teen pregnancy. Parasocial interaction demonstrated the same pattern of results, with the addition of also predicting fewer behavioral intentions to avoid teen pregnancy. Last, results revealed that teen girls' perceptions that the message of 16 and Pregnant was encouraging of teen pregnancy predicted homophily and parasocial interaction with the teen moms. Theoretical and practical implications are discussed. PMID- 24628489 TI - Synthesis of cellulose nanocrystals carrying tyrosine sulfate mimetic ligands and inhibition of alphavirus infection. AB - We present two facile approaches for introducing multivalent displays of tyrosine sulfate mimetic ligands on the surface of cellulose nanocrystals (CNCs) for application as viral inhibitors. We tested the efficacy of cellulose nanocrystals, prepared either from cotton fibers or Whatman filter paper, to inhibit alphavirus infectivity in Vero (B) cells. Cellulose nanocrystals were produced by sulfuric acid hydrolysis leading to nanocrystal surfaces decorated with anionic sulfate groups. When the fluorescent marker expressing Semliki Forest virus vector, VA7-EGFP, was incubated with CNCs, strong inhibition of virus infectivity was achieved, up to 100 and 88% for cotton and Whatman CNCs, respectively. When surface sulfate groups of CNCs were exchanged for tyrosine sulfate mimetic groups (i.e. phenyl sulfonates), improved viral inhibition was attained. Our observations suggest that the conjugation of target-specific functionalities to CNC surfaces provides a means to control their antiviral activity. Multivalent CNCs did not cause observable in vitro cytotoxicity to Vero (B) cells or human corneal epithelial (HCE-T) cells, even within the 100% virus inhibitory concentrations. Based on the similar chemistry of known polyanionic inhibitors, our results suggest the potential application of CNCs as inhibitors of other viruses, such as human immunodeficiency virus (HIV) and herpes simplex viruses. PMID- 24628490 TI - Localized reduction of graphene oxide by electrogenerated naphthalene radical anions and subsequent diazonium electrografting. AB - Herein, we describe a new localized functionalization method of graphene oxide (GO) deposited on a silicon oxide surface. The functionalization starts with the reduction of GO by electrogenerated naphthalene radical anions. The source of reducers is a microelectrode moving close to the substrate in a typical scanning electrochemical microscopy (SECM) configuration. Then, the recovery of electronic conductivity upon reduction enables the selective electrochemical functionalization of the patterns. The illustrative example is the electrografting of reduced-GO with a diazonium salt bearing a protonated amino group that can further immobilize gold nanoparticles by simple immersion. This study opens new routes for the construction of multifunctional patterned surfaces. PMID- 24628491 TI - Haemophagocytic lymphohistiocytosis following fludarabine/cyclophosphamide chemotherapy for chronic lymphocytic leukaemia. PMID- 24628492 TI - The effects of a xanthan gum-based thickener on the swallowing function of patients with dysphagia. AB - BACKGROUND: Increasing bolus viscosity of thin liquids is a basic therapeutic strategy to protect patients with oropharyngeal dysphagia (OD) from aspiration. However, conventional starch thickeners increase post-deglutitive residue. AIM: To assess the therapeutic effect of a new xanthan gum-based thickener, Resource ThickenUp Clear (Nestle Health Science, Vevey, Switzerland) on patients with oropharyngeal dysphagia. METHODS: We studied the effect of Resource ThickenUp Clear using a clinical method and videofluoroscopy on 120 patients with oropharyngeal dysphagia (66 with stroke, 41 older and 13 with neurodegenerative diseases) and 14 healthy volunteers while swallowing thin-liquid, nectar-like and spoon-thick boluses. We assessed the prevalence of signs of impaired safety and efficacy of swallow and the physiology of the swallow response. RESULTS: Increasing bolus viscosity with Resource ThickenUp Clear: (i) improved safety of swallow demonstrated by a reduction in the prevalence of cough and voice changes in the clinical study and penetrations and aspirations during video fluoroscopy. Prevalence of aspirations was 12.7% with thin liquid, 7.7% with nectar-like (P < 0.01) and 3.4% with spoon-thick (P < 0.01) viscosities. Penetration-Aspiration Scale was reduced from 3.24 +/- 0.18 at thin liquid to 2.20 +/- 0.18 at nectar like (P < 0.001) and to 1.53 +/- 0.13 at spoon-thick (P < 0.001) viscosities; (ii) did not enhance pharyngeal residue; (iii) nectar-like viscosity did not affect bolus velocity nor timing of swallow response and (iv) spoon-thick viscosity reduced bolus velocity. CONCLUSIONS: Resource ThickenUp Clear improves the safety of swallow without increasing residue providing a viscosity-dependent therapeutic effect for patients with oropharyngeal dysphagia. At nectar viscosity, the effect is due to intrinsic texture properties, spoon-thick viscosity adding changes in swallow physiology. NCT01158313. PMID- 24628493 TI - Difficult cannulation as defined by a prospective study of the Scandinavian Association for Digestive Endoscopy (SADE) in 907 ERCPs. AB - BACKGROUND: The definition of a "difficult" cannulation varies considerably in reports of endoscopic retrograde cholangiopancreatography (ERCP). AIMS: To define a difficult cannulation, which translates into higher risk of post-ERCP pancreatitis. PATIENTS AND METHODS: Prospective consecutive recording of 907 cannulations in Scandinavian centers done by experienced endoscopists. Inclusion: indication for biliary access in patients with intact papilla. Exclusion: acute non-biliary and chronic pancreatitis at time of procedure. RESULTS: The primary cannulation succeeded in 74.9%, with median values for time 0.88 min (53 s), with two attempts and with zero pancreatic passages or injections. The overall cannulation success was 97.4% and post-ERCP pancreatitis (PEP) rate was 5.3%. The median time for all successful cannulations was 1.55 min (range 0.02-94.2). If the primary cannulation succeeded, the pancreatitis rate was 2.8%; after secondary methods, it rose to 11.5%. Procedures lasting less than 5 min had a PEP rate of 2.6% versus 11.8% in those lasting longer. With one attempt, the PEP rate was 0.6%, with two 3.1%, with three to four 6.1%, and with five and more 11.9%. With one accidental pancreatic guide-wire passage, the risk of the PEP was 3.7%, and with two passages, it was 13.1%. CONCLUSIONS: If the increasing rate of PEP is taken as defining factor, the wire-guided cannulation of a native papilla can be considered difficult after 5 min, five attempts, and two pancreatic guide-wire passages when any of those limits is exceeded. PMID- 24628494 TI - A novel luminescence-based method for the detection of functionally active antibodies to muscarinic acetylcholine receptors of the M3 type (mAchR3) in patients' sera. AB - In different bioassays, functional antibodies reacting with the human muscarinic acetylcholine receptor M3(mAchR3) have been detected in sera from patients with Sjogren's syndrome (SS), and there is strong evidence that those antibodies may have pathogenetic relevance. However, depending on the method of detection, their prevalence varied. Furthermore, those bioassays are difficult to standardize. We report on the development and optimization of a novel test system based on a luminometric method to determine downstream signalling of mAchR3 which produces specific and reproducible results. Chinese hamster ovarian (CHO) cells were transfected with plasmids encoding mAchR3 and a green fluorescence protein (GFP)/aequorin fusion protein. Incubation of cells with carbachol resulted in an increase in intracellular [Ca(2+)], which was detected by measuring light emission with a luminometer, and the effect of incubation with patients' immunoglobulins (Ig) was evaluated. Optimal cell density, Ig preparation and time of incubation with patients' sera were determined. Sera from patients with primary Sjogren's syndrome (pSS; n = 40), systemic sclerosis (SSc; n = 47), myasthenia gravis (MG; n = 133) and 50 blood donors were analysed. Optimal assay conditions were obtained with a cell density of 100 000 cells/ml, isolation of Ig by ammonium sulphate precipitation and short-term incubation. Based on this highly reliable assay, 50% of the pSS patients had antibodies which inhibited carbachol-induced activation of mAchR3; none of the SSc patients, 6% of the patients with MG and 12% of the blood donors had antibodies which reacted with the mAchR3. This method facilitates the determination of functional anti-mAchR3 antibodies in patients' sera, confirmed their high prevalence in pSS patients and may, therefore, help to analyse their pathogenetic and clinical relevance in more detail. PMID- 24628495 TI - Medicaid primary care physician fees and the use of preventive services among Medicaid enrollees. AB - OBJECTIVE: The Patient Protection and Affordable Care Act (ACA) increases Medicaid physician fees for preventive care up to Medicare rates for 2013 and 2014. The purpose of this paper was to model the relationship between Medicaid preventive care payment rates and the use of U.S. Preventive Services Task Force (USPSTF)-recommended preventive care use among Medicaid enrollees. DATA SOURCES/STUDY SESSION: We used data from the 2003 and 2008 Medical Expenditure Panel Survey (MEPS), a national probability sample of the U.S. civilian, noninstitutionalized population, linked to Kaiser state Medicaid benefits data, including the state Medicaid-to-Medicare physician fee ratio in 2003 and 2008. STUDY DESIGN: Probit models were used to estimate the probability that eligible individuals received one of five USPSF-recommended preventive services. A difference-in-difference model was used to separate out the effect of changes in the Medicaid payment rate and other factors. DATA COLLECTION/EXTRACTION METHODS: Data were linked using state identifiers. PRINCIPAL FINDINGS: Although Medicaid enrollees had a lower rate of use of the five preventive services in univariate analysis, neither Medicaid enrollment nor changes in Medicaid payment rates had statistically significant effects on meeting screening recommendations for the five screenings. The results were robust to a number of different sensitivity tests. Individual and state characteristics were significant. CONCLUSIONS: Our results suggest that although temporary changes in primary care provider payments for preventive services for Medicaid enrollees may have other desirable effects, they are unlikely to substantially increase the use of these selected USPSTF recommended preventive care services among Medicaid enrollees. PMID- 24628497 TI - VLSI-compatible carbon nanotube doping technique with low work-function metal oxides. AB - Single-wall carbon nanotubes (SWCNTs) have great potential to become the channel material for future high-speed transistor technology. However, as-made carbon nanotube field effect transistors (CNFETs) are p-type in ambient, and a consistent and reproducible n-type carbon nanotube (CNT) doping technique has yet to be realized. In addition, for very large scale integration (VLSI) of CNT transistors, it is imperative to use a solid-state method that can be applied on the wafer scale. Herein we present a novel, VLSI-compatible doping technique to fabricate n-type CNT transistors using low work-function metal oxides as gate dielectrics. Using this technique we demonstrate wafer-scale, aligned CNT transistors with yttrium oxide (Y2Ox) gate dielectrics that exhibit n-type behavior with Ion/Ioff of 10(6) and inverse subthreshold slope of 95 mV/dec. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) analyses confirm that slow (~1 A/s) evaporation of yttrium on the CNTs can form a smooth surface that provides excellent wetting to CNTs. Further analysis of the yttrium oxide gate dielectric using X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) techniques revealed that partially oxidized elemental yttrium content increases underneath the surface where it acts as a reducing agent on nanotubes by donating electrons that gives rise to n-type doping in CNTs. We further confirm the mechanism for this technique with other low work-function metals such as lanthanum (La), erbium (Er), and scandium (Sc) which also provide similar CNT NFET behavior after transistor fabrication. This study paves the way to exploiting a wide range of materials for an effective n-type carbon nanotube transistor for a complementary (p- and n-type) transistor technology. PMID- 24628498 TI - Factors predicting relapse in elderly patients with major depressive disorder treated with escitalopram in an outpatient setting. AB - OBJECTIVE: We investigated which factors can best predict relapse in older patients with major depressive disorder (MDD) who have achieved remission with escitalopram. METHODS: A total of 405 patients who were 65 years or older with a primary diagnosis of MDD received 12 week, open-label escitalopram 10 or 20 mg/day. Patients in remission (MADRS <=12) at Week 12 were randomized to 24 weeks of double-blind treatment with either placebo or escitalopram (fixed dose from Week 6). RESULTS: After randomization of 312 patients in remission, patients whose dose had been increased to 20 mg escitalopram after 2 weeks of open-label treatment had a high escitalopram relapse rate (16.7%) and a placebo relapse rate of 32.5% with a hazard ratio (HR) of 2.2, whereas patients titrated to 20 mg escitalopram at Weeks 4 or 6 had a high placebo relapse rate (41.2%) and an escitalopram relapse rate of 5.7% with a HR = 8.9. A high placebo relapse rate was also observed for patients with a baseline MADRS below median, while low escitalopram relapse rates were characteristic of patients who had achieved remission by Week 6 or 8 (HR = 8.9), had a current depressive episode length below median, baseline MADRS below median (HR = 11.8), or received 10 mg for 12 weeks (HR = 6.3). A key limitation of the study was that some analyses were post hoc and that none of the comparisons between complementary subgroups had nominal p-values <0.05. CONCLUSIONS: In this post-hoc analysis of elderly patients with MDD, several factors, including female gender, early remission, low baseline MADRS score, major depressive episode (MDE) duration, and escitalopram dosage, significantly affected the relapse rate after randomization to escitalopram or placebo. PMID- 24628499 TI - Trade-offs among catch, bycatch, and landed value in the American Samoa longline fishery. AB - The interspecific preferences of fishes for different depths and habitats suggest fishers could avoid unwanted catches of some species while still effectively targeting other species. In pelagic longline fisheries, albacore (Thunnus alalunga) are often caught in relatively cooler, deeper water (>100 m) than many species of conservation concern (e.g., sea turtles, billfishes, and some sharks) that are caught in shallower water (<100 m). From 2007 to 2011, we examined the depth distributions of hooks for 1154 longline sets (3,406,946 hooks) and recorded captures by hook position on 2642 sets (7,829,498 hooks) in the American Samoa longline fishery. Twenty-three percent of hooks had a settled depth <100 m. Individuals captured in the 3 shallowest hook positions accounted for 18.3% of all bycatch. We analyzed hypothetical impacts for 25 of the most abundant species caught in the fishery by eliminating the 3 shallowest hook positions under scenarios with and without redistribution of these hooks to deeper depths. Distributions varied by species: 45.5% (n = 10) of green sea turtle (Chelonia mydas), 59.5% (n = 626) of shortbill spearfish (Tetrapturus angustirostris), 37.3% (n = 435) of silky shark (Carcharhinus falciformis), and 42.6% (n = 150) of oceanic whitetip shark (C. longimanus) were caught on the 3 shallowest hooks. Eleven percent (n = 20,435) of all tuna and 8.5% (n = 10,374) of albacore were caught on the 3 shallowest hooks. Hook elimination reduced landed value by 1.6 9.2%, and redistribution of hooks increased average annual landed value relative to the status quo by 5-11.7%. Based on these scenarios, redistribution of hooks to deeper depths may provide an economically feasible modification to longline gear that could substantially reduce bycatch for a suite of vulnerable species. Our results suggest that this method may be applicable to deep-set pelagic longline fisheries worldwide. PMID- 24628500 TI - Nodal distribution, stage migration due to diameter measurement and the prognostic significance of metastasis volume in melanoma sentinel lymph nodes: a validation study. AB - To validate metastasis location, maximum metastasis diameter (MMD) measurement induced stage migration and the prognostic significance of total metastatic volume (TMV) in melanoma sentinel lymph nodes (SLNs). A new 227 patient SLN cohort examined by complete step sectioning (250 MUm) was tested for TMV and MMD prognostic significance; metastasis location by three different three-level protocols (Central vs Peripheral vs Global); and potential treatment changing down-staging by two restricted five-level protocols [Reduced Central (250 MUm) vs Reduced Even (500 MUm) sections]. Both TMV and MMD independently predicted recurrence (TMV, hazard ratio (HR): 1.21; 95% confidence interval (CI) 1.07-1.37; p = 0.003; and MMD, HR: 1.46; 95% CI 1.08-1.98, p = 0.02) and melanoma-specific death (TMV, HR: 1.30; 95% CI 1.11-1.51; p = 0.001; and MMD, HR: 1.82; 95% CI 1.25 2.66, p = 0.002). The Central, Peripheral and Global protocols detected 72%, 76% and 83% of metastases found by complete step sectioning. Based on MMD, using the Reduced Central or Reduced Even protocols, potential treatment changing down staging occurred in 20 (20%) or 13 (13%) of SLN-positive patients. This validation study establishes that: (i) metastases are globally located in melanoma SLNs; (ii) MMD but not TMV leads to uni-directional stage migration; and (iii) TMV analysis is of prognostic significance. PMID- 24628496 TI - Accumulation of high-value lipids in single-cell microorganisms: a mechanistic approach and future perspectives. AB - In recent years attention has been focused on the utilization of microorganisms as alternatives for industrial and nutritional applications. Considerable research has been devoted to techniques for growth, extraction, and purification of high-value lipids for their use as biofuels and biosurfactants as well as high value metabolites for nutrition and health. These successes argue that the elucidation of the mechanisms underlying the microbial biosynthesis of such molecules, which are far from being completely understood, now will yield spectacular opportunities for industrial scale biomolecular production. There are important additional questions to be solved to optimize the processing strategies to take advantage of the assets of microbial lipids. The present review describes the current state of knowledge regarding lipid biosynthesis, accumulation, and transport mechanisms present in single-cell organisms, specifically yeasts, microalgae, bacteria, and archaea. Similarities and differences in biochemical pathways and strategies of different microorganisms provide a diverse toolset to the expansion of biotechnologies for lipid production. This paper is intended to inspire a generation of lipid scientists to insights that will drive the biotechnologies of microbial production as uniquely enabling players of lipid biotherapeutics, biofuels, biomaterials, and other opportunity areas into the 21st century. PMID- 24628501 TI - Contribution of extrahepatic collaterals to liver parenchymal circulation after proper hepatic artery embolization. AB - BACKGROUND AND AIM: To retrospectively evaluate proper hepatic artery embolization, with respect to the development of extrahepatic collaterals. METHODS: Proper hepatic artery embolization was performed in 18 patients with hemorrhagic arterial lesions in the hepatic hilum. Post-procedural development of extrahepatic collaterals was evaluated by computed tomography or angiography. Embolization data and liver function tests were assessed. The correlation of outcomes with portal venous stenosis, hepatic failure prior to embolization, elevation of prothrombin time, and insufficient collateral development were analyzed. RESULTS: Postoperative bleeding occurred in 17/18 patients, and one was treated for an idiopathic aneurysm of the proper hepatic artery; all treatments achieved technical success. Extrahepatic collaterals were confirmed in 13 patients. Elevations of liver function test values were transient and returned to baseline within 14 days in patients with collateral development (n = 13), but were unimproved in patients without collaterals (n = 5) (P < 0.001). Portal venous stenosis; prior hepatic failure; unrecovered, elevation of prothrombin time; and insufficient collateral development were significantly correlated with poor outcomes (P < 0.05, respectively). CONCLUSIONS: Proper hepatic artery embolization is effective for hemostasis, and extrahepatic collateral development is expected. Therefore, this is a safe treatment without prolonged hepatic ischemic damage, especially in patients without severe portal venous stenosis or prior hepatic failure. PMID- 24628502 TI - DFT study on the mechanisms and stereoselectivities of the [4 + 2] cycloadditions of enals and chalcones catalyzed by N-heterocyclic carbene. AB - The possible reaction mechanisms of stereoselective [4 + 2] cycloaddition of enals and chalcones catalyzed by N-heterocyclic carbene (NHC) have been investigated using density functional theory (DFT). The calculated results indicate that the most favorable reaction channel occurs through five steps. The first step is the nucleophilic attack on the enal by NHC. Then, there are two consecutive acid (AcOH)-assisted proton-transfer steps. Subsequently, the fourth step is the [4 + 2] cycloaddition process associated with the formation of two chiral centers, followed by dissociation of NHC and product. Our computational results demonstrate that the [4 + 2] cycloaddition is the rate-determining and stereoselectivity-determining step. The energy barrier for the SS configurational channel (17.62 kcal/mol) is the lowest one, indicating the SS configurational product should be the main product, which is in agreement with experiment. Moreover, the role of NHC catalyst in the [4 + 2] cycloaddition of enal and chalcone was explored by the analysis of global reactivity indexes. This work should be helpful for realizing the significant roles of catalyst NHC and the additive AcOH and thus provide valuable insights on the rational design of potential catalyst for this kind of reactions. PMID- 24628503 TI - DSM-5 and the miracle that never happens. PMID- 24628504 TI - Educational and skills-based interventions for preventing relationship and dating violence in adolescents and young adults. PMID- 24628505 TI - Logical metonymy resolution in a words-as-cues framework: evidence from self paced reading and probe recognition. AB - Logical metonymy resolution (begin a book -> begin reading a book or begin writing a book) has traditionally been explained either through complex lexical entries (qualia structures) or through the integration of the implicit event via post-lexical access to world knowledge. We propose that recent work within the words-as-cues paradigm can provide a more dynamic model of logical metonymy, accounting for early and dynamic integration of complex event information depending on previous contextual cues (agent and patient). We first present a self-paced reading experiment on German subordinate sentences, where metonymic sentences and their paraphrased version differ only in the presence or absence of the clause-final target verb (Der Konditor begann die Glasur -> Der Konditor begann, die Glasur aufzutragen/The baker began the icing -> The baker began spreading the icing). Longer reading times at the target verb position in a high typicality condition (baker + icing -> spread ) compared to a low-typicality (but still plausible) condition (child + icing -> spread) suggest that we make use of knowledge activated by lexical cues to build expectations about events. The early and dynamic integration of event knowledge in metonymy interpretation is bolstered by further evidence from a second experiment using the probe recognition paradigm. Presenting covert events as probes following a high typicality or a low-typicality metonymic sentence (Der Konditor begann die Glasur -> AUFTRAGEN/The baker began the icing -> SPREAD), we obtain an analogous effect of typicality at 100 ms interstimulus interval. PMID- 24628506 TI - Effects of carbon dioxide on the mobilization of metals from aquifers. AB - Potential leakages of CO2 from storage sites to shallow aquifers could have adverse impacts on the quality of potable groundwater. The mineralogy of well sorted silica sand is modified by the pH-controlled precipitation of eight metals (Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd). Continuous flow tests are performed in two fixed-bed columns packed with the modified sand by coinjecting gas CO2/distilled water (2-phase column) and distilled water (1-phase column/control test) at constant influx rates for a period of two months. The concentration of dissolved metals is measured in the effluents of columns with atomic absorption spectroscopy (AAS). Mineralogical analysis of the surface of sand grains is done before and after the flow tests with scanning electron microscopy-X-ray energy dispersive spectroscopy (SEM-EDS) and X-ray photoelectron spectroscopy (XPS), whereas the precise quantitative measurement of the metal content in the sand is done with AAS. A dynamic numerical model that couples the flow and mass-transfer processes in porous media with the equilibrium and kinetically driven metal desorption processes is developed. Inverse modeling of the continuous flow test enables us to quantify and rank the selectivity of metal mobility in terms of equilibrium and kinetic desorption parameters. The continuous CO2 dissolution and water acidification causes significant mobilization and dissolution of several metals (Mn, Ni, Cu, Zn, Co), moderate mobilization of Cr, acceleration of Cd dissolution, whereas Fe remains strongly bonded on the sand grains as goethite. The parameters estimated from lab-scale column tests might be helpful for interpreting field-scale CO2 leakage scenarios and installing relevant early warning monitoring systems. PMID- 24628507 TI - Return to system within 30 days of discharge following pediatric shunt surgery. AB - OBJECT: The rate of readmission after CSF shunt surgery is significant and has caught the attention of purchasers of health care. However, a detailed description of clinical scenarios that lead to readmissions and reoperations after index shunt surgery is lacking in the medical literature. METHODS: This study included 1755 shunt revision and insertion surgeries that were performed at a single institution between May 1, 2009, and April 30, 2013. Demographic, socioeconomic, and clinical characteristics were prospectively collected in the administrative, business, and operating room databases. Clinical events within the 30 days following discharge were reviewed and analyzed. Two events of interest, Emergency Department (ED) utilization and reoperation, were further analyzed for risk factor associations by using multivariate logistic regression. RESULTS: There were 290 readmissions within 30 days of discharge (16.5%). Admission sources included ED (n = 216), hospital transfers (n = 23), and others. Of the 290 readmissions, 184 were associated with an operation, but only 165 of these were performed by the neurosurgical service. These included surgeries for shunt occlusion and externalization (n = 150), wound revision (n = 7), and other neurosurgical procedures that were not shunt related (n = 8). The remaining readmissions (n = 106) were not associated with an operation, and only 59 patients were admitted for issues related to the index shunt surgery. When return to the ED was the dependent variable in a multivariate regression model, patients who returned to the ED were more likely to be from the Atlanta metropolitan area and to be either uninsured or insured with public assistance. When reoperation was the dependent variable, patients whose surgery started after 3 p.m. were more likely to undergo subsequent CSF shunt revision surgery on readmission. CONCLUSIONS: Of the readmissions within 30 days of shunt surgery, 74.5% were related to the index shunt surgery. Whether and to what extent these readmissions are preventable continues to be controversial. Further study is needed to identify modifiable risk factors that may eventually improve patient care. PMID- 24628508 TI - Avoiding routine postoperative head CT in children. PMID- 24628509 TI - Risk of radiation-induced malignancies from CT scanning in children who underwent shunt treatment before 6 years of age: a retrospective cohort study with a minimum 10-year follow-up. AB - OBJECT: A number of mathematical models predict the risk of future cancer from the ionizing radiation exposure of CT scanning. The predictions are alarming. Some models predict 29,000 future cancers and 14,500 deaths in the US will be directly caused by 1 year's worth of CT scanning. However, there are very few clinical data to justify or refute these claims. Young children are theoretically highly susceptible to the damaging effects of radiation. In this study, the authors examined children who underwent CSF shunt placement before 6 years of age. The authors chose to study shunt-treated patients with the assumption that these patients would undergo future imaging, facilitating surveillance. They chose a study period of 1991-2001 to allow more than 10 years of follow-up data. METHODS: The authors studied 104 consecutive children who underwent CSF shunt placement prior to 6 years of age and who had at least 10 years of follow-up data. Sixty-two of these patients underwent shunt placement prior to 1 year of age. The age at the initial scanning session, the number of future CT scanning sessions, diagnosis, and results of any future studies were recorded. The age specific radiation dose was calculated for children younger than 1 year. Children younger than 1 year at the time of shunt placement were evaluated separately, based on the assumption that they represented the highest risk cohort. The authors examined all data for any evidence of future leukemia or head/neck tumor (benign or malignant). RESULTS: These children underwent a total of 1584 CT scanning sessions over a follow-up period of 1622 person-years. A total of 517 scanning sessions were performed prior to 6 years of age, including 260 in the 1st year of life. Children who underwent shunt placement before 1 year of age underwent an average of 16.3 +/- 13.5 CT sessions (range 1-41). Children undergoing placement between 1 and 6 years of age received an average of 14.1 +/- 12.5 CT studies (range 5-52). There were no subsequent tumors (benign or malignant) or leukemia detected. CONCLUSIONS: Previously published models predict a significant number of future cancers directly caused by CT scanning. However, there are very few published clinical data. In the authors' study, zero future radiation-induced malignancies were detected after routine CT scanning in a high risk group. While the authors do not consider their single-institution study adequate to define the actual risk, their data suggest that the overall risk is low. The authors hope this study encourages future collaborative efforts to define the actual risk to patients. PMID- 24628510 TI - Traumatic rupture of the neurocentral synchondrosis of the axis in a child. AB - The authors report the first case of unilateral traumatic rupture of the C-2 neurocentral synchondrosis. A 26-month-old child was in a vehicular collision that caused his head to be rotated sharply to the left with the neck flexed. He had severe neck pain but was neurologically normal. Computerized tomography scanning showed rupture of the left C-2 neurocentral synchondrosis, a right C-2 pars interarticularis fracture, and anterior angulation of C-2 on C-3. The neck injury was unrecognized until postinjury Day 9 when an MRI study showed a tear of the posterior longitudinal ligament at C2-3 and separation of the C-2 body from the inferior anular epiphysis. A second CT showed widening of the synchondrosis fracture, increased angulation of C-2 on C-3, and distraction of the right C-2 pars fracture. The mechanism of the neurocentral synchondrosis fracture is thought to be hyperflexion-axial loading combined with leftward rotation, which provided the lateral force that overcame the cartilaginous synchondrosis and extruded the lateral mass. The patient underwent open reduction and posterior fusion of C1-3, and was maintained in a halo jacket for 4 months, when CT scans demonstrated solid C1-C3 fusion and ossification of the injured synchondrosis. Unilateral traumatic rupture of the C-2 neurocentral synchondrosis is one component of several injuries involving C-2 sustained before synchondrosis closure. The resulting C2-3 relationship is highly unstable. Reduction and C1-C3 fusion are necessary in patients with significant displacement of the adjacent bony units. PMID- 24628511 TI - Filum terminale lipomas: imaging prevalence, natural history, and conus position. AB - OBJECT: Filum terminale lipomas (FTLs) are being identified with increasing frequency due to the increasing utilization of MRI. Although an FTL may be associated with tethered cord syndrome (TCS), in many cases FTLs are diagnosed incidentally in patients without any symptoms of TCS. The natural history of FTLs is not well defined. METHODS: The authors searched the clinical and imaging records at a single institution over a 14-year interval to identify patients with FTLs. For patients with an FTL, the clinical records were reviewed for indication for imaging, presenting symptoms, perceived need for surgery, and clinical outcome. A natural history analysis was performed using all patients with more than 6 months of clinical follow-up. RESULTS: A total of 436 patients with FTL were identified. There were 217 males and 219 females. Of these patients, 282 (65%) were adults and 154 (35%) were children. Symptoms of TCS were present in 22 patients (5%). Fifty-two patients underwent surgery for FTL (12%). Sixty-four patients (15%) had a low-lying conus and 21 (5%) had a syrinx. The natural history analysis included 249 patients with a mean follow-up time of 3.5 years. In the follow-up period, only 1 patient developed new symptoms. CONCLUSIONS: Filum terminale lipomas are a common incidental finding on spinal MRI, and most patients present without associated symptoms. The untreated natural history is generally benign for asymptomatic patients. PMID- 24628512 TI - Commentary: (how) does the experience of parental divorce in childhood contextualize adult development? Reflections on Fergusson et al. (2014). PMID- 24628513 TI - "Not used but almost..."--a gender and agency analysis of the grey zone between consensual and nonconsensual sexual intercourse. AB - Rape is a widespread but underreported problem among women. In this article I explore the complexities surrounding the fine line between consensual and nonconsensual sexual intercourse, by studying a rape through which a young woman was infected with HIV. I provide an analysis of how to understand and interpret this episode by applying a gender perspective based on patriarchy-namely, women's submissive position in heterosexual situations compared with men-and the concept of agency, that is, the individual's own decision-making ability, own choices, and different courses of action available, to outline the frame of action available to the informant. The inclusion of agency and a gender perspective offers new dimensions on how to understand and give meaning to narratives that are seldom told. PMID- 24628514 TI - Review article: the investigation and management of gastric neuroendocrine tumours. AB - BACKGROUND: Gastric carcinoids (GCs) or neuroendocrine tumours (NETs) are increasingly identified at endoscopy, and account for 0.6-2% of all gastric polyps identified. The SEER database in the US has demonstrated a rising incidence of gastric NETs amongst all NETs; from 2.2% between 1950 and 1969 to 6.0% between 2000 and 2007. AIM: To review the literature and assist clinicians in managing patients with GCs. METHODS: A literature search was conducted through MEDLINE using search terms: gastric, carcinoid, neuroendocrine tumour, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles. RESULTS: There are three types of GCs with important epidemiological, pathophysiological, histological and endoscopic differences that affect prognosis and management. Type 1 and 2 GCs develop in the context of hypergastrinaemia that originates from achlorhydria in atrophic gastritis and a gastrinoma, respectively. Type 3 GCs occur sporadically and independent of gastrin. The histological type, grade and Ki67 index are used to determine prognosis and direct clinical management. Type 1 GCs >1 cm in size and type 2 GCs should be assessed for invasion beyond the submucosa with EUS prior to endoscopic resection with EMR or ESD. Type 3 GCs should be managed as per recommendations for gastric adenocarcinoma. The treatment of advanced disease is multimodal. CONCLUSIONS: Patients with gastric carcinoids should be discussed in a specialist neuroendocrine tumour multidisciplinary meeting to ensure all treatment options are explored in localised and advanced disease. Areas of controversy exist that need further research. PMID- 24628516 TI - Seeded growth of metal-doped plasmonic oxide heterodimer nanocrystals and their chemical transformation. AB - We have developed a generalized seeded-growth methodology for the synthesis of monodisperse metal-doped plasmonic oxide heterodimer nanocrystals (NCs) with a near-unity morphological yield. Using indium-doped cadmium oxide (ICO) as an example, we show that a wide variety of preformed metal NCs (Au, Pt, Pd, FePt, etc.) can serve as the seeds for the tailored synthesis of metal-ICO heterodimers with exquisite size, shape, and composition control, facilitated by the delayed nucleation mechanism of the CdO phase. The metal-ICO heterodimers exhibit broadly tunable near-infrared localized surface plasmon resonances, and dual plasmonic bands are observed for Au-ICO heterodimers. We further demonstrate that the oxide domain of the Au-ICO heterodimers can be selectively and controllably transformed into a series of partially and completely hollow cadmium chalcogenide nanoarchitectures with unprecedented structural complexity, leaving the metal domain intact. Our work not only represents an exciting addition to the rapidly expanding library of chemical reactions that produce colloidal hybrid NCs, but it also provides a general route for the bottom-up chemical design of multicomponent metal-oxide-semiconductor NCs in a rational and sequential manner. PMID- 24628515 TI - F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. AB - Total lymphoid irradiation (TLI) followed by high-dose chemotherapy and autologous haematopoietic stem cell transplant (aHSCT) is an effective strategy for patients with relapsed/refractory classical Hodgkin lymphoma (HL). We report outcomes for patients with relapsed/refractory HL who received TLI followed by high-dose chemotherapy and aHSCT. Pre-transplant fludeoxyglucose positron emission tomography (FDG-PET) studies were scored on the 5-point Deauville scale. Of 51 patients treated with TLI and aHSCT, 59% had primary refractory disease and 63% had active disease at aHSCT. The 10-year progression-free survival (PFS) and overall survival (OS) for all patients was 56% and 54%, respectively. Patients with complete response (CR) by PET prior to aHSCT had a 5-year PFS and OS of 85% and 100% compared to 52% and 48% for those without CR (P = 0.09 and P = 0.007, respectively). TLI and aHSCT yields excellent disease control and long-term survival rates for patients with relapsed/refractory HL, including those with high-risk disease features. Achievement of CR with salvage therapy is a powerful predictor of outcome. PMID- 24628517 TI - Rearrangement of N-oxyenamines and related reactions. PMID- 24628519 TI - Shift in trophic level of Mediterranean mariculture species. AB - The mean trophic level of the farmed fish species in the Mediterranean has been increasing. We examined the farming-up hypothesis (i.e., the increase in the production of high-trophic-level species) in the Mediterranean by determining the trophic level of the aquafeeds (i.e., what the fish are fed) of 5 species of farmed marine fishes: common dentex (Dentex dentex), common pandora (Pagellus erythrinus), European seabass (Dicentrarchus labrax), gilthead seabream (Sparus aurata), and red porgy (Pagrus sp.). The mean trophic level of aquafeed used in mariculture from 1950 to 2011 was higher (3.93) than the prey farmed fish consume in the wild (3.72) and increased at a faster rate (0.48/decade) compared with that based on their diets in the wild (0.43/decade). Future expected replacement of the fishmeal and oil in aquafeeds by plant materials may reverse the farming up trend, although there are a number of concerns regarding operational, nutritional, environmental, and economic issues. The farming-up reversal can be achieved in an ecologically friendly manner by facilitating the mariculture of low-trophic-level fishes and by promoting high efficiency in the use of living marine resources in aquafeeds. PMID- 24628520 TI - Using pharmacogenetics in real time to guide therapy: the warfarin example. PMID- 24628518 TI - Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia. AB - Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE2 (prostaglandin E2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder. PMID- 24628521 TI - Self-propulsion of dew drops on lotus leaves: a potential mechanism for self cleaning. AB - This study shows that condensation on the hierarchically structured lotus leaf can facilitate self-propulsion of water droplets off the surface. Droplets on leaves inclined at high angles can be completely removed from the surface by self propulsion with the assistance of gravity. Due to the small size of mobile droplets, light breezes may also fully remove the propelled droplets, which are typically projected beyond the boundary layer of the leaf cuticle. Moreover the self-propelled droplets/condensate were able to remove contaminants (eg silica particles) from the leaf surface. The biological significance of this process may be associated with maintaining a healthy cuticle surface when the action of rain to clean the surface via the lotus effect is not possible (due to no precipitation). Indeed, the native lotus plants in this study were located in a region with extended time periods (several months) without rain. Thus, dew formation on the leaf may provide an alternative self-cleaning mechanism during times of drought and optimise the functional efficiency of the leaf surface as well as protecting the surface from long term exposure to pathogens such as bacteria and fungi. PMID- 24628522 TI - "Looking out for each other": a qualitative study on the role of social network interactions in asthma management among adult Latino patients presenting to an emergency department. AB - OBJECTIVE: The objective of this study was to identify the types of interactions between asthma patients and their social networks such as close family and friends that influence the management of asthma. METHODS: Participants were Latino adults presenting for a repeat visit to the emergency department for asthma treatment. Qualitative interviews were conducted with 76 participants. They were asked to describe the experiences of their social networks that have asthma and how interactions with these individuals influenced their own asthma management. Responses were transcribed and analyzed using Grounded Theory as a qualitative analytic approach. Responses were assigned codes; similar codes were grouped into concepts and then categorized to form overarching themes. RESULTS: Four themes emerged: (1) Perceptions of severity of asthma may be based on the experiences of social networks; (2) Economic factors may contribute to the sharing and borrowing of asthma medications between patients and their social networks; (3) Economic factors may contribute to using home remedies instead of prescribed medications; (4) Social network members may be unaware of the factors that trigger asthma and therefore, contribute to asthma exacerbations. CONCLUSION: This study identified important social network interactions that may impact asthma management in Latino adults. These results can be used to broaden the current focus of asthma self-management programs to incorporate discussions on the role of social networks. A focus on social network interactions addresses the social epidemiology of asthma and advances our understanding of root causes that may underlie the high prevalence of asthma in many Latino communities. PMID- 24628523 TI - The quality of life of Brazilian adolescents with asthma: associated clinical and sociodemographic factors. AB - OBJECTIVE: Asthma is the most common chronic disease among adolescents. This study assessed the quality of life (QOL) related to health in adolescents with asthma and its determining factors (demographic, socioeconomic, and clinical). We also separately evaluated each of the parameters that comprised the asthma control classification. METHODS: This was an observational, cross-sectional study of 114 adolescents who had doctor-diagnosed asthma. QOL was assessed using a version of the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) that was adapted and validated for Brazil, and higher scores indicated a better QOL. The level of asthma control was assessed using the rating system proposed by the Global Initiative for Asthma, and sociodemographic factors were evaluated. RESULTS: When the averages of the PAQLQ domains and overall scores were compared to the potentially explanatory variables, significantly lower average PAQLQ scores were obtained for individuals with an inadequate level of asthma control (p < 0.001). Of the control components, daytime symptoms, nighttime symptoms, and limited physical activity were related to QOL. However, the use of the beta2 agonist and the peak flow functional parameter were not related to QOL. CONCLUSIONS: The level of asthma control was related to QOL, but this association manifested mainly in the subjective control domains, such as nighttime and daytime symptoms and physical activity limitations. The objective domain for control classification, represented by pulmonary function, was not an independent predictor or determinant of the QOL of adolescent asthma patients. PMID- 24628524 TI - Effects on asthma and induction of interleukin-8 caused by Asian dust particles collected in western Japan. AB - OBJECTIVE: Asian dust storms (ADS) contain various airborne particles that may augment airway inflammation by increasing the level of interleukin-8. The objective of the study was to investigate the association of exposure to an ADS with worsening of symptoms of adult asthma and the effect of ADS particles on interleukin-8 transcriptional activity. METHODS: The subjects were 112 patients with mild to moderate asthma who recorded scores for their daily upper and lower respiratory tract symptoms and measured morning peak expiratory flow (PEF) from March to May 2011. Interleukin-8 transcriptional activity was assessed in THP-G8 cells that were exposed to airborne particles collected during days of ADS exposure. RESULTS: Of the 112 patients, 31 had comorbid allergic rhinitis (AR) and/or chronic sinusitis (CS), and had worsened scores for upper respiratory tract symptoms on ADS days compared to non-ADS days. Scores for lower respiratory tract symptoms during ADS days were higher than non-ADS days in all patients. Three patients also had unscheduled hospital visits for exacerbation of asthma on ADS days. However, there was no significant difference in daily morning PEF between ADS and non-ADS days. Airborne particles collected on ADS days induced interleukin-8 transcriptional activity in THP-G8 cells compared to the original soil of the ADS. CONCLUSION: Exposure to an ADS aggravates upper and lower tract respiratory symptoms in patients with adult asthma. ADS airborne particles may increase airway inflammation through enhancement of interleukin-8 transcriptional activity. PMID- 24628525 TI - Age at menarche and risk of asthma: systematic review and meta-analysis. AB - BACKGROUND: Several studies have suggested a relationship between the age at menarche and risk of asthma development. OBJECTIVE: To conduct a systematic review and meta-analysis of the relationship between the age at menarche and the risk of asthma. METHODS: This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta analyses (PRISMA). A pre specified literature search strategy was used to identify studies of potential relevance and independent reviews were carried out by two authors. Raw data was pooled using the software package RevMan to calculate summary odds ratios. The risk of publication bias was assessed graphically by using a funnel plot and the robustness of the overall estimate obtained was assessed by using sensitivity analyses. RESULTS: The searches identified 61 potentially relevant articles of which seven articles, with a total of 22,859 subjects, matched the inclusion criteria for the meta-analysis. Pooling of the seven studies showed that girls with early menarche (<12 years) had an increased risk of asthma relative to girls with late menarche; random effects odds ratio = 1.37 (1.15-1.64), (p = 0.0005). Substantial heterogeneity was revealed (I(2) = 55%). Sensitivity analysis showed that the risk estimate was not markedly changed when excluding any of the studies. The funnel plot did not indicate publication bias. CONCLUSIONS: Early menarche appears to be associated with increased risk of asthma. Hormonal, immunological, genetic and environmental factors may act in a developmental context to explain this relationship. Future studies are warranted to further determine the mechanisms responsible for this observation. PMID- 24628526 TI - Asthma and mental health among youth in high-risk service settings. AB - OBJECTIVE: To investigate the prevalence of asthma and mental health problems among representative samples of youth in high-risk service settings and the community, and to examine the relationship between asthma and mental health in these groups. METHODS: Data were drawn from the Alternative Service Use Patterns of Youth with Serious Emotional Disturbance Study (SED) (n = 1181), a combined representative, cross-sectional sample of youth in various clinical settings and the community. Multiple logistic regression analyses were used to examine the association between asthma and mental disorders. Demographic characteristics were investigated as potential confounders. RESULTS: Asthma was common among 15.2% of youth in service settings and 18.8% of youth in the community. The prevalence of mental disorders was extremely high among youth with and without asthma in all service settings, and asthma was associated with increased prevalence of mental disorders among youth in the community, but not among youth in service settings. The relationship between asthma and internalizing disorders among youth in the community does not appear entirely attributable to confounding by demographics. CONCLUSIONS: Findings are consistent with and extend previous data by showing that both asthma and mental disorders are disproportionately common among youth in high-risk service settings. Almost half of youth with asthma in service settings meet diagnostic criteria for a mental disorder. Clinicians and policy makers who are responsible for the health care of youth in these high-risk groups should be aware that asthma is common, and that the prevalence of internalizing disorders are especially common among those with asthma. PMID- 24628527 TI - Azacitidine and low-dose cytarabine in palliative patients with acute myeloid leukemia and high bone marrow blast counts--a retrospective single-center experience. AB - We retrospectively analyzed and compared the efficacy and toxicity of azacitidine (AZA) and low-dose cytarabine (LD-Ara-C) in 65 palliative patients with acute myeloid leukemia (AML) showing high bone marrow blast counts (>=30%) before start of treatment. Twenty-seven and 38 patients received AZA and LD-Ara-C, respectively. The median patient age was 71 yr. Patient and disease characteristics did not differ between the treatment groups, except for BM blast counts, and peripheral leukocyte and blast counts which were significantly higher in the LD-Ara-C group. AZA and LD-Ara-C were first-line treatment in 12 (44%) and 17 patients (45%), respectively. Response and hematologic improvement rates were low and similar in both treatment groups. In both treatment groups, most common non-hematologic toxicities included febrile neutropenia, pneumonia, and bleedings without significant differences regarding frequencies. Estimated 1-yr survival rates were 15% (95% CI 8-22) and 13% (95% CI 7-19) in the AZA and LD-Ara-C groups, respectively, without statistically significant difference. In multivariate analysis (n = 65), previous treatment (HR 2.27, 95% CI 1.00-5.22, P = 0.05) and adverse cytogenetics (HR 2.50, 95% CI 1.20-5.22, P = 0.02) were independent predictors of poor survival. In our center and within the limitations of a retrospective study, both treatment regimens showed similar but limited efficacy in palliative patients with AML and high BM blast counts. PMID- 24628529 TI - Vertical III-V nanowire device integration on Si(100). AB - We report complementary metal-oxide-semiconductor (CMOS)-compatible integration of compound semiconductors on Si substrates. InAs and GaAs nanowires are selectively grown in vertical SiO2 nanotube templates fabricated on Si substrates of varying crystallographic orientations, including nanocrystalline Si. The nanowires investigated are epitaxially grown, single-crystalline, free from threading dislocations, and with an orientation and dimension directly given by the shape of the template. GaAs nanowires exhibit stable photoluminescence at room temperature, with a higher measured intensity when still surrounded by the template. Si-InAs heterojunction nanowire tunnel diodes were fabricated on Si(100) and are electrically characterized. The results indicate a high uniformity and scalability in the fabrication process. PMID- 24628528 TI - Incident user cohorts for assessing medication cost-offsets. AB - OBJECTIVE: To develop and test incident drug user designs for assessing cost savings from statin use in diabetics. DATA SOURCE: Random 5 percent sample of Medicare beneficiaries, 2006-2008. STUDY DESIGN: Seven-step incident user design to assess impact of statin initiation on subsequent Medicare spending: (1) unadjusted pre/post initiation test; (2) unadjusted difference-in-difference (DID) with comparison series; (3) adjusted DID; (4) propensity score (PS)-matched DID with static and dynamic baseline covariates; (5) PS-matched DID by drug adherence strata; (6) PS-matched DID for high adherers controlling for healthy adherer bias; and (7) replication for ACE-inhibitor/ARB initiators. DATA COLLECTION/EXTRACTION METHODS: Subjects with prevalent diabetes and no statin use (January-June 2006) and statin initiation (July 2006-January 2008) compared to nonusers with a random "potential-initiation" month. Monthly Medicare spending tracked 24 months pre- and post-initiation. PRINCIPAL FINDINGS: Statistically significant savings in Medicare spending were observed beginning 7 months post initiation for statins and 13 months post-initiation for ACEIs/ARBs. However, these savings were only observed for adherent patients in steps 5 and 6. CONCLUSIONS: Drug initiator designs are more robust to confounding than prevalent user designs in assessing cost-offsets from drug use but still require other adjustments and sensitivity analysis to ensure proper inference. PMID- 24628530 TI - Current approaches for prophylactic cranial irradiation in extrapulmonary small cell carcinoma. AB - BACKGROUND: Small cell lung cancer (SCLC) patients, who have achieved complete or partial response after chemotherapy, should be followed with prophylactic cranial irradiation (PCI). PCI for extrapulmonary small cell carcinoma (EPSCC) is not routinely recommended. The purpose of this review is to discuss all aspects of PCI in management of EPSCC. SCOPE: The PubMed database and the database of online abstracts of the American Society of Oncology (ASCO), ASCO Genitourinary (GU) Cancers meetings and clinical trials were searched up to 15 October 2013 using the following search keywords: 'SCC or EPSCC of each organ site and prophylactic cranial radiotherapy'. The language of screened abstracts and manuscripts was limited to English. The papers which included the largest case series and data of cases about prophylactic cranial radiotherapy and/or were published in the last 10 years were selected. FINDINGS: Many single center studies showed low incidence of brain metastasis in patients with esophageal small cell carcinoma (SCC). Due to the low incidence of brain metastasis, PCI is not recommended for esophageal SCC. Genitourinary, colorectal, small bowel and appendix cranial metastatic SCCs are extremely rare. Therefore, PCI is not recommended. The frequency of brain metastasis of prostate small cell carcinoma is much higher (16-19%) compared to other counterparts of EPSCC. PCI can be performed in selected cases of prostate SCC. High rates (41%) of brain metastasis develop in head and neck SCC. PCI should be considered for patients with head neck SCC. CONCLUSION: In the literature, the brain metastasis incidence of EPSCC might vary from 1.7% up to 40%. In many patients with ESPCC, PCI is not recommended. However, we have to keep in mind that primary head and neck and prostate SCC are exceptions due to the high incidence of cranial metastasis; PCI should be recommended for these patients on an individual basis. PMID- 24628531 TI - Lithium tremor, beta-blockers, and depression. PMID- 24628532 TI - Cross-cultural differences in categorical memory errors. AB - Cultural differences occur in the use of categories to aid accurate recall of information. This study investigated whether culture also contributed to false (erroneous) memories, and extended cross-cultural memory research to Turkish culture, which is shaped by Eastern and Western influences. Americans and Turks viewed word pairs, half of which were categorically related and half unrelated. Participants then attempted to recall the second word from the pair in response to the first word cue. Responses were coded as correct, as blanks, or as different types of errors. Americans committed more categorical errors than did Turks, and Turks mistakenly recalled more non-categorically related list words than did Americans. These results support the idea that Americans use categories either to organize information in memory or to support retrieval strategies to a greater extent than Turks and suggest that culture shapes not only accurate recall but also erroneous distortions of memory. PMID- 24628533 TI - Immunohistochemical expression of GPR30 in breast carcinoma of Egyptian patients: an association with immunohistochemical subtypes. AB - Breast carcinoma in Egyptian women is a biologically more aggressive disease than those diagnosed in Western women, although a substantial number of cases are hormone responsive. G protein-coupled receptor-30 (GPR30), a seven transmembrane domain protein, is currently recognized as an estrogen receptor. This study aimed at evaluating the expression of GPR30 in breast carcinomas of Egyptian patients and its association with clinicopathologic parameters and immunohistochemical subtypes of breast carcinoma. Immunohistochemical staining for GPR30 was applied on 51 archival formalin-fixed paraffin-embedded cases of invasive ductal carcinoma. Staining was assessed using a semiquantitative scoring system taking staining intensity and extent into consideration. GPR30 was observed in 33/51 (65%) of invasive ductal carcinoma cases. GPR30 was significantly associated with larger tumor size (p = 0.009), increased number of positive lymph nodes (p = 0.04), definite lymph-vascular invasion (LVI) (p = 0.002), peri-nodal invasion (p = 0.02), and the presence of coagulative tumor cell necrosis (p = 0.02). Moreover, a significant association between positive GPR30 expression and ER positivity (p = 0.02), as well as HER2/neu positivity (p = 0.03), were also observed. Most of the luminal A and B subtypes were GPR30 positive; however, all the triple negative cases were GPR30 negative (p = 0.010). GPR30 might contribute to the aggressive behavior of Egyptian breast carcinoma. Therefore, it could be useful in the therapeutic decision making in breast cancer patients. PMID- 24628534 TI - Comparison of microwave ablation and surgical resection for treatment of hepatocellular carcinomas conforming to Milan criteria. AB - BACKGROUND AND AIM: To compare the efficacy of microwave ablation (MWA) and surgical resection (RES) in the treatment of hepatocellular carcinoma (HCC) conforming to Milan criteria. METHODS: Two hundred twenty-four patients met the inclusion criteria and were enrolled in the study. One hundred and seventeen patients received MWA, and 107 patients underwent RES. The primary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: The 1-, 3-, and 5 year OS rates were 94%, 70%, 52% for the MWA group and 94%, 72%, 60% for the RES group (P = 0.513). The corresponding DFS rates for the two groups were 77%, 38%, 18% and 85%, 57%, 31% (P = 0.005). In subgroup analyses of patients with solitary HCC <= 3 cm, there were no significant differences in OS rates and DFS rates between the two groups (P = 0.577 and P = 0.140). For patients with solitary HCC 3 to 5 cm, there was no significant differences in OS rates between the two groups (P = 0.820), the DFS rates was significantly higher in the RES group than in the MWA group (P = 0.014). CONCLUSIONS: MWA results in lower DFS rates than RES for HCC conforming to Milan criteria. However, the OS rates are comparable between the two therapies. For solitary HCC <= 3 cm, MWA is as effective as RES. PMID- 24628536 TI - Mechanisms of degradation of the natural high-potency sweetener (2R,4R)-monatin in mock beverage solutions. AB - The sodium, potassium, or mixed sodium/potassium salt of the naturally occurring high-potency sweetener (2R,4R)-monatin, also known by the common name arruva, degrades over time in model beverage solutions in the presence of light. By use of UHPLC, LC-MS/MS, and peroxide assays, it has been demonstrated that degradation is accelerated by UV/visible light and the presence of trace metal ions. Data are presented that are consistent with a role for singlet oxygen (1O2), free radicals, and peroxides (both H2O2 and organic peroxides) in monatin oxidation. Separation of degradation products by UHPLC/HPLC or LC-MS/MS provided evidence for the formation of hydroxylated and peroxide species formed on the indole ring (mass increases 16 and 32, respectively) as well as multiple ring and side-chain oxidation and scission products. Model oxidation systems using the photosensitizer Rose Bengal as a source of 1O2 support the proposed photodegradation pathways. PMID- 24628537 TI - Palladium-catalyzed decarboxylative trifluoroethylation of aryl alkynyl carboxylic acids. AB - A trifluoroethylation of alkynes through a palladium-catalyzed decarboxylative coupling reaction was developed. When alkynyl carboxylic acids and ICH2CF3 were allowed to react with [Pd(eta(3)-allyl)Cl]2/XantPhos and Cs2CO3 in N,N dimethylformamide (DMF) at 80 degrees C for 1 h, the desired products were formed in good yields. This catalytic system showed high functional group tolerance. PMID- 24628538 TI - Insight into proton transfer in phosphotungstic acid functionalized mesoporous silica-based proton exchange membrane fuel cells. AB - We have developed for fuel cells a novel proton exchange membrane (PEM) using inorganic phosphotungstic acid (HPW) as proton carrier and mesoporous silica as matrix (HPW-meso-silica) . The proton conductivity measured by electrochemical impedance spectroscopy is 0.11 S cm(-1) at 90 degrees C and 100% relative humidity (RH) with a low activation energy of ~14 kJ mol(-1). In order to determine the energetics associated with proton migration within the HPW-meso silica PEM and to determine the mechanism of proton hopping, we report density functional theory (DFT) calculations using the generalized gradient approximation (GGA). These DFT calculations revealed that the proton transfer process involves both intramolecular and intermolecular proton transfer pathways. When the adjacent HPWs are close (less than 17.0 A apart), the calculated activation energy for intramolecular proton transfer within a HPW molecule is higher (29.1 18.8 kJ/mol) than the barrier for intermolecular proton transfer along the hydrogen bond. We find that the overall barrier for proton movement within the HPW-meso-silica membranes is determined by the intramolecular proton transfer pathway, which explains why the proton conductivity remains unchanged when the weight percentage of HPW on meso-silica is above 67 wt %. In contrast, the activation energy of proton transfer on a clean SiO2 (111) surface is computed to be as high as ~40 kJ mol(-1), confirming the very low proton conductivity on clean silica surfaces observed experimentally. PMID- 24628539 TI - Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. AB - BACKGROUND: Autoimmune hepatitis can be rendered treatment-free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear. AIM: To describe the frequency that autoimmune hepatitis can be rendered treatment-free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result. METHODS: Studies cited in Pub Med from 1972-2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected. RESULTS: The frequency of a treatment-free state varies from 19% to 40% in patients observed for >=3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment-dependence. Persistent liver damage and the generation of neo antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age-related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment-free state accommodates all candidates for this outcome, and it can be modified to a long-term maintenance strategy as warranted by the clinical response. CONCLUSIONS: Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence. PMID- 24628541 TI - Molecular organization of crystalline beta-carotene in carrots determined with polarization-dependent second and third harmonic generation microscopy. AB - Polarization-in, polarization-out (PIPO) second harmonic generation (SHG) and third harmonic generation (THG) microscopy was used to study the crystalline organization of beta-carotene molecules within individual aggregates contained in the chromoplasts of orange carrots in vivo. Multimodal PIPO SHG and PIPO THG studies of the aggregates revealed one dominant SHG and THG dipole signifying that beta-carotene molecules are oriented along a single axis. Three-dimensional visualization of the orientation of beta-carotene molecules with respect to the aggregate axis was also performed with both microscopy modalities and revealed organization of the aggregates as ribbon-like structures consisting of twists and folds. Therefore, PIPO SHG and PIPO THG microscopy provides information on the crystalline organization and the orientation of ordered biological structures in vivo where multimodal polarization dependent SHG and THG investigations are particularly advantageous as both noncentrosymmetric and centrosymmetric crystalline organizations can be probed. PMID- 24628543 TI - Inhibitor eradication with rituximab in haemophilia: where do we stand? AB - Rituximab is a humanized chimeric anti-CD20 monoclonal antibody initially developed for the treatment of some haematological malignancies. Thanks to its ability to rapidly and specifically deplete B cells, it has also been used in a variety of autoimmune disorders, haematological or not. In this context, during the last decade several small case series have documented successful inhibitor eradication with rituximab, alone or in combination with other immunosuppressive agents, in patients with acquired haemophilia A refractory to standard therapy. In addition, a number of investigators have recently used this agent in patients with congenital haemophilia A or B and alloantibodies refractory to first-line treatment. This article critically reviews the current knowledge on the use of rituximab in acquired haemophilia or congenital haemophilia complicated by alloantibodies, also providing treatment algorithms for the management of these conditions. PMID- 24628544 TI - Fine-scale in situ measurement of riverbed nitrate production and consumption in an armored permeable riverbed. AB - Alteration of the global nitrogen cycle by man has increased nitrogen loading in waterways considerably, often with harmful consequences for aquatic ecosystems. Dynamic redox conditions within riverbeds support a variety of nitrogen transformations, some of which can attenuate this burden. In reality, however, assessing the importance of processes besides perhaps denitrification is difficult, due to a sparseness of data, especially in situ, where sediment structure and hydrologic pathways are intact. Here we show in situ within a permeable riverbed, through injections of (15)N-labeled substrates, that nitrate can be either consumed through denitrification or produced through nitrification, at a previously unresolved fine (centimeter) scale. Nitrification and denitrification occupy different niches in the riverbed, with denitrification occurring across a broad chemical gradient while nitrification is restricted to more oxic sediments. The narrow niche width for nitrification is in effect a break point, with the switch from activity "on" to activity "off" regulated by interactions between subsurface chemistry and hydrology. Although maxima for denitrification and nitrification occur at opposing ends of a chemical gradient, high potentials for both nitrate production and consumption can overlap when groundwater upwelling is strong. PMID- 24628545 TI - Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia. AB - Anophthalmia/microphthalmia (A/M) is a developmental ocular malformation defined as complete absence or reduction in size of the eye. A/M is a heterogenous disorder with numerous causative genes identified; however, about half the cases lack a molecular diagnosis. We undertook whole exome sequencing in an A/M family with two affected siblings, two unaffected siblings, and unaffected parents; the ocular phenotype was isolated with only mild developmental delay/learning difficulties reported and a normal brain magnetic resonance imaging (MRI) in the proband at 16 months. No pathogenic mutations were identified in 71 known A/M genes. Further analysis identified a shared heterozygous mutation in COL4A1, c.2317G>A, p.(Gly773Arg) that was not seen in the unaffected parents and siblings. Analysis of 24 unrelated A/M exomes identified a novel c.2122G>A, p.(Gly708Arg) mutation in an additional patient with unilateral microphthalmia, bilateral microcornea and Peters anomaly; the mutation was absent in the unaffected mother and the unaffected father was not available. Mutations in COL4A1 have been linked to a spectrum of human disorders; the most consistent feature is cerebrovascular disease with variable ocular anomalies, kidney and muscle defects. This study expands the spectrum of COL4A1 phenotypes and indicates screening in patients with A/M regardless of MRI findings or presumed inheritance pattern. PMID- 24628546 TI - Development and characterization of a differentiated thyroid cancer cell line resistant to VEGFR-targeted kinase inhibitors. AB - BACKGROUND: Vascular endothelial growth factor-targeted kinase inhibitors have emerged as highly promising therapies for radioiodine-refractory metastatic differentiated thyroid cancer. Unfortunately, drug resistance uniformly develops, limiting their therapeutic efficacies and thereby constituting a major clinical problem. APPROACH AND METHODS: To study acquired drug resistance and elucidate underlying mechanisms in this setting, BHP2-7 human differentiated thyroid cancer cells were subjected to prolonged continuous in vitro selection with 18 MUM pazopanib, a clinically relevant concentration; acquisition of pazopanib resistance was serially assessed, with the resulting resistant cells thereafter subcloned and characterized to assess potential mechanisms of acquired pazopanib resistance. RESULTS: Stable 2- to 4-fold in vitro pazopanib resistance emerged in response to pazopanib selection associated with similar in vitro growth characteristics but with markedly more aggressive in vivo xenograft growth. Selected cells were cross-resistant to sunitinib and to a lesser extent sorafenib but not to MAPK kinase (MEK1/2) inhibition by GSK1120212. Genotyping demonstrated acquisition of a novel activating KRAS codon 13 GGC to GTT (glycine to valine) mutation, consistent with the observed resistance to upstream vascular endothelial growth factor receptor inhibition yet sensitivity to downstream MAPK kinase (MEK1/2) inhibition. CONCLUSIONS: Selection of thyroid cancer cells with clinically utilized therapeutics can lead to acquired drug resistance and altered in vivo xenograft behavior that can recapitulate analogous drug resistance observed in patients. This approach has the potential to lead to insights into acquired treatment-related drug resistance in thyroid cancers that can be subjected to subsequent validation in serially collected patient samples and that has the potential to yield preemptive and responsive approaches to dealing with this important clinical problem. PMID- 24628547 TI - Blood thrombogenicity is independently associated with serum TSH levels in post non-ST elevation acute coronary syndrome. AB - CONTEXT: Higher serum TSH levels, both within the reference range and in those with subclinical hypothyroidism (SCH), have been associated with increased risk of atherosclerosis and cardiovascular (CV) events in a number of cross-sectional and longitudinal studies. OBJECTIVE: Our objective was to evaluate blood thrombogenicity in patients post-non-ST elevation acute coronary syndrome (NSTE ACS) in relation to their thyroid function. DESIGN, PATIENTS, AND OUTCOME MEASURE: At 1 week after troponin-positive NSTE-ACS, 70 patients who had been treated with optimal antiplatelet and secondary prevention therapy were studied. Patients with known thyroid disease or on medications affecting thyroid function were excluded. Blood thrombogenicity was assessed using the ex vivo Badimon perfusion chamber. RESULTS: Serum TSH was associated with higher thrombus burden (beta = .30; P = .01) independent of other well-established CV risk factors. Patients with SCH (n = 12; 17%) had a higher thrombus burden than euthyroid individuals as evidenced by the area of the thrombus: mean (SD) 23 608 (10 498) vs 16 661 (10 902) MUm(2)/mm (P = .02). However, this association was not evident when the analysis was limited to patients with serum TSH within the reference range. In addition, neither serum free T4 nor free T3 had any significant association with thrombus area. CONCLUSION: Serum TSH levels, particularly in the SCH range, are associated with higher thrombus burden despite optimal recommended secondary prevention therapy after NSTE-ACS. This may explain the higher CV risk seen in SCH patients. Future trials to assess the effect of individualized antithrombotic as well as thyroid hormone replacement therapy to reduce atherothrombotic risk in this population are needed. PMID- 24628548 TI - Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. AB - CONTEXT: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. OBJECTIVES: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. SETTING AND PARTICIPANTS: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. MAIN OUTCOME MEASURES: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. RESULTS: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. CONCLUSIONS: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis. PMID- 24628549 TI - Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study. AB - CONTEXT: Low testosterone (T) is associated with prevalent cardiovascular disease (CVD) and mortality. DHT, a more potent androgen, may also be associated with CVD and mortality, but few studies have examined this. OBJECTIVE: The study objective was to examine whether T and DHT are risk factors for incident CVD and mortality. DESIGN: In a longitudinal cohort study, we evaluated whether total T, calculated free T (cFT), DHT, and calculated free DHT were associated with incident CVD and mortality in men in the Cardiovascular Health Study (mean age 76, range 66-97 years) who were free of CVD at the time of blood collection. MAIN OUTCOME: The main outcomes were incident CVD and all-cause mortality. RESULTS: Among 1032 men followed for a median of 9 years, 436 incident CVD events and 777 deaths occurred. In models adjusted for cardiovascular risk factors, total T and cFT were not associated with incident CVD or all-cause mortality, whereas DHT and calculated free DHT had curvilinear associations with incident CVD (P < .002 and P = .04, respectively) and all-cause mortality (P < .001 for both). CONCLUSIONS: In a cohort of elderly men, DHT and calculated free DHT were associated with incident CVD and all-cause mortality. Further studies are needed to confirm these results and to clarify the underlying physiologic mechanisms. PMID- 24628551 TI - Serum periostin is associated with fracture risk in postmenopausal women: a 7 year prospective analysis of the OFELY study. AB - PURPOSE: Periostin (POSTN) is a secreted gamma-carboxyglutamic acid-containing protein expressed mainly in the periosteum in adult individuals. POSNT deficient mice develop periodontis and osteoporosis with decreased bone strength. The relationship between serum POSTN and bone metabolism and fracture risk in postmenopausal women is unknown. SUBJECTS AND METHODS: Serum POSTN was measured in 607 postmenopausal women (mean age 66.6 +/- 8.4 y) from the Os des Femmes de Lyon cohort at the ninth annual follow-up visit (baseline visit of the current analysis). Nonvertebral and clinical vertebral incident fragility fractures were reported annually during 7 years. Areal bone mineral density (BMD; measured by dual energy X-ray absorptiometry) of the hip and bone markers (intact N-terminal propeptide of type I collagen, osteocalcin, and serum type I collagen C telopeptide) were also measured. RESULTS: At baseline, serum POSTN did not correlate with age, bone markers, and BMD. After a median of 7 years of follow up, 75 women sustained an incident clinical vertebral or nonvertebral fragility fracture. The proportion of women who had an incident fracture was significantly higher in women with levels of POSTN in the highest quartile than that of women in the three other quartiles (19.5% vs 10.1%, P = .018) after adjustment for age and prevalent fracture. The highest quartile of POSTN was associated with an increased risk of incident fracture with a relative risk (95% confidence interval) of 1.88 (1.1-3.2) after adjustment for age, prevalent fracture, and hip BMD T-score. Patients with both low hip BMD (T-score < -2.5) and high levels of POSTN (fourth quartile) had a relative risk of fracture of 7.1 (95% confidence interval 2.4-21.8) after adjustment for age. CONCLUSION: High serum POSTN levels are independently associated with increased fracture risk in postmenopausal women. These data suggest that serum POSTN could be useful to improve fracture risk assessment. PMID- 24628550 TI - Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib. AB - CONTEXT: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES: Progression free survival, best response, and median OS were measured. RESULTS: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy. PMID- 24628552 TI - Multinodular Goiter in children: an important pointer to a germline DICER1 mutation. PMID- 24628553 TI - Carbohydrate coingestion delays dietary protein digestion and absorption but does not modulate postprandial muscle protein accretion. AB - BACKGROUND: Dietary protein digestion and absorption is an important factor modulating muscle protein accretion. However, there are few data available on the effects of coingesting other macronutrients with protein on digestion and absorption kinetics and the subsequent muscle protein synthetic response. OBJECTIVE: The objective of the study was to determine the impact of carbohydrate coingestion with protein on dietary protein digestion and absorption and muscle protein accretion in healthy young and older men. DESIGN: Twenty-four healthy young (aged 21+/- 1 y, body mass index 21.8 +/-0.5 kg/m(2)) and 25 older (aged 75 +/- 1 y, body mass index 25.4 +/- 0.6 kg/m(2)) men received a primed continuous L [ring-(2)H5]-phenylalanine and L-[ring-3,5-(2)H2]-tyrosine infusion and ingested 20 g intrinsically L-[1-(13)C]-phenylalanine-labeled protein with (Pro+CHO) or without (Pro) 60 g carbohydrate. Plasma samples and muscle biopsies were collected in a postabsorptive and postprandial state. RESULTS: Carbohydrate coingestion delayed the appearance of exogenous phenylalanine in the circulation (P = .001). Dietary protein-derived phenylalanine availability over the 5-hour postprandial period was lower in the older (62 +/- 2%) when compared with the young subjects (74 +/- 2%; P = .007), with no differences between conditions (P = .20). Carbohydrate coingestion did not modulate postprandial muscle protein synthesis rates (0.035 +/- 0.003 vs 0.043 +/- 0.004 and 0.033 +/- 0.002 vs 0.035 +/- 0.003%/h after Pro vs Pro+CHO in the young and older group, respectively). In accordance, no differences in muscle protein-bound L-[1-(13)C]-phenylalanine enrichments were observed between conditions (0.020 +/- 0.002 vs 0.020 +/- 0.002 and 0.019 +/- 0.003 vs 0.022 +/- 0.004 mole percent excess after Pro vs Pro+CHO in the young and older subjects, respectively). CONCLUSION: Carbohydrate coingestion with protein delays dietary protein digestion and absorption but does not modulate postprandial muscle protein accretion in healthy young or older men. PMID- 24628554 TI - Irisin levels during pregnancy and changes associated with the development of preeclampsia. AB - CONTEXT: Irisin is a recently discovered adipomyokine that regulates the differentiation and phenotype of adipose tissue. OBJECTIVE: In this study, we investigated the levels of irisin over the three trimesters of gestation in healthy and preeclamptic women and during the follicular and luteal phase of the menstrual cycle in a cohort of healthy eumenoherric women. METHODS: Serum irisin was measured by an ELISA in a longitudinal prospective cohort study in 40 healthy pregnant women, 10 mild preeclamptic women, and 20 healthy eumenoherric women during the menstrual cycle to assess irisin levels and correlations with other metabolic parameters. We identified the protein expression of fibronectin type III domain-containing protein 5, the irisin precursor, in human placenta using immunohistochemical approaches in humans. RESULTS: Serum irisin levels are higher in the luteal than in the follicular phase in eumenorrheic women. Fibronectin type III domain-containing protein 5, the irisin precursor, is expressed in human placenta, and its serum levels are higher during the entire pregnancy when compared with nonpregnant women. Serum irisin correlates positively with the homeostasis model assessment of estimated insulin resistance in the first trimester of normal pregnancy. Serum irisin levels do not change throughout gestation in preeclamptic women; however, there were lower irisin levels during the third trimester when compared with the normal pregnant group. CONCLUSION: Our results suggest that irisin may be involved in reproductive function and in the pregnancy-associated metabolic changes, and this condition may be an irisin resistant state during gestation. PMID- 24628555 TI - Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells. AB - CONTEXT: Vitamin D deficiency is common among reproductive-aged women and has a role in female reproduction. OBJECTIVE: This study evaluated the role of 1,25 dihydroxyvitamin D3 (vit D3) in ovarian follicular development and steroidogenesis by using a human granulosa cell (GC) model. DESIGN, SETTING, AND PARTICIPANTS: Fifty-four women who underwent in vitro fertilization were enrolled. INTERVENTION: Follicular fluid (FF) and mural and cumulus GCs were collected from small and large follicles. In separate experiments, primary cumulus GCs were cultured with or without vit D3 followed by RT-PCR for mRNA expression levels. The effect of recombinant anti-Mullerian hormone (AMH) on nuclear localization of phospho-Smad 1/5/8 was evaluated in the presence or absence of vit D3 by using immunofluorescence. 25-Hydroxyvitamin D levels in FF as well as cell culture media AMH, progesterone, and estradiol (E2) concentrations were determined by ELISA and RIA. MAIN OUTCOME MEASURES: The following were measured: 1) mRNA expression levels; 2) 3beta-hydroxysteroid dehydrogenase (3beta-HSD) enzyme activity; 3) FSH-induced aromatase mRNA and E2 production; and 4) nuclear localization of phospho-Smad 1/5/8. RESULTS: In a multivariate analysis, 25 OH-D levels in FF negatively correlated with AMH and AMH receptor (AMHR)-II mRNA levels in cumulus GCs of small follicles. Compared with women with replete 25-hydroxyvitamin D levels in FF, those with insufficient/deficient levels had a 2-fold increase in AMHR-II mRNA levels in cumulus GCs of small follicles (P = .02). Treatment with vit D3 caused a decrease in AMHR-II and FSH receptor mRNA but an increase in 3-betaHSD mRNA levels compared with control (P < .05). Vit D3 enhanced 3-betaHSD enzyme activity as assessed by increasing progesterone release; however, vit D3 did not affect FSH induced aromatase mRNA and E2 production, but it decreased the phosphorylation of Smad 1/5/8 and its nuclear localization. CONCLUSION: These data suggest that vit D3 alters AMH signaling and steroidogenesis in human cumulus GCs, possibly reflecting a state of GC luteinization potentiation. PMID- 24628557 TI - Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing's syndrome. AB - CONTEXT: The comparison of variability, reproducibility, and diagnostic performance of late-night salivary cortisol (LNSF) and urinary free cortisol (UFC) using concurrent and consecutive samples in Cushing's syndrome (CS) is lacking. Objectives, Patients, and Methods: In a prospective study, we evaluated 3 simultaneous and consecutive samples of LNSF by RIA and UFC by liquid chromatography associated with tandem mass spectrometry in Cushing's disease (CD) patients (n = 43), adrenal CS patients (n = 9), and obese subjects (n = 18) to compare their diagnostic performances. In CS patients, we also performed a modified CS severity index. RESULTS: There was no difference in the coefficient of variation (percentage) between LNSF and UFC among the 3 samples obtained for each patient with Cushing's disease (35 +/- 26 vs 31 +/- 24), adrenal CS (28 +/- 14 vs 22 +/- 14), and obesity (39 +/- 37 vs 48 +/- 20). LNSF confirmed the diagnosis of hypercortisolism even in the presence of normal UFC in 17.3% of CS, whereas the inverse situation was not observed for UFC. The area under the receiver-operating characteristic curves for LNSF was 0.999 (95% credible interval [CI] 0.990-1.00) and for UFC was 0.928 (95% CI 0.809-0.987). The ratio between areas under the curve was 0.928 (95% CI 0.810-0.988), indicating better performance of LNSF than UFC in diagnosing CS. There was no association between the CS severity index and the degree of biochemical hypercortisolism. CONCLUSION: Our data show that despite similar variability between both methods, LNSF has a superior diagnostic performance than UFC and should be used as the primary biochemical diagnostic test for CS diagnosis. PMID- 24628556 TI - Glycation of the complement regulatory protein CD59 is a novel biomarker for glucose handling in humans. AB - CONTEXT: Human CD59, an inhibitor of the membrane attack complex of complement, is inactivated by glycation. Glycation inactivation of CD59 enhances complement mediated injury in target organs of diabetes complications. OBJECTIVE: We hypothesized that circulating soluble glycated CD59 (GCD59) represents a novel biomarker of blood glucose handling and aimed to conduct human study protocols to test this hypothesis. DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Using a newly developed ELISA, we measured circulating soluble GCD59 in samples from 3 separate human studies evaluating acute and chronic glucose handling and glucose responses to insulin therapy. Study 1 (normal vs diabetic subjects) evaluated the cross-sectional association between GCD59 and glycated hemoglobin (HbA1c) in 400 subjects with and without type 2 diabetes. Study 2 (oral glucose tolerance test [OGTT] in nondiabetics) evaluated whether fasting GCD59 independently predicted the 2-hour glucose response to an OGTT in 109 subjects without a diagnosis of diabetes. Study 3 (intensified insulin treatment) evaluated the effect of intensification of glycemic control with insulin on GCD59 in 21 poorly controlled individuals with diabetes. RESULTS: In study 1 (normal vs diabetic subjects), GCD59 was independently and positively associated with HbA1c in individuals with and without diabetes (beta = 1.1, P < .0001 and beta = 1.1 P < .001, respectively). In study 2 (OGTT in nondiabetics), a single GCD59 measurement independently predicted the results of the 2-hour OGTT (beta = 19.8, P < .05) after multivariate modeling. In study 3 (intensified insulin treatment), intensification of glucose control with insulin resulted in a concomitant and parallel reduction of average weekly glucose and GCD59 within 2 weeks. CONCLUSIONS: We observed robust relationships between a single measurement of blood levels of GCD59 and both acute (2-hour OGTT) and chronic (HbA1c) measures of glucose handling. Lowering of GCD59 levels closely reflected lowering of average weekly glucose within 2 weeks. The role of GCD59 in the diagnosis, management, and vascular risk stratification in diabetes warrants further investigation. PMID- 24628558 TI - Lack of racial disparity in incident prediabetes and glycemic progression among black and white offspring of parents with type 2 diabetes: the pathobiology of prediabetes in a biracial cohort (POP-ABC) study. AB - BACKGROUND: Although the incidence of type 2 diabetes (T2D) among persons with prediabetes is well known (~10%/y), the incidence of prediabetes among normoglycemic persons is unclear. Also, in the Diabetes Prevention Program, no racial/ethnic differences were seen in diabetes incidence, whereas marked racial/ethnic disparities are reported in the prevalence of T2D. We aimed to obtain estimates of incident prediabetes and determine whether racial disparities manifest during transition to prediabetes. DESIGN AND METHODS: We enrolled 376 (217 black, 159 white) nondiabetic offspring of parents with T2D (mean age 44.2 y) and followed them up quarterly for 5.5 years. Assessments included anthropometry, body composition, oral glucose tolerance test, biochemistries, energy expenditure, insulin sensitivity, and insulin secretion. The primary outcome was progression to impaired fasting glucose and/or impaired glucose tolerance (or diabetes). RESULTS: Of 343 participants with evaluable data, 101 subjects (49 white, 52 black) developed prediabetes, and 10 (4 white, 6 black) developed diabetes during a mean follow-up of 2.62 years. There was no significant racial difference in the cumulative incidence of prediabetes (32.7% white, 30% black) or combined prediabetes/diabetes (35% white, 30% black). Significant predictors of prediabetes included age, gender, trunk fat, 2-hour postload glucose (2hrPG), insulin sensitivity, and insulin secretion. In a Cox proportional-hazards model, with adjustment for age and sex, the 2hrPG and abdominal obesity were independent predictors of incident prediabetes/diabetes [relative hazards (95% confidence interval [CI]) for the 90th vs 10th percentile: trunk fat mass 2.90 (95% CI 1.74-4.82), P < .0001; 2hrPG 2.54 (95% CI 1.46-4.40), P = .0009]. Having the trunk fat mass and the 2hrPG at the 90th percentile conferred a 7-fold hazard of prediabetes compared with persons at the 10th percentile for both measures. CONCLUSION: Black and white offspring of parents with type 2 diabetes develop prediabetes at a similar high rate of approximately 11% per year. Therefore, close surveillance, with prompt intervention to prevent dysglycemia, is warranted in persons with parental diabetes. PMID- 24628559 TI - Longitudinal relationships of circulating reproductive hormone with functional disability, muscle mass, and strength in community-dwelling older men: the Concord Health and Ageing in Men project. AB - CONTEXT: The relationship between functional disability and reproductive hormones and whether it is mediated by muscle mass and strength in older men are unclear. OBJECTIVES: The objective of the study was to identify the relationships between hormones and change in functional disability over a 2-year follow-up and to examine whether muscle mass and strength explain any of the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: A total of 1318 men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at both baseline and 2-year follow-up. T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. OUTCOME MEASURES: Functional disability was measured by basic Activities of Daily Living scale at both time points. Grip and quadricep strength were measured using dynamometers and lean (muscle) mass was determined by dual X-ray absorptiometry. RESULTS: All hormones were significantly associated with functional decline in univariate analyses. Only T, E2, E1, and calculated free T remained associated in multivariate analyses. Men in the lowest T quartile (vs the highest quartile) had an increased risk functional decline (odds ratio 1.96, 95% confidence interval 1.01-3.82). Similar associations were observed in E2, E1, and calculated free T. When muscle variables were added into the multivariate model, the associations between these hormones and functional decline were no longer statistically significant. CONCLUSION: Low T, E2, and E1 were significantly associated with prospective functional decline over 2 years. This relationship was no longer significant when muscle mass or strength were added, suggesting that the hormonal associations are mediated through their sequential effect on muscle mass and strength. PMID- 24628560 TI - Normative misperceptions of peer seat belt use among high school students and their relationship to personal seat belt use. AB - OBJECTIVES: This research examined gender-specific perceptions of peer seat belt use norms among high school students and their relationship with one's own seat belt use. We expected that students would underestimate the seat belt use of their peers and that these perceptions would be positively associated with their own seat belt use. METHODS: High school students from 4 schools (N = 3348; 52% male) completed measures assessing perceived seat belt use and personal seat belt use. RESULTS: Findings demonstrated that students perceived that others engaged in less seat belt use than they do and that perceived norms were positively associated with one's own seat belt use. CONCLUSIONS: Peer influences are a strong predictor of behavior, especially among adolescents. Ironically, adolescents' behaviors are often influenced by inaccurate perceptions of their peers. This research establishes the presence of a misperception related to seat belt use and suggests that misperception is associated with own behaviors. This research provides a foundation for social norms-based interventions designed to increase seat belt use by correcting normative misperceptions among adolescents. PMID- 24628561 TI - The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice. AB - OBJECTIVES: Increasing numbers of reports have described hematopoietic improvement after iron chelation therapy in iron-overloaded patients. These observations indicate that excess iron could affect hematopoiesis unfavorably. To investigate how excess iron affects hematopoiesis in vivo, we generated iron overloaded mice and examined hematopoietic parameters in these mice. METHODS: We generated iron-overloaded mice by injecting 200 mg of iron dextran into C57BL/6J mice, and immature hematopoietic cells in the bone marrow were evaluated by flow cytometric analyses, colony-forming assays, and bone marrow transplantation analyses. We also examined changes in molecular profiles of the hematopoietic microenvironment. RESULTS AND CONCLUSIONS: Iron-overloaded (IO) mice did not show significant defects in the hematopoietic data of the peripheral blood. Myeloid progenitor cells in the bone marrow were increased in IO mice, but the number and function of the erythroid progenitors and hematopoietic stem cells were not significantly affected. However, bone marrow transplantation from normal donors to IO recipients showed delayed hematopoietic reconstitution, which indicates that excess iron impacts the hematopoietic microenvironment negatively. Microarray and quantitative RT-PCR analyses on the bone marrow stromal cells demonstrated remarkably reduced expression of CXCL12, VCAM-1, Kit-ligand, and IGF 1 in the iron-overloaded mice. In addition, erythropoietin and thrombopoietin levels were significantly suppressed, and increased oxidative stress was observed in the IO bone marrow and liver. Consequently, our findings indicate that excess iron can damage bone marrow stromal cells and other vital organs, disrupting hematopoiesis presumably by increased oxidative stress. PMID- 24628562 TI - Allometric relationship between body mass and aerobic metabolism in zebrafish Danio rerio. AB - The relationship between body mass (M) and metabolic rate was investigated through the assessment of active (R(A)) and standard (R(S)) metabolic rate at different life stages in zebrafish Danio rerio (5 day-old larvae, 2 month-old juveniles and 6 month-old adults). Scaling exponents and constants were assessed for standard (R(S) = 0.273M(0.965) in mgO(2) g(-1) h(-1)) and active metabolic rate (R(A) = 0.799M(0.926) in mgO(2) g(-1) h(-1)). These data provide the basis for further experiments regarding the effects of environmental factors on aerobic metabolism throughout the life cycle of this species. PMID- 24628563 TI - Nanocrystalline rutile electron extraction layer enables low-temperature solution processed perovskite photovoltaics with 13.7% efficiency. AB - We demonstrate low-temperature (70 degrees C) solution processing of TiO2/CH3NH3PbI3 based solar cells, resulting in impressive power conversion efficiency (PCE) of 13.7%. Along with the high efficiency, a strikingly high open circuit potential (VOC) of 1110 mV was realized using this low-temperature chemical bath deposition approach. To the best of our knowledge, this is so far the highest VOC value for solution-processed TiO2/CH3NH3PbI3 solar cells. We deposited a nanocrystalline TiO2 (rutile) hole-blocking layer on a fluorine-doped tin oxide (FTO) conducting glass substrate via hydrolysis of TiCl4 at 70 degrees C, forming the electron selective contact with the photoactive CH3NH3PbI3 film. We find that the nanocrystalline rutile TiO2 achieves a much better performance than a planar TiO2 (anatase) film prepared by high-temperature spin coating of TiCl4, which produces a much lower PCE of 3.7%. We attribute this to the formation of an intimate junction of large interfacial area between the nanocrystalline rutile TiO2 and the CH3NH3PbI3 layer, which is much more effective in extracting photogenerated electrons than the planar anatase film. Since the complete fabrication of the solar cell is carried out below 100 degrees C, this method can be easily extended to plastic substrates. PMID- 24628564 TI - GH gene polymorphisms and expression associated with egg laying in muscovy ducks (Cairina moschata). AB - Accumulated evidence suggests that the growth hormone (GH) gene plays a physiological role in the control of reproductive function. Here, we examined the correlation between egg-laying traits and GH gene polymorphisms and expression patterns in the muscovy duck (Cairina moschata). PCR single-strand conformation polymorphism was used to identify polymorphisms in intron 3 of GH. One single nucleotide polymorphism (g.3270 A > G) was detected by sequencing, and the frequencies of the A and G alleles in the population were 0.65 and 0.35, respectively. A comparison test showed that the AA genotype group had more consecutive laying days and more eggs at 300 days than the GG genotype group (P < 0.05); however, there was no significant difference for the age at first laying (P > 0.05). Such a significant correlation between GH polymorphisms and egg laying performance suggested that GH could be a candidate locus affecting the laying trait in muscovy duck. Furthermore, real-time fluorescent quantitative PCR demonstrated that GH is expressed in all selected tissues, but is highly expressed in the hypothalamic-pituitary-gonadal axis and heart. This unique expression pattern suggested that GH may exert its local physiological function through the autocrine or paracrine pathway during gonad development and growth in the muscovy duck. The data presented in this paper revealed GH polymorphisms and expression patterns in the muscovy duck and indicated a potential regulatory effect of GH on reproduction. PMID- 24628565 TI - Demonstration of compatibility of multiple arterial blood gas syringes with current multi-parameter analyzers. AB - OBJECTIVE: Since there is a lack of current evidence to support the compatibility of the most commonly used arterial blood gas syringes with the latest multi parameter analyzers, the objective of this study was to assess the agreement of analyte values between three heparinized arterial blood gas syringes using three different analyzers. METHODS: Venous blood from 25 healthy volunteers was drawn into the study syringes (BD Drihep A-Line, PICO50, and Portex Line Draw Plus) by four clinician volunteers in a random order (441 total) and immediately (<15 minutes) analyzed (ABL800 FLEX, RAPIDPoint 500, i-STAT System) in a randomized order. The Bland-Altman method was used to assess agreement of analyte values between the syringes for each analyzer. The results by analyte and analyzer were compared across syringes using one-way ANOVA, and Tukey's approach was used to identify statistically significant differences between pairs of syringes. RESULTS: Comparison of the syringes' mean differences and standard deviations showed close agreement for all three analyzers. There were no statistically significant differences between syringes in 14 of the analytes for any of the analyzers (p > 0.05). For RAPIDPoint and i-STAT, the Ca(2+) value was significantly less for A-Line than for the other syringes. The value for Na(+) was significantly greater for the PICO50 than the A-Line and Line Draw syringes with the i-STAT. Both results were within two standard deviations of the mean of the other two syringes and are not considered clinically significant; however, comparisons were not made between the values from the different analyzers. CONCLUSIONS: Dry-balanced lithium heparin ABG syringes used for blood draws should provide reliable results, regardless of syringe type, provided that the clinicians use proper pre-analytical techniques. PMID- 24628567 TI - More about asthma in PAI. PMID- 24628569 TI - GCC women: causes and processes of midlife weight gain. AB - Perimenopausal obesity is a particular problem in Gulf Cooperation Council (GCC) countries. This study examined the culturally specific views of perimenopausal GCC women, and the causes and processes of midlife weight gain using a qualitative descriptive design with semistructured interviewing and content analysis. Constructs derived from the health belief model and Kleiman's explanatory model were used to identify and sort themes into conceptual categories. The findings of this study suggest that weight-management program plans targeting perimenopausal GCC women should take into consideration the multiple levels of factors and cultural influences on their behavior. PMID- 24628568 TI - Validation of control of allergic rhinitis and asthma test for children (CARATKids)--a prospective multicenter study. AB - BACKGROUND: Control of Allergic Rhinitis and Asthma Test for Children (CARATKids) is the first questionnaire that assesses simultaneously allergic rhinitis and asthma control in children. It was recently developed, but redundancy of questions and its psychometric properties were not assessed. This study aimed to (i) establish the final version of the CARATKids questionnaire and (ii) evaluate its reliability, responsiveness, cross-sectional validity, and longitudinal validity. METHODS: A prospective observational study was conducted in 11 Portuguese centers. During two visits separated by 6 wk, CARATKids, visual analog scale scales and childhood asthma control test were completed, and participant's asthma and rhinitis were evaluated by his/her physician without knowing the questionnaires' results. Data-driven item reduction was conducted, and internal consistency, responsiveness analysis, and associations with external measures of disease status were assessed. RESULTS: Of the 113 children included, 101 completed both visits. After item reduction, the final version of the questionnaire has 13 items, eight to be answered by the child and five by the caregiver. Its Cronbach's alpha was 0.80, the Guyatt's responsiveness index was 1.51, and a significant (p < 0.001) within-patient change of CARATKids score in clinical unstable patients was observed. Regarding cross-sectional validity, correlation coefficients of CARATKids with the external measures of control were between 0.45 and -0.69 and met the a priori predictions. In the longitudinal validity assessment, the correlation coefficients between the score changes of CARATKids and those of external measures of control ranged from 0.34 to 0.46. CONCLUSION: CARATKids showed adequate psychometric properties and is ready to be used in clinical practice. PMID- 24628570 TI - Gene profile in the spleen under massive partial hepatectomy using complementary DNA microarray and pathway analysis. AB - BACKGROUND AND AIM: In general, the spleen is one of the abdominal organs connected by the portal system, and a splenectomy improves hepatic functions in the settings of partial hepatectomy (Hx) for portal hypertensive cases or living donor liver transplantation with excessive portal vein flow. Those precise mechanisms remain still unclear; therefore, we investigated the DNA expression profile in the spleen after 90% Hx in rats using complementary DNA microarray and pathway analysis. METHODS: Messenger RNAs (mRNAs) were prepared from three rat spleens at each time point (0, 3, and 6 h after 90% Hx). Using the gene chip, mRNA was hybridized to Affymetrix GeneChip Rat Genome 230 2.0 Array (Affymetrix(r)) and pathway analysis was done with Ingenuity Pathway Analysis (IPA(r)). RESULTS: We determined the 3-h or 6-h/0-h ratio to assess the influence of Hx, and cut-off values were set at more than 2.0-fold or less than 1/2 (0.5) fold. Chemokine activity-related genes including Cxcl1 (GRO1) and Cxcl2 (MIP-2) related pathway were upregulated in the spleen. Also, immediate early response genes including early growth response-1 (EGR1), FBJ murine osteosarcoma (FOS) and activating transcription factor 3 (ATF3) related pathway were upregulated in the spleen. CONCLUSIONS: We concluded that in the spleen the expression of numerous inflammatory-related genes would occur after 90% Hx. The spleen could take a harmful role and provide a negative impact during post Hx phase due to the induction of chemokine and transcription factors including GRO1 and EGR1. PMID- 24628571 TI - DNA methylation detection and inhibitor screening based on the discrimination of the aggregation of long and short DNA on a negatively charged indium tin oxide microelectrode. AB - On the basis of the different diffusivity and existence of electrostatic repulsion between long and short DNA on the negatively changed indium tin oxide (ITO) microelectrode, a simple but sensitive immobilization free solution-phase electrochemical method for DNA methylation detection and inhibitor screening has been developed. Electroactive substance (methylene blue) tagged at the penultimate base T close to the 3'-terminal first, in the absence of DNA methylation, methylene blue-labeled electroactive fragments cannot be generated by Dpn I and results in a weak electrochemical response being detected on the ITO electrode. On the contrary, a remarkable electrochemical response can be achieved by the cleavage in the presence of DNA methylation since methylene blue-labeled electroactive fragments can be generated and aggregate on the ITO electrode. The proposed system does not need complex operation procedures such as bisulfite treatment, PCR amplification, and electrode immobilization. Six ITO microelectrodes had been assembled on the same microchip, which can achieve the parallel detection of the same sample and improve the experimental efficiency of drug screening. The system was used to conveniently and specifically monitor the change of the DNA methylation level with high sensitivity and selectivity. The proposed system has the potential application to screen the drugs as inhibitors on the activity of methyltransferase in the clinic. PMID- 24628572 TI - CoSe2 nanoparticles grown on carbon fiber paper: an efficient and stable electrocatalyst for hydrogen evolution reaction. AB - Development of a non-noble-metal hydrogen-producing catalyst is essential to the development of solar water-splitting devices. Improving both the activity and the stability of the catalyst remains a key challenge. In this Communication, we describe a two-step reaction for preparing three-dimensional electrodes composed of CoSe2 nanoparticles grown on carbon fiber paper. The electrode exhibits excellent catalytic activity for a hydrogen evolution reaction in an acidic electrolyte (100 mA/cm(2) at an overpotential of ~180 mV). Stability tests though long-term potential cycles and extended electrolysis confirm the exceptional durability of the catalyst. This development offers an attractive catalyst material for large-scale water-splitting technology. PMID- 24628573 TI - Molecular dosimetry of endogenous and exogenous O(6)-methyl-dG and N7-methyl-G adducts following low dose [D3]-methylnitrosourea exposures in cultured human cells. AB - For DNA-reactive chemicals, a low dose linear assessment of cancer risk is the science policy default. In the present study, we quantitated the endogenous and exogenous N7-methyl-G and O(6)-methyl-dG adducts in human lymphoblastoid cells exposed to low dose [D3]-methylnitrosourea. Endogenous amounts of both adducts remained nearly constant, while the exogenous adducts showed linear dose responses. The data show that O(6)-methyl-dG adducts >=1.8/10(8) dG correlated with published studies that demonstrated significant increases of mutations under these conditions. The combined results do not support linear extrapolations to zero when data are available for science-based regulations. PMID- 24628574 TI - High index of suspicion for early diagnosis of alendronate-induced stage zero osteonecrosis of jaw in thalassaemia major. PMID- 24628575 TI - Absolute asymmetric photocyclization of triisopropylbenzophenone derivatives in crystals and their morphological changes. AB - Although 4-(2,4,6-triisopropylbenzoyl)benzylbenzamide is an achiral molecule, chiral crystals can form through spontaneous crystallization in a methanol solution. In the M crystal, twofold helical hydrogen-bond chains form in a counterclockwise direction among the molecules along the a axis to generate crystal chirality. The solid-state circular dichroism spectra of the two enantiomorphous crystals as Nujol mulls show a good mirror-image relationship. UV irradiation of the M crystal at >290 nm caused highly enantioselective Norrish type II photocyclization to yield the (R)-cyclobutenol with 94% ee in 100% yield as the sole product, resulting in successful absolute asymmetric synthesis. In contrast, the (S)-cyclobutenol was obtained from the P crystal with 95% ee in 100% yield. The high enantiodifferentiation in the crystalline-state photocyclization is attributed to the shorter distance between the carbonyl oxygen atom and one of the methine gamma-hydrogen atoms of the two o-isopropyl groups as well as the smooth transformation with minimum molecular motion because of the similar shapes of the reactant and product molecules. UV irradiation of the platelike crystals resulted in a crack in the direction perpendicular to the long axis (the a axis of the unit cell), likely because the hydrogen-bond chains were broken during the photocyclization. PMID- 24628576 TI - Staging bipolar disorder: clinical, biochemical, and functional correlates. AB - OBJECTIVE: There are several models of staging in bipolar disorder (BD), but none has been validated. The aims of this study were to empirically investigate clinical variables that may be useful to classify patients in clusters according to stage and study the association with biomarkers as biological validators. METHOD: This was a historical cohort study. Patients (n = 115) diagnosed with BD and not in an acute episode and first-degree relatives of patients diagnosed with BD (n = 25) were recruited. Sociodemographic, clinical, and functional data were collected. Serum cytokines, brain-derived neurotrophic factor, and biomarkers of lipid and protein oxidation were assessed. Cluster analysis was carried out to build a model of staging, and logistic regression was conducted to study associations between the model and biomarkers. RESULTS: Cluster analysis divided the sample into two equitable groups, denominated early and late stage, with empirical cutoffs for the Functioning Assessment Short Test score, number of episodes, age at onset of the disorder, and time elapsed since first episode. In the logistic regression, IL-6 was associated with late stage (P = 0.029). CONCLUSION: This study supports that clinical, functional, and biochemical variables may help to define a classification of staging in BD. PMID- 24628577 TI - Effect of supplementation with a lipid-based nutrient supplement on the micronutrient status of children aged 6-18 months living in the rural region of Intibuca, Honduras. AB - BACKGROUND: Lipid-based nutrient supplements (LNS) have been effective in the treatment of acute malnutrition among children. We evaluated the use of LNS supplementation for improving the micronutrient status of young children. METHODS: A 12-month randomised controlled trial was conducted among children aged 6-18 months living in Intibuca, Honduras. Communities (n = 18) were randomised into clusters matched by poverty indicators (9 intervention, n = 160 and 9 controls, n = 140). Intervention participants received LNS. All children received food vouchers and nutrition education. Primary outcomes included measures of micronutrient status: at baseline, 6 and 12 months' blood were collected for assessment of folate, iron, zinc, riboflavin, and vitamin B12 status; haemoglobin was measured every 3 months; and dietary and anthropometry collected monthly. Longitudinal analyses were based on intent to treat and LNS adherence. Generalised estimating equations were used in the estimation of generalised linear regression models specified for the data. RESULTS: At 6-month follow-up, children in the intervention group had a lower proportion classified as deficient for B12 (43.6%) compared with the control (67.7%; P = 0.03). The intervention group had a higher mean concentration for folate at 6 months (P = 0.06), and improvements continued through 12 months for folate (P = 0.002) and vitamin A deficiency (P = 0.03). This pattern of results, with improved significance, remained in subanalysis based on LNS adherence. CONCLUSION: These data demonstrate that LNS improved select micronutrient status in young non malnourished Honduran children. PMID- 24628578 TI - Cutaneous scalp metastases from retroperitoneal leiomyosarcoma: a case report. AB - A 71-year-old woman presented with five scalp nodules that were clinically suspicious for pilar cysts. Histopathologic examination showed a proliferation of mitotically active pleomorphic spindle cells arranged into intersecting fascicles in the dermis and subcutis. Tumor cells displayed deeply eosinophilic cytoplasm and expressed desmin but were negative for S100 protein by immunohistochemistry. Before 10 years, the patient was diagnosed with high-grade retroperitoneal leiomyosarcoma and underwent resection with intraoperative radiation. Metastatic disease involving the lungs, liver and soft tissue developed, requiring treatment with resections, radiation and chemotherapy. Owing to the presentation of multiple scalp nodules with microscopic features of leiomyosarcoma in conjunction with the clinical history of retroperitoneal leiomyosarcoma, a diagnosis of metastatic leiomyosarcoma was made. Scalp metastasis from retroperitoneal leiomyosarcoma is extremely rare and portends a poor prognosis. To our knowledge, only two other cases have been reported in the English literature, and a further search discovered only nine additional cases of scalp metastasis from soft tissue leiomyosarcoma of any non-gynecologic anatomic site. This case highlights the striking microscopic similarity between primary cutaneous and metastatic leiomyosarcoma and illustrates the necessity of adequate clinical information and an appropriate index of suspicion in excluding the possibility of cutaneous metastases of leiomyosarcoma from somatic soft tissue. PMID- 24628579 TI - The EP-score to assess treatment efficacy in RRMS patients: a preliminary study. AB - AIM OF THE STUDY: The aim of this retrospective study was to preliminarily assess whether the EP-score, a summary score derived from multimodal evoked potentials tests, might be used as a measure of treatment efficacy in multiple sclerosis (MS). MATERIALS AND METHODS: A sample of 56 relapsing remitting MS (RRMS) patients who at diagnosis started treatment with interferon beta (INFbeta, n = 19), glatiramer acetate (GA, n = 15) or refused any chronic treatment were assessed at baseline (before treatment) and at a median of 1.7 and 3.6 years thereafter. Outcome variables were Expanded Disability Status Scale (EDSS), EP Score, visual evoked potentials (VEP) and somatosensory evoked potentials (SEP) scores measured as differences between baseline and follow-ups. Statistical differences between groups and follow-ups were assessed using non-parametric analyses. RESULTS: Treatment effects were not significant for EDSS both at the first and at the second follow-up, while a trend toward significance was observed in the EP-score only in the first follow-up (p = 0.07). Post-hoc analysis showed a greater decrease in median VEP-score for the IFNbeta group compared to the GA and DF groups at both the first and second follow-ups. CONCLUSIONS: We found no evidence that either INFbeta or GA significantly improved disability in RRMS patients. Using the EP-score as an outcome measure, we found that it was improved at both follow-ups in the INFbeta group mainly due to a decrease in the VEP score. This finding supports the proposal to include the EP-score as an additional outcome variable in future studies of treatment efficacy in MS. PMID- 24628580 TI - Knockdown of interleukin-1 receptor 1 is not neuroprotective in the 6 hydroxydopamine striatal lesion rat model of Parkinson's disease. AB - It is well established that neuroinflammation is associated with the progression of many neurodegenerative diseases, including Parkinson's disease (PD). Activated microglia and elevated levels of pro-inflammatory cytokines such as interleukin 1beta (IL-1beta) have been found in the brain and cerebrospinal fluid of PD patients, suggesting that IL-1beta may be involved in the pathogenesis of this disease. This study aimed to knock down the expression of the interleukin-1 type 1 receptor (IL-1R1) to evaluate any potential therapeutic effect of limiting the action of IL-1beta in the substantia nigra following a unilateral intrastriatal 6 hydroxydopamine (6-OHDA) lesion in rats. Adult Sprague-Dawley rats received intranigral injections of shRNA specific for IL-1R1, followed 2 weeks later by intrastriatal 6-OHDA. Injection of IL-1R1 shRNA did not prevent 6-OHDA-induced loss of motor function or loss of nigral dopamine neurons. IL-1R1 expression was increased in the midbrain following 6-OHDA injection; this effect was attenuated in 6-OHDA-treated animals that had received IL-1R1 shRNA. These data suggest that while IL-1R1 was increased in 6-OHDA-treated animals and reduced following shRNA injection, the neurodegeneration induced by 6-OHDA was not mediated through IL 1R1. PMID- 24628581 TI - Potential neuroprotective role of transforming growth factor beta1 (TGFbeta1) in the brain. AB - TGFbeta1 is a growth factor that is known to be expressed in most neurodegenerative diseases and after vascular accidents in the brain. TGFbeta1 downregulates the activity of activated microglia and promotes astrogliosis. It also prevents cell death by a known mechanism dependant on astrocytes and the secretion of the plasminogen activator inhibitor 1 (PAI-1). This mechanism can provide light on what is the mechanism of action of TGFbeta1 as a protective factor and it can provide the pharmacological principles in which this pathway could be used with therapeutic purposes. TGFbeta1 is upregulated in most neurodegenerative diseases, however, its expression appears dramatically blocked in Huntington's disease, the fastest of those diseases in progress after the onset. This fact suggests that TGFbeta1 slows down the neurodegenerative process, preventing tissue damage and neural apoptotic death. However, the exact details of TGFbeta1 action are still unknown and the physiological roles on the diseases are still mysterious. Interestingly, all the data regarding the roles of TGFbeta1 in health and disease have been also confirmed with the use of transgenic knockouts and TGFbeta1 overexpressing mice. What possibly came as a surprise from the study of TGFbeta1 overexpressing models is that combining its neuroprotective and antiproliferative effects, this cytokine generates a significant disruption in the hippocampal circuitry with its consequent learning and memory deficit. PMID- 24628582 TI - Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene. AB - Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy. PMID- 24628583 TI - Rare earth element distributions and trends in natural waters with a focus on groundwater. AB - Systematically varying properties and reactivities have led to focused research of the environmental forensic capabilities of rare earth elements (REE). Increasing anthropogenic inputs to natural systems may permanently alter the natural signatures of REE, motivating characterization of natural REE variability. We compiled and analyzed reported dissolved REE concentration data over a wide range of natural water types (ground-, ocean, river, and lake water) and groundwater chemistries (e.g., fresh, brine, and acidic) with the goal of quantifying the extent of natural REE variability, especially for groundwater systems. Quantitative challenges presented by censored data were addressed with nonparametric distributions and regressions. Reported measurements of REE in natural waters range over nearly 10 orders of magnitude, though the majority of measurements are within 2-4 orders of magnitude, and are highly correlated with one another. Few global correlations exist among dissolved abundance and bulk solution properties in groundwater, indicating the complex nature of source-sink terms and the need for care when comparing results between studies. This collection, homogenization, and analysis of a disparate literature facilitates interstudy comparison and provides insight into the wide range of variables that influence REE geochemistry. PMID- 24628585 TI - Three new bioactive phenolic glycosides from Liparis odorata. AB - Chemical investigation of the ethanol extract from the whole plant Liparis odorata (Willd.) Lindl (orchid family) has led to the isolation of three new phenolic glycosides named liparisglycoside A-C (1-3) along with six known compounds (4-9). The structures of compounds were elucidated by means of extensive spectroscopic data analysis and comparison with the literature data. In addition, compounds 3 and 9 revealed inhibitory effects on lipopolysaccharide stimulated nitric oxide production, and compounds 1, 3 and 9 displayed hypolipidaemic effects in in vitro bioassays. PMID- 24628584 TI - Topical photodynamic therapy using different porphyrin precursors leads to differences in vascular photosensitization and vascular damage in normal mouse skin. AB - Different distributions of hexyl aminolevulinate (HAL), aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) in the superficial vasculature are not well studied but they are hypothesized to play an important role in topical photodynamic therapy (PDT). The colocalization of fluorescent CD31 and protoporphyrin IX (PpIX) was calculated using confocal microscopy of mouse skin sections to investigate the vascular distribution after topical application. Vascular damage leads to disruption of the normal endothelial adherens junction complex, of which CD144 is an integral component. Therefore, normal CD31 combined with loss of normal fluorescent CD144 staining was visually scored to assess vascular damage. Both the vascular PpIX concentration and the vascular damage were highest for HAL, then ALA and then MAL. Vascular damage in MAL was not different from normal contralateral control skin. This pattern is consistent with literature data on vasoconstriction after PDT, and with the hypothesis that the vasculature plays a role in light fractionation that increases efficacy for HAL and ALA-PDT but not for MAL. These findings indicate that endothelial cells of superficial blood vessels synthesize biologically relevant PpIX concentrations, leading to vascular damage. Such vascular effects are expected to influence the oxygenation of tissue after PDT which can be important for treatment efficacy. PMID- 24628588 TI - Levels of evidence and traffic light alerts. PMID- 24628587 TI - Tooth movement in orthodontic treatment with low-level laser therapy: a systematic review of human and animal studies. AB - OBJECTIVE: This review attempts to organize the existing published literature regarding tooth movement in orthodontic treatment when low-level laser therapy (LLLT) is applied. BACKGROUND DATA: The literature discusses different methods that have been developed to motivate the remodeling and decrease the duration of orthodontic treatment. The application of LLLT has been introduced to favor the biomechanics of tooth movements. However there is disagreement between authors as to whether LLLT reduces orthodontic treatment time, and the parameters that are used vary. MATERIALS AND METHODS: Studies in humans and animals in which LLLT was applied to increase the dental movement were reviewed. Three reviewers selected the articles. The resulting studies were analyzed according to the parameters used in the application of laser and existing changes clinically and histopathologically. RESULTS: Out of 84 studies, 5 human studies were selected in which canine traction had been performed after removing a premolar, and 11 studies in rats were selected in which first premolar traction was realized. There were statistically significant changes in four human studies and eight animal studies. CONCLUSIONS: Varying the wavelength with a reasonable dose in the target zone leads to obtaining the desired biological effect and achieving a reduction of the orthodontic treatment time, although there are studies that do not demonstrate any benefit according to their values. PMID- 24628586 TI - Recommendations for management of equine athletes with cardiovascular abnormalities. AB - Murmurs and arrhythmias are commonly detected in equine athletes. Assessing the relevance of these cardiovascular abnormalities in the performance horse can be challenging. Determining the impact of a cardiovascular disorder on performance, life expectancy, horse and rider or driver safety relative to the owner's future expectations is paramount. A comprehensive assessment of the cardiovascular abnormality detected is essential to determine its severity and achieve these aims. This consensus statement presents a general approach to the assessment of cardiovascular abnormalities, followed by a discussion of the common murmurs and arrhythmias. The description, diagnosis, evaluation, and prognosis are considered for each cardiovascular abnormality. The recommendations presented herein are based on available literature and a consensus of the panelists. While the majority of horses with cardiovascular abnormalities have a useful performance life, periodic reexaminations are indicated for those with clinically relevant cardiovascular disease. Horses with pulmonary hypertension, CHF, or complex ventricular arrhythmias should not be ridden or driven. PMID- 24628589 TI - Infantile neuroaxonal dystrophy caused by uniparental disomy. AB - Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the phospholipase A2 group 6 (Pla2G6) gene. Affected individuals usually present between the ages of 6 months and 2 years with rapid cognitive and motor regression and axial hypotonia. Gait disturbance, limb spasticity, cerebellar signs, and optic atrophy are other common features associated with INAD. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. In this case report, we describe the first individual (female) with INAD due to a combination of uniparental heterodisomy and isodisomy; we discuss the possible underlying mechanism and highlight the importance of parental carrier testing in accurately predicting the recurrence risk in these families. We also confirm the recent report of hypertrophy of the clava (also known as the 'gracile tubercle') as a useful MRI sign in INAD. PMID- 24628590 TI - A systematic review of interventions for children with cerebral palsy: the state of the evidence. PMID- 24628591 TI - The right interventions for each child with cerebral palsy. PMID- 24628592 TI - Danger of limiting interventions for children with cerebral palsy to level one evidence. PMID- 24628593 TI - Comments on a systematic review of interventions for children with cerebral palsy. PMID- 24628594 TI - Please proceed with caution. PMID- 24628595 TI - Early intervention is more than motor treatment. PMID- 24628596 TI - Critical considerations regarding 'the state of the evidence' for interventions in children with cerebral palsy. PMID- 24628597 TI - How to bridge the gap between systematic reviews and clinical guidelines. PMID- 24628598 TI - Red, yellow, green: can a traffic light system help systematic reviews? PMID- 24628599 TI - Researching conductive education. PMID- 24628600 TI - Novak et al. reply. PMID- 24628601 TI - Occurrence of Gobiidae larvae in a tropical Brazilian estuary, with particular emphasis on the use of size classes to categorize species guilds. AB - The structure and seasonal dynamics of larvae of the Gobiidae family in the Mucuri Estuary (Bahia, Brazil) were studied for nine consecutive years. Sampling was conducted at three stations in the lower estuary channel, between 2002 and 2010, in relation to season, day and night and tidal variations. A total of 5802 Gobiidae larvae, representing 15 taxa (12 species and three morphotypes), were collected in the Mucuri Estuary during this time. The highest mean +/- s.d. density of fish larvae, 54.7 +/- 79.8 larvae 100 m(-3), was recorded during the flood tide and night sampling. Ctenogobius boleosoma was the most abundant species (68%), being dominant in the rainy and dry seasons and had a long reproductive period. This species was classed as a marine estuarine-opportunist because it was observed at high frequencies and active larvae entering the estuary between 6.1 and 12.0 mm standard length (L(S)). Gobionellus oceanicus, second in abundance (12%), occurred only in later larval stages but did not use the estuary as a preferred location for spawning, being classed a marine estuarine dependent. Microgobius carri (11%) was represented in all L(S) classes and was resident in the estuary for spawning, remaining there throughout their life cycle. The other species were considered rare due to their low densities and could not be classified in any guild. PMID- 24628602 TI - Range-wide genetic structure of maritime pine predates the last glacial maximum: evidence from nuclear DNA. AB - Using nuclear simple sequence repeats (nuSSRs), we determined the genetic variability in the natural distribution range of maritime pine (Pinus pinaster) in the western Mediterranean region. We analysed the role of global and significant climatic fluctuations in driving the evolutionary diversification of this species. We attempted to determine the impact of the last glacial maximum (LGM) and human activity on genetic variation and to identify the effect of bottlenecks, admixing, migration, time to the most recent common ancestor (TMRCA), and recent splits. A total of 972 individuals were analysed. The sample represented 27 natural populations from the western Mediterranean region, which encompasses most of the natural range of P. pinaster. Using eight nuSSRs, we analysed genetic diversity indices for each population and group of populations. We also examined the interpopulation structure by the frequency and distance method and investigated genetic barriers, signals of historical demographic fluctuations, phylogeographic structure, admixing, rate of mutation, migration, as well as testing the hypothesis of isolation by distance (IBD). Both cluster analyses showed similar population genetic structure with three genetic barriers that divided the samples into four large groups. Intensive migration was only detected during the period of the last glacial maximum (LGM), which permitted the mutation rate of the markers used to be calculated. The majority of the population was found to exhibit signs of a recent bottleneck and its timing showed a clear northeast-southwest geographic distribution. A clearly defined phylogeographic structure (Nst > Gst and Rst > Gst ) under IBD was established, and showed the highest divergence between groups of populations separated by physical barriers, such as the Strait of Gibraltar, the Mediterranean Sea and the Pyrenees. The high level of intergroup genetic differentiation (PhiIS = 20.26) was attributed to a long historical isolation (which occurred before the last 18 000 years) between the principal maritime pine population groups that occurred due to physical barriers that limited pollen and seed transfer, combined with a minimal effective radius of distribution. The low level of genetic diversity among the populations was combined with genetic drift and a recent bottleneck during the period of human activity. Significant migration across barriers was due to spontaneous phenomena during the LGM, which had no significant impact on the genetic structure owing to its relatively short duration and the fragmented species. The phylogeographic structure under the assumption of IBD was well established for P. pinaster in each of the principal population groups. PMID- 24628603 TI - Epigallocatechin gallate decreases the micellar solubility of cholesterol via specific interaction with phosphatidylcholine. AB - The mechanisms underlying the effect of epigallocatechin gallate (EGCG) on the micellar solubility of cholesterol were examined. EGCG eliminated both cholesterol and phosphatidylcholine (PC) from bile salt micelles in a dose dependent manner in vitro. When the bile salt micelles contained a phospholipid other than PC, neither cholesterol nor the phospholipid was eliminated following the addition of EGCG. When vesicles comprised of various phospholipids were prepared and, EGCG was added to the vesicles, EGCG effectively and exclusively eliminated only PC. An intermolecular nuclear Overhauser effect (NOE) was observed between PC and EGCG in bile salt micelles with EGCG added, but not between cholesterol and EGCG, by using a NOE-correlated spectroscopy nuclear magnetic resonance method. The results of binding analyses using surface plasmon resonance (SPR) showed that EGCG did not bind to cholesterol. These observations strongly suggest that EGCG decreases the micellar solubility of cholesterol via specific interaction with PC. PMID- 24628604 TI - Coordination number of Li+ in nonaqueous electrolyte solutions determined by molecular rotational measurements. AB - The coordination number of Li(+) in acetonitrile solutions was determined by directly measuring the rotational times of solvent molecules bound and unbound to it. The CN stretch of the Li(+) bound and unbound acetonitrile molecules in the same solution has distinct vibrational frequencies (2276 cm(-1) vs 2254 cm(-1)). The frequency difference allows the rotation of each type of acetonitrile molecule to be determined by monitoring the anisotropy decay of each CN stretch vibrational excitation signal. Regardless of the nature of anions and concentrations, the Li(+) coordination number was found to be 4-6 in the LiBF4 (0.2-2 M) and LiPF6 (1-2 M) acetonitrile solutions. However, the dissociation constants of the salt are dependent on the nature of anions. In 1 M LiBF4 solution, 53% of the salt was found to dissociate into Li(+), which is bound by 4 6 solvent molecules. In 1 M LiPF6 solution, 72% of the salt dissociates. 2D IR experiments show that the binding between Li(+) and acetonitrile is very strong. The lifetime of the complex is much longer than 19 ps. PMID- 24628605 TI - Plasma cell myeloma with unusual morphology--a series of 6 cases. AB - Morphological variants of plasma cells have been described in cases of Plasma cell neoplasm. Presence of these atypical forms poses difficulty in morphological diagnosis and demands the use of ancillary techniques to ascertain the nature of these atypical cells. We hereby report a series of 6 such cases where the bone marrow examination showed plasma cells with atypical morphology, leading to varied differential diagnosis; however immunophenotyping by flow cytometry in adjunct to serum electrophoresis, immunofixation and free light chain assays confirmed the diagnosis. PMID- 24628606 TI - Aerosol-based fabrication of modified chitosans and their application for gene transfection. AB - Modified chitosan nanoparticles were conveniently obtained by a one-step aerosol method, and their potential for gene transfection was investigated. Droplets containing modified chitosans were formed by collison atomization, dried to form solid particles, and collected and studied for potential use as nanocarriers. Modified chitosans consisted of a chitosan backbone and an additional component [covalently attached cholesterol; or blends with poly(l-lysine) (PLL), polyethyleneimine (PEI), or poly(ethylene glycol) (PEG)]. Agarose gel retardation assays confirmed that modified chitosans could associate with plasmid DNA. Even though the average cell viability of cholesterol-chitosan (Ch-Cs) showed a slightly higher cytotoxicity (~90% viability) than that for unmodified chitosan (Cs, ~95%), transfection (>7.5 * 10(5) in relative light units (RLU) mg(-1)) was more effective than it was for Cs (~7.6 * 10(4) RLU mg(-1)). The blending of PEI with Cs (i.e., a Cs/PEI) to produce transfection complexes enhanced the transfection efficiency (~1.3 * 10(6) RLU mg(-1)) more than did the addition of PLL (i.e., a Cs/PLL, ~9.3 * 10(5) RLU mg(-1)); however, it also resulted in higher cytotoxicity (~86% viability for Cs/PEI vs ~94% for Cs/PLL). The average cell viability (~92%) and transfection efficiency (~1.9 * 10(6) RLU mg(-1)) were complemented further by addition of PEG in Cs/PEI complexes (i.e., a Cs/PEI-PEG). This work concludes that gene transfection of Cs can be significantly enhanced by adding cationic polymers during aerosol fabrication without wet chemical modification processes of Cs. PMID- 24628607 TI - "My legs affect me a lot. ... I can no longer walk to the forest to fetch firewood": challenges related to health and the performance of daily tasks for older women in a high HIV context. AB - Compromised health negatively impacts older persons' ability to participate in expected social roles. Researchers have published little empirical work, however, to explore these issues in HIV endemic African settings. Qualitative interviews with 30 women, aged 60-plus, in rural South Africa, provide insight into the relationship between health and daily activities, with attention to the fulfillment of social roles. In this poor HIV endemic context, older women make connections between their compromised health and their (lack of) capacity to perform the daily tasks that they view as expected of them. By expanding the conceptualization of health to include the capacity to achieve the expectations and perform the tasks expected of one, we better understand how and why health and performance of daily activities are so intricately linked in the minds of respondents. This also provides a starting point for thinking about the social and structural support needed by older persons in these settings, especially as HIV erodes familial supports. PMID- 24628608 TI - Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort. AB - OBJECT: The aim of this study was to determine the prospective hemorrhage rate in a group of retrospectively identified patients in whom symptoms had an unclear relationship to an intracerebral cavernous malformation (ICM) or the malformation itself was an incidental finding. METHODS: Patients with incidentally discovered ICMs diagnosed between 1989 and 1999 were identified from a previously published cohort. Those with ICMs having an unclear relationship with existing symptoms were also eligible for analysis. Updated clinical and radiographic data pertaining to symptomatic intracerebral hemorrhage related to the ICM or new seizures were obtained through medical chart review and mail survey. In select patients, phone calls were made and death certificates were obtained when possible. The prospective hemorrhage rate was calculated as the number of prospective hemorrhages divided by the number of patient-years of follow-up. RESULTS: There were 1311 patient-years of follow-up among the 107 patients (49.5% male; mean age at diagnosis 52 years) eligible for this study. Forty-four patients died in the follow-up period, and the cause of death could be determined in 34 (77%). Two patients had a prospective hemorrhage, which was definitively related to the ICM in only one. Thus, the definitive prospective bleed rate was 0.08% per patient-year. No new seizures developed in any of the patients during the follow-up period. CONCLUSIONS: The risk of prospective hemorrhage in patients presenting asymptomatically with ICM is very low. This information can be useful in managing such patients and may be most applicable to those with a single ICM. PMID- 24628609 TI - Erratum: Highly cited works in neurosurgery. Part II: the citation classics. PMID- 24628610 TI - High-resolution ultrasonography and diffusion tensor tractography map normal nerve fascicles in relation to schwannoma tissue prior to resection. AB - The goals of the present study were to demonstrate the ability of high-resolution ultrasonography to delineate normal nerve fascicles within or around peripheral nerve sheath tumors (NSTs). A blinded examiner evaluated 2 patients with symptomatic upper limb NSTs with high-resolution ultrasonography performed in the perioperative suite using a portable ultrasonography system. Ultrasonographic examinations located the tumor mass and identified the normal nerve fascicles associated with the mass. The locations of normal nerve tissue were mapped and correlated with results of MR tractography, operative inspection, and intraoperative electrophysiological monitoring. The study demonstrated a close correlation between normal nerve fascicles identified by ultrasonography, MR tractography, and intraoperative electrophysiological mapping. In particular, ultrasonographic examinations accurately identified the surface regions of the tumor without overlying normal nerve tissue. These preliminary data suggest that preoperative ultrasonographic examinations may provide valuable information, supplementary to the information obtained from intraoperative electrophysiological monitoring. Identification of normal nerve tissue prior to surgery may provide additional information regarding the risk of iatrogenic nerve injury during percutaneous tumor biopsy or open resection of the tumor and may also aid in selecting the optimum surgical approach. PMID- 24628611 TI - Suppression of cerebral aneurysm formation in rats by a tumor necrosis factor alpha inhibitor. AB - OBJECT: Although cerebral aneurysmal subarachnoid hemorrhage is a devastating disease for humans, effective medical treatments have not yet been established. Recent reports have shown that regression of some inflammatory-related mediators has protective effects in experimental cerebral aneurysm models. This study corroborated the effectiveness of tumor necrosis factor-alpha (TNF-alpha) inhibitor for experimentally induced cerebral aneurysms in rats. METHODS: Five week-old male rats were prepared for induction of cerebral aneurysms and divided into 3 groups, 2 groups administered different concentrations of a TNF-alpha inhibitor (etanercept), and 1 control group. One month after aneurysm induction, 7-T MRI was performed. The TNF-alpha inhibitor groups received subcutaneous injection of 25 MUg or 2.5 MUg of etanercept, and the control group received subcutaneous injection of normal saline every week. The TNF-alpha inhibitor administrations were started at 1 month after aneurysm induction to evaluate its suppressive effects on preexisting cerebral aneurysms. Arterial circles of Willis were obtained and evaluated 3 months after aneurysm induction. RESULTS: Rats administered a TNF-alpha inhibitor experienced significant increases in media thickness and reductions in aneurysmal size compared with the control group. Immunohistochemical staining showed that treatment with a TNF-alpha inhibitor suppressed matrix metalloproteinase (MMP)-9 and inducible nitric oxide synthase (iNOS) expression through the luminal surface of the endothelial cell layer, the media and the adventitia at the site of aneurysmal formation, and the anterior cerebral artery-olfactory artery bifurcation. Quantitative polymerase chain reaction also showed suppression of MMP-9 and iNOS by TNF-alpha inhibitor administration. CONCLUSIONS: Therapeutic administration of a TNF-alpha inhibitor significantly reduced the formation of aneurysms in rats. These data also suggest that TNF-alpha suppression reduced some inflammatory-related mediators that are in the downstream pathway of nuclear factor-kappaB. PMID- 24628612 TI - Flow re-direction endoluminal device. PMID- 24628613 TI - Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors: evaluation of a new method. AB - OBJECT: The authors developed a new mapping technique to overcome the temporal and spatial limitations of classic subcortical mapping of the corticospinal tract (CST). The feasibility and safety of continuous (0.4-2 Hz) and dynamic (at the site of and synchronized with tissue resection) subcortical motor mapping was evaluated. METHODS: The authors prospectively studied 69 patients who underwent tumor surgery adjacent to the CST (< 1 cm using diffusion tensor imaging and fiber tracking) with simultaneous subcortical monopolar motor mapping (short train, interstimulus interval 4 msec, pulse duration 500 MUsec) and a new acoustic motor evoked potential alarm. Continuous (temporal coverage) and dynamic (spatial coverage) mapping was technically realized by integrating the mapping probe at the tip of a new suction device, with the concept that this device will be in contact with the tissue where the resection is performed. Motor function was assessed 1 day after surgery, at discharge, and at 3 months. RESULTS: All procedures were technically successful. There was a 1:1 correlation of motor thresholds for stimulation sites simultaneously mapped with the new suction mapping device and the classic fingerstick probe (24 patients, 74 stimulation points; r(2) = 0.98, p < 0.001). The lowest individual motor thresholds were as follows: > 20 mA, 7 patients; 11-20 mA, 13 patients; 6-10 mA, 8 patients; 4-5 mA, 17 patients; and 1-3 mA, 24 patients. At 3 months, 2 patients (3%) had a persistent postoperative motor deficit, both of which were caused by a vascular injury. No patient had a permanent motor deficit caused by a mechanical injury of the CST. CONCLUSIONS: Continuous dynamic mapping was found to be a feasible and ergonomic technique for localizing the exact site of the CST and distance to the motor fibers. The acoustic feedback and the ability to stimulate the tissue continuously and exactly at the site of tissue removal improves the accuracy of mapping, especially at low (< 5 mA) stimulation intensities. This new technique may increase the safety of motor eloquent tumor surgery. PMID- 24628614 TI - Microsurgical anatomy of the cisternal anterior choroidal artery with special emphasis on the preoptic and postoptic subdivisions. AB - OBJECT: The object of this study was to delineate the microsurgical anatomy of the cisternal segment of the anterior choroidal artery (AChA). The authors also propose a new classification of this segment on the basis of its complicated course within the carotid and crural cisterns in relation to important neurovascular structures, and the site of origin, course, and areas of supply of perforating arteries. METHODS: Thirty cadaveric cerebral hemispheres injected with colored latex were dissected under surgical magnification to view the cisternal segment of the AChA and its perforators. Fiber dissections using the Klingler technique were performed in two additional latex injected hemispheres to follow the penetration points, courses, and terminal areas of supply of perforating branches that arise from the cisternal segment of the AChA. RESULTS: The cisternal segment of the AChA was divided into pre- and postoptic parts that meet at the artery's genu, the most medial extension point of the cisternal segment where the artery makes an abrupt turn after passing under the optic tract. The preoptic part of the AChA extended from its origin at the inferomedial side of the internal carotid artery to the artery's genu, which is commonly located just inferomedial to the initial part of the optic tract. The postoptic part coursed within the crural cistern and extended from the genu to the inferior choroidal point. The genu of the AChA was 8 mm medial to the artery's origin and was located medial to the optic tract in 13% of the hemispheres. The postoptic part was longer than the preoptic part in all hemispheres and had more perforating arteries supplying critical deep structures (preoptic 3.4 per hemisphere vs postoptic 4.6 per hemisphere), and these results were statistically significant (p = 0.01). At the preoptic part, perforating arteries arose from the superolateral portion of the artery and coursed laterally; at the postoptic part, perforators arose from the inferomedial portion of the artery and coursed medially. Perforating arteries from both segments passed most commonly to the optic tract, followed by the anterior segment and apex of uncus in the preoptic part and the cerebral peduncle in the postoptic part. CONCLUSIONS: Both parts of the cisternal segment of the AChA come into surgical view during surgeries for different pathologies in and around the perimesencephalic cisterns. However, attending to the artery's genu and defining pre- and postoptic parts during surgery may help the surgeon locate the origin and eventual course of these perforators, and even estimate the terminal areas of supply of most of the perforating arteries. The proposed classification system can prove helpful in planning any operative procedure along the crural cistern and may reduce the probability of inadvertent injury to perforating branches of the cisternal segment. PMID- 24628615 TI - Flow Re-direction Endoluminal Device in treatment of cerebral aneurysms: initial experience with short-term follow-up results. AB - OBJECT: Flow diverter (FD) stents are relatively new and important devices in the treatment of cerebral aneurysms. The Flow Re-Direction Endoluminal Device has been recently released for clinical use. The authors' aim in this paper is to report their initial single-center FRED experience with short-term results. METHODS: Between February 2012 and May 2013, 33 patients with 37 aneurysms (35 unruptured and 2 previously ruptured aneurysms) were treated with the FRED. Clinical and radiological data of the patients were retrospectively reviewed. RESULTS: In all patients only 1 device was used without any additional device or material, such as a stent or coil. All procedures were successfully performed. The procedural complication rate was 3% (1 of 33). Thirty patients underwent clinical and radiological follow-up. During the follow-up period, changes in stent morphology, such as "fish mouth" and "foreshortening" phenomena, occurred in 5 patients. The mortality and permanent morbidity rates were 0%. The complete occlusion rates were 32% (6 of 19) at 0-1 month, 67% (8 of 12) at 2-3 months, 80% (4 of 5) at 4-6 months, and 100% (8 of 8) at 7-12 months. The rates for some aneurysms were assessed at more than one time point. CONCLUSIONS: The FRED has an ability to serve neurointerventionalists in the treatment of cerebral aneurysms with its different technical advantages. The occlusion rates with FRED are similar to those with other FD devices. However, these short-term results need to be confirmed with mid- and long-term follow-up results of multicenter large series. PMID- 24628616 TI - Comparison of CT and clinical findings of Terson's syndrome in 121 patients: a 1 year prospective study. AB - OBJECT: Terson's syndrome (TS) is a vitreous hemorrhage in association with subarachnoid hemorrhage (SAH). Its diagnosis is often delayed, which may result in vision loss secondary to treatable conditions. Methods to hasten early diagnosis and consequent ophthalmic referral are desirable. The aims of this study were 1) to assess the specificity and sensitivity of conventional head CT for diagnosing TS in patients with aneurysmal SAH (aSAH); and 2) to determine the incidence of TS and its association with age, sex, aSAH severity, and overall mortality. METHODS: Patients admitted to Helsinki University Central Hospital who underwent surgery or endovascular treatment for a ruptured intracranial aneurysm during 2011 were participants in this prospective study. They underwent serial dilated fundoscopic examinations during a 6-month period. Two radiologists independently reviewed ocular findings suggestive of TS on conventional CT head scans obtained in all patients as a routine diagnostic procedure. Associations between TS and relevant clinical, radiological, and demographic data were analyzed with uni- and multivariate logistic regression. RESULTS: Of 121 participants, 13 (11%) presented with TS, and another 22 (18%) with intraretinal hemorrhages. For reviewing CT head scans, the overall observed agreement between the 2 raters was 96% (116 of 121 cases), with a substantial kappa of 0.69 (95% CI 0.56-0.82). The sensitivity of the CT findings for TS was 42%, and the specificity was 97%. Associations of the World Federation of Neurosurgical Societies (WFNS) and Hunt and Hess grades on admission, the presence of intracerebral hemorrhage, female sex, and aneurysm length with TS were all statistically significant. Logistic regression demonstrated that sex and WFNS grade were independently associated with TS and provided the best fit to the data. CONCLUSIONS: Routinely looking for TS findings in CT head scans may prove valuable in clinical practice. Terson's syndrome is associated with female sex and poor clinical condition on admission. PMID- 24628617 TI - Observer reliability of arteriovenous malformations grading scales using current imaging modalities. AB - OBJECT: The aim of this study was to examine observer reliability of frequently used arteriovenous malformation (AVM) grading scales, including the 5-tier Spetzler-Martin scale, the 3-tier Spetzler-Ponce scale, and the Pollock Flickinger radiosurgery-based scale, using current imaging modalities in a setting closely resembling routine clinical practice. METHODS: Five experienced raters, including 1 vascular neurosurgeon, 2 neuroradiologists, and 2 senior neurosurgical residents independently reviewed 15 MRI studies, 15 CT angiograms, and 15 digital subtraction angiograms obtained at the time of initial diagnosis. Assessments of 5 scans of each imaging modality were repeated for measurement of intrarater reliability. Three months after the initial assessment, raters reassessed those scans where there was disagreement. In this second assessment, raters were asked to justify their rating with comments and illustrations. Generalized kappa (kappa) analysis for multiple raters, Kendall's coefficient of concordance (W), and interclass correlation coefficient (ICC) were applied to determine interrater reliability. For intrarater reliability analysis, Cohen's kappa (kappa), Kendall's correlation coefficient (tau-b), and ICC were used to assess repeat measurement agreement for each rater. RESULTS: Interrater reliability for the overall 5-tier Spetzler-Martin scale was fair to good (ICC = 0.69) to extremely strong (Kendall's W = 0.73) on initial assessment and improved on reassessment. Assessment of CT angiograms resulted in the highest agreement, followed by MRI and digital subtraction angiography. Agreement for the overall 3 tier Spetzler-Ponce grade was fair to good (ICC = 0.68) to strong (Kendall's W = 0.70) on initial assessment, improved on reassessment, and was comparable to agreement for the 5-tier Spetzler-Martin scale. Agreement for the overall Pollock Flickinger radiosurgery-based grade was excellent (ICC = 0.89) to extremely strong (Kendall's W = 0.81). Intrarater reliability for the overall 5-tier Spetzler-Martin grade was excellent (ICC > 0.75) in 3 of the 5 raters and fair to good (ICC > 0.40) in the other 2 raters. CONCLUSION: The 5-tier Spetzler-Martin scale, the 3-tier Spetzler-Ponce scale, and the Pollock-Flickinger radiosurgery based scale all showed a high level of agreement. The improved reliability on reassessment was explained by a training effect from the initial assessment and the requirement to defend the rating, which outlines a potential downside for grades determined as part of routine clinical practice to be used for scientific purposes. PMID- 24628618 TI - Higher latitude and lower solar radiation influence on anaphylaxis in Chilean children. AB - BACKGROUND: Recent studies suggest an association between higher latitude, a proxy of vitamin D (VD) status, and allergic diseases. Chile provides an ideal setting to study this association due to its latitude span and high rates of VD deficiency in southern regions. The aim of this study is to explore the associations of latitude and solar radiation with anaphylaxis admission rates. METHODS: We reviewed anaphylaxis admissions in Chile's hospital discharge database between 2001 and 2010 and investigated associations with latitude and solar radiation. RESULTS: 2316 anaphylaxis admissions were registered. Median age of patients was 41 yr; 53% were female. National anaphylaxis admission rate was 1.41 per 100,000 persons per year. We observed a strong north-south increasing gradient of anaphylaxis admissions (beta 0.04, p = 0.01), with increasing rates south of latitude 34 degrees S. A significant association was also observed between solar radiation and anaphylaxis admissions (beta -0.11, p = 0.009). Latitude was associated with food-induced (beta 0.05, p = 0.02), but not drug induced (beta -0.002, p = 0.27), anaphylaxis. The association between latitude and food-induced anaphylaxis was significant in children (beta 0.01, p = 0.006), but not adults (beta 0.003, p = 0.16). Anaphylaxis admissions were not associated with regional sociodemographic factors like poverty, rurality, educational level, ethnicity, or physician density. CONCLUSIONS: Anaphylaxis admission rates in Chile are highest at higher latitudes and lower solar radiation, used as proxies of VD status. The associations appear driven by food-induced anaphylaxis. Our data support a possible role of VD deficiency as an etiological factor in the high anaphylaxis admission rates found in southern Chile. PMID- 24628619 TI - Eha, a transcriptional regulator of hemolytic activity of Edwardsiella tarda. AB - Hemolysis causes major symptoms such as the reddening skin and systemic hemorrhagic septicemia of diseased fish infected by Edwardsiella tarda. Cytolysin A (ClyA) is a pore-forming cytotoxic protein encoded by the clyA gene in Escherichia coli K-12. In this study, we observed that the heterologous expression of the eha gene from E. tarda could confer hemolytic activity upon a hemolytic-silent E. coli strain. The transcription of clyA is positively controlled by the eha gene in E. tarda by RT-PCR. We cloned and purified Eha protein which had shown preferential binding ability to the clyA sequences in its promoter region, as evidenced by gel shift assay. The eha controls the transcriptional start predominantly at 72 bp upstream in the clyA promoter region, as determined by primer extension assays. We suggest that Eha protein is a new positive regulator found in E. tarda. In addition, we constructed the eha mutant and complementary strains of E. tarda. The hemolytic activity of the eha mutant was found to be attenuated compared with the wild-type strain. The complementary strains restored the hemolytic activity to levels between those of the wild type and the eha mutation. Our results indicate that the Eha protein is an important positive regulator in the hemolytic properties of E. tarda. PMID- 24628620 TI - Analysis of transmembrane domains and lipid modified peptides with matrix assisted laser desorption ionization-time-of-flight mass spectrometry. AB - Protein-lipid interactions within the membrane are difficult to detect with mass spectrometry because of the hydrophobicity of tryptic cleavage peptides on the one hand and the noncovalent nature of the protein-lipid interaction on the other hand. Here we describe a proof-of-principle method capable of resolving hydrophobic and acylated (e.g., myristoylated) peptides by optimizing the steps in a mass spectrometric workflow. We then use this optimized workflow to detect a protein-lipid interaction in vitro within the hydrophobic phase of the membrane that is preserved via a covalent cross-link using a photoactivatable lipid. This approach can also be used to map the site of a protein-lipid interaction as we identify the peptide in contact with the fatty acid part of ceramide in the START domain of the CERT protein. PMID- 24628621 TI - Establishing HbA1c -mean blood glucose formulae for patients on continuous ambulatory peritoneal dialysis. AB - AIM: To determine the relationship between HbA1c and mean blood glucose concentrations by using HbA1c -mean blood glucose formulae for people on continuous ambulatory peritoneal dialysis. METHODS: A total of 305 people on continuous ambulatory peritoneal dialysis, including 13 people with Type 1 diabetes mellitus, 161 people with Type 2 diabetes mellitus and 131 people without diabetes, from a single peritoneal dialysis centre at the First Affiliated Hospital of Sun Yat-sen University, were enrolled between January 2006 and June 2011. Serum HbA1c concentration was measured quarterly and other laboratory variables, including blood glucose, were measured every month. The formulae were established using regression analysis and adjusted for other factors. The estimated blood glucose level calculated using our formulae was compared with that using previous formulae namely the Diabetes Control and Complications Trial and A1c -Derived Average Glucose formulae for people not on dialysis and the Hoshino formula for people on haemodialysis. RESULTS: The HbA1c mean blood glucose formulae obtained by linear regression analysis were: 1) mBGmmol/l = 0.107 * HbA1c (mmol/mol) + 1.764 [adjusted R(2) (Radj2) = 0.494]; 2) mBGmmol/l = 0.101 * HbA1c (mmol/mol) - 0.001 * Cr (MUmol/l) + 2.850 (Radj2 = 0.507); 3) mBGmmol/l = 0.102 * HbA1c (mmol/mol) - 0.095 * Alb (g/l) + 5.394 (Radj2 = 0.521); and 4) mBGmmol/l = 0.099 * HbA1c (mmol/mol) - 0.001 * Cr (MUmol/l)-0.084 * Alb (g/l) + 5.754 (Radj2 = 0.526), where mBG is mean blood glucose, Cr is serum creatinine and Alb is serum albumin. These new formulae performed as well as or better than previous formulae. CONCLUSIONS: The relationship between HbA1c and mean blood glucose for people on continuous ambulatory peritoneal dialysis differs from that for people not on dialysis or for those on haemodialysis. Clinicians and patients can determine glycaemic control targets by applying our formulae. PMID- 24628622 TI - Endoscopic ultrasound guided fine needle aspiration with fluorescence in situ hybridization analysis in 104 patients with pancreatic mass. AB - BACKGROUND AND AIM: Diagnosis of pancreatic malignancy is often based on cytological specimens collected by endoscopic ultrasound guided fine needle aspiration (EUS FNA). Several factors can decrease sensitivity of EUS FNA for pancreatic cancer: well-differentiated tumors, pancreatitis, blood, necrosis and slides with low cellularity. The objective of this study is to report on the use of fluorescence in situ hybridization (FISH) analysis combined with cytology in pancreatic masses. METHODS: EUS database and medical records of patients referred for EUS between January 2009 through august 2013 were reviewed. Data on cytology, FISH and surgical pathology were reviewed. Surgical pathology, death or extended clinical follow-up were used to verify correct diagnosis of malignancy. FISH performed using a four-set DNA probe for chromosomes 3, 7, 17, and band 9p21 in patients with inconclusive immediate cytology reading. Sensitivity of cytology and FISH were compared. RESULTS: Study cohort comprised of 104 patients with FISH analysis on EUS FNA specimens of pancreatic masses (74 adenocarcinoma, 7 neuroendocrine tumor and 23 benign. Sensitivity of cytology and FISH for carcinoma was respectively: 62% and 81%. Sensitivity of FISH + cytology was 89%. The specificity of FISH and cytology was 100%. The most common abnormality on FISH was a 9p21 deletion seen in 43 patients (58%) followed by polysomy of 7 (46%). FISH detected malignancy in 23 patients with negative cytology. CONCLUSIONS: In patients with inconclusive immediate cytology reading, FISH is superior to cytology and improves overall sensitivity. The 9p21 deletion is the most common abnormality seen in this cohort of patients with pancreatic cancer. PMID- 24628624 TI - A prospective, randomized, double-blind clinical trial study to evaluate a method for uvular repair during primary palatoplasty. AB - The purpose of this study was to evaluate the efficacy of a new technique for uvular repair in patients with cleft palate. This is a prospective, randomized, double blind controlled trial study with Ethical Committee approval between two groups of 30 patients each with cleft palate who were operated on using the conventional and proposed method of uvular repair from 2005-2007. Data was from the Outreach Surgical Center Program, Lima, Peru. Two groups of 30 patients each with cleft palate were operated on using the new technique by the Outreach Surgical Center Program Lima since 2007. Data collection was accomplished by physical exam to evaluate the appearance of the constructed uvula, as well as the presence or absence of a fistula and by a speech therapist. This comparative study did not find a statistically significant association between the conventional and the proposed method for uvular repair or the presence of postoperative hypernasal speech determined at 1-5 years of age during follow-up (p = 0.640). This study observed no increase in the rate of fistulas and/or VPI between these two groups so it was concluded that the use of the proposed method for uvular reconstruction does not affect the closure of the velopharyngeal sphincter and, thus, the development of VPI is not increased. PMID- 24628623 TI - Combined melanocytic and sweat gland neoplasm: cell subsets harbor an identical HRAS mutation in phacomatosis pigmentokeratotica. AB - Phacomatosis pigmentokeratotica (PPK) is characterized by the co-existence of epidermal nevi and large segmental speckled lentiginous nevi of the papulosa type. PPK, previously explained as 'twin spot' mosaicism due to the postzygotic crossing-over of two homozygous recessive mutations, has recently been shown to derive from one postzygotic activating RAS mutation. Epidermal nevi, including those in PPK, are known to give rise to neoplasms such as trichoblastoma and basal cell carcinoma. Within speckled lentiginous nevi, Spitz nevi and melanoma have been well documented. We report a case of PPK with a combined melanocytic and adnexal neoplasm presenting where the nevi conjoined. Using next-generation sequencing techniques, we were able to identify the same HRAS G13R mutation within both components of the tumor, and to show the absence of additional mutated modifier genes in a panel of 300 cancer-related genes. Given the genetic findings in this rare tumor-type, we suggest that this case may be used as a model for understanding the development of biphenotypic neoplasia or intratumoral heterogeneity in some cases. PMID- 24628625 TI - Direct observation of metal-insulator transition in single-crystalline germanium telluride nanowire memory devices prior to amorphization. AB - Structural defects and their dynamics play an important role in controlling the behavior of phase-change materials (PCM) used in low-power nonvolatile memory devices. However, not much is known about the influence of disorder on the electronic properties of crystalline PCM prior to a structural phase-change. Here, we show that the application of voltage pulses to single-crystalline GeTe nanowire memory devices introduces structural disorder in the form of dislocations and antiphase boundaries (APB). The dynamic evolution and pile-up of APBs increases disorder at a local region of the nanowire, which electronically transforms it from a metal to a dirty metal to an insulator, while still retaining single-crystalline long-range order. We also observe that close to this metal-insulator transition, precise control over the applied voltage is required to create an insulating state; otherwise the system ends up in a more disordered amorphous phase suggesting the role of electronic instabilities during the structural phase-change. PMID- 24628627 TI - Is academic geriatrics a special case? PMID- 24628626 TI - ATF7IP as a novel PDGFRB fusion partner in acute lymphoblastic leukaemia in children. AB - We identified ATF7IP as a novel PDGFRB fusion partner in B-progenitor acute lymphoblastic leukaemia (B-ALL) and showed that B-ALL with ATF7IP/PDGFRB translocation is included within the genomic lesions of a Philadelphia chromosome (Ph)-like ALL subgroup. Comprehensive analyses of previous repositories of gene expression data sets disclosed that B-ALL cases with high PDGFRB expression level in the context of the Ph-like ALL gene are likely to have a PDGFRB translocation. Thus, it is possible that measurement of the PDGFRB expression level can be utilized as a screening test for the detection of the cryptic PDGFRB translocation, especially within the Ph-like ALL subgroup. PMID- 24628629 TI - Effect of a transitional pharmaceutical care intervention at hospital discharge on registration of changes in medication regimens in primary care. PMID- 24628628 TI - Challenges to cost-effective care of older adults with multiple chronic conditions: perspectives of Program of All-Inclusive Care for the Elderly medical directors. PMID- 24628630 TI - Medication reconciliation in an outpatient geriatrics clinic: does accuracy improve if patients "brown bag" their medications for appointments? PMID- 24628631 TI - Can we repackage omeprazole capsules into multicompartment compliance AIDS? PMID- 24628632 TI - Comprehensive geriatric assessment reveals sleep disturbances in community dwelling elderly adults associated with even slight cognitive decline. PMID- 24628633 TI - Geriatric inclusive art and risk of in-hospital mortality in inpatients with dementia: results from a quasi-experimental study. PMID- 24628634 TI - Establishing CUTOFF values for the Simplified Barthel Index in elderly adults in residential care homes. PMID- 24628635 TI - Reasons and outcomes for long-term care transfers to the hospital: a retrospective review. PMID- 24628636 TI - Long-term outcomes in individuals aged 75 and older with pulmonary embolism. PMID- 24628637 TI - Unveiling a prescribing cascade in an older man. PMID- 24628638 TI - Nurturing syndrome in an elderly woman without dementia. PMID- 24628639 TI - Multiple cardiac clots in an individual with essential thrombocythemia and heart failure. PMID- 24628640 TI - Sustained 4-year cognitive and functional response in early Alzheimer's disease with pioglitazone. PMID- 24628641 TI - Hypoactive delirium caused by pulmonary embolus in an elderly adult. PMID- 24628642 TI - Bilateral oral nodules after the use of a dermal filler containing polymethylmethacrylate microspheres in an older woman. PMID- 24628643 TI - Chasing the "white whale" of Alzheimer's. PMID- 24628644 TI - Comment on "Is once-weekly resistance training enough to prevent sarcopenia?". PMID- 24628645 TI - Response to Drs. Safer and Safer. PMID- 24628646 TI - Response to Drs. Safer and Safer. PMID- 24628647 TI - Re: Effects of resistance versus multicomponent training on body composition and functional fitness in institutionalized elderly women. PMID- 24628649 TI - Pig-to-baboon liver xenoperfusion utilizing GalTKO.hCD46 pigs and glycoprotein Ib blockade. AB - BACKGROUND: Although transplantation of genetically modified porcine livers into baboons has yielded recipient survival for up to 7 days, survival is limited by profound thrombocytopenia, which becomes manifest almost immediately after revascularization, and by subsequent coagulopathy. Porcine von Willebrand's factor (VWF), a glycoprotein that adheres to activated platelets to initiate thrombus formation, has been shown to constitutively activate human platelets via their glycoprotein Ib (GPIb) receptors. Here, we report our pig-to-primate liver xenoperfusion model and evaluate whether targeting the GPIb-VWF axis prevents platelet sequestration. METHODS: Twelve baboons underwent cross-circulation with the following extracorporeal livers: one allogeneic control with a baboon liver, 4 xenogeneic controls with a GalTKO.hCD46 pig liver, 3 GalTKO.hCD46 pig livers in recipients treated with alphaGPIb antibody during perfusion, and 4 GalTKO.hCD46 pig livers pre-treated with D-arginine vasopressin (DDAVP) in recipients treated with alphaGPIb antibody during perfusion. RESULTS: All perfused livers appeared grossly and macroscopically normal and produced bile. Xenograft liver perfusion experiments treated with alphaGPIb antibody may show less platelet sequestration during the initial 2 h of perfusion. Portal venous resistance remained constant in all perfusion experiments. Platelet activation studies demonstrated platelet activation in all xenoperfusions, but not in the allogeneic perfusion. CONCLUSION: These observations suggest that primate platelet sequestration by porcine liver and the associated thrombocytopenia are multifactorial and perhaps partially mediated by a constitutive interaction between porcine VWF and the primate GPIb receptor. Control of platelet sequestration and consumptive coagulopathy in liver xenotransplantation will likely require a multifaceted approach in our clinically relevant perfusion model. PMID- 24628651 TI - A6U3Sb2P8S32 (A = Rb, Cs): quinary uranium(IV) thiophosphates containing the [Sb(PS4)3](6-) anion. AB - The reaction of A2S3/U/P2S5/S at 500 degrees C affords the quinary U(IV) thiophosphates A6U3Sb2P8S32 (A = Rb, Cs). These compounds contain {U3(PS4)2[Sb(PS4)3]2}(6-) layers separated by alkali metal cations. The layers are composed of trimeric uranium units connected to each other by the thiophosphato-antimonite anion, [Sb(PS4)3](6-). This unit contains a central Sb(III) cation bound by three [PS4](3-) anions, creating a trigonal pyramidal environment around Sb(III). Each uranium cation is surrounded by eight sulfides in a distorted square antiprism that shares two edges with two other US8 units to form a trimeric [U3S18](24-) cluster. Magnetic susceptibility measurements indicate that the close proximity of the U(IV) within these clusters leads to antiferromagnetic ordering at 53 K. Reflectance spectroscopy indicates that these compounds are semiconductors with a band gap of 1.48 eV. PMID- 24628652 TI - Editorial: reducing stigma by changing the name of epilepsy. PMID- 24628650 TI - Efficacy of omeprazole powder paste or enteric-coated formulation in healing of gastric ulcers in horses. AB - BACKGROUND: GastroGard, an omeprazole powder paste formulation, is considered the standard treatment for gastric ulcers in horses and is highly effective. Gastrozol, an enteric-coated omeprazole formulation for horses, has recently become available, but efficacy data are controversial and sparse. OBJECTIVES: To investigate the efficacy of GastroGard and Gastrozol at labeled doses (4 and 1 mg of omeprazole per kg bwt, respectively, PO q24h) in healing of gastric ulcers. ANIMALS: 40 horses; 9.5 +/- 4.6 years; 491 +/- 135 kg. METHODS: Prospective, randomized, blinded study. Horses with an ulcer score >=1 (Equine Gastric Ulcer Council) were randomly divided into 2 groups and treated for 2 weeks each with GastroGard followed by Gastrozol (A) or vice versa (B). After 2 and 4 weeks, scoring was repeated and compared with baseline. Plasma omeprazole concentrations were measured on the first day of treatment after administration of GastroGard (n = 5) or Gastrozol (n = 5). RESULTS: Compared with baseline (squamous score (A) 1.65 +/- 0.11, (B) 1.98 +/- 0.11), ulcer scores at 2 weeks ((A) 0.89 +/- 0.11, (B) 1.01 +/- 0.11) and 4 weeks ((A) 1.10 +/- 0.12, (B) 0.80 +/- 0.12) had significantly decreased in both groups (P < .001), independent of treatment (P = .7). Plasma omeprazole concentrations were significantly higher after GastroGard compared with Gastrozol administration (AUCGG = 2856 (1405-4576) ng/mL * h, AUCGZ = 604 (430-1609) ng/mL * h; P = .03). The bioavailability for Gastrozol was 1.26 (95% CI 0.56-2.81) times higher than for GastroGard. CONCLUSIONS AND CLINICAL IMPORTANCE: Both Gastrozol and GastroGard, combined with appropriate environmental changes, promote healing of gastric ulcers in horses. However, despite enteric coating of Gastrozol, plasma omeprazole concentrations after single labeled doses were significantly higher with GastroGard. PMID- 24628653 TI - Commentary on Cavernoma-related epilepsy: review and recommendations for management-report of the surgical task force of the ILAE commission on therapeutic strategies. PMID- 24628654 TI - In response to commentary on cavernoma-related epilepsy: review and recommendations for management-report of the surgical task force of the ILAE commission on therapeutic strategies. PMID- 24628655 TI - Alcohol and substance use among transgender women in San Francisco: prevalence and association with human immunodeficiency virus infection. AB - INTRODUCTION AND AIMS: Alcohol and substance use can have negative health consequences among both human immunodeficiency virus (HIV)-positive and -negative individuals, and are associated with behaviors that facilitate HIV transmission and acquisition. The relationship of substance use and HIV is well documented among key populations at risk for HIV. However, although transwomen (male-to female transgender) are disproportionately impacted by HIV, this overlap remains understudied in this population. We sought to evaluate the association between HIV, alcohol and substance use among transwomen. DESIGN AND METHODS: We conducted a secondary data analysis of Respondent Driven Sampling study which collected information on self-reported alcohol and substance use among 314 transwomen. We used multivariable logistic regression to assess relationship between HIV infection and classes and patterns of alcohol and substance use. RESULTS: We found that 58% of transwomen used alcohol, and 43.3% used substances. The most common substances used were: marijuana (29%), methamphetamine (20.1%), crack cocaine (13.4%), and 'club drugs' (13.1%). Transwomen who reported any methamphetamine use [adjusted odds ratio (AOR) 3.02 (95% confidence interval (CI) = 1.51-6.02)], methamphetamine use before or during anal intercourse [AOR 3.27 (95% CI = 1.58-6.77)], and at least weekly methamphetamine use [AOR 3.89 (95% CI = 1.64-9.23)] had significantly greater odds of testing positive for HIV. DISCUSSION AND CONCLUSIONS: Transfemales have high prevalence of alcohol and substance use; those tested positive for HIV used significantly more methamphetamine in general, and in conjunction with sex. Given the disproportionate prevalence of HIV and substance use in this population, interventions aimed at addressing both substance use and HIV risk among transwomen are urgently needed. PMID- 24628656 TI - Photosystem I shows a higher tolerance to sorbitol-induced osmotic stress than photosystem II in the intertidal macro-algae Ulva prolifera (Chlorophyta). AB - The photosynthetic performance of the desiccation-tolerant, intertidal macro algae Ulva prolifera was significantly affected by sorbitol-induced osmotic stress. Our results showed that photosynthetic activity decreased significantly with increases in sorbitol concentration. Although the partial activity of both photosystem I (PS I) and photosystem II (PS II) was able to recover after 30 min of rehydration, the activity of PS II decreased more rapidly than PS I. At 4 M sorbitol concentration, the activity of PS II was almost 0 while that of PS I was still at about one third of normal levels. Following prolonged treatment with 1 and 2 M sorbitol, the activity of PS I and PS II decreased slowly, suggesting that the effects of moderate concentrations of sorbitol on PS I and PS II were gradual. Interestingly, an increase in non-photochemical quenching occurred under these conditions in response to moderate osmotic stress, whereas it declined significantly under severe osmotic stress. These results suggest that photoprotection in U. prolifera could also be induced by moderate osmotic stress. In addition, the oxidation of PS I was significantly affected by osmotic stress. P700(+) in the thalli treated with high concentrations of sorbitol could still be reduced, as PS II was inhibited by 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), but it could not be fully oxidized. This observation may be caused by the higher quantum yield of non-photochemical energy dissipation in PS I due to acceptor-side limitation (Y(NA)) during rehydration in seawater containing DCMU. PMID- 24628657 TI - What is your diagnosis? Blood smear from a foal. PMID- 24628658 TI - Considerations for recommending extended use and limited reuse of filtering facepiece respirators in health care settings. AB - Public health organizations, such as the Centers for Disease Control and Prevention (CDC), are increasingly recommending the use of N95 filtering facepiece respirators (FFRs) in health care settings. For infection control purposes, the usual practice is to discard FFRs after close contact with a patient ("single use"). However, in some situations, such as during contact with tuberculosis patients, limited FFR reuse (i.e., repeated donning and doffing of the same FFR by the same person) is practiced. A related practice, extended use, involves wearing the same FFR for multiple patient encounters without doffing. Extended use and limited FFR reuse have been recommended during infectious disease outbreaks and pandemics to conserve FFR supplies. This commentary examines CDC recommendations related to FFR extended use and limited reuse and analyzes available data from the literature to provide a relative estimate of the risks of these practices compared to single use. Analysis of the available data and the use of disease transmission models indicate that decisions regarding whether FFR extended use or reuse should be recommended should continue to be pathogen- and event-specific. Factors to be included in developing the recommendations are the potential for the pathogen to spread via contact transmission, the potential that the event could result in or is currently causing a FFR shortage, the protection provided by FFR use, human factors, potential for self-inoculation, the potential for secondary exposures, and government policies and regulations. While recent findings largely support the previous recommendations for extended use and limited reuse in certain situations, some new cautions and limitations should be considered before issuing recommendations in the future. In general, extended use of FFRs is preferred over limited FFR reuse. Limited FFR reuse would allow the user a brief respite from extended wear times, but increases the risk of self-inoculation and preliminary data from one study suggest that some FFR models may begin to lose effectiveness after multiple donnings. PMID- 24628659 TI - Synergistic antitumor effect of combining metronomic chemotherapy with adoptive cell immunotherapy in nude mice. AB - Adoptive cell immunotherapy with cytokine-induced killer cell (CIK cell) represents a promising non-toxic anticancer therapy. However, the clinical efficacy of CIK cells is limited because of abnormal tumor vasculature. Metronomic chemotherapy shows promising anticancer activity by its potential antiangiogenic effect and reduced toxicity. We hypothesized that metronomic chemotherapy with paclitaxel could improve the antitumor effect of adoptive CIK cell immunotherapy. Mice health status was analyzed by measuring mice weight and observing mice behavior. Immunohistochemistry was used to investigate the recruitment of CIK cells, the expression of endothelial cell molecules, as well as the hypoxic tumor area. Metronomic paclitaxel synergized with adoptive CIK cell immunotherapy to inhibit the growth of non-small cell lung cancer (NSCLC). Metronomic paclitaxel reduced hypoxic tumor area and increased CIK cell infiltration. Hypoxia impeded the adhesion of CIK cells and reduced the expression of endothelial cell adhesion molecules. In vivo studies demonstrated that more CIK cells were found in endothelial cell adhesion molecules high expressed area. Our study provides a new rationale for combining metronomic chemotherapy with adoptive cell immunotherapy in the treatment of xenograft NSCLC tumors in immunodeficient mice. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach. PMID- 24628660 TI - Fine-mapping natural alleles: quantitative complementation to the rescue. AB - Mapping the genes responsible for natural variation and divergence is a challenging task. Many studies have mapped genes to genomic regions or generated lists of candidates, but few studies have implicated specific genes with a high standard of evidence. I propose that combining recent advances in genomic engineering with a modified version of the quantitative complementation test will help turn candidate genes into causal genes. By creating loss-of-function mutations in natural strains, and using these mutations to quantitatively fail-to complement natural alleles, fine mapping should be greatly facilitated. As an example, I propose that the CRISPR/Cas9 system could be combined with the FLP/FRT system to fine-map genes in the numerous systems where inversions have frustrated these efforts. PMID- 24628661 TI - Effect of growing area on tocopherols, carotenoids and fatty acid composition of Pistacia lentiscus edible oil. AB - In this investigation, we aim to study, for the first time, the effect of the growing area on tocopherols, carotenoids and fatty acid content of Pistacia lentiscus fixed oil. Fruits were harvested from eight different sites located in the north and the centre of Tunisia. Tocopherols, carotenoids and fatty acid content of the fixed oils were determined. The highest carotenoid content was exhibited by Feija oil (10.57 mg/kg of oil). Oueslatia and Tabarka oils displayed the highest alpha-tocopherol content (96.79 and 92.79 mg/kg of oil, respectively). Three major fatty acids were determined: oleic, palmitic and linoleic acids. Oleic acid was the main fatty acid presenting more than 50% of the total fatty acid content. Kebouche oil presented the highest oleic acid content (55.66%). All these results highlight the richness of carotenoids, tocopherols and unsaturated fatty acids in P. lentiscus seed oil and underscore the nutritional value of this natural product. PMID- 24628662 TI - College students who endorse a sub-threshold number of DSM-5 alcohol use disorder criteria: alcohol, tobacco, and illicit drug use in DSM-5 diagnostic orphans. AB - OBJECTIVES: Diagnostic orphans (DOs) represent a group of individuals with no formal diagnosis, despite endorsing some criteria of an alcohol use disorder (AUD). Prior research has indicated that rates of DSM-IV DOs in college are high and closely resemble those with an alcohol abuse diagnosis across pertinent alcohol use risk factors. However, significant changes to the DSM-IV AUD criteria have been made for the current DSM-5 manual, which may impact how DOs are classified. This study examined the unique alcohol and illicit drug use characteristics of a group of 2,620 DSM-5 DOs in college and tested whether DOs differed from those with and without a DSM-5 AUD across pertinent alcohol and drug use risk factors. METHODS: Participants were 2,620 DSM-5 DO undergraduate college students, between the ages of 18 and 30, recruited from three public universities in the Southeastern, United States. RESULTS: Diagnostic orphans represented 19.6% (n = 506) of the sample; with the most frequently endorsed criteria being tolerance and consuming alcohol in hazardous situations. DOs reported significantly greater alcohol consumption, alcohol and drug related problems, and illicit drug use compared to those with no DSM-5 AUD diagnosis. Alternatively, DOs reported significantly lower alcohol use and illicit drug use compared to those with a DSM-5 AUD. CONCLUSION: The present findings indicate that DSM-5 DOs in college represent a distinct group of drinkers relative to those with and without a DSM-5 AUD. Current screening initiatives should target this group to prevent future escalation of problem drinking. PMID- 24628663 TI - Cd-metallothioneins in three additional tetrahymena species: intragenic repeat patterns and induction by metal ions. AB - Ciliate metallothioneins (MTs) possess many unique features compared to the "classic" MTs in other organisms, but they have only been studied in a small number of species. In this study, we investigated cDNAs encoding subfamily 7a metallothioneins (CdMTs) in three Tetrahymena species (T. hegewischi, T. malaccensis, and T. mobilis). Four CdMT genes (ThegMT1, ThegMT2, TmalMT1, and TmobMT1) were cloned and characterized. They share high sequence similarity to previously identified subfamily 7a MT members. Tetrahymena CdMTs exhibit a remarkably regular intragenic repeat homology. The CdMT sequences were divided into two main types of modules, which had been previously described, and which we name "A" and "B". ThegMT2 was identified as the first MT isoform solely composed of module "B". A phylogenetic analysis of individual modules of every characterized Tetrahymena CdMT rigorously documents the conclusion that modules are important units of CdMT evolution, which have undergone frequent and rapid gain/loss and shuffling. The transcriptional activity of the four newly identified genes was measured under different heavy metal exposure (Cd, Cu, Zn, Pb) using real-time quantitative PCR. The results showed that these genes were differentially induced after short (1 h) or long (24 h) metal exposure. The evolutionary diversity of Tetrahymena CdMTs is further discussed with regard to their induction by metal ions. PMID- 24628664 TI - AH peptide-mediated formation of charged planar lipid bilayers. AB - Planar lipid bilayers on solid supports provide a controllable platform to mimic biological membranes. Adsorption and spontaneous rupture of vesicles is the most common method to form planar bilayers. While many substrates support vesicle adsorption, vesicles rupture spontaneously on only a few materials. In order to form planar bilayers on materials intractable to conventional vesicle fusion, an amphipathic, alpha-helical (AH) peptide has been identified that can rupture adsorbed vesicles and form planar bilayers on previously intractable materials. Most studies using AH peptide have employed zwitterionic lipid compositions only, and the range of suitable lipid compositions remains to be elucidated. Herein, using quartz crystal microbalance-dissipation and ellipsometry, we investigated the effects of membrane surface charge on AH peptide-mediated bilayer formation via the rupture of surface-adsorbed vesicles on titanium oxide. Our findings demonstrate that AH peptide can promote the formation of positively and negatively charged bilayers. Importantly, the kinetics of vesicle rupture by AH peptide are strongly influenced by the membrane surface charge. Although the titanium oxide surface is negatively charged, the formation of negatively charged bilayers was quickest among the tested lipid compositions. Taken together, the experimental data supports that the effects of membrane surface charge on the rupture kinetics are related to variations in the extent of vesicle destabilization prior to vesicle rupture. Given the wide range of lipid compositions amenable to AH peptide-mediated vesicle rupture, this work further suggests that AH peptide is largely unique among membrane-active peptides, thereby substantiating its position as a promising broad-spectrum antiviral agent. PMID- 24628665 TI - Rhodotorula mucilaginosa skin infection in a patient treated with sorafenib. PMID- 24628667 TI - Interactions of three soil bacteria species with phyllosilicate surfaces in hybrid silica gels. AB - To simulate iron consumption in soils, iron leaching from silicate minerals due to three heterotrophic bacterial strains and a chemical treatment was studied using hybrid silica gel (HSG) doped with two phyllosilicates, nontronite (NAu-2) or low-iron-content montmorillonite (SWy-2). HSG methodology, a novel way of separating bacteria cells from a colloidal mineral source, consisted in embedding colloidal mineral particles into an amorphous porous silica matrix using a classical sol-gel procedure. Pantoae agglomerans PA1 and Rahnella aquatilis RA1 were isolated from silicate-rich soils, that is, beech and wheat rhizospheres (Vosges, France); Burkholderia sp. G5 was selected from acidic and nutrient-poor podzol soils (Vosges, France). Fe release from clay minerals and production of bacterial metabolites, that is, low molecular weight organic acids (LMWOA) and siderophores, were monitored. Two LMWOA profiles were observed with major gluconate production (> 9000 MUM) for Burkholderia sp. G5 and moderate production of lactate, acetate, propionate, formate, oxalate, citrate, and succinate (< 300 MUM) for R. aquatilis RA1 and P. agglomerans PA1. HSG demonstrated its usefulness in revealing clay mineral-microorganisms interactions. The effect of bacterial exsudates was clearly separated from physical contact effect. PMID- 24628666 TI - Hypereosinophilic syndrome and hemimelia in a patient with chromosome 6p22.3 deletion. PMID- 24628668 TI - Temporal and spatial dynamics of nrf2-antioxidant response elements mediated gene targets in cortex and hippocampus after controlled cortical impact traumatic brain injury in mice. AB - The pathophysiological importance of oxidative damage after traumatic brain injury (TBI) has been extensively demonstrated. The transcription factor nuclear factor erythoid related factor 2 (Nrf2) mediates antioxidant and cytoprotective genes by binding to antioxidant response elements (ARE) present in nuclear DNA. In this study, we characterized the time course of Nrf2-ARE-mediated expression in the cortex and hippocampus using a unilateral controlled cortical impact model of focal TBI. Ipsilateral hippocampal and cortical tissue was collected for Western-blot protein analysis (n=6/group) or quantitative reverse transcription polymerase chain reaction for mRNA (n=3/group) at 3, 6, 12, 24, 48, and 72 h or 1 week post-injury. Multiple genes mediated by Nrf2-ARE were altered post-TBI. Specifically, Nrf2 mRNA increased significantly post-TBI at 48 and 72 h in the cortex and at 48 and 72 h and 1 week in the hippocampus with a coincident increase in glial fibrillary acidic protein mRNA, thereby implying this response is likely occurring in astrocytes. Presumably linked to Nrf2 activation, heme oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone-oxidoreductase 1, glutathione reductase, and catalase mRNA overlap throughout the post-injury time course. This study demonstrates the first evidence of such changes during the first week after focal TBI and that increases in expression of some Nrf2-ARE mediated cytoprotective genes are not observed until 24-48 h post-injury. Unfortunately, this does not precede, but rather coincides with, the occurrence of lipid peroxidative damage. This is the first known comparison between the time course of peroxidative damage and that of Nrf2-ARE activation during the first week post-TBI. These results underscore the necessity to discover pharmacological agents to accelerate and amplify Nrf2-ARE-mediated expression early post-TBI. PMID- 24628670 TI - Determination of halide impurities in ionic liquids by total reflection X-ray fluorescence spectrometry. AB - The determination and quantification of halide impurities in ionic liquids is highly important because halide ions can significantly influence the chemical and physical properties of ionic liquids. The use of impure ionic liquids in fundamental studies on solvent extraction or catalytic reactions can lead to incorrect experimental data. The detection of halide ions in solution by total reflection X-ray fluorescence (TXRF) has been problematic because volatile hydrogen halide (HX) compounds are formed when the sample is mixed with the acidic metal standard solution. The loss of HX during the drying step of the sample preparation procedure gives imprecise and inaccurate results. A new method based on an alkaline copper standard Cu(NH3)4(NO3)2 is presented for the determination of chloride, bromide, and iodide impurities in ionic liquids. The 1 butyl-3-methylimidazolium ([C4mim]) ionic liquids with the anions acetate ([C4mim][OAc]), nitrate ([C4mim][NO3]), trifluoromethanesulfonate ([C4mim][OTf]), and bis(trifluoromethylsulfonyl)imide ([C4mim][Tf2N]) were synthesized via a halide-free route and contaminated on purpose with known amounts of [C4mim]Cl, [C4mim]Br, [C4mim]I, or potassium halide salts in order to validate the new method and standard. PMID- 24628669 TI - Similar weight-adjusted insulin secretion and insulin sensitivity in short duration late autoimmune diabetes of adulthood (LADA) and type 2 diabetes: Action LADA 9 [corrected]. AB - AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). beta-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups. CONCLUSIONS: We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI. PMID- 24628671 TI - Immunomodulatory Effects of Alginate Oligosaccharides on Murine Macrophage RAW264.7 Cells and Their Structure-Activity Relationships. AB - This study evaluated the immunomodulatory activities, including regulation of nitric oxide (NO), reactive oxygen species (ROS), and tumor necrosis factor (TNF) alpha production in RAW264.7 murine macrophages, of alginate oligosaccharides (AOS) and investigated their structure-activity relationships. Our results revealed that unsaturated guluronate oligosaccharide prepared by enzymatic degradation (GOS-ED) induced NO production and inducible nitric oxide synthase (iNOS) expression, dose and time dependently, and stimulated ROS and TNF-alpha production; however, other AOS prepared by different ways or polymers showed very low and even no such effects. Moreover, GOS-ED induced macrophage activation to release the above-mentioned mediators partly involved in nuclear factor (NF) kappaB and mitogen-activated protein (MAP) kinase signaling pathways. We also show that the structural characteristics of AOS, especially the unsaturated terminal structure, molecular size, and M/G ratio, play important roles in determining the macrophage-activating effects. GOS-ED could be applicable for agriculture, drug, and food industry as a potent immune-modulatory agent. PMID- 24628672 TI - Evolving endoscopic surgery. AB - Since the days of Albukasim in medieval Spain, natural orifices have been regarded not only as a rather repugnant source of bodily odors, fluids and excreta, but also as a convenient invitation to explore and treat the inner passages of the organism. However, surgical ingenuity needed to be matched by appropriate tools and devices. Lack of technologically advanced instrumentation was a strong deterrent during almost a millennium until recent decades when a quantum jump materialized. Endoscopic surgery is currently a vibrant and growing subspecialty, which successfully handles millions of patients every year. Additional opportunities lie ahead which might benefit millions more, however, requiring even more sophisticated apparatuses, particularly in the field of robotics, artificial intelligence, and tissue repair (surgical suturing). This is a particularly exciting and worthwhile challenge, namely of larger and safer endoscopic interventions, followed by seamless and scarless recovery. In synthesis, the future is widely open for those who use together intelligence and creativity to develop new prototypes, new accessories and new techniques. Yet there are many challenges in the path of endoscopic surgery. In this new era of robotic endoscopy, one will likely need a virtual simulator to train and assess the performance of younger doctors. More evidence will be essential in multiple evolving fields, particularly to elucidate whether more ambitious and complex pathways, such as intrathoracic and intraperitoneal surgery via natural orifice transluminal endoscopic surgery (NOTES), are superior or not to conventional techniques. PMID- 24628673 TI - Primary cutaneous epithelioid rhabdomyosarcoma: a rare, recently described entity with review of the literature. AB - We report a case of a primary cutaneous epithelioid rhabdomyosarcoma that presented as a single raised pink-purple lesion (3.3 * 2.2 cm) on the left base of neck in a 75-year-old man. Histopathologic examination revealed an exophytic, nodular tumor within the dermis and superficial subcutis with overlying ulceration. The tumor exhibited sheet-like growth, infiltration of adjacent structures, and was composed of uniform epithelioid cells with abundant eosinophilic cytoplasm and eccentrically placed vesicular nuclei with irregular nuclear contours and prominent central nucleoli. Numerous mitotic figures were present [28/10 high power fields (HPF)] but only mild cytologic pleomorphism was identified. By immunohistochemistry, tumor cells were diffusely and strongly positive for desmin and MYOD1. Focal positive staining for myogenin and cytokeratin CK903 was identified. Stains for Melan-A, S-100, SOX10, p63 and CK5/6 were negative. These histopathologic and immunophenotypic features support a diagnosis of epithelioid rhabdomyosarcoma. No evidence of a deep soft tissue primary lesion was identified. In summary, epithelioid rhabdomyosarcoma can present as a primary cutaneous lesion and dermatopathologists should be aware of this entity. PMID- 24628674 TI - Prognostic impact of gained chromosomes in high-hyperdiploid childhood acute lymphoblastic leukaemia: a collaborative retrospective study of the Tokyo Children's Cancer Study Group and Japan Association of Childhood Leukaemia Study. PMID- 24628675 TI - Oriented assembled TiO2 hierarchical nanowire arrays with fast electron transport properties. AB - Developing high surface area nanostructured electrodes with rapid charge transport is essential for artificial photosynthesis, solar cells, photocatalysis, and energy storage devices. Substantial research efforts have been recently focused on building one-dimensional (1D) nanoblocks with fast charge transport into three-dimensional (3D) hierarchical architectures. However, except for the enlargement in surface area, there is little experimental evidence of fast electron transport in these 3D nanostructure-based solar cells. In this communication, we report single-crystal-like 3D TiO2 branched nanowire arrays consisting of 1D branch epitaxially grown from the primary trunk. These 3D branched nanoarrays not only demonstrate 71% enlargement in large surface area (compared with 1D nanowire arrays) but also exhibit fast charge transport property (comparable to that in 1D single crystal nanoarrays), leading to 52% improvement in solar conversion efficiency. The orientated 3D assembly strategy reported here can be extended to assemble other metal oxides with one or multiple components and thus represents a critical avenue toward high-performance optoelectronics. PMID- 24628676 TI - Juvenile (age 13-18) smoking incidence determinants in Greece. AB - Smoking is a form of medical addiction, usually adopted during adolescence. The aim was to determine the prevalence of smoking in adolescents, aged 13-18 years old, to investigate their attitudes towards smoking and determine the contribution of social influences to onset and continuation of smoking. An anonymous self-report questionnaire was filled in by 873 high school students of Central Greece. Smoking incidence was 19.2%, with a 13.7% of regular smokers. The presence of a smoker in the family and a smoker friend were correlated with increased smoking rates. School grades were correlated negatively with smoking attitude and positively with allowance. Age was correlated negatively with social influence. Social influence appears stronger on younger ages and is a main determinant of smoking behavior. A more susceptible attitude towards smoking is formed during late adolescence. Certain social predictive factors for attitude towards smoking are proposed. PMID- 24628677 TI - Retrospective follow up of gross motor development in children using propranolol for treatment of infantile haemangioma at Sydney Children's Hospital. AB - Questions have been raised as to whether propranolol, which crosses the blood brain barrier, when used early in life may have an adverse effect on gross motor development. A retrospective survey asking questions about gross motor development was sent to the families of children who had been prescribed oral propranolol for infantile haemangioma at Sydney Children's Hospital between 2008 and 2013. It was found that of the 84 patients surveyed, four were delayed in walking unassisted. There was a statistically significant influence if the child was taking other medications which included prednisolone, vincristine, omeprazole, ranitidine, salbutamol, Flixotide, Timoptol and antibiotics. This was not further analysed in this study because of the low numbers involved. There was no statistically significant influence of gestational age, birth weight or length of time on propranolol. This study adds to the retrospective data available; however large-scale prospective studies are needed to identify unexpected long term side-effects. PMID- 24628678 TI - The deposition of Notch1 in hepatitis B virus-associated nephropathy and its role in hepatitis B virus X protein-induced epithelial-mesenchymal transdifferentiation and immunity disorder in renal tubular epithelial cells. AB - SUMMARY: Notch1 plays an important role in the regulation of immune responses and epithelial-mesenchymal transdifferentiation (EMT). Previous studies have observed inflammatory cell infiltration and tubulointerstitial fibrosis in the renal biopsies from patients with HBV-associated glomerulonephritis (HBV-GN). We hypothesized that Notch1 may be involved in the progression of HBV-GN. In this study, we evaluated the distribution of Notch1 in patients with HBV-GN. Our results showed that Notch1 was mainly distributed in renal tubules and the interstitial area, and the expression levels of Notch1 had a positive correlation with the renal tubular pathology. In this respect, we used human proximal tubular epithelial cells (HK-2) as target cells, which were transiently transfected with the hepatitis B virus X (HBx) gene using a eukaryotic vector. HBx expression resulted in significantly increased detection of Notch1, alpha-smooth muscle actin (alpha-SMA), major histocompatibility complex-II (MHC-II), CD40 and interleukin-4 (IL-4). At the same time, E-cadherin and interferon-gamma (IFN gamma) expression levels were significantly inhibited. These HBx-induced phenotypes were exacerbated by upregulation of Notch1. Knock-down of Notch1 by specific shRNA caused decreases of alpha-SMA, MHC-II, CD40 and IL-4, and increases of E-cadherin and IFN-gamma. These findings suggest that Notch1 is significantly associated with renal tubular and interstitial lesions. Notch1 can mediate HBx-induced EMT of HK-2 cells, promote HBx-induced increases in immune molecule expression and exacerbation of cytokine disorders, which may contribute to the progression of HBV-GN. Inhibitors of Notch1 signalling may be useful as new therapeutics for the treatment of HBV-GN. PMID- 24628679 TI - Collaborative recall of details of an emotional film. AB - Collaborative inhibition refers to the phenomenon that when several people work together to produce a single memory report, they typically produce fewer items than when the unique items in the individual reports of the same number of participants are combined (i.e., nominal recall). Yet, apart from this negative effect, collaboration may be beneficial in that group members remove errors from a collaborative report. Collaborative inhibition studies on memory for emotional stimuli are scarce. Therefore, the present study examined both collaborative inhibition and collaborative error reduction in the recall of the details of emotional material in a laboratory setting. Female undergraduates (n = 111) viewed a film clip of a fatal accident and subsequently engaged in either collaborative (n = 57) or individual recall (n = 54) in groups of three. The results show that, across several detail categories, collaborating groups recalled fewer details than nominal groups. However, overall, nominal recall produced more errors than collaborative recall. The present results extend earlier findings on both collaborative inhibition and error reduction to the recall of affectively laden material. These findings may have implications for the applied fields of forensic and clinical psychology. PMID- 24628681 TI - Photocatalytic CO2 reduction in N,N-dimethylacetamide/water as an alternative solvent system. AB - N,N-Dimethylacetamide (DMA) was used for the first time as the reaction solvent in the photocatalytic reduction of CO2. DMA is highly stable against hydrolysis and does not produce formate even if it is hydrolyzed. We report the catalytic activities of [Ru(bpy)2(CO)2](PF6)2 (bpy = 2,2'-bipyridine) in the presence of [Ru(bpy)3](PF6)2 as a photosensitizer and 1-benzyl-1,4-dihydronicotinamide (BNAH) as an electron donor in DMA/water. In the photochemical CO2 reduction, carbon monoxide (CO) and formate are catalytically produced, while dihydrogen (H2) from the reduction of water is scarcely evolved. We verified that BNAH is oxidized to afford BNA dimers during the photocatalyses in DMA/water. The plots of the production for the CO2 reduction versus the water content in DMA/water show that the 10 vol % water content gives the highest amount of the reduction products, whose reaction quantum yields (Phi') are determined to be 11.6% and 3.2% for CO and formate, respectively. The results are compared with those in the N,N dimethylformamide (DMF)/water system, which has been typically used as the solvent system for the CO2 reduction. PMID- 24628680 TI - Variability in coefficient of restitution in human facial skin. AB - BACKGROUND: If particles rebound on human facial skin, they can be re-entrained into the airflow and subsequently inhaled, increasing aspiration efficiency estimates. A realistic estimate of facial skin coefficient of restitution (CoR) is necessary to accurately model particle bounce. This study investigated the effects of sampling location, temperature, humidity levels, age, gender, and BMI on facial skin CoR. METHODS: A torsional ballistometer was used to measure facial CoR for 30 participants divided into three age groups (18-30, 31-40, and 41-65 years), at three temperatures and three humidity levels. The study was repeated twice: once in the late winter and once in the early summer to capture the seasonal variability. RESULTS: The CoR significantly varied across five facial locations, with values ranging from 0.55 to 0.75. Gender, sampling season and the interaction between sampling location and age were found to be significant, but changes in values were relatively small (0.05 at most) and are not considered practically significant. CONCLUSION: CoR was non-uniform across the face. The use of uniform CoR value as modeling input parameters or for mannequin facial surfaces in experimental wind tunnel studies may not be accurate due to the high variability in CoR between facial sampling locations. PMID- 24628682 TI - The big night out: what happens on the most recent heavy drinking occasion among young Victorian risky drinkers? AB - INTRODUCTION AND AIMS: In spite of the major focus on risky, single-occasion drinking by young people in Australia, little is known about the specific circumstances of risky drinking occasions. This study examines drinking behaviours and drinking contexts for the most recent risky, single-occasion drinking episode in a representative sample of young risky drinkers in Victoria, Australia. DESIGN AND METHODS: A representative sample of 802 young risky drinkers was recruited across metropolitan Melbourne and surveyed about their drinking and related behaviours. Specific questions focused on participants' most recent high-risk (>10 Australian standard drinks for males, >7 Australian standard drinks for females) drinking occasion in terms of self-reported amount drunk, alcohol expenditure (including buying rounds) and drinking partners for up to 10 different drinking settings. RESULTS: Participants reported drinking a mean of 13 Australian standard drinks on their last episode of risky, single-occasion drinking; for half of the participants, this occurred less than 20 days prior to being surveyed. The majority (62%) of risky single occasion drinking sessions commenced at private homes in the company of close friends (81%). Around 40% of the sample reported going to one (42%) or two (37%) drinking locations, and only 5% reported going to more than three drinking locations. DISCUSSION AND CONCLUSIONS: Contrary to public portrayals, a significant amount of risky drinking by young people occurs in private settings. These contexts are rarely mentioned except in relation to underage drinking. Further work is needed to understand how these drinking behaviours and contexts link to harm. PMID- 24628683 TI - Relationship among serum creatinine, serum gastrin, calcium-phosphorus product, and uremic gastropathy in cats with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) in cats is associated with gastrointestinal signs commonly attributed to uremic gastropathy. Consequently, patients often are treated with antacids and gastrointestinal protectants. This therapeutic regimen is based on documented gastric lesions in uremic humans and dogs, but the nature and incidence of uremic gastropathy in cats are unknown. HYPOTHESIS/OBJECTIVES: Evaluate uremic gastropathy in CKD cats to facilitate refinement of medical management for gastrointestinal signs. ANIMALS: Thirty seven CKD cats; 12 nonazotemic cats METHODS: Stomachs were evaluated for the presence of classic uremic gastropathy lesions. Histopathologic lesions were compared with serum creatinine concentrations, calcium-phosphorus product (CPP), and serum gastrin concentrations. RESULTS: Gastric ulceration, edema, and vascular fibrinoid change were not observed. The most important gastric lesions in CKD cats were fibrosis and mineralization. Sixteen CKD cats (43%) had evidence of gastric fibrosis of varying severity and 14 CKD cats (38%) had gastric mineralization. CKD cats were more likely to have gastric fibrosis and mineralization than nonazotemic controls (P = .005 and P = .021, respectively). Only cats with moderate and severe azotemia had gastric mineralization. CPP was correlated with disease severity; severely azotemic CKD cats had significantly higher CPP when compared with nonazotemic controls, and to mildly and moderately azotemic cats (P < .05). Gastrin concentrations were significantly higher in CKD cats when compared with nonazotemic controls (P = .003), but increased concentrations were not associated with gastric ulceration. CONCLUSIONS AND CLINICAL IMPORTANCE: Uremic gastropathy in CKD cats differs from that described in other species and this difference should be considered when devising medical management. PMID- 24628684 TI - Clinical significance of pretreatment serum interferon-gamma-inducible protein 10 concentrations in chronic hepatitis C patients treated with telaprevir-based triple therapy. AB - AIM: We aimed to determine whether pretreatment serum interferon-gamma-inducible protein (IP)-10 concentration can predict response to telaprevir (TVR)-based triple therapy in patients with genotype 1 chronic hepatitis C (CHC), and to examine the effects of IP-10 concentration on liver histology. METHODS: Baseline IP-10 concentrations were measured in 97 patients with genotype 1 CHC treated with TVR-based triple therapy, and the associations between baseline IP-10 and treatment outcome were assessed by univariate and multivariate analyses. Associations between baseline serum IP-10 concentration and laboratory data and liver histological findings were also investigated. RESULTS: Median IP-10 concentration in these patients was 461.83 pg/mL (range, 151.35-4297.62). Multivariate analysis showed that IL28B genotype (P = 0.025) and IP-10 level (P = 0.004) were factors significantly predictive of rapid virological response (RVR), whereas in pretreatment factors only, IL28B genotype (P = 0.001) and liver fibrosis (P = 0.035) were independent predictors of sustained virological response. Using a cut-off IP-10 concentration of 460 pg/mL, patients with IL28B risk allele and low IP-10 had a significantly higher RVR rate than those with high IP-10 (P = 0.005). IP-10 concentration was significantly correlated with liver fibrosis (P = 0.001) and inflammation activity (P = 0.006) and had the highest areas under the curve for liver histological findings. CONCLUSION: Baseline serum IP-10 level is a useful predictor of virological response in patients with genotype 1 CHC treated with TVR-based triple therapy, especially in patients with IL28B risk allele. IP-10 was well correlated with liver fibrosis and inflammation. PMID- 24628685 TI - The role of climatic tolerances and seed traits in reduced extinction rates of temperate polygonaceae. AB - The latitudinal diversity gradient (LDG) is one of the most striking and consistent biodiversity patterns across taxonomic groups. We investigate the species richness gradient in the buckwheat family, Polygonaceae, which exhibits a reverse LDG and is, thus, decoupled from dominant gradients of energy and environmental stability that increase toward the tropics and confound mechanistic interpretations. We test competing age and evolutionary diversification hypotheses, which may explain the diversification of this plant family over the past 70 million years. Our analyses show that the age hypothesis, which posits that clade richness is positively correlated with the ecological and evolutionary time since clade origin, fails to explain the richness gradient observed in Polygonaceae. However, an evolutionary diversification hypothesis is highly supported, with diversification rates being 3.5 times higher in temperate clades compared to tropical clades. We demonstrate that differences in rates of speciation, migration, and molecular evolution insufficiently explain the observed patterns of differential diversification rates. We suggest that reduced extinction rates in temperate clades may be associated with adaptive responses to selection, through which seed morphology and climatic tolerances potentially act to minimize risk in temporally variable environments. Further study is needed to understand causal pathways among these traits and factors correlated with latitude. PMID- 24628686 TI - Promoting HIV and sexual safety behaviour in people with severe mental illness: a systematic review of behavioural interventions. AB - People diagnosed with severe mental illness (SMI) are at greater risk of HIV than the general population. However, little attention has been given to how best to reduce sexual risk taking in this group. The aim of the review was to evaluate the effectiveness of behavioural interventions to promote sexual safety behaviour in people diagnosed with SMI. A comprehensive search of relevant databases was undertaken, and studies were included if they were randomized, controlled trials; behavioural intervention related to sexual behaviour; included adults diagnosed with SMI; and if a behavioural outcome was reported. The Cochrane Assessment of Bias Tool was used. Of the initial 515 papers identified, 11 trials were included for quality assessment and data extraction. The studies were heterogeneous in content and dose of intervention, as well as outcome measure and follow-up periods, and all had some risk of bias. Four of the studies demonstrated significant improvement in safer sexual behaviour at follow up, but this effect diminished over time. The effect sizes were extremely variable. There is emerging evidence to suggest that a behavioural intervention has the potential to reduce sexual risks in people diagnosed with SMI. However, further high-quality research is needed in this area. PMID- 24628687 TI - Stable confinement of positron emission tomography and magnetic resonance agents within carbon nanotubes for bimodal imaging. AB - AIMS: Simultaneous positron emission tomography/MRI has recently been introduced to the clinic and dual positron emission tomography/MRI probes are rare and of growing interest. We have developed a strategy for producing multimodal probes based on a carbon nanotube platform without the use of chelating ligands. MATERIALS & METHODS: Gd(3+) and (64)Cu(2+) ions were loaded into ultra-short single-walled carbon nanotubes by sonication. Normal, tumor-free athymic nude mice were injected intravenously with the probe and imaged over 48 h. RESULTS & CONCLUSION: The probe was stable for up to 24 h when challenged with phosphate buffered saline and mouse serum. Positron emission tomography imaging also confirmed the stability of the probe in vivo for up to 48 h. The probe was quickly cleared from circulation, with enhanced accumulation in the lungs. Stable encapsulation of contrast agents within ultra-short single-walled carbon nanotubes represents a new strategy for the design of advanced imaging probes with variable multimodal imaging capabilities. PMID- 24628688 TI - Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin. AB - BACKGROUND: Treatment with daunorubicin (DNR) in acute myeloid leukemia is moderately effective and associated with significant side effects, including cardiac toxicity. We recently developed a nanomicellar formulation of DNR that specifically targets acute myeloid leukemia stem cells. MATERIALS & METHODS: Pharmacokinetics analysis of free DNR, DNR in nanomicellar formulations was performed in Balb/c mice and Sprague-Dawley rats. Histochemical staining, caspase 3/7, troponin and creatine kinase MB isoenzyme were used to assess toxicity. RESULTS: Compared with free DNR, the nanomicellar formulations of DNR had less cardiotoxicity as evidenced by milder histopathological changes, lower caspase 3/7 activity in heart tissue (p = 0.002), lower plasma creatine kinase MB isoenzyme (p = 0.002) and troponin concentrations (p = 0.001) postinjection. The area under curve concentration of DNR in micelles increased by 31.9-fold in mice (p < 0.0001) and 22.0-fold higher in rats (p < 0.001). CONCLUSION: Leukemia stem cell-targeting micelles dramatically change the pharmacokinetics and reduce the cardiac toxicity of DNR, which may enable improved DNR-based treatment of acute myeloid leukemia. PMID- 24628689 TI - Zinc oxide nanoparticles impair bacterial clearance by macrophages. AB - AIM: The extensive development of nanoparticles (NPs) and their widespread employment in daily life have led to an increase in environmental concentrations of substances that may pose a biohazard to humans. The aim of this work was to examine the effects of zinc oxide nanoparticles (ZnO-NPs) on the host's pulmonary immune system response to nontypeable Haemophilus influenzae (NTHi) infection. MATERIALS & METHODS: A murine infection model was employed to assess pulmonary inflammation and bacterial clearance in response to exposure to ZnO-NPs. The molecular mechanisms underlying ZnO-NP-impaired macrophage activation were investigated. RESULTS: Treatment with ZnO-NPs impaired macrophage activation, leading to a delay in NTHi clearance in the bronchial alveolar lavage fluids and lungs. Exposure to ZnO-NPs followed by NTHi challenge decreased levels of nitric oxide compared with NTHi infection alone. The effects of ZnO-NPs involved downregulation of NTHi-activated expression of inducible nitric oxide synthase and the translocation of active NF-kB into the nucleus. CONCLUSION: These results demonstrate that exposure to ZnO-NPs can impair innate immune responses and attenuate macrophage responses to bacterial infection. PMID- 24628690 TI - Phenolic and antioxidant profiles of rowan (Sorbus L.) fruits. AB - Fruits of different Sorbus L. species have been traditionally used in food production and in the treatment of various ailments. Besides common antioxidant active phytochemicals such as ascorbic acid, tocopherols and carotenoids, fruits are rich in phenolic compounds that are of particular interest. In this study, profiles of separate antioxidant active compounds (reducing and radical scavenging activities) were investigated using online assays with post-column reactions. Significant variations in phenolic acids and flavonoids contents and antioxidant activity values were observed in the fruits of Sorbus L. species studied. Neochlorogenic and chlorogenic acids were determined as markers of antioxidant activity. Characteristic patterns of antioxidant profiles obtained using HPLC post-column FRAP and ABTS assays significantly depend on specific Sorbus L. species and are suitable for equivalency research of Sorbus L. fruits. PMID- 24628692 TI - Rhinitis as a risk factor for depressive mood in pre-adolescents: a new approach to this relationship. AB - BACKGROUND: Respiratory allergic symptoms impact on social life and school activities, influencing the patient's mood states. We evaluated the relationships between allergic respiratory diseases and depressive/anxious mood in a large sample of Italian middle school students, using the partial directed acyclic graph (P-DAG). METHODS: We studied 1283 subjects aged 10-13. A health respiratory questionnaire including questions relevant to socioeconomic status (HCI) and a test for depression and anxiety were administered. All subjects performed spirometry and skin prick tests. RESULTS: A causal role of rhinitis on depression was found: the likelihood of being depressed increased from 11.2 to 17.7%, when rhinitis was present. Moreover, a direct effect of low HCI on depressive mood was shown (p < 0.0001) as well as the correlation between anxiety and depression (p < 0.0001). Gender was not a direct causal factor for depressive mood, but their relation was mediated through anxious mood. Anxiety appeared to have a stronger association with depression than gender. Allergic sensitization was significantly related to both asthma and rhinitis (p < 0.0001, respectively). Asthma and rhinitis were also directly associated (p < 0.0001). Conversely, asthma was not directly associated with depressive mood, but their relation was mediated through rhinitis. Body mass index (BMI) and impaired lung function (IPF) were not associated with the other variables. CONCLUSIONS: The use of this novel approach to analyzing the dynamic relationships allowed us to find a causal role of rhinitis on depressive state. Moreover, anxious condition and low socioeconomic status contributed to induce depressive mood. PMID- 24628691 TI - The CO donor CORM-2 inhibits LPS-induced vascular cell adhesion molecule-1 expression and leukocyte adhesion in human rheumatoid synovial fibroblasts. AB - BACKGROUND AND PURPOSE: Infection with Gram-negative bacteria has been recognized as an initiator of rheumatoid arthritis, which is characterized by chronic inflammation and infiltration of immune cells. Carbon monoxide (CO) exhibits anti inflammatory properties. Here we have investigated the detailed mechanisms of vascular cell adhesion molecule-1 (VCAM-1) expression induced by LPS and if CO inhibited LPS-induced leukocyte adhesion to synovial fibroblasts by suppressing VCAM-1 expression. EXPERIMENTAL APPROACH: Human rheumatoid arthritis synovial fibroblasts (RASFs) were incubated with LPS and/or the CO-releasing compound CORM 2. Effects of LPS on VCAM-1 levels were determined by analysing mRNA expression, promoter activity, protein expression, and immunohistochemical staining. The molecular mechanisms were investigated by determining the expression, activation, and binding activity of transcriptional factors using target signal antagonists. KEY RESULTS: CORM-2 significantly inhibited inflammatory responses in LPS-treated RASFs by down-regulating the expression of adhesion molecule VCAM-1 and leukocyte infiltration. The down-regulation of LPS-induced VCAM-1 expression involved inhibition of the expression of phosphorylated-NF-kappaB p65 and AP-1 (p-c-Jun, c Jun and c-Fos mRNA levels). These results were confirmed by chromatin immunoprecipitation assay to detect NF-kappaB and AP-1 DNA binding activity. CONCLUSIONS AND IMPLICATIONS: LPS-mediated formation of the TLR4/MyD88/TRAF6/c Src complex regulated NF-kappaB and MAPKs/AP-1 activation leading to VCAM-1 expression and leukocyte adhesion. CORM-2, which liberates CO to elicit direct biological activities, attenuated LPS-induced VCAM-1 expression by interfering with NF-kappaB and AP-1 activation, and significantly reduced LPS-induced immune cell infiltration of the synovium. PMID- 24628693 TI - Exploring biotic interactions within protist cell populations using network methods. AB - The study of diseased human cells and of cells isolated from the natural environment will likely be revolutionized by single cell genomics (SCG). Here, we used protein similarity networks to explore within- and between-cell DNA differences from SCG data derived from six individual rhizarian cells related to Paulinella ovalis and proteins from the complete genome of another rhizarian, Bigelowiella natans. We identified shared and distinct DNA components within our SCG data and between P. ovalis and B. natans. We show that network properties such as assortativity and degree effectively discriminate genome features between SCG assemblies and that SCG data follow the power law with a small number of protein families dominating networks. PMID- 24628694 TI - Age of first arrest varies by gambling status in a cohort of young adults. AB - BACKGROUND AND OBJECTIVES: To describe the association between social and problem gambling and first criminal arrest by age 23 in a cohort of urban, mainly African American youth. METHODS: Data for this study were derived from several annual interviews being completed on a community sample of 617 participants during late adolescence until age 23. Information on gambling status, engagement in deviant behaviors, illegal drug use, and arrest history were collected through yearly interviews. Analysis was carried out using Nelson-Aalen cumulative hazard models and simple and adjusted Cox proportional hazards models. RESULTS: More problem gamblers had been arrested before age 23 than social gamblers and non-gamblers, ie, 65% of problem gamblers were arrested before age 23, compared to 38% of social gamblers and 24% non-gamblers. Social gambling was only significantly associated with the hazard of first arrest by age 23 in the unadjusted model (HR: 1.6, p < .001), but not after adjustment for covariates (HR: 1.1, p = .47). Problem gambling was significantly associated with the hazard of first arrest by age 23 years in the unadjusted (HR: 3.6, p < .001) and adjusted models (HR: 1.6, p = .05). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Problem gambling was significantly associated with earlier age of being arrested. Dilution effects after adjustment for several deviant behaviors and illegal drug use by age 17 suggest that youth exposure to certain common factors may result in engagement in multiple risky behaviors, including problem gambling. Studies are needed to investigate the developmental pathways that lead to these combined behaviors among youth. (Am J Addict 2014;23:386-392). PMID- 24628695 TI - Evaluation of particles released from single-wall carbon nanotube/polymer composites with or without thermal aging by an accelerated abrasion test. AB - To provide data required for assessing the environmental health and safety risks of nanocomposites, abrasion-induced particle release from single-wall carbon nanotube (SWCNT)/polymer composites with or without thermal aging were evaluated by a shot blast system. First, overall composite weight loss (i.e., overall particle release) as a result of shot blasting was measured. Incorporating 5 wt% SWCNTs in polystyrene (PS) matrix was observed to reduce overall particle release by approximately 30% compared with pure PS. Heat treatment of the 5 wt% SWCNT/PS composites at 100 degrees C for 10 days induced very slight change in overall particle release due to shot blasting. However, heat treatment at 350 degrees C for 1 hr greatly deteriorated the abrasion resistance of the composites, enhancing overall particle release. Second, to verify the existence and form of SWCNTs released from the composites, released particles were observed by electron microscopy. Micron-sized particles with protruding SWCNTs and submicron-sized SWCNT clusters were observed in the particles released from the composites. Heat treatment of the composites at 350 degrees C for 1 hr enhanced SWCNT release, which mainly formed clusters or rope-like bundles. PMID- 24628696 TI - The HUNT continues and gathers pace: shedding light on the relationship between insomnia and ill health. PMID- 24628697 TI - Squamous cell carcinoma arising in hidradenitis suppurativa. PMID- 24628698 TI - Unique determination of "subatomic" contrast by imaging covalent backbonding. AB - The origin of so-called "subatomic" resolution in dynamic force microscopy has remained controversial since its first observation in 2000. A number of detailed experimental and theoretical studies have identified different possible physicochemical mechanisms potentially giving rise to subatomic contrast. In this study, for the first time we are able to assign the origin of a specific instance of subatomic contrast as being due to the back bonding of a surface atom in the tip-sample junction. PMID- 24628699 TI - Treating canine atopic dermatitis with unsaturated fatty acids: the role of mast cells and potential mechanisms of action. AB - Canine atopic dermatitis (CAD) is an inflammatory skin disorder that is characterized by pruritus and associated cutaneous changes. Treatment interventions include allergen avoidance, allergen-specific immunotherapy as well as a symptomatic therapy using glucocorticoids and antihistamines. In addition, a dietary intervention using polyunsaturated fatty acids (PUFA) has been shown to alleviate symptoms in some dogs. Although the beneficial effects of PUFA in the treatment of CAD have been known for several years, their mode of action remains unclear. This review discusses the evidential basis of the therapeutic use of dietary PUFA in the treatment of CAD. Particular emphasis will be placed on the role of cutaneous mast cells. In addition, recent evidence from in vitro studies on the regulation of mast cell exocytosis will be used to build a mechanistic model of the active principle of PUFA. It is proposed that dietary PUFA are integrated into mast cell membranes resulting in a reorganization of membrane microdomains. This may then be accompanied by functional changes of membrane associated proteins such as the phospholipases D (PLD), enzymes having an important impact on mast cell exocytosis processes. PMID- 24628700 TI - Effects of UV-B Radiation Levels on Concentrations of Phytosterols, Ergothioneine, and Polyphenolic Compounds in Mushroom Powders Used As Dietary Supplements. AB - Compositional changes of powder dietary supplements made from mushrooms exposed to different levels of UV-B irradiation were evaluated for the bioactive naturally occurring mushroom antioxidant, ergothioneine; other natural polyphenolic compounds, e.g., flavonoids, lignans, etc.; and selected phytosterols. Four types of mushroom powder consisting of white, brown (Agaricus bisporus), oyster (Pleurotus ostreatus), and shiitake (Lentinula edodes) mushrooms from three different treatment groups (control, low and high UV-B exposures) were evaluated. Ergothioneine concentrations found in mushroom powders were 0.4-10.4 mg/g dry weight (dw) and were not appreciably affected by UV-B radiation. No individual polyphenols were detected above 0.1 MUg/g. Phytosterols ergosterol (2.4-6.2 mg/g dw) and campesterol (14-43 MUg/g dw) were measured in mushroom powder samples. Ergosterol concentrations decreased significantly with the increased level of UV-B treatment for all mushroom powder types, except for white. These results provide some new information on effects of UV-B radiation on these important natural bioactive compounds in mushrooms. PMID- 24628701 TI - Beta-blockers increase the risk of being born small for gestational age or of being institutionalised during infancy. AB - OBJECTIVE: To compare infant outcomes between mothers with hypertension treated by beta-blockers alone and by methyldopa alone during pregnancy. DESIGN: Historical cohort study. SETTING: Saskatchewan, Canada. POPULATION: Women who delivered a singleton birth in Saskatchewan during the periods from 1 January 1980 to 30 June 1987 or from 1 January 1990 to 31 December 2005 (women who delivered between 1 July 1987 and 31 December 1989 were excluded because the information recorded on maternal drug use during pregnancy is incomplete) with a diagnosis of a hypertensive disorder during pregnancy, and who were dispensed only beta-blockers (n = 416) or only methyldopa (n = 1000). METHODS: Occurrences of adverse infant outcomes were compared between women who received beta-blockers only and women who received methyldopa only during pregnancy, first in all eligible women, and then in women with chronic hypertension and in women with gestational hypertension or pre-eclampsia/eclampsia, separately. Multiple logistic regression analyses were performed to adjust for potential confounding. MAIN OUTCOME MEASURES: Small for gestational age (SGA) < 10th percentile, SGA < 3rd percentile, preterm birth, stillbirth, institutionalisation for respiratory distress syndrome (RDS), sepsis, seizure during infancy, and infant death. RESULTS: Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for infants born to mothers with chronic hypertension who were dispensed beta blockers only, as compared with infants born to mothers who were dispensed methyldopa only, during pregnancy were: 1.95 (1.21-3.15), 2.17 (1.06-4.44), and 2.17 (1.09-4.34), respectively, for SGA < 10th percentile, SGA < 3rd percentile, and being institutionalised during infancy. CONCLUSIONS: For infants born to mothers with chronic hypertension, compared with those treated by methyldopa alone, those treated by beta-blockers appear to be at increased rates of SGA and hospitalisation during infancy. PMID- 24628702 TI - Expression of MexAB-OprM efflux pump system and susceptibility to antibiotics of different Pseudomonas aeruginosa clones isolated from patients hospitalized in two intensive care units at University Hospital in Bialystok (northeastern Poland) between January 2002 and December 2009. AB - We investigated the genetic similarities and expression of the MexAB-OprM efflux pump system in different clones of multiresistant Pseudomonas aeruginosa strains collected from 2002 to 2009 at two intensive care units (ICU). Regulatory and structural genes mexB, mexR, and mexA were found in 99%, 98%, and 94% of tested strains, respectively. The presence of class 1 integron was found in 90% of the strains, while class 2 integron in only one strain (Psa506). Class 3 integron was not found in any of the tested strains. Among the eleven clones identified, only two clones, I and D, exhibited higher levels of mexB gene expression than the other clones. Clone I had the highest expression (FC = 10.36, p < 0.05). The results of our study indicated a high level of MexAB-OprM pump expression in groups of strains isolated in the years 2008-2009 (FC = 12.92, p < 0.03) and 2002 2006 (FC = 5.14, p < 0.03). There were no statistically significant differences in resistance to all tested antibiotics among the various clones. The high level of antimicrobial resistance may have been due to the coexistence of different resistance mechanisms among the studied P. aeruginosa strains. However, this does not exclude the contribution of the MexAB-OprM pump, particularly in resistance to meropenem and ciprofloxacin. PMID- 24628703 TI - Cystatin C: a potential biomarker for pulmonary arterial hypertension. AB - BACKGROUND AND OBJECTIVE: Cystatin C (CysC), a novel marker of renal function, predicts left heart failure and cardiovascular mortality. The hypothesis that serum CysC levels correlate with right ventricular (RV) morphology, function and pressure in pulmonary arterial hypertension (PAH) was tested. METHODS: As part of a prospective study, 14 PAH subjects and 10 matched controls underwent same-day echocardiography, cardiac magnetic resonance imaging (CMR), and phlebotomy for CysC, brain natriuretic peptide (BNP), and N-terminal BNP (NT-ProBNP). RV ejection fraction (RVEF), end-diastolic volume, end-systolic volume and mass were calculated using CMR. RV systolic pressure (RVSP), strain and diastolic function (including tricuspid valve (TV) E velocity, A velocity, e' velocity, E/A ratio and E/e' ratio) were assessed using echocardiography. RESULTS: RVSP was significantly elevated in PAH subjects versus controls (57 +/- 17 vs. 28 +/- 8 mm Hg, P < 0.0001). CysC was abnormally elevated in the PAH cohort when compared with controls (1.00 +/- 0.23 vs 0.78 +/- 0.05 mg/L, P = 0.001). CysC positively correlated with RVSP (rho 0.61, P = 0.002), RV end-diastolic volume (rho 0.50, P = 0.01), RV end-systolic volume (rho 0.58, P = 0.003), mass index (rho 0.66, P = 0.0004), strain (rho 0.51, P = 0.01) and strain rate (rho 0.51, P = 0.01) and negatively correlated with RVEF (rho -0.58, P = 0.003) and TV e' (rho -0.75, P < 0.0001). The same correlations with BNP and NT-ProBNP were comparable with CysC. CONCLUSIONS: In a small cohort, CysC accurately correlates with RV pressure, function and morphology. CysC may represent a novel PAH biomarker. PMID- 24628704 TI - Mutations in the lipase-H gene causing autosomal recessive hypotrichosis and woolly hair. AB - Hypotrichosis is characterised by sparse scalp hair, sparse to absent eyebrows and eyelashes, or absence of hair from other parts of the body. In few cases, the condition is associated with tightly curled woolly scalp hair. The present study searched for disease-causing sequence variants in the genes in four Pakistani lineal consanguineous families exhibiting features of hypotrichosis or woolly hair. A haplotype analysis established links in all four families to the LIPH gene located on chromosome 3q27.2. Subsequently, sequencing LIPH identified a novel non-sense mutation (c.328C>T; p.Arg110*) in one and a previously reported 2 bp deletion mutation (c.659_660delTA, p.Ile220ArgfsX29) in three other families. PMID- 24628705 TI - The effects of a Cognitive Stimulation Therapy [CST] programme for people with dementia on family caregivers' health. AB - BACKGROUND: There is growing evidence that Cognitive Simulation Therapy (CST) benefits cognition and quality of life of people with dementia, but little is known about the indirect effects of this intervention on family caregivers. This study sought to investigate the effect of CST on family caregivers general health status of people with dementia living in the community attending the CST intervention. METHOD: Eighty-five family caregivers of people with dementia took part in the study. All the people with dementia received the standard twice weekly seven weeks of the CST intervention plus either 24 weeks of a maintenance CST (MCST) intervention or 24 weeks of treatment as usual. Family caregivers were assessed before and after their relatives the CST programme, and after 3 and 6 months of the MCST programme. A pre and post CST groups comparison was undertaken to evaluate the open trial first phase and an ANCOVA model used to analyse the maintenance phase with its controlled comparison. RESULTS: We found no evidence for a benefit on the family caregiver outcome measures of the intervention before and after CST groups by using a t-test analysis or any significant differences between intervention and control groups for any of the variables considered at any time point (3 and 6 month follow up). CONCLUSION: CST seems to have a relatively specific benefit fpr people with dementia that may not carry over to family carers. Future studies need to further explore and compare the effects that CST might bring to family caregivers of people with dementia attending the intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN26286067. PMID- 24628706 TI - Increased expression of Capn4 is associated with the malignancy of human glioma. AB - AIMS: Recent evidence indicates that the increased expression of calpain small subunit 1 (Capn4) is associated with tumorigenesis. This study was designed to explore the role which Capn4 plays in human glioma. METHODS: We detected the expression of Capn4 by immunohistochemistry in tissue microarrays and tissue samples. Following the down-regulation of Capn4 in glioma cell lines by a specific short hairpin RNA, the function of Capn4 in invasion, migration, and proliferation was assessed. We then evaluated the prognostic role of Capn4 using univariate and multivariate analysis in 94 glioblastoma (GBM) patients. RESULTS: Glioma tissues exhibited notably higher expression of Capn4 compared with control brain tissues and was positively correlated with histological malignancy. The down-regulation of Capn4 in glioma cells led to a decrease in invasion and migration in vitro. Through univariate analysis, the prognosis of GBM patients with Capn4 overexpression was significantly poorer with respect to progression free survival (PFS) and overall survival (OS). Based on the results of the multivariate analysis, Capn4(high) was demonstrated to be a negative independent prognostic indicator for PFS and OS in GBM patients. CONCLUSION: The overexpression of Capn4 is a novel negative prognostic marker, and Capn4 may be used as a new target in therapeutic strategies for human glioma. PMID- 24628707 TI - National trends in the treatment of penile prosthesis infections by explantation alone vs. immediate salvage and reimplantation. AB - INTRODUCTION: A penile prosthesis infection (PPI) is either treated with explantation of the prosthesis with a possible delayed reimplantation or a salvage procedure with an immediate reimplantation of the prosthesis. AIM: We used a large, all-payer national database to investigate the use of the salvage procedure in the setting of PPI. METHODS: The study used years 2000-2009 of the Nationwide Inpatient Sample to identify PPIs treated with immediate salvage or explantation alone. Admissions were then stratified by various parameters to compare differences in the salvage rates. MAIN OUTCOME MEASURES: Salvage Rate of Penile Prosthesis infection. RESULTS: A total of 1,557 patients were treated with an explantation only (82.7%) or salvage (17.3%) for PPI, a proportion that remained stable over the study period. The patients treated with salvage were younger (60.4 vs. 65.1 years), more likely to be discharged home (87.3% vs. 61.9%), and were less likely to have a severe presentation (7.2% vs. 31.6%) than those who were explanted only (P < 0.001). These factors were confirmed on multivariate regression analysis. The regression also revealed that treatment at rural hospitals had lower odds of salvage than treatment at urban teaching hospitals. Race, comorbid diabetes, and insurance status did not independently affect the salvage rate. There was no significant difference in total hospital charges between groups. CONCLUSIONS: Salvage rates have remained low over the past decade. Our study elucidated several factors decreasing the chances of salvage after PPI including age, severity of presentation, and hospital setting. PMID- 24628708 TI - Changes in alcohol policies and public opinions in Finland 2003-2013. AB - INTRODUCTION: There is a constant and ongoing interplay between public opinions and public policies, alcohol policies being no exception. This article describes the development of public opinions regarding alcohol policy in Finland during a 10-year period between 2003 and 2013. Fluctuations in the alcohol policy opinion climate are put in context by looking at concurrent changes in alcohol policies and in total alcohol consumption. DATA AND METHODS: The study is based on data from opinion surveys on alcohol policies commissioned by the National Institute for Health and Welfare and the Finnish Social and Health Association. The opinion polls include questions about the general acceptance of prevailing alcohol policies, appropriate sales channels of different alcoholic beverage categories and opinions about the legal age limits and prices of alcoholic beverages. In the study, changes in alcohol policy during 2003-2013 are surveyed, and their relationship with changes in alcohol policy opinion is examined. RESULTS: There seem to be a strong positive correlation during the study period between the level of alcohol consumption and the share of those wanting a more restrictive alcohol policy in Finland. DISCUSSION: It seems that an increased level of awareness of alcohol-related issues among the general public created a more restrictive opinion climate on alcohol policy issues after the big alcohol excise duty decrease in 2004. The reverse seems to happen but in a lesser degree when alcohol excise duties has been increased after the year 2007. PMID- 24628709 TI - Optical coherence tomography using images of hair structure and dyes penetrating into the hair. AB - BACKGROUND/PURPOSE: Hair dyes are commonly evaluated by the appearance of the hair after dyeing. However, this approach cannot simultaneously assess how deep the dye has penetrated into hair. METHODS: For simultaneous assessment of the appearance and the interior of hair, we developed a visible-range red, green, and blue (RGB) (three primary colors)-optical coherence tomography (OCT) using an RGB LED light source. We then evaluated a phantom model based on the assumption that the sample's absorbability in the vertical direction affects the tomographic imaging. RESULTS: Consistent with theory, our device showed higher resolution than conventional OCT with far-red light. In the experiment on the phantom model, we confirmed that the tomographic imaging is affected by absorbability unique to the sample. Furthermore, we verified that permeability can be estimated from this tomographic image. We also identified for the first time the relationship between penetration of the dye into hair and characteristics of wavelength by tomographic imaging of dyed hair. CONCLUSION: We successfully simultaneously assessed the appearance of dyed hair and inward penetration of the dye without preparing hair sections. PMID- 24628710 TI - Counseling about IUDs: a mixed-methods analysis. AB - CONTEXT: IUDs are infrequently used in the United States. Assessing how counseling about this method is delivered can help identify barriers to IUD use that might be overcome by improving services. METHODS: A sample of 342 family planning visits at six clinics in the San Francisco Bay Area in 2009-2012 were audio-recorded, and patients completed surveys both before and after their visits. Descriptive quantitative analyses of counseling were performed, and correlates of IUDs' being mentioned during counseling were investigated using logistic regression. Qualitative analyses investigated the counseling women received about IUDs generally (in a subset of 42 visits), as well as counseling for women who already had an IUD in place (13 visits) or who felt their provider inappropriately expressed a preference for IUDs (five visits). RESULTS: IUDs were mentioned in 75% of visits. Patient-initiated mention of IUDs was more likely in visits by women aged 35 or older than in those by women younger than 20 (odds ratio, 6.4); provider-initiated discussion of this method was less common if the provider was older than 55 than if he or she was younger than 46 (0.3). Providers more often discussed potential adverse effects of IUD use than benefits; counseling often was noninteractive and did not address how patient preferences related to characteristics of IUDs. Counseling was frequently fragmented by the need for return visits or referral elsewhere for insertion. CONCLUSIONS: IUD counseling may be improved by enhancing comprehensiveness and patient centeredness, and by decreasing fragmentation of care. PMID- 24628711 TI - ICSH guidelines for the verification and performance of automated cell counters for body fluids. AB - One of the many challenges facing laboratories is the verification of their automated Complete Blood Count cell counters for the enumeration of body fluids. These analyzers offer improved accuracy, precision, and efficiency in performing the enumeration of cells compared with manual methods. A patterns of practice survey was distributed to laboratories that participate in proficiency testing in Ontario, Canada, the United States, the United Kingdom, and Japan to determine the number of laboratories that are testing body fluids on automated analyzers and the performance specifications that were performed. Based on the results of this questionnaire, an International Working Group for the Verification and Performance of Automated Cell Counters for Body Fluids was formed by the International Council for Standardization in Hematology (ICSH) to prepare a set of guidelines to help laboratories plan and execute the verification of their automated cell counters to provide accurate and reliable results for automated body fluid counts. These guidelines were discussed at the ICSH General Assemblies and reviewed by an international panel of experts to achieve further consensus. PMID- 24628712 TI - Comparative effectiveness of a bilayered living cellular construct and a porcine collagen wound dressing in the treatment of venous leg ulcers. AB - Using data from a national wound-specific electronic medical record (WoundExpert, Net Health, Pittsburgh, PA), we compared the effectiveness of a bilayered living cellular construct (BLCC) and an acellular porcine small intestine submucosa collagen dressing (SIS) for the treatment of venous leg ulcer. Data from 1,489 patients with 1,801 refractory venous leg ulcers (as defined by failure to have >40% reduction in size in the 4 weeks prior to treatment) with surface areas between 1 and 150 cm(2) in size, treated between July 2009 and July 2012 at 158 wound care facilities across the US were analyzed. Patient baseline demographics and wound characteristics were comparable between groups. Kaplan-Meier-derived estimates of wound closure for BLCC (1,451 wounds) was significantly greater (p = 0.01, log-rank test) by weeks 12 (31% vs. 26%), 24 (50% vs. 41%), and 36 (61% vs. 46%), respectively, compared with SIS (350 wounds). BLCC treatment reduced the median time to wound closure by 44%, achieving healing 19 weeks sooner (24 vs. 43 weeks, p = 0.01, log-rank test). Treatment with BLCC increased the probability of healing by 29% compared with porcine SIS dressing (hazard ratio = 1.29 [95% confidence interval 1.06, 1.56], p = 0.01). PMID- 24628714 TI - Occupational and socioeconomic differences in actigraphically measured sleep. AB - Occupational conditions, together with socioeconomic status, may modulate sleep. This study examined the association of occupational conditions and socioeconomic status with actigraphic measures of sleep in workers. Fifty-five employees (40 +/ 12 years) wore a wrist actigraph during sleep for seven consecutive nights. Sleep variables addressed included total sleep time, sleep efficiency, mean activity during sleep, sleep-onset latency, and wake after sleep onset. We also measured household income, occupational class, work schedule, weekly work hours, job demand, job control, worksite social support, effort-reward imbalance, organizational justice, and workplace social capital. Multiple linear regression models were used to determine the association of occupational indicators, socioeconomic status, as well as age and gender with each sleep variable. Higher workplace social capital was associated consistently with longer total sleep time (P < 0.001), higher sleep efficiency (P < 0.05) and lower mean activity during sleep (P < 0.07). Low occupational class (P < 0.01), higher job demand (P < 0.05) and lower job control (P < 0.05) were associated with longer total sleep time. No associations were significant for sleep-onset latency or wake after sleep onset. These preliminary results suggest that enhanced workplace social capital is closely associated with better quality and quantity of sleep. PMID- 24628713 TI - Norcantharidin inhibits tumor growth and vasculogenic mimicry of human gallbladder carcinomas by suppression of the PI3-K/MMPs/Ln-5gamma2 signaling pathway. AB - BACKGROUND: Vasculogenic mimicry (VM) is a novel tumor blood supply in some highly aggressive malignant tumors. Recently, we reported VM existed in gallbladder carcinomas (GBCs) and the formation of the special passage through the activation of the PI3K/MMPs/Ln-5gamma2 signaling pathway. GBC is a highly aggressive malignant tumor with disappointing treatments and a poor prognosis. Norcantharidin (NCTD) has shown to have multiple antitumor activities against GBCs, etc; however the exact mechanism is not thoroughly elucidated. In this study, we firstly investigated the anti-VM activity of NCTD as a VM inhibitor for GBCs and its underlying mechanisms. METHODS: In vitro and in vivo experiments to determine the effects of NCTD on proliferation, invasion, migration, VM formation, hemodynamic and tumor growth of GBC-SD cells and xenografts were respectively done by proliferation, invasion, migration assays, H&E staining and CD31-PAS double stainings, optic/electron microscopy, tumor assay, and dynamic micro-MRA. Further, immunohistochemistry, immunofluorescence, Western blotting and RT-PCR were respectively used to examine expression of VM signaling-related markers PI3-K, MMP-2, MT1-MMP and Ln-5gamma2 in GBC-SD cells and xenografts in vitro and in vivo. RESULTS: After treatment with NCTD, proliferation, invasion, migration of GBC-SD cells were inhibited; GBC-SD cells and xenografts were unable to form VM-like structures; tumor center-VM region of the xenografts exhibited a decreased signal in intensity; then cell or xenograft growth was inhibited. Whereas all of untreated GBC-SD cells and xenografts formed VM-like structures with the same conditions; the xenograft center-VM region exhibited a gradually increased signal; and facilitated cell or xenograft growth. Furthermore, expression of MMP-2 and MT1-MMP products from sections/supernates of 3-D matrices and the xenografts, and expression of PI3-K, MMP-2, MM1-MMP and Ln-5gamma2 proteins/mRNAs of the xenografts were all decreased in NCTD or TIMP-2 group; (all P < 0.01, vs. control group); NCTD down-regulated expression of these VM signaling-related markers in vitro and in vivo. CONCLUSIONS: NCTD inhibited tumor growth and VM of human GBCs in vitro and in vivo by suppression of the PI3 K/MMPs/Ln-5gamma2 signaling pathway. It is firstly concluded that NCTD may be a potential anti-VM agent for human GBCs. PMID- 24628715 TI - Hyper IgE syndrome: anaphylaxis in a patient carrying the N567D STAT3 mutation. PMID- 24628717 TI - Clinical usage of serum ferritin to assess liver fibrosis in patients with non alcoholic fatty liver disease: Proceed with caution. AB - Serum ferritin was recently reported to have low diagnostic accuracy for the detection of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). To corroborate these findings, we investigated the diagnostic accuracy of serum ferritin levels for detecting liver fibrosis in NAFLD patients utilizing a large Japanese cohort database. A total 1201 biopsy-proven NAFLD patients, seen between 2001 and 2013, were enrolled into the Japan Study Group of NAFLD. Analysis was performed on data from this cohort comparing between serum ferritin levels and hepatic histology. Serum ferritin increased with increasing histological grade of steatosis, lobular inflammation and ballooning. Multivariate analyses revealed that sex differences, steatotic grade and fibrotic stage were independently associated with serum ferritin levels (P < 0.0001, <0.0001, 0.0248, respectively). However, statistical analyses performed using serum ferritin levels demonstrated that the area under the receiver-operator curve for detecting fibrosis was not adequate for rigorous prediction. Several factors including sex differences, steatosis and fibrosis were found to correlate with serum ferritin levels. Therefore, serum ferritin may have low diagnostic accuracy for specifically detecting liver fibrosis in NAFLD patients due to the involvement of multiple hepatocellular processes. PMID- 24628716 TI - Pacific and Atlantic Lepeophtheirus salmonis (Kroyer, 1838) are allopatric subspecies: Lepeophtheirus salmonis salmonis and L. salmonis oncorhynchi subspecies novo. AB - BACKGROUND: The salmon louse Lepeophtheirus salmonis is a parasitic copepod that infects salmonids in the Pacific and Atlantic oceans. Although considered as a single species, morphological and biological differences have been reported between lice from the two oceans. Likewise, studies based on nucleotide sequencing have demonstrated that sequence differences between Atlantic and Pacific L. salmonis are highly significant, albeit smaller than the divergence observed between congeneric copepod species. RESULTS: We demonstrated reproductive compatibility between L. salmonis from the two oceans and successfully established F2 hybrid strains using separate maternal lines from both the Pacific and Atlantic. The infection success for the F2 hybrid strains were similar to results typically observed for non hybrid lice strains in the rearing facility used. Lepeophtheirus salmonis COI and 16S sequences divergence between individuals from the Pacific and the Atlantic oceans was high compared to what may be expected within a copepod species and phylogenetic analysis showed that they consistently formed monophyletic clades representing their origin from the Pacific or Atlantic oceans. CONCLUSIONS: Lepeophtheirus salmonis from the Pacific and Atlantic oceans are reproductively compatible at least until adults at the F2 hybrid stage, and should not be regarded as separate species based on reproductive segregation or sequence divergence levels. Reported biological and genetic differences in L. salmonis seen in conjunction with the reported genetic diversity commonly observed between and within species demonstrate that Atlantic and Pacific L. salmonis should be regarded as two subspecies: Lepeophtheirus salmonis salmonis and L. salmonis oncorhynchi subsp. nov. PMID- 24628718 TI - Inconsistency effects in source memory and compensatory schema-consistent guessing. AB - The attention-elaboration hypothesis of memory for schematically unexpected information predicts better source memory for unexpected than expected sources. In three source-monitoring experiments, the authors tested the occurrence of an inconsistency effect in source memory. Participants were presented with items that were schematically either very expected or very unexpected for their source. Multinomial processing tree models were used to separate source memory, item memory, and guessing bias. Results show an inconsistency effect in source memory accompanied by a compensatory schema-consistent guessing bias when expectancy strength is high, that is, when items are very expected or very unexpected for their source. PMID- 24628720 TI - Biomechanical and functional indicators in male semiprofessional soccer players with increased hip alpha angles vs. amateur soccer players. AB - BACKGROUND: Femoroacetabular impingement (FAI) is predominant in young male athletes, but not much is known about gait differences in cases of increased hip alpha angles. In our study, the hip alpha angle of Notzli of soccer players was quantified on the basis of magnetic resonance imaging (MRI) with axial oblique sequences. The aim of the current study was to compare the rearfoot motion and plantar pressure in male semiprofessional soccer players with increased alpha angles to age-matched amateur soccer players. METHODS: In a prospective analysis, male semiprofessional and amateur soccer players had an MRI of the right hip to measure the alpha angle of Notzli. In a biomechanical laboratory setting, 14 of these participants in each group ran in two shoe conditions. Simultaneously in shoe pressure distribution, tibial acceleration, and rearfoot motion measurements of the right foot were performed. RESULTS: In the semiprofessional soccer group, the mean value of the alpha angle of group was 55.1 +/- 6.58 degrees (range 43.2 76.6 degrees ) and 51.6 +/- 4.43 degrees (range 41.9-58.8 degrees ) in the amateur group. In both shoe conditions, we found a significant difference between the two groups concerning the ground reaction forces, tibial acceleration, rearfoot motion and plantar pressure parameters (P < 0.01, P < 0.05, P = 0.04). Maximum rearfoot motion is about 22% lower in the semiprofessional group compared to the amateur group in both shoe conditions. CONCLUSIONS: This study confirmed that semiprofessional soccer players with increased alpha angles showed differences in gait kinematics compared to the amateur group. These findings support the need for a screening program for competitive soccer players. In cases of a conspicuous gait analysis and symptomatic hip pain, FAI must be ruled out by further diagnostic tests. PMID- 24628721 TI - Nonspecific unilateral, painful acrocyanosis--a dermatological case? Symptomatic stenosis of the axillary artery. PMID- 24628719 TI - Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor. AB - Matrine, a clinical drug in China, has been used to treat viral hepatitis, cardiac arrhythmia and skin inflammations. Matrine also exhibits chemotherapeutic potential through its ability to trigger cancer cell death. However, the mechanisms involved are still largely unknown. The objective of this study was to investigate the major determinant for the cell death induced by matrine in human hepatocellular carcinoma. We use human hepatocellular carcinoma cell line HepG2 and human hepatocellular carcinoma xenograft in nude mice as models to study the action of matrine in hepatocellular cancers. We found that caspase-dependent and independent Program Cell Death (PCD) occurred in matrine-treated HepG2 cells, accompanied by the decreasing of mitochondrial transmembrane potential and the increasing ROS production. Further studies showed that AIF released from the mitochondria to the nucleus, and silencing of AIF reduced the caspase-independent PCD induced by matrine. What's more, AIF nuclear translocation, and the subsequent cell death as well, was prevented by Bid inhibitor BI-6C9, Bid targeted siRNA and ROS scavenger Tiron. In the in vivo study, matrine significantly attenuated tumor growth with AIF release from mitochondria into nucleus in nude mice. These data imply that matrine potently induce caspase independent PCD in HepG2 cells through Bid-mediated AIF translocation. PMID- 24628722 TI - Genetics, genomics, breeding - why scale matters. PMID- 24628724 TI - Inheritance of ectopic ureters in Entlebucher Mountain Dogs. AB - To test the hypothesis of a heritable base of ectopic ureters (EU) in Entlebucher Mountain Dogs (EMD) and to elucidate associated risk factors and mode of inheritance of the disease, 565 EMD were clinically investigated and population genetic analyses performed. Based on the location of the most caudal termination of the ureteral openings, 552 EMD were classified into three phenotype groups trigone, intravesically and extravesically ectopic based on results of abdominal sonography, urethra-cystoscopy and/or contrast-enhanced computed tomography. One third (32.9%) of the phenotyped animals had normal terminations of both ureters in the bladder trigone, 47.3% had at least one intravesicular ectopic termination and 19.8% had at least one extravesicular ectopic termination. Multivariate mixed logistic regression revealed gender as a risk factor associated with EU as males were more often affected than females. Complex segregation analysis indicated a hereditary basis for EU in EMD and the involvement of a major gene in the occurrence of the extravesicular EU phenotype. PMID- 24628723 TI - Polymorphisms in the promoter region of myostatin gene are associated with carcass traits in pigs. AB - Higher average daily gain, more lean meat yield and less fat yield of porcine carcass increase selling profits for animal producers. Myostatin (MSTN), previously called GDF8, is a member of transforming growth factor-beta (TGF-beta) superfamily. It is a negative regulator for both embryonic development and adult homeostasis of skeletal muscle. In this study, the genotypes of the previously described SNPs MSTN g.435G>A and g.447A>G SNPs in 66 Duroc pigs, 33 Landrace pigs, 180 Duroc * Landrace (DL) pigs and 155 Duroc * Yorkshire * Landrace (DYL) pigs were determined by Taqman SNP Genotyping Assays. For Duroc and Landrace pigs, MSTN g.435GG/g.447AA individual had greater backfat thickness (p < 0.05) than g.435AA/g.447GG individual, whereas MSTN g.435AA/g.447GG had greater meat (p < 0.05) and meat percentage (p < 0.05) than g.435GA/g.447AG individual. For DL and DYL pigs, the MSTN g.435GG/g.447AA animals were greater in backfat at ultrasound 10th rib (p < 0.05) and carcass 10th rib (p < 0.01) than g.435AA/g.447GG individual. The MSTN g.435AA/g.447GG individual also had higher values than g.435GG/g.447AA for anterior-end meat (p < 0.05), posterior-end meat (p < 0.01), total meat weight (p < 0.01) and meat percentage (p < 0.01). This study confirmed evidence that MSTN g.435G>A and g.447A>G affected carcass traits in pigs. The effects of the mutated alleles were additive with the maximal effects resulting from two copies of the mutated allele. Selection for MSTN g.435A/g.447G allele is expected to increase muscle of limb and total meat production and decrease backfat thickness. PMID- 24628725 TI - Al-Anon family groups' newcomers and members: Concerns about the drinkers in their lives. AB - BACKGROUND AND OBJECTIVES: Despite Al-Anon's widespread availability and use, knowledge is lacking about the drinkers in attendees' lives. We filled this gap by describing and comparing Al-Anon newcomers' and members' reports about their "main drinker" (main person prompting initial attendance). METHODS: Al-Anon's World Service Office mailed a random sample of groups, yielding completed surveys from newcomers (N = 362) and stable members (N = 265). RESULTS: Newcomers' and members' drinkers generally were comparable. They had known their drinker for an average of 22 years and been concerned about his or her's drinking for 9 years; about 50% had daily contact with the drinker. Most reported negative relationship aspects (drinker gets on your nerves; you disagree about important things). Newcomers had more concern about the drinker's alcohol use than members did, and were more likely to report their drinkers' driving under the influence. Drinkers' most frequent problem due to drinking was family arguments, and most common source of help was 12-step groups, with lower rates among drinkers of newcomers. Concerns spurring initial Al-Anon attendance were the drinker's poor quality of life, relationships, and psychological status; goals for initial attendance reflected these concerns. DISCUSSION AND CONCLUSIONS: The drinker's alcohol use was of less concern in prompting initial Al-Anon attendance, and, accordingly, the drinker's reduced drinking was a less frequently endorsed goal of attendance. SCIENTIFIC SIGNIFICANCE: Family treatments for substance use problems might expand interventions and outcome domains beyond abstinence and relationship satisfaction to include the drinker's quality of life and psychological symptoms and in turn relieve concerns of family members. PMID- 24628726 TI - QT and P-wave dispersions in rheumatic heart disease: prospective long-term follow up. AB - BACKGROUND: Simple electrocardiogram (ECG) markers have been used to evaluate conduction times. Acute rheumatic fever (ARF) is an autoimmune disease that affects these conduction times. The aim of this prospective long-term follow-up study was to evaluate QT, QTc and P-wave dispersions in children with ARF and chronic rheumatic heart disease (CRHD). METHODS: Sixty-four patients with ARF, 33 patients with CRHD and 41 healthy, age- and sex-matched control subjects were included in the study. The ARF patients were divided into two subgroups: carditis and arthritis. Echocardiographic and ECG measurements at the onset of diagnosis and final evaluation were included. RESULTS: QT, QTc and P-wave dispersions were significantly greater in both the ARF carditis and CRHD groups than the ARF arthritis and control subjects during the initial and final analysis (for all, P < 0.001). There was no significant statistical difference in QT, QTc and P-wave dispersion between the initial and final analysis in each groups. Severity of mitral regurgitation and left atrial enlargement were found to be positively correlated with P-wave dispersion (r = 0.438, P < 0.001; r = 0.127, P < 0.001, respectively). QT, QTc and P-wave dispersion greater than 52, 60 and 57 ms, respectively, had higher sensitivity and specificity for predicting ARF carditis. CONCLUSION: These ECG measurements can be used in the diagnosis of ARF carditis as minor criteria with modified Jones criteria. In contrast, this increase in the dispersions is permanent in patients with ARF carditis. PMID- 24628727 TI - Reproductive health decision making among Ghanaian women. AB - INTRODUCTION: Women's reproductive health decision-making and choices, including engaging in sexual intercourse and condom use, are essential for good reproductive health. However, issues concerning sexual intercourse and condom use are shrouded in secrecy in many sub-Saharan African countries. This study investigates factors that affect decision making on engaging in sexual intercourse and use of condom among women aged 15-49. METHOD: A nationally representative sample (N = 3124) data collected in the 2008 Ghana Demographic and Health Survey was used. Multivariate logistic regression was used to study the association between women's economic and socio-demographic characteristics and their decision making on engaging in sexual intercourse and use of condom. RESULTS: One out of five women reported that they could not refuse their partners' request for sexual intercourse while one out of four indicated that they could not demand the use of condoms by their partners. Women aged 35-49 were more likely to make decision on engaging in sexual intercourse (OR = 1.35) compared to those aged 15-24. Furthermore, the higher a woman's education, the more likely that she would make decision regarding condom use. Also, if a woman had primary (OR = 1.37) or secondary (OR = 1.55) education, she is more likely to make decision regarding engaging in sexual intercourse compared to a woman who had no formal education. Compared to women in the Greater Accra region (the capital city region), women in the Western region (OR = 2.10), Central region (OR = 2.35), Brong Ahafo (OR = 1.70), Upper East (OR = 7.71) and Upper West (OR = 3.56) were more likely to make decision regarding the use of condom. Women who were in the richest, rich and middle wealth index categories were more likely to make decision regarding engaging in sexual intercourse as well as condom use compared to the poorest. CONCLUSION: Interventions and policies geared at empowering women to take charge of their reproductive health should focus particularly on women from less wealthy backgrounds and those with low educational attainments. PMID- 24628728 TI - Diffusion magnetic resonance imaging diagnostic relevance in pyogenic ventriculitis with an atypical presentation: a case report. AB - BACKGROUND: Pyogenic ventriculitis is a rare and severe cerebral infection characterized by the presence of suppurative fluid in the cerebral ventricles. It is a life-threatening condition and may present with an aspecific neurological picture. Brain imaging techniques usually demonstrate intraventricular debris and pus, but negative imaging along with a misleading clinical picture may delay the diagnosis. CASE PRESENTATION: The described patient underwent a number of surgical procedures and eventually developed an unusual clinical picture characterized by psychomotor slowing, facial dyskinesias and myoclonic jerks without complaint of headache and in absence of meningeal irritation signs or focal neurological deficits. Cerebrospinal fluid cultural examination showed methicillin-resistant Staphylococcus aureus and vancomycin treatment lead to a complete recovery. Brain computed tomography scan was normal, while only diffusion magnetic resonance imaging sequences were able to define the presence of purulent material within the brain lateral ventriculi. CONCLUSION: The present case underlines the importance of taking into account the diagnosis of pyogenic ventriculitis even when the neurological picture does not match the suspect of a central nervous system infection. Moreover, brain computed tomography scan and standard magnetic resonance imaging sequences may be unable to confirm the diagnosis, whereas diffusion-weighted sequences prove a unique role in diagnosing cerebral pyogenic ventriculitis. PMID- 24628729 TI - Chewing gum in preventing postoperative ileus in women undergoing caesarean section: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: The incidence of postoperative ileus (POI) after gynaecological surgery is 10-15% Chewing gum following general surgery improves outcomes, including early flatus, early bowel sounds, and shortening of hospitalisation periods. There is currently no guideline that supports the use of chewing gum after caesarean sections. OBJECTIVES: To systematically analyse the published randomised controlled trials regarding the effectiveness of chewing gum in preventing POI in women undergoing caesarean sections. SEARCH STRATEGY: Systematic search of medical databases up to March 2013. SELECTION CRITERIA: Randomised controlled trials that reported the role of chewing gum in preventing POI in women undergoing caesarean sections. DATA COLLECTION AND ANALYSIS: Two authors independently identified the relevant studies for inclusion, extracted outcome-related data, and analysed it systematically using REVMAN((r)). The combined outcome was expressed as an odds ratio and standardised mean difference. MAIN RESULTS: Seven randomised controlled trials involving 1462 women (728 in the chewing gum group, 734 controls) were systematically analysed. There was significant heterogeneity (chi(2) = 29.02, df = 7; P < 0.0001; I(2) = 76%) among the included trials. Among women undergoing caesarean sections, chewing gum reduced the risk of POI (odds ratio 0.36; 95% confidence interval 0.19-0.69; z = 3.08; P < 0.002) but did not affect duration of hospitalisation (P = 0.32). CONCLUSIONS: Chewing gum for 30-60 minutes at least three times a day appears to be effective in reducing the incidence and consequences of POI following caesarean sections. PMID- 24628730 TI - Neuropsychiatric symptoms in patients with dementia in primary care: a study protocol. AB - BACKGROUND: Neuropsychiatric symptoms (NPS) frequently occur in patients with dementia. To date, prospective studies on the course of NPS have been conducted in patients with dementia in clinical centers or psychiatric services. The primary goal of this study is to investigate the course of NPS in patients with dementia and caregiver distress in primary care. We also aim to detect determinants of both the course of NPS in patients with dementia and informal caregiver distress in primary care. METHODS/DESIGN: This is a prospective observational study on the course of NPS in patients with dementia in primary care. Thirty-seven general practitioners (GPs) in 18 general practices were selected based on their interest in participating in this study. We will retrieve electronic medical files of patients with dementia from these general practices. Patients and caregivers will be followed for 18 months during the period January 2012 to December 2013. Patient characteristics will be collected at baseline. Time to death or institutionalization will be measured. Co-morbidity will be assessed using the Charlson index. Psychotropic drug use and primary and secondary outcome measures will be measured at 3 assessments, baseline, 9 and 18 months. The primary outcome measures are the Neuropsychiatric Inventory score for patients with dementia and the Sense of Competence score for informal caregivers. In addition to descriptive analyses frequency parameters will be computed. Univariate analysis will be performed to identify determinants of the course of NPS and informal caregiver distress. All determinants will then be tested in a multivariate regression analysis to determine their unique contribution to the course of NPS and caregiver distress. DISCUSSION: The results of this study will provide data on the course of NPS, which is clinically important for prognosis. The data will help GPs and other professionals in planning follow-up visits and in the timing for offering psycho-education, psychosocial interventions and the provision of care. In addition, these data will enlarge health professionals' awareness of NPS in their patients with dementia. PMID- 24628731 TI - Microbial community dynamics alleviate stoichiometric constraints during litter decay. AB - Under the current paradigm, organic matter decomposition and nutrient cycling rates are a function of the imbalance between substrate and microbial biomass stoichiometry. Challenging this view, we demonstrate that in an individual-based model, microbial community dynamics alter relative C and N limitation during litter decomposition, leading to a system behaviour not predictable from stoichiometric theory alone. Rather, the dynamics of interacting functional groups lead to an adaptation at the community level, which accelerates nitrogen recycling in litter with high initial C : N ratios and thus alleviates microbial N limitation. This mechanism allows microbial decomposers to overcome large imbalances between resource and biomass stoichiometry without the need to decrease carbon use efficiency (CUE), which is in contrast to predictions of traditional stoichiometric mass balance equations. We conclude that identifying and implementing microbial community-driven mechanisms in biogeochemical models are necessary for accurately predicting terrestrial C fluxes in response to changing environmental conditions. PMID- 24628732 TI - Saccharomyces boulardii expresses neuraminidase activity selective for alpha2,3 linked sialic acid that decreases Helicobacter pylori adhesion to host cells. AB - Helicobacter pylori is a major causative agent of gastritis and peptic ulcer disease and is an established risk factor for gastric malignancy. Antibiotic combination therapy can eradicate H. pylori. As these same regimens can evoke adverse effects and resistance, new alternative therapies or adjunctive treatments are needed. A probiotic approach may provide a novel strategy for H. pylori treatment. In the current study, two probiotic bacteria, Lactobacillus acidophilus and Lactobacillus reuteri, and a probiotic yeast, Saccharomyces boulardii, were evaluated for their ability to influence H. pylori viability, adherence to gastric and duodenal cells, as well as the effect of S. boulardii on cell surface expression of sialic acid. Our results indicate that S. boulardii contains neuraminidase activity selective for alpha(2-3)-linked sialic acid. This neuraminidase activity removes surface alpha(2-3)-linked sialic acid, the ligand for the sialic acid-binding H. pylori adhesin, which in turn, inhibits H. pylori adherence to duodenal epithelial cells. PMID- 24628733 TI - Astrocytic JWA expression is essential to dopaminergic neuron survival in the pathogenesis of Parkinson's disease. AB - AIMS: To investigate the role of astrocytic JWA expression in dopaminergic (DA) neuron degeneration and in the pathogenesis of Parkinson's disease (PD). METHODS: Conditional astrocytic JWA null (JWA?2/?2/GFAP-Cre) mice and U251 glioma cells were used to evaluate the effects of JWA gene on DA neuron degeneration. The oxidative stress-driven molecular events were determined in both in vivo and in vitro models. RESULTS: Conditional astrocytic JWA knockout resulted in significant activation of astrocytes measured by increase in glial fibrillary acidic protein-positive cells (1.34*10(3)+/-74.5 vs. 8.44*10(3)+/-1.35*10(3), P<0.01) in mouse substantia nigra, accompanied by loss of DA neurons (1.03*10(4)+/-238 vs. 6.17*10(3)+/-392, P<0.001). Deficiency of JWA significantly aggravated reactive oxygen species (ROS) accumulation in substantia nigra compared with the wild-type mice. Increasing JWA expression in U251 glioma cells inhibited ROS with a concomitant increase in intracellular glutathione. Furthermore, suppression of IKKbeta-nuclear factor (NF)-kappaB signaling pathway was shown to regulate JWA in a PD model. CONCLUSIONS: The JWA gene exerts neuroprotective roles against DA neuronal degeneration via modulating intracellular redox status and NF-kappaB signaling pathway and is a potential treatment target for PD. PMID- 24628734 TI - Changes in the concentration of fumonisins in forage rice during the growing period, differences among cultivars and sites, and identification of the causal fungus. AB - To clarify the changes in rice fumonisin (FUM) concentrations, we conducted field cultivation of 10 forage rice cultivars and inoculation with fumonisin-producing fungal isolates. We cultivated 10 forage rice cultivars at the NARO Institute of Livestock and Grassland Science and one cultivar at two additional farmland sites in Japan in 2011 and 2012. Fusarium fujikuroi, which primarily infects plants shortly after heading, was inoculated on rice just after heading, and we sampled heads at the yellow-ripe and full-ripe stages to assess FUM concentrations. We found differences among cultivars in the FUM concentration and differences among the sites for the same cultivar, but no cultivar had high levels in leaves and stems. Fusarium fujikuroi was the main fumonisin producer. The FUM concentration in heads increases from <1 to 4760 MUg/kg DM after the yellow-ripe stage. To control FUM levels, it is necessary to select low-FUM cultivars and manage the cultivation environment. PMID- 24628735 TI - Predictive factor of re-bleeding after negative capsule endoscopy for obscure gastrointestinal bleeding: over 1-year follow-up study. AB - BACKGROUND AND AIM: Capsule endoscopy (CE) is now widely accepted as a first-line diagnostic modality for obscure gastrointestinal bleeding (OGIB), with a high diagnostic yield compared to other modalities. However, even after negative CE examination, re-bleeding is often known to occur. The aim of the present study was to identify predictive factors of re-bleeding after negative CE, and to clarify the clinical utility of double-balloon enteroscopy (DBE) after negative CE for OGIB. METHODS: Two hundred and sixty patients who underwent CE for OGIB between October 2007 and September 2012 were included, and followed up for at least 1 year after CE examination. Demographic and clinical parameters associated with re-bleeding after negative CE were investigated. RESULTS: A total of 154 patients (59.2%) had negative findings. Thirteen of those patients (8.4%) had one or more re-bleeding episodes during the follow-up period. In comparing patients with and without re-bleeding, Cox hazard regression analysis revealed that advanced age was a predictive factor for re-bleeding after negative CE (hazard ratio 1.05 [1.01-1.10], P = 0.03). Subsequent DBE for reasons other than re bleeding was carried out in 51 patients (33.1%). Mucosal lesions (ulcer or multiple erosions) were subsequently detected in seven patients (13.7%), and endoscopic therapies were carried out in two patients (3.9%). CONCLUSIONS: In patients of advanced age, more extensive follow up is needed, even if the CE result is negative. In addition, DBE subsequent to negative CE may be useful to detect lesions that were overlooked on CE. PMID- 24628736 TI - Duration of erection: does it really matter? A randomized, double-blind clinical trial to assess the impact of vardenafil ODT on duration of erection and its correlation with patients' and partners' sexual quality of life and duration of intercourse: the VADEOPEN study. AB - INTRODUCTION: Stopwatch-assessed duration of erection has been proposed as an objective and reliable efficacy end point for erectile dysfunction (ED) treatments. AIM: The aim of this study is to assess vardenafil orodispersible tablets' (ODTs) efficacy in terms of duration of erection and (i) its correlation with other efficacy end points and male and female sexual quality of life (QoL) and (ii) its impact on intercourse duration. METHODS: Randomized, double-blind, placebo-controlled, multicenter study comparing the efficacy and safety of vardenafil ODT 10 mg on-demand over 12 weeks in 127 patients with ED was carried out. MAIN OUTCOME MEASURES: Primary efficacy end points were stopwatch-assessed duration of erection (min) at any attempt and when leading to successful intercourse, and the erectile function domain of the International Index of Erectile Function (EF-IIEF) score. Secondary end points were sexual encounter profile (SEP) 3 response rate and male sexual QoL. End points in participating women (N = 46) were stopwatch-assessed duration of intercourse and sexual QoL. RESULTS: At week 12/last observation carried forward, patients taking vardenafil ODT had longer duration of erections (at any attempt or leading to successful intercourse) vs. placebo (least square mean +/- standard error 10.2 +/- 0.9 minutes vs. 7.9 +/- 1.0 minutes, and 10.4 +/- 0.8 vs. 8.3 +/- 1.0 minutes, respectively), and significant increases in EF-IIEF scores, the SEP-3 response, and all sexual QoL items. An increased duration of intercourse was also observed. Female sexual QoL improved significantly. Both duration end points strongly correlated with EF-IIEF scores, and the three end points correlated well with SEP 3 response. Correlation was good with sexual QoL scores in men and women and with duration of intercourse, with differences between treatment groups only for duration end points. Safety was similar in both groups. CONCLUSION: This study provides further evidence for the consistency and reliability of the stopwatch assessed duration of erection as an efficacy end point for ED treatments, with "duration of erection leading to successful intercourse" showing better properties than duration at any attempt. PMID- 24628737 TI - Chronotype is associated with the timing of the circadian clock and sleep in toddlers. AB - Chronotype is a construct reflecting individual differences in diurnal preference. Although chronotype has been studied extensively in school-age children, adolescents and adults, data on young children are scarce. This study describes chronotype and its relationship to the timing of the circadian clock and sleep in 48 healthy children aged 30-36 months (33.4 +/- 2.1 months; 24 males). Parents completed the Children's Chronotype Questionnaire (CCTQ) ~2 weeks before the start of the study. The CCTQ provides three measures of chronotype: midsleep time on free days, a multi-item morningness/eveningness score and a single item chronotype score. After 5 days of sleeping on their habitual schedule (assessed with actigraphy and sleep diaries), children participated in an in-home salivary dim light melatonin onset assessment. Average midsleep time on free days was 1:47 +/- 0:35, and the average morningness/eveningness score was 26.8 +/- 4.3. Most toddlers (58.4%) were rated as 'definitely a morning type' or 'rather morning than evening type', while none (0%) were rated as 'definitely evening type'. More morning types (midsleep time on free days and morningness/eveningness score, respectively) had earlier melatonin onset times (r = 0.45, r = 0.26), earlier habitual bedtimes (r = 0.78, r = 0.54), sleep onset times (r = 0.80, r = 0.52), sleep midpoint times (r = 0.90, r = 0.53) and wake times (r = 0.74, r = 0.34). Parent ratings using the single-item chronotype score were associated with melatonin onset (r = 0.32) and habitual bedtimes (r = 0.27), sleep onset times (r = 0.33) and sleep midpoint times (r = 0.27). Morningness may best characterize circadian preference in early childhood. Associations between chronotype and circadian physiology and sleep timing suggest adequate validity for the CCTQ in this age group. These findings have important implications for understanding the marked variability in sleep timing during the early years of life. PMID- 24628738 TI - Migraine and erythrocyte biology: a review. AB - Migraine is a common disabling headache disorder that is conventionally classified according to the presence or absence of aura. The pathogenesis of this disorder entails a complex interplay of neurovascular factors, that trigger reduction of cerebral blood flow followed by reactive vasodilatation. Despite major emphasis has been placed on the investigation of putative biomarkers that could predict response to specific treatments and prophylaxis, less focus has been directed at the association between migraine and erythrocytosis. Erythrocytosis is typically accompanied by hyperviscosity, that is now considered a crucial determinant in the pathogenesis of migraine. The results of some epidemiological investigations are in substantial agreement to confirm the existence of a significant relationship between increased haemoglobin levels and migraine, whereas some case reports have also reported an effective improvement of symptoms after reduction of erythrocyte count by therapeutic venesection. Interesting evidence has recently emerged from the assessment of red blood cell distribution width (RDW), a simple and inexpensive measure of anysocytosis that has been also associated with a variety of ischaemic and thrombotic disorders other than migraine. The aim of this review was to provide an overview of the current clinical and epidemiological evidence linking migraine and erythrocyte biology. PMID- 24628739 TI - The ebb and flow of attitudes and policies on alcohol in Ireland 2002-2010. AB - INTRODUCTION AND AIMS: This paper examines the level of public support for alcohol control policies during a period of policy evolution in Ireland. DESIGN AND METHODS: A comparison of attitudes to alcohol policy at three points in time was undertaken. The first survey took place in 2002 and was repeated in 2006 and 2010 using a national quota sample of 1000 adults with face-to-face interviews. Policy areas examined were drunk-driving, price, availability and promotion. RESULTS: In 2002, the highest level of public support was for drink-driving countermeasures (84% favoured random breath testing) and measures to restrict alcohol promotions (67% favoured restrictions). Support for stricter measures on price and availability was lower. Trends showed a decline in support for tax increases and for early closing time, whereas support for fewer outlets (off trade) increased. DISCUSSION AND CONCLUSION: When public concerns (level of support) for stricter alcohol policies were seen to be meet, as occurred with price and hours through increased tax and reversal of opening hours, public concern/support declined. When concerns were not met, as with outlets, support continued to rise most likely influenced by greater number of off-trade outlets and cheaper alcohol. Support for liberal alcohol policies was low and the majority favoured the status quo on price and availability. Public support for policy is one element of the complexity of policymaking along with consensus building across government and management of vested interests, so that the policy outcome is seldom assured. PMID- 24628741 TI - A novel randomised controlled trial design in prostate cancer. PMID- 24628740 TI - Associations of pentraxin 3 with cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: Pentraxin 3 (PTX3) is probably a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis. APPROACH AND RESULTS: Two thousand eight hundred and thirty eight participants free of prevalent CVD with measurements of PTX3 were included in the present study. After adjustment for age, sex, and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C reactive protein (CRP), and carotid intima-media thickness (all P < 0.045). A one standard deviation increase in PTX3 level (1.62 ng mL(-1) ) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk of 1.05; 95% confidence interval [CI] 1.01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio [HR] 1.51; 95% [CI] 1.16 1.97), combined CVD events (HR 1.23; 95% [CI] 1.05-1.45), and combined CHD events (HR 1.33; 95% [CI] 1.10-1.60), but not stroke, CVD-related mortality, or all cause death. CONCLUSIONS: In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independently of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP, and may provide additional insights into the development and progression of atherosclerosis. PMID- 24628743 TI - Study of the impacts of patient-educators on the course of basic sciences in dental studies. AB - Ever since 2006, Nantes University dental educators have started organising lectures led by the mother of a young patient suffering from ectodermic dysplasia (patient-educator) to help second-year students to better understand how important it is for their future dental work to better understand basic sciences. In this study, we have analysed this training experience on students' motivation. For this purpose, students were asked to complete questionnaires 10 days after the patient-educator's lecture (early assessment; n = 193) and 4 years later, during the last year of their dental studies (delayed assessment; n = 47). Moreover, 3 years after the first lecture, we analysed the ability of students to diagnose a mother carrying the ectodermic dysplasia genetic disorder, using a case-based learning exercise with a patient showing dental features similar to those exposed by the patient-educator (measure of knowledge; n = 42). Ten days after the lecture, the early assessment shows that all the students were interested in the lecture and 59% of the students declared being motivated to find out more about genetics whilst 54% declared the same thing about embryology courses. Moreover, 4 years later, 67% of the students remembered the patient educator's lecture a little or very well. Three years after the course, 83% of the students diagnosed ectodermal dysplasia whilst studying the case-based example that listed typical dental phenotypes. In conclusion, this study shows that this original educational approach enhances dental students' motivation in learning basic sciences and that patient-educators could offer many benefits for students and patients. PMID- 24628742 TI - Health and social harms associated with crystal methamphetamine use among street involved youth in a Canadian setting. AB - BACKGROUND AND OBJECTIVES: Despite recent increases in crystal methamphetamine use among high-risk populations such as street-involved youth, few prospective studies have examined the health and social outcomes associated with active crystal methamphetamine use. METHODS: We enrolled 1,019 street-involved youth in Vancouver, Canada, in a prospective cohort known as the at-risk youth study (ARYS). Participants were assessed semi-annually and a generalized estimating equation (GEE) logistic regression was used to identify factors independently associated with active crystal methamphetamine use. RESULTS: Among 1,019 participants recruited into ARYS between 2005 and 2012 the median follow up duration was 17 months, 320 (31.4%) participants were female and 454 (44.6%) had previously used crystal methamphetamine at baseline. In adjusted GEE analyses, active crystal methamphetamine use was independently associated with Caucasian ethnicity (adjusted odds ratio [AOR] = 1.37; 95% confidence interval [CI]: 1.04 1.81), homelessness (AOR = 1.34; 95% CI: 1.15-1.56), injection drug use (AOR = 3.40; 95% CI: 2.76-4.19), non-fatal overdose (AOR = 1.46; 95%CI: 1.07-2.00), being a victim of violence (AOR = 1.19; 95% CI: 1.02-1.38), involvement in sex work (AOR = 1.39; 95% CI: 1.03-1.86), and drug dealing (AOR = 1.60; 95% CI: 1.35 1.90). DISCUSSION AND CONCLUSIONS: Prevalence of crystal methamphetamine use was high in this setting and active use was independently associated with a range of serious health and social harms. SCIENTIFIC SIGNIFICANCE: Evidence-based strategies to prevent and treat crystal methamphetamine use are urgently needed. PMID- 24628744 TI - Langerhans cell histiocytosis in IPEX syndrome: possible role for natural regulatory T cells? PMID- 24628745 TI - Evidence for the evolutionary origin of goldfish derived from the distant crossing of red crucian carp * common carp. AB - BACKGROUND: Distant hybridization can generate transgressive hybrid phenotypes that lead to the formation of new populations or species with increased genetic variation. In this study, we produced an experimental hybrid goldfish (EG) by distant crossing of red crucian carp (Carassius auratus) * common carp (Cyprinus carpio) followed by gynogenesis. RESULTS: We evaluated the phenotype, ploidy level, gonadal structure, and 5S rDNA of the EG. Diploid EG possessed a high level of genetic variation, which was stably inherited. In particular, the EG combined transgressive phenotypes, including a forked tail and shortened caudal peduncle, traits that are present in common goldfish. The EG and common goldfish share a number of morphological and genetic similarities. CONCLUSIONS: Using the EG, we provide new evidence that goldfish originated from hybridization of red crucian carp * common carp. PMID- 24628746 TI - Association of leptin/receptor and TNF-alpha gene variants with adolescent obesity in Malaysia. AB - BACKGROUND: Leptin (LEP) G-2548A (rs7799039), leptin receptor (LEPR) Q223R (rs1137101) and tumor necrosis factor (TNF)-alpha G-308A (rs1800629) gene variants have been reported to be associated with obesity, although results for subjects from different countries have been controversial. The aim of this study was to determine the prevalence of overweight and obesity in Malaysian adolescents and the association of these polymorphisms with overweight and obese or over-fat adolescents. METHODS: A total of 613 adolescents (241 Malay, 219 Chinese, 153 Indian) were enrolled. Anthropometric measurements of body mass index (BMI) and body fat percentage were used to classify subjects as controls (non-overweight/obese or normal fat) or as cases (overweight/obese or over-fat). Genomic DNA was extracted from oral buccal mucosa cells for genotyping using polymerase chain reaction-restriction fragment length polymorphism and data obtained were statistically analyzed. RESULTS: A total of 23.3% of subjects were overweight/obese whereas 11.4% were over-fat; there were significantly more overweight/obese and over-fat Indian and Malay adolescents compared to Chinese (P < 0.001). A allele was the minor one for LEPR Q223R and TNF-alpha G-308A in all ethnic groups, whereas G allele was minor for LEP G-2548A in Chinese and Malay adolescents, except for Indian adolescents. Indian male adolescents with AA genotype for LEP G-2548A were associated with overweight/obesity (P = 0.025; odds ratio, 3.64; 95% confidence interval: 1.15-11.54). Despite the lack of association observed for LEPR Q223R and TNF-alpha G-308A, Indian and Chinese subjects with AA risk genotype for LEPR Q223R/LEP G-2548A and TNF-alpha G 308A/LEP G-2548A, respectively, had increased mean BMI (P = 0.049, P = 0.016). CONCLUSIONS: Genotype distribution and association of these polymorphisms with overweight/obesity vary between ethnic groups and genders. Nevertheless, the LEP G-2548A risk allele may be associated with overweight/obese Indian male adolescents in Malaysia. PMID- 24628747 TI - Randomized clinical trial of hydrocodone/acetaminophen versus codeine/acetaminophen in the treatment of acute extremity pain after emergency department discharge. AB - OBJECTIVES: The objective was to test the hypothesis that hydrocodone/acetaminophen (Vicodin [5/500]) provides more efficacious analgesia than codeine/acetaminophen (Tylenol #3 [30/300]) in patients discharged from the emergency department (ED). Both are currently Drug Enforcement Administration (DEA) Schedule III narcotics. METHODS: This was a prospective, randomized, double blind, clinical trial of patients with acute extremity pain who were discharged home from the ED, comparing a 3-day supply of oral hydrocodone/acetaminophen (5 mg/500 mg) to oral codeine/acetaminophen (30 mg/300 mg). Pain was measured on a valid and reproducible verbal numeric rating scale (NRS) ranging from 0 to 10, and patients were contacted by telephone approximately 24 hours after being discharged. The primary outcome was the between-group difference in improvement in pain at 2 hours following the most recent ingestion of the study drug, relative to the time of phone contact after ED discharge. Secondary outcomes compared side-effect profiles and patient satisfaction. RESULTS: The median time from ED discharge to follow-up was 26 hours (interquartile range [IQR] = 24 to 39 hours). The mean NRS pain score before the most recent dose of pain medication after ED discharge was 7.6 NRS units for both groups. The mean decrease in pain scores 2 hours after pain medications were taken were 3.9 NRS units in the hydrocodone/acetaminophen group versus 3.5 NRS units in the codeine/acetaminophen group, for a difference of 0.4 NRS units (95% confidence interval [CI] = -0.3 to 1.2 NRS units). No differences were found in side effects or patient satisfaction. CONCLUSIONS: Both medications decreased NRS pain scores by approximately 50%. However, the oral hydrocodone/acetaminophen failed to provide clinically or statistically superior pain relief compared to oral codeine/acetaminophen when prescribed to patients discharged from the ED with acute extremity pain. Similarly, there were no clinically or statistically important differences in side-effect profiles or patient satisfaction. If the DEA reclassifies hydrocodone as a Schedule II narcotic, as recently recommended by its advisory board, our data suggest that the codeine/acetaminophen may be a clinically reasonable Schedule III substitute for hydrocodone/acetaminophen at ED discharge. These findings should be regarded as tentative and require independent validation in similar and other acute pain models. PMID- 24628748 TI - Rising opioid prescribing in adult U.S. emergency department visits: 2001-2010. AB - OBJECTIVES: The objective was to describe trends in opioid and nonopioid analgesia prescribing for adults in U.S. emergency departments (EDs) over the past decade. METHODS: Data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2001 through 2010 were analyzed. ED visits for adult patients (>=18 years of age) during which an analgesic was prescribed were included. Trends in the use of six commonly prescribed opioids, stratified by Drug Enforcement Agency (DEA) schedule, as well as nonopioid analgesics were explored, along with the frequency of pain-related ED visits. For 2005 through 2010, data were further divided by whether the opioid was administered in the ED versus prescribed at discharge. RESULTS: Between 2001 and 2010, the percentage of overall ED visits (pain-related and non-pain-related) where any opioid analgesic was prescribed increased from 20.8% to 31.0%, an absolute increase of 10.2% (95% confidence interval [CI] = 7.0% to 13.4%) and a relative increase of 49.0%. Use of DEA schedule II analgesics increased from 7.6% in 2001 to 14.5% in 2010, an absolute increase of 6.9% (95% CI = 5.2% to 8.5%) and a relative increase of 90.8%. Use of schedule III through V agents increased from 12.6% in 2001 to 15.6% in 2010, an absolute increase of 3.0% (95% CI = 2.0% to 5.7%) and a relative increase of 23.8%. Prescribing of hydrocodone, hydromorphone, morphine, and oxycodone all increased significantly, while codeine and meperidine use declined. Prescribing of nonopioid analgesics was unchanged, 26.2% in 2001 and 27.3% in 2010 (95% CI = -1.0% to 3.4%). Hydromorphone and oxycodone had the greatest increase in ED administration between 2005 and 2010, while oxycodone and hydrocodone had the greatest increases in discharge prescriptions. There was no difference in discharge prescriptions for nonopioid analgesics. The percentage of visits for painful conditions during the period increased from 47.1% in 2001 to 51.1% in 2010, an absolute increase of 4.0% (95% CI = 2.3% to 5.8%). CONCLUSIONS: There has been a dramatic increase in prescribing of opioid analgesics in U.S. EDs in the past decade, coupled with a modest increase in pain-related complaints. Prescribing of nonopioid analgesics did not significantly change. PMID- 24628749 TI - Barriers and facilitators to intraosseous access in adult resuscitations when peripheral intravenous access is not achievable. AB - OBJECTIVES: Studies suggest that intraosseous (IO) access is underutilized in adult resuscitations, despite recommendations from advanced trauma and cardiac life support guidelines. The objective was to determine factors associated with IO access use by physicians during adult resuscitations when intravenous (IV) access is not immediately achievable. METHODS: This study was an online survey among physicians purposefully recruited from various clinical care areas at three teaching hospitals. Questions were generated from the qualitative results of 20 iterative interviews, verified for internal validity, and piloted. The interview guide was based on the constructs of the Theory of Planned Behavior (TPB), which elicits salient attitudes, social influences, and control beliefs that potentially influence intention to use IO access. Recruitment took place in September 2012 until reaching more than 100% of the required sample size (n = 200). Internal consistency was measured using Cronbach's alpha, and the effect of TPB constructs and specific beliefs were assessed with regression analyses. RESULTS: For the 205 respondents, the mean age was 35 years (range = 20 to 66 years), and 53.3% were male. Participants' departmental affiliations were 50.3% emergency medicine (EM), 16.9% internal medicine, 14.9% anesthesia, 10.8% general surgery, and 7.2% critical care. Residents comprised 60.7% of the sample, and 39.3% were attending physicians. Median intention to use IO access when IV is not immediately achievable was 4.67 (interquartile range [IQR] = 4 to 5) out of 5 (5 highest) and predicted by the following TPB constructs: attitudes (AdjCoefficients = 0.504; 95% confidence interval [CI] = 0.334 to 0.673), social influences (AdjCoefficients = 0.285; 95% CI = 0.172 to 0.398), and control beliefs (AdjCoefficients 0.217; 95% CI = 0.113 to 0.320). Physicians were more likely to use IO access if they believed that it provided rapid vascular access for delivering large volumes of fluids, could prevent delays in care, and was associated with a low complication rate. Conversely, the perception that nurses are not familiar or supportive of IO access and a lack of physician confidence regarding the appropriate indications for IO access were barriers to use. CONCLUSIONS: These data are an important step in the knowledge-to-action process, as they identify specific factors associated with physician use of IO access. Interventions addressing these actionable facilitators and barriers are likely to have a positive effect on increasing the appropriate physician use of this potentially life-saving technique in adult patients requiring emergent vascular access. PMID- 24628750 TI - Combination of intravenous ascorbic acid administration and hypothermia after resuscitation improves myocardial function and survival in a ventricular fibrillation cardiac arrest model in the rat. AB - OBJECTIVES: Intravenous (IV) administration of ascorbic acid during cardiopulmonary resuscitation (CPR) was reported to facilitate defibrillation and improves survival in ventricular fibrillation (VF) cardiac arrest. We investigated whether IV administration of ascorbic acid after return of spontaneous circulation (ROSC) can improve outcomes in VF cardiac arrest in a rat model and its interaction with therapeutic hypothermia. METHODS: Ventricular fibrillation-induced cardiac arrest followed by CPR and defibrillation was performed in male Wistar rats. After ROSC, the animals were equally randomized to the normothermia (NormoT), hypothermia (HypoT), ascorbic acid (AA+NormoT), and ascorbic acid plus hypothermia (AA+HypoT) groups. The AA+NormoT and AA+HypoT groups received IV ascorbic acid (100 mg/kg). In the HypoT and AA+HypoT groups, therapeutic hypothermia was maintained at 32 degrees C for 2 hours. RESULTS: There were 12 rats in each group. Within 4 hours after ROSC, the HypoT, AA+NormoT, and AA+HypoT groups had significantly lower myocardial lipid peroxidation than the NormoT group. Within 4 hours following ROSC, the AA+NormoT group had a significantly better systolic function (dp/dt40 ) than the NormoT group (6887.9 mm Hg/sec, SD +/- 1049.7 mm Hg/sec vs. 5953.6 mm Hg/sec, SD +/- 1161.9 mm Hg/sec; p < 0.05). The AA+HypoT group also showed a significantly better diastolic function (-dp/dtmax ) than the HypoT group (dp/dt40 : 8524.8, SD +/- 1166.7 mm Hg/sec vs. 7399.8 mm Hg/sec, SD +/- 1114.5 mmHg/sec; dp/dtmax : 8183.4 mm Hg/sec, SD +/- 1359.0 mm Hg/sec vs. -6573.7 mm Hg/sec, SD +/- 1110.9 mm Hg/sec; p < 0.05) at the fourth hour following ROSC. Also at 4 hours, there was less myocytolysis in the HypoT, AA+NormoT, and AA+HypoT groups than the NormoT group. The HypoT, AA+NormoT, and AA+HypoT groups had significantly better survival rates and neurologic outcomes than the NormoT group. Compared with only five surviving animals in the NormoT group, there were nine, eight, and 10 in the HypoT, AA+NormoT, and AA+HypoT groups, respectively, with good neurologic outcomes at 72 hours. CONCLUSIONS: Intravenous ascorbic acid administration after ROSC in normothermia may mitigate myocardial damage and improve systolic function, survival rate, and neurologic outcomes in VF cardiac arrest of rat. Combination of ascorbic acid and hypothermia showed an additive effect in improving both systolic and diastolic functions after ROSC. PMID- 24628751 TI - Reduction of admit wait times: the effect of a leadership-based program. AB - OBJECTIVES: Prolonged admit wait times in the emergency department (ED) for patients who require hospitalization lead to increased boarding time in the ED, a significant cause of ED congestion. This is associated with decreased quality of care, higher morbidity and mortality, decreased patient satisfaction, increased costs for care, ambulance diversion, higher numbers of patients who leave without being seen (LWBS), and delayed care with longer lengths of stay (LOS) for other ED patients. The objective was to assess the effect of a leadership-based program to expedite hospital admissions from the ED. METHODS: This before-and-after observational study was undertaken from 2006 through 2011 at one community hospital ED. A team of ED and hospital leaders implemented a program to reduce admit wait times, using a computerized hospital-wide tracking system to monitor inpatient and ED bed status. The team collaboratively and consistently moved ED patients to their inpatient beds within an established goal of 60 minutes after an admission decision was reached. Top leadership actively intervened in real time by contacting staff whenever delays occurred to expedite immediate solutions to achieve the 60-minute goal. The primary outcome measures were the percentage of ED patients who were admitted to inpatient beds within 60 minutes from the time the beds were requested and ED boarding time. LOS, patient satisfaction, LWBS rate, and ambulance diversion hours were also measured. RESULTS: After ED census, hospital admission rates, and ED bed capacity were controlled for using a multivariable linear regression analysis, the admit wait time reduction program contributed to an increase in patients being admitted to the hospital within 60 minutes by 16 percentage points (95% confidence intervals [CI] = 10 to 22 points; p < 0.0001) and a decrease in boarding time per admission of 46 minutes (95% CI = 63 to 82 minutes; p < 0.0001). LOS decreased for admitted patients by 79 minutes (95% CI = 55 to 104 minutes; p < 0.0001), for discharged patients by 17 minutes (95% CI = 12 to 23 minutes; p < 0.0001), and for all patients by 34 minutes (95% CI = 25 to 43 minutes; p < 0.0001). Patient satisfaction increased 4.9 percentage points (95% CI = 3.8 to 6.0 points; p < 0.0001). LWBS patients decreased 0.9 percentage points (95% CI = 0.6 to 1.2 points; p < 0.0001) and monthly ambulance diversion decreased 8.2 hours (95% CI = 4.6 to 11.8 hours; p < 0.0001). CONCLUSIONS: A leadership-based program to reduce admit wait times and boarding times was associated with a significant increase in the percentage of patients admitted to the hospital within 60 minutes and a significant decrease in boarding time. Also associated with the program were decreased ED LOS, LWBS rate, and ambulance diversion, as well as increased patient satisfaction. PMID- 24628752 TI - Reducing blood culture contamination in community hospital emergency departments: a multicenter evaluation of a quality improvement intervention. AB - OBJECTIVES: Blood culture contamination is a common and preventable problem in the emergency department (ED). In a previous single-center study, changing the process of ED blood culture collection from the traditional "clean," nonsterile procedure to a fully sterile procedure with standardized use of sterile gloves, large-volume chlorhexidine skin antisepsis, and fenestrated sterile drapes resulted in a substantial reduction in contamination. The objective of the current study was to evaluate the effectiveness of this sterile blood culture collection process for reducing blood culture contamination in two community hospital EDs. METHODS: The authors implemented the sterile blood culture collection process in the ED of two hospitals, including Hospital A, which historically had a contamination rate of approximately 5%, and Hospital B, with a 2.5% historical contamination rate. With an interrupted times-series design and segmented regression analysis to adjust for secular trends and autocorrelation, the monthly percentages of cultures contaminated at each hospital during an intervention period (sterile technique) were compared to a 10-month baseline period immediately preceding implementation (clean technique). At Hospital A, the full sterile blood culture collection process was used throughout the 16-month intervention period. At Hospital B, user feedback indicated poor adherence to the process due to difficulty implementing the fenestrated drape component; therefore, the process was simplified to the modified sterile collection process, in which the fenestrated drape component was dropped and sterile gloves and large volume skin antisepsis were emphasized. Hence, at Hospital B, two intervention periods were compared to the baseline period: the 8-month intervention period 1 (full sterile process) and the subsequent 8-month intervention period 2 (modified sterile process). RESULTS: At Hospital A, during the baseline period, 165 of 3,417 (4.83%) cultures were contaminated, while 142 of 5,238 (2.71%) were contaminated during the intervention period (p < 0.01). In the segmented regression model, the full sterile blood culture collection process was associated with an immediate 2.68% (95% confidence interval [CI] = 1.43% to 3.52%) absolute reduction in contamination and sustained reductions during the entire intervention period. At Hospital B, during the baseline, 63 of 2,509 (2.51%) cultures were contaminated. In intervention period 1 with the full sterile process, 51 of 1,865 (2.73%) cultures were contaminated (p = 0.65), with segmented regression results showing no changes compared to baseline. After simplification of the process to address poor adherence, the modified sterile process during intervention period 2 was associated with a significant reduction in contamination, with 17 of 1,860 (0.91%) cultures contaminated (p < 0.01 compared to baseline). The segmented regression model demonstrated the modified sterile process was associated with an immediate 1.53% (95% CI = 1.00% to 1.88%) absolute reduction in contamination with significant sustained reductions. CONCLUSIONS: Changing the method of blood culture collection from the commonly used nonsterile technique to a sterile process resulted in significant reductions in blood culture contamination at two community hospital EDs, including one with low baseline contamination. Monitoring the implementation process at both sites was important to identify and overcome operational challenges. At one study site, simplification of the process by removing the fenestrated drape component was a key for successful implementation. PMID- 24628753 TI - Effect of microEEG on clinical management and outcomes of emergency department patients with altered mental status: a randomized controlled trial. AB - OBJECTIVES: Altered mental status (AMS) is a common presentation in the emergency department (ED). A previous study revealed 78% electroencephalogram (EEG) abnormalities, including nonconvulsive seizure (NCS; 5%), in ED patients with AMS. The objective of this study was to assess the impact of EEG on clinical management and outcomes of ED patients with AMS. METHODS: This was a randomized controlled trial at two urban teaching hospitals. Adult patients (>=18 years old) with AMS were included. Excluded patients had immediately correctable AMS (e.g., hypoglycemia) or were admitted before enrollment. Patients were randomized to routine care (control) or routine care plus EEG (intervention). Research assistants used a scalp electrode set with a miniature, wireless EEG device (microEEG) to record standard 30-minute EEGs at presentation, and results were reported to the ED attending physician by an off-site epileptologist within 30 minutes. Primary outcomes included changes in ED management (differential diagnosis, diagnostic work-up, and treatment plan from enrollment to disposition) as determined by surveying the treating physicians. Secondary outcomes were length of ED and hospital stay, intensive care unit (ICU) requirement, and in hospital mortality. RESULTS: A total of 149 patients were enrolled (76 control and 73 intervention). Patients in the two groups were comparable at baseline. EEG in the intervention group revealed abnormal findings in 93% (95% confidence interval [CI] = 85% to 97%), including NCS in 5% (95% CI = 2% to 13%). Using microEEG was associated with change in diagnostic work-up in 49% (95% CI = 38% to 60%) of cases and therapeutic plan in 42% (95% CI = 31% to 53%) of cases immediately after the release of EEG results. Changes in probabilities of differential diagnoses and the secondary outcomes were not statistically significant between the groups. CONCLUSIONS: An EEG can be obtained in the ED with minimal resources and can affect clinical management of AMS patients. PMID- 24628754 TI - Urinary catheter use and appropriateness in U.S. emergency departments, 1995 2010. AB - OBJECTIVES: Catheter-associated urinary tract infection (CAUTI) is the most prevalent hospital-acquired infection, yet little is known about emergency department (ED) use of urinary catheters. The objective was to describe use of urinary catheters in U.S. EDs and determine the proportion that was potentially avoidable. METHODS: The National Hospital Ambulatory Medical Care Survey (NHAMCS), a weighted probability sample of U.S. ED visits, was analyzed from 1995 through 2010 for use of urinary catheters in adults. Use of a urinary catheter was a specific chart review element and was classified as potentially avoidable if none of the Centers for Disease Control and Prevention (CDC) list of appropriate indications were met by ED visit diagnoses or patient disposition. Annual frequency of urinary catheter use and appropriateness were calculated. Predictors of ED-placed urinary catheters for admitted patients were assessed with multivariate logistic regression. RESULTS: The annual rate of ED-placed urinary catheters varied from 2.2 to 3.3 per 100 adult ED visits. Among admitted patients, 8.5% (95% confidence interval [CI] = 8.0% to 9.1%) received urinary catheters; 64.9% (95% CI = 56.9% to 72.9%) were potentially avoidable. Among discharged patients 1.6% (95% CI = 1.5% to 1.7%) received urinary catheters. There was no significant trend over time in the use of urinary catheters or potentially avoidable urinary catheters (PAUCs). Predictors of catheter use in admitted patients included indicators of patient severity, female sex, and race/ethnicity. Hospital characteristics predicting catheter use included region, ownership type, and urban location. Predictors of potentially avoidable urinary catheter use were lower patient severity, female sex, care by a midlevel practitioner, and nonurban location. CONCLUSIONS: Reducing use of urinary catheters outside of CDC guideline criteria in ED patients is a promising strategy to reduce CAUTIs. PMID- 24628755 TI - Bleeding following rattlesnake envenomation in patients with preenvenomation use of antiplatelet or anticoagulant medications. AB - OBJECTIVES: Rattlesnake envenomations commonly produce coagulopathy and thrombocytopenia, yet clinically significant bleeding is uncommon. It is unknown if patients who use antiplatelet or anticoagulant medications prior to envenomation are at increased risk for bleeding after envenomation. METHODS: This was a retrospective cohort study of patients age 14 years and older who were admitted to a single academic medical center for rattlesnake envenomation. Patients who reported use of antiplatelet or anticoagulant medications prior to envenomation were compared to patients not on those medications. Severity and timing of bleeding was compared between groups, as was a composite endpoint of major bleeding at any time, shock, readmission, or death. RESULTS: A total of 319 patients met inclusion criteria; 31 (9.7%) were documented to be taking antiplatelet or anticoagulant medications including aspirin, clopidogrel, and/or warfarin. Seventeen of the 319 patients developed bleeding associated with envenomation (major = 9; minor = 4; trivial = 4), with major bleeding occurring in five patients on antiplatelet or anticoagulant medications versus four patients not on antiplatelet or anticoagulant medications (p < 0.001). Seven of the 17 presented with early bleeding. This early bleeding occurred in three of 31 (9.7%) patients on antiplatelet or anticoagulant medications and four of 288 (1.4%) patients not on antiplatelet or anticoagulant medications (relative risk [RR] = 6.9; 95% confidence interval [CI] = 1.6 to 29.4; p = 0.022). Clinical outcome data were available for 300 of the 319 (94%) subjects following discharge. Late bleeding (bleeding after discharge from the index hospitalization) occurred in nine subjects, one of whom also had early bleeding (major = 2, minor = 3, trivial = 4). Three of these nine subjects with late bleeding were on antiplatelet or anticoagulant medications, compared with six not on antiplatelet or anticoagulant medications (p = 0.042). Both cases of late major bleeding occurred in patients on antiplatelet or anticoagulant medications. Therefore, among patients with follow-up data available, the overall rate of bleeding (early and late) was seven of 28 (25%) in patients taking antiplatelet or anticoagulant medications and 10 of 273 (3.7%) in patients not taking antiplatelet or anticoagulant medications (p < 0.001). The use of antiplatelet or anticoagulant medications was also associated with an increased risk of reaching the composite endpoint of major bleeding, shock, readmission, or death (6 of 31, or 19.4% vs. 14 of 288, or 4.9%; RR = 3.98; 95% CI = 1.65 to 9.62; p = 0.008). CONCLUSIONS: The risk of developing bleeding following rattlesnake envenomation is increased in patients who use antiplatelet or anticoagulant medications. This risk is greatest early after envenomation during the index hospitalization. However, risk of late, major bleeding appears also to be greatest in patients on antiplatelet or anticoagulant medications. Extra vigilance should be taken in patients on antiplatelet or anticoagulant medications and a careful risk/benefit analysis should be undertaken before continuing these medications in the weeks following the envenomation. PMID- 24628756 TI - Conflict prevention, conflict mitigation, and manifestations of conflict during emergency department consultations. AB - OBJECTIVES: The objective was to determine the causes of and mitigating factors for conflict between emergency physicians and other colleagues during consultations. METHODS: From March to September 2010, a total of 61 physicians (31 residents and 30 attendings from emergency medicine [EM], internal medicine, and general surgery) were interviewed about how junior learners should be taught about emergency department (ED) consultations. During these interviews, they were asked if and how conflict manifests during the ED consultation process. Two investigators reviewed the transcripts independently to generate themes related to conflict until saturation was reached. Disagreements were resolved by consensus. The trustworthiness of the analysis was ensured by generating an audit trail, which was subsequently audited by an investigator not involved with the initial analysis. This analysis was compared to previously proposed models of trust and conflict from the sociology and business literature. RESULTS: All participants recalled some manifestation of conflict. There were 12 negative conflict-producing themes and 10 protective conflict-mitigating themes. When comparing these themes to a previously developed model of the domains of trust, each theme mapped to domains of the model. CONCLUSIONS: Conflict affects the ED consultation process. Areas that lead to conflict are identified that map to previous models of trust and conflict. This work extends the current understanding about intradisciplinary conflict in the clinical realm. These new findings may improve the understanding of the nature of conflicts that occur and form the foundation for interventions that may decrease conflict during ED consultations. PMID- 24628757 TI - Enhancing the quality of morbidity and mortality rounds: the Ottawa M&M model. AB - OBJECTIVES: The objective of this study was to determine the feasibility and acceptability of a structured morbidity and mortality (M&M) rounds model through an innovative educational intervention. METHODS: The authors engaged the Departments of Emergency Medicine (EM) and Trauma Services at a tertiary care teaching hospital. A needs assessment was performed; the Ottawa M&M rounds model was developed, implemented, and then evaluated as a four-part intervention. This consisted of: 1) physician training on case selection and analysis, 2) engaging interprofessional members, 3) disseminating lessons learned, and 4) creating an administrative pathway for acting on issues identified through the M&M rounds. The measures of intervention feasibility included the proportion of sessions adherent to the new model and M&M rounds attendance. Pre- and postintervention surveys of presenters and attendees were used to determine intervention acceptability. M&M presentation content was reviewed to determine the most frequently adopted components of the model. RESULTS: Nine of 14 (64.3%) sessions were adherent to three of four components of the Ottawa M&M Model. Of those M&M attendees who responded to the survey (796 of 912, 87.2%), improvements were found in M&M rounds attendance as well as perceived effect on clinical practice at both individual and departmental levels. Thirty-seven case presentations were analyzed and improvements postintervention were found in appropriate case selection and recognition of cognitive and system issues. CONCLUSIONS: The Ottawa M&M Model was a feasible intervention that was perceived to be effective by both presenters and attendees. The authors believe that this could be readily applied to any hospital department seeking to enhance quality of care and patient safety. PMID- 24628758 TI - Critical appraisal of emergency medicine education research: the best publications of 2012. AB - OBJECTIVES: The objective was to critically appraise and highlight medical education research published in 2012 that was methodologically superior and whose outcomes were pertinent to teaching and education in emergency medicine (EM). METHODS: A search of the English language literature in 2012 querying Education Resources Information Center (ERIC), PsychInfo, PubMed, and Scopus identified EM studies using hypothesis-testing or observational investigations of educational interventions. Two reviewers independently screened all of the publications and removed articles using established exclusion criteria. This year, publications limited to a single-site survey design that measured satisfaction or self assessment on unvalidated instruments were not formally reviewed. Six reviewers then independently ranked all remaining publications using one of two scoring systems depending on whether the study methodology was primarily qualitative or quantitative. Each scoring system had nine criteria, including four related to methodology, that were chosen a priori, to standardize evaluation by reviewers. The quantitative study scoring system was used previously to appraise medical education published annually in 2008 through 2011, while a separate, new qualitative study scoring system was derived and implemented consisting of parallel metrics. RESULTS: Forty-eight medical education research papers met the a priori criteria for inclusion, and 33 (30 quantitative and three qualitative studies) were reviewed. Seven quantitative and two qualitative studies met the criteria for inclusion as exemplary and are summarized in this article. CONCLUSIONS: This critical appraisal series aims to promote superior education research by reviewing and highlighting nine of the 48 major education research studies with relevance to EM published in 2012. Current trends and common methodologic pitfalls in the 2012 papers are noted. PMID- 24628759 TI - A profile of acute care in an aging America: snowball sample identification and characterization of United States geriatric emergency departments in 2013. AB - BACKGROUND: The aging of America poses a challenge to emergency departments (EDs). Studies show that elderly patients have poor outcomes despite increased testing, prolonged periods of observation, and higher admission rates. In response, emergency medicine (EM) leaders have implemented strategies for improved ED elder care, enhancing expertise, equipment, policies, and protocols. One example is the development of geriatric EDs gaining in popularity nationwide. To the authors' knowledge, this is the first research to systematically identify and qualitatively characterize the existence, locations, and features of geriatric EDs across the United States. OBJECTIVES: The primary objective was to determine the number, distribution, and characteristics of geriatric EDs in the United States in 2013. METHODS: This was a survey with potential respondents identified via a snowball sampling of known geriatric EDs, EM professional organizations' geriatric interest groups, and a structured search of the Internet using multiple search engines. Sites were contacted by telephone, and those confirming geriatric EDs presence received the survey via e-mail. Category questions included date of opening, location, volumes, staffing, physical plant changes, screening tools, policies, and protocols. Categories were reported based on general interest to those seeking to understand components of a geriatric ED. RESULTS: Thirty-six hospitals confirmed geriatric ED existence and received surveys. Thirty (83%) responded to the survey and confirmed presence or plans for geriatric EDs: 24 (80%) had existing geriatric EDs, and six (20%) were planning to open geriatric EDs by 2014. The majority of geriatric EDs are located in the Midwest (46%) and Northeast (30%) regions of the United States. Eighty percent serve from 5,000 to 20,000 elder patients annually. Seventy percent of geriatric EDs are attached to the main ED, and 66% have from one to 10 geriatric beds. Physical plant changes include modifications to beds (96%), lighting (90%), flooring (83%), visual aids (73%), and sound level (70%). Seventy-seven percent have staff overlapping with the nongeriatric portion of their ED, and 80% require geriatric staff didactics. Sixty-seven percent of geriatric EDs report discharge planning for geriatric ED patients, and 90% of geriatric EDs had direct follow-up through patient callbacks. CONCLUSIONS: The snowball sample identification of U.S. geriatric EDs resulted in 30 confirmed respondents. There is significant variation in the components constituting a geriatric ED. The United States should consider external validation of self-identified geriatric EDs to standardize the quality and type of care patients can expect from an institution with an identified geriatric ED. PMID- 24628760 TI - Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness. AB - BACKGROUND: KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. METHODS: We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n = 5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. RESULTS: KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB 231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. CONCLUSIONS: Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it may represent a novel target for biomarker development and a novel therapeutic target for breast cancer. PMID- 24628761 TI - Novel application of simultaneous multi-image display during complex robotic abdominal procedures. AB - BACKGROUND: The surgical robot offers the potential to integrate multiple views into the surgical console screen, and for the assistant's monitors to provide real-time views of both fields of operation. This function has the potential to increase patient safety and surgical efficiency during an operation. Herein, we present a novel application of the multi-image display system for simultaneous visualization of endoscopic views during various complex robotic gastrointestinal operations. All operations were performed using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) with the assistance of Tilepro, multi input display software, during employment of the intraoperative scopes. Three robotic operations, left hepatectomy with intraoperative common bile duct exploration, low anterior resection, and radical distal subtotal gastrectomy with intracorporeal gastrojejunostomy, were performed by three different surgeons at a tertiary academic medical center. RESULTS: The three complex robotic abdominal operations were successfully completed without difficulty or intraoperative complications. The use of the Tilepro to simultaneously visualize the images from the colonoscope, gastroscope, and choledochoscope made it possible to perform additional intraoperative endoscopic procedures without extra monitors or interference with the operations. CONCLUSION: We present a novel use of the multi input display program on the da Vinci Surgical System to facilitate the performance of intraoperative endoscopies during complex robotic operations. Our study offers another potentially beneficial application of the robotic surgery platform toward integration and simplification of combining additional procedures with complex minimally invasive operations. PMID- 24628762 TI - Effect of the prolonged high-fat diet on the fatty acid metabolism in rat blood and liver. AB - BACKGROUND: Contradictory data on consequences of prolonged high-fat diet requires a detailed study of the influence of nutritional high-fat load mechanisms on the peculiarity of lipid metabolism in blood and liver. The present study was undertaken to investigate the fatty acid composition of polar and neutral lipids of the blood plasma, erythrocytes and liver in Wistar rats under the conditions of a prolonged high-fat diet. METHODS: The study was conducted on 60 adult white male Wistar rats. The animals were fed on a high-fat diet consisted of the beef fat and cholesterol (19% and 2% of the total diet, respectively) up to 180 days. The fatty acid composition of the polar and neutral lipids of plasma, erythrocytes and liver were analyzed by the gas chromatography. Statistical data processing was performed by the methods of descriptive statistics with Statistica 6.0. RESULTS: The prolonged unbalanced diet rich in cholesterol and saturated fatty acids resulted in compensatory biosynthesis of the fatty acids in the rat's liver, the inhibition of synthesis of apoproteins and lipoproteins, disruption of the active transport of fatty acids to tissue cells. This launched the accumulation of 20:4n-6, 20:5n-3, 22:5n-3, and 22:6n-3 in the liver and blood plasma and deficiency of 18:2n-6, 20:5n-3 and 22:6n-3 in the erythrocytes. CONCLUSIONS: Adaptive adjustment of lipid metabolism un0064er conditions of the high-fat diet induced inhibition of the formation of lipoproteins (VLDL cholesterol) in the liver, compensatory synthesis of 18:1n-9, 20:5n-3, and 20:3n-6 with primary esterification of PUFA n-3 series to neutral lipids. PMID- 24628763 TI - Ultrasound imaging for neurofibromatosis: from the dermatologist's perspective. PMID- 24628764 TI - Intention to use long acting and permanent contraceptive methods and factors affecting it among married women in Adigrat town, Tigray, Northern Ethiopia. AB - BACKGROUND: Despite the increase in contraceptive use worldwide over the last decade, there is still discrepancy in the need to limit birth and utilization of modern contraceptives specifically long acting and permanent contraceptive methods in sub-Saharan Africa including Ethiopia. Intention to use long acting and permanent methods of contraception is an important indicator of the potential demand for family planning services. OBJECTIVE: To assess intention to use long acting and permanent contraceptive methods (LAPMs) and identifying associated factors among currently married women in Adigrat town. METHODS: A community based cross sectional study design complemented with a qualitative method was conducted in three selected Kebeles of Adigrat town. A total of 594 study subjects were interviewed. Systematic random sampling method was used to select study subjects. Quantitative data were analyzed using SPSS version 16. Open code software version 3.6.2.0 was used to facilitate coding of the qualitative data. Factors associated with intention were identified using logistic regression model and content analysis was done on the qualitative data. RESULTS: Intention to use LAPMs was 48.4%. Intention to use LAPMs was higher among women who knew at least one of LAPMs (AOR = 4.7, 95% CI = 1.58, 14.01) and women who do not want to have birth within the next 2 years (AOR = 1.9, 95% CI = 1.22, 3.13). Intention to use LAMPs was less among women who perceive poor support from their husbands (AOR = 0.2, 95% CI = 0.09, 0.45) and those who perceive LAPMs are harmful for the womb (AOR = 0.24, 95% CI = 0.14, 0.41). Similarly, participants in the focus group discussion have expressed their concern on the return of fertility after using implants or IUCD as well as insertion and removal procedures. CONCLUSIONS: The magnitude of intention to use LAPMs in the study area was low. The main limiting factors were fear of side effect, infertility after LAPMs use, knowledge on LAPMs and perception on partner's support of LAPMs use. To further promote the use of LAPMs addressing associated misconceptions through effective communication strategies and involving spouses in family planning programs is essential. PMID- 24628765 TI - Persistency of accuracy of genomic breeding values for different simulated pig breeding programs in developing countries. AB - Genetic improvement of pigs in tropical developing countries has focused on imported exotic populations which have been subjected to intensive selection with attendant high population-wide linkage disequilibrium (LD). Presently, indigenous pig population with limited selection and low LD are being considered for improvement. Given that the infrastructure for genetic improvement using the conventional BLUP selection methods are lacking, a genome-wide selection (GS) program was proposed for developing countries. A simulation study was conducted to evaluate the option of using 60 K SNP panel and observed amount of LD in the exotic and indigenous pig populations. Several scenarios were evaluated including different size and structure of training and validation populations, different selection methods and long-term accuracy of GS in different population/breeding structures and traits. The training set included previously selected exotic population, unselected indigenous population and their crossbreds. Traits studied included number born alive (NBA), average daily gain (ADG) and back fat thickness (BFT). The ridge regression method was used to train the prediction model. The results showed that accuracies of genomic breeding values (GBVs) in the range of 0.30 (NBA) to 0.86 (BFT) in the validation population are expected if high density marker panels are utilized. The GS method improved accuracy of breeding values better than pedigree-based approach for traits with low heritability and in young animals with no performance data. Crossbred training population performed better than purebreds when validation was in populations with similar or a different structure as in the training set. Genome-wide selection holds promise for genetic improvement of pigs in the tropics. PMID- 24628766 TI - Psychiatric illness in women requesting caesarean section. AB - OBJECTIVE: To compare psychiatric in- and outpatient care during the 5 years before first delivery in primiparae delivered by caesarean section on maternal request with all other primiparae women who had given birth during the same time period. DESIGN: Prospective, population-based register study. SETTING: Sweden. SAMPLE: Women giving birth for the first time between 2002 and 2004 (n = 64 834). METHODS: Women giving birth by caesarean section on maternal request (n = 1009) were compared with all other women giving birth (n = 63 825). The exposure of interest was any psychiatric diagnosis according to the International Statistical Classification of Diseases and Related Health Problems (ninth revision, ICD-9, 290-319; tenth revision, ICD-10, F00-F99) in The Swedish national patient register during the 5 years before first delivery. MAIN OUTCOME MEASURES: Psychiatric diagnoses and delivery data. RESULTS: The burden of psychiatric illnesses was significantly higher in women giving birth by caesarean section on maternal request (10 versus 3.5%, P < 0.001). The most common diagnoses were 'Neurotic disorders, stress-related disorders and somatoform disorders' (5.9%, aOR 3.1, 95% CI 1.1-2.9), and 'Mood disorders' (3.4%, aOR 2.4, 95% CI 1.7-3.6). The adjusted odds ratio for caesarean section on maternal request was 2.5 (95% CI 2.0-3.2) for any psychiatric disorder. Women giving birth by caesarean section on maternal request were older, used tobacco more often, had a lower educational level, higher body mass index, were more often married, unemployed, and their parents were more often born outside of Scandinavia (P < 0.05). CONCLUSIONS: Women giving birth by caesarean section on maternal request more often have a severe psychiatric disease burden. This finding points to the need for psychological support for these women as well as the need to screen and treat psychiatric illness in pregnant women. PMID- 24628767 TI - Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. AB - BACKGROUND: Dengue infection carries a potential risk of death despite stringent management of plasma leak and haemorrhage. It appears that the extent of liver dysfunction determines the outcome. METHODS: We present a postmortem study of five patients, died of dengue shock syndrome who had markedly elevated liver enzymes and irreparable circulatory failure. RESULTS: All were females with a median age of 46 years (range 20-50 years). All had positive NS1 and IgM. Clinically, one patient developed severe degree of hepatic encephalopathy whilst three patients developed uncontrollable bleeding manifestations. Dengue virus was detected in three liver specimens by reverse transcription PCR. Histology of the liver revealed massive necrosis with haemorrhages in these patients with evidence of micro and macrovesicular steatosis with significant periportal inflammatory infiltrate. No significant ischaemic changes or necrosis was observed in the other organs. CONCLUSIONS: Severe haemorrhagic necrosis of the liver was the cause of death in these patients probably due to direct viral infection. Predilection for severe liver disease remains unknown. Therefore, it is prudent to think beyond plasma leak as the main pathology of dengue infection and attempts should be made to develop other treatment modalities to prevent and manage unforeseen fatal complications of dengue infection. PMID- 24628768 TI - Attitudes of Pakistani and Pakistani heritage medical students regarding professionalism at a medical college in Karachi, Pakistan. AB - BACKGROUND: An increased interest in professionalism has been reported in the field of medical education due to concerns regarding deterioration of humanism and professional values in the teaching and practice of medicine. The primary aim of this study was to assess attitudes of Pakistani and Pakistani heritage students at a medical college in Pakistan about important elements of professionalism that an ideal medical doctor should possess. A further objective of the study was to determine students' preferred ways of learning professionalism. METHODS: A written survey was distributed to undergraduate medical students at a public sector medical college at Karachi, Pakistan in 2011. Using the Penn State College of Medicine (PSCOM) Professionalism Questionnaire, attitudes of medical students of semester 1, 5, and 8 regarding professionalism were assessed anonymously. RESULTS: The mean age of the students was 21.11 +/- 2.72 years. Forty-three percent of the respondents were male. Forty percent of the students held Pakistani citizenship. Thirty-five percent students were US citizens with Pakistani parents and twenty-five percent were Pakistani heritage students that had dual citizenships. No significant differences in the elements of professionalism (Accountability, Altruism, Duty, Excellence, Honesty & Integrity and Respect) mean scores or in the overall mean score of professionalism among the various classes were found. The total overall Cronbach alpha value for all elements of the professionalism in the selected classes was above 0.9. The most preferred methods for learning professionalism were role modeling by faculty, case based scenarios and role plays. CONCLUSION: The students rated all the attributes of professionalism as important and there was no difference across the study years. The overall internal consistency of each element of professionalism was high in different classes. Faculty role models, case based scenarios and role plays may be used to teach professionalism. As a great majority of students were having a Pakistani heritage rather than complete Pakistani born and bred background, hence findings of the survey may not be taken as representative of typical Pakistani medical students. PMID- 24628769 TI - Neonatal diagnosis of Down syndrome in The Netherlands: suspicion and communication with parents. AB - OBJECTIVES: To analyse which dysmorphic features are most recognised in newborns with Down syndrome (DS). Furthermore to evaluate the communication techniques used by clinicians to inform parents about the postnatal diagnosis and compare these to current best practice guidelines. STUDY DESIGN: Prospective study of a birth cohort of newborns with DS born between 1 January 2003 and 31 December 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU). RESULTS: A total of 586 children with trisomy 21 were analysed. Most recognised dysmorphic features in DS newborns were 'upslanted palpebral fissures' (74.1%; n = 426), 'hypotonia' (73.7%; n = 424) and 'epicanthic folds' (68.5%; n = 394). The majority of parents were informed about the suspected diagnosis on the day of birth (76.5%; n = 390). Hospital deliveries had a significantly earlier suspected diagnosis (mean age 3-4 days) compared with home deliveries (mean age 7 days) (P < 0.05). In 10% (n = 44), paediatricians described dissatisfaction with the first conversation with parents. In 88.9% (n = 499) parents were both present when the diagnosis was told, however the child was not present during the conversation in 51.3% (n = 288). In 10.8% (n = 61) parents were not informed about local parent support groups or community resources. CONCLUSION: DS is still often diagnosed after birth, usually on the first day of postnatal life. Most identified clinical features were upslanted palpebral fissures, epicanthic folds and hypotonia. Special attention for recognition of all present clinical features is needed for early diagnosis. Appropriate communication with the parents of the message that their child has DS can be difficult. Guidelines can help to make counselling easier and more effective, which in turn may increase parental satisfaction. Not all recommendations for the first conversation with parents were fully implemented in Dutch clinical practice. PMID- 24628770 TI - It's not about sex. PMID- 24628772 TI - Development and validation of a clinical decision-making aid for screening bowel symptoms in community pharmacies. AB - RATIONALE, AIMS AND OBJECTIVES: Bowel symptoms are common, and community pharmacies are an ideal setting for health advice about these symptoms. The aim of this study was to develop and validate a questionnaire for use with adults presenting to community pharmacies with lower bowel symptoms. The purpose of the questionnaire was to stratify people into those requiring medical follow-up for symptoms and those with self-limiting symptoms. METHOD: A self-administered questionnaire, named the Jodi Lee test (JLT), was developed in three stages - review of the literature, questionnaire design and statistical validation - against a validated screening tool, the patient consultation questionnaire (PCQ), to assess the sensitivity and specificity of JLT. The questionnaire was developed to be simple, easy for all pharmacy staff to use and require no score calculation. Its application was designed to facilitate referral from pharmacy assistants to pharmacists and from pharmacists to medical practitioners. RESULTS: The questionnaire comprises eight questions. It has a Flesh-Kincaid reading score of 79.5. By considering different score thresholds on the PCQ, a receiver operator characteristic (ROC) curve was calculated to assess the effectiveness of the JLT. From a sample of 118 subjects, the area under the ROC curve was 0.94. At a threshold score of 30 on the PCQ, the sensitivity was 100%. The specificity was 65%. CONCLUSION: The JLT has high sensitivity for identifying patients with symptoms of serious bowel disease. It is also likely to identify patients who have symptoms of relatively benign disease who would benefit from medical advice. PMID- 24628771 TI - Extracellular environment modulates the formation and propagation of particular amyloid structures. AB - Amyloidogenic proteins, including prions, assemble into multiple forms of structurally distinct fibres. The [PSI(+)] prion, endogenous to the yeast Saccharomyces cerevisiae, is a dominantly inherited, epigenetic modifier of phenotypes. [PSI(+)] formation relies on the coexistence of another prion, [RNQ(+)]. Here, in order to better define the role of amyloid diversity on cellular phenotypes, we investigated how physiological and environmental changes impact the generation and propagation of diverse protein conformations from a single polypeptide. Utilizing the yeast model system, we defined extracellular factors that influence the formation of a spectrum of alternative self propagating amyloid structures of the Sup35 protein, called [PSI(+)] variants. Strikingly, exposure to specific stressful environments dramatically altered the variants of [PSI(+)] that formed de novo. Additionally, we found that stress also influenced the association between the [PSI(+)] and [RNQ(+)] prions in a way that it superceded their typical relationship. Furthermore, changing the growth environment modified both the biochemical properties and [PSI(+)]-inducing capabilities of the [RNQ(+)] template. These data suggest that the cellular environment contributes to both the generation and the selective propagation of specific amyloid structures, providing insight into a key feature that impacts phenotypic diversity in yeast and the cross-species transmission barriers characteristic of prion diseases. PMID- 24628773 TI - Spurious white blood cell count from a new automated Sysmex XN hematology analyzer. PMID- 24628775 TI - A laboratory-based study on patients with Parkinson's disease and seborrheic dermatitis: the presence and density of Malassezia yeasts, their different species and enzymes production. AB - BACKGROUND: Seborrheic dermatitis (SD) and Parkinson's disease (PD) are frequently associated conditions. Aims of this study were: to determine severity of SD, presence of different species and density of Malassezia yeasts; to assess yeast lipases and phosphatases production in vitro and to compare these results between SD patients with and without PD. METHODS: This case-control prospective study was conducted at the Dermatology and Neurology Units, Clinical Centre of Serbia and at the National Medical Mycology Reference Laboratory, University of Belgrade Medical School, Serbia. A total of 90 patients and 70 healthy controls (HC) were investigated: 60 patients with SD (SDN) and 30 patients with SD and PD (SDP). Culture-based mycological examination was carried out on lesional skin (LS) and non-lesional skin (NLS). A yeasts density was determined by counting the Malassezia colony forming units per tape (CFU/tape). Enzymes production by isolated Malassezia was investigated. RESULTS: The most patients with SD were male (76.7%; SDP and 63.3%; SDN) and the intensity of SD was dominantly severe or moderate (76.7%; SDP and 75%; SDN). The presence of Malassezia was high on LS in both groups (87.3%; SDP and 86.7%; SDN) (p=0.667).The highest yeasts density (mean CFU/tape=67.8) was detected on LS in 53% of SDP group and in 21.7% of SDN group (mean CFU/tape=31.9) (p < 0.01). The presence of negative cultures was lower in SDP group (13.3%) in comparison to HC and SDN groups (37% and 31.7%, respectively). Malassezia density on NLS in SDP group (mean CFU/tape=44.3) was significantly higher in comparison to SDN and HC (p=0.018). M. globosa was the most abundant species identified amongst isolates from the SDP group (42.3%) and exhibited high production of phosphatase and lipase in vitro. CONCLUSION: From this laboratory-based study a positive correlation between SD, PD, M. globosa incidence, high yeast density and high phosphatase and lipase activity was established. Our data lead to conclusion that local skin performance of PD patient's characterized with increased sebum excretion ratio play a role in SD by stimulation of yeasts replication and enzyme production. PMID- 24628774 TI - Cognitive performance profiles by latent classes of drug use. AB - BACKGROUND AND OBJECTIVES: The relationship between substance use and cognitive deficits is complex and requires innovative methods to enhance understanding. The present study is the first to use LCA to examine associations of drug use patterns with cognitive performance. METHODS: Cocaine/heroin users (N = 552) completed questionnaires, and cognitive measures. LCA identified classes based on past-month drug use and adjusted for probabilities of group membership when examining cognitive performance. Latent indicators were: alcohol (ALC), cigarettes (CIG), marijuana (MJ), crack smoking (CS), nasal heroin (NH), injection cocaine (IC), injection heroin (IH), and injection speedball (IS). Age and education were included as covariates in model creation. RESULTS: Bootstrap likelihood ratio test (BLRT) supported a 5-class model. Prevalent indicators (estimated probability of over 50%) for each class are as follows: "Older Nasal Heroin/Crack Smokers" (ONH/CS, n = 166.9): ALC, CIG, NH, CS; "Older, Less Educated Polysubstance" (OLEP, n = 54.8): ALC, CIG, CS, IH, IC, and IS; "Younger Multi-Injectors" (MI, n = 128.7): ALC, CIG, MJ, IH, IC, and IS; "Less Educated Heroin Injectors" (LEHI, n = 87.4): CIG, IH; and "More Educated Nasal Heroin" users (MENH, n = ALC, CIG, NH. In general, all classes performed worse than established norms and older, less educated classes performed worse, with the exception that MENH demonstrated worse cognitive flexibility than YMI. DISCUSSION AND CONCLUSIONS: This study demonstrated novel applications of a methodology for examining complicated relationships between polysubstance use and cognitive performance. SCIENTIFIC SIGNIFICANCE: Education and/or nasal heroin use are associated with reduced cognitive flexibility in this sample of inner city drug users. PMID- 24628776 TI - Abnormally altered patterns of whole brain functional connectivity network of posterior cingulate cortex in remitted geriatric depression: a longitudinal study. AB - AIMS: A longitudinal study investigated the remitted geriatric depression (RGD) patients' persistent cognitive impairment and potential correlation with their PCC functional connectivity network. METHODS: A total of 14 RGD patients and 18 matched controls were recruited. All subjects finished the neuropsychological tests and functional magnetic resonance imaging scan at baseline and follow-up. A spherical region of interest was placed in PCC to calculate the functional connectivity, and further analysis was employed to detect correlations between longitudinal changes in the brain regions and neuropsychological data. RESULTS: There were significant cognitive declines in RGD patients at baseline and follow up. Altered patterns of functional connectivity were detected within the RGD group showing correlations with neuropsychological tests. The longitudinal change in functional connectivity between PCC and cerebellum posterior lobe was correlated with longitudinal changes in auditory verbal memory test-recall (r=0.550, P=0.042). The longitudinal change in functional connectivity between PCC and right parahippocampal gyrus was correlated with Trail Making Test-A (r=0.631, P=0.015). The longitudinal change in functional connectivity between PCC and supramarginal_R was correlated with Mini-Mental State Examination (r= 0.630, P=0.016). CONCLUSIONS: RGD patients performed worse cognitive function, and altered PCC functional connectivity network might have a role in these cognitive declines. PMID- 24628777 TI - Recurrence of drug-induced reactions in DRESS patients. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) may relapse following introduction of drugs structurally unrelated to the initial culprit drug. OBJECTIVE: To assess the frequency and characteristics of recurrent drug eruptions in patients with history of DRESS. METHODS: Patients who had developed adverse cutaneous reaction after DRESS occurrence were recruited from the regional database of Upper Normandy in France. Rate of recurrences were compared with patients with Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson syndrome (SJS) patients during the same time frame. RESULTS: Of the 60 cases of DRESS collected, 15 (25%) with recurrences were retained for analysis. Seven patients had a single recurrence, whereas eight patients had several relapses. In the patients with pre-existing DRESS, recurrences were incomplete, corresponding to cutaneous rash in 13 cases and associated with eosinophilia in seven cases. Internal organ involvement was observed in two cases. In contrast, a single recurrence was found out of 61 patients with TEN/SJS. CONCLUSION: Incomplete recurrences with structurally unrelated culprit drugs are a frequent phenomenon in DRESS patients. PMID- 24628778 TI - Characterization of the arginine decarboxylase gene (ORF HP0422, speA) involved in acid tolerance in Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori is a motile microaerophilic bacterium that colonizes the human stomach. H. pylori infection triggers gastric diseases, such as gastritis, peptic ulcer and gastric cancer. Stomach represents a barrier for microorganism colonization, particularly because of its high hydrochloric acid concentration. The main mechanism developed by H. pylori to maintain intracellular pH homeostasis in this environment is the urease activity. However, urease negative strains can be also isolated from clinical samples, suggesting that H. pylori presents other components involved in acid resistance. OBJECTIVE: Here, we present some evidence that the arginine decarboxylase gene (speA) in H. pylori could be involved in an acid adaptation mechanism similar to the one in Enterobacteriaceae, which is dependent on the presence of arginine. METHODS: Indeed, speA mRNA and protein expression are acutely induced by acid stress. RESULTS: Moreover, we showed that H. pylori uses arginine in an acid response mechanism required for its growth in acid conditions. CONCLUSION: Altogether, these results provide novel information regarding the H. pylori physiology and acid response mechanism. PMID- 24628779 TI - Coronary artery occlusions diagnosed by transthoracic Doppler. AB - BACKGROUND: Our aim was to assess whether anterograde flow velocities in septal perforating branches could identify an occluded contralateral coronary artery, and to assess the feasibility and accuracy of diagnosing occlusions in the three main coronary arteries by the combined use of several noninvasive parameters indicating collateral flow. METHODS: A total of 108 patients scheduled for coronary angiography because of chest pain or acute coronary syndromes were studied using transthoracic Doppler echocardiography. RESULTS: Anterograde peak diastolic flow velocities (pDV) in septal perforating branches were higher in patients with angiographic occluded contralateral artery compared with corresponding velocities in patients without significant disease in the contralateral artery (0.80 +/- 0.31 m/sec versus 0.37 +/- 0.13 m/sec, p < 0.001). Receiver operating characteristic curve showed pDV >= 0.57 m/sec to be the optimal cutoff value to identify occluded contralateral artery, with a sensitivity of 79% and a specificity of 69%. Demonstration of at least one positive parameter (retrograde flow in main coronary arteries, reversed flow in septal perforating and left circumflex marginal branches, pDV >= 0.57 m/sec, or demonstration of other epicardial or intramyocardial collaterals) indicating collateral flow to an occluded main coronary artery had sensitivity, specificity, positive and negative predictive value of 89%, 94%, 63%, and 99%, respectively, for detection of a coronary occlusion. With this combined use of several parameters, 25 of 28 coronary occlusions were identified. CONCLUSIONS: By investigating several parameters indicating collateral flow, we were able to identify most of the main coronary occlusions in the patient cohort. Furthermore, our study demonstrated that coronary artery occlusions may result in complex and diverging coronary pathophysiology depending on which coronary artery segment is occluded and the extent of accompanying coronary artery disease. TRIAL REGISTRATION: ClinicalTrials.gov number NTC00281346. PMID- 24628780 TI - Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells. AB - BACKGROUND: The serine-threonine kinase AKT1 plays essential roles during normal mammary gland development as well as the initiation and progression of breast cancer. AKT1 is generally considered a ubiquitously expressed gene, and its persistent activation is transcriptionally controlled by regulatory elements characteristic of housekeeping gene promoters. We recently identified a novel Akt1 transcript in mice (Akt1m), which is induced by growth factors and their signal transducers of transcription from a previously unknown promoter. The purpose of this study was to examine whether normal and neoplastic human breast epithelial cells express an orthologous AKT1m transcript and whether its expression is deregulated in cancer cells. METHODS: Initial sequence analyses were performed using the UCSC Genome Browser and GenBank to assess the potential occurrence of an AKT1m transcript variant in human cells and to identify conserved promoter sequences that are orthologous to the murine Akt1m. Quantitative RT-PCR was used to determine the transcriptional activation of AKT1m in mouse mammary tumors as well as 41 normal and neoplastic human breast epithelial cell lines and selected primary breast cancers. RESULTS: We identified four new AKT1 transcript variants in human breast cancer cells that are orthologous to the murine Akt1m and that encode the full-length kinase. These transcripts originate from an alternative promoter that is conserved between humans and mice. Akt1m is upregulated in the majority of luminal-type and basal type mammary cancers in four different genetically engineered mouse models. Similarly, a subset of human breast cancer cell lines and primary breast cancers exhibited a higher expression of orthologous AKT1m transcripts. CONCLUSIONS: The existence of an alternative promoter that drives the expression of the unique AKT1m transcript may provide a mechanism by which the levels of AKT1 can be temporally and spatially regulated at particular physiological states, such as cancer, where a heightened activity of this kinase is required. PMID- 24628781 TI - The effect of statins on erectile dysfunction: a systematic review and meta analysis. AB - INTRODUCTION: It is not known if statins will improve symptoms in patients with established erectile dysfunction (ED). AIM: We carried out a systematic review and meta-analysis to assess the effect of statins on ED. METHODS: A literature review was performed to identify all published randomized double-blind, placebo controlled trials of statins for the treatment of ED. The search included the following databases: MEDLINE, Embase, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. A systematic review and meta-analysis were conducted. MAIN OUTCOME MEASURES: Six publications involving a total of 462 patients were used in the analysis, including three randomized controlled trials (RCTs) that compared statins with placebo and three RCTs that compared statins plus sildenafil with placebo plus sildenafil. RESULTS: For the comparison of statins (+/- sildenafil) with placebo (+/- sildenafil), the mean International Index of Erectile Function (IIEF-5) (the standardized mean difference [SMD] = 3.23, 95% confidence interval [CI] = -1.65 to 4.80, P < 0.0001) indicated that statins (+/- sildenafil) showed statistically significantly greater improvements in the mean IIEF-5 compared with placebo (+/- sildenafil). For the comparison of statins with placebo, the mean IIEF-5 (SMD = 2.13, 95% CI = -1.46 to 5.73, P = 0.24) indicated that there was no significant difference in erectile function between the statins and placebo. For the comparison of statins plus sildenafil with placebo plus sildenafil, the mean IIEF 5 (SMD = 3.60, 95% CI = 2.64 to 4.56, P < 0.00001), the IIEF domain (SMD = 4.88, 95%CI = 3.01 to 6.74, P < 0.00001), and the global efficacy question (odds ratio = 6.44, 95% CI = 2.92 to 14.23, P < 0.00001) showed that compared with placebo plus sildenafil, statins plus sildenafil clearly improved erectile function. CONCLUSIONS: This meta-analysis indicates that statins (+/- sildenafil) may improve ED compared with placebo (+/- sildenafil). PMID- 24628782 TI - Role of physical activity in bone health in peripubertal boys. AB - BACKGROUND: The aim of the present cross-sectional study was to investigate the relationship of physical activity level to bone mineral parameters in 11-13-year old boys. METHODS: In total, 264 boys, divided into normal weight (n = 154) and overweight (n = 110), participated in this study. Physical activity was measured via 7 day accelerometry and bone mineral parameters using dual-energy X-ray absorptiometry. RESULTS: In overweight boys, vigorous physical activity was associated with total bone mineral density (BMD), total bone mineral content (BMC), while moderate-vigorous physical activity MVPA was associated with femoral neck BMD. In normal weight boys, however, only vigorous physical activity was associated with femoral neck BMD. When the normal weight group was divided into tertiles according to MVPA, femoral neck BMD was higher in the highest tertile compared to the lowest tertile. No other significant differences were found in bone mineral parameters according to the tertiles of MVPA. CONCLUSIONS: In overweight peripubertal boys, physical activity is more associated with bone mineral parameters compared to normal weight subjects. In addition to vigorous physical activity, moderate physical activity has a significant impact on bone mineral parameters in overweight subjects. PMID- 24628783 TI - Can bioinformed design promote healthy indoor ecosystems? PMID- 24628784 TI - Fungi in homes--how do we measure? PMID- 24628785 TI - Response to Rylander. PMID- 24628786 TI - Adipocyte dysfunction in rats with streptozotocin-nicotinamide-induced diabetes. AB - Administration of streptozotocin (STZ) and nicotinamide (NA) to adult rats allows for the induction of mild diabetes. However, this experimental model has not been fully characterized. This study was undertaken to determine the metabolic and secretory activity of adipose tissue in rats with STZ-NA-induced diabetes. Experiments were performed using epididymal adipocytes isolated from control and mildly diabetic rats. Lipogenesis, glucose transport as well as glucose and alanine oxidation, lipolysis, anti-lipolysis, cAMP levels and adipokine secretion were compared in cells isolated from the control and diabetic rats. Lipogenesis, glucose transport and oxidation were diminished in the adipocytes of diabetic rats compared with the fat cells of control animals. However, alanine oxidation appeared to be similar in the cells of non-diabetic and diabetic animals. Lipolytic response to low epinephrine concentrations was slightly increased in the adipocytes of diabetic rats; however, at higher concentrations of the hormone, lipolysis was similar in both groups of cells. The epinephrine-induced rise in cAMP levels was higher in the adipocytes of STZ-NA-induced diabetic rats, even in the presence of insulin. Lipolysis stimulated by dibutyryl-cAMP did not significantly differ, whereas anti-lipolytic effects of insulin were mildly decreased in the cells of diabetic rats. Secretion of adiponectin and leptin was substantially diminished in the adipocytes of diabetic rats compared with the cells of control animals. Our studies demonstrated that the balance between lipogenesis and lipolysis in the adipose tissue of rats with mild diabetes induced by STZ and NA is slightly shifted towards reduced lipid accumulation. Simultaneously, adiponectin and leptin secretion is significantly impaired. PMID- 24628787 TI - CX3CR1 RNAi inhibits hypoxia-induced microglia activation via p38MAPK/PKC pathway. AB - There is accumulating evidence which demonstrates that chronic cerebral ischaemia can induce white matter lesions (WMLs), and microglia-activation-mediated cytokines and proteases releasing during the ischaemia might play a vital role in pathogenesis. In addition, hypoxia-induced upregulated expression of fractalkine promotes the activation of microglia and their migration to the lesions through interaction with its receptor CX3CR1. However, the specific mechanisms involved in fractalkine/CX3CR1-mediated microglial activation have not been fully identified. In the present study, we constructed lentivirus encoding shRNA against CX3CR1 and transduced into microglial cells in under hypoxic conditions. Moreover, we analysed the proliferation, cytokine secretion and signal-pathway activation of the microglia. We found that CX3CR1 RNAi-mediated gene downregulation could attenuate hypoxic-induced microglial proliferation, cytokine secretion [including tumuor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta)] and matrix metalloproteinase-2 (MMP-2) synthesis. These effects were shown to be nediated through p38MAPK/PKC activation. Therefore, our results reveal a novel mechanism of fractalkine/CX3CR1 involvement in activation of microglia. Thus CX3CR1 RNAi might provide a therapeutic strategy which could be useful in chronic cerebral ischaemia. PMID- 24628788 TI - Acute enteritis associated with Coxsackievirus A19 in a kidney transplant patient. AB - Diarrhea is a frequent complication after kidney transplantation, with an incidence rate between 22% and 51%. In many cases, the cause remains unknown. We describe here the first case, to our knowledge, of persistent diarrhea associated with Coxsackievirus A19 (CVA19) in a kidney transplant recipient. The patient was a 46-year-old man who received a deceased-donor kidney. He experienced delayed graft function because of donor kidney donation after circulatory determination of death. Maintenance immunosuppression consisted of low-dose cyclosporine, high dose mycophenolate mofetil (MMF) (3 g/day), and prednisone (10 mg/day). He had severe diarrhea for 2 weeks associated with acute renal failure. No pathogens were found in the stool cultures. Enterovirus detection was positive by real-time polymerase chain reaction, and sequence analysis found CVA19 (from Enterovirus C group). Area under the curve of MMF was 48 mg.h/L. Because of the persistence of diarrhea, MMF was stopped and replaced by azathioprine. The diarrhea disappeared, but serum creatinine did not return to baseline. CVA19 rarely causes gastroenteritis. This case illustrates that MMF is not always the direct cause of diarrhea, and that new clinical infectious diseases will be detected with the expansion of molecular-based DNA diagnostics. PMID- 24628789 TI - Long-term booster schedules with AS03A-adjuvanted heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults. AB - BACKGROUND: The pandemic potential of avian influenza A/H5N1 should not be overlooked, and the continued development of vaccines against these highly pathogenic viruses is a public health priority. METHODS: This open-label extension booster study followed a Phase III study of 1206 adults who had received two 3.75 MUg doses of primary AS03A-adjuvanted or non-adjuvanted H5N1 split-virus vaccine (A/Vietnam/1194/2004; clade 1) (NCT00449670). The aim of the extension study was to evaluate different timings for heterologous AS03A adjuvanted booster vaccination (A/Indonesia/5/2005; clade 2.1) given at Month 6, 12, or 36 post-primary vaccination. Immunogenicity was assessed 21 days after each booster vaccination and the persistence of immune responses against the primary vaccine strain (A/Vietnam) and the booster strain (A/Indonesia) was evaluated up to Month 48 post-primary vaccination. Reactogenicity and safety were also assessed. RESULTS: After booster vaccination given at Month 6, HI antibody responses to primary vaccine, and booster vaccine strains were markedly higher with one dose of AS03A-H5N1 booster vaccine in the AS03A-adjuvanted primary vaccine group compared with two doses of booster vaccine in the non-adjuvanted primary vaccine group. HI antibody responses were robust against the primary and booster vaccine strains 21 days after boosting at Month 12 or 36. At Month 48, in subjects boosted at Month 6, 12, or 36, HI antibody titers of >=1:40 against the booster strain persisted in 39.2%, 61.2%, and 95.6% of subjects, respectively. Neutralizing antibody responses and cell-mediated immune responses also showed that AS03A-H5N1 heterologous booster vaccination elicited robust immune responses within 21 days of boosting at Month 6, 12, or 36 post-primary vaccination. The booster vaccine was well tolerated, and no safety concerns were raised. CONCLUSIONS: In Asian adults primed with two doses of AS03A-adjuvanted H5N1 pandemic influenza vaccine, strong cross-clade anamnestic antibody responses were observed after one dose of AS03A-H5N1 heterologous booster vaccine given at Month 6, 12, or 36 after priming, suggesting that AS03A-adjuvanted H5N1 vaccines may provide highly flexible prime-boost schedules. Although immunogenicity decreased with time, vaccinated populations could potentially be protected for up to three years after vaccination, which is likely to far exceed the peak of the a pandemic. PMID- 24628790 TI - Implementing newer agents for the management of castrate-resistant prostate cancer: what is known and what is needed? AB - Men receiving androgen-deprivation therapy will in time develop metastatic castrate-resistant prostate cancer (mCRPC). Whilst effective treatment options for mCRPC have traditionally been limited, new agents are becoming available. Since 2010, the number and class of agents available to treat mCRPC has increased dramatically. As such, there is a need for clear guidance on the optimum treatment and sequence of treatments for mCRPC before and after chemotherapy. This evidence-based statement, reflecting the views of the authors, provides suggestions on the continued relevance of conventional approaches to first- and second-line treatment in mCRPC, the potential role of novel treatments, and factors that may influence the choice of hormonal agents and/or chemotherapy. PMID- 24628791 TI - Genetic heterogeneity of hepatitis C virus cell entry receptors seems to have no influence on selection of virus variants. AB - BACKGROUND: No information is available on the possible influence of the genetic heterogeneity of major hepatitis C virus (HCV) cell receptors on selection of virus variants. FINDINGS: Anti-D globulin preparations contaminated with the HCV strain AD78 caused hepatitis C infection in more than 3000 women in East Germany in 1978. Analysis of the core to NS2 gene sequences of this strain in several globulin batches revealed the presence of three closely related but distinct virus variants of the same strain. Apparently even distribution of these three virus variants was observed in 91 patients infected with the AD78 strain. None of these patients was infected with more than one virus variant, suggesting a selection mechanism of a particular virus variant in each patient. To verify the hypothesis that heterogeneity of HCV cell receptors might influence the virus variant selection, single-nucleotide polymorphisms (SNPs) in low-density lipoprotein receptor (LDLR), occludin (OCLN), and scavenger receptor B1 (SCARB1) genes in AD patients were analyzed. No evident correlation between receptor polymorphisms and presence of a particular virus variant was noted. CONCLUSION: SNPs of HCV cell entry receptors have no influence on virus selection in patients infected with an inoculum containing different virus variants. PMID- 24628793 TI - Bioethics and forensic psychiatry. PMID- 24628792 TI - Proper functioning of the GINS complex is important for the fidelity of DNA replication in yeast. AB - The role of replicative DNA polymerases in ensuring genome stability is intensively studied, but the role of other components of the replisome is still not fully understood. One of such component is the GINS complex (comprising the Psf1, Psf2, Psf3 and Sld5 subunits), which participates in both initiation and elongation of DNA replication. Until now, the understanding of the physiological role of GINS mostly originated from biochemical studies. In this article, we present genetic evidence for an essential role of GINS in the maintenance of replication fidelity in Saccharomyces cerevisiae. In our studies we employed the psf1-1 allele (Takayama et al., 2003) and a novel psf1-100 allele isolated in our laboratory. Analysis of the levels and specificity of mutations in the psf1 strains indicates that the destabilization of the GINS complex or its impaired interaction with DNA polymerase epsilon increases the level of spontaneous mutagenesis and the participation of the error-prone DNA polymerase zeta. Additionally, a synergistic mutator effect was found for the defects in Psf1p and in the proofreading activity of Pol epsilon, suggesting that proper functioning of GINS is crucial for facilitating error-free processing of terminal mismatches created by Pol epsilon. PMID- 24628794 TI - Sex-dependent genetic effects on immune responses to a parasitic nematode. AB - BACKGROUND: Many disease aetiologies have sex specific effects, which have important implications for disease management. It is now becoming increasingly evident that such effects are the result of the differential expression of autosomal genes rather than sex-specific genes. Such sex-specific variation in the response to Trichuris muris, a murine parasitic nematode infection and model for the human parasitic nematode T. trichiura, has been well documented, however, the underlying genetic causes of these differences have been largely neglected. We used the BXD mouse set of recombinant inbred strains to identify sex-specific loci that contribute to immune phenotypes in T. muris infection. RESULTS: Response phenotypes to T. muris infection were found to be highly variable between different lines of BXD mice. A significant QTL on chromosome 5 (TM5) associated with IFN-gamma production was found in male mice but not in female mice. This QTL was in the same location as a suggestive QTL for TNF-alpha and IL 6 production in male mice suggesting a common control of these pro-inflammatory cytokines. A second QTL was identified on chromosome 4 (TM4) affecting worm burden in both male and female cohorts. We have identified several genes as potential candidates for modifying responses to T. muris infection. CONCLUSIONS: We have used the largest mammalian genetic model system, the BXD mouse population, to identify candidate genes with sex-specific effects in immune responses to T. muris infection. Some of these genes may be differentially expressed in male and female mice leading to the difference in immune response between the sexes reported in previous studies. Our study further highlights the importance of considering sex as an important factor in investigations of immune response at the genome-wide level, in particular the bias that can be introduced when generalizing results obtained from only one sex or a mixed sex population. Rather, analyses of interaction effects between sex and genotype should be part of future studies. PMID- 24628795 TI - ATP directed agent, 8-chloro-adenosine, induces AMP activated protein kinase activity, leading to autophagic cell death in breast cancer cells. AB - BACKGROUND: 8-chloro-adenosine (8-Cl-Ado) is a unique ribonucleoside analog which is currently in a phase I clinical trial for hematological malignancies. Previously, we demonstrated in breast cancer cells that a 3-day treatment with 10 MUM 8-Cl-Ado causes a 90% loss of clonogenic survival. In contrast, there was only a modest induction of apoptosis under these conditions, suggesting an alternative mechanism for the tumoricidal activity of 8-Cl-Ado. METHODS: Cellular metabolism, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway signaling, as well as autophagy induction was evaluated in breast cancer cell lines treated with 8-Cl-Ado. The effects of knocking down essential autophagy factors with small interfering RNA on 8-Cl-Ado-inhibited cell survival was assessed in breast cancer cells by examining apoptosis induction and clonogenic survival. In vivo efficacy of 8-Cl-Ado was measured in two breast cancer orthotopic model systems. RESULTS: We demonstrate that in breast cancer cell lines, the metabolism of 8-Cl-Ado results in depletion of endogenous ATP that subsequently induces the phosphorylation and activation of the energy sensor, AMPK. This was associated with an attenuation of mTOR signaling and an induction of the phosphorylation of the autophagy factor, Unc51-like kinase 1 on Ser555. 8-Cl-Ado-mediated induction of autophagy was evident by increased aggregates of microtubule-associated protein 1 light chain 3B (LC3B) which was associated with its conversion to its lipidated form, LC3B-II, p62 degradative flux, and increased formation of acidic vesicular organelles. Additionally, transfection of MCF-7 cells with siRNA to ATG7 or beclin 1 provided partial protection of the cells to 8-Cl-Ado cytotoxicity as measured by clonogenicity. In vivo, 8-Cl-Ado inhibited growth of both MCF-7 and BT-474 xenograft tumors. Moreover, in 9 of 22 BT-474 tumors treated with 100 mg/kg/day 3 times a week, there was an absence of macroscopically detectable tumor after 3 weeks of treatment. CONCLUSIONS: Our data demonstrates that 8-Cl-Ado treatment activates the AMPK pathway leading to autophagy induction of in breast cancer cells, eliciting, in part, its tumoricidal effects. Additionally, 8-Cl-Ado effectively inhibited in vivo tumor growth in mice. Based on this biological activity, we are planning to test 8-Cl-Ado in the clinic for patients with breast cancer. PMID- 24628796 TI - Genome-wide association study for egg production and quality in layer chickens. AB - Discovery of genes with large effects on economically important traits has for many years been of interest to breeders. The development of SNP panels which cover the whole genome with high density and, more importantly, that can be genotyped on large numbers of individuals at relatively low cost, has opened new opportunities for genome-wide association studies (GWAS). The objective of this study was to find genomic regions associated with egg production and quality traits in layers using analysis methods developed for the purpose of whole genome prediction. Genotypes on over 4500 birds and phenotypes on over 13,000 hens from eight generations of a brown egg layer line were used. Birds were genotyped with a custom 42K Illumina SNP chip. Recorded traits included two egg production and 11 egg quality traits (puncture score, albumen height, yolk weight and shell colour) at early and late stages of production, as well as body weight and age at first egg. Egg weight was previously analysed by Wolc et al. (2012). The Bayesian whole genome prediction model--BayesB (Meuwissen et al. 2001) was used to locate 1 Mb regions that were most strongly associated with each trait. The posterior probability of a 1 Mb window contributing to genetic variation was used as the criterion for suggesting the presence of a quantitative trait locus (QTL) in that window. Depending upon the trait, from 1 to 7 significant (posterior probability >0.9) 1 Mb regions were found. The largest QTL, a region explaining 32% of genetic variance, was found on chr4 at 78 Mb for body weight but had pleiotropic effects on other traits. For the other traits, the largest effects were much smaller, explaining <7% of genetic variance, with regions on chromosomes 2, 12 and 17 explaining above 5% of genetic variance for albumen height, shell colour and egg production, respectively. In total, 45 of 1043 1 Mb windows were estimated to have a non-zero effect with posterior probability > 0.9 for one or more traits. PMID- 24628797 TI - Cross-sectional and prospective relation of cannabis potency, dosing and smoking behaviour with cannabis dependence: an ecological study. AB - BACKGROUND AND AIMS: Increased delta-9-tetrahydrocannabinol (THC) concentrations in cannabis may lead to higher THC exposure, cannabis dependence and treatment need, but users may also adapt the actual intake of THC through reduced inhalation of THC containing smoke (titration). We investigated whether consumers of stronger cannabis use less cannabis per joint or inhale less smoke than those using less potent cannabis and whether these factors predict cannabis dependence severity. METHODS: Heavy cannabis users (n = 98) brought their own cannabis, rolled a joint and smoked it ad libitum in a naturalistic setting. We analysed the content of the joint, its association with smoking behaviour and the cross sectional and prospective (1.5-year follow-up) relations between smoking behaviour and cannabis dependence severity (total number of DSM-IV dependence symptoms). RESULTS: THC concentration in cannabis (range 1.10-24.70%) was correlated positively with cannabis dose per joint (b = 0.008, P = 0.01), but the resulting THC concentration per joint (range 0.24-15.72%) was associated negatively with inhalation volume (b = -0.05, P = 0.03). Smoking behaviour measures (number of puffs, inhaled volume, reduction of puff volume and puff duration while smoking) predicted follow-up dependence severity, independently of baseline dependence severity and monthly THC dose (number of joints * cannabis dose * cannabis THC concentration). Monthly THC dose only predicted follow-up dependence severity when unadjusted for baseline severity. CONCLUSIONS: Cannabis users titrate their delta-9-tetrahydrocannabinol intake by inhaling lower volumes of smoke when smoking strong joints, but this does not fully compensate for the higher cannabis doses per joint when using strong cannabis. Thus, users of more potent cannabis are generally exposed to more delta-9-tetrahydrocannabinol. Smoking behaviour appears to be a stronger predictor for cannabis dependence severity than monthly delta-9-tetrahydrocannabinol dose. PMID- 24628798 TI - Polyphenols from olive mill waste affect biofilm formation and motility in Escherichia coli K-12. AB - Olive mill wastes are sources of phenolic compounds with a wide array of biological activities, including antimicrobial effects. A potential option for bioremediation to overcome ecological problems is the reutilization of these natural compounds in food production. The aim of this work was to gain a better understanding of the antimicrobial mode of action of a phenols extract from olive vegetation water (PEOVW) at molecular level by studying Escherichia coli as a model microorganism. Genome-wide transcriptional analysis was performed on E. coli K-12 exposed to PEOVW. The repression of genes for flagellar synthesis and the involvement of genes linked to biofilm formation and stress response were observed. Sub-inhibitory concentrations of PEOVW significantly decreased biofilm formation, swarming and swimming motility, thus confirming the gene expression data. This study provides interesting insights on the molecular action of PEOVW on E. coli K-12. Given these anti-biofilm properties and considering that biofilm formation is a serious problem for the food industry and human health, PEOVW has proved to be a high-value natural product. PMID- 24628800 TI - Papular pseudolymphoma of adults as a variant of acral pseudolymphomatous angiokeratoma of children (APACHE). PMID- 24628799 TI - A qualitative assessment of provider perspectives on smoking cessation counselling. AB - RATIONALE, AIMS AND OBJECTIVES: Few studies have examined doctors' views about counselling unmotivated smokers. This study explored doctors' perceptions of useful strategies to motivate patients to quit, how receptive they felt patients were to these strategies, and the benefits and drawbacks of discussing smoking cessation with patients. METHODS: Fourteen semi-structured qualitative interviews were conducted with doctors and resident doctors. RESULTS: Strategies reported by providers included: educating about the health risks of smoking, using 'scare tactics' to highlight the harmful effects and providing advice about how to quit. Providers believed that most patients were receptive to their strategies, but noted that they lacked feedback to know for sure. Providers saw the possibility of improving patients' health and decreasing overall health care costs as potential benefits, but cited the potential to damage rapport, competing priorities during already rushed visits and uncertainty about the effectiveness of their efforts as drawbacks that reduced their motivation to raise the issue with patients. CONCLUSIONS: Doctors believe in the potential benefits of smoking cessation counselling but predominantly report focusing on enhancing patient's risk perceptions. They did not report attempting to use the wider array of recommended and empirically supported methods to counsel their patients. Providing doctors with increased training in motivational counselling and feedback about the efficacy their efforts or supplementing doctor care with behaviour change specialists would likely increase the benefits of counselling to patients. PMID- 24628801 TI - Structural insights into Noonan/LEOPARD syndrome-related mutants of protein tyrosine phosphatase SHP2 (PTPN11). AB - BACKGROUND: The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders. RESULTS: Although multiple studies have reported the biochemical and biological consequences of NS- and LS-associated PTPN11 mutations, their structural consequences have not been analyzed fully. Here we report the crystal structures of WT SHP2 and five NS/LS-associated SHP2 mutants. These findings enable direct structural comparisons of the local conformational changes caused by each mutation. CONCLUSIONS: Our structural analysis agrees with, and provides additional mechanistic insight into, the previously reported catalytic properties of these mutants. The results of our research provide new information regarding the structure-function relationship of this medically important target, and should serve as a solid foundation for structure-based drug discovery programs. PMID- 24628802 TI - Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review. AB - BACKGROUND: Idiopathic renal hypouricemia (iRHUC) is an autosomal recessive hereditary disorder, characterized by impaired tubular uric acid transport, re absorption insufficiency and/or the acceleration of secretions. Some patients present with severe complications, such as exercise-induced acute kidney injury (EIAKI) and nephrolithiasis. CASE PRESENTATION: Herein, we report the case of a girl with severe iRHUC (serum urate 0.05 mg/dL, fractional excretion of uric acid 295.99%) associated with recurrent EIAKI, in whom the disease was caused by a homozygous mutation (g.68G > A in exon 3) in the SLC2A9 gene. Her family members (father, mother and brother) carried the same mutation but were heterozygous, without any signs of severe hypouricemia. CONCLUSIONS: Our findings indicate that iRHUC is a rare disorder but that it should also be considered in patients with EIAKI, especially in those patients who manifest with moderately elevated or normal serum concentrations of uric acid during the acute phase of AKI. Mutational screening of the SLC2A9 gene is necessary for the diagnosis of iRHUC, and homozygous mutations of the SLC2A9 alleles can cause severe hypouricemia. Careful attention should be paid to any signs of hypouricemia during the recovery phase of AKI and long-term follow-up. PMID- 24628803 TI - Early onset of Chanarin-Dorfman syndrome with severe liver involvement in a patient with a complex rearrangement of ABHD5 promoter. AB - BACKGROUND: alpha/beta-hydrolase domain-containing protein 5 (ABHD5) plays an important role in the triacylglycerols (TAG) hydrolysis. Indeed, ABHD5 is the co activator of adipose triglyceride lipase (ATGL), that catalyses the initial step of TAG hydrolysis. Mutations in ABHD5 gene are associated with the onset of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive lipid storage disorder, characterized by non-bullous congenital ichthyosiform erythroderma (NCIE), hepatomegaly and liver steatosis. CASE PRESENTATION: We describe here a 5 years-old Brazilian child who presented with NCIE at birth and diffuse micro and macro-vesicular steatosis on liver biopsy since she was 2 years old. Molecular analysis of coding sequence and putative 5' regulatory region of ABHD5 gene was performed. A homozygous novel deletion, affecting the promoter region and the exon 1, was identified, confirming the suspected diagnosis of CDS for this patient. RT-PCR analysis showed that the genomic rearrangement completely abolished the ABHD5 gene expression in the patient, while only a partial loss of expression was detected in her parents. This is the first report describing the identification of a large deletion encompassing the promoter region of ABHD5 gene. The total loss of ABHD5 expression may explain the early onset of CDS and the severe liver involvement. After molecular diagnosis, the patient started a special diet, poor in fatty acids with medium chain triglycerides (MCT), and showed hepatic and dermatologic improvement in spite of severe molecular defect. CONCLUSIONS: This case report extends the spectrum of disease-causing ABHD5 mutations in CDS providing evidence for a novel pathogenic mechanism for this rare disorder. Moreover, our preliminary data show that early diagnosis and prompt treatment of neutral lipid accumulation might be useful for CD patients. PMID- 24628804 TI - SILAC labeling coupled to shotgun proteomics analysis of membrane proteins of liver stem/hepatocyte allows to candidate the inhibition of TGF-beta pathway as causal to differentiation. AB - BACKGROUND: Despite extensive research on hepatic cells precursors and their differentiated states, much remains to be learned about the mechanism underlying the self-renewal and differentiation. RESULTS: We apply the SILAC (stable isotope labeling by amino acids in cell culture) approach to quantitatively compare the membrane proteome of the resident liver stem cells (RLSCs) and their progeny spontaneously differentiated into epithelial/hepatocyte (RLSCdH). By means of nanoLC-MALDI-TOF/TOF approach, we identified and quantified 248 membrane proteins and 57 of them were found modulated during hepatocyte differentiation. Functional clustering of differentially expressed proteins by Ingenuity Pathway Analysis revealed that the most of membrane proteins found to be modulated are involved in cell-to-cell signaling/interaction pathways. Moreover, the upstream prediction analysis of proteins involved in cell-to-cell signaling and interaction unveiled that the activation of the mesenchymal to epithelial transition (MET), by the repression of TGFB1/Slug signaling, may be causal to hepatocyte differentiation. CONCLUSIONS: Taken together, this study increases the understanding of the underlying mechanisms modulating the complex biological processes of hepatic stem cell proliferation and differentiation. PMID- 24628805 TI - Factor-associated caregiver burden in medically complex patients with special health-care needs. AB - BACKGROUND: Many medically complex patients with special health-care needs (PSHCN) receive home-based medical support, placing a major burden on their caregivers. We characterized the caregiving factors involved in PSHCN and their relationship with caregiver burden. METHODS: The PSHCN and their families were recruited from children's hospitals and rehabilitation centers. A medical information handbook was distributed to the families on enrollment, followed by a self-report questionnaire 1 year later. Data on the type of caregiving involved, family circumstances, and caregiver burden were collected. The Zarit caregiver burden scale (ZS) was used to evaluate caregiver burden. Logistic regression (proportional odds model) was used to determine associations between each variable and caregiver burden in each of two PSHCN age groups: <15 years old (younger group) and >= 15 years (older group). RESULTS: Sixty-eight PSHCN and their families were included in the analysis. The mean age of the PSHCN was 15.4 +/- 11.8 years. On multivariate analysis there was a significant positive correlation between ZS score and older siblings (odds ratio [OR], 3.65), but no significant correlation between caregiver burden and type of care involved in the younger group. In the older group, a positive correlation was observed between caregiver burden and home mechanical ventilation with tracheostomy (OR, 15.16), but a negative correlation with younger siblings (OR, 0.04). CONCLUSIONS: Family circumstances play a bigger role than type of care required in increasing caregiver burden in families of PSHCN aged less than 15 years. PMID- 24628806 TI - Commentary on 'accelerating clinical development of HIV vaccine strategies: methodological challenges and considerations in constructing an optimized multi arm phase I/II trial design'. PMID- 24628807 TI - Inordinate glucose variation poststroke is associated with poor neurological improvement in patients without history of diabetes. AB - INTRODUCTION: Glucose variation is an important risk factor for the complications of diabetes mellitus. The plasma glucose level poststroke is in continuous fluctuation. However, whether the variation influences neurological improvement remains unknown. AIMS: This observational study aimed to investigate the association of glucose variation with neurological improvement poststroke. METHODS: We consecutively enrolled 216 ischemic stroke patients with no history of diabetes mellitus within 72 h of onset, with instant blood glucose <11.1 mmol/L at admission. The glucometabolic status was evaluated by an oral glucose tolerance test 1 day after admission and 14 days after stroke, respectively. The severity of neurological deficit was assessed with the National Institute of Health Stroke Scale (NIHSS). RESULTS: Fourteen days after stroke, 31% patients were found to have impaired glucose tolerance and 30.6% were newly diagnosed diabetes mellitus by oral glucose tolerance test. A higher level of instant blood glucose at admission or fasting plasma glucose (FPG) at 1 day correlated with a less neurological improvement. The number of patients with no <20% decrease in NIHSS was significantly decreased in patient group with higher than 30% variation of either FPG or 2-h postprandial glucose. Similar correlation between glucose variation and neurological improvement was also found in 117 patients with 2-h postprandial glucose >=7.8 mmol/L at 1 day. CONCLUSIONS: Inordinate glucose variation correlated with less neurological improvement poststroke, giving the evidence that the fluctuation of glucose levels in stroke patients should be taken into consideration during glucose modulation. PMID- 24628808 TI - Androgenetic alopecia is associated with increased arterial stiffness in asymptomatic young adults. AB - BACKGROUND: Association of androgenetic alopecia (AGA) with increased incidence of hypertension, a strong risk factor for coronary artery disease, has been suggested. However, there are no data on arterial stiffness measures of asymptomatic young adults with AGA. OBJECTIVE: In this study, we aimed to investigate the association of the AGA with arterial stiffness assessed by cardio ankle vascular index (CAVI), in asymptomatic young men. METHODS: A total of 162 asymptomatic men aged between 18 and 45 years were consecutively enrolled to the study. Subjects were considered to have AGA if they have >=3 grade vertex alopecia according to Hamilton-Norwood scale. Arterial stiffness was assessed by CAVI and defined as abnormal if CAVI is >=8. RESULTS: Frequency of abnormal CAVI was higher in patients with AGA (29.3% vs. 10.0%, P = 0.003). Subjects with AGA had higher mean CAVI than subjects without AGA (7.56 +/- 0.93 vs. 7.15 +/- 0.79, P = 0.004). Binary logistic regression analysis demonstrated that presence of AGA (OR, 5.6; 95% CI, 1.7-20.0, P = 0.006), age (OR, 1.1; 95% CI, 1.0-1.2, P = 0.03) and diastolic blood pressure (OR, 1.1; 95% CI, 1.0-1.3, P = 0.005) were independently associated with abnormal CAVI. CONCLUSION: We concluded that, AGA might be an indicator of arterial stiffness in asymptomatic young adults. PMID- 24628809 TI - Phaeohyphomycosis fungal infections in solid organ transplant recipients: clinical presentation, pathology, and treatment. AB - BACKGROUND: Dematiaceous, or dark-pigmented, fungi are known to cause infections such as phaeohyphomycosis, chromoblastomycosis, and mycetoma. These fungi are becoming increasingly important opportunistic pathogens in solid organ transplant recipients (SOTR). We present a retrospective chart review of 27 SOTR who developed phaeohyphomycosis infections post transplant from 1988 to 2009. METHODS: Cases were reviewed for fungal species isolated, date and source of culture, immunosuppressive and fungal therapy used, and outcome. The majority of isolates obtained were from the skin and soft tissue, with 3 pulmonary and brain abscesses. RESULTS: The time from transplantation to onset of infection ranged from 2 months to 11 years. The species isolated were Exophiala (11), Ochroconis (3), Alternaria (2), Phoma (2), Wangiella (1), Cladosporium (1), Aureobasidium (1), Chaetomium (1), Coniothyrium (1), and non-sporulating fungi (2). An additional 4 patients had infections confirmed by pathology, but no cultures were done. Most of the affected skin lesions were surgically debrided and treated with itraconazole; 2 patients were treated with voriconazole and 2 with amphotericin D. Death from fungal disease occurred only in patients with pulmonary and brain abscesses. CONCLUSIONS: As the number of SOTR increases, so does the incidence of fungal infections in that population. Surgery, along with antifungal therapy and a reduction in immunosuppression, are the cornerstones of treatment. PMID- 24628810 TI - Hfq reduces envelope stress by controlling expression of envelope-localized proteins and protein complexes in enteropathogenic Escherichia coli. AB - Gram-negative bacteria possess several envelope stress responses that detect and respond to damage to this critical cellular compartment. The sigma(E) envelope stress response senses the misfolding of outer membrane proteins (OMPs), while the Cpx two-component system is believed to detect the misfolding of periplasmic and inner membrane proteins. Recent studies in several Gram-negative organisms found that deletion of hfq, encoding a small RNA chaperone protein, activates the sigma(E) envelope stress response. In this study, we assessed the effects of deleting hfq upon activity of the sigma(E) and Cpx responses in non-pathogenic and enteropathogenic (EPEC) strains of Escherichia coli. We found that the sigma(E) response was activated in Deltahfq mutants of all E. coli strains tested, resulting from the misregulation of OMPs. The Cpx response was activated by loss of hfq in EPEC, but not in E. coli K-12. Cpx pathway activation resulted in part from overexpression of the bundle-forming pilus (BFP) in EPEC Deltahfq. We found that Hfq repressed expression of the BFP via PerA, a master regulator of virulence in EPEC. This study shows that Hfq has a more extensive role in regulating the expression of envelope proteins and horizontally acquired virulence genes in E. coli than previously recognized. PMID- 24628812 TI - International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer: comment. PMID- 24628811 TI - Parental history of substance use disorders (SUD) and SUD in offspring: a controlled family study of bipolar disorder. AB - BACKGROUND AND OBJECTIVES: Adolescents with bipolar disorder (BPD) have been previously shown to be at very high risk for substance use disorders (SUD). We now examine the influence of a parental history of substance use disorders on SUD risk in offspring with and without BPD. METHODS: We studied 190 parents ascertained through 104 adolescent BPD probands and 189 parents ascertained through 98 control probands using structured interviews. We compared the prevalence of SUD using logistic regression. RESULTS: While adjusting for BPD in our combined sample, probands with a parental history of SUD were more likely to have an alcohol use disorder compared to probands without a parental history. Probands with a parental history of SUD were not more likely to have a drug use disorder or overall SUD compared to probands without a parental history. BPD in the offspring did not pose any additional risk between parental history of SUD and offspring SUD. CONCLUSION: Alcohol use disorders were more common in the offspring of parents with a SUD history compared to parents without SUD and the risk was not influenced by offspring BPD. SCIENTIFIC SIGNIFICANCE: Clarifying the mechanisms linking parental SUD to offspring SUD, particularly in children and adolescents with BPD, would help clinicians to educate and monitor high-risk families, which would facilitate strategies to mitigate risks associated with parental substance abuse. PMID- 24628814 TI - Human factors, non-technical skills, professionalism and flight safety: their roles in improving patient outcome. PMID- 24628813 TI - Global transcript and phenotypic analysis of yeast cells expressing Ssa1, Ssa2, Ssa3 or Ssa4 as sole source of cytosolic Hsp70-Ssa chaperone activity. AB - BACKGROUND: Cytosolic Hsp70 is a ubiquitous molecular chaperone that is involved in responding to a variety of cellular stresses. A major function of Hsp70 is to prevent the aggregation of denatured proteins by binding to exposed hydrophobic regions and preventing the accumulation of amorphous aggregates. To gain further insight into the functional redundancy and specialisation of the highly homologous yeast Hsp70-Ssa family we expressed each of the individual Ssa proteins as the sole source of Hsp70 in the cell and assessed phenotypic differences in prion propagation and stress resistance. Additionally we also analysed the global gene expression patterns in yeast strains expressing individual Ssa proteins, using microarray and RT-qPCR analysis. RESULTS: We confirm and extend previous studies demonstrating that cells expressing different Hsp70-Ssa isoforms vary in their ability to propagate the yeast [PSI+] prion, with Ssa3 being the most proficient. Of the four Ssa family members the heat inducible isoforms are more proficient in acquiring thermotolerance and we show a greater requirement than was previously thought, for cellular processes in addition to the traditional Hsp104 protein disaggregase machinery, in acquiring such thermotolerance. Cells expressing different Hsp70-Ssa isoforms also display differences in phenotypic response to exposure to cell wall damaging and oxidative stress agents, again with the heat inducible isoforms providing better protection than constitutive isoforms. We assessed global transcriptome profiles for cells expressing individual Hsp70-Ssa isoforms as the sole source of cytosolic Hsp70, and identified a significant difference in cellular gene expression between these strains. Differences in gene expression profiles provide a rationale for some phenotypic differences we observed in this study. We also demonstrate a high degree of correlation between microarray data and RT-qPCR analysis for a selection of genes. CONCLUSIONS: The Hsp70-Ssa family provide both redundant and variant-specific functions within the yeast cell. Yeast cells expressing individual members of the Hsp70-Ssa family as the sole source of Ssa protein display differences in global gene expression profiles. These changes in global gene expression may contribute significantly to the phenotypic differences observed between the Hsp70-Ssa family members. PMID- 24628816 TI - Quality of life and sexual function of patients following radical hysterectomy and vaginal extension. AB - INTRODUCTION: Radical hysterectomy (RH) has negative consequences on sexual function due to a shortened vagina, vaginal dryness, and dyspareunia. Peritoneovaginoplasty aims to extend vagina by vesical peritoneum and anterior rectal wall to improve postoperative sexual function. AIM: The aim of this study was to investigate whether vaginal extension can improve sexual function and quality of life and the problem of sexual dysfunction in early-stage cervical cancer survivors (CCSs) in China. METHODS: Case-control and questionnaire-based methods were employed. Thirty-one patients who had undergone vaginal extension following RH and 28 patients with matching factors after RH alone were enrolled in the study. MAIN OUTCOME MEASURES: Both groups were assessed retrospectively by questionnaires at least 6 months after treatment. The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire cervical cancer module and the Sexual Function Vaginal Changes Questionnaire are validated measurements for disease- and treatment-specific issues. RESULTS: Vaginal length was 10.03 +/- 1.26 cm and 5.92 +/- 1.05 cm in study and control group, respectively (P < 0.05). In the study group, 67.7% patients and 64.3% of control group resumed sexual activity at the time of interview, averaging 6 months between treatment and sexual activity. While difficulty emptying bladder, incomplete emptying, and constipation were the most commonly reported symptoms, no significant difference was observed regarding pelvic floor symptoms. Reduced vagina size and shortened vagina was significantly more prominent in the control group, whereas both group presented with hypoactive sexual desire (88.1%), orgasm dysfunction (71.8%), and low enjoyment or relaxation after sex (51.3%). CONCLUSION: Shortened vagina was significantly less reported in study group, while no difference was observed in other sex-related dimensions. Vaginal extension does not worsen pelvic floor symptoms. Sexual rehabilitation interventions are of significance and should be paid more attention to the CCSs in China. PMID- 24628815 TI - Optimal body weight for health and longevity: bridging basic, clinical, and population research. AB - Excess body weight and adiposity cause insulin resistance, inflammation, and numerous other alterations in metabolic and hormonal factors that promote atherosclerosis, tumorigenesis, neurodegeneration, and aging. Studies in both animals and humans have demonstrated a beneficial role of dietary restriction and leanness in promoting health and longevity. Epidemiological studies have found strong direct associations between increasing body mass index (BMI) and risks of developing type 2 diabetes, cardiovascular disease, and several types of cancer, beginning from BMI of 20-21 kg m(-2). Although a recent meta-analysis suggests that overweight individuals have significantly lower overall mortality than normal-weight individuals, these data are likely to be an artifact produced by serious methodological problems, especially confounding by smoking, reverse causation due to existing chronic disease, and nonspecific loss of lean mass and function in the frail elderly. From a clinical and public health point of view, maintaining a healthy weight through diet and physical activity should remain the cornerstone in the prevention of chronic diseases and the promotion of healthy aging. PMID- 24628817 TI - Baseline staging tests based on molecular subtype is necessary for newly diagnosed breast cancer. AB - BACKGROUND: Bone scanning (BS), liver ultrasonography (LUS), and chest radiography (CXR) are commonly recommended for baseline staging in patients with newly diagnosed breast cancer. The purpose of this study is to demonstrate whether these tests are indicated for specific patient subpopulation based on clinical staging and molecular subtype. METHODS: A retrospective study on 5406 patients with newly diagnosed breast cancer was conducted to identify differences in occurrence of metastasis based on clinical staging and molecular subtypes. All patients had been evaluated by BS, LUS and CXR at diagnosis. RESULTS: Complete information on clinical staging was available in 5184 patients. For stage I, II, and III, bone metastasis rate was 0%, 0.6% and 2.7%, respectively (P < 0.01); liver metastasis rate was 0%, 0.1%, and 1.0%, respectively (P < 0.01); lung metastasis rate was 0.1%, 0.1%, and 0.7%, respectively (P < 0.01). Complete information on molecular subtype was available in 3411 patients. For Luminal A, Luminal B (HER2-), Luminal BH (HER2+), HER2+ overexpression, and Basal-like, bone metastasis rate was 1.4%, 0.7%, 2.5%, 2.7%, and 0.9%, respectively (P < 0.05); liver metastasis rate was 0.1%, 0.1%, 1.0%, 1.1%, and 0.9%, respectively (P < 0.01); lung metastasis rate was 0.20%, 0%, 0%, 0.27%, and 0.9%, respectively (P < 0.05). cT (tumor size), cN (lymph node), PR (progesterone receptor), and HER2 status predicted bone metastasis (P < 0.05). cT, cN, ER (estrogen receptor), PR, and HER2 status predicted liver metastasis (P < 0.05). cT, cN, and PR status predicted lung metastasis (P < 0.05). CONCLUSION: These data indicate that based on clinical staging and molecular subtypes, BS, LUS and CXR are necessary for patients with newly diagnosed breast cancer. PMID- 24628818 TI - Genetic variants determining body fat distribution and sex hormone-binding globulin among Chinese female young adults. AB - BACKGROUND: Measures of body fat distribution (i.e. waist : hip ratio [WHR]) are major risk factors for diabetes, independent of overall adiposity. The genetic variants related to body fat distribution show sexual dimorphism and particularly affect females. Substantial literature supports a role for sex hormone-binding globulin (SHBG) in the maintenance of glucose homeostasis. The aim of the present study was to examine the association of the genetic risk score of body fat distribution with SHBG levels and insulin resistance in young (14-30 years) Chinese females. METHODS: In all, 675 young Chinese females were evaluated in the present study. A genetic risk score (GRS) was calculated on the basis of 12 established variants associated with body fat distribution. The main outcome variable was serum SHBG levels and homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: The GRS of body fat distribution was significantly associated with decreasing serum SHBG levels (P = 0.018), independent of body mass index and WHR. In addition, the GRS and SHBG showed additive effects on HOMA IR (P = 0.004). CONCLUSIONS: The GRS of body fat distribution reflects serum SHBG levels, and the GRS and SHBG jointly influence the risk of insulin resistance. PMID- 24628819 TI - IL10 single nucleotide polymorphisms are related to upregulation of constitutive IL-10 production and susceptibility to Helicobacter pylori infection. AB - BACKGROUND: Helicobacter pylori infection is a strong risk factor for gastric cancer, likely due to the extensive inflammation in the stomach mucosa caused by these bacteria. Many studies have reported an association between IL10 polymorphisms, the risk of gastric cancer, and IL-10 production. The aim of the study was to evaluate the association between IL10 genetic variants, Helicobacter pylori infection, and IL-10 production by peripheral blood leukocytes in children. MATERIALS AND METHODS: We genotyped a total of 12 single nucleotide polymorphisms in IL10 in 1259 children aged 4-11 years living in a poor urban area in Salvador, Brazil, using TaqMan probe based, 5' nuclease assay minor groove binder chemistry. Association tests were performed by logistic regression for Helicobacter pylori infection and linear regression for IL-10 spontaneous production (whole-blood cultures) including sex, age, and principal components for informative ancestry markers as covariates, using PLINK. RESULTS: Our results shown that IL10 single nucleotide polymorphisms rs1800896 (OR = 1.63; 95% CI = 1.11-2.39), rs3024491 (OR = 1.71; 95% CI = 1.14-2.57), rs1878672 (OR = 1.79; 95% CI = 1.19-2.68), and rs3024496 (OR = 1.48; 95% CI = 1.05-2.08) were positively associated with Helicobacter pylori infection. Eight single nucleotide polymorphisms were associated with spontaneous production of IL-10 in culture, of which three (rs1800896 and rs1878672, p = .04; rs3024491, p = .01) were strongly associated with infection by Helicobacter pylori. CONCLUSIONS: Our results indicate that IL10 variants rs1800896, rs3024491, rs1878672, and rs3024496 are more consistently associated with the presence of anti-H. pylori IgG by inducing increased production of IL-10. Further studies are underway to elucidate the role of additional genetic variants and to investigate their impact on the occurrence of gastric cancer. PMID- 24628820 TI - Cutaneous legionellosis: case report and review of the medical literature. AB - Discrete nodules developed on the leg of a 27-year-old immunosuppressed woman after an allogeneic stem cell transplant. Biopsy and culture grew Legionella pneumophila serogroup 8. On day 7 of azithromycin treatment, respiratory distress and abnormal liver transaminases developed, and the patient died on day 14. Review of the medical literature identified 19 reports of Legionella species associated skin or soft tissue infections (total of 20 patients, 13 with confirmed infection). Manifestations of the 13 confirmed cases included erythematous macular rash (n = 7), erythema after thoracentesis (n = 1), abscess formation (n = 4), respiratory symptoms (n = 6), and abnormal chest radiographs (n = 8). Six required surgical exploration and debridement, and 7 were immunocompromised. Rash and respiratory infection improved with antibiotics in 10, but 3 died. Immunosuppression may predispose transplant recipients to Legionella infections. Diagnostic biopsies may facilitate appropriate treatment. PMID- 24628822 TI - Dyadic coping and relationship functioning in couples coping with cancer: a systematic review. AB - OBJECTIVES: Cancer not only affects the patient but also the partner. In fact, couples may react as a unit rather than as individuals while coping with cancer (i.e., dyadic coping). We assessed (1) the relationship between dyadic coping and relationship functioning in couples coping with cancer and (2) whether intervention studies aimed at improving dyadic coping were able to enhance the relationship functioning of these couples. Recommendations for future studies are provided. METHOD: A systematic search was conducted to identify all eligible papers between January 1990 and September 2012. The databases PubMed, PsycINFO, the Cochrane Library, and EMBASE were screened. RESULTS: Most studies (n = 33) used an appropriate study design, adequate measurements, adequate analytical techniques, and a sufficient number of included participants to answer addressed research questions. However, the definition and assessment of dyadic coping strategies differed, which hampered comparison. Coping styles characterized by open and constructive (cancer-related) communication, supportive behaviours, positive dyadic coping, and joint problem solving were related to higher relationship functioning, whereas dysfunctional communication patterns (e.g., protective buffering, demand-withdraw communication), unsupportive behaviours, and negative dyadic coping were related to lower relationship functioning. The results of the intervention studies were inconsistent: while some studies reported a beneficial effect on relationship functioning, other studies report no such effect, or only found a positive effect in couples with fewer personal relationship resources. CONCLUSIONS: This review showed that adequate dyadic coping may improve relationship functioning, while dysfunctional dyadic coping may impede relationship functioning. In order to increase the comparability of the reported findings, a more uniformly conceptualized perspective on dyadic coping is needed. A better understanding of the dyadic challenges couples coping with cancer may face and more insight on how to expand the dyadic coping of these coupes might facilitate improvements in the quality of cancer care. Couple-based intervention studies may increase the couples' relationship functioning. However, future research is needed to examine more specifically which couples may benefit from such interventions. Statement of contribution What is already known on this subject? Dyadic coping may influence the distress experienced by both members of the couple and their relationship functioning. Several reviews already reported on the potential of couple-based interventions to improve the dyadic coping of couples coping with cancer and on the beneficial effects of this coping on the psychosocial adjustment and relationship functioning of patients and partners (e.g., Badr & Krebs, 2012; Martire, Shulz, Helgeson, Small, & Saghafi, 2010; Regan et al., 2012). However, even though we now know that couple-based intervention might be useful, no systematic review has been conducted that focuses specifically on the mechanisms of dyadic coping itself. What does this study add? This review showed the importance of stress communication, supportive behaviours, and positive dyadic coping for the maintenance or enhancement of relationship functioning in couples coping with cancer. In addition, the dyadic intervention studies send an important message that encourages to further examine the potential benefit of such interventions in future. However, more consensus in the conceptualization and assessment of the dyadic coping styles is needed in order to increase the comparability of the reported findings. PMID- 24628821 TI - Time to be BRAVE: is educating surgeons the key to unlocking the potential of randomised clinical trials in surgery? A qualitative study. AB - BACKGROUND: Well-designed randomised clinical trials (RCTs) provide the best evidence to inform decision-making and should be the default option for evaluating surgical procedures. Such trials can be challenging, and surgeons' preferences may influence whether trials are initiated and successfully conducted and their results accepted. Preferences are particularly problematic when surgeons' views play a key role in procedure selection and patient eligibility. The bases of such preferences have rarely been explored. Our aim in this qualitative study was to investigate surgeons' preferences regarding the feasibility of surgical RCTs and their understanding of study design issues using breast reconstruction surgery as a case study. METHODS: Semistructured qualitative interviews were undertaken with a purposive sample of 35 professionals practicing at 15 centres across the United Kingdom. Interviews were transcribed verbatim and analysed thematically using constant comparative techniques. Sampling, data collection and analysis were conducted concurrently and iteratively until data saturation was achieved. RESULTS: Surgeons often struggle with the concept of equipoise. We found that if surgeons did not feel 'in equipoise', they did not accept randomisation as a method of treatment allocation. The underlying reasons for limited equipoise were limited appreciation of the methodological weaknesses of data derived from nonrandomised studies and little understanding of pragmatic trial design. Their belief in the value of RCTs for generating high-quality data to change or inform practice was not widely held. CONCLUSION: There is a need to help surgeons understand evidence, equipoise and bias. Current National Institute of Health Research/Medical Research Council investment into education and infrastructure for RCTs, combined with strong leadership, may begin to address these issues or more specific interventions may be required. PMID- 24628823 TI - Genome rearrangements derived from homoeologous recombination following allopolyploidy speciation in coffee. AB - Allopolyploidization is widespread and has played a major role in flowering plant diversification. Genomic changes are common consequences of allopolyploidization, but their mechanisms of occurrence and dynamics over time are still poorly understood. Coffea arabica, a recently formed allotetraploid, was chosen as a model to investigate genetic changes in allopolyploid using an approach that exploits next-generation sequencing technologies. Genes affected by putative homoeolog loss were inferred by comparing the numbers of single-nucleotide polymorphisms detected using RNA-seq in individual accessions of C. arabica, and between accessions of its two diploid progenitor species for common sequence positions. Their physical locations were investigated and clusters of genes exhibiting homoeolog loss were identified. To validate these results, genome sequencing data were generated from one accession of C. arabica and further analyzed. Genomic rearrangements involving homoeologous exchanges appear to occur in C. arabica and to be a major source of genetic diversity. At least 5% of the C. arabica genes were inferred to have undergone homoeolog loss. The detection of a large number of homoeologous exchange events (HEEs) shared by all accessions of C. arabica strongly reinforces the assumption of a single allopolyploidization event. Furthermore, HEEs were specific to one or a few accessions, suggesting that HEE accumulates gradually. Our results provide evidence for the important role of HEE in allopolyploid genome evolution. PMID- 24628824 TI - Improving family communication after a new genetic diagnosis: a randomised controlled trial of a genetic counselling intervention. AB - BACKGROUND: Genetic information given to an individual newly diagnosed with a genetic condition is likely to have important health implications for other family members. The task of communicating with these relatives commonly falls to the newly diagnosed person. Talking to relatives about genetic information can be challenging and is influenced by many factors including family dynamics. Research shows that many relatives remain unaware of relevant genetic information and the possible impact on their own health. This study aims to evaluate whether a specific genetic counselling intervention for people newly diagnosed with a genetic condition, implemented over the telephone on a number of occasions, could increase the number of at-risk relatives who make contact with genetics services after a new genetic diagnosis within a family. METHODS: This is a prospective, multi-centre randomised controlled trial being conducted at genetics clinics at five public hospitals in Victoria, Australia. A complex genetic counselling intervention has been developed specifically for this trial. Probands (the first person in a family to present with a diagnosis of a genetic condition) are being recruited and randomised into one of two arms - the telephone genetic counselling intervention arm and the control arm receiving usual care. The number of at-risk relatives for each proband will be estimated from a family pedigree collected at the time of diagnosis. The primary outcome will be measured by comparing the proportion of at-risk relatives in each arm of the trial who make subsequent contact with genetics services. DISCUSSION: This study, the first randomised controlled trial of a complex genetic counselling intervention to enhance family communication, will provide evidence about how best to assist probands to communicate important new genetic information to their at-risk relatives. This will inform genetic counselling practice in the context of future genomic testing. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000642381. PMID- 24628825 TI - Important considerations when studying the impact of physical education on health in youth. AB - Klakk et al. conducted an intervention study by increasing the frequency of physical education lessons in children aged 8 to 13 years, and they examined its effect on body fat during two school years. Physical education has potential to provide health in childhood and adolescence. For achieving these benefits, one of the most relevant aspects that need to be addressed during physical education classes is to provide students with high levels of physical activity. A well recognized recommendation suggests that students should engage in moderate to vigorous physical activity for at least 50% of the time they spend in physical education classes. Therefore, it would be crucial to know what is happening during physical education classes before increasing their frequency. On the other hand, it seems that the main concern of health-related researchers is provide evidence on the impact of physical education on physical health outcomes (e.g. obesity), whereas other dimensions of health such as social, emotional, intellectual, and spiritual health are understudied. New evidence on the role of physical education on other health outcomes beyond physical health would also be important for the recognition of this curricular subject. PMID- 24628826 TI - Predicting dopaminergic effects of L-DOPA in the treatment for Parkinson's disease. PMID- 24628827 TI - Treatment of onychomycosis using the 1 064 nm Nd:YAG laser: a clinical pilot study. AB - BACKGROUND: Nd:YAG lasers could be a safe and effective treatment modality for onychomycosis, without the side effects of drugs. Long and short-pulsed Nd:YAG lasers were used in this clinical study in a side-comparison manner without removal of onychomycotic nail material before treatment. PATIENTS AND METHODS: Big toenails of 10 patients were treated twice in a side-comparison manner with the short-pulsed Nd:YAG laser. Fungal cultures were taken and a histological examination was performed before treatment and after 9 months. Two independent investigators rated clearance using the "Onychomycosis Severity Index (OSI)" and standardized photographs at 3-month intervals. RESULTS: OSI-Scores decreased for 3.8 (15 %; p = 0.006), 4.8 (19 %; p = 0.0002) and 2.9 points (12 %; p = 0.04) within 3, 6 and 9 months. The positive culture rate at 9 months was significantly reduced to 35 % (p = 0.0003). Classification of severity of onychomycosis showed no change. The difference between the treatment regimens was not significant. CONCLUSIONS: These results suggest that treatment of onychomycosis with the Nd:YAG laser without removing mycotic nail material can lead to a temporary clinical improvement, a reduction of positive fungal cultures and an improvement of the Onychomycosis Severity Index. The treatment regimen should be optimized to be used as an effective antimycotic monotherapy. PMID- 24628828 TI - Clinical and treatment characteristics determining therapeutic outcome in patients undergoing autologous non-cultured outer root sheath hair follicle cell suspension for treatment of stable vitiligo. AB - BACKGROUND: Autologous non-cultured outer root sheath hair follicle cell suspension (NCORSHFS) is a recently described novel cellular graft technique for the treatment of stable vitiligo. There is lack of data about various factors determining the repigmentation rate in vitiligo patients undergoing this novel surgical therapy. OBJECTIVE: To study the clinical characteristics and treatment variables determining therapeutic outcome in patients of stable vitiligo undergoing NCORSHFS. METHODS: Non-cultured outer root sheath hair follicle cell suspension was prepared from anagen hairs extracted from the occipital area. The number of melanocytes and hair follicle stem cells (HFSC) in the suspension was quantified by staining with anti-HMB45 and anti-CD200 antibody, respectively. In all patients, a 2 mm punch skin biopsy was taken from one of the vitiligo patch to be treated prior to surgery for assessment of histomorphological features. Post surgery patients were followed up at regular intervals for 24 weeks. RESULTS: Thirty patients (21 females, 9 males) with a clinical diagnosis of stable vitiligo, with a total of 60 target lesions were included in this study. The mean age of the study population was 21.10 +/- 5.64 years. The number of melanocytes (P = 0.04) and HFSC (P = 0.01) transplanted were significantly higher among patients achieving optimum repigmentation (>75% repigmentation). There was a strong correlation between repigmentation at 24 week and number of melanocytes and HFSC transplanted. Number of HFSC transplanted and absence of dermal inflammation were significant predictors of achieving optimum repigmentation. CONCLUSION: The number of melanocytes and HFSC transplanted and absence of dermal inflammation were important determents of optimal repigmentation in patients undergoing NCORSHFS for treatment of stable vitiligo. Hence, refining the technique of NCORSHFS on the basis of these factors would help in achieving better surgical outcomes. PMID- 24628829 TI - Relationship between hyperglycemia, hormone disturbances, and clinical evolution in severely hyperglycemic post surgery critically ill children: an observational study. AB - BACKGROUND: To study hormonal changes associated with severe hyperglycemia in critically ill children and the relationship with prognosis and length of stay in intensive care. METHODS: Observational study in twenty-nine critically ill children with severe hyperglycemia defined as 2 blood glucose measurements greater than 180 mg/dL. Severity of illness was assessed using pediatric index of mortality (PIM2), pediatric risk of mortality (PRISM) score, and pediatric logistic organ dysfunction (PELOD) scales. Blood glucose, glycosuria, insulin, C peptide, cortisol, corticotropin, insulinlike growth factor-1, growth hormone, thyrotropin, thyroxine, and treatment with insulin were recorded. beta-cell function and insulin sensitivity and resistance were determined on the basis of the homeostatic model assessment (HOMA), using blood glucose and C-peptide levels. RESULTS: The initial blood glucose level was 249 mg/dL and fell gradually to 125 mg/dL at 72 hours. Initial beta-cell function (49.2%) and insulin sensitivity (13.2%) were low. At the time of diagnosis of hyperglycemia, 50% of the patients presented insulin resistance and beta-cell dysfunction, 46% presented isolated insulin resistance, and 4% isolated beta-cell dysfunction. beta-cell function improved rapidly but insulin resistance persisted. Initial glycemia did not correlate with any other factor, and there was no relationship between glycemia and mortality. Patients who died had higher cortisol and growth hormone levels at diagnosis. Length of stay was correlated by univariate analysis, but not by multivariate analysis, with C-peptide and glycemic control at 24 hours, insulin resistance, and severity of illness scores. CONCLUSIONS: Critically ill children with severe hyperglycemia initially present decreased beta-cell function and insulin sensitivity. Nonsurvivors had higher cortisol and growth hormone levels and developed hyperglycemia later than survivors. PMID- 24628830 TI - Ziprasidone versus clozapine in the treatment of dually diagnosed (DD) patients with schizophrenia and cannabis use disorders: a randomized study. AB - BACKGROUND AND OBJECTIVES: Clozapine is considered to be particularly effective in the treatment of dually diagnosed (DD) patients with psychosis and substance use disorders. However, its use is restricted by potentially severe side effects. The aim of the present pilot study was to compare the effects of clozapine with the newer second generation antipsychotic (SGA) ziprasidone in DD-patients. METHODS: Thirty (n = 30) patients with schizophrenia and cannabis abuse/dependence were randomized to ziprasidone or clozapine and were followed up for up to 12 months. RESULTS: Cannabis use was reduced in both groups during follow-up. Clozapine treatment was associated with less positive symptoms of schizophrenia, more side effects and poorer compliance with treatment. CONCLUSIONS: Results from this small pilot RCT suggest beneficial effects of both clozapine and ziprasidone in the treatment of cannabis use disorders in psychotic patients. Larger-scale RCTs are needed in order to assess advantages and disadvantages of the different SGAs in dually diagnosed populations. PMID- 24628831 TI - Copeptin, a surrogate marker for arginine vasopressin, is associated with cardiovascular risk in patients with polycystic ovary syndrome. AB - BACKGROUND: Women with polycystic ovary syndrome (PCOS) have higher risk for cardiovascular disease (CVD). Copeptin has been found to be predictive for myocardial ischemia. We tested whether copeptin is the predictor for CVD in PCOS patients, who have an increased risk of cardiovascular disease. METHODS: This was a cross sectional controlled study conducted in a training and research hospital. The study population consisted of 40 reproductive-age PCOS women and 43 control subjects. We evaluated anthropometric and metabolic parameters, carotid intima media thickness and copeptin levels in both PCOS patients and control group. RESULTS: Mean fasting insulin, homeostasis model assessment insulin resistance index (HOMA-IR), triglyceride, total cholesterol, low density lipoprotein cholesterol (LDL-C), free testosterone, 17-OH progesterone, Dehydroepiandrosterone sulfate (DHEAS), carotid intima media thickness (CIMT) levels were significantly higher in PCOS patients. Mean copeptin level was in 12.61 +/- 3.05 pmol/L in PCOS patients while mean copeptin level was 9.60 +/- 2.80 pmol/L in healthy control women (p < 0.001). After adjustment for age and BMI, copeptin level was positive correlated with fasting insulin, free testosterone levels, CIMT, and HOM A-IR. CONCLUSIONS: Copeptin appeared to have an important role in metabolic response and subsequent development of atherosclerosis in insulin resistant, hyperandrogenemic PCOS patients. PMID- 24628833 TI - Phosphoproteomic analysis of the non-seed vascular plant model Selaginella moellendorffii. AB - BACKGROUND: Selaginella (Selaginella moellendorffii) is a lycophyte which diverged from other vascular plants approximately 410 million years ago. As the first reported non-seed vascular plant genome, Selaginella genome data allow comparative analysis of genetic changes that may be associated with land plant evolution. Proteomics investigations on this lycophyte model have not been extensively reported. Phosphorylation represents the most common post translational modifications and it is a ubiquitous regulatory mechanism controlling the functional expression of proteins inside living organisms. RESULTS: In this study, polyethylene glycol fractionation and immobilized metal ion affinity chromatography were employed to isolate phosphopeptides from wild growing Selaginella. Using liquid chromatography-tandem mass spectrometry analysis, 1593 unique phosphopeptides spanning 1104 non-redundant phosphosites with confirmed localization on 716 phosphoproteins were identified. Analysis of the Selaginella dataset revealed features that are consistent with other plant phosphoproteomes, such as the relative proportions of phosphorylated Ser, Thr, and Tyr residues, the highest occurrence of phosphosites in the C-terminal regions of proteins, and the localization of phosphorylation events outside protein domains. In addition, a total of 97 highly conserved phosphosites in evolutionary conserved proteins were identified, indicating the conservation of phosphorylation-dependent regulatory mechanisms in phylogenetically distinct plant species. On the other hand, close examination of proteins involved in photosynthesis revealed phosphorylation events which may be unique to Selaginella evolution. Furthermore, phosphorylation motif analyses identified Pro-directed, acidic, and basic signatures which are recognized by typical protein kinases in plants. A group of Selaginella-specific phosphoproteins were found to be enriched in the Pro-directed motif class. CONCLUSIONS: Our work provides the first large scale atlas of phosphoproteins in Selaginella which occupies a unique position in the evolution of terrestrial plants. Future research into the functional roles of Selaginella-specific phosphorylation events in photosynthesis and other processes may offer insight into the molecular mechanisms leading to the distinct evolution of lycophytes. PMID- 24628834 TI - The use of electrical stimulation to guide epidural and intrathecal needle advancement at the L5 -L6 intervertebral space in dogs. AB - OBJECTIVE: To determine the minimal electrical threshold (MET) necessary to elicit appropriate muscle contraction when the tip of an insulated needle is positioned epidurally or intrathecally at the L5-6 intervertebral space (phase-I) and to determine whether the application of a fixed electrical current during its advancement could indicate needle entry into the intrathecal space (phase-II) in dogs. STUDY DESIGN: Prospective, blinded study. ANIMALS: Thirteen (phase-I) and seventeen (phase-II) dogs, scheduled for a surgical procedure where L5-6 intrathecal administration was indicated. METHODS: Under general anesthesia, an insulated needle was first inserted into the L5-6 epidural space and secondly into the intrathecal space and the MET necessary to obtain a muscular contraction of the pelvic limb or tail at each site was determined (phase-I). Under similar conditions, in dogs of phase-II an insulated needle was inserted through the L5-6 intervertebral space guided by the use of a fixed electrical current (0.8 mA) until muscular contraction of the pelvic limb or tail was obtained. Intrathecal needle placement was confirmed by either free flow of cerebrospinal fluid (CSF) or myelography. RESULTS: The current required to elicit a motor response was significantly lower (p < 0.0001) when the tip of the needle was in the intrathecal space (0.48 +/- 0.10 mA) than when it was located epidurally (2.56 +/ 0.57). The use of a fixed electrical stimulation current of 0.8 mA resulted in correct prediction of intrathecal injection, corroborated by either free flow of CSF (n = 12) or iohexol distribution pattern (n = 5), in 100% of the cases. CONCLUSION AND CLINICAL RELEVANCE: Nerve stimulation may be employed as a tool to distinguish epidural from intrathecal insulated needle position at the L5-6 intervertebral space in dogs. This study demonstrates the feasibility of using an electrical stimulation test to confirm intrathecal needle position in dogs. PMID- 24628832 TI - Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers. AB - BACKGROUND: The risk of venous thrombosis (VT) associated with oral hormone therapy (HT) may differ by type of estrogen compound. OBJECTIVE: To compare the thrombotic profile of women using oral conjugated equine estrogens (CEE) with that of women using oral estradiol (E2). METHODS: In postmenopausal, female, health maintenance organization (HMO) members with no history of VT, we measured thrombin generation, levels of factor VII activity, antithrombin activity and total protein S antigen. Mean levels of hemostasis biomarkers were cross sectionally compared by use and type of estrogen using multiple linear regressions. The type of estrogen used was determined primarily by the HMO formulary, which changed its preferred estrogen from CEE to E2 during the study period. RESULTS: The sample included 92 E2 users and 48 CEE users, with a mean age of 64.1 years and mean BMI of 29.1 kg m(-2) . Twenty-seven per cent of HT contained medroxyprogesterone acetate. Compared with E2 users, CEE users had greater thrombin generation peak values and endogenous thrombin potential, and lower total protein S (multivariate adjusted differences of 49.8 nm (95% CI, 21.0, 78.6), 175.0 nm * Min (95% CI, 54.4, 295.7) and -13.4% (95% CI, -19.8, 6.9), respectively). Factor VII and antithrombin levels were not different between E2 and CEE users. Results were similar in subgroups of users of unopposed HT, opposed HT, low-dose estrogen and standard dose estrogen. CONCLUSION: The hemostatic profile of women using CEE is more prothrombotic than that of women using E2. These findings provide further evidence for a different thrombotic risk for oral CEE and oral E2. PMID- 24628835 TI - Western corn rootworm (Diabrotica virgifera virgifera) transcriptome assembly and genomic analysis of population structure. AB - BACKGROUND: Western corn rootworm (WCR) is one of the most significant insect pests of maize in North America. WCR has dramatically increased its range in the last century, invading key maize production areas in the US and abroad. In addition, this species has a history of evolving traits that allow it to escape various control options. Improved genetic and genomic resources are crucial tools for understanding population history and the genetic basis of trait evolution. Here we produce and analyze a transcriptome assembly for WCR. We also perform whole genome population resequencing, and combine these resources to better understand the evolutionary history of WCR. RESULTS: The WCR transcriptome assembly presented here contains approximately 16,000 unigenes, many of which have high similarity to other insect species. Among these unigenes we found several gene families that have been implicated in insecticide resistance in other species. We also identified over 500,000 unigene based SNPs among 26 WCR populations. We used these SNPs to scan for outliers among the candidate genes, and to understand how population processes have shaped genetic variation in this species. CONCLUSIONS: This study highlights the utility of transcriptomic and genomic resources as foundational tools for dealing with highly adaptive pest species. Using these tools we identified candidate gene families for insecticide resistance and reveal aspects of WCR population history in light of the species' recent range expansion. PMID- 24628836 TI - n-3 polyunsaturated fatty acids worsen inflammation and fibrosis in experimental nonalcoholic steatohepatitis. AB - BACKGROUND & AIMS: n-3 polyunsaturated fatty acids (PUFA) ameliorate fatty liver in experimental models, but their effects on inflammation and fibrosis during steatohepatitis are either controversial or lacking. We compared the effects of supplementation with olive oil (OO) alone or OO and n-3 PUFA on the development and progression of experimental steatohepatitis. METHODS: Balb/C mice (>=5 mice/group) were fed a methionine- and choline-deficient (MCD) diet or a control diet for 4 or 8 weeks. At the same time, mice were supplemented with n-3 PUFA (eicosapentaenoic and docosahexahenoic acid, 25 mg together with 75 mg OO), or OO alone (100 mg), two times a week by intragastric gavage. RESULTS: After 8 weeks, mice on MCD/n-3 had higher ALT levels compared to MCD/OO and more severe scores of inflammation, including a significant increase in the number of lipogranulomas (26.4 +/- 8.4 vs. 5.1 +/- 5 per field, P < 0.001). Intrahepatic expression of TNF alpha and CCL2 was higher in MCD/n-3 mice at both time points. In addition, increased expression of the profibrogenic genes TIMP-1 and TGF-beta, and more severe histological scores of fibrosis were evident in MCD/n-3 mice. After 8 week of MCD diet, portal pressure was higher in mice receiving n-3 than in those on OO alone (5.1 +/- 1.4 vs. 7.0 +/- 0.9 mmHg, P < 0.05). Analysis of hepatic fatty acid profile showed that supplementation resulted in effective incorporation of n 3 PUFA. CONCLUSIONS: In a murine model of steatohepatitis, supplementation with n 3 PUFA and OO is associated with more severe necro-inflammation and fibrosis than in mice treated with OO only. PMID- 24628837 TI - Successful withdrawal of antiviral treatment in kidney transplant recipients with chronic hepatitis B viral infection. AB - BACKGROUND: The optimal duration of antiviral therapy for kidney transplant recipients (KTR) with chronic hepatitis B virus (HBV) infection remains unclear. We reported the long-term outcomes after withdrawal of antiviral agent in KTR with chronic HBV infection. METHODS: We retrospectively investigated the hepatitis B surface antigen (HBsAg)-positive KTR with antiviral agents between January 2002 and January 2012. Antiviral treatments were withdrawn in patients who met all of the following 7 criteria: (i) no clinical and histologic evidence of cirrhosis, (ii) normal liver biochemistry, (iii) negative for both HBV DNA and hepatitis B envelope antigen (HBeAg), (iv) no resistance to antiviral agent, (v) antiviral therapy > 9 months, (vi) maintenance dosage of immunosuppressant for > 3 months, and (vii) no history of acute rejection during recent 6 months. All patients were followed regularly at approximately 3-6 months for liver enzyme, viral markers, and HBV DNA level after antiviral withdrawal. RESULTS: Among a total of 445 KTR, 14 HBsAg-positive patients were included in this study. Antiviral agents were used, with lamivudine in 11 patients, and with adefovir, entecavir, and telbivudine in 3 patients, respectively. Discontinuation of antiviral agent was attempted in 6 (42.9%) of 14 patients who satisfied the criteria. The median duration of antiviral therapy before withdrawal was 14.3 months (range, 9-24 months). Four (66.7%) of 6 patients were successfully withdrawn and remained negative for HBV DNA for a median 60.5 months (range, 47 82 months). The baseline HBV DNA level was not related to maintenance of remission after withdrawal. Two reactivated patients resumed antiviral treatment immediately, with subsequent normalization of HBV DNA. During the follow-up, 1 patient developed hepatocellular carcinoma; however, no patient death or graft failure was reported for all HBsAg-positive KTR. CONCLUSIONS: Antiviral therapy can be discontinued successfully and safely in selected KTR with chronic HBV infection, after complete suppression of HBV and sufficient duration of antiviral therapy. PMID- 24628838 TI - Regression methods for investigating risk factors of chronic kidney disease outcomes: the state of the art. AB - BACKGROUND: Chronic kidney disease (CKD) is a progressive and usually irreversible disease. Different types of outcomes are of interest in the course of CKD such as time-to-dialysis, transplantation or decline of the glomerular filtration rate (GFR). Statistical analyses aiming at investigating the association between these outcomes and risk factors raise a number of methodological issues. The objective of this study was to give an overview of these issues and to highlight some statistical methods that can address these topics. METHODS: A literature review of statistical methods published between 2002 and 2012 to investigate risk factors of CKD outcomes was conducted within the Scopus database. The results of the review were used to identify important methodological issues as well as to discuss solutions for each type of CKD outcome. RESULTS: Three hundred and four papers were selected. Time-to-event outcomes were more often investigated than quantitative outcome variables measuring kidney function over time. The most frequently investigated events in survival analyses were all-cause death, initiation of kidney replacement therapy, and progression to a specific value of GFR. While competing risks were commonly accounted for, interval censoring was rarely acknowledged when appropriate despite existing methods. When the outcome of interest was the quantitative decline of kidney function over time, standard linear models focussing on the slope of GFR over time were almost as often used as linear mixed models which allow various numbers of repeated measurements of kidney function per patient. Informative dropout was accounted for in some of these longitudinal analyses. CONCLUSIONS: This study provides a broad overview of the statistical methods used in the last ten years for investigating risk factors of CKD progression, as well as a discussion of their limitations. Some existing potential alternatives that have been proposed in the context of CKD or in other contexts are also highlighted. PMID- 24628839 TI - The role of psychosocial working conditions on burnout and its core component emotional exhaustion - a systematic review. AB - AIMS: To analyze the association between psychosocial working conditions and burnout and its core component emotional exhaustion, a systematic literature review was undertaken including cohort studies, case-control studies, and randomized controlled trials. METHODS: The literature search in Medline and PsycInfo was based on a defined search string and strict exclusion and inclusion criteria. Evaluation of the 5,599 initially identified search hits by two independent reviewers and a detailed quality assessment resulted in six methodologically adequate cohort studies considering the relationship between psychosocial working conditions and burnout (one study) as well as the burnout core component emotional exhaustion (five studies). RESULTS: The results of our systematic review point to a relationship between psychosocial working conditions and the development of emotional exhaustion/burnout. Particularly high job demands seem to play a role in the development of emotional exhaustion. However, strong intercorrelations between workplace factors, as a matter of principle, make the identification of a single psychosocial workplace factor (being associated with an especially high or low risk of burnout) difficult. CONCLUSIONS: Multidimensional approaches including reduction of work demands, enhancement of decision latitude and improving the social climate might be promising for preventing burnout and emotional exhaustion. However, methodologically adequate intervention studies are urgently needed to prove the effectiveness of workplace interventions. PMID- 24628840 TI - Pilot study of Creating Change, a new past-focused model for PTSD and substance abuse. AB - BACKGROUND AND OBJECTIVES: Creating Change (CC) is a new past-focused behavioral therapy model developed for comorbid posttraumatic stress disorder (PTSD) and substance use disorder (SUD). It was designed to address current gaps in the field, including the need for a past-focused PTSD/SUD model that has flexibility, can work with complex clients, responds to the staffing and resource limitations of SUD and other community-based treatment programs, can be conducted in group or individual format, and engages clients and clinicians. It was designed to follow the style, tone, and format of Seeking Safety, a successful present-focused PTSD/SUD model. CC can be used in conjunction with SS and/or other models if desired. METHODS: We conducted a pilot outcome trial of the model with seven men and women outpatients diagnosed with current PTSD and SUD, who were predominantly minority and low-income, with chronic PTSD and SUD. Assessments were conducted pre- and post-treatment. RESULTS: Significant improvements were found in multiple domains including some PTSD and trauma-related symptoms (eg, dissociation, anxiety, depression, and sexual problems); broader psychopathology (eg, paranoia, psychotic symptoms, obsessive symptoms, and interpersonal sensitivity); daily life functioning; cognitions related to PTSD; coping strategies; and suicidal ideation (altogether 19 variables, far exceeding the rate expected by chance). Effect sizes were consistently large, including for both alcohol and drug problems. No adverse events were reported. DISCUSSION AND CONCLUSIONS: Despite study methodology limitations, CC is promising. SCIENTIFIC SIGNIFICANCE: Clients can benefit from past-focused therapy that addresses PTSD and SUD in integrated fashion. PMID- 24628841 TI - Discriminant content validity: a quantitative methodology for assessing content of theory-based measures, with illustrative applications. AB - OBJECTIVES: In studies involving theoretical constructs, it is important that measures have good content validity and that there is not contamination of measures by content from other constructs. While reliability and construct validity are routinely reported, to date, there has not been a satisfactory, transparent, and systematic method of assessing and reporting content validity. In this paper, we describe a methodology of discriminant content validity (DCV) and illustrate its application in three studies. METHODS: Discriminant content validity involves six steps: construct definition, item selection, judge identification, judgement format, single-sample test of content validity, and assessment of discriminant items. In three studies, these steps were applied to a measure of illness perceptions (IPQ-R) and control cognitions. RESULTS: The IPQ-R performed well with most items being purely related to their target construct, although timeline and consequences had small problems. By contrast, the study of control cognitions identified problems in measuring constructs independently. In the final study, direct estimation response formats for theory of planned behaviour constructs were found to have as good DCV as Likert format. CONCLUSIONS: The DCV method allowed quantitative assessment of each item and can therefore inform the content validity of the measures assessed. The methods can be applied to assess content validity before or after collecting data to select the appropriate items to measure theoretical constructs. Further, the data reported for each item in Appendix S1 can be used in item or measure selection. Statement of contribution What is already known on this subject? There are agreed methods of assessing and reporting construct validity of measures of theoretical constructs, but not their content validity. Content validity is rarely reported in a systematic and transparent manner. What does this study add? The paper proposes discriminant content validity (DCV), a systematic and transparent method of assessing and reporting whether items assess the intended theoretical construct and only that construct. In three studies, DCV was applied to measures of illness perceptions, control cognitions, and theory of planned behaviour response formats. Appendix S1 gives content validity indices for each item of each questionnaire investigated. Discriminant content validity is ideally applied while the measure is being developed, before using to measure the construct(s), but can also be applied after using a measure. PMID- 24628842 TI - beta-Amyloid pathology alters neural network activation during retrieval of contextual fear memories in a mouse model of Alzheimer's disease. AB - Although episodic memory deficits are the most conspicuous cognitive change in patients with Alzheimer's disease (AD), patients also display alterations in emotional expression, including anxiety and impaired conditioned fear behaviours. The neural circuitry underlying emotional learning is known to involve the amygdala and hippocampus, although the precise impact of amyloid pathology on the interaction between these brain regions remains unclear. Recent evidence suggests that Tg2576 mice, which express a human amyloid precursor protein (APP) mutation associated with early-onset AD, demonstrate normal acquisition of conditioned freezing to auditory and contextual stimuli paired with footshock. However, examination of the expression of c-Fos revealed altered neural network activity in transgenic mice. In the present study we examined the effects of the APP mutation on the expression of c-Fos following the retrieval of emotional memories. To this end, stimulus-induced cellular activity was measured by analysing expression of the immediate-early gene c-Fos after the retrieval of auditory or contextual fear memories. To characterize regional interdependencies of c-Fos expression, structural equation modelling was used to compare patterns of neural network activity. Consistent with previous findings, Tg2576 mice displayed reduced freezing elicited by the auditory stimulus but not by the conditioning context. Interestingly, the analysis of c-Fos expression revealed that the APPswe mutation disrupted dentate gyrus and amygdala function, as well as altering the influence of these regions on the neural network dynamics activated during context memory retrieval. These results provide novel insight into the influence of excess amyloid production on neural network activity during memory retrieval. PMID- 24628843 TI - Helicobacter pylori modulates cisplatin sensitivity in gastric cancer by down regulating miR-141 expression. AB - BACKGROUND: Recent studies found that gastric cancer patients with Helicobacter pylori infection had a better response to chemotherapy and had an improved overall prognosis compared with those without. However, the underlying mechanism remains unknown. METHODS: Quantitative real-time PCR (qRT-PCR) was utilized to determine the expression profile of miR-141 in H. pylori infected cells and tissues and their respective controls. qRT-PCR and Western blot were used to determine the expression level of KEAP-1. Luciferase reporter assays were used to determine whether KEAP-1 was a direct target of miR-141 in the gastric cancer cells. MTT and apoptosis assay were performed to detect the survival of cells under cisplatin treatment. RESULT: We found that H. pylori infection can significantly down-regulate miR-141 expression. Knockdown miR-141 expression in 7901/DDP and 7901 cells could significantly improve cisplatin sensitivity. Over expression of miR-141 resulted in enhanced resistance to cisplatin in both gastric cancer cells. We also demonstrated that miR-141 directly targets KEAP1 by luciferase reporter assay, and that down-regulation of KEAP1 induces cisplatin resistance. Conversely, over-expression of KEAP1 significantly enhanced cisplatin sensitivity. Our 75 pairs of tissues also showed that KEAP1 was significantly up regulated in H. pylori-positive tissues. CONCLUSION: Altogether, these findings demonstrated that the H. pylori infection could modulate cisplatin sensitivity through miR-141-mediated regulation of KEAP1. PMID- 24628844 TI - Prevention of dental erosion of a sports drink by nano-sized hydroxyapatite in situ study. AB - AIM: To evaluate the inhibitory effects of the sports drink containing nano-sized hydroxyapatite (nano-HA) on dental erosion in situ. DESIGN: The study had a single-blind, two-treatment crossover design. The two treatment groups were a control group (CG; Powerade only) and an experimental group (EG; 0.25% wt/vol nano-HA was added to Powerade). Ten subjects wore removable palatal appliances containing bovine enamel specimens. The appliances were immersed in each drink for 10 mins, 4 times a day for 10 days. The tooth surface microhardness (SMH) was tested, and the erosion depth and the morphology of the tooth surface were observed. The data were analysed by repeated measures anova and t-test. RESULTS: Between the baseline and the 10th day, SMH was decreased by 80% in the specimens of the CG (P < 0.001), whereas there was only a 6% decrease in the SMH of the specimens in the EG. An erosion depth of 12.70 +/- 4.66 MUm and an irregular tooth surface were observed on the 10th day in the specimens of the CG. No dental erosions, however, was observed in the specimens of the EG. CONCLUSIONS: The sports drink containing 0.25% nano-HA was effective in preventing dental erosion in situ. PMID- 24628845 TI - Evolution of bacterial communities in the wheat crop rhizosphere. AB - The gap between current average global wheat yields and that achievable through best agronomic management and crop genetics is large. This is notable in intensive wheat rotations which are widely used. Expectations are that this gap can be reduced by manipulating soil processes, especially those that involve microbial ecology. Cross-year analysis of the soil microbiome in an intensive wheat cropping system revealed that rhizosphere bacteria changed much more than the bulk soil community. Dominant factors influencing populations included binding to roots, plant age, site and planting sequence. We demonstrated evolution of bacterial communities within the field rhizosphere. Early in the season, communities tightly bound to the root were simplest. These increased in diversity with plant age and senescence. Loosely bound communities also increased in diversity from vegetative to reproductive plant stages but were more stable than those tightly bound to roots. Planting sequence and, to a lesser extent, wheat genotype also significantly affected rhizosphere bacteria. Plasticity in the rhizosphere generated from crop root system management and genetics offers promise for manipulating the soil ecology of intense cereal systems. Analyses of soil microbiomes for the purpose of developing agronomic benefit should include roots as well as soil loosely adhered to the roots, and the bulk soil. PMID- 24628846 TI - Atopy patch test with Aleuroglyphus ovatus antigen in patients with atopic dermatitis. AB - BACKGROUND: Epicutaneous test made with dust mite antigens. OBJECTIVE: Evaluation of the response of the epicutaneous test with Aleuroglyphus ovatus antigen in atopic patients. METHODS: We patch tested 119 individuals, 48 with atopic dermatitis, 50 with respiratory allergy and 21 healthy controls. We compare the positive response frequency to a closed patch test using Aleuroglyphus ovatus antigen in different concentrations and 48 and 96h reading times among those individuals. RESULTS: Six patients with atopic dermatitis (12.5%) and 4 with respiratory atopy (8.0%) had positive reactions. None of the non-atopic controls had a positive response. As the antigen concentration raised, the number of positive reactions to epicutaneous test raised as well. CONCLUSION: Our data suggest a positive relation between Atopy Patch Test positive responses and Aleuroglyphus ovatus antigen concentration, no matter the kind of the atopic clinical expression. PMID- 24628847 TI - Research in practice: the impact of interferon-alpha therapy on immune tolerance. AB - Interferon-alpha (IFN-alpha) is the only drug approved for adjuvant therapy of malignant melanoma and is also used in the treatment of hematological and solid tumors. Along with its proven clinical efficacy, IFN-alpha produces several side effects, particularly with regard to autoimmune disorders. Curious about symptoms of autoimmunity during IFN-alpha therapy, we asked whether IFN-alpha directly impacts on immune tolerance. We found that IFN-alpha does alter the function of tolerogenic dendritic cells (DC) as well as of induced and naturally occurring T regulatory cells (nTregs). IFN-alpha blocks the tolerogenic phenotype of DC by inducing maturation and thus preventing the induction of inducible Tregs by DC. It also has direct effects on nTregs. IFN-alpha reduces cAMP in Tregs via ERK/phosphodiesterase-mediated pathways. Since cAMP is essentially involved in suppression by nTregs, the IFN-alpha-dependent reduction of cAMP levels abolishes the suppressive capacity of nTregs. Therefore, Tregs are incapable of suppressing the activity of effector T cells and natural killer cells, resulting in tumor rejection. Thus, IFN-alpha overcomes immunological tolerance processes, leading to an improved immunostimulation and efficient tumor rejection, but also increases the risk of autoimmunity. PMID- 24628848 TI - Self-management programmes in stages 1-4 chronic kidney disease: a literature review. AB - BACKGROUND: Chronic kidney disease (CKD) is a complex health problem, which requires individuals to invest considerable time and energy in managing their health and adhering to multifaceted treatment regimens. OBJECTIVES: To review studies delivering self-management interventions to people with CKD (Stages 1-4) and assess whether these interventions improve patient outcomes. DESIGN: Systematic review. METHODS: Nine electronic databases (MedLine, CINAHL, EMBASE, ProQuest Health & Medical Complete, ProQuest Nursing & Allied Health, The Cochrane Library, The Joanna Briggs Institute EBP Database, Web of Science and PsycINFO) were searched using relevant terms for papers published between January 2003 and February 2013. RESULTS: The search strategy identified 2,051 papers, of which 34 were retrieved in full with only 5 studies involving 274 patients meeting the inclusion criteria. Three studies were randomised controlled trials, a variety of methods were used to measure outcomes, and four studies included a nurse on the self-management intervention team. There was little consistency in the delivery, intensity, duration and format of the self-management programmes. There is some evidence that knowledge- and health-related quality of life improved. Generally, small effects were observed for levels of adherence and progression of CKD according to physiologic measures. CONCLUSION: The effectiveness of self-management programmes in CKD (Stages 1-4) cannot be conclusively ascertained, and further research is required. It is desirable that individuals with CKD are supported to effectively self-manage day-to-day aspects of their health. PMID- 24628849 TI - Risk stratification using data from electronic medical records better predicts suicide risks than clinician assessments. AB - BACKGROUND: To date, our ability to accurately identify patients at high risk from suicidal behaviour, and thus to target interventions, has been fairly limited. This study examined a large pool of factors that are potentially associated with suicide risk from the comprehensive electronic medical record (EMR) and to derive a predictive model for 1-6 month risk. METHODS: 7,399 patients undergoing suicide risk assessment were followed up for 180 days. The dataset was divided into a derivation and validation cohorts of 4,911 and 2,488 respectively. Clinicians used an 18-point checklist of known risk factors to divide patients into low, medium, or high risk. Their predictive ability was compared with a risk stratification model derived from the EMR data. The model was based on the continuation-ratio ordinal regression method coupled with lasso (which stands for least absolute shrinkage and selection operator). RESULTS: In the year prior to suicide assessment, 66.8% of patients attended the emergency department (ED) and 41.8% had at least one hospital admission. Administrative and demographic data, along with information on prior self-harm episodes, as well as mental and physical health diagnoses were predictive of high-risk suicidal behaviour. Clinicians using the 18-point checklist were relatively poor in predicting patients at high-risk in 3 months (AUC 0.58, 95% CIs: 0.50 - 0.66). The model derived EMR was superior (AUC 0.79, 95% CIs: 0.72 - 0.84). At specificity of 0.72 (95% CIs: 0.70-0.73) the EMR model had sensitivity of 0.70 (95% CIs: 0.56-0.83). CONCLUSION: Predictive models applied to data from the EMR could improve risk stratification of patients presenting with potential suicidal behaviour. The predictive factors include known risks for suicide, but also other information relating to general health and health service utilisation. PMID- 24628850 TI - Candida species distribution, genotyping and virulence factors of Candida albicans isolated from the oral cavity of kidney transplant recipients of two geographic regions of Brazil. AB - BACKGROUND: Candida albicans is a diploid yeast that in some circumstances may cause oral or oropharyngeal infections. This investigation aimed to study the prevalence of Candida spp. and to analyze the ABC genotypes of 76 clinical isolates of C. albicans obtained from the oral cavity of kidney transplant patients from two distinct geographic regions of Brazil. METHODS: We typed 48 strains with ABC genotyping and Microsatelitte using primer M13 and tested three virulence factors in vitro: phospholipase activity, morphogenesis and the ability to evade from polymorphonuclear neutrophils phagocytosis. RESULTS: C. albicans was the most prevalent species (86.4%), followed by C. tropicalis (4.5%). C. albicans genotype A was the most prevalent (58 isolates; 76.4%), followed by genotype C (15 isolates; 19.7%) and genotype B (3 isolates; 3.9%). When Microsatellite technique with primer M13 was applied, 80% of the isolates from the South were placed within the same cluster. The majority of Genotype C strains were grouped together within two different clusters. Genotype C was considered more resistant to PMNs attack than genotypes A and B. Strains isolated from the South of Brazil showed also better ability to combat PMNs phagocytosis. CONCLUSIONS: We found a high rate of C. albicans genotype C strains isolated from the oral cavity of this group of patients. This study characterized oral C. albicans strains isolated from kidney transplant recipients and will contribute to a better understanding of the pathogenesis of oral candidiasis. PMID- 24628851 TI - Identification and characterization of the MicroRNA profile in aging rats with erectile dysfunction. AB - INTRODUCTION: Aging-related erectile dysfunction (A-ED) is a neurovascular and refractory disorder with complicated pathophysiological mechanisms and a high prevalence. MicroRNAs (miRNAs), which modulate a variety of cell functions, may be involved in the pathophysiological processes of this disorder. AIM: To investigate the miRNA profile in the corpus cavernosum (CC) of aging rats with ED, and to analyze the target genes and signaling pathways regulated by the dysregulated miRNAs. METHODS: According to the apomorphine test, the experimental animals were divided into three groups: aging rats with ED (group AE), aging rats with normal erectile function (group AN), and young rats as normal controls (group YN). After the erectile functional test, CCs from each group were then collected for histological and molecular measurements. MAIN OUTCOME MEASURES: Intracavernous pressure response to electric stimulation of the cavernous nerve was used to evaluate erectile function. Histological changes within CC were evaluated using immunofluorescent staining. GeneChip array was used to analyze the miRNA expression profiling. The miRNA profilings were further validated by real-time polymerase chain reaction. The TargetScan or DAIAN web platform and DAVID were used for bioinformatic analysis. RESULTS: Accompanied with significantly decreased erectile function, the content of smooth muscle and endothelium within the CC of rats with A-ED was significantly decreased compared with both AN group and YN group. miR-1, miR-200a, miR-203, and miR-206 were found and validated up-regulating with above twofold change in AE group. According to the bioinformatics analysis, the four up-expressing miRNAs could regulate eNOS/NO/PKG and PGE1/PKA pathways through regulating 13 target genes. CONCLUSIONS: Four miRNAs were found up-regulated significantly in the CC of rats with A-ED. The four miRNAs might play important roles in the development of A-ED by regulating the eNOS/NO/PKG and PGE1/PKA pathways despite lots of experiments still need to be validated. PMID- 24628852 TI - Expression and activity of Rac1 is negatively affected in the dehydroepiandrosterone induced polycystic ovary of mouse. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is characterized by the presence of multiple follicular cysts, giving rise to infertility due to anovulation. This syndrome affects about 10% of women, worldwide. The exact molecular mechanism leading to PCOS remains obscure. RhoGTPase has been associated with oogenesis, but its role in PCOS remains unexplored. Therefore, we attempted to elucidate the Vav-Rac1 signaling in PCOS mice model. METHODS: We generated a PCOS mice model by injecting dehydroepiandrosterone (DHEA) for a period of 20 days. The expression levels of Rac1, pRac1, Vav, pVav and Caveolin1 were analyzed by employing immuno blotting and densitometry. The association between Vav and Rac1 proteins were studied by immuno-precipitation. Furthermore, we analyzed the activity of Rac1 and levels of inhibin B and 17beta-estradiol in ovary using biochemical assays. RESULTS: The presence of multiple follicular cysts in ovary were confirmed by histology. The activity of Rac1 (GTP bound state) was significantly reduced in the PCOS ovary. Similarly, the expression levels of Rac1 and its phosphorylated form (pRac1) were decreased in PCOS in comparison to the sham ovary. The expression level and activity (phosphorylated form) of guanine nucleotide exchanger of Rac1, Vav, was moderately down-regulated. We observed comparatively increased expressions of Caveolin1, 17beta-estradiol, and inhibin B in the polycystic ovary. CONCLUSION: We conclude that hyperandrogenization (PCOS) by DHEA diminishes ovarian Rac1 and Vav expression and activity along with an increase in expression of Caveolin1. This is accompanied by an increase in the intra-ovarian level of '17 beta-estradiol and inhibin B. PMID- 24628853 TI - Improving prediction of recanalization in acute large-vessel occlusive stroke. AB - BACKGROUND: Recanalization in acute ischemic stroke with large-vessel occlusion is a potent indicator of good clinical outcome. OBJECTIVE: To identify easily available clinical and radiologic variables predicting recanalization at various occlusion sites. METHODS: All consecutive, acute stroke patients from the Acute STroke Registry and Analysis of Lausanne (2003-2011) who had a large-vessel occlusion on computed tomographic angiography (CTA) (< 12 h) were included. Recanalization status was assessed at 24 h (range: 12-48 h) with CTA, magnetic resonance angiography, or ultrasonography. Complete and partial recanalization (corresponding to the modified Treatment in Cerebral Ischemia scale 2-3) were grouped together. Patients were categorized according to occlusion site and treatment modality. RESULTS: Among 439 patients, 51% (224) showed complete or partial recanalization. In multivariate analysis, recanalization of any occlusion site was most strongly associated with endovascular treatment, including bridging therapy (odds ratio [OR] 7.1, 95% confidence interval [CI] 2.2-23.2), and less so with intravenous thrombolysis (OR 1.6, 95% CI 1.0-2.6) and recanalization treatments performed beyond guidelines (OR 2.6, 95% CI 1.2-5.7). Clot location (large vs. intermediate) and tandem pathology (the combination of intracranial occlusion and symptomatic extracranial stenosis) were other variables discriminating between recanalizers and non-recanalizers. For patients with intracranial occlusions, the variables significantly associated with recanalization after 24 h were: baseline National Institutes of Health Stroke Scale (NIHSS) (OR 1.04, 95% CI 1.02-1.1), Alberta Stroke Program Early CT Score (ASPECTS) on initial computed tomography (OR 1.2, 95% CI 1.1-1.3), and an altered level of consciousness (OR 0.2, 95% CI 0.1-0.5). CONCLUSIONS: Acute endovascular treatment is the single most important factor promoting recanalization in acute ischemic stroke. The presence of extracranial vessel stenosis or occlusion decreases recanalization rates. In patients with intracranial occlusions, higher NIHSS score and ASPECTS and normal vigilance facilitate recanalization. Clinical use of these predictors could influence recanalization strategies in individual patients. PMID- 24628854 TI - Inhibitors of differentiation-1 promotes nitrosopyrrolidine-induced transformation of HPV 16-immortalized cervical epithelial cell. AB - Our previous study implied a correlation between inhibitors of differentiation-1 (Id-1) and cervical cancer development. However, how Id-1 contributes to cervical carcinogenesis is unknown. In the present study, we used an in vitro transformation model to investigate the role of Id-1 in the transformation of cervical cells. Human papillomavirus (HPV)-immortalized cervical epithelial cells (H8) were successfully transformed by exposure to the carcinogen N nitrosopyrrolidine (NPYR). The expression of both Id-1 RNA and protein was significantly increased in transformed H8 cells, suggesting a possible role of Id 1 in cervical cell transformation. Ectopic expression of Id-1 in H8 cells potentiated NPYR-induced cell transformation. In contrast, silencing of Id-1 suppressed NPYR-induced H8 cell transformation. In addition, the expression of HPV E6 and E7 oncoproteins was upregulated while that of the tumor suppressors p53 and pRb was suppressed after H8 cell transformation. Our results suggest that Id-1 plays an oncogenic role in HPV-related cervical carcinogenesis, which sheds light on cervical cancer development mechanisms and implies that Id-1 is a potential target for cervical cancer prevention and therapy. PMID- 24628855 TI - Circulating Angiopoietin-2 levels predict mortality in kidney transplant recipients: a 4-year prospective case-cohort study. AB - Angiopoietin 2 (Angpt2) impairs endothelial function by preventing angiopoietin 1 from binding to their common endothelial-specific receptor Tie2. Here, we examined whether circulating Angpt2 predicts outcome in kidney transplant recipients. For this case-cohort study, we selected 130 kidney transplant recipients who had died or returned to dialysis within the first 2 years of follow-up of our cohort study, as well as 130 age- and gender-matched kidney transplant recipients without an event (controls) from a total of 993 kidney transplant recipients. The total of 260 selected patients were followed in median 4 years. Serum Angpt2 at baseline was measured using an in-house immunoluminometric assay. Median Angpt2 concentrations were significantly higher in patients who died [median (interquartile range--IQR) 3.6 (2.8-5.9) ng/ml] as compared to patients who did not die during the study period [2.8 (2.1-4.1) ng/ml; P < 0.001]. Ln (natural log) Angpt2 levels correlated positively with C reactive protein levels (r = 0.315, P < 0.001) and the Charlson Comorbidity Index (r = 0.188, P = 0.002) and were inversely associated with eGFR (r = -0.301, P < 0.001) hemoglobin (r = -0.269, P < 0.001), and serum albumin concentrations (r = 0.382, P < 0.001). On multivariate analyses, baseline Angpt2 levels independently predicted all-cause mortality (multivariable-adjusted hazard ratio associated with one natural log unit higher Angpt2 level: 1.70 (95% confidence interval: 1.10-2.61)). In our analysis, circulating Angpt2 was an independent predictor of all-cause mortality in stable, prevalent kidney transplant recipients. PMID- 24628856 TI - Fluorescence in situ hybridization investigation of potentially pathogenic bacteria involved in neonatal porcine diarrhea. AB - BACKGROUND: Neonatal diarrhea is a multifactorial condition commonly present on pig farms and leads to economic losses due to increased morbidity and mortality of piglets. Immature immune system and lack of fully established microbiota at birth predispose neonatal piglets to infection with enteric pathogens. The microorganisms that for decades have been associated with enteritis and diarrhea in suckling piglets are: rotavirus A, coronavirus, enterotoxigenic Escherichia coli (ETEC), Clostridium perfringens type C, Cryptosporidium spp., Giardia spp., Cystoisospora suis and Strongyloides ransomi. However, in recent years, the pig industry has experienced an increased number of neonatal diarrhea cases in which the above mentioned pathogens are no longer detected. Potentially pathogenic bacteria have recently received focus in the research on the possible etiology of neonatal diarrhea not caused by common pathogens. The primary aim of this study was to investigate the role of E. coli, Enterococcus spp., C. perfringens and C. difficile in the pathogenesis of neonatal porcine diarrhea with no established casual agents. Fluorescence in situ hybridization with oligonucleotide probes was applied on the fixed intestinal tissue samples from 51 diarrheic and 50 non diarrheic piglets collected from four Danish farms during outbreaks of neonatal diarrhea not caused by well-known enteric pathogens. Furthermore, an association between the presence of these bacteria and histological lesions was evaluated. RESULTS: The prevalence of fluorescence signals specific for E. coli, C. perfringens and C. difficile was similar in both groups of piglets. However, Enterococcus spp. was primarily detected in the diarrheic piglets. Furthermore, adherent bacteria were detected in 37 % diarrheic and 14 % non-diarrheic piglets. These bacteria were identified as E. coli and Enterococcus spp. and their presence in the intestinal mucosa was associated with histopathological changes. CONCLUSIONS: The results of this study showed that simultaneous colonization of the intestinal mucosa by adherent non-ETEC E. coli and Enterococcus spp. can be involved in the pathogenesis of neonatal porcine diarrhea. These bacteria should be considered in diagnosis of diarrhea in piglets, when detection of common, well known enteric agents is unsuccessful. PMID- 24628857 TI - AlgaePath: comprehensive analysis of metabolic pathways using transcript abundance data from next-generation sequencing in green algae. AB - BACKGROUND: Algae are important non-vascular plants that have many research applications, including high species diversity, biofuel sources, and adsorption of heavy metals and, following processing, are used as ingredients in health supplements. The increasing availability of next-generation sequencing (NGS) data for algae genomes and transcriptomes has made the development of an integrated resource for retrieving gene expression data and metabolic pathway essential for functional analysis and systems biology. In a currently available resource, gene expression profiles and biological pathways are displayed separately, making it impossible to easily search current databases to identify the cellular response mechanisms. Therefore, in this work the novel AlgaePath database was developed to retrieve transcript abundance profiles efficiently under various conditions in numerous metabolic pathways. DESCRIPTION: AlgaePath is a web-based database that integrates gene information, biological pathways, and NGS datasets for the green algae Chlamydomonas reinhardtii and Neodesmus sp. UTEX 2219-4. Users can search this database to identify transcript abundance profiles and pathway information using five query pages (Gene Search, Pathway Search, Differentially Expressed Genes (DEGs) Search, Gene Group Analysis, and Co-expression Analysis). The transcript abundance data of 45 and four samples from C. reinhardtii and Neodesmus sp. UTEX 2219-4, respectively, can be obtained directly on pathway maps. Genes that are differentially expressed between two conditions can be identified using Folds Search. The Gene Group Analysis page includes a pathway enrichment analysis, and can be used to easily compare the transcript abundance profiles of functionally related genes on a map. Finally, the Co-expression Analysis page can be used to search for co-expressed transcripts of a target gene. The results of the searches will provide a valuable reference for designing further experiments and for elucidating critical mechanisms from high-throughput data. CONCLUSIONS: AlgaePath is an effective interface that can be used to clarify the transcript response mechanisms in different metabolic pathways under various conditions. Importantly, AlgaePath can be mined to identify critical mechanisms based on high-throughput sequencing. To our knowledge, AlgaePath is the most comprehensive resource for integrating numerous databases and analysis tools in algae. The system can be accessed freely online at http://algaepath.itps.ncku.edu.tw. PMID- 24628858 TI - S-(+)-Linalool from Lippia alba: sedative and anesthetic for silver catfish (Rhamdia quelen). AB - OBJECTIVE: The present study describes the isolation of linalool from the essential oil of Lippia alba (Mill.) N. E. Brown, and its anesthetic effect in silver catfish (Rhamdia quelen) in comparison with essential oil. The potentiation of depressant effects of linalool with a benzodiazepine (BDZ) and the involvement of GABAergic system in its antagonism by flumazenil were also evaluated. STUDY DESIGN: Prospective experimental study. ANIMALS: Juvenile silver catfish unknown sex weighing mean 9.24 +/- 2.83 g (n = 6 for each experimental group per experiment). METHODS: Column chromatography was used for the isolation of S-(+)-linalool. Fish (n = 6 for each concentration) were transferred to aquaria with linalool (30, 60, and 180 MUL L(-1)) or EO of L. alba (50, 100, and 300 MUL L(-1)) to determine the induction time for anesthesia. After induction, the animals were transferred to anesthetic-free aquaria to assess their recovery time. To observe the potentiation, fish were exposed to linalool (30, 60, and 180 MUL L(-1)) in the presence or absence of BDZ (diazepam 150 MUm). In another experiment, fish exposed to linalool (30 and 180 MUL L(-1) or BDZ were transferred to an anesthetic-free aquaria containing flumazenil (5 MUm) or water to assess recovery time. RESULTS: Linalool had a similar sedation profile to the essential oil at a proportional concentration in silver catfish. However, the anesthesia profile was different. Potentiation of linalool effect occurred only when tested at low concentration. Fish exposed to BDZ showed faster anesthesia recovery in water with flumazenil, but the same did not occur with linalool. CONCLUSIONS AND CLINICAL RELEVANCE: The use of linalool as a sedative and anesthetic for silver catfish was effective at 30 and 180 MUL L(-1), respectively. The mechanism of action seems not to involve the benzodiazepine site of the GABAergic system. PMID- 24628859 TI - Impact of angina frequency on health utility values of patients with chronic stable angina. AB - BACKGROUND: Chronic angina is a profoundly symptomatic disease. We evaluated the relationship between angina frequency and health utility. METHODS: We used data from stable angina patients reporting >=3 attacks/week enrolled in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial. Angina frequency was classified using the Seattle Angina Questionnaire angina frequency (SAQAF) domain into no (100); monthly (61-99); weekly (31-60); and daily (0-30) angina. EuroQol (EQ)-5D health utility scores were derived from SAQ data using two mapping equations. Median EQ-5D utility scores for each SAQAF classification after the 6-week trial period were calculated (reported as: Equation 1/Equation 2). Changes in EQ-5D utility scores from baseline to end-of-trial for patients achieving and not achieving a >=20-point improvement in SAQAF score and improving and not improving >=1 SAQAF classification were compared. RESULTS: Median EQ-5D utility scores (n = 548) were 0.68/0.60. Compared to patients reporting no angina symptoms (n = 28; 0.89/0.87) patients reporting monthly (n = 188; 0.80/0.76), weekly (n = 283; 0.72/0.65) and daily (n = 49; 0.65/0.54) symptoms had poorer health utility (p < 0.001 for both equations). Patients improving >=1SAQAF classification (n = 254/541, 47%) experienced a median 0.05/0.07 greater improvement in EQ-5D health utility compared to those not improving >=1 classification (p < 0.001 for both equations). Patients improving >=20-points on the SAQAF (n = 355/541, 66%) experienced a median 0.06/0.07 greater improvement in health utility compared to those not achieving a >=20-point improvement (p < 0.001 for both). CONCLUSIONS: Chronic angina patient health utility decreases as angina frequency increases. Patients reporting clinically important improvement in angina frequency experience a tangible improvement in health utility. CLINICAL TRIAL REGISTRATION: NCT00091429. PMID- 24628860 TI - Patients' experiences of an initial consultation in oncology: knowing and not knowing. AB - OBJECTIVES: The aim of this paper was to explore how patients experience an initial oncology consultation. This study was part of a larger mixed methods research project designed to address the issue of improving communication and enhancing patient satisfaction with oncology consultations. DESIGN: Interpretive phenomenological analysis was used to interpret the participants' meanings of their experiences in their initial consultation. It is an idiographic approach that focuses in depth on a small set of cases in order to explore how individuals make sense of a similar experience. This retains the complexity and diversity of experiences. METHODS: In the larger study, semi-structured interviews were carried out with 36 patients as soon as possible after a consultation in oncology to explore their experiences. Five cases were selected for this study on the basis of homogeneity; they had all undergone some prior investigations of their illness, and this was their first consultation in oncology; they all provided rich accounts relating to how they had experienced the consultation. RESULTS: Patients' experiences of being given their diagnosis differed both between participants and within the same participant. Various defences seemed to be used in order to protect them from fully engaging with the knowledge they were given. Their accounts of what they wished to know in the consultation could be affected by a desire to protect themselves and/or family members from distress and by the practical need to know that may vary over time. CONCLUSION: The complexity of patients' needs and preferences regarding information means that the doctor's role in communicating that information in a patient-centred way is difficult. The findings are discussed in relation to open awareness theory as to how the emotional context of the consultation process affects information needs. Doctors need strategies to elicit information from patients about their needs from the consultation. This needs to be done at the start of consultations and throughout investigations and treatment, as needs may change over time. Statement of contribution What is already known on this subject? Patients' desire to know information is sometimes tempered with by a desire to avoid distress to themselves. Patients do not always understand or make accurate sense of what they have been told. Receiving a diagnosis of cancer is distressing for patients. What does this study add? Doctors need strategies to elicit information from patients about their needs for each consultation. This needs to be done consistently throughout the patient journey as needs may change over time. Patients control what they do or do not do with information but do not openly share this with the doctor. Our interpretations of the interviews stray beyond the conscious accounts of the consultations and draw on (unconscious) absences that may also be of significance in making sense of overall experience. The complexity of patients' needs and preferences regarding information means that the doctors' role is very difficult. Patients have a right to know but not a duty to know their diagnosis and prognosis. PMID- 24628861 TI - GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system. AB - GABAA receptors (GABAA Rs) are ligand-gated Cl(-) channels that mediate most of the fast inhibitory neurotransmission in the central nervous system (CNS). Multiple GABAA R subtypes are assembled from a family of 19 subunit genes, raising the question of the significance of this heterogeneity. In this review, we discuss the evidence that GABAA R subtypes represent distinct receptor populations with a specific spatio-temporal expression pattern in the developing and adult CNS, being endowed with unique functional and pharmacological properties, as well as being differentially regulated at the transcriptional, post-transcriptional and translational levels. GABAA R subtypes are targeted to specific subcellular domains to mediate either synaptic or extrasynaptic transmission, and their action is dynamically regulated by a vast array of molecular mechanisms to adjust the strength of inhibition to the changing needs of neuronal networks. These adaptations involve not only changing the gating or kinetic properties of GABAA Rs, but also modifying the postsynaptic scaffold organised by gephyrin to anchor specific receptor subtypes at postsynaptic sites. The significance of GABAA R heterogeneity is particularly evident during CNS development and adult neurogenesis, with different receptor subtypes fulfilling distinct steps of neuronal differentiation and maturation. Finally, analysis of the specific roles of GABAA R subtypes reveals their involvement in the pathophysiology of major CNS disorders, and opens novel perspectives for therapeutic intervention. In conclusion, GABAA R subtypes represent the substrate of a multifaceted inhibitory neurotransmission system that is dynamically regulated and performs multiple operations, contributing globally to the proper development, function and plasticity of the CNS. PMID- 24628862 TI - Simplified models for exhaled airflow from a cough with the mouth covered. AB - Covering a cough can be useful in reducing the transmission of airborne infectious diseases. However, no simple method is available in the literature for predicting the exhaled airflow from a cough with the mouth covered. This investigation used smoke to visualize the airflow exhaled by 16 human subjects. Their mouths were covered by a tissue, a cupped hand, a fist, and an elbow with and without a sleeve. This study then developed simplified models for predicting the airflow on the basis of the smoke visualization data. In addition, this investigation performed numerical simulations to assess the influence of mouth coverings on the receptor's exposure to exhaled particles. It was found that covering a cough with a tissue, a cupped hand, or an elbow can significantly reduce the horizontal velocity and cause the particles to move upward with the thermal plumes generated by a human body. In contrast with an uncovered cough, a covered cough or a cough with the head turned away may prevent direct exposure. PRACTICAL IMPLICATIONS: This study developed simplified models for predicting the exhaled airflow from a cough with the mouth covered. The proposed models can easily be used to investigate the risk of transmission of airborne infectious diseases in enclosed environments. PMID- 24628863 TI - Depth of cure of sealants polymerized with high-power light emitting diode curing lights. AB - OBJECTIVE: To determine whether recommended short curing times of three high power light emitting diode (LED) curing lights are sufficient to polymerize sealant materials. METHODS: Opaque-unfilled sealant (Delton LC Opaque), opaque filled sealant (UltraSeal XT plus), and clear-filled sealant (FluroShield) were light cured in a covered slot-mold using the manufacturers' shortest recommended curing times with three high-power LED lights (3-s VALO, 5-s Fusion, 10-s Smartlite). A 40-s cure with a quartz-tungsten halogen (QTH) light was used as control. Vickers hardness was measured 24 h after curing at the sealant surface and through the depth (0.5 mm increments) (N = 10). Results were analyzed with two-way anova (pair-wise multiple comparisons, significance level 0.05). RESULTS: The high-power LEDs did not cure the sealants as deep as the QTH. Delton LC Opaque showed the least depth of cure as hardness values beyond a depth of 0.5 mm were not measurable regardless of the curing light. Even for UltraSeal XT plus, when surface hardness was about the same with all lights, hardness decreased more rapidly with depth for the LEDs. FluroShield showed the slowest decline in hardness through the depth for all lights. CONCLUSIONS: Manufacturers' recommendations for shortest possible curing time with high-power LEDs were not sufficient for adequate polymerization of the tested sealants. PMID- 24628864 TI - Tissue storage and primer selection influence pyrosequencing-based inferences of diversity and community composition of endolichenic and endophytic fungi. AB - Next-generation sequencing technologies have provided unprecedented insights into fungal diversity and ecology. However, intrinsic biases and insufficient quality control in next-generation methods can lead to difficult-to-detect errors in estimating fungal community richness, distributions and composition. The aim of this study was to examine how tissue storage prior to DNA extraction, primer design and various quality-control approaches commonly used in 454 amplicon pyrosequencing might influence ecological inferences in studies of endophytic and endolichenic fungi. We first contrast 454 data sets generated contemporaneously from subsets of the same plant and lichen tissues that were stored in CTAB buffer, dried in silica gel or freshly frozen prior to DNA extraction. We show that storage in silica gel markedly limits the recovery of sequence data and yields a small fraction of the diversity observed by the other two methods. Using lichen mycobiont sequences as internal positive controls, we next show that despite careful filtering of raw reads and utilization of current best-practice OTU clustering methods, homopolymer errors in sequences representing rare taxa artificially increased estimates of richness c. 15-fold in a model data set. Third, we show that inferences regarding endolichenic diversity can be improved using a novel primer that reduces amplification of the mycobiont. Together, our results provide a rationale for selecting tissue treatment regimes prior to DNA extraction, demonstrate the efficacy of reducing mycobiont amplification in studies of the fungal microbiomes of lichen thalli and highlight the difficulties in differentiating true information about fungal biodiversity from methodological artefacts. PMID- 24628865 TI - An evaluation of rabies vaccination rates among canines and felines involved in biting incidents within the Wellington-Dufferin-Guelph Public Health Department. AB - The objectives of this study were to determine the rate of animal bite incidents occurring in the human population of a local health department, and to determine the proportion of these canines and felines that were not up to date on their rabies vaccination at the time the incident occurred. Data were obtained from animal bite incidents reported to Wellington-Dufferin-Guelph Public Health during 2010 and 2011. Descriptive statistics of 718 eligible reports revealed the average rate of animal biting was 1.55 bites per 1000 residents per year. Approximately 54% of these animals were vaccinated against rabies, 32% were not up to date with their rabies vaccination, and the remaining 14.5% were of unknown status. The unit of analysis was the municipality, and the four outcomes of interest were: (i) number of animal bite incidents per 1000 residents, (ii) number of dog bite incidents per 1000 residents, (iii) proportion of animals involved in bite incidents that were not up to date with their rabies vaccination, and (iv) proportion of dogs that were not up to date. Associations between the outcomes and selected demographic variables were investigated using regression analysis. The number of veterinary clinics per 10,000 residents, and whether the municipality was urban or rural were identified as significant predictors for the number of animal bites per 1000 residents, and the number of dog bites. There were no significant predictors for the proportion of unvaccinated animals or dogs. Spatial clustering and the location of spatial clusters were assessed using the empirical Bayes index and spatial scan test. This analysis identified five municipalities within the health department that have a high rate of biting incidents and a high proportion of animals that were not up to date on their rabies vaccination. Such municipalities are ideal for targeted educational campaigns regarding the importance of vaccination in pets. PMID- 24628867 TI - Genome sequence of type strain of Staphylococcus aureus subsp. aureus. AB - BACKGROUND: Staphylococcus aureus is a pathogen that causes food poisoning and community-associated infection with antibiotic resistance. This species is an indigenous intestinal microbe found in infants and not found in adult intestine. The relatively small genome size and rapid evolution of antibiotic resistance genes in the species have been drawing an increasing attention in public health. To extend our understanding of the species and use the genome data for comparative genomic studies, we sequenced the type strain of S. aureus subsp. aureus DSM 20231T. RESULTS: Seventeen contigs were generated using hybrid assembly of sequences derived from the Roche 454 and Illumina systems. The length of the genome sequence was 2,902,619 bases with a G + C content of 32.8%. Among the 2,550 annotated CDSs, 44 CDSs were annotated to antibiotic resistance genes and 13 CDSs were related to methicillin resistance. It is interesting to note that this strain was first isolated in 1884 before methicillin was generally used on patients. CONCLUSIONS: The present study analyzed the genome sequence of S. aureus subsp. aureus type strain as the reference sequence for comparative genomic analyses of clinical isolates. Methicillin resistance genes found in the genome indicate the presence of antibiotic resistance mechanism prior to the usage of antibiotics. Further comparative genomic studies of methicillin resistant strains based on this reference genome would help to understand the evolution of resistance mechanism and dissemination of resistance genes. PMID- 24628866 TI - The association between cerebral developmental venous anomaly and concomitant cavernous malformation: an observational study using magnetic resonance imaging. AB - BACKGROUND: Some studies reported that cerebral developmental venous anomaly (DVA) is often concurrent with cavernous malformation (CM). But there is lack of statistical evidence and study of bulk cases. The factors associated with concurrency are still unknown. The purpose of this study was to determine the prevalence of concomitant DVA and CM using observational data on Chinese patients and analyze the factors associated with the concurrency. METHODS: The records of all cranial magnetic resonance imaging (MRI) performed between January 2001 and December 2012 in Beijing Tiantan Hospital were reviewed retrospectively. The DVA and CM cases were selected according to imaging reports that met diagnostic criteria. Statistical analysis was performed using the Pearson chi-square statistic for binary variables and multivariable logistic regression analysis for predictors associated with the concurrent CM. RESULTS: We reviewed a total of 165,230 cranial MR images performed during the previous 12 year period, and identified 1,839 cases that met DVA radiographic criteria. There were 205 patients who presented concomitant CM among the 1,839 DVAs. The CM prevalence in DVA cases (11.1%) was significantly higher than that in the non-DVA cases (2.3%) (P<0.01). In the multivariate analysis, we found that DVAs with three or more medullary veins in the same MRI section (adjusted OR = 2.37, 95% CI: 1.73-3.24), infratentorial DVAs (adjusted OR = 1.71, 95% CI: 1.26-2.33) and multiple DVAs (adjusted OR = 2.08, 95% CI: 1.04-4.16) have a higher likelihood of being concomitant with CM. CONCLUSIONS: CM are prone to coexisting with DVA. There is a higher chance of concurrent CM with DVA when the DVA has three or more medullary veins in the same MRI scanning section, when the DVA is infratentorial, and when there are multiple DVAs. When diagnosing DVA cases, physicians should be alerted to the possibility of concurrent CM. PMID- 24628868 TI - Superficial temporal artery pseudoaneurysm following trigeminal nerve stimulator placement. PMID- 24628869 TI - Mechanical ventricular assist device as a bridge to recovery post-ABO incompatible heart transplantation for failed Fontan circulation. AB - A girl received an ABO-incompatible heart transplantation (ABOiHTx) at the age of 3.5 years for failed univentricular palliation with protein-losing enteropathy (PLE). She was born with a hypoplastic left heart syndrome and underwent multistage palliation to a Fontan circulation at 21/2 years of age. After the Fontan surgery, she developed PLE, necessitating a Fontan revision, followed by a Fontan takedown and eventually HTx, which was performed with a blood group B heart into an O recipient. Right ventricular (RV) failure secondary to increased pulmonary vascular resistance (PVR) evolved immediately after HTx. A temporary right ventricular assist device (RVAD) was implanted and later switched to a pneumatic pulsatile RVAD. With the adaption of PVR on the RVAD, the PLE resolved and the RVAD was explanted. In the following 12 months, she developed multiple relapses of PLE which eventually resolved after exchange of the calcineurin inhibitor. PMID- 24628870 TI - Ethanol extract of Poria cocos reduces the production of inflammatory mediators by suppressing the NF-kappaB signaling pathway in lipopolysaccharide-stimulated RAW 264.7 macrophages. AB - BACKGROUND: Poria cocos Wolf, a medicinal fungus, is widely used in traditional medicines in East Asian countries owing to its various therapeutic potentials. Although several studies have demonstrated the anti-inflammatory activity of this fungus, its underlying mechanisms have not yet been clearly defined. METHODS: In the present study, we have demonstrated the anti-inflammatory effects of ethanol extract of P. cocos (EEPC) in lipopolysaccaride (LPS)-stimulated RAW 264.7 macrophages. As inflammatory parameters, the productions of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1beta and tumor necrosis factor (TNF) alpha were evaluated. We also examined the EEPC's effect on the nuclear factor kappaB (NF-kappaB) signaling pathway. RESULTS: Our results indicated that EEPC exhibits a potent inhibitory effect on NO production and inhibits PGE2 release in LPS-induced macrophages without affecting cell viability. EEPC also significantly attenuated LPS-induced secretion of inflammatory cytokines IL-1beta and TNF alpha. Additionally, LPS-induced expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, IL-1beta, and TNF-alpha was decreased by pre-treatment with EEPC at the transcriptional level. Moreover, EEPC clearly inhibited LPS induced nuclear translocation of NF-kappaB p65 subunits, which correlated with EEPC's inhibitory effects on inhibitor kappaB (IkappaB) degradation. Moreover, EEPC clearly suppressed the LPS-induced DNA-binding activity of NF-kappaB, as well as the nuclear translocation of the NF-kappaB p65, which correlated with EEPC's inhibitory effects on inhibitor kappaB (IkappaB) degradation. CONCLUSIONS: Taken together, our data indicates that EEPC targets the inflammatory response of macrophages via inhibition of iNOS, COX-2, IL-1beta, and TNF-alpha through inactivation of the NF-kappaB signaling pathway, supporting the pharmacological basis of P. cocos as a traditional herbal medicine for treatment of inflammation and its associated disorders. PMID- 24628871 TI - Evaluation of the nasal microbiota in slaughter-age pigs and the impact on nasal methicillin-resistant Staphylococcus aureus (MRSA) carriage. AB - BACKGROUND: The nasal microbiota of pigs has been poorly assessed but could play a role in carriage of important microorganisms such as methicillin-resistant Staphylococcus aureus (MRSA). The objectives of this study were to describe the nasal microbiota in slaughter age pigs, to evaluate the impact of farm management on the nasal microbiota and to provide a preliminary assessment of the influence of the microbiota on MRSA carriage. RESULTS: Nasal swabs were collected from five MRSA positive and eight MRSA negative pigs on one farm that used a liquid feeding system and routine tylosin treatment, and seven MRSA negative pigs from an antibiotic-free farm that used conventional feeding. A total of 946310 sequences passed all quality control filters. The number of sequences per sample ranged from 4307 to 165656 (mean 56092, SD 40007). CatchAll analysis of richness predicted a mean of 1749 OTUs (range 213-3736, SD 996). Overall, 6291 OTUs were identified, yet 5125 (81%) were identified less than 10 times and the 12 most abundant OTUs accounted for 80.7% of sequences. Proteobacteria predominated in all but two samples. Liquid-fed/tylosin-exposed pigs had significantly lower relative abundances of Verrucomicrobia (P = 0.004), Fibrobacteres (P = <0.0001) and sequences unclassified at the phylum level (P = 0.028). When comparing only liquid-fed pigs, MRSA carriers had significantly more Bacteroidetes (P = 0.037) than MRSA negative pigs. 124 genera were identified, with Moraxella accounting for 35.4% of sequences. In the Jaccard index tree, five of eight MRSA positive pigs clustered closely together, as did six of the seven conventionally-fed pigs. A significant difference was identified between conventional and liquid-fed pigs using parsimony test with the Jaccard (P < 0.001) but not the Yue&Clayton (P = 0.26) index. There were no significant differences between MRSA positive and negative pigs (P = 0.133 and 0.175). OTUs belonging to Firmicutes were the main indicators of MRSA negative pigs, including Lactobacillus and another Lactobacillaceae and Staphylococcus. CONCLUSIONS: Farm management can influence the nasal microbiota in pigs, but no impact of the microbiota on MRSA carriage was identified. Studies that further define the impact of management on the microbiota, and the impact of the microbiota on pathogen carriage are indicated. PMID- 24628872 TI - Primary cutaneous follicle centre lymphoma presenting as diffuse facial erythema. PMID- 24628873 TI - Traditional measures of normal anal sphincter function using high-resolution anorectal manometry (HRAM) in 115 healthy volunteers. AB - BACKGROUND: High-resolution anorectal manometry (HRAM) is a relatively new method for collection and interpretation of data relevant to sphincteric function, and for the first time allows a global appreciation of the anorectum as a functional unit. Historically, traditional anal manometry has been plagued by lack of standardization and healthy volunteer data of variable quality. The aims of this study were: (i) to obtain normative data sets for traditional measures of anorectal function using HRAM in healthy subjects and; (ii) to qualitatively describe novel physiological phenomena, which may be of future relevance when this method is applied to patients. METHODS: 115 healthy subjects (96 female) underwent HRAM using a 10 channel, 12F solid-state catheter. Measurements were performed during rest, squeeze, cough, and simulated defecation (push). Data were displayed as color contour plots and analysed using a commercially available manometric system (Solar GI HRM v9.1, Medical Measurement Systems). Associations between age, gender and parity were subsequently explored. KEY RESULTS: HRAM color contour plots provided clear delineation of the high-pressure zone within the anal canal and showed recruitment during maneuvers that altered intra-anal pressures. Automated analysis produced quantitative data, which have been presented on the basis of gender and parity due to the effect of these covariates on some sphincter functions. In line with traditional manometry, some age and gender differences were seen. Males had a greater functional anal canal length and anal pressures during the cough maneuver. Parity in females was associated with reduced squeeze increments. CONCLUSIONS & INFERENCES: The study provides a large healthy volunteer dataset and parameters of traditional measures of anorectal function. A number of novel phenomena are appreciated, the significance of which will require further analysis and comparisons with patient populations. PMID- 24628874 TI - Oxygen and pulse oximetry in childhood pneumonia: surveys of clinicians and student clinicians in Cambodia. AB - OBJECTIVE: To better understand the availability of oxygen and pulse oximetry, barriers to use, clinician perceptions and practices regarding their role in the management of childhood pneumonia, and the formal education and training regarding these technologies received by student clinicians in Cambodia. METHODS: In the clinician survey, we surveyed 81 clinicians practising at all national paediatric, provincial and district referral hospitals throughout Cambodia. Respondents were primarily physicians whose scope of practice included paediatrics, and most reported the presence of oxygen (93% (95% confidence interval (CI) [87, 98])) but less availability of pulse oximetry (51% (95% CI [39, 61])). RESULTS: Common barriers to use included a lack of policies and guidelines, as well as a lack of training. In the student clinician survey, 332 graduating medical and nursing students were surveyed, and most reported learning about oxygen (96% (95% CI [94, 98])) and pulse oximetry (72% (95% CI [67, 77])) during their training. CONCLUSIONS: Data from both surveys indicate that despite their utility, oxygen and pulse oximetry may be underused in Cambodia. The reported barriers and perceptions of the tools indicate a clear role for improved training for clinicians and students on the use of oxygen and pulse oximetry, the value of oxygen and pulse oximetry for managing childhood pneumonia, and the need for improved policies and guidelines governing their use. PMID- 24628875 TI - The thrombospondin-1 receptor CD36 is an important mediator of ovarian angiogenesis and folliculogenesis. AB - BACKGROUND: Ovarian angiogenesis is a complex process that is regulated by a balance between pro- and anti-angiogenic factors. Physiological processes within the ovary, such as folliculogenesis, ovulation, and luteal formation are dependent upon adequate vascularization and anything that disrupts normal angiogenic processes may result in ovarian dysfunction, and possibly infertility. The objective of this study was to evaluate the role of the thrombospondin-1 (TSP 1) receptor CD36 in mediating ovarian angiogenesis and regulating ovarian function. METHODS: The role of CD36 was evaluated in granulosa cells in vitro and ovarian morphology and protein expression were determined in wild type and CD36 null mice. RESULTS: In vitro, CD36 inhibition increased granulosa cell proliferation and decreased apoptosis. Granulosa cells in which CD36 was knocked down also exhibited an increase in expression of survival and angiogenic proteins. Ovaries from CD36 null mice were hypervascularized, with increased expression of pro-angiogenic vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. Ovaries from CD36 null mice contained an increase in the numbers of pre-ovulatory follicles and decreased numbers of corpora lutea. CD36 null mice also had fewer number of offspring compared to wild type controls. CONCLUSIONS: The results from this study demonstrate that CD36 is integral to the regulation of ovarian angiogenesis by TSP-1 and the expression of these family members may be useful in the control of ovarian vascular disorders. PMID- 24628876 TI - The effect of epidural injection speed on epidural pressure and distribution of solution in anesthetized dogs. AB - OBJECTIVE: To determine the effect of injection speed on epidural pressure (EP), injection pressure (IP), epidural distribution (ED) of solution, and extent of sensory blockade (SB) during lumbosacral epidural anesthesia in dogs. STUDY DESIGN: Prospective experimental trial. ANIMALS: Ten healthy adult Beagle dogs weighing 8.7 +/- 1.6 kg. METHODS: General anesthesia was induced with propofol administered intravenously and maintained with isoflurane. Keeping the dogs in sternal recumbency, two spinal needles connected to electrical pressure transducers were inserted into the L6-L7 and the L7-S1 intervertebral epidural spaces for EP and IP measurements, respectively. Bupivacaine 0.5% diluted in iohexol was administered epidurally to each dog via spinal needle at L7-S1 intervertebral space, at two rates of injection (1 and 2 mL minute(-1) groups), with a 1-week washout period. Epidural distribution was verified with computed tomography, and SB was evaluated after arousal by pinching the skin with a mosquito hemostatic forceps over the vertebral dermatomes. The results were analyzed according to each injection speed, using paired t- and Wilcoxon signed rank tests. RESULTS: Mean +/- SD of baseline EP and IP values were 2.1 +/- 6.1 and 2.6 +/- 7.1 mmHg, respectively. Significant differences were observed between 1 and 2 mL minute(-1) groups for peak EP (23.1 +/- 8.5 and 35.0 +/- 14.5 mmHg, p = 0.047) and peak IP (68.5 +/- 10.7 and 144.7 +/- 32.6 mmHg, p <0.001). However, the median (range) of the ED, 11.5 (4-22) and 12 (5-21) vertebrae, and SB, 3.5 (0 20) and 1 (0-20) dermatomes, values of the two groups were not related to injection speed. CONCLUSIONS AND CLINICAL RELEVANCE: The EP profile during injection was measured by separating the injection and pressure monitoring lines. The increase in epidural injection speed increased the EP, but not the ED or the SB in dogs. PMID- 24628877 TI - Economic solvency in the context of violence against women: a concept analysis. AB - The aim of this concept analysis is to define economic solvency in the context of violence against women. Poverty, or lack of resources, is often discussed as a risk factor for intimate partner violence. The concept of economic solvency, which may be a protective factor for women, is less often discussed and not well defined. Databases searched for the analysis included EBSCOhost, CINAHL, PubMed and Gender Watch. The Rodgers evolutionary method was used to perform the concept analysis. A total of 134 articles were retrieved, using the specified search terms 'economic solvency and women', 'economic self-reliance and women' and 'economic self-sufficiency and women'. Articles were included if they were peer reviewed, contained the keywords with sufficient context to determine the author's intended meaning, and focused on women only or contrasted men to women. Thirty-five articles were used in the concept analysis. The definition of economic solvency drawn from the concept analysis is: a long-term state that occurs when there is societal structure that supports gender equity and external resources are available and can be used by a woman who has necessary human capital, sustainable employment and independence. Just as poverty and violence are cyclical, so are economic solvency and empowerment of women. To decrease women's risk of intimate partner violence around the world and further improve the status of women, we recommend continued research on economic solvency, including the individual, family, community and societal resources required to obtain economic solvency and the human capital characteristics needed for sustainability. PMID- 24628878 TI - Genomic structure of nucleotide diversity among Lyon rat models of metabolic syndrome. AB - BACKGROUND: The metabolic syndrome (MetS), a complex disorder involving hypertension, obesity, dyslipidemia and insulin resistance, is a major risk factor for heart disease, stroke, and diabetes. The Lyon Hypertensive (LH), Lyon Normotensive (LN) and Lyon Low-pressure (LL) rats are inbred strains simultaneously derived from a common outbred Sprague Dawley colony by selection for high, normal, and low blood pressure, respectively. Further studies found that LH is a MetS susceptible strain, while LN is resistant and LL has an intermediate phenotype. Whole genome sequencing determined that, while the strains are phenotypically divergent, they are nearly 98% similar at the nucleotide level. Using the sequence of the three strains, we applied an approach that harnesses the distribution of Observed Strain Differences (OSD), or nucleotide diversity, to distinguish genomic regions of identity-by-descent (IBD) from those with divergent ancestry between the three strains. This information was then used to fine-map QTL identified in a cross between LH and LN rats in order to identify candidate genes causing the phenotypes. RESULTS: We identified haplotypes that, in total, contain at least 95% of the identifiable polymorphisms between the Lyon strains that are likely of differing ancestral origin. By intersecting the identified haplotype blocks with Quantitative Trait Loci (QTL) previously identified in a cross between LH and LN strains, the candidate QTL regions have been narrowed by 78%. Because the genome sequence has been determined, we were further able to identify putative functional variants in genes that are candidates for causing the QTL. CONCLUSIONS: Whole genome sequence analysis between the LH, LN, and LL strains identified the haplotype structure of these three strains and identified candidate genes with sequence variants predicted to affect gene function. This approach, merged with additional integrative genetics approaches, will likely lead to novel mechanisms underlying complex disease and provide new drug targets and therapies. PMID- 24628880 TI - The complete genome sequence for putative H2- and S-oxidizer Candidatus Sulfuricurvum sp., assembled de novo from an aquifer-derived metagenome. AB - We reconstructed the complete 2.4 Mb-long genome of a previously uncultivated epsilonproteobacterium, Candidatus Sulfuricurvum sp. RIFRC-1, via assembly of short-read shotgun metagenomic data using a complexity reduction approach. Genome based comparisons indicate the bacterium is a novel species within the Sulfuricurvum genus, which contains one cultivated representative, S. kujiense. Divergence between the species appears due in part to extensive genomic rearrangements, gene loss and chromosomal versus plasmid encoding of certain (respiratory) genes by RIFRC-1. Deoxyribonucleic acid for the genome was obtained from terrestrial aquifer sediment, in which RIFRC-1 comprised ~ 47% of the bacterial community. Genomic evidence suggests RIFRC-1 is a chemolithoautotrophic diazotroph capable of deriving energy for growth by microaerobic or nitrate /nitric oxide-dependent oxidation of S degrees , sulfide or sulfite or H2oxidation. Carbon may be fixed via the reductive tricarboxylic acid cycle. Consistent with these physiological attributes, the local aquifer was microoxic with small concentrations of available nitrate, small but elevated concentrations of reduced sulfur and NH(4)(+) /NH3-limited. Additionally, various mechanisms for heavy metal and metalloid tolerance and virulence point to a lifestyle well adapted for metal(loid)-rich environments and a shared evolutionary past with pathogenic Epsilonproteobacteria. Results expand upon recent findings highlighting the potential importance of sulfur and hydrogen metabolism in the terrestrial subsurface. PMID- 24628879 TI - Determining the impact of smoking point of sale legislation among youth (Display) study: a protocol for an evaluation of public health policy. AB - BACKGROUND: Tobacco advertising and product promotions have been largely banned in the UK but point of sale (POS) tobacco advertising is one of the few places where tobacco products may be legitimately advertised. POS displays have been shown to increase susceptibility to smoking, experimentation and initiation into smoking. These displays may also influence perceived prevalence of smoking and the perception that tobacco products are easily obtained and are a 'normal' product. A ban of POS tobacco advertising was introduced in Scotland in large tobacco retail outlets of over 280 m2 internal sales floor areas (mainly supermarkets) in April 2013 and will be extended to include smaller tobacco retail outlets in April 2015. However, the impact of POS bans on smoking attitudes, behaviours and prevalence has yet to be determined. METHODS/DESIGN: This study has a multi-modal before and after design and uses mixed methods to collect data, at baseline and then with longitudinal follow-up for 4 years, in four purposively selected communities. For the purposes of the study, community is defined as the catchment areas of the secondary schools selected for study. There are four main components to the on-going study. In each of the four communities, at baseline and in follow-up years, there will be: mapping and spatial analyses of tobacco retail outlets; tobacco advertising and marketing audits of tobacco retail outlets most used by young people; cross-sectional school surveys of secondary school pupils; and focus group interviews with purposive samples of secondary school pupils. The tobacco audit is supplemented by interviews and observations conducted with a panel of tobacco retailers recruited from four matched communities. DISCUSSION: This study examines the impact of the implementation of both a partial and comprehensive ban on point of sale (POS) tobacco advertising on attitudes to smoking, brand awareness, perceived ease of access to tobacco products and youth smoking prevalence. The results will be of considerable interest to policy makers both from the UK and other jurisdictions where they are considering the development and implementation of similar legislation. PMID- 24628881 TI - Skin reduction technique for correction of lateral deviation of the erect straight penis. AB - INTRODUCTION: Lateral deviation of the erect straight penis (LDESP) refers to a penis that despite being straight in the erect state, points laterally, yet can be directed forward manually without the use of force. While LDESP should not impose a negative impact on sexual function, it may have a negative cosmetic impact. AIM: This work describes skin reduction technique (SRT) for correction of LDESP. METHODS: Counseling was offered to males with LDESP after excluding other abnormalities. Surgery was performed in case of failed counseling. In the erect state, the degree and direction of LDESP were noted. Skin on the base of the penis on the contralateral side of LDESP was excised from the base of the penis and the edges approximated to correct LDESP. Further excision was repeated if needed. The incision was closed in two layers. MAIN OUTCOME MEASURE: Long-term efficacy of SRT was the main outcome measure. RESULTS: Out of 183 males with LDESP, 66.7% were not sexually active. Counseling relieved 91.8% of cases. Fifteen patients insisted on surgery, mostly from among the sexually active where the complaint was mutual from the patient and partner. SRT resulted in full correction of the angle of erection in 12 cases out of 15. Two had minimal recurrence, and one had major recurrence indicating re-SRT. CONCLUSIONS: LDESP is more common a complaint among those who have not experienced coital relationship, and is mostly relieved by counseling. However, sexually active males with this complaint are more difficult to relieve by counseling. A minority of patients may opt for surgical correction. SRT achieves a forward erection in such patients, is minimally invasive, and relatively safe, provided the angle of erection can be corrected manually without force. Shaeer O. Skin reduction technique for correction of lateral deviation of the erect straight penis. PMID- 24628882 TI - Annual failure rates and marginal bone-level changes of immediate compared to conventional loading of dental implants. A systematic review of the literature and meta-analysis. AB - BACKGROUND: Immediate loading of dental implants appears to be a successful option. Questions still remain whether annual failure rates (AFRs) as well as annual marginal bone-level changes are comparable with conventionally loaded implants. HYPOTHESIS: Immediately loaded implants (<=24 h after implantation) do not show different annual survival rates or peri-implant bone-level changes as compared to conventionally loaded implants (>=3 months after implantation). MATERIAL AND METHODS: An electronic search in the National Library of Medicine and in Cochrane Central Register of Controlled Trials was performed for articles published up to November 2013. Only publications in English were considered. Additionally, the bibliographies of the full-text papers were searched. Primary outcome variable was percentage AFR; secondary outcome variable was annual radiographic bone-level change. RESULTS: Electronic search yielded 154 full-text articles; ten randomized controlled clinical trials were eventually meta analyzed. Annual failure rates were 2.3% and 3.4% for conventionally and immediately loaded implants, respectively. No difference in implant failure rates was found (RR: 0.82). Regarding marginal bone-level changes, the weighted mean difference (WMD) between immediate and conventional loading amounted to 0.02 mm at 1 year (P > 0.05), to 0.08 mm at 2 years (P > 0.05), -0.10 mm at 3 years (P > 0.05) and -0.3 mm at 5 years (P < 0.05). The total WMD for the combined follow-up was 0.01 mm (P > 0.05). CONCLUSION: No clinically relevant differences regarding annual failure rates or radiographic bone-level changes between conventionally and immediately loaded implants can be found for up to 5 years of follow-up. PMID- 24628883 TI - Response to cold acclimation in diapause pupae of Hyles euphorbiae (Lepidoptera: Sphingidae): candidate biomarker identification using proteomics. AB - The distribution range of Hyles euphorbiae covers distinct climates across the Palaearctic. Previous investigations showed a correlation between mitochondrial DNA identity of populations and climatic conditions related to winter; however, the lack of biomarkers hampers investigations to test whether geographically distinct populations do show specific molecular responses to low temperatures or whether they possess specific genetic identity at loci functionally related to cold response. The present study was designed to identify candidate protein biomarkers and biological processes that are associated with cold acclimation of overwintering H. euphorbiae diapause pupae. Specimens taken from a single central European population were gradually cooled from 20 degrees C to -2 degrees C over 36 days and 12 differentially abundant proteins were identified. In addition, DeepSuperSAGE sequencing technology was applied to study differentially regulated genes. There was incongruence between differentially abundant proteins and differentially expressed genes, but functional characteristics of regulated proteins and analyses of gene ontology term enrichment among differentially regulated genes pointed to activation of the same biological processes, e.g. oxidative stress response. As proteins represent biologically active molecules, candidate biomarkers derived from proteomics are considered well suited to explore intraspecific patterns of local adaptation to different climates. PMID- 24628884 TI - Social network correlates of participation in telephone continuing care for alcohol dependence. AB - BACKGROUND AND OBJECTIVES: Research on face-to-face treatment for substance misuse suggests that patients' social networks may impact treatment entry and participation, but there has been no similar research on entry and participation in telephone-based continuing care. We examined whether alcohol-specific social support predicted engagement and participation in telephone continuing care for alcohol dependence, and whether treatment participation resulted in beneficial changes in participants' social networks. METHODS: Participants were 252 adults (162 male) enrolled in a randomized clinical trial testing the effectiveness of telephone continuing care for alcohol dependence. Participants who completed 3 weeks of intensive outpatient treatment were randomly assigned to treatment as usual, telephone monitoring (TM; N = 83), or telephone monitoring and brief counseling (TMC; N = 83). TM and TMC included 18 months of telephone treatment. Alcohol-specific social support was measured with the Important People Inventory at baseline and 6, 12, 18, and 24-month follow-up. RESULTS: Alcohol-specific social support did not predict entry into TM or TMC. Among those who entered telephone treatment (N = 127), participants with higher network percentage of daily drinkers, higher percentage of network members who accept drinking, and lower percentage of network members who do not accept drinking completed more continuing care calls. There was no effect of continuing care participation on alcohol-specific social support over 24 months of follow-up. CONCLUSION: Participants with more problematic social networks may self-select additional support in the form of telephone continuing care. Telephone continuing care does not appear to result in social network change. PMID- 24628885 TI - Immunohistochemical localization and mRNA quantification of osteopontin and Tamm Horsfall protein in canine renal tissue after potassium oxalate injection. AB - BACKGROUND: Urinary macromolecules contribute to promoting or inhibiting crystal retention in renal tissue and stone formation. Osteopontin (OPN) and Tamm Horsfall protein (THP) are the most important proteins involved in this process. Although these two proteins were discovered a long time ago, their role in setting kidney stone formation has not yet been fully investigated. We conducted a study to explore the role of OPN and THP in canine renal oxalosis. Ten dogs were carefully examined prior to the study. Six dogs were assigned to the treatment group and were injected intravenously with 0.5 M potassium oxalate (KOx). The other four dogs were assigned to a control group and were injected intravenously with 0.9% NaCl three times a day (tid) for 7 consecutive days. Then kidneys were harvested for pathological, immunohistochemical examination and OPN and THP mRNA expression levels were quantified by quantitative real-time PCR. RESULTS: Calcium oxalate crystals deposition was observed in both renal cortex and medulla. Immunohistochemistry examination revealed increased tissue expression of OPN in the renal tissue while THP was significantly decreased. OPN mRNA expression level significantly increased in treated dogs compared to that in the controls, while THP mRNA level significantly decreased. CONCLUSION: Together, these results suggest that THP and OPN are both involved in the pathogenesis and response to oxalate exposure. PMID- 24628886 TI - Notch signaling in the pigmented epithelium of the anterior eye segment promotes ciliary body development at the expense of iris formation. AB - The ciliary body and iris are pigmented epithelial structures in the anterior eye segment that function to maintain correct intra-ocular pressure and regulate exposure of the internal eye structures to light, respectively. The cellular and molecular factors that mediate the development of the ciliary body and iris from the ocular pigmented epithelium remain to be fully elucidated. Here, we have investigated the role of Notch signaling during the development of the anterior pigmented epithelium by using genetic loss- and gain-of-function approaches. Loss of canonical Notch signaling results in normal iris development but absence of the ciliary body. This causes progressive hypotony and over time leads to phthisis bulbi, a condition characterized by shrinkage of the eye and loss of structure/function. Conversely, Notch gain-of-function results in aniridia and profound ciliary body hyperplasia, which causes ocular hypertension and glaucoma like disease. Collectively, these data indicate that Notch signaling promotes ciliary body development at the expense of iris formation and reveals novel animal models of human ocular pathologies. PMID- 24628887 TI - Isolation of a Campylobacter lanienae-like bacterium from laboratory chinchillas (Chinchilla laniger). AB - Routine necropsies of 27 asymptomatic juvenile chinchillas revealed a high prevalence of gastric ulcers with microscopic lymphoplasmacytic gastroenteritis and typhlocolitis. Polymerase chain reaction (PCR) analysis using Campylobacter genus-specific partial 16S rRNA primers revealed the presence of Campylobacter spp. DNA in the faeces of 12 of 27 animals (44.4%). Species-specific partial 16S rRNA PCR and sequencing confirmed that these animals were colonized with Campylobacter lanienae, a gram-negative, microaerophilic bacterium that was first identified on routine faecal screening of slaughterhouse employees and subsequently isolated from faeces of livestock. Campylobacter lanienae was isolated from the faeces of six PCR-positive animals and identified with species specific PCR and full 16S rRNA sequencing. Phylogenetic analysis showed that these isolates clustered with C. lanienae strain NCTC 13004. PCR analysis of DNA extracted from gastrointestinal tissues revealed the presence of C. lanienae DNA in the caecum and colon of these chinchillas. Gastrointestinal lesions were scored and compared between C. lanienae-positive and C. lanienae-negative animals. There was no correlation between colonization status and lesion severity in the stomach, liver, duodenum, or colon. Possible routes of C. lanienae infection in chinchillas could include waterborne transmission and faecal-oral transmission from wild mice and rats or livestock. Based on these findings, the authors conclude that C. lanienae colonizes the lower bowel of chinchillas in the absence of clinical disease. This is the first report of C. lanienae in any rodent species. Campylobacter lanienae isolates from different mammalian species demonstrate heterogeneity by 16S rRNA sequence comparison. Analysis using rpoB suggests that isolates and clones currently identified as C. lanienae may represent multiple species or subspecies. PMID- 24628889 TI - Performance evaluation of a health insurance in Nigeria using optimal resource use: health care providers perspectives. AB - BACKGROUND: Performance measures are often neglected during the transition period of national health insurance scheme implementation in many low and middle income countries. These measurements evaluate the extent to which various aspects of the schemes meet their key objectives. This study assesses the implementation of a health insurance scheme using optimal resource use domains and examines possible factors that influence each domain, according to providers' perspectives. METHODS: A retrospective, cross-sectional survey was done between August and December 2010 in Kaduna state, and 466 health care provider personnel were interviewed. Optimal-resource-use was defined in four domains: provider payment mechanism (capitation and fee-for-service payment methods), benefit package, administrative efficiency, and active monitoring mechanism. Logistic regression analysis was used to identify provider factors that may influence each domain. RESULTS: In the provider payment mechanism domain, capitation payment method (95%) performed better than fee-for-service payment method (62%). Benefit package domain performed strongly (97%), while active monitoring mechanism performed weakly (37%). In the administrative efficiency domain, both promptness of referral system (80%) and prompt arrival of funds (93%) performed well. At the individual level, providers with fewer enrolees encountered difficulties with reimbursement. Other factors significantly influenced each of the optimal resource-use domains. CONCLUSIONS: Fee-for-service payment method and claims review, in the provider payment and active monitoring mechanisms, respectively, performed weakly according to the providers' (at individual-level) perspectives. A short-fall on the supply-side of health insurance could lead to a direct or indirect adverse effect on the demand-side of the scheme. Capitation payment per enrolees should be revised to conform to economic circumstances. Performance indicators and providers' characteristics and experiences associated with resource use can assist policy makers to monitor and evaluate health insurance implementation. PMID- 24628888 TI - Structural and functional interaction of fatty acids with human liver fatty acid binding protein (L-FABP) T94A variant. AB - The human liver fatty acid-binding protein (L-FABP) T94A variant, the most common in the FABP family, has been associated with elevated liver triglyceride levels. How this amino acid substitution elicits these effects is not known. This issue was addressed using human recombinant wild-type (WT) and T94A variant L-FABP proteins as well as cultured primary human hepatocytes expressing the respective proteins (genotyped as TT, TC and CC). The T94A substitution did not alter or only slightly altered L-FABP binding affinities for saturated, monounsaturated or polyunsaturated long chain fatty acids, nor did it change the affinity for intermediates of triglyceride synthesis. Nevertheless, the T94A substitution markedly altered the secondary structural response of L-FABP induced by binding long chain fatty acids or intermediates of triglyceride synthesis. Finally, the T94A substitution markedly decreased the levels of induction of peroxisome proliferator-activated receptor alpha-regulated proteins such as L-FABP, fatty acid transport protein 5 and peroxisome proliferator-activated receptor alpha itself meditated by the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid in cultured primary human hepatocytes. Thus, although the T94A substitution did not alter the affinity of human L-FABP for long chain fatty acids, it significantly altered human L-FABP structure and stability, as well as the conformational and functional response to these ligands. PMID- 24628890 TI - Ex vivo lung perfusion to improve donor lung function and increase the number of organs available for transplantation. AB - This paper describes the initial clinical experience of ex vivo lung perfusion (EVLP) at the Fondazione Ca' Granda in Milan between January 2011 and May 2013. EVLP was considered if donor PaO2 /FiO2 was below 300 mmHg or if lung function was doubtful. Donors with massive lung contusion, aspiration, purulent secretions, pneumonia, or sepsis were excluded. EVLP was run with a low-flow, open atrium and low hematocrit technique. Thirty-five lung transplants from brain death donors were performed, seven of which after EVLP. EVLP donors were older (54 +/- 9 years vs. 40 +/- 15 years, EVLP versus Standard, P < 0.05), had lower PaO2 /FiO2 (264 +/- 78 mmHg vs. 453 +/- 119 mmHg, P < 0.05), and more chest X-ray abnormalities (P < 0.05). EVLP recipients were more often admitted to intensive care unit as urgent cases (57% vs. 18%, P = 0.05); lung allocation score at transplantation was higher (79 [40-84] vs. 39 [36-46], P < 0.05). After transplantation, primary graft dysfunction (PGD72 grade 3, 32% vs. 28%, EVLP versus Standard, P = 1), mortality at 30 days (0% vs. 0%, P = 1), and overall survival (71% vs. 86%, EVLP versus Standard P = 0.27) were not different between groups. EVLP enabled a 20% increase in available donor organs and resulted in successful transplants with lungs that would have otherwise been rejected (ClinicalTrials.gov number: NCT01967953). PMID- 24628891 TI - Odor memories regulate olfactory receptor expression in the sensory periphery. AB - Odor learning induces structural and functional modifications throughout the olfactory system, but it is currently unknown whether this plasticity extends to the olfactory receptors (Or) in the sensory periphery. Here, we demonstrate that odor learning induces plasticity in olfactory receptor expression in the honeybee, Apis mellifera. Using quantitative RT-PCR analysis, we show that six putative floral scent receptors were differentially expressed in the bee antennae depending on the scent environment that the bees experienced. Or151, which we characterized using an in vitro cell expression system as a broadly tuned receptor binding floral odorants such as linalool, and Or11, the specific receptor for the queen pheromone 9-oxo-decenoic acid, were significantly down regulated after honeybees were conditioned with the respective odorants in an olfactory learning paradigm. Electroantennogram recordings showed that the neural response of the antenna was similarly reduced after odor learning. Long-term odor memory was essential for inducing these changes, suggesting that the molecular mechanisms involved in olfactory memory also regulate olfactory receptor expression. Our study demonstrates for the first time that olfactory receptor expression is experience-dependent and modulated by scent conditioning, providing novel insight into how molecular regulation at the periphery contributes to plasticity in the olfactory system. PMID- 24628892 TI - Common and specific impairments in attention functioning in girls with chromosome 22q11.2 deletion, fragile X or Turner syndromes. AB - BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention. METHODS: Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices. RESULTS: Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system. CONCLUSIONS: These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory. PMID- 24628893 TI - The interaction between malaria and human immunodeficiency virus infection in severely anaemic Malawian children: a prospective longitudinal study. AB - OBJECTIVE: Malaria and human immunodeficiency virus (HIV) infection are co prevalent in sub-Saharan Africa and cause severe anaemia in children. Interactions between these infections occur in adults, although these are less clear in children. The aim of study was to determine their interaction in a cohort of severely anaemic children. METHODS: Severely anaemic Malawian children were enrolled, tested for HIV and malaria, transfused and followed for 18 months for malaria incidence. Antiretrovirals were not widely available in Malawi during the study period. RESULTS: Of 381 children (haemoglobin <5 g/dl), 357 consented for HIV testing, 12.6% were HIV-infected, and 59.5% had malaria parasitaemia. At enrolment, HIV-infected children had similar malaria parasitaemia prevalence (59.1% vs. 58.7%; P = 0.96) and parasite density (geometric mean [parasites/MUl] 6903 vs. 12417; P = 0.18) as HIV-negative children. There were no differences in mean CD4%, or prevalence of severe immunosuppression, between those with and without malaria parasitaemia. Plasma viral load correlated negatively with log parasitaemia (r = -0.78; P = 0.01). During follow-up, HIV-infected children did not experience more frequent parasitaemias or symptomatic malaria episodes. Adjusted risk estimates (95% CI) for malaria parasitaemia in HIV-infected children at 6 and 18 months follow-up were 0.39 (0.13-1.14) and 0.40 (0.11-1.51), respectively. CONCLUSIONS: Severely anaemic HIV-infected children showed no increased susceptibility to asymptomatic or symptomatic malaria during or following their anaemic episode, although all experienced lower parasite prevalence during follow-up. This contrasts with data in adults and may relate to the malaria immunity of young children which is insufficiently developed to be impaired by HIV. The negative correlation between viral load and malaria parasitaemia remains unexplained. PMID- 24628894 TI - Treatment of neuromyelitis optica/neuromyelitis optica spectrum disorders with methotrexate. AB - BACKGROUND: To review our experience using methotrexate as a single long-term immunosuppressant (IS) therapy in neuromyelitis optica/neuromyelitis optica spectrum disorders (NMO/NMOSD). METHODS: We performed a retrospective chart review of all patients with a diagnosis of NMO/NMOSD, supported by a positive NMO IgG testing, who were treated with methotrexate. A paired sample 2 tailed t test was used to assess the annualized relapse rate during 18 months pre treatment with methotrexate to annualized relapse rate 18 months post treatment with methotrexate. RESULTS: We followed 9 patients meeting criteria for the study for a median of 62 months. All patients were stabilized during attacks with high-dose steroids and/or plasmapheresis. Five patients (55.55%) were started on methotrexate as an initial long-term immunosuppressant strategy. Three patients (33.33%) were initially treated with pulse cyclophosphamide followed by methotrexate as a preplanned step-down strategy. One patient was started on azathioprine prior to methotrexate. No patient had side effects requiring change in methotrexate therapy. Five patients (55.55%) had stabilization of Expanded Disability Status Scale (EDSS) on methotrexate. One patient had a small increase in EDSS due to concomitant illness. Three patients (33.33%) had methotrexate treatment failure evidenced by worsening EDSS and ongoing relapses while on methotrexate, mandating a change in methotrexate therapy. Average annualized relapse rate in the entire group comparing 18 months prior versus 18 months after methotrexate treatment was reduced by an absolute value of 64% (3.11 vs 1.11). A paired t-test showed this reduction was highly significant (p = .009). CONCLUSION: In our experience, methotrexate is safe and possibly efficacious as a single long-term IS therapy along with low dose corticosteroids that can reasonably be offered to patients with NMO/NMOSD. PMID- 24628895 TI - Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review. AB - Only a few years ago the American Society of Assisted Reproductive Medicine (ASRM), the European Society for Human Reproduction and Embryology (ESHRE) and the British Fertility Society declared preimplantation genetic screening (PGS#1) ineffective in improving in vitro fertilization (IVF) pregnancy rates and in reducing miscarriage rates. A presumably upgraded form of the procedure (PGS#2) has recently been reintroduced, and is here assessed in a systematic review. PGS#2 in comparison to PGS#1 is characterized by: (i) trophectoderm biopsy on day 5/6 embryos in place of day-3 embryo biopsy; and (ii) fluorescence in-situ hybridization (FISH) of limited chromosome numbers is replaced by techniques, allowing aneuploidy assessments of all 24 chromosome pairs. Reviewing the literature, we were unable to identify properly conducted prospective clinical trials in which IVF outcomes were assessed based on "intent to treat". Whether PGS#2 improves IVF outcomes can, therefore, not be determined. Reassessments of data, alleged to support the efficacy of PGS#2, indeed, suggest the opposite. Like with PGS#1, the introduction of PGS#2 into unrestricted IVF practice again appears premature, and threatens to repeat the PGS#1 experience, when thousands of women experienced reductions in IVF pregnancy chances, while expecting improvements. PGS#2 is an unproven and still experimental procedure, which, until evidence suggests otherwise, should only be offered under study conditions, and with appropriate informed consents. PMID- 24628896 TI - Spinal cord stimulation and sacral nerve stimulation for postlaminectomy syndrome with significant low back pain. PMID- 24628897 TI - Pollen limitation and pollinator preferences in Scorzonera hispanica. AB - The plant life cycle is often affected by animal-plant interactions. In insect pollinated plants, interaction with pollinators is very important. When pollen transfer due to a lower abundance of pollinators limits seed production, selection pressures on plant traits related to plant attraction to pollinators might occur, e.g. on flowering phenology, height or number of flowerheads. Landscape changes (e.g. habitat fragmentation or changed habitat conditions) may cause plant-pollinator systems to lose balance and consequently affect population dynamics of many plant species. We studied the relationship between measured plant traits, environmental variables and pollinator preferences in Scorzonera hispanica (Asteraceae), a rare perennial, allogamous herb of open grasslands. We estimated the pollen limitation by comparing seed set of supplemental-pollinated plants with that of open-pollinated ones. Pollinators selected plants based on position within the locality (isolated plants close to trees) rather than on their traits. In spite of a high proportion of undeveloped seeds on the plants, we demonstrated that they are not pollen limited. Instead, seed set and weight of seeds was correlated with plant size traits (height and flowerhead number), with larger plants producing more and larger seeds. This suggests that the studied plants are likely resource limited. Overall, the results suggest that pollinators are not a selection factor in this system, in contrast to studies on various plant species, including self-compatible species of the Asteraceae. The lack of any effect of pollinators in the system may be caused by a strong negative effect of ungulate herbivores, which could play a decisive role in functioning of the system. PMID- 24628898 TI - Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route. AB - OBJECTIVE: To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously (IV) administered detomidine. STUDY DESIGN: Randomised, prospective clinical study. ANIMALS: Twenty dairy calves aged 12.4 +/- 4.4days (mean +/- SD), weight 50.5 +/- 9.0 kg. METHODS: Detomidine at 80 MUg kg(-1) was administered to ten calves sublingually (GEL) and at 30 MUg kg(-1) to ten control calves IV (V. jugularis). Meloxicam (0.5 mg kg(-1) ) and local anaesthetic (lidocaine 3 mg kg( 1) ) were administered before heat cauterization of horn buds. Heart rate (HR), body temperature and clinical sedation were monitored over 240 minutes. Blood was collected from the V. cephalica during the same period for drug concentration analysis. Pharmacokinetic variables were calculated from the plasma detomidine concentration-time data using non-compartmental methods. Statistical analyses compared routes of administration by Student's t-test and linear mixed models as relevant. RESULTS: The maximum plasma detomidine concentration after GEL was 2.1 +/- 1.2 ng mL(-1) (mean +/-SD) and the time of maximum concentration was 66.0 +/- 36.9 minutes. The bioavailability of detomidine was approximately 34% with GEL. Similar sedation scores were reached in both groups after administration of detomidine, but maximal sedation was reached earlier in the IV group (10 minutes) than in the GEL group (40 minutes). HR was lower after IV than GEL from 5 to 10 minutes after administration. All animals were adequately sedated, and we were able to administer local anaesthetic without resistance to all of the calves before disbudding. CONCLUSIONS AND CLINICAL RELEVANCE: Oromucosally administered detomidine is an effective sedative agent for calves prior to disbudding. PMID- 24628899 TI - Modulation of sebum oxidation and interleukin-1alpha levels associates with clinical improvement of mild comedonal acne. AB - BACKGROUND: Sebum plays a key role in the initiation of the acne lesions. Oxidized sebum lipids cause keratynocytes hyperproliferation and inflammatory cytokines release. Association between sebum oxidation and comedogenesis has been little investigated in comedonal acne. OBJECTIVES: Evaluation of sebum oxidation parameters and levels of inflammatory cytokines (IL-1alpha) in patients with mild comedonal acne (MCA) before and after the treatment with a mixed RetinSphere(r) - vitamin E formulation. METHODS: Sebum excretion rate (SER), squalene concentration, and oxidation degree of sebum were measured in 18 MCA patients and 10 controls. IL-1alpha levels in the stratum corneum were measured in both lesional and non-lesional facial areas of MCA patients. Sebum parameters and IL 1alpha were measured at week 4 of topical treatment. Reflectance confocal microscopy (RCM) was performed in a subset of four patients at the baseline and at week 4 and all patients were assessed clinically before and following the 8 week-treatment. RESULTS: Sebum excretion rate and squalene concentration were comparable between MCA patients and healthy controls. Lipid peroxidation (LPO) and the percentage of oxidized squalene (SQOX) were significantly elevated in the sebum of MCA patients. The concentration of the proinflammatory cytokine IL 1alpha in stratum corneum was significantly higher in the lesional area compared with non-lesional area of the MCA patients at the baseline. At week 4, while SER and squalene concentration did not vary significantly, the LPO levels and the SQOX percentage resulted decreased at a significant extent. Following the treatment, IL-1alpha concentration in the lesional area reached values comparable to those of unaffected areas. Consistent with the biochemical data, RCM showed the reduction of hyperkeratinization and of inflammatory cells infiltration of the adnexal structures epithelium, significant clinical improvement was recorded at week 8. CONCLUSION: The data further support the involvement of lipid oxidation and particularly by-products of squalene oxidation in comedogenesis. PMID- 24628900 TI - Intracellular killing of bacteria: is Dictyostelium a model macrophage or an alien? AB - Predation of bacteria by phagocytic cells was first developed during evolution by environmental amoebae. Many of the core mechanisms used by amoebae to sense, ingest and kill bacteria have also been conserved in specialized phagocytic cells in mammalian organisms. Here we focus on recent results revealing how Dictyostelium discoideum senses and kills non-pathogenic bacteria. In this model, genetic analysis of intracellular killing of bacteria has revealed a surprisingly complex array of specialized mechanisms. These results raise new questions on these processes, and challenge current models based largely on studies in mammalian phagocytes. In addition, recent studies suggest one additional level on complexity by revealing how Dictyostelium recognizes specifically various bacterial species and strains, and adapts its metabolism to process them. It remains to be seen to what extent mechanisms uncovered in Dictyostelium are also used in mammalian phagocytic cells. PMID- 24628901 TI - C9ORF72 familial motor neuron disease - frontotemporal dementia associated with lung adenocarcinoma and anti-Ma2/Ta antibodies: a chance association? PMID- 24628902 TI - SPG31 presenting with orthostatic tremor. PMID- 24628903 TI - Diffusion tensor imaging before, during and after progressive multifocal leukoencephalopathy. PMID- 24628905 TI - Evaluating the late career nurse initiative: a cross-sectional survey of senior nurses in Ontario. AB - AIM: This study evaluated the impact of the late career nurse initiative on nurse perceptions of their work environment, workplace burnout, job satisfaction, organisational commitment and intention to remain. BACKGROUND: The Ontario Ministry of Health and Long-Term Care introduced the late career nurse initiative with the goal of improving the retention of front-line nurses aged 55 and over by implementing a 0.20 full-time equivalent reduction of physically or psychologically demanding duties, enabling nurses to engage in special projects for the improvement of their organisations and patient care. METHODS: A sample of 902 nurses aged 55 and over from acute and long-term care facilities were surveyed using valid and reliable questionnaires. RESULTS: Nurses who had participated in the initiative did not differ significantly from those who had not in terms of workplace burnout, job satisfaction, length of service or intention to remain within their current organisation. The late career nurse initiative participants reported significantly higher perceptions of managers' ability, leadership and support and their level of participation in hospital affairs. CONCLUSION: The late career nurse initiative was associated with perceived differences in nurses' work environment but not outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: Leaders need to pay attention to how late career nurses are selected and matched to organisational projects. PMID- 24628906 TI - Phenotypic and allelic distribution of the ABO and Rhesus (D) blood groups in the Cameroonian population. AB - Data on blood group phenotypes are important for blood transfusion programs, for disease association and population genetics studies. This study aimed at reporting the phenotypic and allelic distribution of ABO and Rhesus (Rh) groups in various ethnolinguistic groups in the Cameroonians. We obtained ABO and Rhesus blood groups and self-identified ethnicity from 14,546 Cameroonian students. Ethnicity was classified in seven major ethnolinguistic groups: Afro-Asiatic, Nilo-Saharan, Niger-Kordofanian/West Atlantic, Niger-Kordofanian/Adamawa-Ubangui, Niger-Kordofanian/Benue-Congo/Bantu/Grassfield, Niger-Kordofanian/Benue Congo/Bantu/Mbam and Niger-Kordofanian/Benue-Congo/Bantu/Equatorial. ABO allelic frequencies were determined using the Bernstein method. Differences in phenotypic distribution of blood groups were assessed using the chi-square test; a P value <0.05 being considered as statistically significant. The frequencies of the antigens of blood groups O, A, B and AB were 48.62%, 25.07%, 21.86% and 4.45%, respectively. Rhesus-positive was 96.32%. The allelic frequencies of O, A and B genes were 0.6978, 0.1605 and 0.1416, respectively. Phenotypic frequencies of the blood groups in the general study population and in the different ethnolinguistic groups were in agreement with Hardy-Weinberg equilibrium expectations (P > 0.05). The frequencies of O, A, and B blood phenotypes were significantly lower, respectively, in the Nilo-Saharan group (P = 0.009), the Niger-Kordofanian/Benue Congo/Bantu groups (P = 0.021) and the Niger-Kordofanian/West-Atlantic group. AB blood group was most frequent in the Niger-Kordofanian/Adamawa-Ubangui group (P = 0.024). Our study provides the first data on ethnic distribution of ABO and Rhesus blood groups in the Cameroonian population and suggests that its general profile is similar to those of several sub-Saharan African populations. We found some significant differences in phenotypic distribution amongst major ethnolinguistic groups. These data may be important for blood donor recruitment policy and blood transfusion service in Cameroon. PMID- 24628907 TI - An antennae-enriched carboxylesterase from Spodoptera exigua displays degradation activity in both plant volatiles and female sex pheromones. AB - Carboxyl/cholinesterase (CCE) is a large gene family of diverse functions, but in insects its function with respect to catabolism of sex pheromone components and plant volatiles is not well understood. In the present study, we cloned and functionally characterized one putative odorant-degrading enzyme (ODE) of the CCE family, SexiCXE14, from Spodoptera exigua. The tissue-temporal expression pattern revealed that the mRNA level of SexiCXE14 is antennae-enriched, sex equivalent and peaks at 3 days after moth eclosion. Functional study using the recombinant enzyme determined that SexiCXE14 has high degrading activity (Vmax) to host plant volatiles, suggesting its role in degradation of these volatiles. In addition, SexiCXE14 may also play a role in the degradation of sex pheromone components, as the Vmax and affinity parameter (Km) values with the sex pheromones are similar to those of reported pheromone degrading enzymes (PDEs). Further analysis of the relationship between substrate structure and enzymatic activity demonstrated that carbon chain length is a major influential factor, while the number of double bonds also affects the enzymatic activity. In addition, SexiCXE14 displays lower activity at acidic pH levels (pH 5.0) than in neutral conditions (pH 6.5). By characterizing this new ODE the present study provides insights in understanding of the high sensitivity of the moth olfactory system. PMID- 24628908 TI - Identification of candidate genes involved in coronary artery calcification by transcriptome sequencing of cell lines. AB - BACKGROUND: Massively-parallel cDNA sequencing (RNA-Seq) is a new technique that holds great promise for cardiovascular genomics. Here, we used RNA-Seq to study the transcriptomes of matched coronary artery disease cases and controls in the ClinSeq(r) study, using cell lines as tissue surrogates. RESULTS: Lymphoblastoid cell lines (LCLs) from 16 cases and controls representing phenotypic extremes for coronary calcification were cultured and analyzed using RNA-Seq. All cell lines were then independently re-cultured and along with another set of 16 independent cases and controls, were profiled with Affymetrix microarrays to perform a technical validation of the RNA-Seq results. Statistically significant changes (p < 0.05) were detected in 186 transcripts, many of which are expressed at extremely low levels (5-10 copies/cell), which we confirmed through a separate spike-in control RNA-Seq experiment. Next, by fitting a linear model to exon level RNA-Seq read counts, we detected signals of alternative splicing in 18 transcripts. Finally, we used the RNA-Seq data to identify differential expression (p < 0.0001) in eight previously unannotated regions that may represent novel transcripts. Overall, differentially expressed genes showed strong enrichment (p = 0.0002) for prior association with cardiovascular disease. At the network level, we found evidence for perturbation in pathways involving both cardiovascular system development and function as well as lipid metabolism. CONCLUSIONS: We present a pilot study for transcriptome involvement in coronary artery calcification and demonstrate how RNA-Seq analyses using LCLs as a tissue surrogate may yield fruitful results in a clinical sequencing project. In addition to canonical gene expression, we present candidate variants from alternative splicing and novel transcript detection, which have been unexplored in the context of this disease. PMID- 24628909 TI - Sexual and reproductive health communication and awareness of contraceptive methods among secondary school female students, northern Ethiopia: a cross sectional study. AB - BACKGROUND: Adolescent girls continue to fall victim to unintended pregnancy and its consequences, with particular problems arising in low income countries. Awareness about methods of contraception is an important step towards gaining access and using suitable contraceptive methods. However, studies assessing the relationship between sexual and reproductive health communication and awareness of contraceptive methods among secondary school female students are lacking. METHODS: A cross sectional study was conducted among 807 female students in six secondary schools in Mekelle town, Ethiopia. Study participants were selected with a stratified cluster sampling technique. Data collection was carried out using a structured, self-administered questionnaire, and data entry was done using EPI Info Version 3.3.2 software. The data were then cleaned and analyzed using SPSS version 20. Bivariate and multivariate logistic regressions were used to determine factors associated with awareness of female students on methods of contraception. RESULT: Of all the students, 127(15.8%) reported ever having had sex, of whom 109(85.8%) had ever used contraceptives. Twenty (16%) of the sexually active students reported having been pregnant, of whom 18(90%) terminated their pregnancies with induced abortion. Discussion on sexual and reproductive health matters with their parent/s and peer/s in the six months prior to the study was reported by 351(43.5%) and 493(61.1%) of the students respectively. 716(88%) students were aware of different methods of contraception. Discussing sexual and reproductive health issues with parents (AOR=2.56(95% CI: 1.45, 4.50)) and peers (AOR=2.46(95% CI: 1.50, 4.03)) were found to be independent predictors for contraceptive awareness among students. CONCLUSIONS: Discussion on sexual and reproductive health issues with family and peers has a positive effect on contraceptive awareness of students. Therefore, strategies to improve open parent-child communication, and appropriate peer-to-peer communication in schools on sexual and reproductive health should be established and strengthened. PMID- 24628911 TI - FK520 interacts with the discrete intrahelical amino acids of multidrug transporter Cdr1 protein and acts as antagonist to selectively chemosensitize azole-resistant clinical isolates of Candida albicans. AB - FK520, a homolog of antifungal FK506, displays fungicidal synergism with azoles in Candida albicans and inhibits drug efflux mediated by ABC multidrug transporter. This study establishes the molecular basis of interaction of FK520 with Cdr1 protein, which is one of the major ABC multidrug transporters of C. albicans. For this, we have exploited an in-house library of Cdr1 protein consisting of 252 mutant variants where the entire primary structure of the two transmembrane domains comprising of 12 transmembrane helices was subjected to alanine scanning. With these mutant variants of Cdr1 protein, we could identify the critical amino acids of the transporter protein, which if replaced with alanine, not only abrogated FK520-dependent competitive inhibition of drug efflux but simultaneously decreased susceptibility to azoles. Notably, the replacement of most of the residues with alanine was inconsequential; however, there were close to 13% mutant variants, which showed abrogation of drug efflux and reversal of fungicidal synergy with azoles. Of note, all the intrahelical residues of Cdr1 protein, which abrogated inhibitor's ability to block the efflux and reversed fungicidal synergy, were common. Taken together, our results provide evidence of cross-talk of FK520 with Cdr1 by interacting with the select intrahelical residues of the protein to chemosensitize isolates of Candida. PMID- 24628912 TI - Cue-induced craving in dependence upon prescription opioids and heroin. AB - BACKGROUND AND OBJECTIVES: Cues associated with heroin use (eg, needles, powder) elicit robust craving responses in individuals dependent upon heroin. Elevated cue-induced craving may be a risk factor for relapse and can persist after periods of drug abstinence. Despite the growing prevalence of opioid dependence involving prescription opioids, published studies have yet to examine whether cue induced craving is also present in prescription opioid dependence. METHODS: A sample of 50 adults diagnosed with opioid dependence (20 prescription opioid users, 25 heroin users, and 5 mixed opioid users) completed a cue reactivity assessment. Participants were administered a series of 90 pictures, including heroin-specific, prescription opioid-specific, and neutral images, and were asked to rate craving and cue salience after each image. RESULTS: Both the prescription opioid and heroin groups experienced significantly more craving to drug than to neutral stimuli. The prescription opioid group reported significantly less craving to prescription opioid stimuli than the heroin group to heroin stimuli; however, this effect was smaller and non-significant when controlling for group differences in cue salience. DISCUSSION AND CONCLUSIONS: This study found evidence for cue-induced craving in individuals dependent upon prescription opioids. Further research is needed to better understand the role of cue reactivity in the course and treatment of opioid dependence involving prescription opioid use. SCIENTIFIC SIGNIFICANCE: As elevated craving reactivity to drug cues may reflect a risk factor for relapse, understanding the nature of cue-induced craving in individuals with opioid dependence is important to improving treatments for this population. PMID- 24628910 TI - Bone regenerative medicine: classic options, novel strategies, and future directions. AB - This review analyzes the literature of bone grafts and introduces tissue engineering as a strategy in this field of orthopedic surgery. We evaluated articles concerning bone grafts; analyzed characteristics, advantages, and limitations of the grafts; and provided explanations about bone-tissue engineering technologies. Many bone grafting materials are available to enhance bone healing and regeneration, from bone autografts to graft substitutes; they can be used alone or in combination. Autografts are the gold standard for this purpose, since they provide osteogenic cells, osteoinductive growth factors, and an osteoconductive scaffold, all essential for new bone growth. Autografts carry the limitations of morbidity at the harvesting site and limited availability. Allografts and xenografts carry the risk of disease transmission and rejection. Tissue engineering is a new and developing option that had been introduced to reduce limitations of bone grafts and improve the healing processes of the bone fractures and defects. The combined use of scaffolds, healing promoting factors, together with gene therapy, and, more recently, three-dimensional printing of tissue-engineered constructs may open new insights in the near future. PMID- 24628913 TI - Geographic information system-based analysis of the spatial and spatio-temporal distribution of zoonotic cutaneous leishmaniasis in Golestan Province, north-east of Iran. AB - Zoonotic cutaneous leishmaniasis (ZCL), a vector-borne disease, poses serious psychological as well as social and economic burden to many rural areas of Iran. The main objectives of this study were to analyse yearly spatial distribution and the possible spatial and spatio-temporal clusters of the disease to better understand spatio-temporal epidemiological aspects of ZCL in rural areas of an endemic province, located in north-east of Iran. Cross-sectional survey was performed on 2983 recorded cases during the period of 2010-2012 at village level throughout the study area. Global clustering methods including the average nearest-neighbour distance, Moran's I, general G indices and Ripley's K-function were applied to investigate the annual spatial distribution of the existing point patterns. Presence of spatial and spatio-temporal clusters was investigated using the spatial and space-time scan statistics. For each year, semivariogram analysis and all global clustering methods indicated meaningful persistent spatial autocorrelation and highly clustered distribution of ZCL, respectively. Eight significant spatial clusters, mainly located in north and northeast of the province, and one space-time cluster, observed in northern part of the province and during the period of September 2010-November 2010, were detected. Comparison of the location of ZCL clusters with environmental conditions of the study area showed that 97.8% of cases in clusters were located at low altitudes below 725 m above sea level with predominantly arid and semi-arid climates and poor socio economic conditions. The identified clusters highlight high-risk areas requiring special plans and resources for more close monitoring and control of the disease. PMID- 24628914 TI - Metabotropic glutamate receptor 1 mediates melanocyte transformation via transactivation of insulin-like growth factor 1 receptor. AB - Our laboratory previously described the oncogenic properties of metabotropic glutamate receptor 1 (mGluR1) in melanocytes. mGluR1 transformed immortalized mouse melanocytes in vitro and induced vigorous tumor formation in vivo. Subsequently, we observed the activation of PI3K/AKT in mGluR1-mediated melanocytic tumorigenesis in vivo. In particular, we identified AKT2 being the predominant isoform contributing to the activation of AKT. Suppression of Grm1 or AKT2 using an inducible Tet-R siRNA system resulted in a 60 or 30% reduction, respectively, in in vivo tumorigenesis. We show that simultaneous downregulation of Grm1 plus AKT2 results in a reduction of approximately 80% in tumor volumes, suggesting that both mGluR1 and AKT2 contribute to the tumorigenic phenotype in vivo. The discrepancy between the mild in vitro transformation characteristics and the aggressive in vivo tumorigenic phenotypes of these stable mGluR1 melanocytic clones led us to investigate the possible involvement of other growth factors. Here, we highlight a potential crosstalk network between mGluR1 and tyrosine kinase, insulin-like growth factor 1 receptor (IGF-1R). PMID- 24628915 TI - Describing the evolution of medication nonadherence from pretransplant until 3 years post-transplant and determining pretransplant medication nonadherence as risk factor for post-transplant nonadherence to immunosuppressives: the Swiss Transplant Cohort Study. AB - Although medication nonadherence (MNA) is a major risk factor for poor outcomes, the evolution of MNA from pre- to 3 years post-transplant among the four major organ transplant groups remains unknown. Therefore, this study described this evolution and investigated whether pretransplant MNA predicts post-transplant immunosuppressive medication nonadherence (IMNA). Adult participants (single transplant, pretransplant and <=1 post-transplant assessment, using medications pretransplant) in the Swiss Transplant Cohort Study (a prospective nation-wide cohort study) were included. Nonadherence, defined as any deviation from dosing schedule, was assessed using two self-report questions pretransplant and at 6, 12, 24 and 36 months post-transplant. Nonadherence patterns were modelled using generalized estimating equations. The sample included 1505 patients (average age: 52.5 years (SD: 13.1); 36.3% females; 924 renal, 274 liver, 181 lung, 126 heart). The magnitude and variability of self-reported MNA decreased significantly from pretransplant to 6 months post-transplant (OR = 0.21; 95% CI: 0.16-0.27). Post transplant IMNA increased continuously from 6 months to 3 years post-transplant (OR = 2.75; 95% CI: 1.97-3.85). Pretransplant MNA was associated with threefold higher odds of post-transplant IMNA (OR = 3.10; 95% CI: 2.29-4.21). As pretransplant MNA predicted post-transplant IMNA and a continuous increase in post-transplant IMNA was observed, early adherence-supporting interventions are indispensible. PMID- 24628917 TI - Sociodemographic, clinical and organisational factors associated with delayed hospital discharges: a cross-sectional study. AB - BACKGROUND: Evidence from studies conducted in Western countries indicates that a significant proportion of hospital beds are occupied by patients who experience a delayed hospital discharge (DHD). However, evidence about this topic is lacking in Italy, and little is known on the patients' and organisational characteristics that influence DHDs. Therefore, we carried out a survey in all the hospitals of a Northern Italian region to analyse the prevalence and the determinants of DHD. METHODS: A cross-sectional study was carried out during an index period of 15 days in 256 operative units in Emilia-Romagna, a Northern Italian region with 4.4 million inhabitants, to identify patients medically fit for discharge but still hospitalised. The characteristics of these patients (n = 510) were compared with all the other patients (n = 5,815) hospitalised in the same operative units during the index period using multilevel logistic regression models. RESULTS: The one-day prevalence of DHD was 8.1%. More than half of DHD patients (52.7%) waited to access long-term/rehabilitation units or residential care homes, 16.7% experienced a delay for family-related reasons, and 14.5% were waiting to be admitted to other rehabilitation services. Among DHD patients hospitalised in long-term/rehabilitation units, 45.3% were waiting to be transferred to residential care homes. Patients' characteristics associated with a higher likelihood of DHD in multilevel logistic regression were older age, provision of intensive care, a diagnosis of dementia, tumours or femoral/shoulder fractures, and a number of comorbidities. Patients hospitalised in long-term/rehabilitation units, as well as in orthopaedics/traumatology units, were significantly more likely to have a DHD compared with patients hospitalised in general surgery units. Moreover, compared with Local Health Authority Hospitals, being hospitalised in Hospital Trusts was associated with a higher likelihood of DHD. CONCLUSIONS: Although the prevalence of DHD in the present study is markedly lower than that reported in the literature, we submit that the DHD problem should be addressed with major organisational innovations, with a special focus on the ageing of the population and epidemiological trends. Organisational changes imply new ways of managing emerging clusters of patients whose needs are not efficiently or effectively met by traditional organisation models and services. PMID- 24628916 TI - A knot in the protein structure - probing the near-infrared fluorescent protein iRFP designed from a bacterial phytochrome. AB - The possibility of engineering near-infrared fluorescent proteins and biosensors from bacterial phytochrome photoreceptors (BphPs) has led to substantial interest in this family of proteins. The near-infrared fluorescent proteins have allowed non-invasive bio-imaging of deep tissues and whole organs in living animals. BphPs and derived near-infrared fluorescent proteins contain a structural element, called a knot, in their polypeptide chains. The formation of knot structures in proteins was refuted for a long time. Here, we studied the denaturation and renaturation processes of the near-infrared fluorescent probe iRFP, engineered from RpBphP2, which utilizes a heme-derived tetrapyrrole compound biliverdin as a chromophore. iRFP contains a unique figure-of-eight knot. The denaturation and renaturation curves of the iRFP apoform coincided well, suggesting efficient refolding. However, the iRFP holoform exhibited irreversible unfolding and aggregation associated with the bound chromophore. The knot structure in the apoform did not prevent subsequent binding of biliverdin, resulting in the functional iRFP holoform. We suggest that the irreversibility of protein unfolding is caused by post-translational protein modifications, such as chromophore binding, rather than the presence of the knot. These results are essential for future design of BphP-based near-infrared probes, and add important features to our knowledge of protein folding. PMID- 24628918 TI - Systematic review and meta-analysis: Patient and programme impact of fixed-dose combination antiretroviral therapy. AB - OBJECTIVES: To compare the advantages to patients and to programmes between fixed dose combination (FDC) antiretroviral therapy and separate tablet regimens. METHODS: Three electronic databases and two conference abstract sites were searched from inception to 01 March 2013 without geographical, language or date limits. Studies were included if they reported data on clinical outcomes, patient reported outcomes and programme-related outcomes that could be related to pill burden for adult and adolescent patients on ART. For the primary outcomes of adherence and virological suppression, relative risks and 95% confidence intervals were calculated, and these were pooled using random effects meta analysis. RESULTS: Twenty-one studies including information on 27,230 subjects were reviewed. Data from randomised trials showed better adherence among patients receiving FDCs than among patients who did not (relative risk 1.10, 95%CI 0.98 1.22); these findings were consistent with data from observational cohorts (RR 1.17, 95% CI 1.07-1.28). There was also a tendency towards greater virological suppression among patients receiving FDCs in randomised trials (RR 1.04, 95%CI 0.99-1.10) and observational cohort studies (RR 1.07, 95% CI 0.97-1.18). In all studies reporting patient preference, FDCs were preferred. The overall quality of the evidence was rated as low. CONCLUSIONS: Fixed-dose combinations appear to offer multiple advantages for programmes and patients, particularly with respect to treatment adherence. PMID- 24628919 TI - Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation. AB - BACKGROUND: MLK3 gene mutations were described to occur in about 20% of microsatellite unstable gastrointestinal cancers and to harbor oncogenic activity. In particular, mutation P252H, located in the kinase domain, was found to have a strong transforming potential, and to promote the growth of highly invasive tumors when subcutaneously injected in nude mice. Nevertheless, the molecular mechanism underlying the oncogenic activity of P252H mutant remained elusive. METHODS: In this work, we performed Illumina Whole Genome arrays on three biological replicas of human HEK293 cells stably transfected with the wild type MLK3, the P252H mutation and with the empty vector (Mock) in order to identify the putative signaling pathways associated with P252H mutation. RESULTS: Our microarray results showed that mutant MLK3 deregulates several important colorectal cancer- associated signaling pathways such as WNT, MAPK, NOTCH, TGF beta and p53, helping to narrow down the number of potential MLK3 targets responsible for its oncogenic effects. A more detailed analysis of the alterations affecting the WNT signaling pathway revealed a down-regulation of molecules involved in the canonical pathway, such as DVL2, LEF1, CCND1 and c-Myc, and an up-regulation of DKK, a well-known negative regulator of canonical WNT signaling, in MLK3 mutant cells. Additionally, FZD6 and FZD10 genes, known to act as negative regulators of the canonical WNT signaling cascade and as positive regulators of the planar cell polarity (PCP) pathway, a non-canonic WNT pathway, were found to be up-regulated in P252H cells. CONCLUSION: The results provide an overall view of the expression profile associated with mutant MLK3, and they support the functional role of mutant MLK3 by showing a deregulation of several signaling pathways known to play important roles in the development and progression of colorectal cancer. The results also suggest that mutant MLK3 may be a novel modulator of WNT signaling, and pinpoint the activation of PCP pathway as a possible mechanism underlying the invasive potential of MLK3 mutant cells. PMID- 24628921 TI - The role of the substantia nigra in posture control. AB - Disorders implicating the basal ganglia are often characterized by postural deficits, but little is known about the role of the basal ganglia in posture control. Using wireless multi-electrode recording, we measured single unit activity from GABAergic and dopaminergic neurons in the substantia nigra as unrestrained mice stood on an elevated platform while introducing continuous postural disturbances in the roll plane. We found two major types of neurons - those activated by tilt to the left side of the body and suppressed by tilt to the right side, and others activated by tilt to the right side and suppressed by tilt to the left side. Contrary to the prevailing view that the basal ganglia output from the substantia nigra pars reticulata either inhibits or disinhibits downstream structures in an all or none fashion, we showed that it continuously sends anti-phase signals to their downstream targets. We also demonstrated for the first time that nigrostriatal dopaminergic transmission is modulated by postural disturbances. PMID- 24628920 TI - Embryonic rat vascular smooth muscle cells revisited - a model for neonatal, neointimal SMC or differentiated vascular stem cells? AB - BACKGROUND: The A10 and A7r5 cell lines derived from the thoracic aorta of embryonic rat are widely used as models of non-differentiated, neonatal and neointimal vascular smooth muscle cells in culture. The recent discovery of resident multipotent vascular stem cells within the vessel wall has necessitated the identity and origin of these vascular cells be revisited. In this context, we examined A10 and A7r5 cell lines to establish the similarities and differences between these cell lines and multipotent vascular stem cells isolated from adult rat aortas by determining their differentiation state, stem cell marker expression and their multipotency potential in vitro. METHODS: Vascular smooth muscle cell differentiation markers (alpha-actin, myosin heavy chain, calponin) and stem cell marker expression (Sox10, Sox17 and S100beta) were assessed using immunocytochemistry, confocal microscopy, FACS analysis and real-time quantitative PCR. RESULTS: Both A10 and A7r5 expressed vascular smooth muscle differentiation, markers, smooth muscle alpha - actin, smooth muscle myosin heavy chain and calponin. In parallel analysis, multipotent vascular stem cells isolated from rat aortic explants were immunocytochemically myosin heavy chain negative but positive for the neural stem cell markers Sox10+, a neural crest marker, Sox17+ the endoderm marker, and the glia marker, S100beta+. This multipotent vascular stem cell marker profile was detected in both embryonic vascular cell lines in addition to the adventitial progenitor stem cell marker, stem cell antigen-1, Sca1+. Serum deprivation resulted in a significant increase in stem cell and smooth muscle cell differentiation marker expression, when compared to serum treated cells. Both cell types exhibited weak multipotency following adipocyte inductive stimulation. Moreover, Notch signaling blockade following gamma-secretase inhibition with DAPT enhanced the expression of both vascular smooth muscle and stem cell markers. CONCLUSIONS: We conclude that A10 and A7r5 cells share similar neural stem cell markers to both multipotent vascular stem cells and adventitial progenitors that are indicative of neointimal stem-derived smooth muscle cells. This may have important implications for their use in examining vascular contractile and proliferative phenotypes in vitro. PMID- 24628922 TI - Cutaneous manifestations of the subtypes of polycystic ovary syndrome in Korean patients. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrinological disorder in women of childbearing-age. Although PCOS has common dermatological manifestations, including hirsutism, acne and androgenetic alopecia, little is known about the dermatological characteristics of PCOS patients in Asia. OBJECTIVE: The goal of this study is to elucidate the dermatological characteristics and metabolic and hormonal parameters of Korean PCOS patients classified by the three ASRM/ESHERE criteria. METHODS: We investigated 40 untreated PCOS patients who were newly diagnosed in the Department of Obstetrics & Gynecology of Seoul National University Hospital. Patients were classified according to the presence of irregular menstruation (IM), polycystic ovary morphology (PCOM) and hyperandrogenism (HA). Acne specific questionnaire, physical examination, and blood sampling were thoroughly conducted. RESULTS: Twenty four patients (60.0%) met the criteria for the IM/HA/PCOM group and sixteen (40.0%) belonged to the IM/PCOM group. Acne was the most commonly observed dermatological manifestation (95.0%) followed by hirsutism (60.0%), seoborrhea (47.5%), acanthosis nigricans (20.0%) and androgenetic alopecia (12.5%). Hirsutism was more frequently observed in the IM/HA/PCOM group; the prevalence of other cutaneous manifestations did not differ significantly. Acne was most often observed on the face and most acne lesions were distributed on the forehead and cheek. Serum dehydroepiandrosterone sulphate level was higher in IM/HA/PCOM group, while serum cholesterol and high density lipoprotein concentrations were higher in the IM/PCOM group. CONCLUSION: We described several dermatological manifestations and serum hormonal and metabolic parameters in Korean PCOS patients. Cutaneous manifestations might be the first signs of PCOS; therefore, dermatologists should be more aware of cutaneous manifestations of various ethnicities. PMID- 24628923 TI - Pooled analysis of the safety and tolerability of onabotulinumtoxinA in the treatment of chronic migraine. AB - BACKGROUND AND PURPOSE: OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed. METHODS: The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received >=1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. RESULTS: OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA. CONCLUSIONS: Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM. PMID- 24628924 TI - Effects of isoflurane, sevoflurane and methoxyflurane on the electroencephalogram of the chicken. AB - OBJECTIVE: Anaesthetics have differing effects on mammalian electroencephalogram (EEG) but little is known about the effects on avian EEG. This study explored how inhalant anaesthetics affect chicken EEG. STUDY DESIGN: Experimental study. ANIMALS: Twelve female Hyline Brown chickens aged 6-11 weeks. METHODS: Each chicken was anaesthetized with isoflurane, sevoflurane, and methoxyflurane. For each, anaesthesia was adjusted to 1, 1.5 and 2 times Minimum Anaesthetic Concentration (MAC). Total Power (Ptot), Median Frequency (F50), Spectral Edge Frequency (F95) and Burst Suppression Ratio (BSR) were calculated at each volume concentration. BSR data were analyzed using doubly repeated measures anova. Neither isoflurane nor sevoflurane could be included in analysis of F50, F95 and Ptot because of extensive burst suppression; Methoxyflurane data were analyzed using RM anova. RESULTS: There was a significant interaction between anaesthetic and concentration on BSR [F(4,22) = 10.65, p < 0.0001]. For both isoflurane and sevoflurane, BSR increased with concentration. Isoflurane caused less suppression than sevoflurane at 1.5 MAC and at final 1 MAC while methoxyflurane caused virtually no burst suppression. Methoxyflurane concentration had a significant effect on F50 [F(2,20) = 3.83, p = 0.04], F95 [F(2,20) = 4.03, p = 0.03] and Ptot [F(2,20) = 5.22, p = 0.02]. Decreasing methoxyflurane from 2 to 1 MAC increased F50 and F95. Ptot increased when concentration decreased from 1.5 to 1 MAC and tended to be higher at 1 MAC than at 2 MAC. CONCLUSIONS AND CLINICAL RELEVANCE: Isoflurane and sevoflurane suppressed chicken EEG in a dose-dependent manner. Higher concentrations of methoxyflurane caused an increasing degree of synchronization of EEG. Isoflurane and sevoflurane suppressed EEG activity to a greater extent than did methoxyflurane at equivalent MAC multiples. Isoflurane caused less suppression than sevoflurane at intermediate concentrations. These results indicate the similarity between avian and mammalian EEG responses to inhalant anaesthetics and reinforce the difference between MAC and anaesthetic effects on brain activity in birds. PMID- 24628926 TI - Comment on 'Safety of the breast-feeding infant after maternal anesthesia' Dalal PG, Bosak J, Berlin C. PMID- 24628927 TI - Response to Silvani and Camporesi, regarding their comment on our paper Safety of the breast-feeding infant after maternal anesthesia. PMID- 24628925 TI - Genomic convergence and network analysis approach to identify candidate genes in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is one of the leading genetically complex and heterogeneous disorder that is influenced by both genetic and environmental factors. The underlying risk factors remain largely unclear for this heterogeneous disorder. In recent years, high throughput methodologies, such as genome-wide linkage analysis (GWL), genome-wide association (GWA) studies, and genome-wide expression profiling (GWE), have led to the identification of several candidate genes associated with AD. However, due to lack of consistency within their findings, an integrative approach is warranted. Here, we have designed a rank based gene prioritization approach involving convergent analysis of multi dimensional data and protein-protein interaction (PPI) network modelling. RESULTS: Our approach employs integration of three different AD datasets- GWL,GWA and GWE to identify overlapping candidate genes ranked using a novel cumulative rank score (SR) based method followed by prioritization using clusters derived from PPI network. SR for each gene is calculated by addition of rank assigned to individual gene based on either p value or score in three datasets. This analysis yielded 108 plausible AD genes. Network modelling by creating PPI using proteins encoded by these genes and their direct interactors resulted in a layered network of 640 proteins. Clustering of these proteins further helped us in identifying 6 significant clusters with 7 proteins (EGFR, ACTB, CDC2, IRAK1, APOE, ABCA1 and AMPH) forming the central hub nodes. Functional annotation of 108 genes revealed their role in several biological activities such as neurogenesis, regulation of MAP kinase activity, response to calcium ion, endocytosis paralleling the AD specific attributes. Finally, 3 potential biochemical biomarkers were found from the overlap of 108 AD proteins with proteins from CSF and plasma proteome. EGFR and ACTB were found to be the two most significant AD risk genes. CONCLUSIONS: With the assumption that common genetic signals obtained from different methodological platforms might serve as robust AD risk markers than candidates identified using single dimension approach, here we demonstrated an integrated genomic convergence approach for disease candidate gene prioritization from heterogeneous data sources linked to AD. PMID- 24628928 TI - Pain score guided morphine titration is risky and inappropriate. PMID- 24628929 TI - Night terrors and emergence delirium. PMID- 24628930 TI - Are children with Prader Willi syndrome at higher risk for anesthetic complications? PMID- 24628931 TI - Pediatric sedation and magnetic resonance imaging: the potential for motion correction. PMID- 24628932 TI - Comment on Ultrasound-guided parasacral approach to the sciatic nerve block in children. PMID- 24628933 TI - Response to Cullen et al., regarding Ultrasound-guided rectus sheath block for pyloromyotomie in infants: a retrospective analysis of a case series. PMID- 24628934 TI - A case series of general anesthesia in children with laminin alpha2 (merosin) deficient congenital muscular dystrophy. PMID- 24628935 TI - Nature's microbiome: introduction. PMID- 24628937 TI - Interspecific variation in pollen-ovule ratio is negatively correlated with pollen transfer efficiency in a natural community. AB - The pollination efficiency hypothesis has long been proposed as an explanation for interspecific variation in pollen-ovule (P:O) ratios. However, no empirical study on P:O ratios has directly and quantitatively measured pollen transfer efficiency (PE). Here, we use a PE index, defined as the proportion of pollen grains removed from anthers that are subsequently deposited on conspecific stigmas, as a direct and quantitative measure of PE. We investigated P:O ratios, pollen removal and pollen deposition in 26 plant species in an alpine meadow, over three consecutive years. Our community survey showed that nearly 5% of removed pollen was successfully deposited on conspecific stigmas. The PE index ranged from 0.01% up to 78.56% among species, and correlated negatively with the P:O ratio across years. This correlation was not changed by controlling for phylogenetic relationships among species, suggesting that the interspecific variation in P:O ratios can be attributed to the probability of pollen grains reaching a stigma. The results indicate that the pollination efficiency hypothesis can help to explain interspecific variation in P:O ratios. PMID- 24628936 TI - Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells. AB - BACKGROUND: Activin A, an important member of transforming growth factor-beta superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation. RESULTS: Using the 2 acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2 acetylaminofluorene/partial hepatectomy model. CONCLUSION: Activin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells. PMID- 24628939 TI - Small flies to tackle big questions: assaying complex bacterial virulence mechanisms using Drosophila melanogaster. AB - A successful raid on a fortress requires ingenious strategies in addition to a large number of soldiers. When a microorganism faces a potential host many factors are important, including not only the capacity to proliferate but also the ability to hide, escape or subvert the defence arsenal of the infected organism. This ability confers microbial pathogenicity and relies on complex virulence mechanisms, which are tightly regulated during the course of the infection. The amazing versatility of some microbes that can infect a wide broad of hosts undoubtedly relies on virulence factors intent on fighting evolutionarily conserved innate immune mechanisms. This makes the use of alternative invertebrate models, which are of outstanding interest because they demand less ethical consideration and lower experimental costs, extremely relevant. These simpler organisms are used to analyse genes and mechanisms involved in resistance or tolerance to microorganisms. They can also be used to study bacterial virulence factors that allow proliferation or persistence in the host. In particular, the Drosophila fruit fly has a complex immune response (similar to the mammalian innate immune response) and is particularly appropriate for deciphering many events underlying bacterial pathogenicity from acute virulence to biofilm formation. As highlighted in this review, Drosophila has been notably extensively used to study virulence traits of the opportunistic bacteria Pseudomonas aeruginosa, such as proliferation or persistence, translocation through an epithelial barrier, subversion of the phagocytic machinery, in vivo biofilm formation and enhanced virulence provided by commensal flora or a polymicrobial community. Moreover, these small flies now appear to be a useful system for assaying chemicals with therapeutic potential. PMID- 24628938 TI - Cardiovascular health: a cross-national comparison between the Maine Syracuse Study (Central New York, USA) and ORISCAV-LUX (Luxembourg). AB - BACKGROUND: Cardiovascular disease is the number one cause of death in the United States and in most European countries. Cardiovascular health, as defined by the American Heart Association, is comprised of seven health metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting plasma glucose). No studies have compared US data with data collected elsewhere, using this index of cardiovascular health METHODS: We performed comparative analyses of cardiovascular health status in participants from 2 study sites in 2 different countries: the Maine-Syracuse Study, conducted in Central New York, USA in 2001-2006 (n=673), and the Observation of Cardiovascular Risk Factors in Luxembourg, conducted in 2007-2009 (n=1145). RESULTS: The Cardiovascular Health Score, the sum of the total number of metrics at ideal levels, was higher in the Luxembourg site than in the Central New York site. Ideal cardiovascular health levels for body mass index, smoking, physical activity, and diet were more prevalent in the Luxembourg site than the Central New York site. Ideal levels for blood pressure were more prevalent in Central New York. Differences between the two sites remained with control for age, gender and socioeconomic indicators. CONCLUSIONS: Cardiovascular health, as indexed by seven health metrics, was higher in the European study site than in the US study site. The largest differences were for the four lifestyle/behavior metrics, namely body mass index, smoking, physical activity, and diet. Preventative and intervention strategies will continue to be important for both countries in order to improve cardiovascular health. PMID- 24628940 TI - More than just a filler - the role of hyaluronan for skin homeostasis. AB - In recent years, hyaluronan (HA) has become an increasingly attractive substance as a non-immunogenic filler and scaffolding material in cosmetic dermatology. Despite its wide use for skin augmentation and rejuvenation, relatively little is known about the molecular structures and interacting proteins of HA in normal and diseased skin. However, a comprehensive understanding of cutaneous HA homeostasis is required for future the development of HA-based applications for skin regeneration. This review provides an update on HA-based structures, expression, metabolism and its regulation, function and pharmacological targeting of HA in skin. PMID- 24628941 TI - Portal Venous Oxygen Persufflation of the Donation after Cardiac Death pancreas in a rat model is superior to static cold storage and hypothermic machine perfusion. AB - Success of clinical pancreatic islet transplantation depends on the mass of viable islets transplanted and the proportion of transplanted islets that survive early ischaemia reperfusion injury. Novel pancreas preservation techniques to improve islet preservation and viability can increase the utilization of donation after cardiac death donor pancreases for islet transplantation. Rat pancreases were retrieved after 30 min of warm ischaemia and preserved by static cold storage, hypothermic machine perfusion or retrograde portal venous oxygen persufflation for 6 h. They underwent collagenase digestion and density gradient separation to isolate islets. The yield, viability, morphology were compared. In vitro function of isolated islets was compared using glucose stimulated insulin secretion test. Portal venous oxygen persufflation improved the islet yield, viability and morphology as compared to static cold storage. The percentage of pancreases with good in vitro function (stimulation index > 1.0) was also higher after oxygen persufflation as compared to static cold storage. Retrograde portal venous oxygen persufflation of donation after cardiac death donor rat pancreases has the potential to improve islet yield. PMID- 24628942 TI - Neural correlates of infant accent discrimination: an fNIRS study. AB - The present study investigated the neural correlates of infant discrimination of very similar linguistic varieties (Quebecois and Parisian French) using functional Near InfraRed Spectroscopy. In line with previous behavioral and electrophysiological data, there was no evidence that 3-month-olds discriminated the two regional accents, whereas 5-month-olds did, with the locus of discrimination in left anterior perisylvian regions. These neuroimaging results suggest that a developing language network relying crucially on left perisylvian cortices sustains infants' discrimination of similar linguistic varieties within this early period of infancy. PMID- 24628943 TI - Effects of varenicline, nicotine or placebo on depressive symptoms in postmenopausal smokers. AB - BACKGROUND: Varenicline carries a black box warning for neuropsychiatric adverse events. OBJECTIVE: We examined varenicline use and past history of major depressive disorder (MDD) on depressive symptoms during smoking cessation. METHOD: This is a secondary analysis of two smoking cessation studies in 152 postmenopausal women who received placebo or nicotine patch, or 78 women who received varenicline with relaxation. Lifetime history of MDD (LH-MDD) was assessed at baseline and women with current MDD were excluded. Center for Epidemiologic Study Depression scale (CESD) measured depressive symptoms at baseline, 6 and 12 weeks. RESULTS: Baseline CESD scores were 5.3 + 4.4. Those with a LH-MDD reported higher CESD scores (p > .001). Those taking varenicline reported lower scores over all time periods compared to nicotine or placebo (p < .01). The differences between varenicline and the other treatments remained when controlling for LH-MDD, indicating an independent effect. CESD scores were associated with concurrent smoking status (p < .001), and with withdrawal symptoms (p < .001). CONCLUSION: CESD score were lower in those receiving varenicline, whether this is due to an anti-depressant effect, subject selection, use of relaxation or another cause is unknown. Varenicline does not increase depressive symptoms during smoking cessation in postmenopausal women without current MDD. Subjects with a LH-MDD are susceptible to developing depressive symptoms during smoking cessation, regardless of pharmacologic aid. SCIENTIFIC SIGNIFICANCE: Pharmacologic aids did not increase depression symptoms in this select population of postmenopausal women without current depression. Smoking cessation does increase depressive symptoms in those with LH-MDD, though the degree of increase was not clinically meaningful. PMID- 24628944 TI - Metabolic flux responses to genetic modification for shikimic acid production by Bacillus subtilis strains. AB - BACKGROUND: Shikimic acid (SA) is a key chiral starting molecule for the synthesis of the neuramidase inhibitor GS4104 against viral influenza. Microbial production of SA has been extensively investigated in Escherichia coli, and to a less extent in Bacillus subtilis. However, metabolic flux of the high SA producing strains has not been explored. In this study, we constructed with genetic manipulation and further determined metabolic flux with 13C-labeling test of high SA-producing B. subtilis strains. RESULTS: B. subtilis 1A474 had a mutation in SA kinase gene (aroI) and accumulated 1.5 g/L of SA. Overexpression of plasmid-encoded aroA, aroB, aroC or aroD in B. subtilis revealed that aroD had the most significantly positive effects on SA production. Simultaneous overexpression of genes for 3-deoxy-D-arabinoheptulosonate-7-phosphate synthase (aroA) and SA dehydrogenase (aroD) in B. subtilis BSSA/pSAAroA/pDGSAAroD resulted in SA production of 3.2 g/L. 13C-Metabolic flux assay (MFA) on the two strains BSSA/pHCMC04/pDG148-stu and BSSA/pSAAroA/pDGSAAroD indicated the carbon flux from glucose to SA increased to 4.6% in BSSA/pSAAroA/pDGSAAroD from 1.9% in strain BSSA/pHCMC04/pDG148-stu. The carbon flux through tricarboxylic acid cycle significantly reduced, while responses of the pentose phosphate pathway and the glycolysis to high SA production were rather weak, in the strain BSSA/pSAAroA/pDGSAAroD. Based on the results from MFA, two potential targets for further optimization of SA production were identified. Experiments on genetic deletion of phosphoenoylpyruvate kinase gene confirmed its positive influence on SA production, while the overexpression of the transketolase gene did not lead to increase in SA production. CONCLUSION: Of the genes involved in shikimate pathway in B. subtilis, aroD exerted most significant influence on SA accumulation. Overexpression of plasmid-encoded aroA and aroD doubled SA production than its parent strain. MFA revealed metabolic flux redistribution among phosphate pentose pathway, glycolysis, TCA cycle in the low and high SA-producing B. subtilis strains. The high SA producing strain BSSA/pSAAroA/pDGSAAroD had increased carbon flux into shikimate pathway and reduced flux into TCA cycle. PMID- 24628945 TI - Single-port thoracoscopic rib resection: a case report. AB - We describe a method of single-port thoracoscopic rib resection using a Gigli saw. Rib resection is typically performed with a large skin incision and soft tissue dissection. Some authors have described a thoracoscopic approach for rib resection from the inner side of the chest wall instead of the outside to decrease pain and improve quality of life. A 41-year-old Chinese male received single-port thoracoscopic rib resection with satisfactory recovery. We present the technique, which may expand the indications of single-port thoracoscopic procedures. PMID- 24628946 TI - Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma. AB - Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here, we describe a NextGen sequencing approach to fully analyzing 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high-throughput sequencing and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard-of-care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma. PMID- 24628947 TI - Relationship between the IL-4 gene promoter -590C/T (rs2243250) polymorphism and susceptibility to autoimmune diseases: a meta-analysis. AB - OBJECTIVE: Studies investigating the association between interleukin (IL)-4 gene promoter -590C/T (rs2243250) polymorphism and autoimmune diseases report conflicting results. To derive a more precise estimation of the relationship, a meta-analysis was performed. METHODS: A systematic literature search was conducted to identify relevant studies. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to estimate the strength of association. RESULTS: A total of 6001 cases and 6788 controls from 24 studies were analysed. Significant association of the C allele of IL-4 rs2243250 polymorphism with rheumatoid arthritis (RA) was detected (odds ratio (OR) = 0.696, 95% confidence interval (CI) = 0.601-0.807). Stratification by ethnicity indicated an association between the IL-4 rs2243250 polymorphism and RA in Caucasians. Furthermore, the overall ORs of the associations between the C allele and multiple scleorosis (MS) were 1.340 (95% CI = 1.102-1.630). However, we failed to reveal any association between IL-4 rs2243250 polymorphism and systemic lupus erythematosus (SLE), type 1 diabetes (T1D) or Graves' disease (GD). CONCLUSIONS: The present study suggests that the IL-4 rs2243250 polymorphism might be associated with genetic susceptibility to autoimmune diseases, including RA and MS. PMID- 24628948 TI - Discharge instructions for caregivers in the context of pediatric emergency care: a narrative synthesis protocol. AB - BACKGROUND: The period following discharge from a pediatric emergency department (ED) can be a time of significant vulnerability for caregivers who provide ongoing care to their child when they return home. Discharge communication practice varies widely at the individual practitioner and departmental level. At present, there are no nationally accepted guidelines for discharge communication for children and/or their caregivers in the ED.The primary objective of this knowledge synthesis is to understand how and why discharge instructions work and under what conditions. We will also examine the contextual factors and barriers and facilitators associated with discharge communication across varied ED settings. METHODS/DESIGN: Using an integrated narrative approach, we will synthesize different types of evidence and explore relationships within and between included studies to develop a theory-based and knowledge user-informed discharge communication practice guideline. We will follow key principles for knowledge synthesis including: (1) involvement of a multidisciplinary team (for example, information specialists, statisticians, and content experts); (2) developing focused and answerable questions in collaboration with the knowledge users; (3) using a systematic method including specific tools and techniques appropriate for answering questions concerned with effectiveness and the implementation of interventions; and, (4) involving knowledge users throughout the process in an integrated knowledge translation approach. DISCUSSION: This collaborative and narrative approach will be a determining factor in increasing the reliability, validity and relevance of the study findings for healthcare practice and policy decision-makers. TRIAL REGISTRATION: PROSPERO registration number: CRD42014007106. PMID- 24628949 TI - FOXM1 mediates resistance to docetaxel in gastric cancer via up-regulating Stathmin. AB - Docetaxel is commonly used as an effective chemotherapeutic drug for gastric cancer patients recently. With the increasing emergence of docetaxel resistance nowadays, identification of suitable biomarkers for predicting chemosensitivity to docetaxel may be a key role for improving therapeutic effects for gastric cancer patients. In this study, we investigated the correlation between the expression of transcription factor forkhead box protein M1 (FOXM1) and chemotherapy response to docetaxel in gastric cancer, the possible mechanism for which was further explored. As a result, FOXM1 overexpression was shown to mediate resistance to docetaxel in gastric cancers. It altered microtubule dynamics to protect tumour cells from docetaxel-induced apoptosis. Mechanistic investigations revealed that tubulin-destabilizing protein Stathmin, which mediated docetaxel resistance in FOXM1-silenced gastric cancer cells, is a direct down-stream target of FOXM1, whereas another microtubule dynamics protein mitotic centromere-associated kinesin (MCAK), shown to be related to docetaxel resistance in gastric cancer cells, is not associated with FOXM1 expression significantly. These results were further provided by immunohistochemical analysis, indicating that FOXM1 and Stathmin expression levels were correlated in 103 post-operational gastric cancer specimens. Moreover, when we attenuated FOXM1 expression with FOXM1 inhibitor thiostrepton, docetaxel resistance in gastric cancers was found to be reversed, simultaneously with the down-regulation of FOXM1 and Stathmin. Therefore, FOXM1 can be a useful marker for predicting and monitoring docetaxel response. Through the inhibition of FOXM1, docetaxel resistance can be reversed, and thus FOXM1 could be a new therapeutic target in docetaxel-resistant gastric cancer. PMID- 24628951 TI - Subthalamic nucleus lesion improves cell survival and functional recovery following dopaminergic cell transplantation in parkinsonian rats. AB - Subthalamic nucleus (STN) modulation is currently the gold standard in the treatment of Parkinson's disease (PD) cases refractory to medication. Cell transplantation is a tissue-restorative approach and is a promising strategy in the treatment of PD. One of the obstacles to overcome in cell therapy is the poor dopaminergic cell survival. Our experiment investigates the impact of a partial subthalamotomy prior to ventral mesencephalic (VM) embryonic cell transplantation on dopaminergic cell survival and functional outcome. Unilateral dopamine depletion was carried out in rats, via medial forebrain bundle (MFB) injection of 6-hydroxydopamine, and half of the animals went on to receive unilateral excitotoxic lesions of the STN/Zone Incerta (ZI) causing partial lesion of these structures on the same side as the MFB lesion. All MFB-lesioned animals, with or without the STN/ZI lesion, received striatal ipsilateral embryonic VM cell grafts. The data suggest that the STN/ZI lesion could boost the dopamine cell survival in the grafts by 2.6-fold compared with the control grafted-only group. Moreover, performance on the drug-induced rotation and the spontaneous behavior tests were ameliorated on the STN/ZI-lesioned group to a significantly greater extent than the grafted-only group. These data suggest that the STN/ZI partial lesion optimized the striatal environment, promoting an improvement in cell survival. Further studies are needed to see whether the synergy between STN modulation via deep brain stimulation and cell therapy might have clinical applications in the management of PD. PMID- 24628952 TI - A novel cryptochrome in the diatom Phaeodactylum tricornutum influences the regulation of light-harvesting protein levels. AB - Diatoms possess several genes for proteins of the cryptochrome/photolyase family. A typical sequence for a plant cryptochrome was not found in our analysis of the Phaeodactylum tricornutum genome, but one protein grouped with higher plant and green algal cryptochromes. This protein, CryP, binds FAD and 5,10 methenyltetrahydrofolate, according to our spectroscopic studies on heterologously expressed protein. 5,10-Methenyltetrahydrofolate binding is a feature common to both cyclobutane pyrimidine dimer photolyases and DASH cryptochromes. In recombinant CryP, however, the FAD chromophore was present in its neutral radical state and had a red-shifted absorption maximum at 637 nm, which is more characteristic for a DASH cryptochrome than a cyclobutane pyrimidine dimer photolyase. Upon illumination with blue light, the fully reduced state of FAD was formed in the presence of reductant. Expression of CryP was silenced by antisense approaches, and the resulting cell lines showed increased levels of proteins of light-harvesting complexes, the Lhcf proteins, in vivo. In contrast, the levels of proteins active in light protection, the Lhcx proteins, were reduced. Thus, CryP cannot be directly grouped with known members of the cryptochrome/photolyase family. Of all P. tricornutum proteins, it is the most similar in sequence to a plant cryptochrome, and is involved in the regulation of light-harvesting protein expression, but shows spectroscopic features and a chromophore composition that are most typical of a DASH cryptochrome. PMID- 24628950 TI - GASTRICHIP: D2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. AB - BACKGROUND: In Europe, gastric cancer remains diagnosed at advanced stage (serosal and/or lymph node involvement). Despite curative management combining perioperative systemic chemotherapy and gastrectomy with D1-D2 lymph node dissection, 5-year survival rates of T3 and/or N + patients remain under 30%. More than 50% of recurrences are peritoneal and/or locoregional. The use of adjuvant hyperthermic intraperitoneal chemotherapy that eliminates free cancer cells that can be released into peritoneal cavity during the gastrectomy and prevents peritoneal carcinomatosis recurrences, was extensively evaluated by several randomized trials conducted in Asia. Two meta-analysis reported that adjuvant hyperthermic intraperitoneal chemotherapy significantly reduces the peritoneal recurrences and significantly improves the overall survival. As it was previously done for the evaluation of the extension of lymph node dissection, it seems very important to validate on European or caucasian patients the results observed in trials performed in Asia. METHODS/DESIGN: GASTRICHIP is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of hyperthermic intraperitoneal chemotherapy with oxaliplatin on patients with gastric cancer involving the serosa and/or lymph node involvement and/or with positive cytology at peritoneal washing, treated with perioperative systemic chemotherapy and D1-D2 curative gastrectomy. Peroperatively, at the end of curative surgery, patients will be randomized after preoperatively written consent has been given for participation. Primary endpoint will be overall survival from the date of surgery to the date of death or to the end of follow-up (5 years). Secondary endpoint will be 3- and 5-year recurrence free survival, site of recurrence, morbidity, and quality of life. An ancillary study will compare the incidence of positive peritoneal cytology pre- and post gastrectomy in two arms of the study, and assess its impact on 5-year survival. The number of patients to be randomized was calculated to be 306. TRIAL REGISTRATION: EudraCT number: 2012-005748-12, ClinicalTrials.gov identifier: NCT01882933. PMID- 24628953 TI - Hypothesis on the source, transmission and characteristics of infection of avian influenza A (H7N9) virus--based on analysis of field epidemiological investigation and gene sequence analysis. AB - On 31 March 2013, the National Health and Family Planning Commission announced that human infections with influenza A (H7N9) virus had occurred in Shanghai and Anhui provinces, China. H7N9 cases were later detected in Jiangsu and Zhejiang provinces. It was estimated that the virus first spread northward along the route taken by migratory birds and then spread to neighbouring provinces with the sale of poultry. Epidemiological studies were carried out on samples from the external environment of infected cases, transmission routes, farmers markets and live poultry markets. Phylogenetic study of viral sequences from human and avian infections in Zhejiang showed that those from Shanghai and Jiangsu provinces along Taihu Lake were highly homologous with those from the external environment. This suggests that avian viruses carried by waterfowl combined with the virus carried by migratory birds, giving rise to avian influenza virus H7N9, which is highly pathogenic to humans. It is possible that the virus was transmitted by local wildfowl to domestic poultry and then to humans, or spread further by means of trading in wholesale poultry markets. As the weather has turned warm, and with measures adopted to terminate poultry trade and facilitate health communication, the epidemic in the first half of the year has been kept under control. However, the infection source in the triangular area around Taihu Lake still remains. The H7N9 epidemic will probably hit the area later in the year and next spring when the migratory birds return and may even spread to other areas. Great importance should therefore be attached to the wildfowl in Taihu Lake as the repository and disseminator of the virus: investigation and study of this population is essential. PMID- 24628954 TI - Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study. AB - BACKGROUND AND PURPOSE: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long term cardiac monitoring. METHODS: Patients with CS after protocolled work-up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one-lead ECG confirming the diagnosis. RESULTS: Eighty-five patients were monitored for a mean of 569 days (SD +/-310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD +/-48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC). CONCLUSIONS: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF. PMID- 24628955 TI - Continuous infusion of propofol or intermittent bolus of tiletamine-zolazepam in squirrel monkeys (Saimiri sciureus). AB - OBJECTIVE: To investigate an infusion of propofol for anesthesia in comparison to tiletamine-zolazepam anesthesia, evaluating physiological variables and recovery in squirrel monkeys. STUDY DESIGN: Prospective non-blinded randomized study. ANIMALS: Eight healthy squirrel monkeys (Saimiri sciureus), aged 3 years and weighing 0.340-0.695 kg. METHODS: Premedication was intramuscular midazolam (0.5 mg) and meperidine (4 mg). Anesthesia was induced with intravenous (IV) propofol (4 mg kg(-1) minute(-1) ) and maintained with propofol starting at 0.4 mg kg(-1) minute(-1) (PRO, n = 4) or IV tiletamine-zolazepam (5 mg kg(-1) ) and maintained with supplementary doses of TZ (TZ, n = 4). Cardiopulmonary variables were measured continuously. Arterial blood gases and lactate concentration were measured at the end of anesthesia. Quality and times of recovery were determined. Repeatedly measured data for significant differences were tested between groups with t-test and within groups by anova. RESULTS: Median time for induction of anesthesia in PRO was 180 seconds. Mean maintenance infusion rate of propofol was 0.43 +/- 0.05 mg kg(-1) minute(-1) , varying during the 1 hour period. One monkey died after administration of TZ; others required 1, 4, or 8 supplemental doses. Cardiopulmonary variables were similar between groups, but hypotension was recorded. Recovery times to ventral recumbency in PRO (32 +/- 17 minutes) and TZ (84 +/- 11 minutes) and normal ambulation in PRO (58 +/- 22 minutes) and TZ (358 +/- 109minutes) were significantly different (p < 0.05). Recovery quality was superior in PRO, with less ataxia and fewer unsuccessful attempts to stand. Lactate concentration was not different between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiopulmonary variables were similar between protocols, aside from the higher incidence of hypotension in PRO, indicating that further studies with a larger number of animals are required. Compared to tiletamine zolazepam, propofol anesthesia provided faster and superior anesthetic recovery in these animals. PMID- 24628957 TI - Characterization of antiviral and antibacterial activity of Bombyx mori seroin proteins. AB - Lepidopterans as other insects have a very potent innate immune system, which basically comprises cellular and humoral defence mechanisms against bacterial and fungal infections. In lepidopterans, not much is known about the defence mechanisms against viral pathogens, such as baculoviruses. Here we show that small silk proteins of the domesticated silkworm, Bombyx mori, called seroins, act as antiviral agents against a baculovirus pathogen, Bombyx mori nucleopolyhedrovirus (BmNPV). Involvement of these proteins in the inhibition of baculovirus infection was revealed by estimating the viral load upon their dsRNA mediated knockdown. Additionally, we found through antimicrobial assays that seroins are potent inhibitors of bacterial growth. Binding competition assays followed by antimicrobial assays showed that seroins bind to peptidoglycan, a cell wall component of bacteria. Analysis of bacterial load upon knockdown of seroins resulted in higher proliferation of bacteria. Phylogenetic analysis showed the recent origin of seroins in a few moth species and duplication only in Bombycids. The antiviral and antibacterial activity of seroins shown in this study using several biochemical and molecular biological assays provide strong evidence to characterize them as antimicrobial proteins. Hence, we hypothesize that seroins are potent candidates for use in development of transgene-based disease resistant silkworm strains. PMID- 24628956 TI - Comparative transcriptomics of Atlantic Salmo salar, chum Oncorhynchus keta and pink salmon O. gorbuscha during infections with salmon lice Lepeophtheirus salmonis. AB - BACKGROUND: Salmon species vary in susceptibility to infections with the salmon louse (Lepeophtheirus salmonis). Comparing mechanisms underlying responses in susceptible and resistant species is important for estimating impacts of infections on wild salmon, selective breeding of farmed salmon, and expanding our knowledge of fish immune responses to ectoparasites. Herein we report three L. salmonis experimental infection trials of co-habited Atlantic Salmo salar, chum Oncorhynchus keta and pink salmon O. gorbuscha, profiling hematocrit, blood cortisol concentrations, and transcriptomic responses of the anterior kidney and skin to the infection. RESULTS: In all trials, infection densities (lice per host weight (g)) were consistently highest on chum salmon, followed by Atlantic salmon, and lowest in pink salmon. At 43 days post-exposure, all lice had developed to motile stages, and infection density was uniformly low among species. Hematocrit was reduced in infected Atlantic and chum salmon, and cortisol was elevated in infected chum salmon. Systemic transcriptomic responses were profiled in all species and large differences in response functions were identified between Atlantic and Pacific (chum and pink) salmon. Pink and chum salmon up-regulated acute phase response genes, including complement and coagulation components, and down-regulated antiviral immune genes. The pink salmon response involved the largest and most diverse iron sequestration and homeostasis mechanisms. Pattern recognition receptors were up-regulated in all species but the active components were often species-specific. C-type lectin domain family 4 member M and acidic mammalian chitinase were specifically up regulated in the resistant pink salmon. CONCLUSIONS: Experimental exposures consistently indicated increased susceptibility in chum and Atlantic salmon, and resistance in pink salmon, with differences in infection density occurring within the first three days of infection. Transcriptomic analysis suggested candidate resistance functions including local inflammation with cytokines, specific innate pattern recognition receptors, and iron homeostasis. Suppressed antiviral immunity in both susceptible and resistant species indicates the importance of future work investigating co-infections of viral pathogens and lice. PMID- 24628958 TI - Epidemiological and clinical characteristics of imported malaria in the United Arab Emirates. AB - BACKGROUND: The United Arab Emirates (UAE) was certified by the World Health Organization to be free of endemic malaria transmission in 2007. There continued to be, however, a substantial number of imported malaria cases. METHODS: A retrospective laboratory and chart review was performed to describe the epidemiological, clinical, and laboratory characteristics of imported malaria in Dubai, UAE. Laboratory records were reviewed at the largest public hospital in Dubai to identify cases of peripheral blood smear-positive malaria from January 1, 2008 to December 31, 2010. Predefined demographic, clinical, and laboratory information was extracted from the electronic medical record system. RESULTS: A total of 629 cases of malaria were identified including 493, 122, and 14 cases of Plasmodium vivax, Plasmodium falciparum, and mixed P. vivax/P. falciparum infections, respectively. Of these, 567 (90.1%) cases were either from India or Pakistan and 7% from sub-Saharan Africa. There were no cases among the local Emirati population. There were 162 hospitalizations, including 8 requiring intensive care support and 1 death. More than 10% of P. vivax infections required hospitalization. The interval between arrival in the UAE and diagnosis was 3 months or longer for 25% of P. vivax cases. CONCLUSIONS: Imported malaria remains an important cause of morbidity in the UAE. Clinicians need to be aware that P. vivax is not benign and can cause severe disease and that malaria cases may present to health facilities several months after arrival from malaria-endemic regions. PMID- 24628959 TI - Genome-scale metabolic network reconstruction of Saccharopolyspora spinosa for spinosad production improvement. AB - BACKGROUND: Spinosad is a macrolide antibiotic produced by Saccharopolyspora spinosa with aerobic fermentation. However, the wild strain has a low productivity. In this article, a computational guided engineering approach was adopted in order to improve the yield of spinosad in S. spinosa. RESULTS: Firstly, a genome-scale metabolic network reconstruction (GSMR) for S.spinosa based on its genome information, literature data and experimental data was established. The model was consists of 1,577 reactions, 1,726 metabolites, and 733 enzymes after manually refined. Then, amino acids supplying experiments were performed in order to test the capabilities of the model, and the results showed a high consistency. Subsequently, transhydrogenase (PntAB, EC 1.6.1.2) was chosen as the potential target for spinosad yield improvement based on the in silico metabolic network models. Furthermore, the target gene was manipulated in the parent strain in order to validate the model predictions. At last, shake flask fermentation was carried out which led to spinosad production of 75.32 mg/L, 86.5% higher than the parent strain (40.39 mg/L). CONCLUSIONS: Results confirmed the model had a high potential in engineering S. spinosa for spinosad production. It is the first GSMM for S.spinosa, it has significance for a better understanding of the comprehensive metabolism and guiding strain designing of Saccharopolyspora spinosa in the future. PMID- 24628960 TI - A prospective observational study on tolerance and satisfaction to hepatic haemodynamic procedures. AB - BACKGROUND: Understanding patients' attitudes to clinical experiences is essential for developing high-quality patient-centred healthcare, as a better knowledge of patients' tolerance and satisfaction might allow implementing measures that ameliorate comfort, care and use of resources. AIMS: We aimed to describe patients' tolerance and satisfaction to invasive hepatic haemodynamic procedures, and to investigate which factors might influence patients' perspective in this field. METHODS: Visual Analogue Scale (VAS) questionnaires regarding pain and duration (for tolerance), and comfort and general handling (for satisfaction) were prospectively administered to all consecutive patients (N = 327) submitted to hepatic haemodynamic procedures (N = 355) in a tertiary care setting during 2011. VAS scores ranged between 0 and 100 mm and items were defined as excellent if <10 mm; good if 10-20 mm and inadequate if >20 mm. Clinical and laboratory data were also collected. RESULTS: Satisfaction was excellent in >95% of cases (mean 2 +/- 5 mm, median 0 mm) and average tolerance was good (15 +/- 18 mm; median 6 mm). A percentage of 59% of patients had excellent tolerance, 9% good and 32% had inadequate tolerance. Duration and complexity of the procedure and limited operator's experience were associated with inadequate tolerance on univariate analysis; duration of the procedure remained the only independent factor associated with inadequate tolerance on multivariate analysis. Procedures lasting <35 min had a >80% probability of being well tolerated. CONCLUSIONS: Satisfaction and tolerance to hepatic haemodynamic procedures are excellent and good respectively. Tolerance was decreased in long procedures; hence reducing as much as possible the duration of the procedures might further improve tolerance. PMID- 24628962 TI - Two rooms, two representations? Episodic-like memory in toddlers and preschoolers. AB - Episodic memory involves binding together what-where-when associations. In three experiments, we tested the development of memory for such contextual associations in a naturalistic setting. Children searched for toys in two rooms with two different experimenters; each room contained two identical sets of four containers, but arranged differently. A distinct toy was hidden in a distinct container in each room. In Experiment 1, which involved children between 15 and 26 months who were prompted with a very explicit cue (a part of the hidden toy), we found a marked shift in performance with age: while 15- to 20-month-olds concentrated their searches on the two containers that sometimes contained toys, they did not distinguish between them according to context, but 21-26-month-olds did. However, surprisingly, without toy cues, even the youngest children showed a fragile ability to disambiguate the two containers by room context. In Experiment 2, we tested 34- to 40-month-olds and 64- to 72-month-olds without toy cues. The 5-year-olds were nearly perfect, and the 3-year-olds showed a significant preference for the correct container given only the context. In Experiment 3, we filled in the age range, and also investigated the effects of the use of labels (i.e. names of experimenters and rooms) and of familiarization time, in groups of 34- to 40-month-olds, 42- to 48-month-olds, and 50- to 56-month-olds. Neither labels nor familiarization time had an effect. Across experiments, there was regular age-related improvement in context-based memory. Overall, the results suggest that children's episodic memory may undergo an early qualitative change, yet to be precisely characterized, and that continuing increments in the use of contextual cues occur throughout the preschool period. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=DkwEFw0UEz4&list=PLwxXcOKHPC0llAPVcJyW4EtzlA934A2 z&index=1. PMID- 24628961 TI - Effectiveness of a smartphone application for improving healthy lifestyles, a randomized clinical trial (EVIDENT II): study protocol. AB - BACKGROUND: New technologies could facilitate changes in lifestyle and improve public health. However, no large randomized, controlled studies providing scientific evidence of the benefits of their use have been made. The aims of this study are to develop and validate a smartphone application, and to evaluate the effect of adding this tool to a standardized intervention designed to improve adherence to the Mediterranean diet and to physical activity. An evaluation is also made of the effect of modifying habits upon vascular structure and function, and therefore on arterial aging. METHODS/DESIGN: A randomized, double-blind, multicenter, parallel group clinical trial will be carried out. A total of 1215 subjects under 70 years of age from the EVIDENT trial will be included. Counseling common to both groups (control and intervention) will be provided on adaptation to the Mediterranean diet and on physical activity. The intervention group moreover will receive training on the use of a smartphone application designed to promote a healthy diet and increased physical activity, and will use the application for three months. The main study endpoints will be the changes in physical activity, assessed by accelerometer and the 7-day Physical Activity Recall (PAR) interview, and adaptation to the Mediterranean diet, as evaluated by an adherence questionnaire and a food frequency questionnaire (FFQ). Evaluation also will be made of vascular structure and function based on central arterial pressure, the radial augmentation index, pulse velocity, the cardio-ankle vascular index, and carotid intima-media thickness. DISCUSSION: Confirmation that the new technologies are useful for promoting healthier lifestyles and that their effects are beneficial in terms of arterial aging will have important clinical implications, and may contribute to generalize their application in favor of improved population health. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT02016014. PMID- 24628964 TI - The effect of experimentally induced hypothyroidism on the isoflurane minimum alveolar concentration in dogs. AB - OBJECTIVE: To determine the effect of experimentally induced hypothyroidism on isoflurane (ISO) minimum alveolar concentration (MAC) in dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Eighteen adult female mongrel dogs, age 2-4 years and weighing 8.2-13.1 kg. METHODS: Hypothyroidism was induced in nine dogs by the intravenous administration of 1 mCi kg(-1) of (131) Iodine. The remaining nine dogs served as controls. Dogs were studied 9-12 months after the induction of hypothyroidism. Anesthesia was induced with ISO in oxygen via a mask. The trachea was intubated, and anesthesia was maintained using ISO in oxygen using a semi-closed rebreathing circle system. The dogs were mechanically ventilated to maintain an end-tidal carbon dioxide concentration between 35 and 45 mmHg. End-tidal ISO concentrations were measured with an infrared gas analyzer. The MAC was determined in duplicate using a tail clamp technique. The mean values for the groups were compared using a two sample t-test. RESULTS: The mean +/- SD MAC of isoflurane in the hypothyroid and euthyroid dogs was 0.98 +/- 0.31% and 1.11 +/- 0.26%, respectively. The mean MAC of isoflurane in hypothyroid dogs was not significantly different from the mean MAC of isoflurane in the control dogs (p = 0.3553). CONCLUSION AND CLINICAL RELEVANCE: The MAC of ISO in dogs was not significantly affected by experimentally induced hypothyroidism. The dose of ISO in dogs with hypothyroidism does not need to be altered. PMID- 24628963 TI - Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study. AB - BACKGROUND: We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression free survival (PFS) and the predictive role of serum vitamin D in progression free survival and proteinuria onset. METHODS: This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression. RESULTS: Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome. CONCLUSION: The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy. TRIAL REGISTRATION: Trial registration number NCT01203306. PMID- 24628965 TI - Managing spastic foot drop after stroke. PMID- 24628966 TI - The short-term effect of flavonoid-rich dark chocolate on retinal vessel diameter in glaucoma patients and age-matched controls. AB - PURPOSE: To investigate the effect of flavonoid-rich dark chocolate and non flavonoid-rich white chocolate on retinal vessel diameter in glaucoma patients and age-matched controls. METHODS: Thirty glaucoma patients and 30 age-matched subjects were assigned to dark or white chocolate by randomization with forced equal distribution. The number in each of the four groups was 15. Measured parameters included systemic blood pressure (BP), blood glucose levels, static retinal vessel analysis, as measured by central retinal artery equivalent (CRAE) (which relates to the diameter of the central retinal artery), central retinal vein equivalent (CRVE) (which relates to the diameter of central retinal vein) and the arterio-venous ratio (AVR), which represents the CRAE/CRVE ratio, dynamic retinal vessel analysis as measured by the change in vessel diameter in response to flicker light stimulation. Three recording cycles from each were averaged. RESULTS: Blood pressure parameters (systolic BP, diastolic BP and pulse), IOP and blood glucose levels did not differ significantly between both groups before and after consumption of white or dark chocolate. Static vessel analysis did not show any significant changes in CRAE, CRVE or AVR before and after dark or white chocolate in both groups (p > 0.05). Mean dilatation of the venules in the control group was 3.2 +/- 0.9 % before dark chocolate and 4.2 +/- 1.4 % after dark chocolate intake, which was statistically significantly different (p = 0.01). Mean dilatation of the arterioles in the control group was 2.8 +/- 1.8 % before dark chocolate and 3.5 +/- 1.8 % after dark chocolate intake with a trend to statistical significance (p = 0.14), but not reaching the significance level. Mean diameter changes in the glaucoma group did not show any significant differences after dark chocolate consumption. CONCLUSION: The present study showed a significant improvement of venous vasodilatation 2 hr after dark chocolate intake in the control group, but not in the glaucoma group. This effect might be indicative of an increased bioavailability of nitric oxide (NO) after dark chocolate consumption. The lack of finding a significant venous response after dark chocolate in the glaucoma group might be related to the already impaired endothelial function in these patients. PMID- 24628967 TI - Organ and tissue donation in clinical settings: a systematic review of the impact of interventions aimed at health professionals. AB - In countries where presumed consent for organ donation does not apply, health professionals (HP) are key players for identifying donors and obtaining their consent. This systematic review was designed to verify the efficacy of interventions aimed at HPs to promote organ and tissue donation in clinical settings. CINAHL (1982 to 2012), COCHRANE LIBRARY, EMBASE (1974 to 2012), MEDLINE (1966 to 2012), PsycINFO (1960 to 2012), and ProQuest Dissertations and Theses were searched for papers published in French or English until September 2012. Studies were considered if they met the following criteria: aimed at improving HPs' practices regarding the donation process or at increasing donation rates; HPs working in clinical settings; and interventions with a control group or pre post assessments. Intervention behavioral change techniques were analyzed using a validated taxonomy. A risk ratio was computed for each study having a control group. A total of 15 studies were identified, of which only 5 had a control group. Interventions were either educational, organizational or a combination of both, and had a weak theoretical basis. The most common behavior change technique was providing instruction. Two sets of interventions showed a significant risk ratio. However, most studies did not report the information needed to compute their efficacy. Therefore, interventions aimed at improving the donation process or at increasing donation rates should be based on sound theoretical frameworks. They would benefit from more rigorous evaluation methods to ensure good knowledge translation and appropriate organizational decisions to improve professional practices. PMID- 24628968 TI - Contact allergy to chlorphenesin. PMID- 24628969 TI - High specialisation in the pollination system of Mandevilla tenuifolia (J.C. Mikan) Woodson (Apocynaceae) drives the effectiveness of butterflies as pollinators. AB - Butterfly pollination in the tropics is considered somewhat effective or solely effective in a few plant species. In the present study, we tested the hypothesis that Mandevilla tenuifolia (Apocynaceae), which has floral attributes associated with psychophily, has strategies adapted to pollination by butterflies, restricting other floral visitors and making these insects act as efficient pollinators. We analysed the floral and reproductive biology of M. tenuifolia, as well as the frequency and efficiency of its flower visitors. M. tenuifolia is an herb whose flowers have strong herkogamy and secondary pollen presentation on the style head, which corresponds to 60.4% of pollen on the anthers. Flower longevity and the long period of receptivity of the stigmatic region associated with the large amount of pollen removed in the first visits suggest that flowers remain functionally female during part of anthesis. Butterflies, mainly of the families Nymphalidae and Pieridae, are the only pollinators of M. tenuifolia. Despite being self-compatible, M. tenuifolia depends on biotic vectors for fruit production. A non-significant difference in fruit set between controlled treatments and natural conditions suggests that the pollinators are efficient. The inclination resulting from the landing of butterflies on flowers, together with flower morphology, guiding the insect proboscis inside the floral tube, as well as the frequency and efficiency of butterfly visits, are evidence of the close relationship between butterflies and M. tenuifolia, and also of the efficiency of these insects as pollinators. PMID- 24628970 TI - Assessment concordance and predictive validity of self-report and biological assay of cocaine use in treatment trials. AB - BACKGROUND AND OBJECTIVES: Cocaine use during randomized clinical trials (RCTs) is typically assessed by participant self-report or biological assay (eg, urinalysis). There have been few direct comparisons of these assessment methods to investigate their concordance and their predictive validity for cocaine use and psychosocial outcomes following treatment completion. METHOD: In a combined sample of 380 participants from 5 cocaine RCTs, the concordance between cocaine use assessment methods was examined. Sequential multiple linear and logistic regression models evaluated the predictive validity of two assessment methods for cocaine use and psychosocial outcomes assessed at 1, 3, 6, and 12 months after treatment. RESULTS: Concordance for self-report and urinalysis indicators of cocaine use was high within-treatment (k = 0.72) and moderate during follow-up (k = 0.51). Rates of concordance were higher in studies using test cups with immediate urinalysis results. Regression analyses indicated that self-report data within-treatment predicted self-reported cocaine use at all post-treatment points (beta 0.22-0.30, p < .01), while urinalysis results within-treatment predicted urinalysis results at 1, 3, and 6 months post-treatment (OR 3.92-20.99, p < .05). Cocaine-positive urinalyses within-treatment were negatively associated with a composite "good outcome" indicator at 1 and 3 months post-treatment (OR 0.17 0.32, p < .05). DISCUSSION AND CONCLUSIONS: These results suggest a significant role of method variance in predicting post-treatment outcomes from within treatment cocaine use indices. SCIENTIFIC SIGNIFICANCE: Results support recommendations that cocaine treatment trials should include both biological assay and self-report assessment. Test cups may facilitate increased self-report accuracy. PMID- 24628971 TI - Gene polymorphism analysis of Yersinia enterocolitica outer membrane protein A and putative outer membrane protein A family protein. AB - BACKGROUND: Yersinia enterocolitica outer membrane protein A (OmpA) is one of the major outer membrane proteins with high immunogenicity. We performed the polymorphism analysis for the outer membrane protein A and putative outer membrane protein A (p-ompA) family protein gene of 318 Y. enterocolitica strains. RESULTS: The data showed all the pathogenic strains and biotype 1A strains harboring ystB gene carried both ompA and p-ompA genes; parts of the biotype 1A strains not harboring ystB gene carried either ompA or p-ompA gene. In non pathogenic strains (biotype 1A), distribution of the two genes and ystB were highly correlated, showing genetic polymorphism. The pathogenic and non pathogenic, highly and weakly pathogenic strains were divided into different groups based on sequence analysis of two genes. Although the variations of the sequences, the translated proteins and predicted secondary or tertiary structures of OmpA and P-OmpA were similar. CONCLUSIONS: OmpA and p-ompA gene were highly conserved for pathogenic Y. enterocolitica. The distributions of two genes were correlated with ystB for biotype 1A strains. The polymorphism analysis results of the two genes probably due to different bio-serotypes of the strains, and reflected the dissemination of different bio-serotype clones of Y. enterocolitica. PMID- 24628973 TI - The development and validation of a rapid genetic method for species identification and genotyping of medically important fungal pathogens using high resolution melting curve analysis. AB - Accurate, rapid and economical fungal species identification has been a major aim in mycology. In this study, our goal was to examine the feasibility of a high resolution melting curve analysis (HRMA) of internal transcribed regions ITS1 and ITS2 in ribosomal DNA (rDNA) for a rapid, simple and inexpensive differentiation of eight clinically relevant Candida species (Candida albicans, Candida glabrata, Candida parapsilosis, Candida krusei, Candida tropicalis, Candida guilliermondii, Candida dubliniensis and Candida lusitaniae). In addition, for the first time, we tested the applicability of HRMA to classify C. albicans strains into four previously described genotypes (A, B, C and D) using a primer set that spans the transposable intron region of 25S of rDNA. Type and unknown clinical oral isolates were used in this study and the melting curve analysis was compared with both amplicons' sequencing and agarose gel electrophoresis analysis. Real-time PCR and subsequent HRMA of the two described rDNA regions generated distinct melting curve profiles that were in accord with sequencing and gel electrophoresis analysis, highly reproducible, and characteristic of each of the eight Candida species and C. albicans genotypes. Moreover, results were obtained in 4 h and without the need for any post-amplification handling, so reducing time and cost. Owing to its simplicity and speed, this technique is a good fit for genotypic analysis of hundreds of clinical strains in large epidemiological settings. PMID- 24628974 TI - Diphtheria toxin conformational switching at acidic pH. AB - Diphtheria toxin (DT), the etiological agent of the homonymous disease, like other bacterial toxins, has to undergo a dramatic structural change in order to be internalized into the cytosol, where it finally performs its function. The molecular mechanism of toxin transit across the membrane is not well known, but the available experimental evidence indicates that one of the three domains of the toxin, called the central alpha-helical domain, inserts into the lipid bilayer, so favoring the translocation of the catalytic domain. This process is driven by the acidic pH of the endosomal lumen. Here, we describe the crystal structure of DT grown at acidic pH in the presence of bicelles. We were unable to freeze the moment of DT insertion into the lipid bilayer, but our crystal structure indicates that the low pH causes the unfolding of the TH2, TH3 and TH4 alpha-helices. This event gives rise to the exposure of a hydrophobic surface that includes the TH5 and TH8 alpha-helices, and the loop region connecting the TH8 and TH9 alpha-helices. Their exposure is probably favored by the presence of lipid bilayers in the crystallization solution, and they appear to be ready to insert into the membrane. DATABASE: Coordinates and structure factors have been deposited in the Protein Data Bank under accession number 4OW6. PMID- 24628972 TI - The effect of a kindergarten-based, family-involved intervention on objectively measured physical activity in Belgian preschool boys and girls of high and low SES: the ToyBox-study. AB - BACKGROUND: The ToyBox-study developed an evidence- and theory-based intervention to improve preschoolers' energy balance-related behaviours - including physical activity (PA) - by targeting the kindergarten environment and involving their parents/caregivers. The present study aimed to examine the effect of the ToyBox intervention on increasing Belgian preschoolers' objectively measured PA levels. METHODS: A sample of 472 preschoolers (4.43 +/- 0.55 years; 55.1% boys) from 27 kindergartens (15 intervention, 12 control kindergartens) in Flanders, Belgium were included in the data analyses. Preschoolers wore an ActiGraph accelerometer for six consecutive days and were included in the data analyses if they had a minimum of two weekdays and one weekend day, both at baseline and follow-up (one year later). Preschoolers' PA outcomes were estimated for an average day, weekday, weekend day, during school hours, and during after school hours. To assess intervention effects, multilevel repeated measures analyses were conducted for the total sample, and for sub-groups (according to sex, kindergarten levels of socio-economic status (SES) and risk groups (low levels of PA at baseline)) of preschoolers. RESULTS: Small intervention effects were found in the total sample. Most intervention effects were found in boys and in preschoolers from high SES kindergartens. Boys from the intervention group had an increase in vigorous PA (beta=1.47, p=0.03) and moderate-to-vigorous PA (beta=1.27, p=0.03) from baseline to follow-up, whereas PA levels in boys from the control group stagnated or decreased. In preschoolers from high SES kindergartens, the largest effects were found for PA outcomes during school hours and during after school hours. CONCLUSION: The results from the Belgian sample demonstrate that effects of the PA-component of the ToyBox-intervention on objectively measured PA were found in preschool boys and in preschoolers from high SES kindergartens, which means that the ToyBox-intervention was mainly effective in those sub-groups. Future interventions should search for alternative strategies to increase preschoolers' PA levels in preschool girls and preschoolers from low SES kindergartens, as these are the most important at-risk groups regarding PA. PMID- 24628975 TI - Carbon monoxide-releasing molecule attenuates allograft airway rejection. AB - Acute rejection after lung transplantation is the main risk factor for the development of bronchiolitis obliterans (BO). Carbon monoxide (CO) can provide anti-inflammatory effects and may serve to limit tissue injury in airway transplant. Here, we tested the ability of carbon monoxide releasing molecule-2 (CORM-2) to prevent airway rejection. Tracheal grafts from BALB/c or C57BL/6 were transplanted to C57BL/6 recipients. Experimental groups were treated with multiple doses of CORM-2. Histopathological evaluation of luminal obliteration was blindly reviewed. Immunohistochemistry and real-time RT-PCR analyses were performed. Allografts treated with CORM-2 revealed a striking reduction of thickening in epithelial and subepithelial airway layers (P < 0.01) at day 7 in orthotopic trachea transplantation model compared with allografts treated with vehicle. In heterotopic trachea transplantation model, CORM-2 treated allografts showed a reduction of luminal obliteration (P < 0.01) at days 14 and 21. There was also a concordant decrease in CD3(+) lymphocytes and macrophages in CORM-2 treated allografts. IFN-gamma, IL-2 and IL17A mRNA expressions were reduced dramatically by systemic administration of CORM-2. These data implicate CORM-2 derived CO has an important protective function in experimental BO, and may represent a target for the therapeutic intervention of chronic lung allograft rejection. PMID- 24628976 TI - Routes to cAMP: shaping neuronal connectivity with distinct adenylate cyclases. AB - cAMP signaling affects a large number of the developmental processes needed for the construction of the CNS, including cell differentiation, axon outgrowth, response to guidance molecules or modulation of synaptic connections. This points to a key role of adenylate cyclases (ACs), the synthetic enzymes of cAMP, for neural development. ACs exist as 10 different isoforms, which are activated by distinct signaling pathways. The implication of specific AC isoforms in neural wiring was only recently demonstrated in mouse mutants, knockout (KO) for different AC isoforms, AC1, AC3, AC5, AC8 and soluble (s)AC/AC10. These studies stressed the importance of three of these isoforms, as sensors of neural activity that could modify the survival of neurons (sAC), axon outgrowth (sAC), or the response of axons to guidance molecules such as ephrins (AC1) or semaphorins (AC3). We summarize here the current knowledge on the role of these ACs for the development of sensory maps, in the somatosensory, visual and olfactory systems, which have been the most extensively studied. In these systems, AC1/AC3 KO revealed targeting mistakes due to the defective pruning and lack of discrimination of incoming axons to signals present in target structures. In contrast, no changes in cell differentiation, survival or axon outgrowth were noted in these mutants, suggesting a specificity of cAMP production routes for individual cellular processes within a given neuron. Further studies indicate that the subcellular localization of ACs could be key to their specific role in axon targeting and may explain their selective roles in neuronal wiring. PMID- 24628977 TI - How long should infants at risk of drug withdrawal be monitored after birth? AB - AIM: Neonatal abstinence syndrome (NAS) is an increasingly common disorder diagnosed in infants exposed to various drugs, causing immense financial and social burden. Recommendations from various bodies are for babies to be monitored for 4 to 7 days following birth so that prompt treatment can commence should symptoms develop. We aimed to determine the best post-natal observation period in babies at risk of NAS. METHODS: A retrospective review was undertaken of infants >=35 weeks' gestation who received treatment for NAS in the period 2001-2010. During this time, the standard post-natal observation period was a minimum of 7 days. Data including drug exposure, day of admission and day of treatment were collected. RESULTS: Two hundred and ten babies were included. Drug exposure was predominantly to opiates (99%); however, most infants (58%) were exposed to additional substances (benzodiazepines, cannabis or amphetamines). Ninety-five per cent of infants were admitted by day 5 of life. Of the babies treated by day 7, 98.5% had been admitted to the nursery by day 5. Infants with polydrug exposure were admitted significantly earlier; however, time to treatment was not significantly different to those exposed to opiate replacement therapy alone. CONCLUSIONS: In our hospital, babies treated for NAS often required admission before day 5. This has implications for hospital resource allocation, suggesting that routine post-natal observation for NAS could be shortened to 5 days. Further research is needed to help identify neonates who require more careful post-natal observation. PMID- 24628978 TI - Overexpression of microRNA-99a attenuates heart remodelling and improves cardiac performance after myocardial infarction. AB - MicroRNAs are involved in the regulation of various cellular processes, including cell apoptosis and autophagy. Expression of microRNA-99a (miR-99a) is reduced in apoptotic neonatal mice ventricular myocytes (NMVMs) subjected to hypoxia. We hypothesize that miR-99a might restore cardiac function after myocardial infarction (MI) by up-regulation of myocyte autophagy and apoptosis. We observed down-regulated miR-99a expression in NMVMs exposed to hypoxia using TaqMan quantitative reverse transcriptase-polymerase chain reaction analysis (RT-PCR). We also observed that miR-99a overexpression decreased hypoxia-mediated apoptosis in cultured NMVMs. To investigate whether overexpression of miR-99a in vivo could improve cardiac function in ischaemic heart, adult C57/BL6 mice undergoing MI were randomized into two groups and were intra-myocardially injected with lenti 99a-green fluorescent protein (GFP) or lenti-GFP (control). Four weeks after MI, lenti-99a-GFP group showed significant improvement in both left ventricular (LV) function and survival ratio, as compared to the lenti-GFP group. Histological analysis, western blotting analysis and electron microscopy revealed decreased cellular apoptosis and increased autophagy in cardiomyocytes of lenti-99a-GFP group. Furthermore, western blotting analysis showed inhibited mammalian target of rapamycin (mTOR) expression in the border zones of hearts in miR-99a-treated group. Our results demonstrate that miR-99a overexpression improves both cardiac function and survival ratio in a murine model of MI by preventing cell apoptosis and increasing autophagy via an mTOR/P70/S6K signalling pathway. These findings suggest that miR-99a plays a cardioprotective role in post-infarction LV remodelling and increased expression of miR-99a may have a therapeutic potential in ischaemic heart disease. PMID- 24628979 TI - Interleukin 20 protein locates to distinct mononuclear cells in psoriatic skin. AB - We previously demonstrated that mRNA for the pro-inflammatory cytokine interleukin 20 (IL-20) is expressed in suprapapillary keratinocytes of lesional psoriatic skin (LS). Here, we describe the distribution of IL-20 protein and the identity of the IL-20-positive cells in LS. We found that the main part of IL-20 immunoreactivity is present in mononuclear cells of the dermal papillae, and that the IL-20-positive cells located in the papillae were langerin+, CD1a+, CD4+ and CD303+. These cells might be immature dendritic cell. In situ hybridization for IL-20 mRNA on non-LS, ex vivo stimulated with IL-1beta revealed a colocalization between IL-20 mRNA and the keratinocyte marker CK14. No IL-20 mRNA was detected in the dermal mononuclear cells. Our results suggest that IL-20 is produced by keratinocytes, released into the epidermis and then possibly taken up by papillary mononuclear cells. Our study supports that IL-20 is involved in the pathogenesis of psoriasis. PMID- 24628980 TI - Associations of short sleep duration with prehypertension and hypertension among Lithuanian children and adolescents: a cross-sectional study. AB - BACKGROUND: Recent epidemiological studies have found that the prevalence of high blood pressure (BP) has significantly increased among children and adolescents. The aim of this study was to examine the associations between short sleep duration and prehypertension and hypertension in Lithuanian children and adolescents aged 12 to 15 years. METHODS: A cross-sectional study was conducted from November 2010 to April 2012. The participants with high BP (>=90th percentile) were screened on two separate occasions. Self-reported sleep duration was evaluated using questionnaires. Data on 6,940 subjects aged 12-15 years were analyzed. Adjusted odds ratios (aORs) with 95% confidence intervals for the associations were estimated using multivariate logistic regression models. Short sleep duration was defined as <8 hours per day (h/day). RESULTS: The prevalence of prehypertension and hypertension in the current sample was 12.6% and 22.5%, respectively. The percentages of the subjects with sleep durations of <7 (h/day), 7-<8 h/day, and >=8 h/day were 8.7%, 21.0%, and 70.3%, respectively. After adjusting for age, sex, body mass index, physical activity, and smoking, significant associations were found between short sleep duration and high BP, including prehypertension (7-<8 h/day: aOR=1.77; 95% CI, 1.48-2.12; <7 h/day: aOR=2.18; 95% CI, 1.70-2.79) and hypertension (7-<8 h/day: aOR=1.99; 95% CI, 1.72 2.31; <7 h/day: aOR=2.28; 95% CI, 1.85-2.80) (all P values<0.001), compared to participants who were sleeping longer (>=8 h/day). CONCLUSIONS: Prehypertension and hypertension were associated with short sleep duration among Lithuanian children and adolescents aged 12 to 15 years. PMID- 24628981 TI - Knowledge about post-anoxic somatosensory evoked potentials--present or not? AB - BACKGROUND AND PURPOSE: Median nerve somatosensory evoked potential (SEP) recordings play an important role in outcome algorithms in comatose patients after cardiopulmonary resuscitation. Knowledge of technical difficulties, clinical implications and uniform interpretation of SEP recordings is crucial. The aim of this study was to evaluate the skills of neurologists to interpret SEP recordings in post-anoxic patients. METHODS: Nationwide Dutch clinical neurophysiology examinations from 2007, 2008 and 2011, containing SEP related questions, were analysed. Participants were classified as neurology residents, neurologists with less than 10 years of experience, neurologists with more than 10 years of experience and clinical neurophysiologists. End-points were the knowledge of all participants about SEP recordings per year as well as improvement in knowledge over the years, as reflected by the test scores. RESULTS: A total of 194 participants completed the examination in 2007, 200 in 2008 and 263 in 2011. Between 2007 and 2008, all groups of respondents showed a significant increase in percentage of correct answers to SEP questions. Sixty-six participants completed all three examinations. The SEP score of this group improved in 2008 [75%, interquartile range (IQR) 50-75, P < 0.001] compared with 2007 (38%, IQR 38-50); there was no further improvement in 2011 (69%, IQR 54-77). CONCLUSION: Continuing education about technical knowledge, possible pitfalls and interpretation of SEP recordings remains of utmost importance. PMID- 24628982 TI - Chromosome-specific physical localisation of expressed sequence tag loci in Corchorus olitorius L. AB - Jute (Corchorus spp.), as a natural fibre-producing species, ranks next only to cotton. Inadequate understanding of its genetic architecture is a major lacuna for genetic improvement of this crop in terms of yield and quality. Establishment of a physical map provides a genomic tool that helps in positional cloning of valuable genes. In this report, an attempt was initiated to study association and localisation of single copy expressed sequence tag (EST) loci in the genome of Corchorus olitorius. The chromosome-specific association of EST was determined based on the appearance of an extra signal for a single copy cDNA probe in mitotic interphase nuclei of specific trisomic(s) for fluorescence in situ hybridisation, and validated using a cDNA fragment of the 26S rRNA gene (600 bp) as molecular probe. The probe exhibited three signals in meiotic interphase nuclei of trisomic 5, instead of two as observed in diploids and other trisomics, indicating its association with chromosome 5. Subsequent hybridisation of the same probe on the pachytene chromosomes of diploids confirmed that 26S rRNA occupies the terminal end of the short arm of chromosome 5 in C. olitorius. Subsequently, chromosome-specific association of 63 single copy EST and their physical localisation were determined on chromosomes 2, 4, 5 and 7. The study describes chromosome-specific physical localisation of genes in jute. The approach used here could be a step towards construction of genome-wide physical maps for any recalcitrant plant species like jute. PMID- 24628983 TI - Comparative analysis of CRISPR cassettes from the human gut metagenomic contigs. AB - BACKGROUND: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a prokaryotic adaptive defence system that provides resistance against alien replicons such as viruses and plasmids. Spacers in a CRISPR cassette confer immunity against viruses and plasmids containing regions complementary to the spacers and hence they retain a footprint of interactions between prokaryotes and their viruses in individual strains and ecosystems. The human gut is a rich habitat populated by numerous microorganisms, but a large fraction of these are unculturable and little is known about them in general and their CRISPR systems in particular. RESULTS: We used human gut metagenomic data from three open projects in order to characterize the composition and dynamics of CRISPR cassettes in the human-associated microbiota. Applying available CRISPR identification algorithms and a previously designed filtering procedure to the assembled human gut metagenomic contigs, we found 388 CRISPR cassettes, 373 of which had repeats not observed previously in complete genomes or other datasets. Only 171 of 3,545 identified spacers were coupled with protospacers from the human gut metagenomic contigs. The number of matches to GenBank sequences was negligible, providing protospacers for 26 spacers.Reconstruction of CRISPR cassettes allowed us to track the dynamics of spacer content. In agreement with other published observations we show that spacers shared by different cassettes (and hence likely older ones) tend to the trailer ends, whereas spacers with matches in the metagenomes are distributed unevenly across cassettes, demonstrating a preference to form clusters closer to the active end of a CRISPR cassette, adjacent to the leader, and hence suggesting dynamical interactions between prokaryotes and viruses in the human gut. Remarkably, spacers match protospacers in the metagenome of the same individual with frequency comparable to a random control, but may match protospacers from metagenomes of other individuals. CONCLUSIONS: The analysis of assembled contigs is complementary to the approach based on the analysis of original reads and hence provides additional data about composition and evolution of CRISPR cassettes, revealing the dynamics of CRISPR-phage interactions in metagenomes. PMID- 24628984 TI - Possible effects of EXT2 on mesenchymal differentiation--lessons from the zebrafish. AB - BACKGROUND: Mutations in the EXT genes disrupt polymerisation of heparan sulphates (HS) and lead to the development of osteochondroma, an isolated/sporadic- or a multifocal/hereditary cartilaginous bone tumour. Zebrafish (Danio rerio) is a very powerful animal model which has shown to present the same cartilage phenotype that is commonly seen in mice model and patients with the rare hereditary syndrome, Multiple Osteochondroma (MO). METHODS: Zebrafish dackel (dak) mutant that carries a nonsense mutation in the ext2 gene was used in this study. A panel of molecular, morphological and biochemical analyses was used to assess at what step bone formation is affected and what mechanisms underlie changes in the bone formation in the ext2 mutant. RESULTS: During bone development in the ext2-/- zebrafish, chondrocytes fail to undergo terminal differentiation; and pre-osteoblasts do not differentiate toward osteoblasts. This inadequate osteogenesis coincides with increased deposition of lipids/fats along/in the vessels and premature adipocyte differentiation as shown by biochemical and molecular markers. Also, the ext2-null fish have a muscle phenotype, i.e. muscles are shorter and thicker. These changes coexist with misshapen bones. Normal expression of runx2 together with impaired expression of osterix and its master regulator--xbp1 suggest that unfolded protein responses might play a role in MO pathogenesis. CONCLUSIONS: Heparan sulphates are required for terminal differentiation of the cartilaginous template and consecutive formation of a scaffold that is needed for further bone development. HS are also needed for mesenchymal cell differentiation. At least one copy of ext2 is needed to maintain the balance between bone and fat lineages, but homozygous loss of the ext2 function leads to an imbalance between cartilage, bone and fat lineages. Normal expression of runx2 and impaired expression of osterix in the ext2-/- fish indicate that HS are required by osteoblast precursors for their further differentiation towards osteoblastic lineage. Lower expression of xbp1, a master regulator of osterix, suggests that HS affect the 'unfolded protein response', a pathway that is known to control bone formation and lipid metabolism. Our observations in the ext2-null fish might explain the musculoskeletal defects that are often observed in MO patients. PMID- 24628985 TI - Skin and soft tissue infections following marine injuries and exposures in travelers. AB - BACKGROUND: Bacterial skin and soft tissue infections (SSTIs) in travelers often follow insect bites and can present a broad spectrum of clinical manifestations ranging from impetigo to necrotizing cellulitis. Significant SSTIs can also follow marine injuries and exposures in travelers, and the etiologies are often marine bacteria. METHODS: To meet the objectives of describing the pathogen specific presenting clinical manifestations, diagnostic and treatment strategies, and outcomes of superficial and deep invasive infections in travelers caused by commonly encountered and newly emerging marine bacterial pathogens, Internet search engines were queried with the key words as MESH terms. RESULTS: Travel medicine practitioners should maintain a high index of suspicion regarding potentially catastrophic, invasive bacterial infections, especially Aeromonas hydrophila, Vibrio vulnificus, Chromobacterium violaceum, and Shewanella infections, following marine injuries and exposures. CONCLUSIONS: Travelers with well-known risk factors for the increasing severity of marine infections, including those with open wounds, suppressed immune systems, liver disease, alcoholism, hemochromatosis, hematological disease, diabetes, chronic renal disease, acquired immunodeficiency syndrome, and cancer, should be cautioned about the risks of marine infections through exposures to marine animals, seawater, the preparation of live or freshly killed seafood, and the accidental ingestion of seawater or consumption of raw or undercooked seafood, especially shellfish. With the exception of minor marine wounds demonstrating localized cellulitis or spreading erysipeloid-type reactions, most other marine infections and all Gram-negative and mycobacterial marine infections will require therapy with antibiotic combinations. PMID- 24628986 TI - Combined treatment of rituximab, idarubicin, dexamethasone, cytarabine, methotrexate with radiotherapy for primary central nervous system lymphoma. AB - The overall response rates and long-term survival of primary central nervous system lymphoma (PCNSL) are still significantly inferior to the results achieved in similar subtypes of extranodal non-Hodgkin's lymphoma. It is clearly necessary to investigate new therapeutic methods on PCNSL. We encountered three patients histologically documented PCNSL as diffuse large B-cell lymphoma (DLBCL). They were treated with R-IDARAM which comprised rituximab, idarubicin, dexamethasone, cytarabine and methotrexate. Patient 1 received stereotactic brachytherapy (SBT) prior to chemotherapy performed with iodine-125 seeds (cumulative therapeutic dose 50 Gy). After six cycles of R-IDARAM at 3-weekly intervals, radiotherapy was applied at a dosage of 2000-4000 cGy in conventional schedule (180 or 200 cGy/day) to whole brain or spinal cord in all patients. Complete remission (CR) was achieved after first two cycles of R-IDARAM in all patients. All three patients remained in CR at the time of this report with a median duration of follow-up of 23 months (ranging from 13 to 41 months). Three patients have been alive for 41, 13, 16 months respectively until now. The patient with the longest survival time was the one given SBT prior to chemotherapy. This study suggests that R-IDARAM combining with radiotherapy maybe a high effective regimen in PCNSL patients especially those with primary central nervous system DLBCL. A comprehensive treatment combining internal radiotherapy by SBT, modified R-IDARAM and followed reduced external radiotherapy may be a new treatment concept for PCNSL with higher efficiency and lower toxicity. PMID- 24628987 TI - A prospective and randomized comparison of limited versus extensive atrial substrate modification after circumferential pulmonary vein isolation in nonparoxysmal atrial fibrillation. AB - INTRODUCTION: The optimal substrate ablation approach in patients with persistent atrial fibrillation (Per AF) remains unclear. This was a prospective randomized study comparing the efficacy of limited (continuous complex fractionated atrial electrogram, CFAE: <60 milliseconds) versus extensive (continuous CFAE plus variable CFAE: <120 milliseconds) atrial substrate modification in Per AF patients. METHODS AND RESULTS: We enrolled 120 Per AF patients in the study, and 30 patients with AF termination after pulmonary vein isolation (PVI) were excluded. In the remaining 90 patients, 45 were treated with limited approach (Group 1) and 45 with an extensive approach (Group 2). The end point of the study was the incidence of an atrial arrhythmia recurrence postblanking period. The patients were followed up for 15 months with 3-month clinical reviews, electrograms (ECGs), Holter recordings, and echocardiographic monitoring. Procedural AF termination and the single procedural efficacy were statistically comparable between the 2 groups (48.9% vs. 63.4% in Groups 1 and 2, respectively, P = 0.289). During the follow-up, patients who received limited ablation had a lower incidence of recurrent AFL (P = 0.04), and better reverse remodeling of the left atrium (LA, P = 0.04). After 2 procedures, the freedom from any atrial arrhythmia was better in Group 2 (62.2% vs. 87.8%, P = 0.009). Those with longstanding AF and a larger baseline LA size responded better to the extensive ablation. CONCLUSIONS: In the Per AF patients who failed to achieve AF termination after PVI alone, a specific atrial substrate modification approach targeting only continuous CFAEs could be considered as an initial ablation strategy. PMID- 24628988 TI - Endovascular treatment of arteriovenous graft pseudoaneurysms, indications, complications, and outcomes: a systematic review. AB - There are limited data regarding endovascular treatment of arteriovenous graft (AVG) pseudoaneurysms using stent grafts. We performed a comprehensive literature review on the use of stent grafts in the treatment of AVG pseudoaneurysms. We included 10 studies (121 patients). The mean AVG age was 3.1 years (95% confidence interval [CI]: 2.2-4) and pseudoaneurysm mean diameter was 34 mm (95% CI: 23-46). The majority (71%) of the pseudoaneurysms were located on the arterial limb of the AVG and 77% presented with venous anastomosis stenosis requiring angioplasty. The mean number of stents used to treat one lesion was 1.4 (95% CI: 1.3-1.5). The technical success rate of pseudoaneurysm isolation was 100% in all studies and 100% of patients received hemodialysis using the AVG after pseudoaneurysm treatment without the need for catheter placement. The primary patency rates for 1, 3, and 6 months were 81%, 73%, and 24%. Secondary patency was 80%, 77%, and 74% at 1, 3, and 6 months. Arteriovenous graft thrombosis occurred in 12% of patients. Arteriovenous graft infection developed in 35% of cases. Arteriovenous graft pseudoaneurysm treatment using stent grafts is effective in managing even large pseudoaneurysms and has acceptable primary and secondary patency rates. Graft infection was a relatively frequent complication. PMID- 24628989 TI - A flow cytometric assay to quantify invasion of red blood cells by rodent Plasmodium parasites in vivo. AB - BACKGROUND: Malaria treatments are becoming less effective due to the rapid spread of drug resistant parasites. Increased understanding of the host/parasite interaction is crucial in order to develop treatments that will be less prone to resistance. Parasite invasion of the red blood cell (RBC) is a critical aspect of the parasite life cycle and is, therefore, a promising target for the development of malaria treatments. Assays for analysing parasite invasion in vitro have been developed, but no equivalent assays exist for in vivo studies. This article describes a novel flow cytometric in vivo parasite invasion assay. METHODS: Experiments were conducted with mice infected with erythrocytic stages of Plasmodium chabaudi adami strain DS. Exogenously labelled blood cells were transfused into infected mice at schizogony, and collected blood samples stained and analysed using flow cytometry to specifically detect and measure proportions of labelled RBC containing newly invaded parasites. A combination of antibodies (CD45 and CD71) and fluorescent dyes, Hoechst (DNA) and JC-1 (mitochondrial membrane potential), were used to differentiate parasitized RBCs from uninfected cells, RBCs containing Howell-Jolly bodies, leukocytes and RBC progenitors. Blood cells were treated ex vivo with proteases to examine the effects on in vivo parasite invasion. RESULTS: The staining and flow cytometry analysis method was accurate in determining the parasitaemia down to 0.013% with the limit of detection at 0.007%. Transfused labelled blood supported normal rates of parasite invasion. Protease-treated red cells resulted in 35% decrease in the rate of parasite invasion within 30 minutes of introduction into the bloodstream of infected mice. CONCLUSIONS: The invasion assay presented here is a versatile method for the study of in vivo red cell invasion efficiency of Plasmodium parasites in mice, and allows direct comparison of invasion in red cells derived from two different populations. The method also serves as an accurate alternative method of estimating blood parasitaemia. PMID- 24628990 TI - SynCAMs extend their functions beyond the synapse. AB - Synaptic cell adhesion molecules are characterized by their potential to trigger synaptogenesis in vitro, even when expressed in non-neuronal cell lines. In addition to the prototypic synaptic cell adhesion molecules (SynCAMs), other structurally unrelated families of synaptic cell adhesion molecules have been identified: neurexins and neuroligins, as well as the leucine-rich repeat transmembrane neuronal protein family. Although in vivo the absence of individual synaptic cell adhesion molecules does not necessarily reduce the number of synapses, it does affect the function of synapses. Not surprisingly, mutations in synaptic cell adhesion molecules have been identified in patients suffering from neurodevelopmental disorders, such as autism spectrum disorders, intellectual disability or schizophrenia. In line with the major function of these genes at the synapse, their role in the pathogenesis of neurodevelopmental diseases has been attributed to synaptogenesis, synapse maintenance and synaptic plasticity. However, one family of synaptic cell adhesion molecules, the SynCAMs, have also been implicated in axon guidance, that is, an earlier step in neural circuit formation. These findings suggest that SynCAMs, and maybe other families of synaptic cell adhesion molecules as well, could contribute to the pathogenesis of neurodevelopmental disorders at multiple steps of neural circuit formation and, thus, shape the distinct symptoms associated with different disease variants or distinct neurodevelopmental disorders in addition to their effect on synaptic function. In this review, we summarize the roles of one family of synaptic cell adhesion molecules, the SynCAMs, at the synapse and beyond in axon guidance and myelination. PMID- 24628991 TI - Reply to 'neutrophil and platelet-to-lymphocyte ratio: new predictors of dropout and recurrence after liver transplantation for hepatocellular cancer?'. PMID- 24628992 TI - Role of oxidative stress and autoimmunity in onset and progression of vitiligo. AB - Vitiligo is an acquired depigmentation disorder characterized by the loss of functional melanocytes from the epidermis. Two major theories of vitiligo pathogenesis include autoimmunity and oxidative stress-mediated toxicity in melanocytes. The present study aimed to evaluate both the hypotheses in vitiligo patients and to investigate their role in the disease onset and progression. Antimelanocyte antibody levels and lipid peroxidation (LPO) levels were evaluated in 427 patients and 440 controls; antithyroid peroxidase (TPO) antibody levels were estimated in 102 patients and 72 controls. Patients showed a significant increase in LPO and antimelanocyte antibody levels compared to controls. Antimelanocyte antibody and LPO levels were higher in active vitiligo compared to stable. Only 9.8% of patients showed the presence of anti-TPO antibodies in their circulation. Oxidative stress may be the initial triggering event to precipitate vitiligo in Gujarat population, which is exacerbated by contributing autoimmune factors together with oxidative stress. PMID- 24628993 TI - Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC. METHODS: Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay. RESULTS: Relative levels of PAX8 protein were elevated (>= + 2 on a scale of 0-3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability. CONCLUSION: PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC. PMID- 24628994 TI - In vivo tracking of tau pathology using positron emission tomography (PET) molecular imaging in small animals. AB - Hyperphosphorylation of the tau protein leading to the formation of neurofibrillary tangles (NFTs) is a common feature in a wide range of neurodegenerative diseases known as tauopathies, which include Alzheimer's disease (AD) and the frontotemporal dementias (FTDs). Although heavily investigated, the mechanisms underlying the pathogenesis and progression of tauopathies have yet to be fully understood. In this context, several rodent models have been developed that successfully recapitulate the behavioral and neurochemical features of tau pathology, aiming to achieve a better understanding of the link between tau and neurodegeneration. To date, behavioral and biochemical parameters assessed using these models have been conducted using a combination of memory tasks and invasive methods such as cerebrospinal fluid (CSF) sampling or post-mortem analysis. Recently, several novel positron emission tomography (PET) radiopharmaceuticals targeting tau tangles have been developed, allowing for non-invasive in vivo quantification of tau pathology. Combined with tau transgenic models and microPET, these tracers hold the promise of advancing the development of theoretical models and advancing our understanding of the natural history of AD and non-AD tauopathies. In this review, we briefly describe some of the most important insights for understanding the biological basis of tau pathology, and shed light on the opportunity for improved modeling of tau pathology using a combination of tau-radiopharmaceuticals and animal models. PMID- 24628995 TI - Implicit meaning in 18-month-old toddlers. AB - A substantial body of evidence demonstrates that infants understand the meaning of spoken words from as early as 6 months. Yet little is known about their ability to do so in the absence of any visual referent, which would offer diagnostic evidence for an adult-like, symbolic interpretation of words and their use in language mediated thought. We used the head-turn preference procedure to examine whether infants can generate implicit meanings from word forms alone as early as 18 months of age, and whether they are sensitive to meaningful relationships between words. In one condition, toddlers were presented with lists of words taken from the same taxonomic category (e.g. animals or body parts). In a second condition, words taken from two other categories (e.g. clothes and food items) were interleaved within the same list. Listening times were found to be longer in the related-category condition than in the mixed-category condition, suggesting that infants extract the meaning of spoken words and are sensitive to the semantic relatedness between these words. Our results show that infants have begun to construct the rudiments of a semantic system based on taxonomic relations even before they enter a period of accelerated vocabulary growth. PMID- 24628996 TI - A successful treatment of buprenorphine withdrawal with the dopamine receptor agonist pramipexole. AB - BACKGROUND: Buprenorphine, used for treating opioid dependence, may have a withdrawal syndrome requiring treatment. Modulation of the dopamine system, which has been implicated in opioid withdrawal, may be a target for withdrawal for opioids such as buprenorphine. CASE REPORT: A case is reported of a buprenorphine withdrawal syndrome with predominant symptoms of restlessness that were resistant to clonidine and benzodiazepines. It was successfully treated with the dopamine agonist pramipexole. SCIENTIFIC SIGNIFICANCE: Dopamine receptor agonists may have a place in the treatment of restlessness associated with opioid withdrawal and may have value for the broader spectrum of opioid withdrawal symptoms. PMID- 24628998 TI - Impact of glucose levels on expression of hypha-associated secreted aspartyl proteinases in Candida albicans. AB - BACKGROUND: Ten secreted aspartyl proteinase (Sap) genes were identified in Candida albicans. The products of SAP genes are considered to be virulent factors of C. albicans that participated in causing mucocutaneous and systemic candidiasis in humans. Depending on environmental conditions, C. albicans may stay in yeast-form or convert into invasive hypha-form, and these issues may affect the expression of SAP genes. In this study we explored the component(s) of culture media that may affect the expression of hypha-associated SAP genes. RESULTS: We demonstrate that glucose levels modulate both the hyphae development and the expression strength of hypha-associated SAP genes (SAP4-6). In contrast to high glucose concentration (2%), lower glucose level (0.1%) is more potent to promote hyphae development and to promptly elicit the expression of hypha associated Sap proteins during yeast-to-hypha transition of C. albicans. Both Cph1-mediated MAP kinase cascade and Efg1-mediated cAMP/PKA pathway, although the latter seemed dominant, participate in convey the glucose signaling to regulate the expression of hypha-associated SAP genes and this glucose level effect may perform at very early stage of yeast-to-hypha transition. In addition, when C. albicans was co-cultured with THP-1 human monocytes, the engulfed C. albicans was developing hypha efficiently within 1 hr and the expression of hypha-associated Sap proteins could be detected on the distal surface of hyphae. CONCLUSION: We propose that the glucose level of bloodstream (approximately 0.1%) may be facilitated for stimulation of C. albicans to develop invasive hypha-form and to elicit promptly production of high-level hypha-associated Sap proteins. PMID- 24628997 TI - Physical activity level and its sociodemographic correlates in a peri-urban Nepalese population: a cross-sectional study from the Jhaukhel-Duwakot health demographic surveillance site. AB - BACKGROUND: Physical inactivity is a leading risk factor for cardiovascular and other noncommunicable diseases in high-, low- and middle-income countries. Nepal, a low-income country in South Asia, is undergoing an epidemiological transition. Although the reported national prevalence of physical inactivity is relatively low, studies in urban and peri-urban localities have always shown higher prevalence. Therefore, this study aimed to measure physical activity in three domains-work, travel and leisure-in a peri-urban community and assess its variations across different sociodemographic correlates. METHODS: Adult participants (n=640) from six randomly selected wards of the Jhaukhel-Duwakot Health Demographic Surveillance Site (JD-HDSS) near Kathmandu responded to the Global Physical Activity Questionnaire. To determine total physical activity, we calculated the metabolic equivalent of task in minutes/week for each domain and combined the results. Respondents were categorized into high, moderate or low physical activity. We also calculated the odds ratio for low physical activity in various sociodemographic variables and self-reported cardiometabolic states. RESULTS: The urbanizing JD-HDSS community showed a high prevalence of low physical activity (43.3%; 95% CI 39.4-47.1). Work-related activity contributed most to total physical activity. Furthermore, women and housewives and older, more educated and self-or government-employed respondents showed a greater prevalence of physical inactivity. Respondents with hypertension, diabetes or overweight/obesity reported less physical activity than individuals without those conditions. Only 5% of respondents identified physical inactivity as a cardiovascular risk factor. CONCLUSIONS: Our findings reveal a high burden of physical inactivity in a peri-urban community of Nepal. Improving the level of physical activity involves sensitizing people to its importance through appropriate multi-sector strategies that provide encouragement across all sociodemographic groups. PMID- 24628999 TI - Initial results from mechanical compression of the cornea during crosslinking for keratoconus. AB - PURPOSE: To compare refractive changes after corneal crosslinking with and without mechanical compression of the cornea. METHODS: In a prospective, open, randomized case-control study conducted at the Department of Ophthalmology, Umea University Hospital, Sweden, sixty eyes of 43 patients with progressive keratoconus aged 18-28 years planned for corneal crosslinking and corresponding age- and sex-matched control subjects were included. The patients were randomized to conventional corneal crosslinking (CXL; n = 30) or corneal crosslinking with mechanical compression using a flat rigid contact lens sutured to the cornea during treatment (CRXL; n = 30). Subjective refraction and ETDRS best spectacle corrected visual acuity (BSCVA), axial length measurement, keratometry and pachymetry were performed before and 1 and 6 months after treatment. RESULTS: The keratoconus patients had poorer BSCVA, higher refractive astigmatism and higher keratometry readings than the control subjects at baseline (p < 0.01). In the CXL group, BSCVA increased from 0.19 +/- 0.26 to 0.14 +/- 0.18 logMar (p = 0.03), and the spherical equivalent improved from -1.9 +/- 2.8 D to -1.4 +/- 2.4 D (p = 0.03). Maximum keratometry readings decreased after CXL from 53.1 +/- 4.9 D to 52.6 +/- 5.2 D (p = 0.02), and the axial length decreased in the CXL group, likely due to post-treatment corneal thinning (p = 0.03). In the CRXL group, all the above variables were unaltered (p > 0.05). CONCLUSION: At 6 months, the refractive results from CRXL did not surpass those of conventional CXL treatment. Rather, some variables indicated a slightly inferior effect. Possibly, stronger crosslinking would be necessary to stabilize the cornea in the flattened configuration achieved by the rigid contact lens. PMID- 24629000 TI - The antibacterial effect of nitric oxide against ESBL-producing uropathogenic E. coli is improved by combination with miconazole and polymyxin B nonapeptide. AB - BACKGROUND: Nitric oxide (NO) is produced as part of the host immune response to bacterial infections, including urinary tract infections. The enzyme flavohemoglobin, coded by the hmp gene, is involved in protecting bacterial cells from the toxic effects of NO and represents a potentially interesting target for development of novel treatment concepts against resistant uropathogenic bacteria. The aim of the present study was to investigate if the in vitro antibacterial effects of NO can be enhanced by pharmacological modulation of the enzyme flavohemoglobin. RESULTS: Four clinical isolates of multidrug-resistant extended spectrum beta-lactamase (ESBL)-producing uropathogenic E. coli were included in the study. It was shown that the NO-donor substance DETA/NO, but not inactivated DETA/NO, caused an initial growth inhibition with regrowth noted after 8 h of exposure. An hmp-deficient strain showed a prolonged growth inhibition in response to DETA/NO compared to the wild type. The imidazole antibiotic miconazole, that has been shown to inhibit bacterial flavohemoglobin activity, prolonged the DETA/NO-evoked growth inhibition. When miconazole was combined with polymyxin B nonapeptide (PMBN), in order to increase the bacterial wall permeability, DETA/NO caused a prolonged bacteriostatic response that lasted for up to 24 h. CONCLUSION: An NO-donor in combination with miconazole and PMBN showed enhanced antimicrobial effects and proved effective against multidrug resistant ESBL-producing uropathogenic E. coli. PMID- 24629001 TI - Use of biological treatments in patients with hidradenitis suppurativa. AB - INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic skin disease which causes a great impact in the quality of life. Multiple therapeutic options have been proposed, and recently the potential use of biological drugs in severe cases has been postulated. MATERIAL AND METHODS: A retrospective study from seven tertiary Spanish centers reviewing the charts of patients with HS treated with biological drugs was performed. Retrieved information included epidemiological data, clinical features, pain intensity, Hurley stage, laboratory data and therapeutic outcomes. RESULTS: Nineteen patients were included in the study; 10 men (52.6%) and 9 women. Eight patients (42%) showed a Hurley severity stage II and 11 a stage III (57.8%). Adalimumab was prescribed as the first biological treatment in nine out of 19 cases (47.3%), whereas infliximab was prescribed in seven cases (36.8%), ustekinumab in two cases (10.5%) and etanercept in one (5.2%). A complete response was observed in three patients (two cases with infliximab and one case with ustekinumab), a partial improvement in 10 patients and in six patients no clinical improvement was noted. One patient referred worsening of the skin symptoms. In 6 cases, a second biological treatment was prescribed. In three of such cases, a partial improvement was noted, whereas in three cases no clinical improvement was observed. In two cases a switch to a third biological drug was indicated, with a partial improvement in one case. DISCUSSION AND CONCLUSIONS: Biological drugs could be a potential and effective therapeutic option for patients with severe HS. Complete and persistent clinical responses are rarely obtained (15%) and partial responses are achieved in approximately 50% of patients. No specific markers for a therapeutic response have been identified. No definitive conclusions regarding the most effective biological drug for HS could be drawn. Higher dosage schedules seem to be associated with higher response rates. The lack of response of one particular drug does not preclude a potential efficacy to another biological treatment. PMID- 24629002 TI - Psychological distress in French college students: demographic, economic and social stressors. Results from the 2010 National Health Barometer. AB - BACKGROUND: Psychological distress (PD) in students is under-investigated, since its prevalence can be high in certain subgroups of students and it has been seen to be associated with other mental health issues and academic achievement. In a sample of French college students, this study investigated factors associated with PD, and looked more closely at the impact of social and interpersonal variables. METHODS: Data were extracted from the 2010 French "National Health Barometer". 946 students were interviewed. Mental health was assessed using the MH-5 five-item scale. RESULTS: The PD rate in this sample was 13.8% (7.2% in males, 19.5% in females). Low income, nonsexual assault in the last 12 months, studying law and low social participation were associated with PD in multivariate analyses. CONCLUSIONS: French students show specific characteristics that are discussed in order to explain the relatively low rate of PD observed. The impact of loneliness and social isolation are a major focus for preventive policies based on community resources and early detection of the symptoms of PD. PMID- 24629003 TI - Plant-derived recombinant immune complexes as self-adjuvanting TB immunogens for mucosal boosting of BCG. AB - Progress with protein-based tuberculosis (TB) vaccines has been limited by poor availability of adjuvants suitable for human application. Here, we developed and tested a novel approach to molecular engineering of adjuvanticity that circumvents the need for exogenous adjuvants. Thus, we generated and expressed in transgenic tobacco plants the recombinant immune complexes (RICs) incorporating the early secreted Ag85B and the latency-associated Acr antigen of Mycobacterium tuberculosis, genetically fused as a single polypeptide to the heavy chain of a monoclonal antibody to Acr. The RICs were formed by virtue of the antibody binding to Acr from adjacent molecules, thus allowing self-polymerization of the complexes. TB-RICs were purified from the plant extracts and shown to be biologically active by demonstrating that they could bind to C1q component of the complement and also to the surface of antigen-presenting cells. Mice immunized with BCG and then boosted with two intranasal immunizations with TB-RICs developed antigen-specific serum IgG antibody responses with mean end-point titres of 1 : 8100 (Acr) and 1 : 24 300 (Ag85B) and their splenocytes responded to in vitro stimulation by producing interferon gamma. 25% of CD4+ proliferating cells simultaneously produced IFN-gamma, IL-2 and TNF-alpha, a phenotype that has been linked with protective immune responses in TB. Importantly, mucosal boosting of BCG-immunized mice with TB-RICs led to a reduced M. tuberculosis infection in their lungs from log10 mean = 5.69 +/- 0.1 to 5.04 +/- 0.2, which was statistically significant. We therefore propose that the plant-expressed TB-RICs represent a novel molecular platform for developing self-adjuvanting mucosal vaccines. PMID- 24629004 TI - Salvage surgery for failed low anterior resection or complex rectal pathology. PMID- 24629005 TI - Stage II colorectal cancer further fine tuning. PMID- 24629006 TI - Beyond enhanced recovery: authors' reply. PMID- 24629010 TI - Sex-specific reproductive components and pollination ecology in the subdioecious shrub Fuchsia microphylla. AB - In subdioecious populations, functional female, male and hermaphrodite individuals coexist. Subdioecy may be a transitional state towards dioecy or a breakdown of dioecy, although lability in sex expression may maintain subdioecy as a stable condition. To better understand the ecological aspects involved in sex ratio dynamics and breeding system evolution, we studied the pollination and female fitness components of female and hermaphrodite individuals of the subdioecious shrub Fuchsia microphylla. In two natural populations at the Trans Mexican Volcanic Belt we estimated female frequency and several reproductive components of female and hermaphrodite plants under natural pollination and experimental pollination treatments. Average female frequency was 42%, and on average, 42.5% of hermaphrodites produced fruits. Female plants showed a 17-fold female fertility advantage over hermaphrodites through increased fruit production, as the number of seeds and germination rates did not differ between morphs. Hermaphrodite flowers were larger, with similar nectar production and concentration to female flowers, and pollinators did not show consistent morph preferences. Some hermaphrodites produced fruits autonomously, and female flowers excluded from pollinators produced fruits putatively by apomixis. Fruit production in hermaphrodites, but not in females, was related to height, suggesting increased investment of hermaphrodites in the female function at higher resource status. For sex ratios to be at equilibrium, the female fertility advantage should be reduced about eightfold. However, it may be that hermaphrodites are maintained by producing fruits at no cost to the male function at higher resource status, as the gender plasticity hypothesis proposes. PMID- 24629011 TI - p38 mitogen-activated protein kinase and mitogen-activated protein kinase activated protein kinase 2 (MK2) signaling in atrophic and hypertrophic denervated mouse skeletal muscle. AB - BACKGROUND: p38 mitogen-activated protein kinase has been implicated in both skeletal muscle atrophy and hypertrophy. T317 phosphorylation of the p38 substrate mitogen-activated protein kinase-activated protein kinase 2 (MK2) correlates with muscle weight in atrophic and hypertrophic denervated muscle and may influence the nuclear and cytoplasmic distribution of p38 and/or MK2. The present study investigates expression and phosphorylation of p38, MK2 and related proteins in cytosolic and nuclear fractions from atrophic and hypertrophic 6-days denervated skeletal muscles compared to innervated controls. METHODS: Expression and phosphorylation of p38, MK2, Hsp25 (heat shock protein25rodent/27human, Hsp25/27) and Hsp70 protein expression were studied semi-quantitatively using Western blots with separated nuclear and cytosolic fractions from innervated and denervated hypertrophic hemidiaphragm and atrophic anterior tibial muscles. Unfractionated innervated and denervated atrophic pooled gastrocnemius and soleus muscles were also studied. RESULTS: No support was obtained for a differential nuclear/cytosolic localization of p38 or MK2 in denervated hypertrophic and atrophic muscle. The differential effect of denervation on T317 phosphorylation of MK2 in denervated hypertrophic and atrophic muscle was not reflected in p38 phosphorylation nor in the phosphorylation of the MK2 substrate Hsp25. Hsp25 phosphorylation increased 3-30-fold in all denervated muscles studied. The expression of Hsp70 increased 3-5-fold only in denervated hypertrophic muscles. CONCLUSIONS: The study confirms a differential response of MK2 T317 phosphorylation in denervated hypertrophic and atrophic muscles and suggests that Hsp70 may be important for this. Increased Hsp25 phosphorylation in all denervated muscles studied indicates a role for factors other than MK2 in the regulation of this phosphorylation. PMID- 24629012 TI - Risk of accidental injuries amongst Parkinson disease patients. AB - BACKGROUND AND PURPOSE: To investigate the spectrum and risks of accidental injuries (AIs) amongst Parkinson disease (PD) patients. METHODS: The participants comprised PD patients aged 50 years and older who were initially diagnosed between 2000 and 2009, and a comparison group of non-PD patients. The incidence rates of accidental injury types amongst PD and non-PD patients were calculated; hazard ratios were calculated and adjusted for comorbidities, using 95% confidence intervals (CIs) of developing such outcomes in PD patients. RESULTS: In total, 4046 PD patients and 16 184 non-PD patients were followed over time. The PD patients demonstrated the following incidence rates and hazard ratios in comparison to the control cohort for accidental injuries: all injuries, 19.78 per 100 person-years (100 PYs), adjusted hazard ratio (HR) 1.30 (95% CI 1.24-1.36); head injury, 2.95 per 100 PYs, HR 1.88 (95% CI 1.64-2.15); bone fracture and dislocation, 4.61 per 100 PYs, HR 1.39 (95% CI 1.25-1.54); burns, 0.66 per 100 PYs, HR 1.01 (95% CI 0.78-1.32); injury to spinal cord, plexus and nerves, 0.15 per 100 PYs, HR 1.25 (95% CI 0.72-2.17); superficial injuries and contusions, 11.41 per 100 PYs, HR 1.20 (95% CI 1.12-1.27). The injury risk for the 69-79 years age group in PD compared with controls of the same age (HR 1.38) was significantly higher compared with that of the 50-69 age groups in PD and controls (HR 1.16). CONCLUSIONS: Parkinson disease patients demonstrate a significantly elevated risk of developing all accidental injury types except burn injuries and injuries to spinal cord, plexus and nerves, compared with age matched controls. The risk increases as age increases. PMID- 24629013 TI - Maternal and fetal factors that contribute to the localization of T regulatory cells during pregnancy. AB - PROBLEM: To determine the interplay between fetal antigenicity and local maternal factors in determining reproductive tract T regulatory (Treg) cell accumulation during pregnancy. METHOD OF STUDY: Examination of maternal Treg composition in the uterus, cervix, and uteroplacental interface (UPI) of murine syngeneic and allogeneic pregnancies and non-pregnant controls by flow cytometry. The impact of fetal antigenicity was defined by either fetal gender in syngeneic pregnancies or by allogeneic paternity. Impact of IL-6 on local Treg composition was determined using syngeneic pregnancies in IL-6(-/-) females. RESULTS: An increased fraction of CD4(+) T cells in the pregnant uterine lymphocytic infiltrate and draining pelvic lymph nodes are Tregs. Maternal IL-6 decreases Treg accumulation within the uterus and to a greater extent in the cervix in syngeneic pregnancy. Fetal antigenicity is matched by accumulation of Tregs to the UPI. Treg accumulation at the UPI of non-antigenic female fetuses is determined by the intrauterine position relative to male siblings. CONCLUSION: Reproductive tract tissue Treg composition during pregnancy is influenced by maternal IL-6 and fetal antigenicity. PMID- 24629014 TI - Sensitivity of parasitological tests in imported Plasmodium vivax malaria in adults and impact of chemoprophylaxis and attack type. AB - BACKGROUND: Plasmodium vivax is the second most common species among cases of imported malaria diagnosed in Europe. The objective of this study is to describe the sensitivity of the parasitological tests in imported P. vivax malaria, and the impact of chemoprophylaxis and attack type (primary infection or relapse). METHODS: A retrospective study included the imported vivax malaria cases admitted in a French military hospital between 2001 and 2013. The reference diagnosis method was microscopy corrected by polymerase chain reaction (PCR). Thin and thick blood films examination, quantitative buffy coat (QBC) test, and a rapid diagnostic test (RDT) had been systematically performed. PCR had been carried out for ambiguous profiles. RESULTS: Eighty-nine cases recorded from 78 patients were included, 65 of them having recently traveled to French Guyana. Forty-two patients had properly followed chemoprophylaxis. Forty-six cases were primary infections while 43 were relapses. The sensitivity was 91% for the thin blood smear, 96% for the concentration techniques (Giemsa thick blood smear and QBC test), and 76% for the RDT. The combination of the three conventional tools has an imperfect sensitivity, both for the positive diagnosis of malaria (96%) and for the diagnosis of vivax species (80%). In 4% of the cases, the positive diagnosis was established only by the PCR. The species identification was established in 20% by the PCR. The sensibility of thin blood smear and of RDT decreased significantly with full compliance of chemoprophylaxis or primary infection, whereas the decrease of sensibility of concentration techniques was not significant. CONCLUSIONS: This study illustrates the difficulties encountered in vivax malaria diagnosis, especially in patients who properly followed chemoprophylaxis or with primary infection due to a lower parasitemia. It underlines the lack of sensitivity of RDT for P. vivax and emphasizes the need for systematically combining various diagnosis methods. PMID- 24629015 TI - Lack of beta2 -adrenoceptors aggravates heart failure-induced skeletal muscle myopathy in mice. AB - Skeletal myopathy is a hallmark of heart failure (HF) and has been associated with a poor prognosis. HF and other chronic degenerative diseases share a common feature of a stressed system: sympathetic hyperactivity. Although beneficial acutely, chronic sympathetic hyperactivity is one of the main triggers of skeletal myopathy in HF. Considering that beta2 -adrenoceptors mediate the activity of sympathetic nervous system in skeletal muscle, we presently evaluated the contribution of beta2 -adrenoceptors for the morphofunctional alterations in skeletal muscle and also for exercise intolerance induced by HF. Male WT and beta2 -adrenoceptor knockout mice on a FVB genetic background (beta2 KO) were submitted to myocardial infarction (MI) or SHAM surgery. Ninety days after MI both WT and beta2 KO mice presented to cardiac dysfunction and remodelling accompanied by significantly increased norepinephrine and epinephrine plasma levels, exercise intolerance, changes towards more glycolytic fibres and vascular rarefaction in plantaris muscle. However, beta2 KO MI mice displayed more pronounced exercise intolerance and skeletal myopathy when compared to WT MI mice. Skeletal muscle atrophy of infarcted beta2 KO mice was paralleled by reduced levels of phosphorylated Akt at Ser 473 while increased levels of proteins related with the ubiquitin--proteasome system, and increased 26S proteasome activity. Taken together, our results suggest that lack of beta2 adrenoceptors worsen and/or anticipate the skeletal myopathy observed in HF. PMID- 24629016 TI - Predictive value of serum myeloperoxidase activity for thrombosis of arteriovenous fistulas. AB - Myeloperoxidase is a proinflammatory protein that appears as a result of increased oxidative stress. It plays an important role in the promotion and progression of atherosclerosis. The aim of this study was to determine the importance of MPO as a predictive parameter for thrombosis of arteriovenous fistula (AVF). The study involved monitoring patients with AVFs for hemodialysis over a period of 2 years. There were 41 patients, 19 (46%) men and 22 (54%) women, with mean age of 65 +/- 12.7 years. Routine laboratory analyses were carried out in all respondents, including determination of MPO concentration. Gender, demographic and anthropometrical characteristics, smoking, alcohol consumption, as well as the presence of diabetic nephropathy, as an etiological factor of kidney disease, were recorded. The group of patients who developed initial thrombosis of the AVFs had significantly different values for leukocytes (8.5 +/- 3.8 vs. 7.3 +/- 2.1, P = 0.024), erythrocytes (2.8 +/- 0.27 vs. 3.2 +/- 0.65; P = 0.019), hemoglobin (88.5 +/- 81 vs. 99.1 +/- 6.02; P = 0.041), and myeloperoxidase (19.3 +/- 4.67 vs. 11.1 +/- 4.43; P = 0.007) when compared with the group without fistula thrombosis. Diabetic nephropathy (P = 0.02) characterized the group of patients with thrombosis of the fistula. Diabetic nephropathy (B = 2.53, P = 0.049) and MPO (B = 0.03, P = 0.029) were statistically significant predictors of fistula thrombosis. In our study, MPO and diabetic nephropathy were predictors of thrombosis of the AVF. PMID- 24629017 TI - DQ molecules are the principal stimulators of de novo donor-specific antibodies in nonsensitized pediatric recipients receiving a first kidney transplant. AB - Data on the different HLA-antibody (Ab) categories in pediatric kidney recipients developing de novo donor-specific Abs (DSA) after transplantation are scarce. We retrospectively evaluated 82 consecutive nonsensitized pediatric recipients of a first kidney graft for de novo HLA Ab occurrence and antigen specificity. At a median follow-up of 6 years, 29% of patients developed de novo DSA, while 45% had de novo non-DSA. DSA appeared at 25-month median time post-transplant and were mostly directed toward HLA-DQ antigens. Considering each HLA antigen, the estimated rate of DQ DSA (7.55 per 100 person-years) was much higher than the rates observed for non-DQ DSA. The HLA-DQ Ab recognized determinants of the DQbeta chain in 70% of cases, alpha chain in 25% of cases, and both chains in one patient. Non-DSA peaked earlier than DSA, and were largely directed against HLA class I specificities that belonged to HLA-A- and HLA-B-related cross-reacting epitope groups (CREG) in 56% of cases. Our results indicate a need for evaluating HLA-DQ compatibilities in kidney allocation, in order to minimize post-transplant development of de novo DSA, known to be responsible for antibody-mediated rejection and graft loss. PMID- 24629018 TI - Anatomical distribution analysis reveals lack of Langerin+ dermal dendritic cells in footpads and tail of C57BL/6 mice. AB - Epidermal Langerhans cells (LCs) and dermal dendritic cells (dDCs) capture cutaneous antigens and present them to T-cells in lymph nodes (LNs). The function of LCs and Langerin+ dDCs was extensively studied in the mouse, but their anatomical repartition is unknown. Here, we found LCs in back skin, footpads and tail skin of C57BL/6, BALB/c, 129/Sv and CBA/J mice. Langerin+ dDCs were readily observed in back skin of all strains, but only in footpads and tail of BALB/c and CBA/J mice. Similarly, while LCs were equally present in all LNs and strains, Langerin+ dDCs were found in popliteal LNs (draining footpads) only in BALB/c and CBA/J mice. The sciatic LNs, which we identified as the major tail-draining lymphoid organ, were devoid of Langerin+ dDCs in all strains. Thus, functionally different DCs reside in different skin areas, with variations among mouse strains, implying a potential impact on the cutaneous immune reaction. PMID- 24629019 TI - Health economic benefits of cyanoacrylate skin protectants in the management of superficial skin lesions. AB - Superficial skin damages, including stage II pressure ulcer, skin tears and moisture-associated skin damages (MASDs) are common and constitute a significant disease burden to the health care system. A cost analysis was conducted by comparing a cyanoacrylate barrier film with routine care in the treatment of superficial skin damages in a chronic care facility. The analysis included 12 patients: four patients with stage II pressure ulcers, six with MASD and two with skin tears. Cost analysis was conducted comparing the cost of care 7 days before and 7 days after the acrylate barrier was used. The total cost took into consideration the time, products and supplies required to manage the skin problem. PMID- 24629021 TI - Unilateral lesion increases oestrogen receptor alpha expression in the intact side of the ventromedial hypothalamic nucleus in ovariectomised rats. AB - To determine the relationship between the right and left sides of the ventrolateral ventromedial hypothalamic nucleus (vlVMN) in regulating the expression of oestrogen receptor (ER)alpha, the unilateral vlVMN was lesioned and the number of ERalpha-immunoreactive cells and the ERalpha mRNA level in the intact side of the vlVMN and arcuate nucleus (ARC) were measured in ovariectomised rats. Twenty-four hours after lesioning, brain samples were collected for analysis of ERalpha expression by immunohistochemistry and the real time reverse transcriptase-polymerase chain reaction. The number of ERalpha immunoreactive cells in the intact side of the vlVMN but not the ARC in the unilateral lesioned group was significantly higher than that in the control or sham-lesioned group. Expression levels of ERalpha mRNA in the intact side of the vlVMN but not the ARC in unilateral lesioned rats were significantly higher than those in the sham-lesioned group. Of transcript variants with alternative 5' untranslated regions (0S, 0N, 0, 0T and E1), the ERalpha 0 transcript level was significantly increased. These results indicate that unilateral damage of vlVMN induces an increase in ERalpha in the intact side by increasing ERalpha transcription in a promoter-specific manner. The findings also suggest the existence of new neuroendocrine control system between the right and left sides for the expression of ERalpha in the vlVMN. PMID- 24629020 TI - Validation of the ligase detection reaction fluorescent microsphere assay for the detection of Plasmodium falciparum resistance mediating polymorphisms in Uganda. AB - BACKGROUND: Malaria remains a major public health problem, and its control has been hampered by drug resistance. For a number of drugs, Plasmodium falciparum single nucleotide polymorphisms (SNPs) are associated with altered drug sensitivity and can be used as markers of drug resistance. Several techniques have been studied to assess resistance markers. The most widely used methodology is restriction fragment length polymorphism (RFLP) analysis. The ligase detection reaction fluorescent microsphere (LDR-FM) assay was recently shown to provide high throughput assessment of P. falciparum SNPs associated with drug resistance. The aim of this study was to validate the reliability and accuracy of the LDR-FM assay in a field setting. METHODS: For 223 samples from a clinical trial in Tororo, Uganda in which P. falciparum was identified by blood smear, DNA was extracted from dried blood spots, genes of interest were amplified by PCR, amplicons were analysed by both RFLP and LDR-FM assays, and results were compared. RESULTS: SNP prevalence (wild type/mixed/mutant) with RFLP analysis was 8/5/87% for pfcrt K76T, 34/37/29% for pfmdr1 N86Y, 64/17/19% for pfmdr1 Y184F, and 42/21/37% for pfmdr1 D1246Y. These prevalences with the LDR-FM assay were 7/5/88%, 31/24/45%, 62/20/18%, and 48/19/33% for the four SNPs, respectively. Combining mixed and mutant outcomes for analysis, agreement between the assays was 97% (K=0.77) for pfcrt K76T, 79% (K=0.55) for pfmdr1 N86Y, 83% (K=0.65) for pfmdr1 Y184F, and 91% (K=0.82) for pfmdr1 D1246Y, with most disagreements due to discrepant readings of mixed genotypes. CONCLUSION: The LDR-FM assay provides a high throughput, relatively inexpensive and accurate assay for the surveillance of P. falciparum SNPs associated with drug resistance in resource-limited countries. PMID- 24629022 TI - Sensitivity of the COPD assessment test (CAT questionnaire) investigated in a population of 681 consecutive patients referring to a lung clinic: the first Italian specific study. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality at global level even if still underestimated. The insufficient use of specific tools for an objective definition and staging, the inadequate awareness of COPD, but also a difficult patient-to-doctor communication, can contribute to the poor management of COPD. A very simple, short and sensitive questionnaire (the "COPD Assessment Test" - CAT questionnaire) is now available for assessing the impact of COPD on the patient's health. The present study was designed to provide such evidence using data generated throughout Italy. METHODS: The Italian validated version of the CAT questionnaire was distributed to 681 consecutive COPD patients of different severity (males = 480), well matched for age, gender, smoking habit, geographical distribution, BMI, dyspnoea score and educational level. The CAT score variability was investigated vs all anagraphic, and clinical variables, and spirometric indices of lung function (regression). No Italian data are available to our knowledge on the CAT use, neither in General Medicine, nor in the specialist setting. RESULTS: Data of this study confirmed that the CAT questionnaire is a sensitive, simple, and quick tool for assessing the respiratory status of COPD patients. The CAT score proved not conditioned by the patient's age, gender, body size, geographical origin, and educational level. It was inversely correlated with the spirometric values, even if not uniquely linked to them. CONCLUSIONS: The CAT score does not represent a surrogate measurement of lung function: it is an instrument which focuses on different areas of respiratory health in COPD patients, thus providing an useful and objective tool for the long-term clinical and therapeutic monitoring of COPD patients in the specialist outpatient setting. PMID- 24629023 TI - IL-37 inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells of patients with systemic lupus erythematosus: its correlation with disease activity. AB - BACKGROUND: Interleukin-37 (IL-37), a new member of IL-1 family cytokine, is recently identified as a natural inhibitor of innate immunity. This study aimed to measure the peripheral blood mononuclear cells (PBMCs) and serum levels of IL 37 in patients with systemic lupus erythematosus (SLE) and to investigate its role in SLE, including its correlation with disease activity, organ disorder and the regulation of inflammatory cytokines. METHODS: The expressions of IL-37 mRNAs in PBMCs and serum IL-37 levels in 66 SLE patients were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). SLE patients PBMCs were stimulated with recombinant IL-37, levels of cytokines TNF-alpha, IL-1beta, IL-6 and IL-10 were detected by RT-PCR and ELISA. RESULTS: IL-37 mRNAs and serum protein levels were higher in patients with SLE compared with healthy controls. Patients with active disease showed higher IL-37 mRNAs and serum protein levels compared with those with inactive disease as well as healthy controls. Serum IL-37 levels correlated with SLEDAI and inversely with C3 and C4. Serum IL-37 levels were higher in SLE patients with renal involvement compared with those without renal disease. In vitro, IL-37 inhibited the production of TNF alpha, IL-1beta and IL-6 in PBMCs of patients with SLE, whereas the production of IL-10 was unaffected. CONCLUSIONS: IL-37 associated with SLE disease activity, especially related with SLE renal disease activity. IL-37 is an important cytokine in the control of SLE pathogenesis by suppressing the production of inflammatory cytokines. Thus, IL-37 may provide a novel research target for the pathogenesis and therapy of SLE. PMID- 24629024 TI - The vitamin E isoforms alpha-tocopherol and gamma-tocopherol have opposite associations with spirometric parameters: the CARDIA study. AB - BACKGROUND: Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the alpha-tocopherol isoform of vitamin E and have not included the isoform gamma tocopherol which we recently demonstrated in vitro opposes the function of alpha tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform alpha-tocopherol protects, but the isoform gamma-tocopherol promotes lung inflammation and airway hyperresponsiveness. METHODS: To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA. RESULTS: In cross-sectional regression analysis at year 0, higher gamma-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher alpha-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of alpha-tocopherol, higher gamma-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of gamma-tocopherol, higher alpha-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum gamma-tocopherol >10 MUM was associated with a 175-545 ml lower FEV1 and FVC at ages 21-55 years. CONCLUSION: Increasing serum concentrations of gamma-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of alpha-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum gamma-tocopherol >10 MUM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum gamma-tocopherol occur in up to 4.5 million adults in the population. PMID- 24629026 TI - Interrelations of stress, optimism and control in older people's psychological adjustment. AB - AIM: To investigate the influence of perceived stress, optimism and perceived control of internal states on the psychological adjustment of older adults. METHOD: The sample consisted of 212 older adults, aged between 58 and 103 (M = 80.42 years, SD = 7.31 years), living primarily in retirement villages in Melbourne, Victoria. Participants completed the Perceived Stress Scale, Life Orientation Test-Revised, Perceived Control of Internal States Scale and the World Health Organisation Quality of Life-Bref. RESULTS: Optimism significantly mediated the relationship between older people's perceived stress and psychological health, and perceived control of internal states mediated the relationships among stress, optimism and psychological health. The variables explained 49% of the variance in older people's psychological adjustment. CONCLUSION: It is suggested that strategies to improve optimism and perceived control may improve the psychological adjustment of older people struggling to adapt to life's stressors. PMID- 24629027 TI - Paediatric cutaneous lymphoma in Korea: a retrospective study at a single institution. AB - BACKGROUND: The clinical features and incidences of cutaneous lymphoma (CL) differ by ethnicity and age. However, there is to our knowledge no study to show characteristics and distribution of paediatric CL in Asian population. OBJECTIVE: The aim of this study was to investigate distinctive clinicopathological features of CL in paediatric population, particularly in Korea. METHODS: We conducted a clinicopathological review of 41 paediatric cases with CL, diagnosed at Asan Medical Center from January 1990 to December 2012. The clinical records, haematoxylin & eosin-stained slides and immunohistochemical stains from paediatric patients with CL were analyzed. In addition, the results in this present paediatric group were compared with previously reported studies in the Korean all-ages group and Western paediatric group. RESULTS: Lymphomatoid papulosis was more common in the present paediatric group than in the all-ages group (34.5% vs. 9.4%) and Western paediatric group (34.5% vs. 17.7%). Mycosis fungoides, the most common cutaneous lymphoma in the all-ages group and Western paediatric group, is the second most common subtype in this study. Three of nine paediatric mycosis fungoides patients (33%) have the follicular variant. Compared with all-ages group, B-lmphoblastic lymphoma was relatively higher incidence (10.3% vs. 1%) and NK-/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma was relatively in lower proportions in the paediatric group. CONCLUSION: The clinical features and distribution of paediatric CL in our study suggest that CL of Asian childhood is quite different from that of adulthood and Western childhood. PMID- 24629025 TI - Imagine a world without cancer. AB - BACKGROUND: Since the "War on Cancer" was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. DISCUSSION: Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient's own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer preventive variables, this approach is likely to result in an optimized anticancer strategy. SUMMARY: Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer. PMID- 24629028 TI - Ready-made allogeneic ABO-specific serum eye drops: production from regular male blood donors, clinical routine, safety and efficacy. AB - PURPOSE: To overcome problems and delays of the preparation of autologous serum eye drops, a production line of ABO-specific allogeneic serum eye drops from male blood donors was set up in a blood bank. Feasibility, clinical routine, safety and efficacy were evaluated in a cohort of patients with severe ocular surface disorders. METHODS: Serum was derived from 450 ml whole-blood donations from regular male blood donors, produced and tested according to good manufacturing practice and legislation regulating blood products in Denmark. Serum was diluted to 20% (v/v) with NaCl 0.9%, filtered, bottled, registered and stored at -30 degrees C in the blood bank. Upon request, frozen ABO-identical serum drops in lots of 14 bottles could be provided immediately. Safety and efficacy were evaluated in 34 patients with severe ocular surface disease refractory to conventional medical therapy. Patients were treated six times daily for minimum 2 4 weeks. Objective findings and subjective symptoms were compared between day 0 and after 4 weeks of treatment using the Wilcoxon signed-rank test. RESULTS: Clinically, no side-effects were observed. In total, 59% of the patients with ocular surface changes improved objectively (slit-lamp examination). Partial or full healing of corneal changes, as well as subjective relief of symptoms, was observed in 16 of 20 patients with keratoconjunctivitis sicca (p < 0.001). The 14 patients with persistent epithelial defect experienced neither objective nor subjective improvements during serum treatment. CONCLUSION: Ready-made ABO identical allogeneic serum eye drops were straightforwardly produced, quality assured and registered as a safe standard blood product for the treatment of certain cases of severe dry eye disease. Therapeutic efficacy was comparable to previous reports on autologous serum drops. PMID- 24629029 TI - Clinical correlates of attentional bias to drug cues associated with cocaine dependence. AB - BACKGROUND AND OBJECTIVE: Preoccupation (attentional bias) related to drug related stimuli has been consistently observed for drug-dependent persons with several studies reporting an association of the magnitude of measured attentional bias with treatment outcomes. The major goal of the present study was to determine if pre-treatment attentional bias to personal drug use reminders in an addiction Stroop task predicts relapse in treatment-seeking, cocaine-dependent subjects. METHODS: We sought to maximize the potential of attentional bias as a marker of risk for relapse by incorporating individualized rather than generalized drug use cues to reflect the personal conditioned associations that form the incentive motivation properties of drug cues in a sample of cocaine dependent subjects (N = 35). RESULTS: Although a significant group Stroop interference effect was present for drug versus neutral stimuli (ie, attentional bias), the level of attentional bias for cocaine-use words was not predictive of eventual relapse in this sample (d = .56). A similar lack of prediction power was observed for a non-drug counting word Stroop task as a significant interference effect was detected but did not predict relapse outcomes (d = .40). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results of the present study do not provide clear support for the predictive value of individual variation in drug-related attentional bias to forecast probability of relapse in cocaine-dependent men. PMID- 24629031 TI - Functional status of testicular macrophages in an immunopriviledged niche in cadmium intoxicated murine testes. AB - PROBLEM: The present study investigates the extent of immunomodulatory effects associated with semenological alterations in the testes, after exposure to cadmium (in vivo) in male Swiss albino mice. Despite residing in an immunopriviledged site, testicular macrophages have immunogenic functions. METHODS OF STUDY: Experimental animals were divided into two groups: (i) control (isotonic saline) and (ii) treated (0.35 mg/kg b.w of cadmium chloride) intraperitoneally for 15 days. Murine testicular macrophages were isolated and the cell function studies such as morphological alteration and tumor-necrosis factor (TNF-alpha) release assay were performed. Among the semenological parameters, sperm count, sperm motility, sperm morphology and the testosterone levels in the epididymal semen samples from both groups were determined. RESULTS: The present work shows that cadmium is responsible for a significant alteration, degenerative changes and reduced cell function in testicular macrophages probably by increasing oxidative damage. Such oxidative stress also causes a parallel dysfunction of the semenological parameters. CONCLUSION: TNF-alpha which is probably unable to bind with the surface receptor in testicular macrophages as because of altered structural morphology with reduction of cell function, render the animals more prone to infection and ultimately causes subfertility. PMID- 24629030 TI - Drug-resistant and hospital-associated Enterococcus faecium from wastewater, riverine estuary and anthropogenically impacted marine catchment basin. AB - BACKGROUND: Enterococci, ubiquitous colonizers of humans and other animals, play an increasingly important role in health-care associated infections (HAIs). It is believed that the recent evolution of two clinically relevant species, Enterococcus faecalis and Enterococcus faecium occurred in a big part in a hospital environment, leading to formation of high-risk enterococcal clonal complexes (HiRECCs), which combine multidrug resistance with increased pathogenicity and epidemicity. The aim of this study was to establish the species composition in wastewater, its marine recipient as well as a river estuary and to investigate the antimicrobial susceptibility of collected isolates. Molecular methods were additionally applied to test the presence of HiRRECC-related E. faecium. RESULTS: Two wastewater treatment plants (WWTPs), their marine outfalls and Vistula river that influence significantly the quality of waters in Gulf of Gdansk were sampled to investigate the presence of Enterococcus spp. Four-hundred twenty-eight isolates were obtained, including E. faecium (244 isolates, 57.0%), E. hirae (113 isolates, 26.4%) and E. faecalis (63 isolates, 14.7%); other species (E. gallinarum/casseliflavus, E. durans and E. avium) accounted for 1.9%. Antimicrobial susceptibility testing revealed the presence of isolates resistant to erythromycin, tetracycline, amipicillin, fluoroquinolones and aminoglycosides (high-level resistance), especially among E. faecium, where such isolates were usually characterized by multilocus sequence types associated with nosocomial lineages 17, 18 and 78 of this species representing HiRECC, formerly called CC17. These isolates not only carried several resistance determinants but were also enriched in genes encoding pathogenicity factors (Esp, pili) and genes associated with mobile genetic elements (MGE), a feature also typical for nosocomial HiRECC. CONCLUSIONS: Our data show that WWTPs constitute an important source of enterococcal strains carrying antimicrobial resistance determinants, often associated with the presence of MGE, for the recipient water environment, thus increasing a pool of such genes for other organisms. The presence of HiRECCs in wastewaters and marine/river environment may indicate that adaptations gained in hospitals may be also beneficial for survival of such clones in other settings. There is an obvious need to monitor the release and spread of such strains in order to elucidate better ways to curb their dissemination. PMID- 24629032 TI - Spatial variations of pulmonary tuberculosis prevalence co-impacted by socio economic and geographic factors in People's Republic of China, 2010. AB - BACKGROUND: The report of the fifth national tuberculosis (TB) epidemiological survey in P. R. China, 2010, roughly showed that pulmonary TB (PTB) prevalence was higher in western China than in central and eastern China. However, accurately estimating the continuous spatial variations of PTB prevalence and clearly understanding factors impacting on spatial variations of PTB prevalence are important for allocating limited resources of national TB programme (NTP) in P. R. China. METHODS: Using ArcGIS Geostatistical Wizard (ESRI, Redlands, CA), an evaluation was performed to decide that which kriging and cokriging methods along with different combinations of types of detrending, semivariogram models, anisotropy and covariables (socio-economic and geographic factors) can accurately construct spatial distribution surface of PTB prevalence using statistic data sampled from the fifth national TB epidemiological survey in P. R. China, 2010, and then the evaluation results were used to explore factors of spatial variations. RESULTS: The global cokriging with socio-economic and geographic factors as covariables proved to be the best geostatistical methods for accurately estimating spatial distribution surface of PTB prevalence. The final continuous surfaces of PTB prevalence distribution demonstrated that PTB prevalence were lower in Beijing, Tianjin, Shanghai and southeastern coast China, higher in western and southwestern China, and crossed between low and high in central China. CONCLUSIONS: The predicted continuous surface perspicuously illustrated the spatial variations of PTB prevalence that were co-impacted by socio-economic and geographic factors, which can be used to better allocate the always limited resources of NTP in P. R. China. PMID- 24629033 TI - Anosognosia, neglect and quality of life of right hemisphere stroke survivors. AB - BACKGROUND AND PURPOSE: Anosognosia and neglect may coexist in stroke patients. Neglect patients often report poor quality of life (QOL), whereas patients suffering from other cognition disorders with poor insight report better QOL. This study investigates the relationship between anosognosia, neglect and QOL amongst stroke survivors. METHODS: Stroke survivors who met the criteria were used as a sampling pool. Sixty stroke patients were observed in this study, amongst whom 20 patients with anosognosia and neglect (A+N+), 20 patients with neglect but not anosognosia (A-N+) and 20 patients with neither anosognosia nor neglect (A-N-) were selected from the sampling pool based on demographic characteristics matched with the A+N+ group. A questionnaire (SS-QOL) was used to collect the QOL perceived by the stroke survivors. RESULTS: The perceived QOL of the A+N+ group was significantly better than those of the other groups, including the subscales of self-care, mobility, work/productivity, upper extremity, mood, family role and social role. However, the A+N+ group had poor balance level and more fall incidents were reported. CONCLUSION: The A+N+ group perceived better QOL but had more falls and poorer balance than the other groups. Health providers should work with caregivers aggressively in preventing accidents. PMID- 24629034 TI - Abstracts of the 12th International Congress on Obesity, 17-20 March 2014, Kuala Lumpur, Malaysia. PMID- 24629037 TI - The straight to test endoscopy service for suspected colorectal cancer: meeting national targets but are we meeting our patients' expectations? AB - AIM: The NHS Cancer Plan describes initiatives to improve patient care in the UK, including the two-week rule cancer referral pathway. To meet this target a straight to test (STT) endoscopy service was devised to expedite diagnosis of suspected colorectal cancer. Our novel study aimed to determine patient satisfaction with this new approach to rapid access investigation. METHOD: An anonymized questionnaire was posted to 300 patients who had undergone STT endoscopy in our unit between January and June 2010. It assessed satisfaction with the service overall, time from referral to investigation, pre-test information, bowel preparation instructions and time to results as well as preference for a traditional pre-test or post-test outpatient appointment and awareness that the referral was for suspected bowel cancer. RESULTS: In all, 174 questionnaires were obtained (58% yield; mean age 68.8; 44.8% men). 82.2% of patients were 'very satisfied' with the service overall, 82.8% with time from referral to test, 75.2% with time from test to results, 73% with endoscopy information and 69.5% with bowel preparation instructions. Eight per cent would rather have seen a specialist prior to endoscopy, 31.6% would have preferred a post-test appointment and 68.4% of patients were aware that referral was for suspected bowel cancer. CONCLUSION: Straight to test is popular with patients. It offers a fast and cost effective service in the diagnosis of colorectal cancer and meets national targets whilst reducing the volume burden on outpatient clinics. However, its success heavily relies on accurate communication between general practitioner, patient and secondary care. PMID- 24629038 TI - Regulation of tight junction gene expression in the kidney of calbindin-D9k and/or -D28k knockout mice after consumption of a calcium- or a calcium/vitamin D deficient diet. AB - BACKGROUND: Calciotropic hormones were thought to facilitate calcium transfer through active transcellular or passive paracellular pathway for calcium homeostasis. While calcium transport proteins such as CaBP-28 k, TRPV5, NCX1, PMCA1b are involved in calcium reabsorption of the renal tubule using transcellular transport, tight junction proteins are known as critically related to calcium absorption through paracellular pathway. The regulation of each pathway for calcium transport was well studied but the correlation was not. It is expected that present study will provide new information about the link between transcellular and paracellular pathway within renal tubules. RESULTS: Transcripts and proteins of tight junction related genes (occludin, ZO-1, and claudins) were examined in CaBP-9 k-and/or-28 k-deficient mice as well as the effect of dietary calcium and/or vitamin D supplementation. With a normal diet, the transcriptional and translational expressions of most tight junction proteins in the kidney was not significantly changed but with a calcium- and vitamin D-deficient diet, and they were significantly increased in the kidney of the CaBP-28 k and CaBP-9 k/28 k double KO (DKO) mice. In these genotypes, the increase of tight junction related transcripts and proteins are referred to as an evidence explaining correlation between transcellular transport and paracellular pathway. CONCLUSIONS: These findings are particularly interesting in evidences that insufficient transcellular calcium transports are compensated by paracellular pathway in calcium or calcium/vitamin D deficient condition, and that both transcellular and paracellular pathways functionally cooperate for calcium reabsorption in the kidney. PMID- 24629036 TI - Calorie intake and patient outcomes in severe acute kidney injury: findings from The Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study trial. AB - INTRODUCTION: Current practice in the delivery of caloric intake (DCI) in patients with severe acute kidney injury (AKI) receiving renal replacement therapy (RRT) is unknown. We aimed to describe calorie administration in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study and to assess the association between DCI and clinical outcomes. METHODS: We performed a secondary analysis in 1456 patients from the RENAL trial. We measured the dose and evolution of DCI during treatment and analyzed its association with major clinical outcomes using multivariable logistic regression, Cox proportional hazards models, and time adjusted models. RESULTS: Overall, mean DCI during treatment in ICU was low at only 10.9 +/- 9 Kcal/kg/day for non-survivors and 11 +/- 9 Kcal/kg/day for survivors. Among patients with a lower DCI (below the median) 334 of 729 (45.8%) had died at 90 days after randomization compared with 316 of 727 (43.3%) patients with a higher DCI (above the median) (P = 0.34). On multivariable logistic regression analysis, mean DCI carried an odds ratio of 0.95 (95% confidence interval (CI): 0.91-1.00; P = 0.06) per 100 Kcal increase for 90-day mortality. DCI was not associated with significant differences in renal replacement (RRT) free days, mechanical ventilation free days, ICU free days and hospital free days. These findings remained essentially unaltered after time adjusted analysis and Cox proportional hazards modeling. CONCLUSIONS: In the RENAL study, mean DCI was low. Within the limits of such low caloric intake, greater DCI was not associated with improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00221013. PMID- 24629039 TI - Ex-vivo lung perfusion. AB - This review outlines the new and promising technique of ex vivo lung perfusion and its clinical potential to increase the number of transplantable lungs and to improve the early and late outcome after transplantation. The rationale, the experimental background, the technique and protocols, and available devices for ex vivo lung perfusion are discussed. The current clinical experience worldwide and ongoing clinical trials are reviewed. PMID- 24629040 TI - Regulatory mechanisms of betacellulin in CXCL8 production from lung cancer cells. AB - BACKGROUND: Betacellulin (BTC), a member of the epidermal growth factor (EGF) family, binds and activates ErbB1 and ErbB4 homodimers. BTC was expressed in tumors and involved in tumor growth progression. CXCL8 (interleukin-8) was involved in tumor cell proliferation via the transactivation of the epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: The present study was designed to investigate the possible interrelation between BTC and CXCL8 in human lung cancer cells (A549) and demonstrated the mechanisms of intracellular signals in the regulation of both functions. Bio-behaviors of A549 were assessed using Cell-IQ Alive Image Monitoring System. RESULTS: We found that BTC significantly increased the production of CXCL8 through the activation of the EGFR-PI3K/Akt-Erk signal pathway. BTC induced the resistance of human lung cancer cells to TNF alpha/CHX-induced apoptosis. Treatments with PI3K inhibitors, Erk1/2 inhibitor, or Erlotinib significantly inhibited BTC-induced CXCL8 production and cell proliferation and movement. CONCLUSION: Our data indicated that CXCL8 production from lung cancer cells could be initiated by an autocrine mechanism or external sources of BTC through the EGFR-PI3K-Akt-Erk pathway to the formation of inflammatory microenvironment. BTC may act as a potential target to monitor and improve the development of lung cancer inflammation. PMID- 24629041 TI - Association of blood pressure with all-cause mortality and stroke in Japanese hemodialysis patients: the Japan Dialysis Outcomes and Practice Pattern Study. AB - The association of low blood pressure (BP) with high mortality is a characteristic for hemodialysis patients. This analysis clarifies the association of BP with mortality and stroke in Japanese hemodialysis (HD) patients and examines the association separately for patients with and without antihypertensive medication (BP meds). We analyzed 9134 patients from Japan in phases 1-4 (1999-2011) of the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective cohort study of in-center HD patients. The association of patient systolic (SBP) and diastolic (DBP) blood pressure with all-cause and cause-specific mortality was assessed using adjusted Cox regression. A U-shaped association between BP and all-cause mortality was observed, with lowest mortality for baseline SBP 140-159 mmHg and DBP 65-74 mmHg. Both SBP and DBP were positively and monotonically associated with stroke-related death: hazard ratio (95% confidence interval) was 1.24 (1.01-1.53) per 20 mmHg higher SBP and 1.23 (1.05-1.44) per 10 mmHg higher DBP. No evidence of interaction was found between SBP and use of BP meds regarding all-cause mortality (P for interaction = 0.97); the association between SBP and stroke-related death was slightly stronger among patients not on BP meds than patients on BP meds (P for interaction = 0.09). In Japanese HD patients, both low and high BP are associated with all-cause mortality. This analysis also documents a positive and monotonic association of BP with stroke-related deaths. Although our analysis indicates that the prescription of BP meds to hypertensive patients might protect against stroke related death, additional study is warranted. PMID- 24629042 TI - Abnormal regurgitation in three cows caused by intrathoracic perioesophageal lesions. AB - BACKGROUND: Three Brown Swiss cows with abnormal regurgitation because of a perioesophageal disorder are described. CASE PRESENTATION: The cows were ill and had poor appetite, salivation and regurgitation of poorly-chewed feed. Collection of rumen juice was successful in one cow, and in another, the tube could be advanced to the level of the 7th intercostal space, and in the third, only saliva could be collected. In one cow, oesophagoscopy revealed a discoloured 10-cm mucosal area with fibrin deposits. Thoracic radiographs were normal. The cows were euthanased and examined postmortem. Cow 1 had a large perioesophageal abscess containing feed material at the level of the thoracic inlet, believed to be the result of a healed oesophageal injury. Cow 2 had an abscess between the oesophagus and trachea 25 cm caudal to the epiglottis with the same presumed aetiology as in cow 1. Cow 3 had a mediastinal carcinoma that enclosed and constricted the oesophagus. CONCLUSIONS: Abnormal regurgitation in cattle is usually the result of an oesophageal disorder. Causes of oesophageal disorders vary widely and their identification can be difficult. PMID- 24629043 TI - Epidemiology and long-term survival of pulmonary arterial hypertension in the Czech Republic: a retrospective analysis of a nationwide registry. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by increased pulmonary vascular resistance, ultimately leading to right heart failure and death. Epidemiological data from national registries are growing worldwide, but are still unavailable in Eastern Europe. METHODS: A PAH registry was initiated in January 2007 using a nationwide network of echocardiographic centers and four diagnostic centers that specialize in PAH. All patients aged above 18 years, diagnosed with PAH and monitored between January 2000 and December 2007 were included. Patients diagnosed with PAH between January and December 2007 were classified as incident. The survival analyses were performed up to the end of 2010. Prognostic factors at the time of diagnosis were identified using uni- and multivariable Cox proportional hazard models. RESULTS: Overall, 191 patients were included (100 prevalent cases, 91 incident cases). Patients were predominantly female (n = 125) and had a mean age of 51.9 +/- 16.9 years. Incident patients were significantly older at the time of diagnosis than prevalent patients (p < 0.001). Most patients (60.7%) had idiopathic PAH; 20.4% had PAH associated with congenital heart disease and 11.4% had PAH associated with connective tissue disease. Estimates of prevalence and incidence of PAH in adults were 22.4 cases per million and 10.7 cases per million per year, respectively. The 1-, 2- and 3-year survival rates in the incident PAH cohort were 89% (95% confidence intervals [CI] 83-95%), 78% (95% CI 70-87%) and 74% (95% CI 65-83%), respectively. Lower survival rates were significantly associated with higher age (hazard ratio [HR] 6.6 95% CI 1.4-30.9) and lower creatinine clearance (HR 3.3 95% CI 1.1-9.7). CONCLUSION: This is the first study in Eastern Europe to describe the prevalence, incidence and survival of patients with PAH from a national representative registry. This registry from the Czech Republic highlights that diagnosis of PAH is frequently made late in the disease continuum when patients have significant functional impairment. PMID- 24629044 TI - Inhibitory effects of hydrogen sulphide on pulmonary fibrosis in smoking rats via attenuation of oxidative stress and inflammation. AB - Accumulating evidence has demonstrated that hydrogen sulphide (H2 S) is involved in the pathogenesis of various respiratory diseases. In the present study, we established a rat model of passive smoking and investigated whether or not H2 S has protective effects against pulmonary fibrosis induced by chronic cigarette smoke exposure. Rat lung tissues were stained with haematoxylin-eosin and Masson's trichrome. The expression of type I collagen was detected by immunohistochemistry. Oxidative stress was evaluated by detecting serum levels of malondialdehyde, superoxide dismutase and glutathione peroxidase and measuring reactive oxygen species generation in lung tissue. Inflammation was assessed by measuring serum levels of inflammatory cytokines, including high-sensitivity C reactive protein, tumour necrosis factor-alpha, interleukin (IL)-1beta and IL-6. The protein expression of Nrf2, NF-kappaB and phosphorylated mitogen-activated protein kinases (MAPKs) in the pulmonary tissue was determined by Western blotting. Our findings indicated that administration of NaHS (a donor of H2 S) could protect against pulmonary fibrosis in the smoking rats. H2 S was found to induce the nuclear accumulation of Nrf2 in lung tissue and consequently up regulate the expression of antioxidant genes HO-1 and Trx-1 in the smoking rats. Moreover, H2 S could also reduce cigarette smoking-induced inflammation by inhibiting the phosphorylation of ERK 1/2, JNK and p38 MAPKs and negatively regulating NF-kappaB activation. In conclusion, our study suggests that H2 S has protective effects against pulmonary fibrosis in the smoking rats by attenuating oxidative stress and inflammation. PMID- 24629045 TI - Physical activity and cannabis cessation. AB - BACKGROUND AND OBJECTIVES: Based on recent empirical and theoretical work suggesting that physical activity (PA) activates many of the same physiological systems as cannabis, the present study sought to investigate the impact of PA level (ie, low [including none] vs. moderate/high) on a cannabis cessation attempt during the first 7 days post-quit. METHODS: The present study was a 2 time-point prospective study of 84 cannabis dependent military veterans (3 female) who responded to study flyers, within a Veterans Affairs Medical Center, seeking individuals interested in engaging in a self-guided cessation attempt. All study measures were self-report. RESULTS: Though no baseline differences between those with low and those with moderate/high levels of physical activity were observed, results revealed that participants who reported low levels of physical activity, versus moderate/high levels, were significantly more likely to report a cannabis lapse during the week following a quit attempt, particularly within the first 4 days of the cessation period. Further, individuals with low levels of PA were also more likely to report greater mean cannabis use during the first 4 days of the cessation period. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Findings suggest that early interventions aimed at increasing physical activity may be useful among individuals with cannabis dependence who are engaged in a cessation attempt. PMID- 24629046 TI - Alcohol consumption, cigarette smoking and the risk of subtypes of head-neck cancer: results from the Netherlands Cohort Study. AB - BACKGROUND: Prospective data on alcohol consumption, cigarette smoking and risk of head-neck cancer (HNC) subtypes, i.e. oral cavity cancer (OCC), oro /hypopharyngeal cancer (OHPC), and laryngeal cancer (LC), are limited. We investigated these associations within the second largest prospective study on this topic so far, the Netherlands Cohort Study. METHODS: 120,852 participants completed a questionnaire on diet and other cancer risk factors in 1986. After 17.3 years of follow-up, 395 HNC (110 OCC, 83 OHPC, and 199 LC) cases and 4288 subcohort members were available for case-cohort analysis using Cox proportional hazards models. RESULTS: For total HNC, the multivariable adjusted incidence rate ratio (RR) was 2.74 (95% confidence interval (CI) 1.85-4.06) for those drinking >=30 g ethanol/day compared with abstainers; in subtypes, RRs were 6.39 for OCC, 3.52 for OHPC, and 1.54 for LC. Compared with never cigarette smokers, current cigarette smokers had a RR of 4.49 (95%CI 3.11-6.48) for HNC overall, and 2.11 for OCC, 8.53 for OHPC, and 8.07 for LC. A significant, positive, multiplicative interaction between categories of alcohol consumption and cigarette smoking was found for HNC overall (P interaction 0.03). CONCLUSIONS: Alcohol consumption and cigarette smoking were independently associated with risk of HNC overall, with a positive, multiplicative interaction. The strength of these associations differed among HNC-subtypes: OCC was most strongly associated with alcohol consumption but most weakly with cigarette smoking, whereas LC was not statistically significantly associated with alcohol consumption. PMID- 24629047 TI - Blackwater fever in an uncomplicated Plasmodium falciparum patient treated with dihydroartemisinin-piperaquine. AB - The mechanism of massive intravascular haemolysis occurring during the treatment of malaria infection resulting in haemoglobinuria, commonly known as blackwater fever (BWF), remains unknown. BWF is most often seen in those with severe malaria treated with amino-alcohol drugs, including quinine, mefloquine and halofantrine. The potential for drugs containing artemisinins, chloroquine or piperaquine to cause oxidant haemolysis is believed to be much lower, particularly during treatment of uncomplicated malaria. Here is an unusual case of BWF, which developed on day 2 of treatment for uncomplicated Plasmodium falciparum infection with dihydroartemisinin-piperaquine (DHA-PIP) with documented evidence of concomitant seropositivity for Chikungunya infection. PMID- 24629048 TI - Parental co-viewing and susceptibility for smoking and drinking in adolescents: an experimental pilot study. AB - BACKGROUND AND OBJECTIVES: The current pilot study is the first experiment to examine whether parents are able to diminish the adverse influences of smoking and drinking depicted in movies through co-viewing. METHODS: For this study, 99 adolescents (M = 12.82 years old; SD = .95; 38.8% boys) watched the 3D version of Titanic in the cinema. Through randomization, adolescents were invited to come with either a parent or a friend. After watching the movie, adolescents filled out a questionnaire that assessed their susceptibility for smoking and drinking and their social images concerning these behaviors. RESULTS: The findings revealed that adolescents who co-viewed the movie with their parents, compared to with their friends, were at the same or an even higher risk for future smoking or drinking after watching the movie. The findings also indicated that only a few parents communicated about smoking and drinking while watching the movie. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Simply co-viewing might not be an effective way for parents to blunt the effect of smoking and drinking in movies. In addition to ensuring more caution when advising parents to simply co-view movies, the present findings encourage additional research on the impact of instructive mediation strategies. PMID- 24629049 TI - Starvation can diversify the population structure and virulence strategies of an environmentally transmitting fish pathogen. AB - BACKGROUND: Generalist bacterial pathogens, with the ability for environmental survival and growth, often face variable conditions during their outside-host period. Abiotic factors (such as nutrient deprivation) act as selection pressures for bacterial characteristics, but their effect on virulence is not entirely understood. "Sit and wait" hypothesis expects that long outside-host survival selects for increased virulence, but maintaining virulence in the absence of hosts is generally expected to be costly if active investments are needed. We analysed how long term starvation influences bacterial population structure and virulence of an environmentally transmitting fish pathogen Flavobacterium columnare. RESULTS: F. columnare populations in distilled water and in lake water were monitored for 5 months. During the experiment, the population structure of F. columnare diversified by rough and soft colony morphotypes appearing among the ancestral rhizoid ones. After 5 months starvation in lake water, the virulence of the starved and ancestral bacterial isolates was tested. The starved rhizoid isolates had significantly higher virulence than the ancestral rhizoid, whereas the virulence of the rough isolates was low. CONCLUSIONS: We suggest that F. columnare population diversification is an adaptation to tolerate unpredictable environment, but may also have other biological significance. Maintaining and increasing virulence ensures efficient invasion into the host especially under circumstances when the host density is low or the outside-host period is long. Changing from rhizoid into a rough morphotype has trade-offs in making bacteria less virulent and unable to exploit the host, but may ensure bacterial survival under unpredictable conditions. Our study gives an example how abiotic selection can diversify virulence of environmentally transmitting bacterial pathogen. PMID- 24629050 TI - Segregation analysis suggests that keratoconus is a complex non-mendelian disease. AB - PURPOSE: Complex segregation analysis of 60 unrelated sporadic keratoconus (KC) families was performed to reveal the presumed mode of inheritance in our dataset. METHODS: Sixty probands, 212 family members and 212 age and gender matched healthy controls underwent clinical and videokeratographic examination. Family aggregation and distribution of videokeratography parameters were examined. Segregation of KSI, KISA and 6mm Fourier asymmetry alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package. RESULTS: In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3-11.9) based on KISA index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non-KC family members as well as normal controls (anova p < 0.001). Hypotheses accepted as most parsimonius models of inheritance (p > 0.1) for all indices indicated the presence of a non mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected. CONCLUSIONS: Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non-mendelian major gene effect. Low genotype-phenotype correlation in sporadic KC families can make linkage studies difficult, thus genome wide association studies, epigenetic and pathway analyses may provide more information on disease pathogenesis in non-familial keratoconus. PMID- 24629051 TI - Clinical outcomes of toe amputation in patients with type 2 diabetes in Tianjin, China. AB - The aim of this study is to determine the predictors for reulceration, reamputation and mortality in patients with diabetes following toe amputation, and the impact of activities of daily living on clinical outcomes. This prospective cohort study included 245 patients who had undergone toe amputation (202 healing and 43 non-healing) and was followed for a 5-year period. Data regarding new foot ulceration, reamputation and mortality were recorded, and the patients' activities of daily living were evaluated. The rate of wound healing was 82.4%. The rate of follow-up in the healed group was 91.6%. In years 1, 3 and 5, the cumulative incidence of patients who developed a new foot ulcer was 27.3%, 57.2% and 76.4%, respectively, leading to reamputation in 12.5%, 22.3% and 47.1%, respectively. The cumulative mortality was 5.8%, 15.1% and 32.7% at 1, 3 and 5 years, respectively. Multivariate analysis showed that GHbA1c > 9% (75 mmol/mol) was identified as an independent predictor of impaired wound healing, reulceration and reamputation. An age of >70 years was identified as an independent predictor of reamputation, mortality and impairment of activities of daily living. Despite a satisfactory initial healing rate after the first toe amputation, with the extension course after the toe amputation, the long-term outcomes are not optimistic. In developing countries like China, taking measures to prevent reulceration and reamputation is very important for patients with diabetic foot minor amputations, especially following toe amputation. PMID- 24629052 TI - Lower rates of appropriate initial diagnosis in older emergency department patients associated with hospital length of stay. AB - AIM: Emergency department (ED) doctors are under time pressure to expedite decision-making. This task would seem more difficult in older patients who present atypically, have multiple comorbidities and require more diagnostic tests. This study aimed to investigate the rate of appropriate initial diagnosis of older ED patients admitted under medical units, and whether time was a factor. METHODS: Retrospective review of all patients admitted under medical units from ED over a one-month period was conducted. RESULTS: Four hundred ninety-three records were reviewed. Mean time to ED review was 87 minutes, and to medical registrar review, 409 minutes. Overall rate of appropriate initial diagnosis made by ED was 85.8%, with significantly lower rate detected in older patients. Overall rate for medical registrar was 94.5%. CONCLUSIONS: Admitted older ED patients received lower rates of appropriate initial diagnosis. Time may be a contributing factor to this lower rate. Length of stay was prolonged if initial diagnosis was inappropriate. PMID- 24629053 TI - Loss-of-function mutations in the gene encoding filaggrin underlie a Japanese family with food-dependent exercise-induced anaphylaxis. AB - BACKGROUND: Food-dependent exercise-induced anaphylaxis (FDEIA) is a serious food allergy in which anaphylaxis develops when exercise is performed within several hours after food intake. The precise mechanism underlying allergic sensitization in FDEIA has been an important issue but remains poorly understood. OBJECTIVES: We aimed to elucidate the pathomechanism including the route of allergen sensitization involved in FDEIA. METHODS: A Japanese family with wheat-dependent exercise-induced anaphylaxis (WDEIA), a specific form of FDEIA, were clinically examined. Mutation analysis of the gene encoding filaggrin (FLG) was also performed. RESULTS: Two of the family members were confirmed as WDEIA on the basis of their medical history and positive provocation test results. Notably, the two affected individuals in the family had concomitant ichthyosis vulgaris. Mutation analysis of FLG revealed that they carry one or more loss-of-function mutations that have not been described in the Japanese population. CONCLUSION: These results indicate that FLG mutations might be involved in the pathogenesis of WDEIA in the present case. PMID- 24629055 TI - Risk factors in patients with perimesencephalic hemorrhage. AB - BACKGROUND AND PURPOSE: Smoking and hypertension are risk factors for aneurysmal subarachnoid hemorrhage (aSAH), whilst excessive alcohol consumption is less consistently linked with aSAH. Perimesencephalic hemorrhage (PMH) is a benign subset of non-aneurysmal subarachnoid hemorrhage. The exact cause of PMH is unknown, and its risk factor profile may help to elucidate the pathogenesis. The influence of smoking, hypertension and excessive alcohol consumption on the occurrence of PMH was studied. METHODS: Seventy-nine patients admitted with a PMH to the University Medical Center Utrecht were studied. As controls 574 persons were selected from five different general practices in the referral region of the University Medical Center Utrecht. All participants filled in a questionnaire about smoking habits, the presence of hypertension and alcohol consumption before their hemorrhage. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the association of risk factors and PMH, and multivariable logistic regression was used to adjust for possible confounding by age and sex. RESULTS: Adjusted ORs for the occurrence of PMH were 1.7 (95% CI 1.0 2.8) for smoking cigarettes, cigars, pipes or any combination of these, 1.1 (95% CI 0.6-2.0) for hypertension and 1.1 (95% CI 0.5-2.1) for excessive alcohol consumption. CONCLUSIONS: Similar to aSAH, smoking is a risk factor for PMH and excessive alcohol consumption is not. In contrast to aSAH, hypertension is not a risk factor for PMH. This implies that the pathophysiological mechanisms causing PMH might be slightly different from those causing aSAH. PMID- 24629057 TI - Transposon Insertion Finder (TIF): a novel program for detection of de novo transpositions of transposable elements. AB - BACKGROUND: Transposition event detection of transposable element (TE) in the genome using short reads from the next-generation sequence (NGS) was difficult, because the nucleotide sequence of TE itself is repetitive, making it difficult to identify locations of its insertions by alignment programs for NGS. We have developed a program with a new algorithm to detect the transpositions from NGS data. RESULTS: In the process of tool development, we used next-generation sequence (NGS) data of derivative lines (ttm2 and ttm5) of japonica rice cv. Nipponbare, regenerated through cell culture. The new program, called a transposon insertion finder (TIF), was applied to detect the de novo transpositions of Tos17 in the regenerated lines. TIF searched 300 million reads of a line within 20 min, identifying 4 and 12 de novo transposition in ttm2 and ttm5 lines, respectively. All of the transpositions were confirmed by PCR/electrophoresis and sequencing. Using the program, we also detected new transposon insertions of P-element from NGS data of Drosophila melanogaster. CONCLUSION: TIF operates to find the transposition of any elements provided that target site duplications (TSDs) are generated by their transpositions. PMID- 24629058 TI - Detection and quantification of extracellular microRNAs in murine biofluids. AB - BACKGROUND: MicroRNAs (miRNAs) are short RNA molecules which regulate gene expression in eukaryotic cells, and are abundant and stable in biofluids such as blood serum and plasma. As such, there has been heightened interest in the utility of extracellular miRNAs as minimally invasive biomarkers for diagnosis and monitoring of a wide range of human pathologies. However, quantification of extracellular miRNAs is subject to a number of specific challenges, including the relatively low RNA content of biofluids, the possibility of contamination with serum proteins (including RNases and PCR inhibitors), hemolysis, platelet contamination/activation, a lack of well-established reference miRNAs and the biochemical properties of miRNAs themselves. Protocols for the detection and quantification of miRNAs in biofluids are therefore of high interest. RESULTS: The following protocol was validated by quantifying miRNA abundance in C57 (wild type) and dystrophin-deficient (mdx) mice. Important differences in miRNA abundance were observed depending on whether blood was taken from the jugular or tail vein. Furthermore, efficiency of miRNA recovery was reduced when sample volumes greater than 50 MUl were used. CONCLUSIONS: Here we describe robust and novel procedures to harvest murine serum/plasma, extract biofluid RNA, amplify specific miRNAs by RT-qPCR and analyze the resulting data, enabling the determination of relative and absolute miRNA abundance in extracellular biofluids with high accuracy, specificity and sensitivity. PMID- 24629059 TI - Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis. AB - Many studies show an association between the accumulation of cholesterol inside lysosomes and the progression towards inflammatory disease states that are closely related to obesity. While in the past, the knowledge regarding lysosomal cholesterol accumulation was limited to its association with plaque severity during atherosclerosis, recently, a growing body of evidence indicates a causal link between lysosomal cholesterol accumulation and inflammation. These findings make lysosomal cholesterol accumulation an important target for intervention in metabolic diseases that are characterized by the presence of an inflammatory response. In this review, we aim to show the importance of cholesterol trapping inside lysosomes to the development of inflammation by focusing upon cardiovascular disease and non-alcoholic steatohepatitis (NASH) in particular. We summarize current data supporting the hypothesis that lysosomal cholesterol accumulation plays a key role in the development of inflammation during atherosclerosis and NASH. In addition, potential mechanisms by which disturbed lysosomal function can trigger the inflammatory response, the challenges in improving cholesterol trafficking in macrophages and recent successful research directions will be discussed. PMID- 24629056 TI - Imperfect centered miRNA binding sites are common and can mediate repression of target mRNAs. AB - BACKGROUND: MicroRNAs (miRNAs) bind to mRNAs and target them for translational inhibition or transcriptional degradation. It is thought that most miRNA-mRNA interactions involve the seed region at the 5' end of the miRNA. The importance of seed sites is supported by experimental evidence, although there is growing interest in interactions mediated by the central region of the miRNA, termed centered sites. To investigate the prevalence of these interactions, we apply a biotin pull-down method to determine the direct targets of ten human miRNAs, including four isomiRs that share centered sites, but not seeds, with their canonical partner miRNAs. RESULTS: We confirm that miRNAs and their isomiRs can interact with hundreds of mRNAs, and that imperfect centered sites are common mediators of miRNA-mRNA interactions. We experimentally demonstrate that these sites can repress mRNA activity, typically through translational repression, and are enriched in regions of the transcriptome bound by AGO. Finally, we show that the identification of imperfect centered sites is unlikely to be an artifact of our protocol caused by the biotinylation of the miRNA. However, the fact that there was a slight bias against seed sites in our protocol may have inflated the apparent prevalence of centered site-mediated interactions. CONCLUSIONS: Our results suggest that centered site-mediated interactions are much more frequent than previously thought. This may explain the evolutionary conservation of the central region of miRNAs, and has significant implications for decoding miRNA regulated genetic networks, and for predicting the functional effect of variants that do not alter protein sequence. PMID- 24629060 TI - Isosorbide dinitrate ointment vs botulinum toxin A (Dysport) as the primary treatment for chronic anal fissure: a randomized multicentre study. AB - AIM: Nitric oxide donors, such as isosorbide dinitrate ointment (ISDN), are considered as first-choice agents in the treatment of chronic anal fissure. Injection with botulinum toxin A in the internal anal sphincter is often used as a second-line therapy, although it may give better results and fewer side effects than nitric oxide donors. The aim of this randomized clinical trial was to investigate whether botulinum toxin A (Dysport) is more effective than ISDN in the primary treatment of chronic anal fissure. METHOD: From April 2005 until October 2009, 60 patients (32 men) with a median age of 42 (25-82) years were randomized to receive either ISDN 10 mg/ml (1%) (n = 33) or injection with 60 units of Dysport (n = 27). The primary end-point was the percentage of complete fissure healing after 8 weeks. RESULTS: After a median of 9 weeks complete fissure healing was noted in 18 of 27 patients in the Dysport group and in 11 of 33 patients in the ISDN group (P = 0.010). Absolute improvement of pain scores after 9 weeks was similar in both groups (P = 0.733). Patients treated with Dysport had fewer side effects than patients treated with ISDN (P = 0.028). Of the patients with a healed fissure, 28% of the Dysport group and 50% of the ISDN group had a recurrence within 1 year (P = 0.286; hazard ratio 2.08; 95% CI = 0.54 7.97). CONCLUSION: Dysport is more effective than ISDN ointment and has fewer side effects in the primary treatment of chronic anal fissure. The recurrence rate within 1 year in both treatment groups is high. PMID- 24629061 TI - Synthesis, characterization, electrospinning and antibacterial studies on triphenylphosphine-dithiphosphonates Copper(I) and Silver(I) complexes. AB - BACKGROUND: The novel amido and O-ferrocenyldithiophosphonates [FcP(S)(SH)(NHR1)] (Fc = Fe(eta5-C5H5)(eta5-C5H4), R1 = 1-(4-fluorophenylethyl and benzyloxycyclopentyl) and [FcP(S)(OR2)S-][H3N+C(CH3)3] (R2 = myrtanyl) were synthesized by the reaction of [(FcPS2)]2 (Fc = Fe(eta5-C5H5)(eta5-C5H4)) and chiral amines, such as (S)-(-)-1-(4-fluorophenylethyl) amine and (1S,2S)-(+) benzyloxycyclopentyl amine, and of (1S), (2S), (5S)-myrtanol in toluene. The reaction of ferrocenyldithiophosphonates and [Cu(PPh3)2]NO3 or AgNO3 and PPh3 gave rise to copper(I) and silver(I) complexes in THF. [Ag2{FcP(OMe)S2}2(PPh3)2] and [Cu(PPh3)2]NO3 were embedded into nanofibers and their antimicrobial activities on fibers were also investigated. RESULTS: The compounds have been characterized by elemental analyses, IR, NMR (1H-, 31P-) spectroscopy as well as MS measurements. Nanofibers were obtained by electrospinning method which is the simplest and most effective method to produce nanoscale fibers under strong electrical field. Antimicrobial activity of the compound 5, [Ag2{FcP(OMe)S2}2(PPh3)2], and [Cu(PPh3)2]NO3 on fibers were studied. CONCLUSIONS: In this study, the new dithiophosphonate ligands were synthesized and utilized in the preparation of copper(I) and silver(I) complexes with ferrocenyldithiophosphonate and triphenylphosphine. Then, the compounds [Ag2{FcP(OMe)S2}2(PPh3)2] and [Cu(PPh3)2]NO3 were added into the PAN solutions (Co-PAN dissolved in dimethylacetamide) and the solutions were electrospun onto microscope slides and PP meltblown surfaces. Antimicrobial activity of the compounds [Ag2{FcP(OMe)S2}2(PPh3)2] and [Cu(PPh3)2]NO3 on fibers were determined in vitro against two indicator strains; M. luteus NCIB and E. coli ATCC25922. The obtained results indicated that these metals showed moderate level antimicrobial activities. PMID- 24629062 TI - Ultrasonographic characteristics of canine renal lymphoma. AB - There is little published information on the ultrasonographic appearance of canine renal lymphoma. The purpose of this retrospective study was to provide additional information regarding the ultrasonographic characteristics of canine renal lymphoma, suggest ultrasonographic description criteria, and evaluate the role of fine-needle aspirate cytology in the diagnosis of this disease. The ultrasonographic features of confirmed renal lymphoma were reviewed in ten dogs. Pyelectasia was found in all dogs. Other ultrasonographic findings were loss of corticomedullary distinction (9/10 dogs), renomegaly (8/10 dogs), renal deformity (6/10 dogs), hypoechoic lesion(s) (6/10 dogs), and hyperechoic lesion(s) (2/10 dogs). Hypoechoic lesions were described as masses, nodules, and indistinct areas. In 30% of the cases (3/10 dogs) ultrasound revealed only minor abnormalities, including grade 1 pyelectasia, mild renomegaly, and focal loss of corticomedullary definition. Bilateral lesions were seen in nine dogs (90%). Renal fine-needle aspirates were performed in 9/10 dogs, yielding a diagnosis in seven on first attempt (78%). Two dogs had been given a provisional cytological diagnosis of round cell neoplasia; in one dog lymphoma was confirmed by second aspirate and by tissue core biopsy in the other. In 1/10 dogs, lymphoma was found at necropsy. Findings indicated that ultrasonographic signs of canine renal lymphoma may be subtle, canine renal lymphoma should be included in the differential diagnosis when the above ultrasonographic features are observed, and fine-needle aspirate cytology is a useful method for diagnosing this disease. PMID- 24629063 TI - Exercise programme with telephone follow-up for people with hand osteoarthritis - protocol for a randomised controlled trial. AB - BACKGROUND: Hand osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases in an adult population and may have a large influence on an individual's functioning, health-related quality of life and participation in society. Several studies have demonstrated that exercises may reduce pain and improve functioning in people with knee OA, with a similar effect suggested for hip OA. For hand OA, available research is very limited and shows conflicting results, and high quality randomised controlled trials are warranted.This paper outlines the protocol for a randomised controlled trial that aims to determine the effect of an exercise intervention on self-reported hand activity performance in people with hand OA. METHODS: Participants with physician-confirmed hand OA according to the ACR clinical criteria are being recruited from two Norwegian OA cohorts: the population-based "Musculoskeletal pain in Ullensaker Study" (MUST) OA cohort, and the hospital-based Oslo Hand OA cohort. Participants are randomised into an intervention- or control group. The control group receives "usual care", whereas the intervention group receives a 12-week exercise intervention. The intervention group attends four group sessions and is instructed to perform the exercise program three times a week at home. Adherence will be captured using self-report. During the eight weeks with no group sessions, the intervention group receives a weekly telephone call. The assessments and group sessions are being conducted locally in Ullensaker Municipality and at Diakonhjemmet Hospital, Oslo. Outcomes are collected at baseline, and at 3 and 6 months. The primary outcome measure is self-reported hand activity performance at 3 months post-randomisation, as measured by the Functional Index for Hand Osteoarthritis (FIHOA); and a patient generated measure of disability, the Patient-Specific Functional Scale (PSFS). Secondary outcome measures are self-reported OA symptoms (e.g. pain, stiffness and fatigue), the Patient Global Assessment of disease activity, measured hand function (e.g. grip strength, thumb web space and hand dexterity) and health related quality of life. Cost-utility and cost-effectiveness analyses will be conducted. DISCUSSION: This study will contribute to the knowledge on both the effect and resource use of an exercise programme with telephone follow-up on self reported hand activity performance among people with hand OA. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov with registration number: NCT01245842. PMID- 24629064 TI - pZMO7-Derived shuttle vectors for heterologous protein expression and proteomic applications in the ethanol-producing bacterium Zymomonas mobilis. AB - BACKGROUND: The ethanol-producing bacterium Zymomonas mobilis has attracted considerable scientific and commercial interest due to its exceptional physiological properties. Shuttle vectors derived from native plasmids have previously been successfully used for heterologous gene expression in this bacterium for a variety of purposes, most notably for metabolic engineering applications. RESULTS: A quantitative PCR (qPCR) approach was used to determine the copy numbers of two endogenous double stranded DNA plasmids: pZMO1A (1,647 bp) and pZMO7 (pZA1003; 4,551 bp) within the NCIMB 11163 strain of Z. mobilis. Data indicated pZMO1A and pZMO7 were present at ca. 3-5 and ca. 1-2 copies per cell, respectively. A ca. 1,900 bp fragment from plasmid pZMO7 was used to construct two Escherichia coli - Z. mobilis shuttle vectors (pZ7C and pZ7-184). The intracellular stabilities and copy numbers of pZ7C and pZ7-184 were characterized within the NCIMB 11163, ATCC 29191 and (ATCC 10988-derived) CU1 Rif2 strains of Z. mobilis. Both shuttle vectors could be stably maintained within the ATCC 29191 strain (ca. 20-40 copies per cell), and the CU1 Rif2 strain (ca. 2-3 copies per cell), for more than 50 generations in the absence of an antibiotic selectable marker. A selectable marker was required for shuttle vector maintenance in the parental NCIMB 11163 strain; most probably due to competition for replication with the endogenous pZMO7 plasmid molecules. N-terminal glutathione S-transferase (GST)-fusions of four endogenous proteins, namely the acyl-carrier protein (AcpP); 2-dehydro-3-deoxyphosphooctonate aldolase (KdsA); DNA polymerase III chi subunit (HolC); and the RNA chaperone protein Hfq; were successfully expressed from pZ7C-derived shuttle vectors, and their protein protein binding interactions were analyzed in Z. mobilis ATCC 29191. Using this approach, proteins that co-purified with AcpP and KdsA were identified. CONCLUSIONS: We show that a shuttle vector-based protein affinity 'pull-down' approach can be used to probe protein interaction networks in Z. mobilis cells. Our results demonstrate that protein expression plasmids derived from pZMO7 have significant potential for use in future biological or biotechnological applications within Z. mobilis. PMID- 24629065 TI - Transforming growth factor-beta1 requires NADPH oxidase 4 for angiogenesis in vitro and in vivo. AB - Angiogenesis, the formation of new blood vessels, is a key physiological event in organ development and tissue responses to hypoxia but is also involved in pathophysiologies such as tumour growth and retinopathies. Understanding the molecular mechanisms involved is important to design strategies for therapeutic intervention. One important regulator of angiogenesis is transforming growth factor-beta1 (TGF-beta1). In addition, reactive oxygen species (ROS) and the ROS forming NADPH oxidase type 4 (Nox4) have been implicated as additional regulators such as during hypoxia. Here, we show that both processes are indeed mechanistically linked. TGF-beta1-stimulated Nox4 expression and ROS formation in endothelial cells. In cells from Nox4-deficient mice, TGF-beta1-induced cell proliferation, migration and tube formation were abolished. In vivo, TGF-beta1 stimulated growth of blood vessels into sponges implanted subcutaneously, and this angiogenesis was markedly reduced in Nox4 knockout mice. Thus, endothelial cells are regulated by a TGF-beta1 signalling pathway involving Nox4-derived ROS to promote angiogenesis. In order to abrogate pathological angiogenesis triggered by a multitude of factors, such as TGF-beta1 and hypoxia, Nox4 may thus be an ideal therapeutic target. PMID- 24629066 TI - Potential causes and consequences of behavioural resilience and resistance in malaria vector populations: a mathematical modelling analysis. AB - BACKGROUND: The ability of mosquitoes to evade fatal exposure to insecticidal nets and sprays represents the primary obstacle to eliminating malaria. However, it remains unclear which behaviours are most important for buffering mosquito and parasite populations against vector control. METHODS: Simulated life histories were used to compare the impact of alternative feeding behaviour strategies upon overall lifetime feeding success, and upon temporal distributions of successful feeds and biting rates experienced by unprotected humans, in the presence and absence of insecticidal nets. Strictly nocturnal preferred feeding times were contrasted with 1) a wider preference window extending to dawn and dusk, and 2) crepuscular preferences wherein foraging is suppressed when humans sleep and can use nets but is maximal immediately before and after. Simulations with diversion and mortality parameters typical of endophagic, endophilic African vectors, such as Anopheles gambiae and Anopheles funestus, were compared with those for endophagic but exophilic species, such as Anopheles arabiensis, that also enter houses but leave earlier before lethal exposure to insecticide-treated surfaces occurs. RESULTS: Insecticidal nets were predicted to redistribute successful feeding events to dawn and dusk where these were included in the profile of innately preferred feeding times. However, predicted distributions of biting unprotected humans were unaffected because extended host-seeking activity was redistributed to innately preferred feeding times. Recently observed alterations of biting activity distributions therefore reflect processes not captured in this model, such as evolutionary selection of heritably modified feeding time preferences or phenotypically plastic expression of feeding time preference caused by associative learning. Surprisingly, endophagy combined with exophily, among mosquitoes that enter houses but then feed and/or rest briefly before rapidly exiting, consistently attenuated predicted insecticide impact more than any feeding time preference trait. CONCLUSIONS: Regardless of underlying cause, recent redistributions of host-biting activity to dawn and dusk necessitate new outdoor control strategies. However, persistently indoor-feeding vectors, that evade intradomiciliary insecticide exposure, are at least equally important. Fortunately, recent evaluations of occupied houses or odour-baited stations, with baffled entrances that retain An. arabiensis within insecticide-treated structures, illustrate how endophagic but exophilic vectors may be more effectively tackled using existing insecticides. PMID- 24629067 TI - Glucocorticoid receptor repression mediated by BRCA1 inactivation in ovarian cancer. AB - BACKGROUND: BRCA mutations are the main known hereditary factor for ovarian cancer. Notably, emerging evidence indicates that the glucocorticoid receptor (GR) has drawn considerable interest in ovarian cancer development. However, dynamic cross-talk between BRCA1 and GR signaling pathways are poorly understood. METHODS: The regulatory effects of BRCA on GR were assessed in 146 serous ovarian cancer patients (28 pairs of BRCA1-mutated or not, 23 pairs of BRCA2-mutated or not, and 22 pairs with hypermethylated BRCA1 promoter or not). BRCA1 promoter methylation was analyzed by bisulfite sequencing using primers flanking the core promoter region. Expression levels of BRCA1 and GR were assessed by immunohistochemistry and real-time PCR. Regression analysis was used to examine the possible relationship between BRCA1 and GR expression levels. The knockdown and overexpression of BRCA1 were achieved using a lentiviral vector in 293 T cells, SKOV3 ovarian cancer cells, and primary non-mutated and BRCA1-mutated ovarian cancer cells. RESULTS: GR expression levels were unchanged in non-BRCA1 mutated, non-BRCA2-mutated and BRCA2-mutated ovarian cancer compared to their normal tissues; BRCA1 repression (BRCA1 mutation or BRCA1 promoter hypermethylation) ovarian cancer showed decreased GR levels compared to normal tissue; there was a positive correlation between BRCA1 and GR expression in human ovarian cancer specimens; BRCA1 knockdown was effective at inhibiting GR expression, and overexpression of BRCA1 induces an increase in GR levels in ovarian cancer cells. CONCLUSIONS: These results suggest that GR may be a potential target for BRCA1 in ovarian cancer progression. PMID- 24629068 TI - Influence of intraoral temperature and relative humidity on the dentin bond strength: an in situ study. AB - STATEMENT OF THE PROBLEM: The effect of the intraoral environment during adhesive restorative procedures remains a concern, especially in the absence of rubber dam isolation. OBJECTIVE: To evaluate the temperature and relative humidity (RH) at anterior and posterior intraoral sites and their effects on the dentin bond strength of two-step etch-and-rinse adhesive systems. METHODS: Sixty human molars were assigned to six groups according to the adhesive systems (Adper Single Bond Plus and One Step Plus) and intraoral sites (incisor and molar sites). The room condition was used as a control group. Dentin fragments were individually placed in custom-made acetate trays and direct composite restorations were performed. The intraoral temperature and RH were recorded during adhesive procedures. Then, specimens were removed from the acetate trays and sectioned to obtain multiple beams for the microtensile bond strength test. In addition, the adhesive interface morphology was evaluated through scanning electron microscopy. Intraoral conditions were statistically analyzed by paired Students' t-tests and the bond strength data by two-way analysis of variance and Tukey test (alpha = 0.05). RESULTS: The posterior intraoral site showed a significant increase in the temperature and RH when compared with the anterior site. However, both intraoral sites revealed higher temperatures and RH than the room condition. In regards to the adhesive systems, the intraoral environment did not affect the bond strength, and the One Step Plus system showed the highest bond strength means. CONCLUSION: Despite the fact that remarkable changes in the intraoral conditions were observed for both anterior and posterior sites, the intraoral environment was not able to compromise the immediate dentin bond strength. CLINICAL SIGNIFICANCE: Some conditions of intraoral temperature and relative humidity may not impair the dentin bond strength of two-step etch-and-rinse adhesive systems. Thus, an adequate relative isolation seems to be a good alternative under the specific clinical conditions in which rubber dam isolation is either impossible or very difficult to perform. PMID- 24629069 TI - Dexamethasone intravitreal implants for retinal vein occlusion in a clinical setting. PMID- 24629070 TI - Maternal and personal religious engagement as predictors of early onset and frequent substance use. AB - BACKGROUND AND OBJECTIVE: This study examined whether maternal and offspring's religiosity independently predict age of onset and frequency of substance use in offspring, and whether gender differentiates these associations. METHODS: Data were from the Mater Hospital and University of Queensland Study of Pregnancy, a birth cohort study. Participants were a cohort of 3,537 persons who were born during 1981-83 and were followed-up to 21 years. Odds ratio (OR) and 95% confidence interval (CI) were used to estimate relative risk of substance use. RESULTS: Both maternal and offspring's religious practice were associated with later onset and less frequent substance use. After adjustment for potential confounding and maternal religious background, offspring who were not attending church were more likely to report early onset of tobacco smoking (OR = 5.1; 95% CI: 2.8-9.4), alcohol drinking (OR = 17.4; 95% CI: 8.9-33.9) and cannabis use (OR = 7.5; 95% CI: 3.4-16.0). DISCUSSION AND CONCLUSIONS: Findings of this study suggest family and personal religious practices are predictors of less substance use problems in adolescents and young adult males and females. SCIENTIFIC SIGNIFICANCE AND FUTURE DIRECTIONS: Religious engagement functions as a deterrent to adolescent tobacco, alcohol, and cannabis use. PMID- 24629071 TI - Approach to hypohidrosis. PMID- 24629072 TI - Human CMV-specific T-cell responses in kidney transplantation; toward changing current risk-stratification paradigm. AB - Despite the great efficacy of current antiviral preventive strategies, hCMV infection is still a major complication after renal transplantation, significantly challenging patient and graft survival. This issue seems to be explained because of the rather poor immunologic monitoring of the antiviral immune response. An important body of evidence has shown that monitoring the hCMV specific T-cell response, at different time points of the transplant setting, seems to add crucial information for predicting the risk of viral infection, thus potentially helping individualization of therapeutic decision-making in clinical transplantation. While several immune-cellular assays have shown its capability for accurately monitoring hCMV-specific T-cell responses, only few such as the IFN-gamma ELISPOT and the ELISA based technology assays might be reliable for its application in the clinic. Nonetheless, an important effort has to be made among the transplant community to standardize and validate such immune assays. Noteworthy, large-scale prospective randomized trials are highly warranted to ultimately introduce them in current clinical practice as a part of the highly desired personalized medicine. PMID- 24629073 TI - Omeprazole-induced acute interstitial nephritis: a possible Th1-Th17-mediated injury? AB - BACKGROUND: Omeprazole is an important cause of drug-induced acute interstitial nephritis (AIN). How omeprazole induces injury is unknown. METHODS AND RESULTS: Detailed clinical assessment of 25 biopsy-proven cases of omeprazole-induced AIN showed that all patients presented with impaired renal function, sterile pyuria with varying amounts of proteinuria but no eosinophiluria and no systemic symptoms to suggest a vasculitis. Histological analyses were characteristic of an acute tubulitis with an inflammatory cellular infiltrate. Using modified Banff scheme criteria, mild tubulitis (t1) was present in 56% of cases, a moderate tubulitis (t2) in 24% of cases, and a severe tubulitis in 20% of cases. Most (78%) of cases had mononuclear cell infiltrates, no significant eosinophilic infiltrates were found, and glomeruli were not involved. Immunostaining for CD4, CD8, IL-17A, IL-17F, Foxp3 and T-bet (T cell subsets), CD20 and CD163 defined the cellular infiltrates. The predominant inflammatory cells were CD4+ lymphocytic aggregates (77% of cases), combined with co-staining of CD4 IL and 17A/F in 44 48% of all cases, suggesting a Th17-mediated inflammatory process. T-bet+ cell infiltrates were present to a lesser degree, suggesting additional Th1 involvement. How omeprazole induces this inflammatory response is unclear, but may include direct effects by IL-17 expressing CD4+ cells on renal tubular cells. CONCLUSION: This large biopsy series of omeprazole-induced AIN demonstrates the features of acute tubulitis, with significant interstitial infiltrates consistent with immunopathological Th17 and Th1 processes. PMID- 24629075 TI - Bismuth-induced effects on optical, lattice vibrational, and structural properties of bulk GaAsBi alloys. AB - Bulk GaAs1 - xBix/GaAs alloys with various bismuth compositions are studied using power- and temperature-dependent photoluminescence (PL), Raman scattering, and atomic force microscopy (AFM). PL measurements exhibit that the bandgap of the alloy decreases with increasing bismuth composition. Moreover, PL peak energy and PL characteristic are found to be excitation intensity dependent. The PL signal is detectable below 150 K at low excitation intensities, but quenches at higher temperatures. As excitation intensity is increased, PL can be observable at room temperature and PL peak energy blueshifts. The quenching temperature of the PL signal tends to shift to higher temperatures with increasing bismuth composition, giving rise to an increase in Bi-related localization energy of disorders. The composition dependence of the PL is also found to be power dependent, changing from about 63 to 87 meV/Bi% as excitation intensity is increased. In addition, S shaped temperature dependence at low excitation intensities is observed, a well known signature of localized levels above valence band. Applying Varshni's law to the temperature dependence of the PL peak energy, the concentration dependence of Debye temperature (beta) and thermal expansion coefficient (alpha) are determined. AFM observations show that bismuth islands are randomly distributed on the surface and the diameter of the islands tends to increase with increasing bismuth composition. Raman scattering spectra show that incorporation of Bi into GaAs causes a new feature at around 185 cm-1 with slightly increasing Raman intensity as the Bi concentration increases. A broad feature located between 210 and 250 cm-1 is also observed and its intensity increases with increasing Bi content. Furthermore, the forbidden transverse optical (TO) mode becomes more pronounced for the samples with higher bismuth composition, which can be attributed to the effect of Bi-induced disorders on crystal symmetry. PACS: 78.55Cr 78.55-m 78.20-e 78.30-j. PMID- 24629074 TI - An inventory of healthy weight practices in federally funded haemophilia treatment centres in the United States. AB - In the haemophilia population, obesity has an adverse effect on health care cost, chronic complications and joint disease. Although staff of federally funded Hemophilia Treatment Centers in the United States (HTCs) anecdotally recognize these outcomes, practices to promote healthy weights have not been reported. This evaluation identifies routine practices among HTCs in body mass index (BMI) assessment, perceptions about need to address obesity and roles in offering evidence-based strategies to promote healthy weights. A telephone survey was developed to assess HTCs practices including patient BMI assessment and counselling, perceptions about the importance of healthy patient weights, and HTCs roles in weight management. Ninety of the 130 federally funded HTCs contacted elected to participate and completed the telephone survey. Of these, 67% routinely calculated BMI and 48% provided results to patients. Approximately one-third classified obesity correctly for children (30%) and adults (32%), using the Centers for Disease Control and Preventions BMI cut-offs. Most HTCs (87%) reported obesity as an issue of 'big' or 'moderate' concern and 98% indicated HTC responsibility to address this issue. Most centres (64%) address patient weight during comprehensive visits. One-third (33%) of centres include a nutritionist; of those without, 61% offer nutrition referrals when needed. Most (89%) HTCs do not have a protocol in place to address healthy weights; 53% indicated that guidelines are needed. HTCs offer services to help improve weight outcomes. Training programmes for calculating and interpreting BMI as well as identifying appropriate guidelines to apply to the HTC patient population are needed. PMID- 24629076 TI - Implementation of pregnancy weight management and obesity guidelines: a meta synthesis of healthcare professionals' barriers and facilitators using the Theoretical Domains Framework. AB - Obesity in pregnancy is rising and is associated with severe health consequences for both the mother and the child. There is an increasing international focus on guidelines to manage the clinical risks of maternal obesity, and for pregnancy weight management. However, passive dissemination of guidelines is not effective and more active strategies are required for effective guideline implementation into practice. Implementation of guidelines is a form of healthcare professional behaviour change, and therefore implementation strategies should be based on appropriate behaviour change theory. This systematic review aimed to identify the determinants of healthcare professionals' behaviours in relation to maternal obesity and weight management. Twenty-five studies were included. Data synthesis of the existing international qualitative and quantitative evidence base used the Theoretical Domains Framework to identify the barriers and facilitators to healthcare professionals' maternal obesity and weight management practice. The domains most frequently identified included 'knowledge', 'beliefs about consequences' and 'environmental context and resources'. Healthcare professionals' weight management practice had the most barriers compared with any other area of maternal obesity practice. The results of this review will be used to inform the development of an intervention to support healthcare professional behaviour change. PMID- 24629077 TI - Self-reported cold sensitivity in patients with traumatic hand injuries or hand arm vibration syndrome - an eight year follow up. AB - BACKGROUND: Cold sensitivity is a common complaint following hand injuries. Our aim was to investigate long-term self-reported cold sensitivity, and its predictors and the importance of sense of coherence (SOC), 8 years after a hand injury as well as in patients treated for Hand Arm Vibration Syndrome (HAVS) during the same time period. METHODS: Responses to the Cold Intolerance Symptom Severity (CISS) questionnaire and the Sense of Coherence (SOC) questionnaire were investigated in hand injured patients (n = 64) and in patients with HAVS (n = 26). The Mann-Whitney U-Test was used to identify significant differences between subgroups. When analysing predictors for cold sensitivity severity, the Spearman rank correlation (rS coefficient) were used for quantitative predictive variables, Mann-Whitney U-Test for dichotomous variables and Kruskal-Wallis Test for multiple categorical data. The Wilcoxon's signed rank test was used to investigate longitudinal changes in outcome. RESULTS: There was a significant change in total CISS score for patients with traumatic hand injury, indicating fewer problems with cold sensitivity over time. Symptoms, such as stiffness, weakness and skin colour change on cold exposure, caused fewer problems, but perceived pain/aching and numbness remained unchanged as well as time needed for relief of symptoms on return to a warm environment. The negative impact of cold sensitivity on daily activities and at work was reduced, but problems when engaged in hobbies or when being exposed to cold wintry weather remained unchanged. None of the investigated predictors related to the hand injury were significantly associated with a change in cold sensitivity at the 8-year follow up. In contrast, no significant change in cold sensitivity was noted in the patients with HAVS for any of the situations included in the CISS questionnaire. A lower sense of coherence score correlated significantly with worse cold sensitivity (CISS score) in both patient groups. CONCLUSIONS: The negative impact of cold sensitivity on daily life was reduced for patients with traumatic hand injury, but did not change over time in patients with HAVS. A low SOC is associated with worse cold sensitivity in such groups of patients. Information about relieving strategies should be provided for patients with cold sensitivity. PMID- 24629079 TI - Size (and shape) is important and sometimes strings should be attached, but quality matters most where the BJUI and stone disease are concerned .... PMID- 24629080 TI - Nationwide prostatectomy practice. PMID- 24629078 TI - Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis. AB - BACKGROUND: The correlations of genotypic and phenotypic tests with treatment, clinical history and the significance of mutations in viruses of HIV-infected patients are used to establish resistance mutations to protease inhibitors (PIs). Emerging mutations in human immunodeficiency virus type 1 (HIV-1) protease confer resistance to PIs by inducing structural changes at the ligand interaction site. The aim of this study was to establish an in silico structural relationship between natural HIV-1 polymorphisms and unusual HIV-1 mutations that confer resistance to PIs. RESULTS: Protease sequences isolated from 151 Mexican HIV-1 patients that were naive to, or subjected to antiretroviral therapy, were examined. We identified 41 unrelated resistance mutations with a prevalence greater than 1%. Among these mutations, nine exhibited positive selection, three were natural polymorphisms (L63S/V/H) in a codon associated with drug resistance, and six were unusual mutations (L5F, D29V, L63R/G, P79L and T91V). The D29V mutation, with a prevalence of 1.32% in the studied population, was only found in patients treated with antiretroviral drugs. Using in silico modelling, we observed that D29V formed unstable protease complexes when were docked with lopinavir, saquinavir, darunavir, tipranavir, indinavir and atazanavir. CONCLUSIONS: The structural correlation of natural polymorphisms and unusual mutations with drug resistance is useful for the identification of HIV-1 variants with potential resistance to PIs. The D29V mutation likely confers a selection advantage in viruses; however, in silico, presence of this mutation results in unstable enzyme/PI complexes, that possibly induce resistance to PIs. PMID- 24629081 TI - The surgical spectacle: a survey of urologists viewing live case demonstrations. PMID- 24629082 TI - Elastographic search for the (high-grade) tree in the (prostatic) forest. PMID- 24629083 TI - Optimal results come from optimal surgery and optimal (neoadjuvant) systemic therapy. PMID- 24629084 TI - Tether your stents! PMID- 24629085 TI - Going with the flow! Relieving lower urinary tract symptoms and preserving ejaculation. PMID- 24629086 TI - Improving risk stratification in patients with prostate cancer managed by active surveillance: nomogram predicting the risk of biopsy progression. PMID- 24629087 TI - Chilaiditi syndrome presenting as chest pain in an adult patient: a case report. AB - INTRODUCTION: A patient with chest contusion and rib fractures presented with severe chest pain. The plain film of his chest showed suspicion of pneumoperitoneum. We present this case to show how to get a correct diagnosis and then avoid unnecessary surgery. CASE PRESENTATION: A 64-year-old Taiwanese man presented to the emergency department complaining of severe right chest pain after a traffic accident. Chest radiography showed right fifth to eighth rib fractures and was suspicious for free air under the bilateral hemi-diaphragm. Computed tomography of the abdomen revealed interposition of bowel loops between the liver and diaphragm. The patient was treated with oral analgesics and then regularly followed in the outpatient department. CONCLUSION: Awareness of Chilaiditi's sign is of paramount importance when free air under the diaphragm is seen in a patient (particularly an older patient) who does not exhibit signs of peritoneal irritation on physical examination. Emergent laparotomy should be delayed and a computed tomography scan should be done first. No inappropriate surgical intervention is needed. PMID- 24629088 TI - Nanoscale changes in chromatin organization represent the initial steps of tumorigenesis: a transmission electron microscopy study. AB - BACKGROUND: Nuclear alterations are a well-known manifestation of cancer. However, little is known about the early, microscopically-undetectable stages of malignant transformation. Based on the phenomenon of field cancerization, the tissue in the field of a tumor can be used to identify and study the initiating events of carcinogenesis. Morphological changes in nuclear organization have been implicated in the field of colorectal cancer (CRC), and we hypothesize that characterization of chromatin alterations in the early stages of CRC will provide insight into cancer progression, as well as serve as a biomarker for early detection, risk stratification and prevention. METHODS: For this study we used transmission electron microscopy (TEM) images of nuclei harboring pre-neoplastic CRC alterations in two models: a carcinogen-treated animal model of early CRC, and microscopically normal-appearing tissue in the field of human CRC. We quantify the chromatin arrangement using approaches with two levels of complexity: 1) binary, where chromatin is separated into areas of dense heterochromatin and loose euchromatin, and 2) grey-scale, where the statistics of continuous mass-density distribution within the nucleus is quantified by its spatial correlation function. RESULTS: We established an increase in heterochromatin content and clump size, as well as a loss of its characteristic peripheral positioning in microscopically normal pre-neoplastic cell nuclei. Additionally, the analysis of chromatin density showed that its spatial distribution is altered from a fractal to a stretched exponential. CONCLUSIONS: We characterize quantitatively and qualitatively the nanoscale structural alterations preceding cancer development, which may allow for the establishment of promising new biomarkers for cancer risk stratification and diagnosis. The findings of this study confirm that ultrastructural changes of chromatin in field carcinogenesis represent early neoplastic events leading to the development of well-documented, microscopically detectable hallmarks of cancer. PMID- 24629089 TI - Ultrasonographic characteristics of the abdominal esophagus and cardia in dogs. AB - Differential diagnoses for regurgitation and vomiting in dogs include diseases of the gastroesophageal junction. The purpose of this cross-sectional study was to describe ultrasonographic characteristics of the abdominal esophagus and gastric cardia in normal dogs and dogs with clinical disease involving this region. A total of 126 dogs with no clinical signs of gastrointestinal disease and six dogs with clinical diseases involving the gastroesophageal junction were included. For seven euthanized dogs, ultrasonographic features were also compared with gross pathology and histopathology. Cardial and abdominal esophageal wall thicknesses were measured ultrasonographically for all normal dogs and effects of weight, sex, age, and stomach filling were tested. Five layers could be identified in normal esophageal and cardial walls. The inner esophageal layer was echogenic, corresponding to the cornified mucosa and glandular portion of the submucosa. The cardia was characterized by a thick muscularis, and a transitional zone between echogenic esophageal and hypoechoic gastric mucosal layers. Mean (+/-SD) cardial wall thicknesses for normal dogs were 7.6 mm (+/-1.6), 9.7 mm (+/-1.8), 10.8 mm (+/-1.6), 13.3 mm (+/-2.5) for dogs in the <10 kg, 10-19.9 kg, 20-29.9 kg and >=30 kg weight groups, respectively. Mean (+/-SD) esophageal wall thicknesses were: 4.1 mm (+/-0.6), 5.1 mm (+/-1.3), 5.6 mm (+/-1), and 6.4 mm (+/-1.1) for the same weight groups, respectively. Measurements of wall thickness were significantly correlated with dog weight group. Ultrasonography assisted diagnosis in all six clinically affected dogs. Findings supported the use of transabdominal ultrasonography as a diagnostic test for dogs with suspected gastroesophageal disease. PMID- 24629092 TI - Therapeutic red blood cell exchange in a child with sickle cell anaemia using the Spectra Optia(r) apheresis system. PMID- 24629091 TI - Influence of Abutment Design on Stiffness, Strength, and Failure of Implant Supported Monolithic Resin Nano Ceramic (RNC) Crowns. AB - BACKGROUND: Recent technical development allows the digital manufacturing of monolithic reconstructions with high-performance materials. For implant-supported crowns, the fixation requires an abutment design onto which the reconstruction can be bonded. PURPOSE: The aim of this laboratory investigation was to analyze stiffness, strength, and failure modes of implant-supported, computer-assisted design and computer-aided manufacturing (CAD/CAM)-generated resin nano ceramic (RNC) crowns bonded to three different titanium abutments. MATERIALS AND METHODS: Eighteen monolithic RNC crowns were produced and loaded in a universal testing machine under quasi-static condition according to DIN ISO 14801. With regard to the type of titanium abutment, three groups were defined: (1) prefabricated cementable standard; (2) CAD/CAM-constructed individualized; and (3) novel prefabricated bonding base. Stiffness and strength were measured and analyzed statistically with Wilcoxon rank sum test. Sections of the specimens were examined microscopically. RESULTS: Stiffness demonstrated high stability for all specimens loaded in the physiological loading range with means and standard deviations of 1,579 +/- 120 N/mm (group A), 1,733 +/- 89 N/mm (group B), and 1,704 +/- 162 N/mm (group C). Mean strength of the novel prefabricated bonding base (group C) was 17% lower than of the two other groups. Plastic deformations were detectable for all implant-abutment crown connections. CONCLUSIONS: Monolithic implant crowns made of RNC seem to represent a feasible and stable prosthetic construction under laboratory testing conditions with strength higher than the average occlusal force, independent of the different abutment designs used in this investigation. PMID- 24629093 TI - Effects of modifying the World Health Organization standard operating procedures for malaria microscopy to improve surveillance in resource poor settings. AB - BACKGROUND: Individuals with fever are screened for malaria in specially established malaria diagnostic laboratories set up in rural hospitals in the Northern and Eastern Provinces of Sri Lanka. Large numbers of blood smears negative for malaria parasites are being screened daily. Good quality smears are essential to maintain a high diagnostic competency among the technical staff. The modifications made to the World Health Organization (WHO) standard operating procedures to improve the quality of smears have been studied. METHODS: A blinded, controlled, interventional study was conducted in 22 intervention and 21 control malaria diagnostic laboratories. Changes were made to the WHO standard operating procedure protocols to prepare, stain and examine blood smears for malaria parasite detection which were implemented in intervention laboratories. These included wipe-cleaning slides, preparing both thick and thin smears on the same slide, reversing the order of collecting blood for thick and thin smears, dry fixing thick smear for 20-25 minutes under table lamp, polishing the edge of spreader slide with sand paper and fixing the thin smear with methanol if not stained within four hours. Parameters with respect to quality of the smear as per WHO criteria were studied using randomly selected slides, and time taken for the report to be issued was recorded in both groups before and after the intervention. RESULTS: There were no significant differences observed in the parameters studied at baseline between the two groups or pre and post intervention in the control group. In the intervention group streak formation in thin smears was reduced from 29.4% to 5.0%. The average fixing time of thick smears was reduced from 2.4 hours to 20 minutes. Inappropriate thickness of thick smears reduced from 18.3% to 1.5%. Overall quality of thick smears and thin smears increased from 76.1% to 98.0% and 81.7% to 87.0%, respectively. The quality of slides bearing both thick and thin smears increased from 60.0% to 87.0%. CONCLUSIONS: New protocols with amendments to the WHO standard technical procedures ensure that good quality blood smears are prepared rapidly to diagnose malaria and the time required to issue the reports was reduced. PMID- 24629090 TI - TGF-beta cascade regulation by PPP1 and its interactors -impact on prostate cancer development and therapy. AB - Protein phosphorylation is a key mechanism by which normal and cancer cells regulate their main transduction pathways. Protein kinases and phosphatases are precisely orchestrated to achieve the (de)phosphorylation of candidate proteins. Indeed, cellular health is dependent on the fine-tune of phosphorylation systems, which when deregulated lead to cancer. Transforming growth factor beta (TGF-beta) pathway involvement in the genesis of prostate cancer has long been established. Many of its members were shown to be hypo- or hyperphosphorylated during the process of malignancy. A major phosphatase that is responsible for the vast majority of the serine/threonine dephosphorylation is the phosphoprotein phosphatase 1 (PPP1). PPP1 has been associated with the dephosphorylation of several proteins involved in the TGF-beta cascade. This review will discuss the role of PPP1 in the regulation of several TGF-beta signalling members and how the subversion of this pathway is related to prostate cancer development. Furthermore, current challenges on the protein phosphatases field as new targets to cancer therapy will be addressed. PMID- 24629094 TI - Alexithymia and the labeling of facial emotions: response slowing and increased motor and somatosensory processing. AB - BACKGROUND: Alexithymia is a personality trait that is characterized by difficulties in identifying and describing feelings. Previous studies have shown that alexithymia is related to problems in recognizing others' emotional facial expressions when these are presented with temporal constraints. These problems can be less severe when the expressions are visible for a relatively long time. Because the neural correlates of these recognition deficits are still relatively unexplored, we investigated the labeling of facial emotions and brain responses to facial emotions as a function of alexithymia. RESULTS: Forty-eight healthy participants had to label the emotional expression (angry, fearful, happy, or neutral) of faces presented for 1 or 3 seconds in a forced-choice format while undergoing functional magnetic resonance imaging. The participants' level of alexithymia was assessed using self-report and interview. In light of the previous findings, we focused our analysis on the alexithymia component of difficulties in describing feelings. Difficulties describing feelings, as assessed by the interview, were associated with increased reaction times for negative (i.e., angry and fearful) faces, but not with labeling accuracy. Moreover, individuals with higher alexithymia showed increased brain activation in the somatosensory cortex and supplementary motor area (SMA) in response to angry and fearful faces. These cortical areas are known to be involved in the simulation of the bodily (motor and somatosensory) components of facial emotions. CONCLUSION: The present data indicate that alexithymic individuals may use information related to bodily actions rather than affective states to understand the facial expressions of other persons. PMID- 24629095 TI - Normothermic machine perfusion of the kidney: better conditioning and repair? AB - Kidney transplantation is limited by hypothermic preservation techniques. Prolonged periods of cold ischaemia increase the risk of early graft dysfunction and reduce long-term survival. To extend the boundaries of transplantation and utilize kidneys from more marginal donors, improved methods of preservation are required. Normothermic perfusion restores energy levels in the kidney allowing renal function to be restored ex vivo. This has several advantages: cold ischaemic injury can be avoided or minimized, the kidney can be maintained in a stable state allowing close observation and assessment of viability and lastly, it provides the ideal opportunity to add therapies to directly manipulate and improve the condition of the kidney. This review explores the experimental and clinical evidence for ex vivo normothermic perfusion in kidney transplantation and its role in conditioning and repair. PMID- 24629096 TI - mrSNP: software to detect SNP effects on microRNA binding. AB - BACKGROUND: MicroRNAs (miRNAs) are short (19-23 nucleotides) non-coding RNAs that bind to sites in the 3'untranslated regions (3'UTR) of a targeted messenger RNA (mRNA). Binding leads to degradation of the transcript or blocked translation resulting in decreased expression of the targeted gene. Single nucleotide polymorphisms (SNPs) have been found in 3'UTRs that disrupt normal miRNA binding or introduce new binding sites and some of these have been associated with disease pathogenesis. This raises the importance of detecting miRNA targets and predicting the possible effects of SNPs on binding sites. In the last decade a number of studies have been conducted to predict the location of miRNA binding sites. However, there have been fewer algorithms published to analyze the effects of SNPs on miRNA binding. Moreover, the existing software has some shortcomings including the requirement for significant manual labor when working with huge lists of SNPs and that algorithms work only for SNPs present in databases such as dbSNP. These limitations become problematic as next-generation sequencing is leading to large numbers of novel variants in 3'UTRs. RESULT: In order to overcome these issues, we developed a web-server named mrSNP which predicts the impact of a SNP in a 3'UTR on miRNA binding. The proposed tool reduces the manual labor requirements and allows users to input any SNP that has been identified by any SNP-calling program. In testing the performance of mrSNP on SNPs experimentally validated to affect miRNA binding, mrSNP correctly identified 69% (11/16) of the SNPs disrupting binding. CONCLUSIONS: mrSNP is a highly adaptable and performing tool for predicting the effect a 3'UTR SNP will have on miRNA binding. This tool has advantages over existing algorithms because it can assess the effect of novel SNPs on miRNA binding without requiring significant hands on time. PMID- 24629098 TI - Identifying and preventing medical errors in patients with limited English proficiency: key findings and tools for the field. AB - Since the 1999 Institute of Medicine (IOM) report To Err is Human, progress has been made in patient safety, but few efforts have focused on safety in patients with limited English proficiency (LEP). This article describes the development, content, and testing of two new evidence-based Agency for Healthcare Research and Quality (AHRQ) tools for LEP patient safety. In the content development phase, a comprehensive mixed-methods approach was used to identify common causes of errors for LEP patients, high-risk scenarios, and evidence-based strategies to address them. Based on our findings, Improving Patient Safety Systems for Limited English Proficient Patients: A Guide for Hospitals contains recommendations to improve detection and prevention of medical errors across diverse populations, and TeamSTEPPS Enhancing Safety for Patients with Limited English Proficiency Module trains staff to improve safety through team communication and incorporating interpreters in the care process. The Hospital Guide was validated with leaders in quality and safety at diverse hospitals, and the TeamSTEPPS LEP module was field-tested in varied settings within three hospitals. Both tools were found to be implementable, acceptable to their audiences, and conducive to learning. Further research on the impact of the combined use of the guide and module would shed light on their value as a multifaceted intervention. PMID- 24629097 TI - Epidermal growth factor receptor gene polymorphisms are associated with prognostic features of breast cancer. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile. METHODS: The study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed. RESULTS: (CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40-0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19-0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 - 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17 0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19 0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes. CONCLUSIONS: The data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors. PMID- 24629099 TI - Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study. AB - BACKGROUND: Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions. METHODS: Fifty nine molecularly confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted. RESULTS: At the first presentation, the mean age was 8.8 +/- 2.8 years (mean +/- standard deviation) in the MATN3 group, and 8.5 +/- 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001). CONCLUSIONS: Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes. PMID- 24629101 TI - Microbiology of folliculitis decalvans: a histological study of 37 patients. PMID- 24629102 TI - Effect of Platform Shift on Crestal Bone Levels and Mucosal Profile Following Flap Surgery and Subcrestal Implant Placement in Presence/Absence of Gap Defects. AB - BACKGROUND: Physiologic remodeling resulting in crestal bone loss appears a common corollary to dental implant surgery. Several hypotheses and clinical strategies have been advanced to explain and avert crestal remodeling; however, causative mechanisms remain unclear and the efficacy of clinical protocols uncertain. PURPOSE: The objective of the present study was to provide a histologic account of crestal bone levels and mucosal profile at implant sites receiving platform shift/switch and standard abutments following conventional flap surgery and subcrestal implant placement in presence or absence of crestal gap defects using a dog model. MATERIALS AND METHODS: Four dental implants were placed into the left/right edentulated posterior mandible in five adult male Hound Labrador mongrel dogs using flap surgery including subcrestal placement with/without a 1 * 5 mm (width * depth) gap defect, and using platform shift/switch and standard abutments. Block biopsies were collected for histological/histometric analysis following an 8-week healing interval. RESULTS: No significant differences in crestal resorption were observed among experimental groups; crestal resorption being significantly more advanced at buccal than at lingual sites (p < .001). Similarly, crestal bone-implant contact was not significantly different among groups; crestal bone-implant contact being consistently below the implant platform at buccal sites (p < .01). Moreover, the peri-implant mucosal profile was not statistically different among groups, the mucosal height being significantly greater at buccal than at lingual sites (p < .001). Also, no significant differences among groups were observed for the apical extension of the epithelial attachment, the epithelial attachment being arrested more than 2 mm above the implant platform at both platform shift/switch and standard abutments. CONCLUSIONS: Using a clinical strategy including flap surgery and subcrestal implant placement, implant technology comparing platform shift/switch with standard abutments, surgical approach, and abutment selection seems to have a limited impact on crestal remodeling, associated bone loss, and mucosal profile. PMID- 24629100 TI - Advances in the cellular immunological pathogenesis of type 1 diabetes. AB - Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells. In recent years, the incidence of type 1 diabetes continues to increase. It is supposed that genetic, environmental and immune factors participate in the damage of pancreatic beta cells. Both the immune regulation and the immune response are involved in the pathogenesis of type 1 diabetes, in which cellular immunity plays a significant role. For the infiltration of CD4(+) and CD8(+) T lymphocyte, B lymphocytes, natural killer cells, dendritic cells and other immune cells take part in the damage of pancreatic beta cells, which ultimately lead to type 1 diabetes. This review outlines the cellular immunological mechanism of type 1 diabetes, with a particular emphasis to T lymphocyte and natural killer cells, and provides the effective immune therapy in T1D, which is approached at three stages. However, future studies will be directed at searching for an effective, safe and long lasting strategy to enhance the regulation of a diabetogenic immune system with limited toxicity and without global immunosuppression. PMID- 24629103 TI - Low hepatitis B vaccine uptake among surgical residents in Cameroon. AB - BACKGROUND: Hepatitis B virus (HBV) infection is one of the most serious occupational hazards faced by healthcare workers. Surgical personnel are particularly at risk. HBV infection is preventable by vaccination, but no previous study has assessed HBV vaccination coverage among healthcare workers in Cameroon. We assessed knowledge of risk factors of HBV infection, awareness of HBV vaccine, and vaccination status of surgical residents in Cameroon. METHODS: A structured pretested questionnaire was administered to 49 of the 70 surgical residents in Cameroon during the 2011-2012 academic year. RESULTS: Since the beginning of their residency program, 28 (57.1%) had had at least one accidental exposure to blood, with a median of 2 (range 1 to 25) exposures. Most of them had a good knowledge of risk factors for HBV infection. Although 98.0% (n = 48) were aware of the HBV vaccine, and 89.8% (n = 44) knew that they were at high risk of infection, only 24.5% (n = 12) had received a full course of at least three doses of the vaccine. In addition, only 33.3% (4/12) underwent post-vaccination testing to confirm a good immunological response (and thus effective protection against HBV infection). Among the 53.1% (n = 28) who had never had any dose of HBV vaccine, the main reasons for not being vaccinated were lack of time (38.5%), lack of money to pay for vaccine (23.1%), and lack of sufficient information on the vaccine (19.2%). Only 20.4% (n = 10) had been sensitized by their training institutions about the importance of HBV vaccination. CONCLUSION: There is a low HBV vaccine uptake among surgical residents in Cameroon. As part of occupational safety measures, complete HBV vaccination should be strongly recommended and offered to surgical trainees before the beginning of their training program. PMID- 24629104 TI - Problematic alcohol use and sexual assault among male college students: The moderating and mediating roles of alcohol outcome expectancies. AB - BACKGROUND AND OBJECTIVES: Extant research shows a strong relationship between alcohol use problems and sexual aggression. However, less is known about the effect of intermediary factors (eg, alcohol expectations) that may increase the likelihood of and/or explain sexual aggression during alcohol-related incidents. The present study examined alcohol outcome expectancies' (OE) mediating and/or moderating influence on the relationship between problematic alcohol use severity and sexual aggression among male college students. METHODS AND RESULTS: One hundred and forty eight (n = 148) male college students volunteered for the study. Seventy-seven males self-reported committing at least one act of sexual aggression in their lifetime. Among those who sexually aggressed, 74% also reported symptoms of problematic drinking. Results show that sexuality-related alcohol OE fully mediated the relationship between problematic alcohol use severity and sexual aggression. Results also showed that aggression-related alcohol OE moderated the relationship between problematic alcohol use severity and sexual aggression. Specifically, aggression-related alcohol OE only influenced the relationship between problematic alcohol use and sexual aggression when alcohol problems were less severe. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Discussion implicates the possible role alcohol prevention may play in reducing sexual aggression on college campuses, particularly as it relates to adjusting alcohol OE among those most likely to perpetrate. PMID- 24629105 TI - Effectiveness of supine/standing urinalysis for differential diagnosis of left renal vein entrapment syndrome combined with or without glomerulopathy. AB - AIM: To assess the effectiveness of supine/standing urinalysis for differential diagnosis of left renal vein entrapment syndrome (LRVES) combined with or without glomerulopathy. METHODS: The enrolled patients with abnormal urinalysis and LRVES demonstrated by Doppler sonography were guided to perform a supine/standing urinalysis. RESULTS: Fifty-two patients were enrolled. Most of them were adolescents (aged 14-29 years, 73.1%) and with low body mass index (BMI, mean BMI, 19.8 +/- 2.4 kg/m(2)). Seventeen cases (32.7%) manifested orthostatic urine abnormalities (OUA, proteinuria and/or haematuria show negative in supine while positive after 15 min standing), two patients who had undergone renal biopsies both showed no evidence of kidney lesions, another two patients were changed from abnormal to normal urinalysis after weight gain. The remaining 35 cases (67.3%) manifested non-orthostatic urine abnormalities (NOUA, proteinuria and/or haematuria show positive both in supine and standing), 15 patients had undergone renal biopsies and showed different degrees of glomerulopathy. After prednisone/immunosuppression therapy, four patients with glomerulonephritis were changed from the NOUA to the OUA classification. Statistics analyses showed that serum total protein and albumin levels were significantly lower (P = 0.028, 0.007, respectively) and urinary protein was significantly higher (P = 0.007) in the NOUA group than in the OUA group. CONCLUSION: After the indication of LRVES by ultrasound, patients with OUA likely have only LRVES, while patients with NOUA likely also have glomerulopathy. Supine/standing urinalysis combined with Doppler sonography can be helpful for differential diagnosis of LRVES combined with or without glomerulopathy. PMID- 24629106 TI - The transposable element Bari-Jheh mediates oxidative stress response in Drosophila. AB - Elucidating the fitness effects of natural genetic variants is one of the current major challenges in evolutionary biology. Understanding the interplay between genotype, phenotype and environment is necessary to make accurate predictions of important biological outcomes such as stress resistance or yield in economically important plants and animals, and disease in humans. Based on population frequency patterns and footprints of selection at the DNA level, the transposable element Bari-Jheh, inserted in the intergenic region of Juvenile Hormone Epoxy Hydrolase (Jheh) genes, was previously identified as putatively adaptive. However, the adaptive effect of this mutation remained elusive. In this work, we integrate information on transcription factor binding sites, available ChIP-Seq data, gene expression analyses and phenotypic assays to identify the functional and the mechanistic underpinnings of Bari-Jheh. We show that Bari-Jheh adds extra antioxidant response elements upstream of Jheh1 and Jheh2 genes. Accordingly, we find that Bari-Jheh is associated with upregulation of Jheh1 and Jheh2 and with resistance to oxidative stress induced by two different compounds relevant for natural D. melanogaster populations. We further show that TEs other than Bari Jheh might be playing a role in the D. melanogaster response to oxidative stress. Overall our results contribute to the understanding of resistance to oxidative stress in natural populations and highlight the role of transposable elements in environmental adaptation. The replicability of fitness effects on different genetic backgrounds also suggests that epistatic interactions do not seem to dominate the genetic architecture of oxidative stress resistance. PMID- 24629107 TI - Electrochemically deposited gallium oxide nanostructures on silicon substrates. AB - We report a synthesis of beta-Ga2O3 nanostructures on Si substrate by electrochemical deposition using a mixture of Ga2O3, HCl, NH4OH, and H2O. The presence of Ga3+ ions contributed to the deposition of Ga2O3 nanostructures on the Si surface with the assistance of applied potentials. The morphologies of the grown structures strongly depended on the molarity of Ga2O3 and pH level of electrolyte. beta-Ga2O3 nanodot-like structures were grown on Si substrate at a condition with low molarity of Ga2O3. However, Ga2O3 nanodot structures covered with nanorods on top of their surfaces were obtained at higher molarity, and the densities of nanorods seem to increase with the decrease of pH level. High concentration of Ga3+ and OH- ions may promote the reaction of each other to produce Ga2O3 nanorods in the electrolyte. Such similar nature of Ga2O3 nanorods was also obtained by using hydrothermal process. The grown structures seem to be interesting for application in electronic and optoelectronic devices as well as to be used as a seed structure for subsequent chemical synthesis of GaN by thermal transformation method. PMID- 24629108 TI - The epigenetics changes in Parkinson's disease: a novel therapeutic target. PMID- 24629109 TI - Management of intracranial surgery for refractory epilepsy in severe factor VII deficiency: choosing the optimal dosing regimen. PMID- 24629110 TI - Improved access to histopathology using a digital system could increase the organ donor pool and improve allocation. AB - Improvements in digital slide scanners have reached a stage that digital whole slide images (WSIs) can be used for diagnostic purposes. A digital system for histopathology, analogous to the systems used in radiology, would allow the establishment of networks of subspecialist histopathologists to provide a regional, national or even international rota to support out of hours histopathology for emergency frozen sections, urgent paraffin sections and to generally improve efficiencies with the provision of histopathology services. Such a system would promote appropriate organ utilization by allowing rapid characterization of unexpected lesions in the donor to determine whether donation should occur and further characterization of the organ, such as the degree of fibrosis in the kidney or steatosis in the liver, to determine whether the organ should be used. If introduced across Europe, this would promote safe and effective exchange of organs and support a cost efficient use of pathologist expertise. This review article outlines current issues with the provision of an urgent out of hours histopathology service and focuses on how such a service has the potential to increase organ donors, improve allocation, sharing and the use of available donor organs. PMID- 24629111 TI - [The Danish Committees on Scientific Dishonesty should be strengthened]. PMID- 24629112 TI - [Assessment of infant motor development]. PMID- 24629113 TI - [The 180 degree study is a simple examination of the motor development of infants]. AB - In this article we present The 180 degree study, a systematic and simple approach to examination of the motor development in infants aged 2-10 month. The examination is simple to learn, easy to practice and gives rich opportunity to generate diagnostic hypotheses. PMID- 24629114 TI - [Systemic treatment of biliary tract cancer]. AB - Biliary tract cancer is a relatively rare disease with a poor prognosis. The disease should be handled in a multidisciplinary setting to ensure proper diagnosis and curative surgery if possible. The majority of patients will, however, need oncologic treatment at a certain time. The standard treatment is combination chemotherapy with gemcitabine and a platinum, and in Denmark the regime consists of gemcitabine, oxaliplatin and capecitabine. Research is focused on tumour markers and clinical trials combining chemotherapy with molecularly targeted agents. PMID- 24629115 TI - [Caffeine as adjuvant analgeticum for treating acute pain]. AB - Based on 19 studies (7,238 participants) a Cochrane review concludes that the addition of caffeine to an analgesic drug provides superior analgesia compared with the analgesic drug alone. The benefit is small, with a number needed to treat of approx. 16. The use of analgesics containing caffeine is associated with an increased risk of the development of physical dependence, overuse headache, and withdrawal symptoms upon abrupt discontinuation. Combination analgesics with caffeine should only be used temporarily and exclusively for the treatment of acute pain conditions. PMID- 24629116 TI - [Crigler-Najjar type 1 in children]. AB - Crigler-Najjar type 1 is a rare congenital disease caused by total lack of activity of bilirubin uridine diphosphate glucuronosyl transferase (UGT1A1) in the liver. The disease is characterised by a persistent severe unconjugated hyperbilirubinaemia. The primary treatment is phototherapy, with oral calcium phosphate as a possible supplementation. The effect of the treatment decreases by age, and if the phototherapy is insufficient the patient will need a liver transplantation. Hepatocyte transplantation has been tried with transient success. The risk of chronic bilirubin encephalopathy is considerable. PMID- 24629117 TI - [Crigler-Najjar's syndrome is a rare cause of perinatal hyperbilirubinaemia]. AB - A seven-day-old, mature girl was hospitalized with serum unconjugated bilirubin 420 micromol/l. She was treated with phototherapy, which continued at home until the age of 14 years. Serum total bilirubin was then 250-300 micromol/l and she received a liver transplantation. At the age of 22 years she had no signs of chronic bilirubin encephalopathy. There was no activity of bilirubin UDP glucuronosyl transferase in the liver, and a mutation was found in one of the coding exons in the gene. The girl suffered from Crigler-Najjar's syndrome type 1. In Denmark the incidence was about 2.7 * 10-6 in the period 1977-2010. The prevalence was about 0.5 * 10-6. PMID- 24629118 TI - [Donepezil therapy by neuropathic pain]. AB - A case report of a successful treatment of neuropathic pain after a plexus brachialis injury is presented. On basis of experience from nerve-injured rat models 5 mg donepezil was added to an already instituted gabapentin therapy of 800 mg x 3 daily. This allowed halving the gapentin dose with fully contained pain alleviation but with a drastic reduction of gabapentin's side effects: ataxia and somnolence. Thus, without adding any new side effects life quality was improved and an increased working capacity was observed together with a weight loss of 9 kg over six months. PMID- 24629119 TI - [Coincidental ipsilateral Colle's fracture and scaphoid fracture after low energy trauma]. AB - Distal radius fractures are frequently seen in the emergency room. Scaphoid fractures are frequently seen as well. However, coincidental occurrence of these two types of fracture is quite rare. A 66-year-old healthy man was taken to the emergency room after a fall. He had pain in his right wrist, and an X-ray examination revealed a Colles' fracture with a 30 degree dorsal angulation and an undislocated transverse fracture of the scaphoid bone. The case illustrates that special attention should be given to the examination of the wrist and the first finger beam to exclude associated injuries. PMID- 24629120 TI - [Diagnosing intracranial aneurysms in children can be difficult]. AB - Intracranial aneurysms are rare in the paediatric population. They are distinct from classical adult aneurysms in having several special features. There is an overall male predominance and the dissecting aneurysms are the most frequent, followed by the saccular, the infectious and the post traumatic aneurysms. We present a case story of a 14-year-old Danish boy with an intracranial, giant, basilar artery aneurysm in. The autopsy was performed at the Forensic Department of Medicine in Copenhagen, Denmark. Prior to the autopsy, a routine computed tomography was performed, followed by a supplementary MRI scan. PMID- 24629121 TI - [Ultrasound guidance during placement of central venous catheter can prevent arrhythmias]. AB - Central venous access under ultrasound guidance is widely supported in current medical practice. This case report describes a new method where the tip of the guide-wire is visualized in real-time, withheld from the heart and thereby avoiding the risk of guide-wire induced arrhythmias. PMID- 24629122 TI - [The plasma anion gap is a useful tool for evaluating children with metabolic acidosis]. AB - Metabolic acidosis occurs frequently in hospitalized children. The causes are many and often apparent from the history and physical examination. However, if the aetiology is unclear, the plasma anion gap is a useful tool for evaluating patients with metabolic acidosis. In this case report we describe two children in which the aetiology to the metabolic acidosis was unknown, one with normal anion gap who was diagnosed with renal tubular acidosis, and one with increased anion gap acidosis due to D-lactic acidosis. PMID- 24629123 TI - [Irritant dermatitis]. PMID- 24629124 TI - An asparagine residue at the N-terminus affects the maturation process of low molecular weight glutenin subunits of wheat endosperm. AB - BACKGROUND: Wheat glutenin polymers are made up of two main subunit types, the high- (HMW-GS) and low- (LMW-GS) molecular weight subunits. These latter are represented by heterogeneous proteins. The most common, based on the first amino acid of the mature sequence, are known as LMW-m and LMW-s types. The mature sequences differ as a consequence of three extra amino acids (MET-) at the N terminus of LMW-m types. The nucleotide sequences of their encoding genes are, however, nearly identical, so that the relationship between gene and protein sequences is difficult to ascertain.It has been hypothesized that the presence of an asparagine residue in position 23 of the complete coding sequence for the LMW s type might account for the observed three-residue shortened sequence, as a consequence of cleavage at the asparagine by an asparaginyl endopeptidase. RESULTS: We performed site-directed mutagenesis of a LMW-s gene to replace asparagine at position 23 with threonine and thus convert it to a candidate LMW-m type gene. Similarly, a candidate LMW-m type gene was mutated at position 23 to replace threonine with asparagine. Next, we produced transgenic durum wheat (cultivar Svevo) lines by introducing the mutated versions of the LMW-m and LMW-s genes, along with the wild type counterpart of the LMW-m gene.Proteomic comparisons between the transgenic and null segregant plants enabled identification of transgenic proteins by mass spectrometry analyses and Edman N terminal sequencing. CONCLUSIONS: Our results show that the formation of LMW-s type relies on the presence of an asparagine residue close to the N-terminus generated by signal peptide cleavage, and that LMW-GS can be quantitatively processed most likely by vacuolar asparaginyl endoproteases, suggesting that those accumulated in the vacuole are not sequestered into stable aggregates that would hinder the action of proteolytic enzymes. Rather, whatever is the mechanism of glutenin polymer transport to the vacuole, the proteins remain available for proteolytic processing, and can be converted to the mature form by the removal of a short N-terminal sequence. PMID- 24629125 TI - BCRgt: a Bayesian cluster regression-based genotyping algorithm for the samples with copy number alterations. AB - BACKGROUND: Accurate genotype calling is a pre-requisite of a successful Genome Wide Association Study (GWAS). Although most genotyping algorithms can achieve an accuracy rate greater than 99% for genotyping DNA samples without copy number alterations (CNAs), almost all of these algorithms are not designed for genotyping tumor samples that are known to have large regions of CNAs. RESULTS: This study aims to develop a statistical method that can accurately genotype tumor samples with CNAs. The proposed method adds a Bayesian layer to a cluster regression model and is termed a Bayesian Cluster Regression-based genotyping algorithm (BCRgt). We demonstrate that high concordance rates with HapMap calls can be achieved without using reference/training samples, when CNAs do not exist. By adding a training step, we have obtained higher genotyping concordance rates, without requiring large sample sizes. When CNAs exist in the samples, accuracy can be dramatically improved in regions with DNA copy loss and slightly improved in regions with copy number gain, comparing with the Bayesian Robust Linear Model with Mahalanobis distance classifier (BRLMM). CONCLUSIONS: In conclusion, we have demonstrated that BCRgt can provide accurate genotyping calls for tumor samples with CNAs. PMID- 24629126 TI - The effect of obesity prevention interventions according to socioeconomic position: a systematic review. AB - Obesity prevention is a major public health priority. It is important that all groups benefit from measures to prevent obesity, but we know little about the differential effectiveness of such interventions within particular population subgroups. This review aimed to identify interventions for obesity prevention that evaluated a change in adiposity according to socioeconomic position (SEP) and to determine the effectiveness of these interventions across different socioeconomic groups. A systematic search of published and grey literature was conducted. Studies that described an obesity prevention intervention and reported anthropometric outcomes according to a measure of SEP were included. Evidence was synthesized using narrative analysis. A total of 14 studies were analysed, representing a range of study designs and settings. All studies were from developed countries, with eight conducted among children. Three studies were shown to have no effect on anthropometric outcomes and were not further analysed. Interventions shown to be ineffective in lower SEP participants were primarily based on information provision directed at individual behaviour change. Studies that were shown to be effective in lower SEP participants primarily included community-based strategies or policies aimed at structural changes to the environment. Interventions targeting individual-level behaviour change may be less successful in lower SEP populations. It is essential that our efforts to prevent obesity do not leave behind the most disadvantaged members of society. PMID- 24629127 TI - Effectiveness and safety of omalizumab in a patient with chronic urticaria and hepatitis C. PMID- 24629128 TI - Assessing Compliance With Established Pneumonia Core Measures at a Comprehensive Cancer Center. AB - Healthcare organizations use Pneumonia Core Measures (PCMs) to ensure delivery of high-quality care. In this study, a multidisciplinary team was organized to optimize care and enhance compliance in a comprehensive cancer emergency center. We performed a four-phase study, three of which were interventional: intense education regarding PCM; microbiologic analysis of the pathogens responsible for the pneumonias; development and implementation of an institutional pneumonia algorithm and order set. In phase 4, we analyzed five PCMs. The percentage of pneumonia patients from whom blood cultures were obtained increased from 73% to 91% after intervention (p < .001); sputum cultures increased from baseline 24.6% to 51% (p = .004) post order-set implementation, and order-set utilization increased from 40% to 77%. We achieved the benchmark for only one PCM, PN 3a. More than 80% of patients met clinical and microbiological criteria for healthcare-associated pneumonia. We identified a gap between our patient population and some PCMs that relates to antibiotics selection. The treatment of cancer patients and pneumonia falls outside established guidelines for treating community-acquired pneumonia. Although the algorithm and order set implemented optimized care and minimized variation, national benchmarks for four of the PCMs were not met. Our findings provide information for policymakers considering pneumonia measurements for antibiotic selection in a cancer care setting. PMID- 24629129 TI - Zinc toxicity and ATP production in Pseudomonas fluorescens. AB - AIMS: To identify the molecular networks in Pseudomonas fluorescens that convey resistance to toxic concentrations of Zn, a common pollutant and hazard to biological systems. METHODS AND RESULTS: Pseudomonas fluorescens strain ATCC 13525 was cultured in growth medium with millimolar concentrations of Zn. Enzymatic activities and metabolite levels were monitored with the aid of in-gel activity assays and high-performance liquid chromatography, respectively. As oxidative phosphorylation was rendered ineffective, the assimilation of citric acid mediated sequentially by citrate lyase (CL), phosphoenolpyruvate carboxylase (PEPC) and pyruvate phosphate dikinase (PPDK) appeared to play a key role in ATP synthesis via substrate-level phosphorylation (SLP). Enzymes generating the antioxidant, reduced nicotinamide adenine dinucleotide phosphate (NADPH) were enhanced, while metabolic modules mediating the formation of the pro-oxidant, reduced nicotinamide adenine dinucleotide (NADH) were downregulated. CONCLUSIONS: Pseudomonas fluorescens reengineers its metabolic networks to generate ATP via SLP, a stratagem that allows the microbe to compensate for an ineffective electron transport chain provoked by excess Zn. SIGNIFICANCE AND IMPACT OF THE STUDY: The molecular insights described here are critical in devising strategies to bioremediate Zn-polluted environments. PMID- 24629130 TI - Manual small incision extracapsular cataract surgery in Australia. AB - BACKGROUND: Examination of the results and describing the technique of manual small incision extracapsular cataract extraction on patients with advanced cataracts in urban Australia. DESIGN: A descriptive case series. PARTICIPANTS: Thirty-eight patients at three public hospitals, one tertiary and two secondary ophthalmic units in urban Australia. METHODS: Forty eyes with dense mature cataracts with hand movement vision or worse underwent a planned manual small incision extracapsular cataract extraction instead of traditional phaco emulsification. MAIN OUTCOME MEASURES: Postoperative visual aquity, surgically induced astigmatism and complications. RESULTS: Seventy-eight per cent of patients had an uncorrected visual acuity of 6/12 or better on the first postoperative day. Eighty-three per cent of patients had a distance corrected visual acuity of 6/9 or better 3 months postoperatively. One case was complicated by a posterior capsule rupture. No cases of endophthalmitis were reported. The summated vector mean of the surgically induced astigmatism was 0.089D at 93 degrees . CONCLUSION: Manual small incision extracapsular cataract extraction is an efficacious cataract surgery technique with good visual outcome and is a safe alternative to phaco-emulsification in suitable cases in a first-world setting. PMID- 24629131 TI - Prognostic implications of ezrin and phosphorylated ezrin expression in non-small cell lung cancer. AB - BACKGROUND: The cytoskeletal organizer ezrin is a member of the ezrin-radixin moesin (ERM) family and plays important roles in not only cell motility, cell adhesion, and apoptosis, but also in various cell signaling pathways. Phosphorylation at Thr-567 and Tyr-353 are key regulatory events in the transition of the dormant to active form of ezrin. This study investigated the prognostic implications of ezrin and phosphorylated ezrin (p-ezrin) expression in non-small cell lung carcinoma (NSCLC). METHODS: Ezrin and p-ezrin protein expressions were examined by immunohistochemistry in 150 NSCLC and adjacent non tumor tissues and 14 normal lung tissues. qRT-PCR was used to determine ezrin mRNA expression levels in fresh tissues. The correlations between overexpression of ezrin and p-ezrin and the clinicopathological features of NSCLC were analyzed. The survival rates were calculated by the Kaplan-Meier method for 108 NSCLC cases. RESULTS: Ezrin and ezrinThr-567 proteins showed cytosolic and membranous staining patterns; however, ezrinTyr-353 protein only showed cytosolic staining. Ezrin and p-ezrin were significantly upregulated in NSCLC compared with the normal counterparts. Increased ezrin, ezrinThr-567, and ezrinTyr-353 levels were correlated with the late stage and poor differentiation of NSCLC. However, only ezrinThr-567 was correlated with the presence of lymph node metastasis. In regard to survival, only ezrinThr-567 was related with the overall survival time of patients with NSCLC, and both ezrin and ezrinThr-567 were associated with shortened survival time for patients with early stage NSCLC. CONCLUSIONS: Ezrin and p-ezrin, especially ezrinThr-567, may prove to be useful as a novel prognostic biomarker of NSCLC. PMID- 24629132 TI - Sympatric Asian felid phylogeography reveals a major Indochinese-Sundaic divergence. AB - The dynamic geological and climatological history of Southeast Asia has spawned a complex array of ecosystems and 12 of the 37 known cat species, making it the most felid-rich region in the world. To examine the evolutionary histories of these poorly studied fauna, we compared phylogeography of six species (leopard cat Prionailurus bengalensis, fishing cat P. viverrinus, Asiatic golden cat Pardofelis temminckii, marbled cat P. marmorata, tiger Panthera tigris and leopard P. pardus) by sequencing over 5 kb of DNA each from 445 specimens at multiple loci of mtDNA, Y and X chromosomes. All species except the leopard displayed significant phylogenetic partitions between Indochina and Sundaland, with the central Thai-Malay Peninsula serving as the biogeographic boundary. Concordant mtDNA and nuclear DNA genealogies revealed deep Indochinese-Sundaic divergences around 2 MYA in both P. bengalensis and P. marmorata comparable to previously described interspecific distances within Felidae. The divergence coincided with serial sea level rises during the late Pliocene and early Pleistocene, and was probably reinforced by repeated isolation events associated with environmental changes throughout the Pleistocene. Indochinese-Sundaic differentiations within P. tigris and P. temminckii were more recent at 72-108 and 250-1570 kya, respectively. Overall, these results illuminate unexpected, deep vicariance events in Southeast Asian felids and provide compelling evidence of species-level distinction between the Indochinese and Sundaic populations in the leopard cat and marbled cat. Broader sampling and further molecular and morphometric analyses of these species will be instrumental in defining conservation units and effectively preserving Southeast Asian biodiversity. PMID- 24629133 TI - Rapid detection of Plasmodium falciparum with isothermal recombinase polymerase amplification and lateral flow analysis. AB - BACKGROUND: Nucleic acid amplification is the most sensitive and specific method to detect Plasmodium falciparum. However the polymerase chain reaction remains laboratory-based and has to be conducted by trained personnel. Furthermore, the power dependency for the thermocycling process and the costly equipment necessary for the read-out are difficult to cover in resource-limited settings. This study aims to develop and evaluate a combination of isothermal nucleic acid amplification and simple lateral flow dipstick detection of the malaria parasite for point-of-care testing. METHODS: A specific fragment of the 18S rRNA gene of P. falciparum was amplified in 10 min at a constant 38 degrees C using the isothermal recombinase polymerase amplification (RPA) method. With a unique probe system added to the reaction solution, the amplification product can be visualized on a simple lateral flow strip without further labelling. The combination of these methods was tested for sensitivity and specificity with various Plasmodium and other protozoa/bacterial strains, as well as with human DNA. Additional investigations were conducted to analyse the temperature optimum, reaction speed and robustness of this assay. RESULTS: The lateral flow RPA (LF RPA) assay exhibited a high sensitivity and specificity. Experiments confirmed a detection limit as low as 100 fg of genomic P. falciparum DNA, corresponding to a sensitivity of approximately four parasites per reaction. All investigated P. falciparum strains (n=77) were positively tested while all of the total 11 non Plasmodium samples, showed a negative test result. The enzymatic reaction can be conducted under a broad range of conditions from 30-45 degrees C with high inhibitory concentration of known PCR inhibitors. A time to result of 15 min from start of the reaction to read-out was determined. CONCLUSIONS: Combining the isothermal RPA and the lateral flow detection is an approach to improve molecular diagnostic for P. falciparum in resource-limited settings. The system requires none or only little instrumentation for the nucleic acid amplification reaction and the read-out is possible with the naked eye. Showing the same sensitivity and specificity as comparable diagnostic methods but simultaneously increasing reaction speed and dramatically reducing assay requirements, the method has potential to become a true point-of-care test for the malaria parasite. PMID- 24629134 TI - Rock outcrop orchids reveal the genetic connectivity and diversity of inselbergs of northeastern Brazil. AB - BACKGROUND: Because of their fragmented nature, inselberg species are interesting biological models for studying the genetic consequences of disjoint populations. Inselbergs are commonly compared with oceanic islands, as most of them display a marked ecological isolation from the surrounding area. The isolation of these rock outcrops is reflected in the high number of recorded endemic species and the strong floristic differences between individual inselbergs and adjacent habitats. We examined the genetic connectivity of orchids Epidendrum cinnabarinum and E. secundum adapted to Neotropical inselbergs of northeastern Brazil. Our goals were to identify major genetic divergences or disjunctions across the range of the species and to investigate potential demographic and evolutionary mechanisms leading to lineage divergence in Neotropical mountain ecosystems. RESULTS: Based on plastid markers, high genetic differentiation was found for E. cinnabarinum (FST = 0.644) and E. secundum (FST = 0.636). Haplotypes were not geographically structured in either taxon, suggesting that restricted gene flow and genetic drift may be significant factors influencing the diversification of these inselberg populations. Moreover, strong differentiation was found between populations over short spatial scales, indicating substantial periods of isolation among populations. For E. secundum, nuclear markers indicated higher gene flow by pollen than by seeds. CONCLUSIONS: The comparative approach adopted in this study contributed to the elucidation of patterns in both species. Our results confirm the ancient and highly isolated nature of inselberg populations. Both species showed similar patterns of genetic diversity and structure, highlighting the importance of seed-restricted gene flow and genetic drift as drivers of plant diversification in terrestrial islands such as inselbergs. PMID- 24629135 TI - Enucleation: a possible mechanism of cancer cell death. AB - There are few major morphologies of cell death that have been described so far: apoptosis (type I), cell death associated with autophagy (type II), necrosis (type III) and anchorage-dependent mechanisms-anoikis. Here, we show for the first time a possibly novel mechanism inducing tumour cell death under in vitro conditions-enucleation. We pursued the influence of colloidal suspensions of Fe3 O4 nanoparticles on tumour cell lines (SK-BR-3 and MCF-7 breast cancer cell lines) grown according to standard cell culture protocols. Magnetite nanoparticles were prepared by combustion synthesis and double layer coated with oleic acid. Scanning and transmission electron microscopy revealed that tumour cells developed a network of intracytoplasmic stress fibres, which induce extrusion of nuclei, and enucleated cells die. Normal adult mesenchymal stem cells, used as control, did not exhibit the same behaviour. Intact nuclei were found in culture supernatant of tumour cells, and were visualized by immunofluorescence. Enucleation as a potential mechanism of tumour cell death might open new horizons in cancer biology research and development of therapeutic agents capable of exploiting this behaviour. PMID- 24629136 TI - Functional outcomes following ankle arthrodesis in males with haemophilia: analyses using the CDC's Universal Data Collection surveillance project. AB - In persons with haemophilia (PWH), repeated ankle haemarthroses lead to pain, loss of joint range of motion (ROM), and limitations in activity and participation in society. PWH are offered ankle arthrodesis (AA) to eliminate pain. In our experience, PWH are hesitant to proceed to AA due to concerns regarding gait anomalies, functional decline and complete loss of ROM. The aim of this study was to report outcomes in ROM, assistive device (AD)/wheelchair use, activity scale and work/school absenteeism for participants in the CDC's Universal Data Collection surveillance project (UDC) pre- and post- AA. Males with haemophilia enrolled in the UDC with first report of AA (1998-2010) were selected. Descriptive statistics were calculated using data from the annual study visit pre-AA and the follow-up visit (~12-24 months) post-AA. The 68 subjects who fulfilled the criteria were: mean age 36.9 years (SD = 12.9); 85.3% white; 85.3% haemophilia A; 72% severe, 20.6% moderate; and 10.3% with inhibitor once during the study period. Mean loss in total arc of ankle motion was 17.02 degrees (SD = 21.8, P <= 0.01) pre- compared to post-AA. For 61.8%, there was no change in use of AD for ambulation/mobility. For 85.3%, there was no change in use of a wheelchair. On a self-reported activity scale, 11.8% improved, 8.8% worsened and 79.4% did not change. Work/school absenteeism averaged 2.7 (SD = 6.4) pre- and 1.5 (SD = 6.4, P = 0.26) days per year post-AA. While ankle ROM was significantly reduced post-AA, for most subjects, there was no change in use of AD/wheelchair for ambulation/mobility. Physical activity was maintained and work/school absenteeism remained stable. PMID- 24629137 TI - Overexpression of BAT3 alleviates prion protein fragment PrP106-126-induced neuronal apoptosis. AB - BACKGROUNDS AND AIMS: Prion diseases are a group of infectious neurodegenerative diseases characterized by neuronal death and degeneration. Human leukocyte antigen-B-associated transcript 3 (BAT3) is an important apoptosis regulator. We therefore investigated the interactions between BAT3 and prion protein and the potential role of BAT3 in PrP106-126-induced apoptosis. METHODS: BAT3 and prion protein were overexpressed in Hela, Neuro2A, or primary neuronal cells by transfection with BAT3-HA or PRNP-EGFP expression plasmids and their relationship studied by immunofluorescence and Western blotting. The effect of BAT3 on PrP106 126-induced cytotoxicity and apoptosis was detected by the CCK-8 assay and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. The expression of cytochrome c and Bcl-2 was examined by Western blotting. RESULTS: BAT3 interacted with prion protein and enhanced PrP expression. After PrP106-126 peptide treated, BAT3 was transported from the nucleus to cytoplasm, increased cell viability, and protected neurons from PrP106-126-induced apoptosis through stabilizing the level of Bcl-2 protein and inhibiting the release of cytochrome c to cytoplasm. CONCLUSIONS: Our present data showed a novel molecular mechanism of PrP106-126-induced apoptotic process regulation through the overexpression of BAT3, which may be important for the basic regulatory mechanism of neuron survival in prion diseases and associated neurodegenerative diseases in vivo. PMID- 24629139 TI - Segmentation of Trabecular Jaw Bone on Cone Beam CT Datasets. AB - BACKGROUND: The term bone quality is often used in a dentomaxillofacial context, for example in implant planning, as bone density and bone structure have been linked to primary implant success. PURPOSE: This research aimed to investigate the performance of adaptive thresholding of trabecular bone in cone beam CT (CBCT) images. The segmentation quality was assessed for different imaging devices and upper and lower jaws. MATERIALS AND METHODS: Four jaws were scanned with eight CBCT scanners and one micro-CT device. Images of the jaws were spatially aligned with the micro-CT images. Two volumes of interest for each jaw were manually delineated. Trabecular bone in the volumes of interest in the micro CT images was segmented so that the micro-CT images could serve as high resolution ground truth images. The volumes of interest in the CBCT images were segmented using both global and adaptive thresholding. RESULTS: Segmentation was significantly better for the lower jaw than for the upper jaw. Differences in performance between the scanners were significant for both jaws. Adaptive thresholding performed significantly better in segmenting the bone structure out of CBCT images. CONCLUSIONS: When assessing jaw bone structure, the observer should always choose adaptive thresholding. It remains a challenge to identify the optimal threshold selection for the structural assessment of jaw bone. PMID- 24629138 TI - Comprehensive profiling of accessible surface glycans of mammalian sperm using a lectin microarray. AB - It is well known that cell surface glycans or glycocalyx play important roles in sperm motility, maturation and fertilization. A comprehensive profile of the sperm surface glycans will greatly facilitate both basic research (sperm glycobiology) and clinical studies, such as diagnostics of infertility. As a group of natural glycan binders, lectin is an ideal tool for cell surface glycan profiling. However, because of the lack of effective technology, only a few lectins have been tested for lectin-sperm binding profiles. To address this challenge, we have developed a procedure for high-throughput probing of mammalian sperm with 91 lectins on lectin microarrays. Normal sperm from human, boar, bull, goat and rabbit were collected and analyzed on the lectin microarrays. Positive bindings of a set of ~50 lectins were observed for all the sperm of 5 species, which indicated a wide range of glycans are on the surface of mammalian sperm. Species specific lectin bindings were also observed. Clustering analysis revealed that the distances of the five species according to the lectin binding profiles are consistent with that of the genome sequence based phylogenetic tree except for rabbit. The procedure that we established in this study could be generally applicable for sperm from other species or defect sperm from the same species. We believe the lectin binding profiles of the mammalian sperm that we established in this study are valuable for both basic research and clinical studies. PMID- 24629140 TI - Culture bag systems for clinical applications of adult human neural crest-derived stem cells. AB - INTRODUCTION: Facing the challenging treatment of neurodegenerative diseases as well as complex craniofacial injuries such as those common after cancer therapy, the field of regenerative medicine increasingly relies on stem cell transplantation strategies. Here, neural crest-derived stem cells (NCSCs) offer many promising applications, although scale up of clinical-grade processes prior to potential transplantations is currently limiting. In this study, we aimed to establish a clinical-grade, cost-reducing cultivation system for NCSCs isolated from the adult human nose using cGMP-grade Afc-FEP bags. METHODS: We cultivated human neural crest-derived stem cells from inferior turbinate (ITSCs) in a cell culture bag system using Afc-FEP bags in human blood plasma-supplemented medium. Investigations of viability, proliferation and expression profile of bag-cultured ITSCs were followed by DNA-content and telomerase activity determination. Cultivated ITSCs were introduced to directed in vitro differentiation assays to assess their potential for mesodermal and ectodermal differentiation. Mesodermal differentiation was determined using an enzyme activity assay (alkaline phosphatase, ALP), respective stainings (Alizarin Red S, Von Kossa and Oil Red O), and RT-PCR, while immunocytochemistry and synaptic vesicle recycling were applied to assay neuroectodermal differentiation of ITSCs. RESULTS: When cultivated within Afc-FEP bags, ITSCs grew three-dimensionally in a human blood plasma-derived matrix, thereby showing unchanged morphology, proliferation capability, viability and expression profile in comparison to three dimensionally cultured ITSCs growing in standard cell culture plastics. Genetic stability of bag-cultured ITSCs was further accompanied by unchanged telomerase activity. Importantly, ITSCs retained their potential to differentiate into mesodermal cell types, particularly including ALP-active, Alizarin Red S-, and Von Kossa-positive osteogenic cell types, as well as adipocytes positive in Oil Red O assays. Bag culture further did not affect the potential of ITSCs to undergo differentiation into neuroectodermal cell types coexpressing beta-III-tubulin and MAP2 and exhibiting the capability for synaptic vesicle recycling. CONCLUSIONS: Here, we report for the first time the successful cultivation of human NCSCs within cGMP grade Afc-FEP bags using a human blood plasma-supplemented medium. Our findings particularly demonstrate the unchanged differentiation capability and genetic stability of the cultivated NCSCs, suggesting the great potential of this culture system for future medical applications in the field of regenerative medicine. PMID- 24629141 TI - Physician shadowing by college students: what do patients think? AB - BACKGROUND: The objective of this study is to determine patients' perceptions of physician shadowing by college students. METHODS: Thirty-two patients who agreed to have a college student shadow their physician participated in semi-structured interviews during July and August 2013 at two outpatient family medicine centers. Qualitative techniques were utilized to analyze the transcripts of the patient interviews and identify common themes. RESULTS: The majority of patients (78.1%) felt the college student had a neutral effect on their visit and denied having concerns about confidentiality (87.5%). No patient felt that having the college student present affected their ability to maintain a trusting relationship with their physician. Three themes emerged from the qualitative analysis: benefits to students, willing participation and sensitive issues. Most patients (78.5%) recognized that the student was in college or was a premedical student. The overwhelming majority of patients stated that they would have a college student shadow their physician again in the future. CONCLUSIONS: Despite concerns raised by other authors about the possible negative effects of physician shadowing by college students, this study shows that patients feel the impact to be primarily neutral and that there are many perceived benefits to both student and patient. PMID- 24629142 TI - Survey of chronic haemodialysis in children between 2007 and 2012 in China. AB - AIM: The prevalence of chronic kidney disease (CKD) in children has been on the rise in China and more and more paediatric patients are now relying on chronic renal replacement therapies to sustain their lives. However, there is still a lack of literature in China about their outcomes, thus making it difficult, if not impossible for the paediatric nephrology community to develop strategies to guide future developments and to better serve this group of sick children. METHODS: Our institution has recently conducted a nation-wide survey to obtain data of children with end-stage renal disease (ESRD) between the years 2007 to 2012. Questionnaires were distributed to 39 member hospitals of the Chinese Paediatric Nephrology Association. Only 28 of our member hospitals were actively providing dialysis services to children and their responses were included in this study. RESULTS: There were a total of 1033 children with ESRD and within this cohort, 474 patients (45.9%) received chronic dialysis and 380 patients (80.2%) preferred haemodialysis. CONCLUSION: Haemodialysis is far more commonly used than peritoneal dialysis in China and the outcomes were similar to the experiences in North America. The data we gained through this survey provides the foundation for future planning and development of the paediatric dialysis services in China. PMID- 24629143 TI - Preoperative chemoradiotherapy in rectal cancer induces changes in the expression of nuclear beta-catenin: prognostic significance. AB - BACKGROUND: Preoperative chemoradiotherapy (CRT) is the cornerstone of treatment for locally advanced rectal cancer (LARC). Although high local control is achieved, overall rates of distant control remain suboptimal. Colorectal carcinogenesis is associated with critical alterations of the Wnt/beta-catenin pathway involved in proliferation and survival. The aim of this study was to assess whether CRT induces changes in the expression of beta-catenin/E-cadherin, and to determine whether these changes are associated with survival. METHODS: The Immunohistochemical expression of nuclear beta-catenin and membranous E-cadherin was prospectively analysed in tumour blocks from 98 stage II/III rectal cancer patients treated with preoperative CRT. Tumour samples were collected before and after CRT treatment. All patients were treated with pelvic RT (46-50 Gy in 2 Gy fractions) and 5-fluorouracil (5FU) intravenous infusion (225 mg/m2) or capecitabine (825 mg/m2) during RT treatment, followed by total mesorectal excision (TME). Disease-free survival (DFS) was analysed using the Kaplan-Meier method and a multivariate Cox regression model was employed for the Multivariate analysis. RESULTS: CRT induced significant changes in the expression of nuclear beta-catenin (49% of patients presented an increased expression after CRT, 17% a decreased expression and 34% no changes; p = 0.001). After a median follow-up of 25 months, patients that overexpressed nuclear beta-catenin after CRT showed poor survival compared with patients that experienced a decrease in nuclear beta catenin expression (3-year DFS 92% vs. 43%, HR 0.17; 95% CI 0.03 to 0.8; p = 0.02). In the multivariate analysis for DFS, increased nuclear beta-catenin expression after CRT almost reached the cut-off for significance (p = 0.06). CONCLUSIONS: In our study, preoperative CRT for LARC induced significant changes in nuclear beta-catenin expression, which had a major impact on survival. Finding a way to decrease CRT resistance would significantly improve LARC patient survival. PMID- 24629144 TI - Simvastatin down-regulates the production of interleukin-8 by neutrophil leukocytes from dyslipidemic patients. AB - BACKGROUND: Neutrophil (PMN) leukocytes participate to the initial phases of atherosclerosis through the release of Interleukin 8 (CxCL8; IL-8) that contribute to amplification of inflammation. Aim of the study is to investigate the production of IL-8 by PMN leukocytes from dyslipidemic patients treated with simvastatin. METHODS: In 15 dyslipidemic subjects with moderately increased cardiovascular risk, assessed by Framingham Risk Score, blood samples were obtain to investigate PMNs IL-8 production [at baseline and after N-formyl-Met-Leu-Phe (fMLP) stimulation] before and after long-term (1-year) simvastatin treatment. RESULTS: The resting release of IL-8 was higher in dyslipidemic patients at baseline when compared with control subjects (p < 0.05). One year of treatment was significantly associated with reduced IL-8 production (p < 0.01). Moreover, the fMLP-induced IL-8 production in dyslipidemic untreated patients was higher than that of controls (p < 0.05) and was reduced after simvastatin treatment (p < 0.01). IL-8 release after 1 year of treatment was reduced to levels which were lower than those observed in control subjects both for resting and stimulated cytokine production (p < 0.01). CONCLUSIONS: Prolonged treatment with simvastatin is associated with a reduction of IL-8 production, suggesting the possibility of statin to modulate the pro-inflammatory response in PMNs of patients with moderately increased cardiovascular risk. PMID- 24629145 TI - Pelvic joint fusion in patients with severe pelvic girdle pain - a prospective single-subject research design study. AB - BACKGROUND: The fusion of the pelvic joints in patients with severe pelvic girdle pain (PGP) is a controversial and insufficiently studied procedure. The aims of this study were to evaluate physical function and pain after sacroiliac joint (SIJ) fusion. METHODS: A single-subject research design study with repeated measurements was conducted; pre-operatively and at 3, 6 and 12 months post operatively. The outcome measures considered were the Oswestry disability index (ODI), visual analogue scale (VAS), and SF-36. Eight patients with severe PGP received open-accessed unilateral anterior SIJ fusion and fusion of the pubic symphysis. RESULTS: Seven patients reported positive results from the surgery. At 1 year post-operation, significant (p < 0.001) reductions in ODI (54 to 37) and VAS (82 to 57) were reported. The physical functioning, bodily pain, and social functioning scores in the SF-36 were also improved. CONCLUSION: Positive and significant changes in disability and pain at 1 year after SIJ fusion were observed. Despite these positive results, open accessed anterior fusion of the SIJ was associated with adverse events and complications such as infection and nerve damage. PMID- 24629146 TI - Hanging drop monoculture for selection of optimal antioxidants during in vitro maturation of porcine oocytes. AB - We analysed the effect of three antioxidants that have different functional mechanisms on the in vitro maturation (IVM) of porcine oocytes. Single oocyte monoculture using the hanging drop (HD) system has some advantages such as improving analysis efficiency brought by the smaller number of samples than the number of oocytes cultured in one drop. Direct effects of ligands on single oocytes could also be detected without considering the effects of paracrine factors from other oocytes. After 22 h of pre-culture, denuded oocytes were cultured for 22 h with 0.01 and 0.1 MUg/ml of L-carnitine (LC), lactoferrin (LF) or sulforaphane (SF) in the presence/non-presence of oxidant stress induced by H2O2 supplementation to evaluate the reducing effects against oxidative stress on nuclear maturation. As a result, compared with LC and SF, LF showed effective reduction in oxidative stress at a lower concentration (0.01 MUg/ml), suggesting that LF is a more effective antioxidant in porcine oocyte IVM. Additionally, LF also increased maturation rate even in culture without H2O2. Our results clearly suggest that the HD monoculture system is useful for screening the substances that affect porcine oocyte culture. PMID- 24629147 TI - Disparities in prevalence and risk indicators of loneliness between rural empty nest and non-empty nest older adults in Chizhou, China. AB - AIM: The goal of the present study was to determine the disparities in prevalence and risk factors of loneliness between rural empty nest and non-empty nest older adults in Chizhou, China. METHODS: A sample of 730 participants (381 empty nest older adults and 349 non-empty nest older adults) were surveyed using the University of California at Los Angeles-Loneliness Scale, the 30-item Geriatric Depression Scale (GDS-30), the Pittsburgh Sleep Quality Index, the Social Support Rate Scale, the Perceived Social Support from Family Scale and the World Health Organization Quality of Life questionnaire abbreviated version. RESULTS: The present study showed that the mean level of loneliness did significantly differ between empty nest older adults and non-empty nest older adults (41.52 +/- 6.98 vs 39.46 +/- 7.38). Empty nesters had significantly higher GDS scores; by contrast, they received lower objective, subjective and family support. Family support, objective support and social interaction were associated significantly with loneliness, which was more pronounced in empty nest older adults, excluding subjective support and psychological domain. The GDS scores (beta = 0.237, P < 0.001) and age (beta = -0.114, P = 0.002) showed stronger significant associations with loneliness in empty nest older adults. CONCLUSIONS: Loneliness obviously prevails among empty nest older adults than non-empty nest older adults. Depressive symptoms showed a stronger risk of empty nest older adults being lonely. Family support was suggested as a protective factor for loneliness in both groups. These findings should be considered when developing intervention strategies to reduce loneliness. PMID- 24629148 TI - [Need to get health care data back to the clinicians]. PMID- 24629149 TI - [Barriers for the use of traditional clinical data]. AB - Data from electronic medical records can be used in describing clinical problems not covered by traditional clinical databases or traditional quality assurance systems. In this article three main barriers for the use of these data are identified: system knowledge, legislation and technical barriers. Legislative deregulation and implementation of strategic initiatives to further the use of the data is suggested. PMID- 24629150 TI - [Cardioversion of atrial fibrillation]. AB - Restoration of sinus rhythm should be considered in patients with atrial fibrillation. Prior to cardioversion, each patient must be assessed individually. In haemodynamically unstable patients due to atrial fibrillation, acute DC cardioversion should be performed. In patients who are candidates for elective treatment, cardioversion can be performed pharmacologically or by DC cardioversion. The choice of the cardioversion method is based on advantages and disadvantages of each method, although both methods are safe and effective in most patients when used correctly. PMID- 24629151 TI - [Radiofrequency ablation of atrial fibrillation]. AB - New non-pharmacological interventions have evolved over the latest decades in order to prevent atrial fibrillation and/or reduce symptoms. Radiofrequency ablation (RFA) has been performed in Denmark since 2001. In 2011, 2,529 catheter based RFAs for atrial fibrillation were performed. RFA is now considered a treatment option in patients with drug-refractory atrial fibrillation or young patients who prefer RFA rather than anti-arrhythmic drugs. RFA aims at minimising the impact of "trigger foci" from the pulmonary veins or inhibiting the evolvement of electrical impulses within the atrium. PMID- 24629152 TI - [Treatment with escharotomy in severe burns]. PMID- 24629153 TI - [Spontaneous rupture of the spleen after infectious mononucleosis]. AB - Non-traumatic rupture of the spleen (NRS) is a rare but serious complication to infectious mononucleosis (IM) and it is important to have in mind, when patients have IM. Although splenectomy has been advocated as the appropriate treatment for this problem, the trend goes towards conservative treatment of the haemodynamically stable patients, but because of its rarity no clear guidelines have been suggested. We present a case of a 18-year-old boy with IM who had NRS with subcapsular haematoma and was treated conservatively. He recovered completely. PMID- 24629154 TI - [Treatment of anaphylaxis after ampicillin prophylaxis in a woman in labour]. AB - A primipara developed anaphylaxis during labour due to intravenous (i.v.) administration of ampicillin given prophylactic against group B streptococcal infection. Initially, she was treated with oxygen, i.v. fluids, antihistamine and a slight left-side position. Fifteen minutes later she was given 0.5 mg adrenaline i.v. due to persistent foetal bradycardia (60-90 bpm). Seven minutes later the foetal heart rate could not be detected. By acute caesarean section a child with Apgar score 1/1 was delivered and resuscitated. Cord arterial blood-pH was 6.97, base excess -9.2 mmol/l and lactate level 12.5 mmol/l. One month later the child appeared normal. PMID- 24629155 TI - [Facial angiofibromas associated to tuberous sclerosis treated with topical sirolimus]. AB - We present a five-year-old boy with facial angiofibromas associated to tuberous sclerosis successfully treated with topical sirolimus 0.4% applied three times a week for six months. After six months we observed a nearly complete resolution of facial angiofibromas. The blood levels of sirolimus remained under a detectable limit and no side-effects were observed. Topically applied sirolimus seems to be a safe and effective alternative to surgery or laser therapy. PMID- 24629156 TI - [Congenital hemifacially infiltrating lipomatosis]. AB - Congenital infiltrating lipomatosis of the face is a rare condition with congenital facial asymmetry due to localized overgrowth and accumulation of mature lipocytes. We describe a boy, followed from the age of five months to ten years, with left facial overgrowth, ipsilateral macroglossia, ptosis of the left upper lip, typical asymmetric dental eruption and regional macrodontia in the left upper gumma. The hypertrophic asymmetry was proportionally unaltered with growth. Magnetic resonance imaging confirmed diffuse fatty infiltration with overgrowth of regional bony and soft tissue structures. Intracranial structures were normal as was the boy's cognitive development. PMID- 24629157 TI - [Resistance to warfarin in a patient with hereditary thrombophilia]. AB - We present a case report of a young man with spontaneous deep venous thrombosis. He tested positive for heterozygote factor V Leiden mutation and was treated with warfarin. However, he turned out to be resistant to warfarin, and another venous thrombosis occurred during the insufficient treatment. The antithrombotic treatment was then successfully replaced by phenprocoumon. This case report emphasizes the importance of critically evaluating the efficacy of a treatment and substitute if proven insufficient. PMID- 24629158 TI - [Lipomatous hypertrophy of the interatrial septum is a rare, benign cause of atrial arrhythmia]. AB - Lipomatous hypertrophy of the interatrial septum is a pathological thickening of the interatrial septum characterized by a benign infiltration of fat. It usually occurs in older, obese persons and in most cases the diagnosis is made incidentally. Atrial arrhythmias may occur and in rare cases also superior vena cava syndrome caused by obstruction of venous inflow to the right atrium. We present a case of lipomatous hypertrophy of the interatrial septum in an 81-year old woman with atrial arrhythmia. PMID- 24629159 TI - [Granuloma annulare]. PMID- 24629160 TI - LDL is out again - through the crosstalk of two atheroprotective mechanisms: ABCA1 of macrophages and NO from endothelial cells. PMID- 24629161 TI - The neurovascular unit - concept review. AB - The cerebral hyperaemia is one of the fundamental mechanisms for the central nervous system homeostasis. Due also to this mechanism, oxygen and nutrients are maintained in satisfactory levels, through vasodilation and vasoconstriction. The brain hyperaemia, or coupling, is accomplished by a group of cells, closely related to each other; called neurovascular unit (NVU). The neurovascular unit is composed by neurones, astrocytes, endothelial cells of blood-brain barrier (BBB), myocytes, pericytes and extracellular matrix components. These cells, through their intimate anatomical and chemical relationship, detect the needs of neuronal supply and trigger necessary responses (vasodilation or vasoconstriction) for such demands. Here, we review the concepts of NVU, the coupling mechanisms and research strategies. PMID- 24629162 TI - How to reduce unnecessary duplication: use PROSPERO. PMID- 24629163 TI - Changes in nuclear morphology and chromatin texture of basal keratinocytes in melasma. AB - BACKGROUND: The pathogenesis of melasma and the role of keratinocytes in disease development and maintenance are not completely understood. Dermal abnormalities, the expression of inflammatory mediators, growth factors, epithelial expression of melanocortin and sexual hormones receptors suggest that not only melanocytes, but entire epidermal melanin unit is involved in melasma physiopathology. OBJECTIVES: To compare nuclear morphological features and chromatin texture between basal keratinocytes in facial melasma and adjacent normal skin. METHODS: We took facial skin biopsies (2 mm melasma and adjacent normal skin) from women processed for haematoxylin and eosin. Thirty non-overlapping basal keratinocyte nuclei were segmented and descriptors of area, highest diameter, perimeter, circularity, pixel intensity, profilometric index (Ra) and fractal dimension were extracted using ImageJ software. RESULTS: Basal keratinocyte nuclei from facial melasma epidermis displayed larger size, irregular shape, hyperpigmentation and chromatin heterogeneity by fractal dimension than perilesional skin. CONCLUSION: Basal keratinocytes from facial melasma display changes in nuclear form and chromatin texture, suggesting that the phenotype differences between melasma and adjacent facial skin can result from complete epidermal melanin unit alterations, not just hypertrophic melanocytes. PMID- 24629164 TI - Gastrointestinal stromal tumour of the stomach mimicking a hepatic tumour: a case report. AB - BACKGROUND: Gastrointestinal stromal tumours are the commonest mesenchymal tumours of the gastrointestinal tract. The stomach and small intestine are the favoured sites of occurrence. The symptoms of these depend on the site, size of the tumour and may include abdominal pain, gastrointestinal bleeding or signs of obstruction. We describe a woman with extra luminal gastrointestinal stromal tumour of the stomach that mimicked a left hepatic tumour presenting as an abdominal mass. CASE PRESENTATION: A 51-year-old woman presented with a history of increasing epigastric pain for two-months duration. Her contrast-enhanced computed tomography of the abdomen revealed a large mass in relation to left lobe of the liver. On laparoscopy there was a large tumour arising from the lesser curvature of the stomach. The tumour was resected and histology was suggestive of gastrointestinal stromal tumour. CONCLUSION: This case shows new evidence for the presentation of extra luminal gastric gastrointestinal stromal tumour that are very rare and can mimic hepatic tumour. PMID- 24629165 TI - Genes with a large intronic burden show greater evolutionary conservation on the protein level. AB - BACKGROUND: The existence of introns in eukaryotic genes is believed to provide an evolutionary advantage by increasing protein diversity through exon shuffling and alternative splicing. However, this eukaryotic feature is associated with the necessity of exclusion of intronic sequences, which requires considerable energy expenditure and can lead to splicing errors. The relationship between intronic burden and evolution is poorly understood. The goal of this study was to analyze the relationship between the intronic burden and the level of evolutionary conservation of the gene. RESULTS: We found a positive correlation between the level of evolutionary conservation of a gene and its intronic burden. The level of evolutionary conservation was estimated using the conservation index (CI). The CI value was determined on the basis of the most distant ortholog of the human protein sequence and ranged from 0 (the gene was unique to the human genome) to 9 (an ortholog of the human gene was detected in plants). In multivariable model, both the number of introns and total intron size remained significant predictors of CI. We also found that the number of alternative splice variants was positively correlated with CI.The expression level of a gene was negatively correlated with the number of introns and total size of intronic region. Genes with a greater intronic burden had lower density of missense and nonsense mutations in the coding regions of the gene, which suggests that they are under a stronger pressure from purifying selection. CONCLUSIONS: We identified a positive association between intronic burden and CI. One of the possible explanations of this is the idea of a cost-benefits balance. Evolutionarily conserved (functionally important) genes can "afford" the negative consequences of maintaining multiple introns because these consequences are outweighed by the benefit of maintaining the gene. Evolutionarily conserved and functionally important genes may use introns to create novel splice variants to tune the gene function to developmental stage and tissue type. PMID- 24629166 TI - Slow pathway modulation in a patient with tricuspid valve atresia. AB - Owing to increased life expectancy, patients with grown-up congenital heart disease nowadays present various types of arrhythmias. We report treatment of a 27-year-old patient with tricuspid and pulmonary atresia who was referred to our department with symptomatic tachycardia. During electrophysiologic study, a diagnosis of typical AV-nodal re-entrant tachycardia was made, and he was successfully treated despite the described anatomic malformation. PMID- 24629167 TI - Mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium exposure of the polluted Jinzu River basin, Toyama, Japan; a 26-year follow-up. AB - BACKGROUND: We aimed to investigate the mortality and causes of deaths of inhabitants with renal dysfunction induced by cadmium (Cd) exposure caused by heavy environmental contamination. METHODS: We conducted a 26-year follow-up survey targeting 7529 inhabitants of the Cd-polluted Jinzu River basin and 2149 controls from non-polluted areas who participated in urinary examinations for proteinuria and glucosuria conducted in 1979 to 1984. When the residents were divided into 4 groups, no finding group, glucosuria group, proteinuria group, glucoproteinuria group, mortality risk ratios for all and specific causes of these groups in the polluted area were compared with that of controls without glucosuria and/or proteinuria after adjustments for age at baseline, smoking status, and history of hypertension using Cox's proportional hazard model. RESULTS: The mortality risk ratios for all causes of proteinuria and glucoproteinuria in men and glucosuria, proteinuria, and glucoproteinuria in women of the polluted areas significantly increased compared with those of the controls with no urinary findings. Respiratory, renal, and cardiovascular diseases and diabetes in men, and all diseases except cerebrovascular diseases in women contributed toward an increased mortality of exposed glucoproteinuria groups, which involved chronic Cd toxicosis with renal tubular dysfunction. In women, the mortality risks for cancer of the colon and rectum, uterus and kidney and urinary tract were significantly higher in the exposed proteinuria and glucoproteinuria groups, suggesting associations between renal damage and cancer risk. In exposed women, the no finding group and glucoproteinuria group also showed increased mortality from ischemic heart diseases, indicating that all exposed women may be at risk for ischemic heart diseases. Although the control glucosuria and/or proteinuria group also showed high mortality for diabetes and renal diseases, the increased risk ratio for renal disease mortality was much higher in exposed subjects with urinary findings, particularly in women. CONCLUSIONS: These findings indicate that inhabitants with renal effects caused by Cd exposure had a poor life prognosis over long-term observation in both genders. Particularly in women, renal tubular dysfunction indicated by glucoproteinuria may increase mortality from cancer, ischemic heart diseases, and renal diseases. PMID- 24629168 TI - A novel role of spinal astrocytic connexin 43: mediating morphine antinociceptive tolerance by activation of NMDA receptors and inhibition of glutamate transporter 1 in rats. AB - AIMS: Connexin 43 (Cx43) has been reported to be involved in neuropathic pain, but whether it contributes to morphine antinociceptive tolerance remains unknown. The present study investigated the role of spinal Cx43 in the development of morphine tolerance and its mechanisms in rats. METHODS: Morphine tolerance was induced by intrathecal (i.t.) administration of morphine (15 MUg) daily for seven consecutive days. The analgesia effect was assessed by hot-water tail-flick test. Expression of proteins was detected by Western blot and immunohistochemistry assay. RESULTS: Chronic morphine markedly increased the expression of spinal Cx43. Gap26, a specific Cx43 mimic peptide, attenuated not only morphine antinociceptive tolerance, but also the up-regulation of spinal Cx43 expression, the activation of astrocytes, and N-methyl-D-aspartic acid (NMDA) receptors (NR1 and NR2B subunits), as well as the decreased GLT-1 expression induced by chronic morphine. MK-801, a noncompetitive NMDA receptors antagonist, suppressed the chronic morphine-induced spinal Cx43 up-regulation, astrocytes activation and decline of GLT-1 expression. CONCLUSIONS: The spinal astrocytic Cx43 contributes to the development of morphine antinociceptive tolerance by activating astrocytes and NMDA receptors, and inhibiting GLT-1 expression. We also demonstrate that the role of interaction between the spinal astrocytic Cx43 and neuronal NMDA receptors is important in morphine tolerant rats. PMID- 24629169 TI - Genetic effects on information processing speed are moderated by age--converging results from three samples. AB - Information processing is a cognitive trait forming the basis of complex abilities like executive function. The Trail Making Test (TMT) is a well established test of information processing with moderate to high heritability. Age of the individual also plays an important role. A number of genetic association studies with the TMT have been performed, which, however, did not consider age as a moderating factor. We report the results of genome-wide association studies (GWASs) on age-independent and age-dependent TMT performance in two population-representative community samples (Munich Antidepressant Response Signature, MARS: N1 = 540; Ludwig Maximilians University, LMU: N2 = 350). Age-dependent genome-wide findings were then evaluated in a third sample of healthy elderly subjects (Sydney Memory and Ageing Study, Sydney MAS: N3 = 448). While a meta-analysis on the GWAS findings did not reveal age-independent TMT associations withstanding correction for multiple testing, we found a genome-wide significant age-moderated effect between variants in the DSG1 gene region and TMT A performance predominantly reflecting visual processing speed (rs2199301, P(meta analysis) = 1.3 * 10(-7)). The direction of the interaction suggests for the minor allele a beneficial effect in younger adults turning into a detrimental effect in older adults. The detrimental effect of the missense single nucleotide polymorphism rs1426310 within the same DSG1 gene region could be replicated in Sydney MAS participants aged 70-79, but not in those aged 80 years and older, presumably a result of survivor bias. Our findings demonstrate opposing effects of DSG1 variants on information processing speed depending on age, which might be related to the complex processes that DSG1 is involved with, including cell adhesion and apoptosis. PMID- 24629170 TI - Hospital admissions in relation to body mass index in UK women: a prospective cohort study. AB - BACKGROUND: Adiposity is associated with many adverse health outcomes but little direct evidence exists about its impact on the use of health care services. We aim to describe the relationship between body mass index (BMI) and rates of hospital admission in middle-aged UK women. METHODS: Among 1,251,619 Million Women Study participants, 50- to 64-years old at entry into the study, routine data on hospital admissions were used to estimate hospitalization rates according to BMI after standardization for age, region of recruitment, socioeconomic status, reproductive history, smoking status, hormonal therapy use and alcohol intake. Proportional hazards models were used to estimate adjusted relative risks of hospitalization separately for 25 common types of admission. RESULTS: During an average of 9.2 years follow-up, there were 2,834,016 incident hospital admissions. In women with BMIs (in kg/m2) of <22.5, 22.5 to <25, 25 to <30, 30 to <35 and 35+ standardized admission rates (and 95% confidence intervals (CIs)) per woman over a 10-year period were 2.4 (2.4 to 2.4), 2.4 (2.3 to 2.4), 2.6 (2.6 to 2.6), 3.0 (3.0 to 3.0) and 3.5 (3.4 to 3.5), respectively (P-value for heterogeneity <0.001). The relative increase in admission rates per 5 kg/m2 increase in BMI was 1.12 (1.12 to 1.13). This relationship did not vary materially by age. Corresponding average durations of stay (in days) per hospital visit within the same categories of BMI were: 3.1 (3.1 to 3.2), 2.8 (2.7 to 2.8), 2.9 (2.9 to 2.9), 3.2 (3.1 to 3.2) and 3.8 (3.7 to 3.8), respectively (P <0.001).Significant increases in the risk of admission with increasing BMI were observed for 19 of the 25 types of hospital admission considered. BMI was most strongly associated with admissions with diabetes, knee-replacement, gallbladder disease and venous thromboembolism, but marked associations were found with many other common categories of admission including cataracts, carpal tunnel syndrome and diverticulitis. CONCLUSIONS: Among women 50- to 84-years old in England, around one in eight hospital admissions are likely to be attributable to overweight or obesity, translating to around 420,000 extra hospital admissions and two million extra days spent in hospital, annually. PMID- 24629171 TI - On the Early Mechanisms of Bone Formation after Maxillary Sinus Membrane Elevation: An Experimental Histological and Immunohistochemical Study. AB - BACKGROUND: Previous studies have shown predictable bone formation in the maxillary sinus after membrane elevation. However, how and where the bone is formed is not well understood. PURPOSE: The aim of the study was to histologically and immunohistochemically study the early bone formation events in primates after membrane elevation in the maxillary sinus. MATERIALS AND METHODS: Nine adult male tufted capuchin primates (Cebus apella) were included in the study. Eight animals were subjected to bilateral maxillary sinus membrane elevation using a lateral replaceable bone window technique. One oxidized dental implant was placed into the maxillary sinus cavity on both sides. In four animals, one sinus was left without any additional treatment, whereas the contralateral sinus was filled with autologous bone grafts from the tibia. In two animals, the implants were inserted under the elevated sinus membrane on both sides. In two animals, the sinus membrane was totally removed. The animals were euthanized after 10 or 45 days. One nonoperated animal representing pristine tissue conditions served as control. The maxillary sinuses with implants were retrieved and further processed for light microscopic ground sections or decalcified sections for immune-histochemical analyses. RESULTS: Bone formation started from the bottom of the sinus floor, sprouting into the granulation tissue along the implant surface under the elevated membrane irrespective of time and surgical technique. Bone formation was not seen in direct conjunction with the sinus membrane. A distinct expression of osteopontin was observed in the serous glands of the lamina propria close to the implant within all groups. CONCLUSION: Bone formation after sinus membrane elevation with or without additional bone grafts starts at the sinus floor and sprouts into the elevated space along the implant surface. The sinus membrane does not seem to present osteoinductive potential in sinus membrane elevation procedures in this study. PMID- 24629172 TI - Comparison of histopathological features of pancreatic carcinoma and type 1 autoimmune pancreatitis. AB - Type 1 autoimmune pancreatitis (AIP-1) is an immunoglobulin G (IgG)-4-related disease (IgG4-RD), characterized by elevated serum immunoglobulin G4 (IgG4) and infiltration by IgG4(+) plasma cells. Pancreatic carcinoma (PC) sometimes shows infiltration by IgG4(+) plasma cells, but details have been unclear. We compared pathological findings and expression of IgG4 and IgG in fibroses in 18 PC patients to those from 9 AIP-1 patients. Fibroses were divided into areas of ductal adenocarcinoma (DA) and obstructive pancreatitis (OP). Serum IgG4 levels were lower than the cut-off value in all PC patients with no IgG4-RD. Diffuse lymphoplasmacytic infiltration and eosinophil infiltration were characteristic of fibroses in PC. Though AIP-1 samples often had storiform fibrosis even in biopsies, PC did not show storiform fibrosis. Ratios of IgG4(+) plasma cells/IgG(+) plasma cells (IgG4/IgG ratios) in DA and OP were significantly lower than in AIP-1. However, high-density IgG4(+) plasma cell foci were detected in PC fibroses, particularly around peripheral nerves, vessels, and lymphoid follicles; between lobules and invasion fronts; and within neutrophilic abscesses. In conclusion, the IgG4/IgG ratio is useful in distinguishing PC from AIP-1, and should be evaluated in three or more areas, as PC can show localized high-density IgG4(+) plasma cell areas. PMID- 24629173 TI - Clinicopathological significance of 'atypical ductal proliferation' in core needle biopsy of the breast. AB - Atypical ductal proliferation or ADP has been used in histopathological diagnosis of core needle biopsy (CNB) but its details have not been well studied. Therefore, we examined the clinicopathological characteristics of the initial CNB cases diagnosed as 'ADP ' who subsequently turned out to be malignant, and compared the findings to those that did not. Among 101 cases initially diagnosed as ADP in CNB, the second biopsy revealed no carcinoma (38), ductal carcinoma in situ (DCIS) (45) and invasive carcinoma (18). Significant differences were detected between those which turned out to be carcinoma and those that did not, in the status of myoepithelial cells identified by p63 immunohistochemistry (P = 0.026) and ultrasound (US) categories (P < 0.001). We further compared the histopathological characteristics of those initially diagnosed as ADP and subsequently as DCIS or invasive ductal carcinoma (IDC) with those initially diagnosed as such. DCIS or IDC cases initially diagnosed as ADP had significantly lower Ki67 labeling index (P < 0.01, P < 0.01) and histological grade using Van nuys prognostic index (P < 0.01) or Nottingham histological grades (P < 0.01) respectively than those initially as DCIS or IDC. An assessment of myoepithelial components with US findings might contribute to determine the subsequent clinical algorithm of the patients diagnosed as ADP at initial CNB. PMID- 24629174 TI - Inflammation of colon adenoma in the setting of type 1 autoimmune pancreatitis. AB - Although immunoglobulin G4-related diseases (IgG4-RD) have been found to affect many organs, little is known about their effects on the colonic mucosae. Pathological examination of colon adenomas has shown inflammatory cell infiltration into the stroma. We therefore assessed the clinicopathological characteristics of colon adenomas in patients with type 1 autoimmune pancreatitis (AIP-1), a representative IgG4-RD. Both colon adenomas from patients with (IgG4 adenomas) and without (Non-IgG4 adenomas) IgG4-RD were characterized by moderate to severe lymphoplasmacytic and eosinophilic inflammation without fibrosis or phlebitis. The ratio of IgG4-positive to IgG-positive plasma cells (IgG4/IgG ratio) and the numbers of IgG4-positive plasma cells were significantly higher in IgG4 adenomas than in Non-IgG4 adenomas. IgG4-positive plasma cells tended to be distributed diffusely in lower areas of the mucosae in IgG4 adenomas. We were unable to confirm whether IgG4 adenomas constituted an IgG4-RD. However, IgG4 adenomas in the setting of IgG4-RD may provide useful pathological information, supplementing a diagnosis of IgG4-RD outside the colon, or may facilitate examination for IgG4-RD, especially AIP-1. IgG4 adenomas warrant further investigation. PMID- 24629175 TI - Young-age-onset pancreatoduodenal carcinoma in Shwachman-Diamond syndrome. AB - Shwachman-Diamond syndrome, which is characterized by pancreatic fatty degeneration, skeletal growth retardation, and hematological dysfunction, is a congenital disease caused by SBDS gene mutations. Although hematological disorders often accompany this syndrome, carcinomas associated with this syndrome have not been reported except in one breast cancer and one moderately differentiated pancreatic cancer case. We report on an autopsy of a 24-year-old case of pancreatoduodenal carcinoma in Shwachman-Diamond syndrome. The histology of the tumor was undifferentiated carcinoma, which seems to have originated from either the pancreatic duct or the duodenal epithelium. The tumor was intermingled with two pathological changes characteristic of Shwachman-Diamond syndrome: fatty degeneration of the pancreas and inflammation of the villous stroma of the duodenum. Considering that SBDS protein regulates mitosis and its suppression causes genomic instability, this case might provide an example of carcinogenesis based on genomic instability, together with degenerative changes and chronic inflammation, at a very young age. PMID- 24629176 TI - Neuroendocrine carcinoma arising in a hepatitis C virus-infected liver: mechanism of the tumor development may be similar to that of development of pancreatic neuroendocrine cells. AB - We experienced a case of neuroendocrine carcinoma (NC). The tumor developed in the cirrhotic liver of a 62-year-old Japanese man who had been infected with hepatitis C virus. The tumor cells showed high N/C ratio, formed many rosettes, and expressed CD56, synaptophysin, HepPar1 and pancreatic and duodenal homeobox 1. MIB1 expression was 65%. Because both liver and pancreas are derived from a common endodermal layer during fetal development, we speculated that the tumor may have formed via the interaction of neurogenin 3, insulinoma-associated 1 gene and NeuroD/beta2, which are involved in the stage at which some pancreatic cells commit to becoming endocrine cells. Molecular analysis revealed that the NC had higher relative expression levels of mRNA of the three molecules than did the nontumorous liver. The results indicate that the NC in this patient may have formed via the same mechanism that acts in the development of pancreatic neuroendocrine cells. PMID- 24629177 TI - T-cell factor 1 expression in germ cell tumors with trophoblastic differentiation. PMID- 24629178 TI - Pancreatic intraepithelial neoplasia-3 arising from ectopic pancreas in the jejunum. PMID- 24629179 TI - Carcinoids among multiple lung tumorlets: carcinoids or aggregates of tumorlets? PMID- 24629180 TI - Risk stratification of adult emergency department syncope patients to predict short-term serious outcomes after discharge (RiSEDS) study. AB - BACKGROUND: While Canadian ED physicians discharge most syncope patients with no specific further follow-up, approximately 5% will suffer serious outcomes after ED discharge. The goal of this study is to prospectively identify risk factors and to derive a clinical decision tool to accurately predict those at risk for serious outcomes after ED discharge within 30 days. METHODS/DESIGN: We will conduct a prospective cohort study at 6 Canadian EDs to include adults with syncope and exclude patients with loss of consciousness>5 minutes, mental status changes from baseline, obvious witnessed seizure, or head trauma prior to syncope. Emergency physicians will collect standardized clinical variables including historical features, physical findings, and results of immediately available tests (blood, ECG, and ED cardiac monitoring) prior to ED discharge/hospital admission. A second emergency physician will evaluate approximately 10% of study patients for interobserver agreement calculation of predictor variables. The primary outcome will be a composite serious outcome occurring within 30 days of ED discharge and includes three distinct categories: serious adverse events (death, arrhythmia); identification of serious underlying disease (structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, subarachnoid hemorrhage, significant hemorrhage, myocardial infarction); or procedures to treat the cause of syncope. The secondary outcome will be any of the above serious outcomes either suspected or those occurring in the ED. A blinded Adjudication Committee will confirm all serious outcomes. Univariate analysis will be performed to compare the predictor variables in patients with and without primary outcome. Variables with p-values <0.2 and kappa values >= 0.60 will be selected for stepwise logistic regression to identify the risk factors and to develop the clinical decision tool. We will enroll 5,000 patients (with 125 positive for primary outcome) for robust identification of risk factors and clinical decision tool development. DISCUSSION: Once successfully developed, this tool will accurately risk-stratify adult syncope patients; however, validation and implementation will still be required. This program of research should lead to standardized care of syncope patients, and improve patient safety. PMID- 24629182 TI - Low free testosterone is associated with loss of appendicular muscle mass in Japanese community-dwelling women. AB - AIM: Sarcopenia accelerates frailty syndrome, and adversely affects activities of daily living and quality of life. The aim of the present study was to assess longitudinal relationships between baseline androgen and muscle mass changes in Japanese women. METHODS: Data were collected from 539 community-dwelling, Japanese women aged 40-79 years at baseline who participated in both baseline and follow-up examinations of a longitudinal study of aging (mean duration 8.3 years). Appendicular skeletal muscle mass was measured with dual-energy X-ray absorptiometry at baseline and follow-up examinations. The cut-off point for sarcopenia was a skeletal muscle index (appendicular skeletal muscle mass/height(2) ) <5.46 kg/m(2) . Participants with sarcopenia at baseline were excluded. Thus, 430 women were included. Total testosterone, free testosterone and dehydroepiandrosterone-sulphate were measured by radioimmunoassay at baseline. The androgens were categorized into three groups by serum levels. Multiple logistic regression models were fit to determine the associations between androgens and sarcopenia while controlling for baseline age, body mass index, leisure-time physical activity, nutritional intakes (total energy, total protein, vitamin D), serum C-reactive protein levels, medical histories (heart disease, osteoporosis, rheumatoid arthritis), menopause and smoking habit. RESULTS: The fully adjusted odds ratio of sarcopenia for the low-free testosterone group (<0.7 pg/mL) compared with the high-free testosterone group (>=1.2 pg/mL) was 3.59 (95% confidence interval 1.25-10.34). Sarcopenia was not significantly related to total testosterone or dehydroepiandrosterone-sulphate. CONCLUSION: A low-free testosterone level appears to be a significant predictor of the risk for loss of appendicular muscle in Japanese women. PMID- 24629183 TI - Bioinformatics tools to identify and quantify proteins using mass spectrometry data. AB - Proteomics tries to understand biological function of an organism by studying its protein expressions. Mass spectrometry is used in the field of shotgun proteomics, and it generates mass spectra that are used to identify and quantify proteins in biological samples. In this chapter, we discuss the bioinformatics algorithms to analyze mass spectrometry data. After briefly describing how mass spectrometry generates data, we illustrate the bioinformatics algorithms and software for protein identification such as de novo approach and database searching approach. We also discuss the bioinformatics algorithms and software to quantify proteins and detect the differential proteins using isotope-coded affinity tags and label-free mass spectrometry data. PMID- 24629181 TI - Rocker-sole footwear versus prefabricated foot orthoses for the treatment of pain associated with first metatarsophalangeal joint osteoarthritis: study protocol for a randomised trial. AB - BACKGROUND: Osteoarthritis affecting the first metatarsophalangeal joint of the foot is a common condition which results in pain, stiffness and impaired ambulation. Footwear modifications and foot orthoses are widely used in clinical practice to treat this condition, but their effectiveness has not been rigorously evaluated. This article describes the design of a randomised trial comparing the effectiveness of rocker-sole footwear and individualised prefabricated foot orthoses in reducing pain associated with first metatarsophalangeal joint osteoarthritis. METHODS: Eighty people with first metatarsophalangeal joint osteoarthritis will be randomly allocated to receive either a pair of rocker-sole shoes (MBT(r) Matwa, Masai Barefoot Technology, Switzerland) or a pair of individualised, prefabricated foot orthoses (Vasyli Customs, Vasyli MedicalTM, Queensland, Australia). At baseline, the biomechanical effects of the interventions will be examined using a wireless wearable sensor motion analysis system (LEGSysTM, BioSensics, Boston, MA, USA) and an in-shoe plantar pressure system (Pedar(r), Novel GmbH, Munich, Germany). The primary outcome measure will be the pain subscale of the Foot Health Status Questionnaire (FHSQ), measured at baseline and 4, 8 and 12 weeks. Secondary outcome measures will include the function, footwear and general foot health subscales of the FHSQ, severity of pain and stiffness at the first metatarsophalangeal joint (measured using 100 mm visual analog scales), global change in symptoms (using a 15-point Likert scale), health status (using the Short-Form-12(r) Version 2.0 questionnaire), use of rescue medication and co-interventions to relieve pain, the frequency and type of self-reported adverse events and physical activity levels (using the Incidental and Planned Activity Questionnaire). Data will be analysed using the intention to treat principle. DISCUSSION: This study is the first randomised trial to compare the effectiveness of rocker-sole footwear and individualised prefabricated foot orthoses in reducing pain associated with osteoarthritis of the first metatarsophalangeal joint, and only the third randomised trial ever conducted for this condition. The study has been pragmatically designed to ensure that the findings can be implemented into clinical practice if the interventions are found to be effective, and the baseline biomechanical analysis will provide useful insights into their mechanism of action. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613001245785. PMID- 24629184 TI - Unraveling oxidation-induced modifications in proteins by proteomics. AB - Oxidative stress-driven modifications can occur in lipids, proteins, and DNA and form the basis of several chronic pathologies. The metabolites generated during oxidative responses consist of very reactive substances that result in oxidative damage and modulation of redox signaling as the main outcomes. Oxidative modifications occurring in proteins are poorly understood; among the several methods employed to study such modifications, the most promising strategies are based on proteomics approaches. Proteomics has emerged as one of the most powerful and sensitive analytical tools for mapping the oxidative changes present in proteins in a wide range of sample types and disease models. This chapter addresses the main aspects of redox processes, including an overview of oxidative stress and its biological consequences on proteins. Moreover, major proteomic strategies that can be employed as powerful tools for understanding protein oxidative modifications detected in chronic pathologies are discussed, highlighting cancer research as a model. PMID- 24629185 TI - Role of proteomics in biomarker discovery: prognosis and diagnosis of neuropsychiatric disorders. AB - One of the major concerns of modern society is to identify putative biomarkers that serve as a valuable early diagnostic tool to identify a subset of patients with increased risk to develop neuropsychiatric disorders. Today, proteomic approaches have opened new possibilities in diagnostics of devastating disorders like neuropsychiatric disorders. Proteomics-based technologies for biomarker discovery have been promising because alterations in protein expression and its protein abundance, structure, or function can be used as indicators of pathological abnormalities prior to development of clinical symptoms of neuropsychiatric disorders. This is because using mass spectrometry spectra analysis, it is possible to identify biomarkers of these diseases based on the identification of proteins in body fluids that is easily available, for example, the cerebrospinal fluid, serum, or blood. An ideal biomarker should be present in the blood before the disease is clinically confirmed, have high sensitivity and specificity, and be reproducible. Despite of advances in the proteomic technologies, it has not yielded significant clinical application in neuropsychiatry research. The review discusses overall proteomic approaches for elucidating molecular mechanisms and its applicability for biomarker discovery, diagnosis, and therapeutics of psychiatric disorders such as anxiety, depression, Alzheimer's disease, schizophrenia, and bipolar disorder. In addition, we have also discussed issues and challenges regarding the implementation of proteomic approaches as a routine diagnostic tool in the clinical laboratory in context with neuropsychiatric disorders. PMID- 24629186 TI - On the use of knowledge-based potentials for the evaluation of models of protein protein, protein-DNA, and protein-RNA interactions. AB - Proteins are the bricks and mortar of cells, playing structural and functional roles. In order to perform their function, they interact with each other as well as with other biomolecules such as DNA or RNA. Therefore, to fathom the function of a protein, we require knowing its partners and the atomic details of its interactions (i.e., the structure of the complex). However, the amount of protein interactions with an experimentally determined three-dimensional structure is scarce. Therefore, computational techniques such as homology modeling are foremost to fill this gap. Protein interactions can be modeled using as templates the interactions of homologous proteins, if the structure of the complex is known, or using docking methods. In both approaches, the estimation of the quality of models is essential. There are several ways to address this problem. In this review, we focus on the use of knowledge-based potentials for the analysis of protein interactions. We describe the procedure to derive statistical potentials and split them into different energetic terms that can be used for different purposes. We extensively discuss the fields where knowledge-based potentials have been successfully applied to (1) model protein-protein, protein DNA, and protein-RNA interactions and (2) predict binding sites (in the protein and in the DNA). Moreover, we provide ready-to-use resources for docking and benchmarking protein interactions. PMID- 24629187 TI - Algorithms, applications, and challenges of protein structure alignment. AB - As a fundamental problem in computational structure biology, protein structure alignment has attracted the focus of the community for more than 20 years. While the pairwise structure alignment could be applied to measure the similarity between two proteins, which is a first step for homology search and fold space construction, the multiple structure alignment could be used to understand evolutionary conservation and divergence from a family of protein structures. Structure alignment is an NP-hard problem, which is only computationally tractable by using heuristics. Three levels of heuristics for pairwise structure alignment have been proposed, from the representations of protein structure, the perspectives of viewing protein as a rigid-body or flexible, to the scoring functions as well as the search algorithms for the alignment. For multiple structure alignment, the fourth level of heuristics is applied on how to merge all input structures to a multiple structure alignment. In this review, we first present a small survey of current methods for protein pairwise and multiple alignment, focusing on those that are publicly available as web servers. In more detail, we also discuss the advancements on the development of the new approaches to increase the pairwise alignment accuracy, to efficiently and reliably merge input structures to the multiple structure alignment. Finally, besides broadening the spectrum of the applications of structure alignment for protein template based prediction, we also list several open problems that need to be solved in the future, such as the large complex alignment and the fast database search. PMID- 24629188 TI - Application of evolutionary based in silico methods to predict the impact of single amino acid substitutions in vitelliform macular dystrophy. AB - Recent developments in high-throughput discovery and genotyping have generated a tremendous amount of information about the existence of single amino acid polymorphisms (SAPs). Detailed understanding of the SAPs that affect protein structure and function can provide us valuable insight into disease genotype phenotype correlations. Functional variants of biological importance are likely to be missed in large-scale analysis. Over the past decade, numerous efforts are underway in understanding and characterizing the potential consequences of variants in assessing the risk associated with vitelliform macular dystrophy (VMD). Yet, in spite of this success, we conducted a first SAP analysis via evolutionary-based in silico pipeline to unravel functional SAPs from a pool, containing both functional and neutral ones. Furthermore, based on the prediction scores, a ranking system was developed to prioritize the functional SAPs in order to minimize the number of SAPs screened for further genotyping. PMID- 24629189 TI - Current state-of-the-art molecular dynamics methods and applications. AB - Molecular dynamics simulations are used to describe the patterns, strength, and properties of protein behavior, drug-receptor interactions, the solvation of molecules, the conformational changes that a protein or molecule may undergo under various conditions, and other events that require the systematic evaluation of molecular properties in dynamic molecular systems. Only few years ago proteins were considered to be rigid body structures with very limited conformational flexibility. However, it is now clear that proteins are highly dynamic structures, the internal organization of which is the key to their 3D spatial arrangement and hence biological function. The study of protein dynamics in the lab is a very complicated, expensive, and time-consuming process. Therefore, a lot of effort and hope lies with the computers and the in silico study of protein structure and molecular dynamics. Herein, an effort has been made to describe the ever-evolving field of molecular dynamics, the different algorithms, and force fields that are being used as well as to provide some insight on what the near future holds for this auspicious field of computational structural biology. PMID- 24629190 TI - Intrinsically disordered proteins--relation to general model expressing the active role of the water environment. AB - This work discusses the role of unstructured polypeptide chain fragments in shaping the protein's hydrophobic core. Based on the "fuzzy oil drop" model, which assumes an idealized distribution of hydrophobicity density described by the 3D Gaussian, we can determine which fragments make up the core and pinpoint residues whose location conflicts with theoretical predictions. We show that the structural influence of the water environment determines the positions of disordered fragments, leading to the formation of a hydrophobic core overlaid by a hydrophilic mantle. This phenomenon is further described by studying selected proteins which are known to be unstable and contain intrinsically disordered fragments. Their properties are established quantitatively, explaining the causative relation between the protein's structure and function and facilitating further comparative analyses of various structural models. PMID- 24629191 TI - Conformational elasticity can facilitate TALE-DNA recognition. AB - Sequence-programmable transcription activator-like effector (TALE) proteins have emerged as a highly efficient tool for genome engineering. Recent crystal structures depict a transition between an open unbound solenoid and more compact DNA-bound solenoid formed by the 34 amino acid repeats. How TALEs switch conformation between these two forms without substantial energetic compensation, and how the repeat-variable di-residues (RVDs) discriminate between the cognate base and other bases still remain unclear. Computational analysis on these two aspects of TALE-DNA interaction mechanism has been conducted in order to achieve a better understanding of the energetics. High elasticity was observed in the molecular dynamics simulations of DNA-free TALE structure that started from the bound conformation where it sampled a wide range of conformations including the experimentally determined apo and bound conformations. This elastic feature was also observed in the simulations starting from the apo form which suggests low free energy barrier between the two conformations and small compensation required upon binding. To analyze binding specificity, we performed free energy calculations of various combinations of RVDs and bases using Poisson-Boltzmann surface area (PBSA) and other approaches. The PBSA calculations indicated that the native RVD-base structures had lower binding free energy than mismatched structures for most of the RVDs examined. Our theoretical analyses provided new insight on the dynamics and energetics of TALE-DNA binding mechanism. PMID- 24629192 TI - Computational approaches and resources in single amino acid substitutions analysis toward clinical research. AB - Single amino acid substitutions (SAPs) belong to a class of SNPs in the coding region, which alter the protein function during the translation process. Storage of more information regarding SAPs in public databases will soon become a major hurdle in characterizing the functional SAPs. In such a demanding era, biology has to rely on bioinformatics, which can work its way through to solve the problems at hand by cutting huge amount of time and resources that are otherwise wasted. Here, we describe an overview of the existing repositories of variant databases and computational methods in predicting the effects of functional SAPs on protein stability, structure, function, drug response, and protein dynamics. This chapter will inspire many biologists with a greater promise in identifying the functional SAPs at the structural level, thereby understanding the molecular effects that are critical for personalized medicine diagnosis, prognosis, and treatment for diseases. PMID- 24629193 TI - [Patients with decompensated cirrhosis should be offered rehabilitation at discharge]. PMID- 24629194 TI - [Long-term travel is a risk factor for venous thromboembolic disease]. PMID- 24629195 TI - [Travel and venous thromboembolism]. AB - A literature study on the association between travel and venous thromboembolism (VTE) is conducted. Studies examining the risk of travel-associated VTE, predisposing factors and prophylactic measures are presented. It is concluded that the absolute risk of travel-associated VTE is low and holds a 2-4 fold increase after travel. The risk increases with duration, presence of other risk factors for VTE and extremes of height. Stockings reduces the risk of asymptomatic VTE. Heparin is presumed to constitute protection whereas there is no evidence of a prophylactic effect of acetylsalicylic acid. PMID- 24629196 TI - [Sedentary behaviour in Denmark is growing and is a possible independent risk factor]. AB - The average amount of time spent sedentary is considerable among all age groups in Denmark and evidence points toward an increasing trend. Based on the current scientific research, sedentary behaviour can be viewed as an independent risk factor for many non-communicable diseases and premature mortality. TV viewing is the most pervasive and common form of sedentary behaviour during leisure time and there is substantial evidence for a detrimental health effect of prolonged TV viewing time. At present, there is insufficient evidence to quantify an upper limit for total sedentary time. PMID- 24629197 TI - [Digital rectal examination is a useful clinical procedure in the work-up of patients with colorectal or urogenital symptoms]. AB - Digital rectal examination (DRE) is a simple and inexpensive clinical procedure to assess colorectal or urogenital complaints and is an essential part of the abdominal examination. DRE is a useful diagnostic and screening tool when reasonable suspicion of disease is present. Improved training and encouragement to perform DRE on a regular basis play an important role in improvement on DRE findings and the diagnostic accuracy improves with experience. PMID- 24629198 TI - [Establishing the first ADHD centre in Denmark]. AB - The ADHD-centre in the Region of Southern Denmark will harmonize evidence-based assessment and treatment for adults with ADHD at all psychiatric departments in the region. The incidence of patients with ADHD differed substantially between departments. The majority of the heads of the departments reported a great need for harmonization of the area and 85% were positive towards a central regional coordination of this. The ADHD-centre will implement educational programmes in assessment instruments throughout the region. PMID- 24629199 TI - [Delayed asthma bronchiale due to epoxy resin]. AB - Epoxy resin is a low molecular weight agent, which can cause both acute and delayed allergic reactions. However, it is known causing skin reactions with direct or airborne contact. Rarely it can cause airway reactions like asthma bronchiale. We describe a case of a windmill worker who developed delayed asthma bronchiale due to airborne contact with epoxy resin. PMID- 24629200 TI - [Increased plasma levels of immunoglobulin E can be due to pulmonary embolism]. AB - Increased plasma levels of immunoglobulin E (IgE) are encountered in various clinical settings, most often infection or atopic/allergic disease. IgE, however, is neither a sensitive, nor a specific marker for any particular disease. We describe a case of a 52-year-old woman presenting with non-specific symptoms and increased plasma IgE levels on admission. Atopy/allergy, infection and malignancy were ruled out, and the only plausible cause remained a pulmonary embolism found incidentally on a computed tomography. The patient's IgE levels rapidly declined after the initiation of anticoagulant therapy. PMID- 24629201 TI - [Ileus caused by trocar sites after laparoscopic hysterectomy]. AB - Trocar site herniation (TSH) is a rare condition after laparoscopy and may cause obstruction of the bowel. TSH may be present despite attempted fascial closure. This case report includes two simultaneous TSH in a patient who had laparoscopic hysterectomy performed. She presented with symptoms with severe abdominal pain, excessive vomiting and bloating of the abdomen. A computed tomography showed herniation of the small bowel at two previous trocar sites. The case resulted in emergency laparoscopy with decompression of the herniated bowel. PMID- 24629202 TI - [Hypoglossus and laryngeal nerves palsy after an intubation for Legionella infection]. AB - Extracranial involvement of the hypoglossal nerve and recurrent laryngeal branch of the vagal nerve can be a complication of anaesthetic airway management (Tapia's syndrome) or focal involvement due to Legionella infection. We present a patient with bilateral hypoglossal and unilateral recurrent laryngeal nerves palsy after a complicated intubation and a Legionella infection. Clarithromycin therapy was started. Within months, tongue mobility and swallowing gradually improved. Two months after discharge persisting unilateral recurrent nerve palsy was observed. PMID- 24629203 TI - [Risk of long-lasting negative cognitive consequences after electroconvulsive therapy]. AB - This case study describes a patient who had a unipolar depression and experienced long-lasting cognitive problems after electroconvulsive therapy (ECT). Neuropsychological testing revealed lower scores on measures of learning, memory and sustained attention. These results stress the importance of informing patients who have ECT of the potential cognitive consequences of this treatment as it may influence the patients' functional capabilities. Prospective studies are needed since we do not have sufficient knowledge regarding the 3-5% of these patients who experience sustained cognitive problems. PMID- 24629204 TI - [Plasmodium falciparum]. PMID- 24629205 TI - Effects of gum chewing on postoperative bowel motility after caesarean section: a meta-analysis of randomised controlled trials. AB - BACKGROUND: Gum chewing has been reported to enhance bowel motility and reduce postoperative ileus (POI). However, the efficacy remains imprecise for women following caesarean section. OBJECTIVES: To summarise and evaluate the current evidence for postoperative gum chewing on the recovery of bowel function following caesarean section. SEARCH STRATEGY: We searched studies from the following electronic databases: PubMed, EMBASE, SCOPUS and Cochrane Library from inception to 30 May 2013. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of women after caesarean section; these RCTs should compared gum chewing with no gum chewing and reported on at least one of the outcomes: time to flatus, time to bowel sound, time to passing stool and length of hospital stay (LOS). DATA COLLECTION AND ANALYSIS: Study outcomes were presented as mean differences (for continuous data) with 95% confidence interval (95% CI). The risk of bias in the study results was assessed using the assessment tool from the Cochrane Handbook. MAIN RESULTS: Six RCTs including 939 women were included in our meta-analysis. The pooled results demonstrated that gum chewing is superior to no gum chewing with a reduction of 6.42 hours (95% CI -7.55 to -5.29) for time to first flatus, 3.62 hours (95% CI -6.41 to -0.83) for time to first bowel sound, 6.58 hours (95% CI -10.10 to -3.07) for time to first stool and 5.94 hours (95% CI -9.39 to -2.49) for LOS. In addition, no evidence emerged for any side effects caused by gum chewing. CONCLUSIONS: The current evidence suggests that gum chewing is associated with early recovery of bowel motility and shorter LOS for women after caesarean section. This safe and inexpensive intervention should be included in routine postoperative care following a caesarean section. PMID- 24629206 TI - Paleontology and evolution-part I. PMID- 24629207 TI - Equol producers can have low leptin levels among prediabetic and diabetic females. AB - OBJECTIVES: Soy isoflavones have received great attention for their beneficial effects on health and disease, i.e., in patients with diabetes. Equol is a biologically active isoflavone-related metabolite with interindividual differences in its production. The current study investigated the relationship between an equol-producing state and the levels of adipocytokine markers in a prediabetic and diabetic population. SUBJECTS AND METHODS: A total of 79 subjects (34 males/45 females) in a prediabetic or diabetic state recruited from the general population were examined regarding their ability to produce equol using urine samples. Clinical data, such as age, smoking as well as anthropometric and biochemical variables, including body mass index (BMI), lipids, insulin, glucose, hemoglobin A1c, leptin and adiponectin, were recorded. RESULTS: Equol producers exhibited lower leptin and leptin/BMI than non-producers among females. Simple correlation tests and stepwise multiple regression analyses revealed a significant inverse correlation between the leptin/BMI and equol-production. This relationship was not found in males. CONCLUSIONS: Female equol producers can have favorable metabolic traits in relation to leptin metabolism in this population. Further studies are needed to confirm these results. PMID- 24629208 TI - Comparison of alternative mixture model methods to analyze bacterial CGH experiments with multi-genome arrays. AB - BACKGROUND: Microarray-based comparative genomic hybridization (aCGH) is used for rapid comparison of genomes of different bacterial strains. The purpose is to evaluate the distribution of genes from sequenced bacterial strains (control) among unsequenced strains (test). We previously compared the use of single strain versus multiple strain control with arrays covering multiple genomes. The conclusion was that a multiple strain control promoted a better separation of signals between present and absent genes. FINDINGS: We now extend our previous study by applying the Expectation-Maximization (EM) algorithm to fit a mixture model to the signal distribution in order to classify each gene as present or absent and by comparing different methods for analyzing aCGH data, using combinations of different control strain choices, two different statistical mixture models, with or without normalization, with or without logarithm transformation and with test-over-control or inverse signal ratio calculation. We also assessed the impact of replication on classification accuracy. Higher values of accuracy have been achieved using the ratio of control-over-test intensities, without logarithmic transformation and with a strain mix control. Normalization and the type of mixture model fitted by the EM algorithm did not have a significant impact on classification accuracy. Similarly, using the average of replicate arrays to perform the classification does not significantly improve the results. CONCLUSIONS: Our work provides a guiding benchmark comparison of alternative methods to analyze aCGH results that can impact on the analysis of currently ongoing comparative genomic projects or in the re-analysis of published studies. PMID- 24629209 TI - [Diffuse normolipemic plane xanthomas associated with monoclonal gammopathy of undetermined significance]. PMID- 24629210 TI - HIV positive male with an excrescent oral mass. PMID- 24629211 TI - Analysis of in-hospital consultations with the department of internal medicine. AB - OBJECTIVE: An important but understudied activity of the departments of internal medicine (IM) is the in-hospital consultations. We analyzed the requests for in hospital consultation with IM and the potential differences between the consultations of medical and surgical departments. PATIENTS AND METHODS: This was an 8-month observational prospective study that analyzed demographic variables related to the origin of the interconsultation, comorbidity, length of stay and hospital mortality, emergency, admission-consultation request delay, appropriateness (not appropriate if another department was consulted for the same reason or if the pathology behind the consultation was that of the requesting service) and, for patients who underwent surgery, whether it was requested before or after the surgery. RESULTS: During the study, 215 in-hospital consultations were conducted (27 consultations/month). The mean age of the patients was 69.8 years (women, 50%). Some 30.7% were requested by medical departments and 69.3% by surgical departments. Thirteen percent of the in-hospital consultations were duplicated. The department of IM was not the appropriate department consulted in 23.3% of cases (13.0% of the cases requested consultations for the same reason with another department; in 14.3% of the cases, the pathology was that of requesting department). More in-hospital consultations were conducted on Mondays and Fridays than on Thursdays (25.1% and 23.7% versus 15.3%, respectively; p=.03). The delay between admission and the request for interconsultation was of 12.6 days. Some 90.7% of the in-hospital consultations for patients undergoing surgery were requested after the intervention. There were no differences in the characteristics of the in-hospital consultations between the medical and surgical departments. CONCLUSIONS: In-hospital consultations directed at IM are frequently duplicate, are not well directed at the appropriate department and their urgency is incorrectly assessed. These characteristics are similar for the consultations with medical and surgical departments. PMID- 24629212 TI - [The current state of teaching of General Pathology in Spain. A proposal for further progress]. PMID- 24629213 TI - Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: a case-control study in Inuit women. AB - BACKGROUND: We have previously reported that chemicals belonging to the persistent organic pollutants (POPs) such as perfluorinated compounds (PFAS) and polychlorinated biphenyls (PCBs) are risk factors in Breast Cancer (BC) development in Greenlandic Inuit women. The present case-control study aimed to investigate the main effect of polymorphisms in genes involved in xenobiotic metabolism and estrogen biosynthesis, CYP1A1, CYP1B1, COMT and CYP17, CYP19 and the BRCA1 founder mutation in relation to BC risk and to explore possible interactions between the gene polymorphisms and serum POP levels on BC risk in Greenlandic Inuit women. METHODS: The study population consisted of 31 BC cases and 115 matched controls, with information on serum levels of POPs. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1> A2; rs743572); CYP19A1 (C> T; rs10046) and CYP19A1 ((TTTA)n repeats) polymorphisms and BRCA1 founder mutation using TaqMan allelic discrimination method and polymerase chain reaction based restriction fragment length polymorphism. The chi2 -test was used to compare categorical variables between cases and controls and the odds ratios were estimated by unconditional logistic regression models. RESULTS: We found an independent association of CYP1A1 (Val) and CYP17 (A1) with BC risk.Furthermore, an increased BC risk was observed for women with high serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and carriers of at least: one CYP1A1 variant Val allele; one variant COMT Met allele; or the common CYP17 A1 allele. No combined effects were seen between PFAS exposure and CYP1B1 and CYP19 polymorphisms. The risk of BC was not found significantly associated with exposure to PCBs and OCPs, regardless of genotype for all investigated SNPs. The frequency of the Greenlandic founder mutation in BRCA1 was as expected higher in cases than in controls. CONCLUSIONS: The BRCA1 founder mutation and polymorphisms in CYP1A1 (Val) and CYP17 (A1) can increase the BC risk among Inuit women and the risk increases with higher serum levels of PFOS and PFOA. Serum PFAS levels were a consistent risk factor of BC, but inter-individual polymorphic differences might cause variations in sensitivity to the PFAS/POP exposure. PMID- 24629214 TI - Neurogenic contraction induced by the antiarrhythmic compound, AVE 0118, in rat small mesenteric arteries. AB - The purpose of this study was to investigate the vasoactivity of two inhibitors of potassium ion (K(+) ) channels, a potential antiarrhythmic compound, AVE 0118, and 4-aminopyridine (4-AP). Basal and stimulated tones of rat small mesenteric arteries as well as the possible involvement of KV 1.5 ion channel in the mechanism of vascular effect induced by the compounds were analysed. The standard organ bath technique for vascular tone and immunohistochemistry for the localization of ion channels in the arterial tissue were performed. Third- or fourth-order branch of arterial segments was mounted in myographs for recording the isometric tension. AVE 0118 (10(-5) M) and 4-AP (10(-5) M) modulated neither the basal tone nor the contraction induced by noradrenaline but increased the contraction evoked by electrical field stimulation, sensitive to the block of alpha-1 adrenergic receptors. KV 1.5 ion channel-specific immunostaining demonstrated the presence of immunoreactive nerves, and Schwann-cell-specific (S100) immunostaining confirmed the presence of myelin sheath in rat small mesenteric arteries. The study supports an indirect, sympathetic effect of AVE 0118 similar to that of 4-AP, which is mediated, at least in part, by blocking neuronal KV 1.5 type potassium ion channels in the medio-adventitial layer of rat small mesenteric artery. PMID- 24629215 TI - Interstitial-type granuloma annulare associated with Sjogren syndrome. PMID- 24629216 TI - The role of previous contraception education and moral judgment in contraceptive use. AB - INTRODUCTION: The knowledge and attitudes that lead to nonuse of contraception are not well understood. The goal of this study was to determine whether an association exists between contraceptive use and specific knowledge and attitudinal factors. METHODS: We conducted a secondary analysis of data from a nationally representative telephone survey of 897 unmarried women aged 18 to 29 years to examine the relationship between contraceptive use and comprehensive sex education, attitude toward pregnancy prevention, perceived infertility, distrust toward the health care system or contraception, and moral attitude toward contraception. RESULTS: Both ever having made a visit to a physician or clinic for women's health care and ever having used any method of contraception to prevent pregnancy were significantly impacted by more comprehensive sex education and less likelihood to view contraception as morally wrong. Consistent with other research, we found no association between the desire to avoid pregnancy and contraceptive use. We found an association between health system distrust and contraceptive use, but health system distrust did not predict contraceptive use. DISCUSSION: Our findings show that contraceptive use among a sample of young women is influenced by previous contraceptive education and moral attitudes toward contraception. Clinicians should be cognizant of these realities, which may need to be addressed in both clinical and nonclinical venues. PMID- 24629217 TI - Comparative effectiveness and cost-effectiveness of antiretroviral therapy and pre-exposure prophylaxis for HIV prevention in South Africa. AB - BACKGROUND: Antiretroviral therapy (ART) and oral pre-exposure prophylaxis (PrEP) are effective in reducing HIV transmission in heterosexual adults. The epidemiologic impact and cost-effectiveness of combined prevention approaches in resource-limited settings remain unclear. METHODS: We develop a dynamic mathematical model of the HIV epidemic in South Africa's adult population. We assume ART reduces HIV transmission by 95% and PrEP by 60%. We model two ART strategies: scaling up access for those with CD4 counts <= 350 cells/MUL (Guidelines) and for all identified HIV-infected individuals (Universal). PrEP strategies include use in the general population (General) and in high-risk individuals (Focused). We consider strategies where ART, PrEP, or both are scaled up to 100% of remaining eligible individuals yearly. We measure infections averted, quality-adjusted life-years (QALYs) gained and incremental cost effectiveness ratios over 20 years. RESULTS: Scaling up ART to 50% of eligible individuals averts 1,513,000 infections over 20 years (Guidelines) and 3,591,000 infections (Universal). Universal ART is the most cost-effective strategy at any scale ($160-$220/QALY versus comparable scale Guidelines ART expansion). General PrEP is costly and provides limited benefits beyond ART scale-up ($7,680/QALY to add 100% PrEP to 50% Universal ART). Cost-effectiveness of General PrEP becomes less favorable when ART is widely given ($12,640/QALY gained when added to 100% Universal ART). If feasible, Focused PrEP is cost saving or highly cost effective versus status quo and when added to ART strategies. CONCLUSIONS: Expanded ART coverage to individuals in early disease stages may be more cost-effective than current guidelines. PrEP can be cost-saving if delivered to individuals at increased risk of infection. PMID- 24629218 TI - Total arch replacement using moderate hypothermic circulatory arrest and unilateral selective antegrade cerebral perfusion. AB - OBJECTIVE: To examine the clinical outcomes and impact of using moderate hypothermic circulatory arrest (MHCA) and unilateral selective antegrade cerebral perfusion (uSACP) in the setting of total aortic arch replacement (TOTAL). METHODS: From 2004 to 2012, 733 patients underwent open arch reconstruction with MHCA and SACP. Of these, 145 (20%) underwent TOTAL. Measured outcomes included death, stroke, temporary neurologic dysfunction (TND), and renal failure. Mean follow-up time was 33 months and ranged from 0 to 95 months. RESULTS: Core temperature at the onset of MHCA was 25.8 degrees C. Cardiopulmonary bypass and myocardial ischemic times were 236 minutes and 181 minutes, respectively. Twenty three patients (16%) underwent emergency repair of acute type A dissection. Fifty four cases (37%) were reoperative and 52 (34%) were stage I elephant trunk procedures. Concomitant root replacement was performed in 50 (35%) patients, including 20 David V valve-sparing procedures. Mean duration of circulatory arrest was 55 minutes. Operative mortality was 9.7%. Overall incidence of stroke and TND was 2.8% and 5.6%, respectively. Four patients (2.8%) required postoperative dialysis. Seven-year survival was significantly reduced (P = .04) after repair of type A dissection (83.8%) compared with elective surgery (89.5%). Higher temperature during TOTAL was not found to be a significant risk factor for adverse events. CONCLUSIONS: TOTAL using MHCA and uSACP can be accomplished with excellent early and late results. MHCA was not associated with adverse neurologic outcomes or higher operative risk, despite prolonged periods of circulatory arrest. PMID- 24629219 TI - Ventriculoarterial coupling in palliated hypoplastic left heart syndrome: Noninvasive assessment of the effects of surgical arch reconstruction and shunt type. AB - OBJECTIVE: To assess the coupling efficiency in hypoplastic left heart syndrome, considering the effect of surgical arch reconstruction and the shunt type received during the Norwood procedure. METHODS: Ventriculoarterial coupling was assessed before Fontan completion in 32 patients with hypoplastic left heart syndrome (19 modified Blalock-Taussig and 13 Sano shunts at stage 1). Cardiovascular magnetic resonance data were analyzed, deriving functional parameters and 3-dimensional volumes. Dimensional indexes were computed from 3 dimensional data sets as the area ratio of the isthmus to the descending aorta (Risthmus) and the isthmus to surgically enlarged transverse arch (Rarch). Wave intensity was calculated from cardiac magnetic resonance, using the peaks of the forward compression and expansion waves in early and late systole as surrogate indicators of ventriculoarterial coupling. RESULTS: Aortic distensibility (3.6+/ 2.7*10(-3) 1/mm Hg) was not associated with the time elapsed from stage 1 palliation (P=.94), suggesting an early loss of elasticity that did not progress thereafter. Risthmus was 1.0+/-0.4, and Rarch was 0.3+/-0.1, indicating the dilated reconstructed arch was the main anatomic feature. The forward compression wave correlated significantly with Rarch (R2=0.23, P=.006) but not with Risthmus (R2<0.01, P=.63). Patients with a reduced ejection fraction exhibited a larger ventricular mass (R2=0.28, P=.003). The Sano shunt patients had a lower ejection fraction (51%+/-6% vs 57%+/-6%, P=.02); however, neither the forward compression nor expansion wave varied significantly between shunt type or the other functional parameters. CONCLUSIONS: Ventriculoarterial coupling in operated hypoplastic left heart syndrome was affected by aortic arch size mismatch but not by the type of shunt placed at the Norwood operation. PMID- 24629221 TI - Activation of canonical transient receptor potential channels preserves Ca2+ entry and endothelium-derived hyperpolarizing factor-mediated function in vitro in porcine coronary endothelial cells and coronary arteries under conditions of hyperkalemia. AB - OBJECTIVES: Although membrane depolarization by hyperkalemia is known to reduce Ca2+ influx in endothelial cells, the mechanism by which endothelial Ca2+ channel is affected by hyperkalemia remains poorly studied. We studied the effect of hyperkalemia on canonical transient receptor potential channels, in particular canonical transient receptor potential channel 3, in modulation of endothelial intracellular Ca2+ concentration. Endothelium-derived hyperpolarizing factor mediated function is Ca2+ dependent, and hyperkalemic cardioplegia/organ preservation solutions impair endothelium-derived hyperpolarizing factor-mediated function. We explored the role of canonical transient receptor potential channel 3 in endothelium-derived hyperpolarizing factor-mediated function and investigated whether modulation of these channels preserves endothelial Ca2+ influx and endothelium-derived hyperpolarizing factor-mediated function under the condition of hyperkalemic/cardioplegic exposure. METHODS: Intracellular Ca2+ concentration was measured with fluorescent dye in primary cultured porcine coronary endothelial cells exposed to hyperkalemic/cardioplegic solutions containing mild to extreme high K+ concentration. Endothelium-derived hyperpolarizing factor-mediated relaxation under hyperkalemic/cardioplegic exposure was studied in small porcine coronary arteries in a myograph in the presence of cyclooxygenase and nitric oxide synthase inhibitors and nitric oxide scavenger. RESULTS: Canonical transient receptor potential channel 3 blocker inhibited bradykinin-induced Ca2+ influx and attenuated endothelium-derived hyperpolarizing factor-mediated response. Hyperkalemic exposure inhibited canonical transient receptor potential channel 3-mediated Ca2+ influx in a K+ concentration-dependent manner (120>20>10 mmol/L). Ca2+ influx decreased in porcine coronary endothelial cells exposed to histidine-tryptophan-ketoglutarate, St Thomas' Hospital, and University of Wisconsin solutions that contained mild (10 mmol/L), moderate (20 mmol/L), and extreme high (125 mmol/L) K+ concentration, respectively. Canonical transient receptor potential channel activator prevented the reduction of Ca2+ influx in porcine coronary endothelial cells exposed to solutions containing mild to moderate high [K+]o and restored endothelium-derived hyperpolarizing factor-mediated response that was impaired by hyperkalemic exposure. CONCLUSIONS: Canonical transient receptor potential channel 3 is involved in endothelium-derived hyperpolarizing factor-mediated function in coronary arteries. Hyperkalemia inhibited canonical transient receptor potential channel 3-mediated Ca2+ influx in endothelial cells. Canonical transient receptor potential channel activation restores Ca2+ influx suppressed by hyperkalemia and prevents dysfunction of endothelium-derived hyperpolarizing factor. PMID- 24629220 TI - 22q11.2 Deletion syndrome is associated with increased perioperative events and more complicated postoperative course in infants undergoing infant operative correction of truncus arteriosus communis or interrupted aortic arch. AB - OBJECTIVE: The effect of genotype on the outcomes of infant cardiac operations has not been well established. The purpose of the present study was to investigate the effect of 22q11.2 deletion (22q11del) on infants with truncus arteriosus communis (TA) and interrupted aortic arch (IAA) undergoing operative correction during infancy. METHODS: We conducted a retrospective cohort study of all infants who had undergone operative correction of TA or IAA at the Children's Hospital of Philadelphia from 1995 to 2007, comparing the perioperative outcomes (hospital length of stay, intensive care, mechanical ventilation, risk of cardiac and noncardiac events, number of consultations, and number of discharge medications) by 22q11del status. RESULTS: A total of 104 patients were studied (55 with TA and 49 with IAA), of whom 40 (38%) were 22q11del positive. The 22q11del status was unknown in 9 (7 with TA and 2 with IAA). In patients with known deletion status, those with 22q11del had a longer hospital and intensive care length of stay. Subjects with 22q11del also required more frequent operative reintervention and more consultations and were prescribed more medications at discharge. No significant difference was found in method of feeding between those with and without 22q11del at discharge. CONCLUSIONS: In this study, 22q11del is associated with perioperative outcomes in infants undergoing operative correction of TA and IAA, with longer hospital stays and greater resource utilization in the perioperative period. These findings should inform counseling and risk stratification and warrant additional study to identify genotype-specific management strategies to improve outcomes. PMID- 24629222 TI - Analysis of the learning curve for beating heart, totally endoscopic, coronary artery bypass grafting. AB - BACKGROUND: Robotic cardiac surgery has been proved safe and feasible in dedicated centers. We systematically analyzed the learning curve issues associated with totally endoscopic coronary artery bypass grafting (TECAB) using a stepwise approach by a single surgeon who had successfully performed >650 cases of various types of robotic cardiac surgery at our single center. METHODS: From January 2007 to March 2013, 230 patients underwent robotic coronary bypass grafting on the beating heart. Of these patients, 90 had successfully undergone beating heart TECAB using the da Vinci S/Si Surgical System without conversion to sternotomy. All beating heart TECAB procedures were completed using the following modules: endoscopic left internal thoracic artery (LITA) harvesting, pericardiotomy and target vessel identification, and anastomosis of the LITA to the target vessel. The perioperative outcomes were compared among 3 quintiles of 30 consecutive patients each and the learning curve results were evaluated. RESULTS: No in-hospital mortality or severe morbidity occurred. The comparison among the 3 quintiles showed a significant decrease in operative time (P=.000), LITA harvesting time (P=.037), and anastomotic time (P=.000). A significant learning curve was observed for the operative time [y(min)=223-17*ln(x); r2=0.217, P=.000]; LITA harvesting time [y(min)=37-3*ln(x); r2=0.097, P=.003]; and LITA-left anterior descending artery anastomotic time [y(min)=18-2*ln(x); r2=0.298, P=.000]. No differences were found in the mean transit flow (P=.102) or perioperative complications among the 3 quintiles. CONCLUSIONS: Modular-based TECAB procedures can be successfully performed; however, each module has a steep learning curve. A stable and well-trained robotic cardiac team and an experienced cardiac surgeon can achieve good, reproducible results after this substantial learning curve. PMID- 24629223 TI - Short- and long-term outcomes after valve replacement surgery for rheumatic heart disease in the South Pacific, conducted by a fly-in/fly-out humanitarian surgical team: a 20-year retrospective study for the years 1991 to 2011. AB - OBJECTIVES: Fiji has one of the highest rates of rheumatic heart disease in the world. Humanitarian fly-in/fly-out surgical teams, including Open Heart International, have been conducting valve replacement surgery in Fiji since 1991. We sought to determine the short- and long-term outcomes of valve replacement for rheumatic heart disease. METHODS: The Open Heart International team performed surgery on 167 patients from 1991 to 2011. Complete follow-up data to death or last evaluation on 149 patients (89.2%) and morbidity data for 152 patients (91%) were extracted from medical records. RESULTS: Patients' average age at the time of surgery was 26.1 years, with the majority being female (63.5%). Valves replaced were isolated mitral valves (52%), isolated aortic valves (19%), and multiple valves (29%). The cumulative mortality rate at 30, 60, and 90 days and at 1, 5, and 10 years was 2.4%, 6.0%, 8.4%, 12.0%, 19.8%, and 23.9%, respectively. Major adverse valve-related events-free survival was 10.1 years (95% confidence interval [CI], 8.32-11.94). After adjusting for confounders, female patients were 3.03 times more likely to die postoperatively than male patients (odds ratio [OR], 3.03; 95% CI, 1.23-7.69). Patients undergoing isolated valve replacement were less likely to have a morbidity event than those undergoing multiple valve replacement (isolated mitral 67% less likely [OR, 0.33; 95% CI, 0.12-0.93] and isolated aortic 76% less likely [OR, 0.34; 95% CI, 0.06 0.96]). CONCLUSIONS: The majority of people undergoing valve replacement for rheumatic heart disease have good outcomes. Mortality and morbidity rates at 1 and 5 years, particularly for female patients, are cause for concern and indicate a need for evaluation of resources toward systematic long-term postoperative surveillance and medical management. PMID- 24629224 TI - 'I feel like a salesperson': the effect of multiple-source care funding on the experiences and views of nursing home nurses in England. AB - The difficulties faced in the recruitment and retention of nursing staff in nursing homes for older people are an international challenge. It is therefore essential that the causes of nurses' reluctance to work in these settings are determined. This paper considers the influence that multiple-source care funding issues have on nursing home nurses' experiences and views regarding the practice and appeal of the role. The methodology for this study was hermeneutic phenomenology. Thirteen nurses from seven nursing homes in the North East of England were interviewed in a sequence of up to five interviews and data were analysed using a literary analysis method. Findings indicate that participants are uncomfortable with the business aspects that funding issues bring to their role. The primary difficulties faced are: tensions between care issues and funding issues; challenges associated with 'selling beds'; and coping with self funding residents' changing expectations of care. The findings of the study suggest that multiple-source care funding systems that operate in nursing homes for older people pose challenges to nursing home nurses. Some of these challenges may impact on their recruitment and retention. PMID- 24629225 TI - Expression and localization of Aquaporin 3 (AQP3) in folliculogenesis of ewes. AB - The mRNA expression and localization of Aquaporin 3 (AQP3) were investigated in the ovarian follicles of ewes at different stages of development (primordial, primary, secondary, small, and large antral). The gene expression was quantified by qPCR, while the protein identification and localization were determined by Western blot and immunohistochemistry, respectively. Analysis revealed that AQP3 mRNA was detected only in the antral follicles, whereas the protein expression was detected in the oocyte and granulosa cells in all stages of follicular development. The latter observation suggests that the presence of AQP3 in follicles of all categories, especially in the antral follicles, provides novel insights on the mechanisms that regulate the flow of water between cells during the formation of antral follicles in sheep. PMID- 24629226 TI - Changes in prevalence of calcaneal spurs in men & women: a random population from a trauma clinic. AB - BACKGROUND: This study reports the changing prevalence of ankle (Achilles and plantar) spurs with age, in order to comment on their significance to rheumatologists. METHODS: 1080 lateral ankle radiographs from each of 9 (50 men and 50 women) age cohorts from 2 to 96 years old of patients attending a trauma clinic were examined and spurs classified as small or large. RESULTS: The prevalence of both Achilles and plantar spurs in relation to the age categories and sex was variable. Overall, there was 38% of the population who had a spur (Achilles or plantar) and only third (11%) with spurs at both sites (Achilles and plantar). Large spurs were more prevalent in older individuals (40 to 79 years). There were no large plantar spurs in individuals <40 years of age and only 2% for the Achilles. The prevalence of spurs (Achilles and plantar) was significantly higher for woman than men in individuals <50 years of age. There was a notable moderate positive correlation (r = 0.71) between both plantar and Achilles spurs for women <30 years of age but no correlation for men (r = -0.03). CONCLUSION: Plantar and Achilles spurs are highly prevalent in older people and the radiographic appearance of spurs differs between men and women. In individuals < 50 years of age, spur (Achilles and plantar) formation is more common in women than in men. Additionally, there was a notable moderate positive correlation between Achilles and plantar spurs for women <30 years of age. PMID- 24629227 TI - The stealthy nano-machine behind mast cell granule size distribution. AB - The classical model of mast cell secretory granule formation suggests that newly synthesized secretory mediators, transported from the rough endoplasmic reticulum to the Golgi complex, undergo post-transitional modification and are packaged for secretion by condensation within membrane-bound granules of unit size. These unit granules may fuse with other granules to form larger granules that reside in the cytoplasm until secreted. A novel stochastic model for mast cell granule growth and elimination (G&E) as well as inventory management is presented. Resorting to a statistical mechanics approach in which SNAP (Soluble NSF Attachment Protein) REceptor (SNARE) components are viewed as interacting particles, the G&E model provides a simple 'nano-machine' of SNARE self-aggregation that can perform granule growth and secretion. Granule stock is maintained as a buffer to meet uncertainty in demand by the extracellular environment and to serve as source of supply during the lead time to produce granules of adaptive content. Experimental work, mathematical calculations, statistical modeling and a rationale for the emergence of nearly last-in, first out inventory management, are discussed. PMID- 24629228 TI - Autophagy, a new determinant of plasma cell differentiation and antibody responses. AB - Plasma cells, the terminal effectors of the B lymphoid lineage, are responsible for the humoral arm of adaptive immunity. Their differentiation from B cells entails a profound cellular reshaping inherently associated with stress. Autophagy is a conserved adaptive cellular strategy recently implicated in differentiation and immunity. We identified a novel autophagic function in plasma cells. Autophagy restricts the expression of the transcriptional repressor Blimp 1 and immunoglobulins through a selective negative control on the endoplasmic reticulum and its stress signaling response, thereby optimizing energy and viability. As a result, autophagy in vivo sustains antibody responses, and is an essential intrinsic determinant of the bone marrow long-lived plasma cell niche. Here, I discuss several immune and biomedical implications, and experimental issues to be addressed in the near future. PMID- 24629229 TI - [The "dizzying" dizziness]. PMID- 24629230 TI - [Subjective dizziness]. AB - Subjective dizziness is defined as non-vertigo dizziness that persists after exclusion of medical causes. It is seen frequently in patients with anxiety and other stress-related disorders, but also in functional somatic syndromes. Mild and moderate cases do not need specific treatment, but underlying factors may need attention, e.g. anxiety or stress. Treatment of chronic cases should be focused on perpetuating factors such as catastrophising and avoidance behaviour. Cognitive therapy, with or without vestibular rehabilitation, is effective, while evidence for antidepressants is limited. PMID- 24629231 TI - [Dizziness related to ophthalmological pathology]. AB - Dizziness stands for vertigo (rotatory and nautic) and dysbalance/unstability. Vertigo originates from the vestibular central nervous system; no eye disease, but nystagmus is often present. Dysbalance/unstability: normal ophthalmological findings exclude ophthalmological pathogenesis. Ophthalmological pathology, especially recently developed may be involved. Uncorrected glasses, eye drops (by systemic absorption), flickering light, and migraine may also cause dysbalance/unstability. Rapid referral to specialist is recommended by fast development of: decreased visual acuity, visual field defects, strabismus, eye movement pathology and nystagmus. PMID- 24629232 TI - [Malfunction of the inner ear is the most frequent cause of dizziness]. AB - Half of all dizziness patients suffer from a malfunction of the inner ear and benign paroxysmal positional vertigo causes 25-30% of these malfunctions. During the latest two decades new vestibular test equipment has been developed and has made it possible to refine the vestibular diagnoses and consequently treat patients more efficiently. This brief overview describes the benefit of Epley's Omniax Chair, video head impulse tests and the Vestibular Autorotation Test. The need for vestibular rehabilitation programmes and for a closer collaboration between physicians and the social authorities is pointed out. PMID- 24629233 TI - [Acute vertigo of neurological origin]. AB - Acute vertigo of neurological origin may be caused by haemorrhages and tumours in the posterior fossa and, most frequently, by ischaemic infarction in the vertebrobasilar circulation. Urgent diagnosis is necessary to avoid further ischaemic episodes, herniation due to cerebellar oedema and/or fatal brainstem infarction. The history should focus on accompanying neurological symptoms. However, vertigo with cerebellar lesions may be monosymptomatic and then bedside evaluation of oculomotor function is the key to correct diagnosis. This paper discusses the pathophysiology, symptomatology and clinical evaluation of acute vertigo of neurological origin. PMID- 24629234 TI - [Dizziness in patients with heart disease]. AB - In patients with heart disease, dizziness is primarily associated with syncope or pre-syncope and mandates further investigation to obtain a specific diagnosis, estimation of risk of sudden death and treatment options. After a focused history and physical examination, the cause of the problem may be determined in more than half of the patients. The reflex syncope is by far the most common form and may usually be handled by reassurance of the benign nature of the problem. Patients with syncope caused by brachy- or tachy-arrhythmia or structural or ischaemic heart disease should be referred to a cardiological department for specific diagnosis and treatment. PMID- 24629235 TI - [Dizziness in geriatric patients]. AB - Dizziness is a common complaint in geriatric patients. Age-related changes in organs of balance control make the elderly more susceptible to diseases affecting the same system causing symptoms as dizziness, balance disturbance, fall and syncope. Work-up should be multifactorial and is feasible in geriatric outpatient clinics. Evidence-based interventions are available. New studies have found high frequency of vestibular dysfunction among old fall patients and suggest an association between vestibular dysfunction and orthostatic hypotension. Further research in this area is needed. PMID- 24629236 TI - [Dizziness as a side effect of pharmacological therapy]. AB - Dizziness is a well-known side effect of a wide range of drugs. However, the side effects reported in the summary of product characteristics are not exclusively based on placebo-controlled trials. Based on a systematic review of the literature including randomised placebo-controlled clinical trials, antihypertensive combination drugs, methylphenidate, high doses of tramadol and serotonin-norepinephrine reuptake inhibitors were associated with an increased risk of dizziness. Antihypertensive monotherapy and selective serotonin reuptake inhibitors were generally not associated with an increased risk of dizziness when compared with placebo. PMID- 24629237 TI - [Vertigo and ear discomfort caused by a bone defect in os temporalis]. AB - Superior semicircular canal dehiscence is a clinical condition where the bone tissue overlying the superior semicircular canal is absent. The symptoms can be nonspecific and include vertigo, oscillopsia and conductive hearing loss. An audiogram will reveal an air-bone-gap in the lower frequencies in an otherwise healthy ear. Diagnosis is confirmed by performing muscular evoked myogenic potentials examination and temporal bone computed tomography. A case of right side superior semicircular canal dehiscence in a 52-year-old woman and the diagnostic course is described. PMID- 24629238 TI - [Delayed diagnosis of a transverse fracture]. PMID- 24629240 TI - The stories we hear and the stories we tell. PMID- 24629239 TI - Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer. AB - BACKGROUND: HIF-1alpha and CXCR4/CXCL12 have crucial roles in the metastatic process of colorectal cancer. Our aim was to study the significance of targeting HIF-1alpha and the CXCR4/CXCL12 axis in colorectal cancer to prevent the dissemination process in vitro. METHODS: We investigated CXCR4 and CXCR7 mRNA and protein expression in human colon carcinomas and the modulation of their expression by hypoxia and HIF-1alpha in colon cancer cell lines. The migration of tumor cells in a Boyden chamber was studied after CXCR4 inhibition with siRNA or the CXCR4/CXCL12 neutraligand, chalcone 4. RESULTS: Analysis of a cohort of colon polyps and chromosome-unstable carcinomas showed that the expression of CXCR4 and CXCR7 was similar to that of the normal mucosa in the polyps and early-stage carcinomas but significantly increased in late stage carcinomas. Our data demonstrate that hypoxia strongly induced the expression of CXCR4 transcript and protein at the cell membrane, both regulated by HIF-1alpha, whereas CXCR7 expression was independent of hypoxia. After transient hypoxia, CXCR4 levels remained stable at the cell membrane up to 48 hours. Furthermore, reducing CXCR4 expression impaired CXCL12-induced Akt phosphorylation, whereas Erk activation remained unchanged. In contrast, reducing CXCR7 expression did not affect Akt nor Erk activation. In the presence of CXCR4 or CXCR7 siRNAs, a significant reduction in cell migration occurred (37% and 17%, respectively). Although irinotecan inhibited cell migration by 20% (p <0.001), the irinotecan and chalcone 4 combination further increased inhibition to 40% (p <0.001). CONCLUSION: We demonstrated, for the first time, that hypoxia upregulated CXCR4 but not CXCR7 expression in tumor cells and that the CXCR4 receptor protein level remains high at the cell membrane when the tumor cells return to normoxia for up to 48 hours. In addition we showed the interest to inhibit the CXCR4 signaling by inhibiting both the HIF-1alpha and CXCR4/CXCL12 pathway. CXCR4 seems to be a relevant target because it is continuously expressed and functional both in normoxic and hypoxic conditions in tumor cells. PMID- 24629241 TI - Using patients' experiences in e-learning design. AB - BACKGROUND: Design of the undergraduate and postgraduate medical curriculum is traditionally the task of medical professionals and educationalists, with regulating bodies approving curriculum content. Although this should ensure a thorough approach to a medical model of the curriculum, it may overlook the importance of the patient's perspective in medical education. The General Medical Council recently issued advice about patient and public involvement in all areas of medical education, including curricular design, but it is not immediately clear how this should be incorporated. METHODS: This article describes and analyses an innovative approach to curriculum design, in which patients' experiences are placed at the centre of learning. Important themes identified from qualitative research with patients (and their carers) with autistic spectrum conditions were compared with a pre-established curriculum for an e-learning module by the Royal College of General Practitioners. RESULTS: Significant divergence was identified between the doctor-designed curriculum and the themes identified through patients' experiences. The divergence was analysed and patients' experiences were used to expand the proposed course. DISCUSSION: This research concerned e-learning about autistic spectrum conditions, but may have implications for other areas and modalities of medical education. Further research is needed to determine whether the inclusion in the curriculum of previously ignored themes, which are nevertheless important to patients, has an impact on the quality of the doctor-patient interaction and relationship. PMID- 24629242 TI - Discovering emotional honesty through devised theatre. AB - BACKGROUND: Despite many calls for a focus on supporting the development of doctors as individuals, many curricula are still characterised by an emphasis on the transmission of predefined knowledge, skills and values. Special study modules (SSMs) were introduced to ensure some element of student selection based on personal interests. We present our experience of an SSM designed to introduce students to drama, as a way of exploring the profession of medicine and their own development as doctors. CONTEXT: We created a 3-week, full-time SSM, based on a devised theatre model for fourth-year medical students in an Irish medical school. This article describes the processes and outcomes of our devised theatre SSM. INNOVATION: A devised piece is not a conventional theatre play, but a theatrical event created from the contributions of all participants, based around a central theme. We found that a devised theatre approach helped students to explore personal perspectives on the profession of medicine, healing and their development as doctors. It then allowed them to perform their insights before an audience of their peers. IMPLICATIONS: By participating, the students developed an emotional honesty with them-selves and with each other. They thought and wrote about their chosen profession. They also learned about physical and interpersonal discipline, ethical issues, teamwork and acquired some lifelong skills. Our experience as evidenced by the students' reflective diaries suggests that devised theatre offers potential as a means of encouraging the personal and professional development of medical students. PMID- 24629243 TI - The efficient use of movies in a crowded curriculum. AB - BACKGROUND: The undergraduate medical curriculum has earned a reputation for being overcrowded. The dilemma for educationalists is to determine what, if anything, can be jettisoned from a congested curriculum to accommodate new ideas or material. CONTEXT: We report on a small study that demonstrated that when movies are used innovatively, they enhance students' understanding of medicine and also have a minimal impact on the 'crowded' curriculum. INNOVATION: During a 5-week-long Public Health module students could borrow from the medical school library, free of charge, one or more movies, each with a public health message. In the final week of the module a 1.5-hour-long class was allocated when each student offered a brief synopsis of a movie that they had watched, and then identified key public health issues discussed in the movie. IMPLICATIONS: Our study supports the view that the creative use of classroom time not only allows for better use of the timetable, but also proves to be an integrative, stimulating, and fun way for medical students to learn. PMID- 24629244 TI - Bridging the gap: from simulation to clinical practice. AB - BACKGROUND: There has been a shift from the initial learning of skills on patients in the clinical setting to initial learning in a simulated environment, using part-task models, with the risk of a task focus to the learning. We contend that quality learning in both the simulated and the clinical environment is crucial to enhance the transferability of skills to the clinical setting. CONTEXT: We describe teaching strategies, with the sequencing of events and increasing complexity, for the simulated training of basic procedural skills. These teaching strategies can be readily implemented into basic skills training to 'bridge' the gap between the simulated environment and the clinical setting. IMPLICATIONS: We suggest that our approach takes basic skills training beyond a task-focused approach to exemplify clinical scenarios encountered in real life. We argue that there is a need to broaden the focus of medical student training in basic procedural skills, and that the use of a preceptor model of supervision in the clinical setting better enables the transferability of the skills. Although our strategies are based on learning theory, well-designed research is required to test the efficacy in improving medical student learning. PMID- 24629245 TI - Ophthalmoscopy using an eye simulator model. AB - BACKGROUND: Ophthalmoscopy is an important skill for the medical student to master. Students have difficulty visualising the retina, and are hesitant to practise with patients. Our study aim was to demonstrate that an eye simulation experience would be beneficial for developing ophthalmoscopy skills. DESIGN: This study was designed for second-year medical students who elected to participate. Students were observed and instructed on the correct use of the ophthalmoscope. Both normal and pathological retinas were used. The students matched what they observed with printed photographs to verify what they had actually seen. A pre- and post-session questionnaire, with comments, was completed. The study was conducted over 4 years. Three of the years were structured as outlined above. One year, the students used the simulator but without an instructor being present. Students were surveyed as senior medical students and asked to rate the value of the simulator experience for preparing them for their clinical years. RESULTS: A total of 64 per cent of the students elected to participate when a faculty member was present to instruct them, whereas only 12 per cent of the class elected for the experience without instruction. The self-rating results from the pre- versus post-session questionnaire showed statistically significant improvement for all items. Student comments reflected that they felt strongly that the experience was valuable to them. CONCLUSIONS: This simulation ophthalmoscopy experience was valuable for increasing confidence and skill. This experience is most valued when an instructor is present. The simulator experience was valuable to students as they applied their ophthalmoscopy skills clinically. PMID- 24629246 TI - Medical students' perceptions of role models on clinical placements. AB - BACKGROUND: Clinical placements have been reported as being challenging, demanding and rewarding for health professional students. For medical students, clinical placements are often their first interaction with other health professionals, who are often graduates. This study was designed to explore medical students' experiences of a clinical placement, in which their perceptions about role models from the same or other disciplines emerged. METHODS: A total of three focus groups (n = 15) were conducted with medical students following the completion of their clinical placement rotation in palliative and rehabilitative settings. FINDINGS: Role models and influential figures were key themes to emerge from the focus group data, reflecting an underlying tension between the practitioners that the students wanted to learn from and the practitioners who were actually willing, and available, to teach and model certain clinical skills. DISCUSSION: The extent to which doctors, nurses and allied health professionals were seen as role models became a central focus in exploring how the professional identity of students is influenced on clinical placement. PMID- 24629247 TI - Reviving post-take surgical ward round teaching. AB - BACKGROUND: Learning in the clinical environment is an important feature of medical education. Ward-round teaching leads to relevant, applied and lasting learning of knowledge, skills and attitudes; however, on fast-paced ward rounds in specialties such as general surgery, the student experience is often suboptimal, and teaching can be overlooked. Clinical teaching fellows (CTFs) are postgraduate doctors ranging from foundation year-2 (FY2) level through to specialty trainees, who have elected to spend up to 2 years out of the programme to teach medical undergraduates. This article explores whether CTFs can successfully support the regular delivery of undergraduate medical teaching on the busy post-take surgical ward round (PTSWR). METHODS: The CTFs at Raigmore Hospital, Inverness, planned and facilitated weekly, structured teaching sessions to accompany the PTSWR. This educational intervention was evaluated using pre- and post-intervention student questionnaires. The questionnaires focused on student enjoyment and depth of learning using Likert scales and free-text components. Students were also asked about barriers to learning on typical PTSWRs. The consultant surgeons leading on these rounds were issued separate questionnaires, to gauge their evaluation of CTF support. RESULTS: The main barrier to effective undergraduate ward round teaching was a lack of time on the part of clinical staff. Ward rounds accompanied by CTF support significantly increased student enjoyment (p < 0.0001) and perceived learning (p < 0.0001). Consultant surgeons were supportive of the teaching initiative. DISCUSSION: Support from CTFs on busy PTSWRs optimised student satisfaction, and was welcomed by clinical staff. CTF support could be widened to other busy ward rounds, e.g. acute medical takes, to enhance student learning and reduce the teaching burden on clinical faculty staff. PMID- 24629248 TI - Role of clinical tutors in volunteering work camps. AB - BACKGROUND: The Universita Campus Bio-Medico (Italy) promotes a summer volunteering work camp (Workcamp Peru) as a social activity for medical and non medical students. Some junior doctors participate as 'clinical tutors', together with tutors from other professions; all clinical tutors have some teaching experience in our teaching hospital. CONTEXT: The campsite is located in the South of Peru in the Canete Valley, an area characterised by extreme poverty and a severe lack of infrastructure. During the five Workcamp Peru trips that have been organised so far, health science students have carried out many activities for disease prevention and health education, and bio-medical engineering students have organised sessions on the safety of electrical installations, for accident prevention. INNOVATION AND IMPLICATIONS: We observed that in this setting tutorial activity is fundamental, because it not only offers students an opportunity to learn but also encourages them to react in a more personal and reflective manner to various stressful situations, which often occur in the work camp. The professional competence of the tutor plays an important role before the work camp, in defining the learning objectives for the students and involving them in training sessions held prior to the work camp. Also, during the camp, tutors work with students and also direct the daily briefing and debriefing sessions that are the most important learning activity. For medical tutors involved in the work camp the volunteering experience is a challenge for developing their specific professional and teaching skills, but it also provides an enriching experience in both professional and personal terms. We consider these work camps to be a useful experience in the training of our clinical tutors. PMID- 24629249 TI - The 'gut bucket': a novel training tool for standardised patients. AB - BACKGROUND: Standardised patients (SPs) are often asked to portray complex physical roles in which authenticity is paramount; however, SPs come from a variety of backgrounds, and may lack knowledge of basic anatomy and physiology that can hamper their portrayal. This lack of knowledge can lead to gaps in accuracy and credibility. CONTEXT: In our efforts to bridge the gap and create training that would lead to authentic and confident portrayals, we developed the 'gut bucket'. This three-dimensional learning tool is tactile, portable, simple and affordable. INNOVATION: The 'gut bucket' has life-size abdominal organs made from fabric resting in a standard plastic washbasin. The organs can be easily removed and manipulated to simulate different disease states (for example: appendicitis, kidney stones or cholecystitis). The tool is visually engaging and durable, encouraging SPs to handle the organs and become familiar with their size and placement within the basin and on themselves. IMPLICATIONS: The SPs in our programme found that the 'gut bucket' provided a deeper level of knowledge, made them more confident in their portrayal and enhanced their experience, and they generally preferred the 'gut bucket' over traditional methods of training. This was demonstrated using 'gut bucket' training evaluation forms. The 'gut bucket' can easily be incorporated into training sessions to provide a kinaesthetic approach as well as increased engagement for the SPs. We hope others may benefit by sharing our experience with the 'gut bucket'. PMID- 24629250 TI - What motivates general practitioners to teach. AB - INTRODUCTION AND AIM: The Australian general practitioner (GP) teaching workforce will need to expand in order to provide for the increasing number of medical students and doctors-in-training. Understanding factors that motivate GPs to become involved in teaching in their clinical practice environments is important for developing recruitment and retention strategies. METHOD: Thirty-one semi structured interviews were conducted with a cross section of GP teachers and were subjected to thematic analysis. Themes were identified and further classified as motivations and prerequisites for teaching. RESULTS: The desire to update clinical knowledge was the most frequently mentioned motivation for teaching, and was described as a strategy for GP teachers to preserve clinical competence through the opportunity to learn new aspects of medicine from junior colleagues. Other motivations included personal fulfillment and enjoyment of teaching, the opportunity to pass on general practice skills and knowledge, promoting general practice as a career, and fulfilling a sense of responsibility to the profession and community. Peers, students and patients also influenced the decision to teach. Most GPs identified that time, workload, availability of space and adequate financial remuneration were prerequisites for teaching. Practice owners also often determined the GP teachers' capacity to teach. DISCUSSION: To increase the recruitment and retention of GP teachers, it is recommended that teaching organisations give more recognition to teaching as a clinical professional development activity, place more emphasis on GPs' personal enjoyment, professional responsibility and pride in teaching, and increase engagement with practice owners. PMID- 24629251 TI - Theatre etiquette course: students' experiences. AB - BACKGROUND: Prior to 2008 medical students at the University of Dundee had no formal teaching in scrubbing, gloving and gowning for theatre. The students had reported high levels of stress, and a lack of knowledge and confidence, when asked to scrub, glove and gown for theatre. We present a cohort study of the effect on students' experiences in theatre following the implementation of a new theatre etiquette course to the undergraduate curriculum. DESIGN: We implemented a new theatre etiquette course for medical students, in which they learned scrubbing, gowning and gloving for theatre. We then identified two cohorts of students: the year group who attended the new course and the year above who did not. At the end of year 4, both cohorts completed a questionnaire about their confidence and experiences in theatre. The results from the year below were compared with the year above, who had no such formal teaching. RESULTS: Questionnaire responses from over 70 per cent of each cohort demonstrated that students attending the new formal course felt significantly more confident in theatre etiquette skills and had an improved experience in the operating theatre, compared with the previous year group. CONCLUSION: The implementation of a theatre etiquette course improved students' preparation and experience in theatre. It also outlines the need for consistent teaching at an undergraduate level. This formal teaching method is recommended for any curriculum in which students attend theatre. PMID- 24629252 TI - Clinical teaching fellows: everyone's a winner. AB - BACKGROUND: The principle teachers of the undergraduate medical curriculum are junior doctors and consultants, who may not necessarily be trained to teach. In addition, pressurised clinical environments may limit teaching time and decrease teaching quality. Clinical teaching fellows (CTFs) are doctors employed to teach, often undergoing a teaching qualification. This makes them well placed to bridge this gap between clinical practice and medical education. QUESTION: How useful are CTFs as a teaching resource for medical students, from a student perspective? METHODS: This is an evaluation of CTF teaching from student perspectives, with discussion relating to the role of CTFs. Questionnaires were given to 70 final year medical students during the academic year 2011-2012. Questions related to teaching throughout medical school and involved scoring teaching numerically, with additional free-text sections for qualitative data. RESULTS: A total of 38/70 (54%) students responded. All had received CTF teaching. All of the students said that CTFs were 'extremely useful' for teaching. There were many reasons given for this. Students also highlighted the managerial and pastoral benefits of CTFs. DISCUSSION: We believe that CTFs could be a useful asset in all medical schools by delivering high-quality, reliable, standardised teaching for students, as an adjunct to consultant teaching, with additional managerial roles and trainee benefits. CTFs can benefit non-CTF trainees by facilitating and encouraging them to teach. CTFs can organise sessions and advise on curriculum topics, allowing trainees to deliver more targeted teaching. Teaching students may improve trainees' communication, management and leadership skills, which are useful for clinical practice. PMID- 24629253 TI - A novel use of Twitter to provide feedback and evaluations. AB - BACKGROUND: Inconsistencies in work schedules and faculty supervision are barriers to monthly emergency medicine (EM) resident doctor evaluations. Direct and contemporaneous feedback may be effective in providing specific details that determine a resident's evaluation. OBJECTIVES: To determine whether Twitter, an easy to use application that is available on the Internet via smartphones and desktops, can provide direct and contemporaneous feedback that is easily accessible, and easy to store and refer back to. METHODS: First- to third-year EM residents were administered a survey to assess their thoughts on the current monthly evaluation system. Subsequently, residents obtained a Twitter account and were instructed to follow a single general faculty Twitter account for ease of data collection. Following completion of an 8-week study period, a second survey was administered to assess resident thoughts on contemporaneous feedback and evaluations versus the traditional form. RESULTS: Of the 24 EM residents, 13 were available for study. A total of 220 'tweets' were provided by seven faculty members, with a mean of 11 tweets (range 8-17) per resident. The 13 residents received a total of eight formal evaluations from 19 faculty members. The second survey demonstrated that this method provided more detailed evaluations and increased the volume of feedback. CONCLUSION: Contemporaneous feedback and evaluation provides a greater volume of feedback that is more detailed than end of-course evaluations. Twitter is an effective and easy means to provide this feedback. Limitations included the length of study time and the inability to have all of the EM residents involved in the study. PMID- 24629254 TI - Progression from an anatomy demonstrator to a surgical trainee. PMID- 24629255 TI - Do we teach medical students acute care skills? PMID- 24629256 TI - Psychoeducation: a new opportunity for postgraduate training. PMID- 24629261 TI - Proteomic analysis of enzyme production by Bacillus licheniformis using different feather wastes as the sole fermentation media. AB - This study evaluates the use of different types of feathers as fermentation media for enzyme production. Bacillus licheniformis was grown on the feathers, which lead to total biodegradation due to bacterial enzymatic hydrolytic excretion. B. licheniformis excretes protease and lipase activity, with feather concentration being the main parameter controlling their generation. Using a proteomic approach, the proteins excreted during fermentation were identified, and the influence of the chemical composition of the feathers on protein secretion was tested. The identified proteins are hydrolytic enzymes such as keratinase, gamma glutamyltranspeptidase, chitosanases, and glicosidases. The diversity of proteins is related to the chemical complexity of the feathers. Understanding the composition of a hydrolytic system, when B. licheniformis is cultured on different feathers, may assist in utilizing such a system for producing different hydrolytic enzymes. The data indicate that proteomics can be a valuable tool for describing the physiological state of B. licheniformis cell populations growing on different wastes. PMID- 24629262 TI - A novel horseradish peroxidase biosensor towards the detection of dopamine: a voltammetric study. AB - A polymerized film of glycine (Gly) was prepared on the surface of carbon paste electrode (CPE) through the cyclic voltammetry (CV) technique. A novel biosensor for the determination of dopamine (DA) has been constructed based on horseradish peroxidase (HRP) and multiwalled carbon nanotubes (MWCNTs) immobilizing on Poly (Gly)/CPE through silica sol-gel (SiSG) entrapment. CV measurements were employed in order to understand the feasibility of poly (Gly) as an electron carrier between the immobilized peroxidase and the surface of CPE. By using differential pulse voltammetry (DPV) the calibration curves of DA was obtained in the range of 15-865 MUM. The limit of detection (LOD) and limit of quantification (LOQ) of DA was found to be 6*10-7 M and 2*10-6 M respectively. The apparent Michaelis-Menten constant (Km(app)) was found to be 0.5 mM and illustrated that the good biological activity of the fixed enzyme. Electrochemical impedance spectroscopy (EIS) results confirmed the rapid electron transfer and also the immobilization of enzyme on the electrode surface. The biosensor showed high sensitivity, selectivity and reproducibility. This method has been used to determine DA in the presence of various interferences and in clinical preparations. PMID- 24629263 TI - Application of lipase immobilized on the biocompatible ternary blend polymer matrix for synthesis of citronellyl acetate in non-aqueous media: kinetic modelling study. AB - This work reports the use of new support for immobilization of lipase Burkholderia cepacia (BCL) matrix made up of polylactic acid (PLA), chitosan (CH), and polyvinyl alcohol (PVA). Initially lipase from various microbial sources and immobilization support composition was screened to obtain a robust biocatalyst. Among various biocatalysts preparation, the PLA:PVA:CH:BCL (1:6:1:2) was worked as a robust biocatalyst for the citronellyl acetate synthesis. Various reaction parameters were studied in detail to obtain the suitable reaction conditions for model citronellyl acetate synthesis reaction. Various kinetic parameters such as r(max), K(i(citronellol)), K(m(citronellol)), K(m(vinyl acetate)) were determined using non-linear regression analysis for the ternary complex as well as bi-bi ping-pong mechanism. The experimental results and kinetic study showed that citronellyl acetate synthesis catalyzed by immobilized lipase BCL followed the ternary complex mechanism with inhibition by alcohol (citronellol). The energy of activation for citronellyl acetate synthesis was found to be lower for immobilized lipase (8.9 kcal/mol) than aggregated lipase (14.8 kcal/mol) enzyme. The developed biocatalyst showed four to fivefold higher catalytic activity and excellent recyclability (up to six cycles) than the aggregated lipase. PMID- 24629264 TI - Identification and characterization of an unusual glycosyltransferase-like enzyme with beta-galactosidase activity from a soil metagenomic library. AB - Glycosyltransferases and glycoside hydrolases are two diversified groups of carbohydrate-active enzymes (CAZymes) in existence, they serve to build and break down the glycosidic bonds, respectively, and both categories have formed many sequence-based families. In this study, a novel gene (glyt110) conferring beta galactosidase activity was obtained from a metagenomic library of Turpan Basin soil. Sequence analysis revealed that glyt110 encoded a protein of 369 amino acids that, rather than belonging to a family typically known for beta galactosidase activity, belonged to glycosyltransferase family 4. Because of this unusual sequence information, the novel gene glyt110 was subsequently expressed in Escherichia coli BL21(DE3), and the recombinant enzyme (Glyt110) was purified and characterized. Biochemical characterization revealed that the beta galactosidase activity of Glyt110 toward o-nitrophenyl-beta-D-galactopyranoside (ONPG) and lactose were identified to be 314+/-18.3 and 32+/-2.7 U/mg, correspondingly. In addition, Glyt110 can synthesize galacto-oligosaccharides (GOS) using lactose as substrate. A GOS yield of 47.2% (w/w) was achieved from 30% lactose solution at 50 degrees S, pH 8.0 after 10 h reaction. However, Glyt110 was unable to glycosylate either N-acetylated saccharides or lactose and galactose using UDP-gal as sugar donor, and its glycosyltransferase activity needs further investigation. These results indicated that Glyt110 is an unusual enzyme with beta-galactosidase activity but phylogenetically related to glycosyltransferase. Our findings may provide opportunities to improve the insight into the relationship between glycosyltransferases and glycoside hydrolases and the sequence-based classification. PMID- 24629265 TI - Rapid enzymatic assays for L-citrulline and L-arginine based on the platform of pyrophosphate detection. AB - Rapid determination of L-citrulline and L-arginine, physiologically important amino acids, is a beneficial technique from the scientific and medical viewpoints. In this study, enzymatic assays for L-citrulline and L-arginine were established and evaluated. L-Citrulline assay was constructed by coupling argininosuccinate synthetase to a pyrophosphate detection system, in which pyruvate phosphate dikinase was employed, so that the citrulline-dependent production of pyrophosphate could be determined. Furthermore, the L-arginine assay was developed by coupling arginine deiminase to the L-citrulline assay. Both assays exhibited high selectivity to L-citrulline and L-arginine without any significant reactivity to other proteinaceous amino acids. These assays were also resistant to various contaminants that interfered with the conventional L citrulline and L-arginine assays. The high accuracy of these assays was demonstrated by measurements in the presence of human plasma. Because these assays can be conducted under the neutral pH without terminating the reaction progress, they allow not only measurements in static analyte solutions, but also real-time monitoring of L-citrulline and L-arginine synthesis in the reaction mixture. The features of these assays also demonstrated that the pyrophosphate detection system served as a useful platform to develop selective and robust enzymatic assays by being coupled to a pyrophosphate-producing enzyme. PMID- 24629266 TI - Efficient glycosylation of puerarin by an organic solvent-tolerant strain of Lysinibacillus fusiformis. AB - A bacterial strain able to glycosylate the plant natural product puerarin was isolated from local soil in Nanjing, China. It was identified as Lysinibacillus fusiformis, and deposited in China General Microbiological Culture Collection (CGMCC) under accession number 4913. Incubation of this strain with puerarin led to efficient production (91.6% conversation rate) of puerarin-7-O-fructoside, a derivative that possesses improved water solubility and antioxidant activity. A minor product puerarin-7-O-isomaltoside was also produced in small amounts, with a conversion rate of less than 1% after 48-h reaction. Both products were characterized based on the spectral data. Among the four tested sugars, sucrose (92.6% conversion rate of puerarin) is the best glycosyl donor for L. fusiformis CGMCC 4913, followed by maltose (39.8% conversion rate of puerarin), while glucose and fructose are not appropriate donors for this biotransformation process. L. fusiformis CGMCC 4913 can survive in the presence of 10% (v/v) organic solvents such as methanol, ethanol, toluene, cyclohexane, and dimethyl sulfoxide. The biotransformation efficiency of puerarin was increased 2-fold in the presence of 10% ethanol at 12 h compared to the transformation solution without ethanol. The optimum pH and substrate concentration are 8.0 and 4 g/L, respectively. Under the optimal conditions, the final conversion rate of puerarin reached 97.6+/-2.3% at 48 h in the presence of 10% ethanol. Therefore, L. fusiformis CGMCC 4913 represents a new and efficient biocatalyst for the biotransformation of puerarin. PMID- 24629267 TI - Characterization of a heat-active archaeal beta-glucosidase from a hydrothermal spring metagenome. AB - Thermostable enzymes are required for application in a wide range of harsh industrial processes. High stability and activity at elevated temperatures, as well as high tolerances toward various reagents and solvents, are needed. In this work, a glycoside hydrolase family 1 beta-glucosidase (Bgl1) of archaeal origin was isolated from a hydrothermal spring metagenome. The enzyme showed a broad substrate spectrum with activity toward cellobiose, cellotriose and lactose. Compared to most enzymes, extremely high specific activity with 3195U/mg was observed at 90 degrees C and pH 6.5. Bgl1 was completely stable at pH 4.5-9.5 for 48 h at 4 degrees C. More than 40% of activity was measured at 105 degrees C. A thermal activation was observed at 90 degrees C after 30 min. Enzyme stability was enhanced (5- and 7-fold) after applying pressure of 100 and 200 bar at 90 degrees C for 2h, respectively. The affinity of the beta-glucosidase to its substrate was significantly increased in the presence of AlCl3. The K(i) value for glucose was 150 mM. These distinctive characteristics distinguish Bgl1 from other enzymes described so far and make this enzyme suitable for application in numerous processes that run at high temperatures. PMID- 24629268 TI - Biosensing methods for xanthine determination: a review. AB - Xanthine (3,7-dihydro-purine-2,6-dione) is generated from guanine by guanine deaminase and hypoxanthine by xanthine oxidase (XOD). The determination of xanthine in meat indicates its freshness, while its level in serum/urine provides valuable information about diagnosis and medical management of certain metabolic disorders such as xanthinuria, hyperurecemia, gout and renal failure. Although chromatographic methods such a HPLC, capillary electrophoresis and mass spectrometry are available for quantification of xanthine in biological materials, these suffer from certain limitations such as complexity, time consuming sample preparation and requirement of expensive apparatus and trained persons to operate. Immobilized XOD based biosensors have emerged as simple, rapid, sensitive and economic tools for determination of xanthine in food industries and clinical diagnosis. This review article describes the various immobilization methods of XOD and different matrices used for construction of xanthine biosensors, their classification, analytical performance and applications along with their merits and demerits. The future perspectives for improvement of present xanthine biosensors are also discussed. PMID- 24629269 TI - Heterologous expression and kinetic characterisation of Neurospora crassa beta xylosidase in Pichia pastoris. AB - To degrade plant hemicelluloses fungi employ beta-xylosidases to hydrolyse xylooligosaccharides, released by endo-xylanases, into xylose. We have expressed the beta-xylosidase from Neurospora crassa in Pichia pastoris under the control of alcohol oxidase 1 (AOX1) promoter. The recombinant enzyme is optimally active at 50 degrees C and pH 5.0 with Km and Vmax values of 8.9 mM and 1052 MUmol min 1 mg-1 respectively against 4-nitrophenyl beta-xylopyranoside. Xylose is a non competitive inhibitor with a K(i) of 1.72 mM. The enzyme is characterised to be an exo-cutting enzyme releasing xylose from the non-reducing ends of beta-1,4 linked xylooligosaccharides (X2, X3 and X4) but also capable of transxylosilation. Catalytic conversion of X2, X3 and X4 decreases (V(max) and k(cat)) with increasing chain length. PMID- 24629270 TI - Construction of glutamate biosensor based on covalent immobilization of glutamate oxidase on polypyrrole nanoparticles/polyaniline modified gold electrode. AB - A method is described for construction of a highly sensitive electrochemical biosensor for detection of glutamate. The biosensor is based on covalent immobilization of glutamate oxidase (GluOx) onto polypyrrole nanoparticles and polyaniline composite film (PPyNPs/PANI) electrodeposited onto Au electrode. The enzyme electrode was characterized by cyclic voltammetry (CV), scanning electron microscopy (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infra-red spectroscopy (FTIR) and electrochemical impedance spectroscopy (EIS). The biosensor showed optimum response within 3s at pH 7.5 (0.1 M sodium phosphate) and 35 degrees C, when operated at 50 mV s-1. It exhibited excellent sensitivity (detection limit as 0.1 nM), fast response time and wider linear range (from 0.02 to 400 MUM). Analytical recovery of added glutamate (5 mM and 10 mM) was 95.56 and 97%, while within batch and between batch coefficients of variation were 3.2% and 3.35% respectively. The enzyme electrode was used 100 times over a period of 60 days, when stored at 4 degrees C. The biosensor measured glutamate level in food stuff, which correlated well with a standard colorimetric method (r=0.99). PMID- 24629271 TI - Attitudes toward simulation-based learning in nursing students: an application of Q methodology. AB - SBL is a highly advanced educational method that promotes technical/non-technical skills, increases team competency, and increases health care team interaction in a safe health care environment with no potential for harm to the patient. Even though students may experience the same simulation, their reactions are not necessarily uniform. This study aims at identifying the diversely perceived attitudes of undergraduate nursing students toward simulation-based learning. This study design was utilized using a Q methodology, which analyzes the subjectivity of each type of attitude. Data were collected from 22 undergraduate nursing students who had an experience of simulation-based learning before going to the clinical setting. The 45 selected Q-statements from each of 22 participants were classified into the shape of a normal distribution using a 9 point scale. The collected data was analyzed using the pc-QUANL program. The results revealed two discrete groups of students toward simulation-based learning: 'adventurous immersion' and 'constructive criticism'. The findings revealed that teaching and learning strategies based on the two factors of attitudes could beneficially contribute to the customization of simulation-based learning. In nursing education and clinical practice, teaching and learning strategies based on types I and II can be used to refine an alternative learning approach that supports and complements clinical practice. Recommendations have been provided based on the findings. PMID- 24629272 TI - A critical consideration of systemic moral catastrophe in modern health care systems: a big idea from an Arendtian perspective. PMID- 24629274 TI - Game changer: steam--a catalyst of modernity. PMID- 24629273 TI - Safety and efficacy of addition of VEGFR and EGFR-family oral small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: The approach of combining cytotoxic chemotherapy with oral small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a variety of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach. PATIENTS AND METHODS: PubMed and the ASCO databases were searched up to March 2013. We included randomized trials in which the FDA approved vascular endothelial growth factor receptor (VEGFR) or epidermal growth factor receptor family (EGFR)-targeted TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR) were calculated. RESULTS: A total of 16,011 patients from 43 trials were included. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32-2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58-2.06), and any severe AE (RR, 1.25; 95% CI, 1.16-1.36). The addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76-0.89), but not OS (HR, 0.99; 95% CI, 0.95-1.03). CONCLUSIONS: It is important for physicians to weigh the risk of toxicity versus the modest PFS benefit associated with chemotherapy plus TKI in patients with solid cancers. PMID- 24629275 TI - In reply. PMID- 24629276 TI - Ewing sarcoma of the occipital bone in an elderly patient. PMID- 24629277 TI - De novo formation of an intracranial aneurysm. PMID- 24629278 TI - Factors associated with Institutional delivery service utilization among mothers in Bahir Dar City administration, Amhara region: a community based cross sectional study. AB - BACKGROUND: High maternal mortality is a continued challenge for the achievement of the fifth millennium development goal in Sub-Saharan African countries including Ethiopia. Although institutional delivery service utilization ensures safe birth and a key to reduce maternal mortality, interventions at the community and/or institutions were unsatisfactorily reduced maternal mortality. Institutional delivery service utilization is affected by the interaction of personal, socio-cultural, behavioral and institutional factors. Therefore this study was designed to assess factors associated with institutional delivery service use among mothers in Bahir Dar city administration. METHODS: A community based cross sectional study was conducted in Bahir Dar City administration Northwest of Addis Ababa, Ethiopia. Four hundred eighty four mothers were included in the study. Data were collected by trained female data collectors. Descriptive statistics, binary and multivariable logistic regression analyses were computed. Statistical significance was considered at p < 0.05 and the strength of statistical association was assessed by odds ratios (OR) with 95% confidence intervals. RESULT: In this study, 78.8% of women gave birth to their current child at health institution. The multivariable logistic regression showed that, attending primary education (AOR = 4.7[95% CI:1.3-16.7], secondary education (AOR = 3.5[95% CI:1.1-10.7]), age at first marriage; first time marriage at 15-19 years (AOR = 5.4[95% CI:2.0-15.0]) and first time marriage at 20-24 years (AOR = 5.0[95% CI:1.5-16.8] and gestational age at first ANC visit (first trimester) (AOR = 5.3[1.3-22.2]) and second trimester (AOR = 2.8[95% CI:0.7-11.]) were independent factors affecting institutional delivery service utilization. CONCLUSION: In this study, institutional delivery service utilization is optimal, urban mothers were more likely to practice institutional delivery. This study indicated that age at first marriage, educational status of the women and gestational age at first ANC visit are independent predictors of delivery service utilization. Hence, intensifying education for women and behavior change communication (BCC) interventions to increase early initiation and up-take of ANC service use in the first trimester and delaying marriage are recommended to promote institutional delivery service utilization. PMID- 24629279 TI - Global elderly care in crisis. PMID- 24629280 TI - Hitting the target: a new framework for mental health trials. PMID- 24629281 TI - Promoting equity through sex-specific medical research. PMID- 24629282 TI - Action on sugar--lessons from UK salt reduction programme. PMID- 24629283 TI - Improving outcomes for ruptured abdominal aortic aneurysm. PMID- 24629287 TI - Nicholas Wald: epidemiologist with a radical prospectus. PMID- 24629288 TI - Investing in health. PMID- 24629289 TI - Investing in health. PMID- 24629290 TI - Investing in health--authors' reply. PMID- 24629291 TI - Investing in health. PMID- 24629292 TI - On global health: stick to sovereignty. PMID- 24629293 TI - What does UHC mean? PMID- 24629294 TI - Deaths from "legal highs": a problem of definitions. PMID- 24629295 TI - BBC must ensure commentators' tobacco industry links are made public. PMID- 24629296 TI - Maternal and child mortality in China. PMID- 24629297 TI - Shortage of paediatricians in China. PMID- 24629298 TI - Mortality from ruptured abdominal aortic aneurysms: clinical lessons from a comparison of outcomes in England and the USA. AB - BACKGROUND: The outcome of patients with ruptured abdominal aortic aneurysm (rAAA) varies by country. Study of practice differences might allow the formulation of pathways to improve care. METHODS: We compared data from the Hospital Episode Statistics for England and the Nationwide Inpatient Sample for the USA for patients admitted to hospital with rAAA from 2005 to 2010. Primary outcomes were in-hospital mortality, mortality after intervention, and decision to follow non-corrective treatment. In-hospital mortality and the rate of non corrective treatment were analysed by binary logistic regression for each health care system, after adjustment for age, sex, year, and Charlson comorbidity index. FINDINGS: The study included 11,799 patients with rAAA in England and 23,838 patients with rAAA in the USA. In-hospital mortality was lower in the USA than in England (53.05% [95% CI 51.26-54.85] vs 65.90%; p<0.0001). Intervention (open or endovascular repair) was offered to a greater proportion of cases in the USA than in England (19,174 [80.43%] vs 6897 [58.45%]; p<0.0001) and endovascular repair was more common in the USA than in England (4003 [20.88%] vs 589 [8.54%]; p<0.0001). Postintervention mortality was similar in both countries (41.77% for England and 41.65% for USA). These observations persisted in age-matched and sex matched comparisons. In both countries, reduced mortality was associated with increased use of endovascular repair, increased hospital caseload (volume) for rAAA, high hospital bed capacity, hospitals with teaching status, and admission on a weekday. INTERPRETATION: In-hospital survival from rAAA, intervention rates, and uptake of endovascular repair are lower in England than in the USA. In England and the USA, the lowest mortality for rAAA was seen in teaching hospitals with larger bed capacities and doing a greater proportion of cases with endovascular repair. These common factors suggest strategies for improving outcomes for patients with rAAA. FUNDING: None. PMID- 24629299 TI - Cutaneous myiasis in a patient with seborrhoeic eczema. PMID- 24629300 TI - An analysis of esophageal stent placement for persistent leak after the operative repair of intrathoracic esophageal perforations. AB - BACKGROUND: Surgical repair of esophageal perforation has been the mainstay of therapy for patients without associated esophageal malignancy or diffuse mediastinal necrosis. However, the leak rate after primary surgical repair is reported to range between 15% and 20% and increases to 45% and 70% in patients whose repair is delayed beyond 24 hours. This analysis reviews patients who experienced a leak after the operative repair of an esophageal perforation treated with esophageal stent placement. METHODS: Patients undergoing esophageal stent placement for the treatment of a leak after the operative repair of an intrathoracic esophageal perforation were identified from a single institution's database, which included patients initially treated at other facilities. Patient outcomes were recorded and analyzed. RESULTS: During a 7-year period, 32 esophageal stents were placed in 29 patients who experienced an esophageal leak after operative repair. Associated surgical procedures were simultaneously performed in 7 (24%) patients. Leak occlusion occurred in 27 patients (93%). Two patients required a reoperative repair. Twenty-five patients (86%) were able to initiate oral nutrition within 72 hours of stent placement. Stent migration in 5 patients (19%) required repositioning (n=2) or replacement (n=3). Stents were removed at a mean of 22+/-16 days after placement. Mean hospital length of stay was 8+/-11 days. CONCLUSIONS: Endoluminal esophageal stent placement is a safe and effective treatment for the majority of leaks after the operative repair of an intrathoracic esophageal perforation. Stent placement resulted in rapid leak occlusion and provided the opportunity for early oral nutrition while eliminating the need for reoperative repair or esophageal exclusion in the majority of patients. PMID- 24629301 TI - Real-time magnetic resonance imaging technique for determining left ventricle pressure-volume loops. AB - BACKGROUND: Rapid determination of the left ventricular (LV) pressure-volume (PV) relationship as loading conditions are varied is the gold standard for assessment of LV function. Cine magnetic resonance imaging (MRI) does not have sufficient spatiotemporal resolution to assess beat-to-beat changes of the LV PV relationship required to measure the LV end-systolic elastance (EES) or preload recruitable stroke work (PRSW). Our aim was to investigate real-time MRI and semiautomated LV measurement of LV volume to measure PV relations in large animals under normal and inotropically stressed physiologic conditions. METHODS: We determined that PV relationships could be accurately measured using an image exposure time Tex less than 100 ms and frame rate Tfr less than 50 ms at elevated heart rates (~140 beats per minute) using a golden angle radial MRI k-space trajectory and active contour segmentation. RESULTS: With an optimized exposure time (Tex=95 ms and frame rate Tfr=2.8 ms), we found that there was no significant difference between cine and real-time MRI at rest in end-diastolic volume, end-systolic volume, ejection fraction, stroke volume, or cardiac output (n=5, p<0.05) at either normal or elevated heart rates. We found EES increased from 1.9+/-0.7 to 3.1+/-0.3 mm Hg/mL and PRSW increased from 6.2+/-1.2 to 9.1+/ 0.9 mm Hg during continuous intravenous dobutamine infusion (n=5, p<0.05). CONCLUSIONS: Real-time MRI can assess LV volumes, EES, and PRSW at baseline and elevated inotropic states. PMID- 24629302 TI - Mortality and morbidity after total aortic arch replacement. AB - BACKGROUND: Total aortic arch replacement is associated with considerable mortality and morbidity. Although operative death is the most extreme adverse clinical end point, postoperative morbidity can also be devastating for survivors. METHODS: We examined the short-term and long-term outcomes of 146 patients who underwent total aortic arch replacements between September 2003 and September 2011. RESULTS: The overall in-hospital mortality was 4.8%, and major postoperative morbidity during hospitalization occurred in 29 patients (19.9%). Multivariate analyses demonstrated that risk factors for hospital death were left thoracotomy (odds ratio [OR], 51.92; p=0.01), high preoperative serum creatinine values (OR, 3.88; p=0.02), and intraoperative blood loss (OR, 1.01; p=0.04). Ruptured aorta (OR, 7.13; p=0.02) and previous myocardial infarction (OR, 5.13; p=0.04) were identified as independent risk factors for major postoperative morbidity. The postoperative survival of all patients at 5 years was 76.7%+/-5%. After hospital discharge, the standardized mortality ratios showed no significant difference between hospital survivors and a comparable Japanese population and were 1.09 (p=0.41) among patients without major morbidity and 1.82 (p=0.12) among those with major morbidity. The development of renal failure requiring hemodialysis increased the risk of long-term death (hazard ratio, 5.59; p=0.03), even among hospital survivors. CONCLUSIONS: Our approach for total arch replacement resulted in low in-hospital mortality and morbidity. Long-term outcomes are stable in hospital survivors, especially in the absence of a postoperative requirement for dialysis. PMID- 24629303 TI - Informed consent for cardiac procedures: deficiencies in patient comprehension with current methods. AB - BACKGROUND: Patients who undergo cardiac catheterization or percutaneous coronary intervention (PCI) often have a poor understanding of their disease and of related therapeutic risks, benefits, and alternatives. This pilot study was undertaken to compare the effectiveness of 2 preprocedural educational approaches to enhance patients' knowledge of standard consent elements. METHODS: Patients undergoing first-time elective, outpatient cardiac catheterization and possible PCI were randomly assigned to a scripted verbal or written consent process (group I) or a web-based, audiovisual presentation (group II). Preconsent and postconsent questionnaires were administered to evaluate changes in patients' self-reported understanding of standard consent elements. RESULTS: One hundred and two patients enrolled at a single institution completed the pre- and postconsent surveys (group I=48; group II=54). Changes in patient comprehension rates were similar between groups for risk and benefit consent elements, but group II had significantly greater improvement in the identification of treatment alternatives than group I (p=0.028). Independent of intervention, correct identification of all risks and alternatives increased significantly after consent (p<0.05); 4 of 5 queried risks were correctly identified by greater than 90% of respondents. However, misperceptions of benefits persisted after consent; increased survival and prevention of future myocardial infarction were identified as PCI-related benefits by 83% and 46% of respondents, respectively. CONCLUSIONS: Although both scripted verbal and audiovisual informed consent improved patient comprehension, important patient misperceptions regarding PCI-related outcomes and alternatives persist, independent of informed consent approach, and considerable challenges still exist in educating patients about contemplated medical procedures. Future research appears warranted to improve patient comprehension. PMID- 24629304 TI - Type A aortic dissection after previous cardiac surgery: results of an integrated surgical approach. AB - BACKGROUND: Stanford type A aortic dissection in patients with previous cardiac surgery (PCS) is a catastrophic disease. This investigation evaluates the results of a standardized integrated approach to type A dissection after PCS. METHODS: Between 1993 and 2013, 629 patients with acute type A dissection (median age 61 [50 to 73] years, 64% males) underwent aortic repair utilizing a standardized integrated approach. Of these, 56 (9%) patients had PCS. Median follow-up was 4.1 (1.9 to 7.4) years (2,812 patient-years). RESULTS: Patients with PCS were older (70 [60 to 75] vs 60 [50 to 72] years, p<0.001), fivefold more likely to have coronary artery disease (p<0.001), and threefold less likely to have cardiac tamponade (p<0.001). They had higher in-hospital mortality rate (25% vs 12%, p=0.011), similar postoperative stroke rate (4% vs 5%, p=0.821), and lower survival (60%+/-7%, 50%+/-7%, 38%+/-8% vs 84%+/-2%, 69%+/-2%, 50%+/-3%) at 1, 5, and 10 years, respectively (log rank, p=0.003). Among PCS patients, the lowest in hospital mortality was in those without prior myocardial revascularization (11% vs 32%, p=0.185). Coronary malperfusion (odds ratio, 9.47; p=0.034) and cardiac tamponade (odds ratio, 5.01; p=0.076) were independent in-hospital mortality risk factors in PCS patients. CONCLUSIONS: Standardized integrated approach to acute type A aortic dissection in PCS patients results in acceptable postoperative mortality. Previous cardiac surgery should not be a reason to deny surgical repair in patients with type A dissection. PMID- 24629305 TI - Platelet utilization: a Canadian Blood Services research and development symposium. AB - Considerable progress has been made in recent years in understanding platelet biology and in strengthening the clinical evidence base around platelet transfusion thresholds and appropriate platelet dosing. Platelet alloimmunization rates have also declined. Nevertheless, controversies and uncertainties remain that are relevant to how these products can best be used for the benefit of platelet transfusion recipients. Platelets are unique among the blood products directly derived from whole blood or apheresis donations in requiring storage, with shaking, at ambient temperature. Storage is accordingly constrained between the need to limit the growth of any microbes in the product and the need to minimize losses in platelet function associated with storage. Proteomic and genomic approaches are being applied to the platelet storage lesion. Platelet inventory management is made challenging by these constraints. Although bacterial screening has enhanced the safety of platelet transfusions, pathogen reduction technology may offer further benefits. Continuing clinical investigations are warranted to understand the value of transfusing platelets prophylactically or only in response to bleeding in different patient groups and how best to manage the most grievously injured trauma patients. Patients refractory to platelet transfusions also require expert clinical management. The engineering of platelet substitute products is an active area of research, but considerable hurdles remain before any clinical uses may be contemplated. Roles for platelets in biological areas distinct from hemostasis are also emerging. Platelet utilization is variably affected by all of the above factors, by demographic changes, by new medications, and by new patient care approaches. PMID- 24629306 TI - Functional imaging of acute kidney injury at 3 Tesla: investigating multiple parameters using DCE-MRI and a two-compartment filtration model. AB - OBJECT: To investigate how MR-based parameters reflect functional changes in kidneys with acute kidney injury (AKI) using dynamic contrast enhanced MRI and a two-compartment renal filtration model. MATERIALS AND METHODS: MRI data of eight male Lewis rats were analyzed retrospectively. Five animals were subjected to AKI, three native rats served as control. All animals underwent perfusion imaging by dynamic contrast-enhanced MRI. Renal blood volume, glomerular filtration rate (GFR) as well as plasma and tubular mean transit times were estimated from regions-of-interest drawn in the renal cortex. Differences between healthy kidneys and kidneys subjected to AKI were analyzed using a paired t-test. RESULTS: Significant differences between ischemic and healthy kidneys could only be detected for the glomerular filtration rate. For all other calculated parameters, differences were present, however not significant. In rats with AKI, average single kidney GFR was 0.66 +/- 0.37 ml/min for contralateral and 0.26 +/- 0.12 ml/ min for diseased kidneys (P = 0.0254). For the healthy control group, the average GFR was 0.39 +/- 0.06 ml/min and 0.41 +/- 0.11 ml/min, respectively. Differences between diseased kidneys of AKI rats and ipsilateral kidneys of the healthy control group were significant (P = 0.0381). CONCLUSION: Significant differences of functional parameters reflecting damage of the renal tissue of kidneys with AKI compared to the contralateral, healthy kidneys could only be detected by GFR. GFR might be a useful parameter that allows for a spatially resolved detection of abnormal changes of renal tissue by AKI. PMID- 24629307 TI - Partial body irradiation of small laboratory animals with an industrial X-ray tube. AB - AIMS: Dedicated precise small laboratory animal irradiation sources are needed for basic cancer research and to meet this need expensive high precision radiation devices have been developed. To avoid such expenses a cost efficient way is presented to construct a device for partial body irradiation of small laboratory animals by adding specific components to an industrial X-ray tube. METHODS AND MATERIALS: A custom made radiation field tube was added to an industrial 200 kV X-ray tube. A light field display as well as a monitor ionization chamber were implemented. The field size can rapidly be changed by individual inserts of MCP96 that are used for secondary collimation of the beam. Depth dose curves and cross sectional profiles were determined with the use of a custom made water phantom. More components like positioning lasers, a custom made treatment couch, and a commercial isoflurane anesthesia unit were added to complete the system. RESULTS: With the accessories described secondary small field sizes down to 10 by 10 mm2 (secondary collimator size) could be achieved. The dosimetry of the beam was constructed like those for conventional stereotactical clinical linear accelerators. The water phantom created showed an accuracy of 1 mm and was well suited for all measurements. With the anesthesia unit attached to the custom made treatment couch the system is ideal for the radiation treatment of small laboratory animals like mice. CONCLUSION: It was feasible to shrink the field size of an industrial X-ray tube from whole animal irradiation to precise partial body irradiation of small laboratory animals. Even smaller secondary collimator sizes than 10 by 10 mm2 are feasible with adequate secondary collimator inserts. Our custom made water phantom was well suited for the basic dosimetry of the X-ray tube. PMID- 24629308 TI - Kinetic modeling in pre-clinical positron emission tomography. AB - Pre-clinical positron emission tomography (PET) has evolved in the last few years from pure visualization of radiotracer uptake and distribution towards quantification of the physiological parameters. For reliable and reproducible quantification the kinetic modeling methods used to obtain relevant parameters of radiotracer tissue interaction are important. Here we present different kinetic modeling techniques with a focus on compartmental models including plasma input models and reference tissue input models. The experimental challenges off deriving the plasma input function in rodents and the effect of anesthesia are discussed. Finally, in vivo application of kinetic modeling in various areas of pre-clinical research is presented and compared to human data. PMID- 24629309 TI - A review of treatment planning for precision image-guided photon beam pre clinical animal radiation studies. AB - Recently, precision irradiators integrated with a high-resolution CT imaging device became available for pre-clinical studies. These research platforms offer significant advantages over older generations of animal irradiators in terms of precision and accuracy of image-guided radiation targeting. These platforms are expected to play a significant role in defining experiments that will allow translation of research findings to the human clinical setting. In the field of radiotherapy, but also others such as neurology, the platforms create unique opportunities to explore e.g. the synergy between radiation and drugs or other agents. To fully exploit the advantages of this new technology, accurate methods are needed to plan the irradiation and to calculate the three-dimensional radiation dose distribution in the specimen. To this end, dedicated treatment planning systems are needed. In this review we will discuss specific issues for precision irradiation of small animals, we will describe the workflow of animal treatment planning, and we will examine several dose calculation algorithms (factorization, superposition-convolution, Monte Carlo simulation) used for animal irradiation with kilovolt photon beams. Issues such as dose reporting methods, photon scatter, tissue segmentation and motion will also be discussed briefly. PMID- 24629310 TI - Placement makes a difference: accuracy of an accelerometer in measuring step number and stair climbing. AB - Accurate and easy-to-use measurement tools are required to evaluate the effect of treatments on patient activity. Comfortable device placement and fixation are important for patient compliance. The aim of this study was the evaluation of the accuracy of an accelerometer at different placements and slow velocities. METHODS: A total of 43 healthy volunteers were included for a literature-based treadmill protocol using five accelerometer positions; a subset of 18 volunteers performed an extended treadmill protocol with velocities between 0.1 and 2.6m/s and finally stair climbing. RESULTS: An alternative accelerometer position at the anterolateral aspect of the middle shank did measure steps more accurately than at the manufacturer suggested position, especially during slow velocities. Participants preferred the alternative placement at the shank. The accuracy of different accelerometer positions was excellent at velocities between 1.0 and 2.2m/s. During slow velocities below 1.0m/s steps were recorded less accurately. Accepting an error of five percent, the accelerometer recorded steps accurately from 0.5m/s at the alternative placement and from 0.8m/s at the manufacturer suggested placement. Stair climbing was not recorded accurately by any accelerometer position. CONCLUSION: For measuring step number during slow velocities, the alternative position should be favoured. Stair climbing was not recorded accurately by any tested placement. PMID- 24629311 TI - Is posturography able to identify fallers in patients with Parkinson's disease? AB - INTRODUCTION: Parkinson' disease (PD) is one of the most prevalent neurodegenerative diseases, and more than half of patients with PD experience falls. Research for clinically useful risk factors predicting falls has yielded inconsistent findings so far. Hence the aim of the study is to validate two different posturography techniques and one modified-timed up and go test (TUG) in discriminating fallers and non-fallers among PD patients. METHODS: 32 patients diagnosed with idiopathic PD were assessed with: Dizziness handicap inventory, Activities-specific balance confidence scale, modified-TUG, sensorial organization test (SOT) and limits of stability (LOS) of computer dynamic posturography, results of free-field body sway analysis with Vertiguard device and number of falls. RESULTS: Fallers had longer time to perform modified-TUG and required more steps. On average, fallers performed SOT and LOS significantly worse and Vertiguard device indicated a higher risk of falling. Based on the area under the curve of receiver operating characteristics analyses, the overall accuracy of directional control of LOS and steps in modified-TUG are close to 0.9 (high accuracy). Also assessment with Vertiguard device is more efficient in identifying fallers than the parameters of SOT. DISCUSSION: Our results indicate that LOS, mobile posturography (Vertiguard), vestibular input of SOT and number of steps taken in modified-TUG are very useful to identify fallers in PD patients. PMID- 24629313 TI - [Clinical research needs new legal framework from the EU]. PMID- 24629314 TI - [Simplification of procedures for clinical drug trials in the EU is coming up]. AB - A proposal for a new regulation on clinical trials that will replace the Clinical Trials Directive has been launched by the EU Commission the 17 July 2012. The proposal contains ideas that undoubtedly will lead to a greater harmonisation within the EU, a more smooth approval procedure, and a lowering of the administrative burden. Details are still to be discussed, and waiting until 2016 when the new rules are adopted is definitely a problem, but all together the new proposal is to be regarded as good news for clinical drug research. PMID- 24629312 TI - Optical coherence tomography angiography of optic disc perfusion in glaucoma. AB - PURPOSE: To compare optic disc perfusion between normal subjects and subjects with glaucoma using optical coherence tomography (OCT) angiography and to detect optic disc perfusion changes in glaucoma. DESIGN: Observational, cross-sectional study. PARTICIPANTS: Twenty-four normal subjects and 11 patients with glaucoma were included. METHODS: One eye of each subject was scanned by a high-speed 1050 nm-wavelength swept-source OCT instrument. The split-spectrum amplitude decorrelation angiography (SSADA) algorithm was used to compute 3-dimensional optic disc angiography. A disc flow index was computed from 4 registered scans. Confocal scanning laser ophthalmoscopy (cSLO) was used to measure disc rim area, and stereo photography was used to evaluate cup/disc (C/D) ratios. Wide-field OCT scans over the discs were used to measure retinal nerve fiber layer (NFL) thickness. MAIN OUTCOME MEASURES: Variability was assessed by coefficient of variation (CV). Diagnostic accuracy was assessed by sensitivity and specificity. Comparisons between glaucoma and normal groups were analyzed by Wilcoxon rank-sum test. Correlations among disc flow index, structural assessments, and visual field (VF) parameters were assessed by linear regression. RESULTS: In normal discs, a dense microvascular network was visible on OCT angiography. This network was visibly attenuated in subjects with glaucoma. The intra-visit repeatability, inter-visit reproducibility, and normal population variability of the optic disc flow index were 1.2%, 4.2%, and 5.0% CV, respectively. The disc flow index was reduced by 25% in the glaucoma group (P = 0.003). Sensitivity and specificity were both 100% using an optimized cutoff. The flow index was highly correlated with VF pattern standard deviation (R(2) = 0.752, P = 0.001). These correlations were significant even after accounting for age, C/D area ratio, NFL, and rim area. CONCLUSIONS: Optical coherence tomography angiography, generated by the new SSADA, repeatably measures optic disc perfusion and may be useful in the evaluation of glaucoma and glaucoma progression. PMID- 24629315 TI - [Diastasis rectus abdominis]. AB - Diastasis rectus abdominis is a common condition, which may be mistaken for a ventral hernia. The literature is generally of poor quality. The evidence for the effect of conservative and surgical treatment is controversial and long-term results are unknown. Present analyses find that complication rates range from 4% to 88% and the most frequent complication is seroma formation. The risk of recurrence is up to 40%. Treatment of rectus diastasis should preferably follow scientific protocols and be restricted to patients with severe physical complaints. PMID- 24629316 TI - [Gut microbiota may have influence on glucose and lipid metabolism]. AB - New gene sequencing-based techniques and the large worldwide sequencing capacity have introduced a new era within the field of gut microbiota. Animal and human studies have shown that obesity and type 2 diabetes are associated with changes in the composition of the gut microbiota and that prebiotics, antibiotics or faecal transplantation can alter glucose and lipid metabolism. This paper summarizes the latest research regarding the association between gut microbiota, diabetes and obesity and some of the mechanisms by which gut bacteria may influence host metabolism. PMID- 24629317 TI - [Primary human intestinal epithelial cells as a tool to clarify disease mechanisms]. AB - A newly available method for culturing primary human intestinal epithelial cells stands for a variety of possibilities within the field of regenerative medicine. Thus, this cell culture represents an excellent ex vivo-model system with numerous possible applications ranging from basic research and drug testing to diagnosis and possible new treatment options in the future. This article describes the method in short and elaborates in the context of future possibilities within the field of regenerative medicine. PMID- 24629318 TI - [Influenza vaccination of cancer patients]. AB - Influenza infection adds to the morbidity and mortality in cancer patients. This paper reviews studies on the ability of adult cancer patients to develop a protective immunological response to influenza vaccination. The studies showed that patients undergoing chemotherapy were able to develop an immunological response and seroprotection. The ideal administration time in the course of a chemotherapy treatment was unclear, but the longest time from chemotherapy was preferred. Repeated vaccination may be beneficial. Influenza vaccination is safe, inexpensive and easily available. PMID- 24629319 TI - [Dapsone-induced methaemoglobinaemia]. AB - Dapsone is used as an antibiotic for dermatological disorders and may cause methaemoglobinaemia. Specific treatment with intravenous methylene blue is the treatment of choice. We present a case of dapsone-induced methaemoglobinaemia. Arterial blood gas analysis showed that pH was 7.4, PaO2 11.7 kPa, PaCO2 4.5 kPa and bicarbonate concentration 21.9 mmol/l. The methaemoglobin level was found to be 32%. The symptoms were headache and tachycardia. Methylene blue was administered and the methaemoglobin level dropped to 5% within three days. PMID- 24629320 TI - [Diabetic ketoacidosis masked by metabolic alkalosis]. AB - Diabetic ketoacidosis is caused by accumulation of acetoacetic and beta hydroxybutyric acids and is a common acute metabolic complication of type 1 diabetes mellitus. A much less common and recognized metabolic complication is diabetic ketoacidosis with alkalaemia ("ketoalkalosis"). Diuretic use, vomiting, alkali ingestion, and hypercortisolism have all been implicated as potential causes of this disorder. We present a case in which a patient displayed significantly elevated blood beta-hydroxy-butyrate (7.8 mmol/l) and glucose (39 mmol/l) concentrations together with arterial alkalosis (pH 7.47). PMID- 24629321 TI - [Galaxy sign (A)]. PMID- 24629322 TI - [Postoperative radiation therapy for a patient with osteogenesis imperfecta: case report]. AB - Osteogenesis imperfecta is an unusual disease also called Lobstein disease. Characterized by abnormalities of collagen biosynthesis, a possible mutation on 17th chromosome is described. On the other hand, 29% of breast cancers present a mutation on the same chromosome. Nevertheless, the association of osteogenesis imperfecta and breast cancer is at the moment unknown. Therapeutic management is very difficult because of a loss in dihydropyrimidine dehydrogenase for patients having osteogenesis imperfecta, generating some toxicity by default in catabolism of 5-fluorouracil. We report the case of a 49-year-old woman with a breast cancer in the context of osteogenesis imperfecta. Dosimetric considerations permitting to reduce chess dose level have been performed for this patient. With a follow-up of 6 months, no imaging fracture has been revealed after radiotherapy. No evident conclusion about radiation injury from a case report could be described in case of osteogenesis imperfecta. To our knowledge, this is the first case which take into account potential radiation induced toxicities. PMID- 24629323 TI - Reward-system effect (BAS rating), left hemispheric "unbalance" (alpha band oscillations) and decisional impairments in drug addiction. AB - The current research explored the impact of cortical frontal asymmetry (left lateralization effect) and Behavioral Activation System (BAS) on Substance Use Disorder (SUD) in decisional processes using the Iowa Gambling Task (IGT). Forty SUD participants and forty-two controls (CG) were tested using the IGT. Behavioral responses (gain/loss options), BIS/BAS scores and lateralized alpha band modulation (LTA) were considered. The SUD group increased the tendency to opt in favor of the immediate reward (loss strategy) more than the long-term option (win strategy) compared to the CG. Secondly, higher reward-subscale scores were observed in SUD. Thirdly, SUD showed an increase in left-hemisphere activation in response to losing (with immediate reward) choices in comparison with the CG. An imbalanced left hemispheric effect related to higher BAS trait could explain this "reward bias," because these components were found to explain (through the regression analysis) the main behavioral deficits. PMID- 24629324 TI - When you see it, let it be: Urgency, mindfulness and adolescent substance use. AB - The emotion-based domains of impulsivity, positive and negative urgency, are facets that have garnered attention due to their associations with substance use, and mindfulness based strategies have shown promise in reducing substance use in adults. The aim of the current study was to examine relations among urgency, mindfulness, and substance use in adolescence. Cross-sectional data were collected from students (N=1,051) at a large, private high school in the Pacific Northwest. Both positive and negative urgency were uniquely associated with greater likelihood of lifetime and current alcohol use; only positive urgency predicted lifetime marijuana use. Mindfulness was associated with a lower likelihood of lifetime alcohol or marijuana use. Interactions between urgency and mindfulness were not supported. Our findings highlight the need to explore relations among baseline mindfulness, skills based mindfulness, and personality in adolescent alcohol and other drug use. PMID- 24629325 TI - Perceived discrimination, depressive symptoms, and substance use in young adulthood. AB - Perceived discrimination is an important health-related stressor. As suggested by the stress-coping model, substance use often serves as a means to reduce the negative effects of perceived discrimination. This study uses data from the National Survey of American Life-Adults to examine the structural relationship of perceived discrimination and depressive symptoms with lifetime and recent substance use among African American and African Caribbean young adults. Respondents (N=1910) were 18-35 years old. Compared with African Caribbeans, African Americans report significantly higher levels of depressive symptoms and both lifetime and recent substance use. Multiple-group structural equation modeling is used to evaluate model fit and test hypothesized models. Results show good fit of the hypothesized models in both African Americans and African Caribbeans. Full measurement and structural invariance is found across ethnicity. Mediation models explain 18.5% and 47.4% of the variance in lifetime substance use for African Americans and African Caribbeans, respectively, and 23.5% and 35.0% of the variance in recent substance use for African Americans and African Caribbeans, respectively. Mediation tests indicate depressive symptoms partially mediate the relationship between perceived discrimination and lifetime substance use and fully mediated this relationship for recent substance use. This study is the first to demonstrate a positive association between perceived racial discrimination and substance use among African Caribbean young adults. Study findings illuminate the influence of perceived discrimination on substance use and the mechanisms of this relationship among African American and African Caribbean young adults. PMID- 24629326 TI - Impulsivity-related cognition in alcohol dependence: Is it moderated by DRD2/ANKK1 gene status and executive dysfunction? AB - Perceived impaired control over alcohol use is a key cognitive construct in alcohol dependence that has been related prospectively to treatment outcome and may mediate the risk for problem drinking conveyed by impulsivity in non dependent drinkers. The aim of the current study was to investigate whether perceived impaired control may mediate the association between impulsivity related measures (derived from the Short-form Eysenck Personality Questionnaire Revised) and alcohol-dependence severity in alcohol-dependent drinkers. Furthermore, the extent to which this hypothesized relationship was moderated by genetic risk (Taq1A polymorphism in the DRD2/ANKK1 gene cluster) and verbal fluency as an indicator of executive cognitive ability (Controlled Oral Word Association Test) was also examined. A sample of 143 alcohol-dependent inpatients provided an extensive clinical history of their alcohol use, gave 10ml of blood for DNA analysis, and completed self-report measures relating to impulsivity, impaired control and severity of dependence. As hypothesized, perceived impaired control (partially) mediated the association between impulsivity-related measures and alcohol-dependence severity. This relationship was not moderated by the DRD2/ANKK1 polymorphism or verbal fluency. These results suggest that, in alcohol dependence, perceived impaired control is a cognitive mediator of impulsivity related constructs that may be unaffected by DRD2/ANKK1 and neurocognitive processes underlying the retrieval of verbal information. PMID- 24629327 TI - Understanding sleep disturbance in athletes prior to important competitions. AB - OBJECTIVES: Anecdotally many athletes report worse sleep in the nights prior to important competitions. Despite sleep being acknowledged as an important factor for optimal athletic performance and overall health, little is understood about athlete sleep around competition. The aims of this study were to identify sleep complaints of athletes prior to competitions and determine whether complaints were confined to competition periods. DESIGN: Cross-sectional study. METHODS: A sample of 283 elite Australian athletes (129 male, 157 female, age 24+/-5 y) completed two questionnaires; Competitive Sport and Sleep questionnaire and the Pittsburgh Sleep Quality Index. RESULTS: 64.0% of athletes indicated worse sleep on at least one occasion in the nights prior to an important competition over the past 12 months. The main sleep problem specified by athletes was problems falling asleep (82.1%) with the main reasons responsible for poor sleep indicated as thoughts about the competition (83.5%) and nervousness (43.8%). Overall 59.1% of team sport athletes reported having no strategy to overcome poor sleep compared with individual athletes (32.7%, p=0.002) who utilised relaxation and reading as strategies. Individual sport athletes had increased likelihood of poor sleep as they aged. The poor sleep reported by athletes prior to competition was situational rather than a global sleep problem. CONCLUSION: Poor sleep is common prior to major competitions in Australian athletes, yet most athletes are unaware of strategies to overcome the poor sleep experienced. It is essential coaches and scientists monitor and educate both individual and team sport athletes to facilitate sleep prior to important competitions. PMID- 24629328 TI - Preface: gas and redox sensors special issue. PMID- 24629329 TI - LINE(1)s of evidence in HBV-driven liver cancer. AB - Hepatitis B virus (HBV) integration in hepatocellular carcinoma (HCC) is a poorly understood event. In a recent Cancer Cell paper, Lau et al. (2014) describe a HBV human fusion transcript (HBx-LINE1) that functions as a lncRNA, influences the epithelial-mesenchymal transition, and correlates with reduced patient survival and tumor formation in mice. PMID- 24629330 TI - Is the intestinal goblet cell a major immune cell? AB - Recent reports indicate that both the inflammasome (Wlodarska et al., 2014) and autophagy (Patel et al., 2013) pathways in goblet cells control mucin secretion, defects in which are linked to difficulties in clearing pathogenic bacteria and maintaining intestinal homeostasis and control colitis. PMID- 24629331 TI - From pathogen recognition to plant immunity: BIK1 cROSses the divide. AB - A rapid production of reactive oxygen species (ROS) represents a hallmark of plant immune responses to infection. However, how pathogen perception induces ROS production remains unclear. Li et al. (2014) fill a missing link by showing that a pattern recognition receptor complex directly associates with and activates a ROS-producing enzyme. PMID- 24629332 TI - Endogenous retroviruses and human cancer: is there anything to the rumors? AB - Xenotropic murine leukemia virus-related virus (XMRV) infection was incorrectly associated with prostate cancer and chronic fatigue syndrome (CFS) in recent years. In this forum, we discuss the story of XMRV and how we can apply lessons learned here to inform the debate surrounding cancers associated with human endogenous retroviruses (HERVs). PMID- 24629333 TI - Viruses for tumor therapy. AB - Oncolytic virotherapy exploits live viruses with selective tropism for cancerous cells and tissues to treat cancer. As discussed here, the field has progressed considerably as a result of both the successes and failures of previous and on going clinical trials for various cancers. These studies indicate that oncolytic viruses are remarkably safe and more efficacious when virus replication stimulates sustained antitumor immune responses. In the future, virotherapy should be combined with immunomodulatory reagents that target immune tolerance to established cancers. PMID- 24629334 TI - Human viral oncogenesis: a cancer hallmarks analysis. AB - Approximately 12% of all human cancers are caused by oncoviruses. Human viral oncogenesis is complex, and only a small percentage of the infected individuals develop cancer, often many years to decades after the initial infection. This reflects the multistep nature of viral oncogenesis, host genetic variability, and the fact that viruses contribute to only a portion of the oncogenic events. In this review, the Hallmarks of Cancer framework of Hanahan and Weinberg (2000 and 2011) is used to dissect the viral, host, and environmental cofactors that contribute to the biology of multistep oncogenesis mediated by established human oncoviruses. The viruses discussed include Epstein-Barr virus (EBV), high-risk human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV, respectively), human T cell lymphotropic virus-1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV). PMID- 24629336 TI - Host immune response to infection and cancer: unexpected commonalities. AB - Both microbes and tumors activate innate resistance, tissue repair, and adaptive immunity. Unlike acute infection, tumor growth is initially unapparent; however, inflammation and immunity affect all phases of tumor growth from initiation to progression and dissemination. Here, we discuss the shared features involved in the immune response to infection and cancer including modulation by commensal microbiota, reactive hematopoiesis, chronic immune responses and regulatory mechanisms to prevent collateral tissue damage. This comparative analysis of immunity to infection and cancer furthers our understanding of the basic mechanisms underlying innate resistance and adaptive immunity and their translational application to the design of new therapeutic approaches. PMID- 24629335 TI - What's the damage? The impact of pathogens on pathways that maintain host genome integrity. AB - Maintaining genome integrity and transmission of intact genomes is critical for cellular, organismal, and species survival. Cells can detect damaged DNA, activate checkpoints, and either enable DNA repair or trigger apoptosis to eliminate the damaged cell. Aberrations in these mechanisms lead to somatic mutations and genetic instability, which are hallmarks of cancer. Considering the long history of host-microbe coevolution, an impact of microbial infection on host genome integrity is not unexpected, and emerging links between microbial infections and oncogenesis further reinforce this idea. In this review, we compare strategies employed by viruses, bacteria, and parasites to alter, subvert, or otherwise manipulate host DNA damage and repair pathways. We highlight how microbes contribute to tumorigenesis by directly inducing DNA damage, inactivating checkpoint controls, or manipulating repair processes. We also discuss indirect effects resulting from inflammatory responses, changes in cellular metabolism, nuclear architecture, and epigenome integrity, and the associated evolutionary tradeoffs. PMID- 24629337 TI - Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis. AB - Helicobacter pylori is a gastric bacterial pathogen that is etiologically linked to human gastric cancer. The cytotoxin-associated gene A (CagA) protein of H. pylori, which is delivered into gastric epithelial cells via bacterial type IV secretion, is an oncoprotein that can induce malignant neoplasms in mammals. Upon delivery, CagA perturbs multiple host signaling pathways by acting as an extrinsic scaffold or hub protein. On one hand, signals aberrantly raised by CagA are integrated into a direct oncogenic insult, whereas on the other hand, they engender genetic instability. Despite its decisive role in the development of gastric cancer, CagA is not required for the maintenance of a neoplastic phenotype in established cancer cells. Therefore, CagA-conducted gastric carcinogenesis progresses through a hit-and-run mechanism in which pro-oncogenic actions of CagA are successively taken over by a series of genetic and/or epigenetic alterations compiled in cancer-predisposing cells during long-standing infection with cagA-positive H. pylori. PMID- 24629339 TI - The FLS2-associated kinase BIK1 directly phosphorylates the NADPH oxidase RbohD to control plant immunity. AB - The Arabidopsis immune receptor FLS2 senses the bacterial flagellin epitope flg22 to activate transient elevation of cytosolic calcium ions, production of reactive oxygen species (ROS), and other signaling events to coordinate antimicrobial defenses, such as stomatal closure that limits bacterial invasion. However, how FLS2 regulates these signaling events remains largely unknown. Here we show that the receptor-like cytoplasmic kinase BIK1, a component of the FLS2 immune receptor complex, not only positively regulates flg22-triggered calcium influx but also directly phosphorylates the NADPH oxidase RbohD at specific sites in a calcium-independent manner to enhance ROS generation. Furthermore, BIK1 and RbohD form a pathway that controls stomatal movement in response to flg22, thereby restricting bacterial entry into leaf tissues. These findings highlight a direct role of the FLS2 complex in the regulation of RbohD-mediated ROS production and stomatal defense. PMID- 24629338 TI - Microbes, microbiota, and colon cancer. AB - Colorectal cancer (CRC) presents a considerable disease burden worldwide. The human colon is also an anatomical location with the largest number of microbes. It is natural, therefore, to anticipate a role for microbes, particularly bacteria, in colorectal carcinogenesis. The increasing accessibility of microbial meta'omics is fueling a surge in our understanding of the role that microbes and the microbiota play in CRC. In this review, we will discuss recent insights into contributions of the microbiota to CRC and explore conceptual frameworks for evaluating the role of microbes in cancer causation. We also highlight new findings on candidate CRC-potentiating species and current knowledge gaps. Finally, we explore the roles of microbial metabolism as it relates to bile acids, xenobiotics, and diet in the etiology and therapeutics of CRC. PMID- 24629340 TI - A2B adenosine receptor induces protective antihelminth type 2 immune responses. AB - The type 2 immune response evoked by intestinal nematode parasites contributes to worm expulsion and tolerance to associated tissue damage. We investigated whether this host response is affected by blocking signaling by the putative endogenous danger signal adenosine, which can be released during inflammation and host cell damage. Specific blockade of the A2B adenosine receptor (A2BAR) inhibited worm elimination and the development of innate and adaptive components of the type 2 primary and memory response. Infected mice lacking A2BAR exhibited decreased M2 macrophage and eosinophil recruitment and reduced IL-4 and IL-13 cytokine production. Additionally, shortly after infection, upregulation of the alarmin IL 33, which drives type 2 immunity, and activation of innate lymphoid type 2 (ILC2) cells was inhibited, while exogenous IL-33 restored ILC2 cell activation and type 2 cytokine expression. Thus, adenosine acts as a danger-associated molecular pattern (DAMP) that initiates helminth-induced type 2 immune responses through A2BAR. PMID- 24629341 TI - Cytomegalovirus hijacks CX3CR1(hi) patrolling monocytes as immune-privileged vehicles for dissemination in mice. AB - Peripheral blood myelomonocytic cells are important for cytomegalovirus dissemination to distal organs such as salivary glands where persistent replication and shedding dictates transmission patterns. We find that this process is markedly enhanced by the murine cytomegalovirus (MCMV)-encoded CC chemokine, MCK2, which promotes recruitment of CX3CR1(hi) patrolling monocytes to initial infection sites in the mouse. There, these cells become infected and traffic via the bloodstream to distal sites. In contrast, inflammatory monocytes, the other major myelomonocytic subset, remain virus negative. CX3CR1 deficiency prevents patrolling monocyte migration on the vascular endothelium and interrupts MCMV dissemination to the salivary glands independent of antiviral NK and T cell immune control. In this manner, CX3CR1(hi) patrolling monocytes serve as immune privileged vehicles to transport MCMV via the bloodstream to distal organs. MCMV commandeers patrolling monocytes to mediate systemic infection and seed a persistent reservoir essential for horizontal transmission. PMID- 24629342 TI - Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. AB - Herpesviruses, including human cytomegalovirus (HCMV), encode multiple microRNAs (miRNA) whose targets are just being uncovered. Moreover, miRNA function during the virus life cycle is relatively unknown. We find that HCMV miRs UL112-1, US5 1, and US5-2 target multiple components of the host secretory pathway, including VAMP3, RAB5C, RAB11A, SNAP23, and CDC42. A HCMV miR UL112-1, US5-1, and US5-2 triple mutant displayed aberrant morphogenesis of the virion assembly compartment (VAC), increased secretion of noninfectious particles, and increased IL-6 release from infected cells. Ectopic expression of miRs UL112-1, US5-1, and US5-2 or siRNAs directed against RAB5C, RAB11A, SNAP23, and CDC42 caused the loss of Golgi stacks with reorganization into structures that resemble the VAC and a decrease in cytokine release. These observations indicate that multiple HCMV miRNAs coordinately regulate reorganization of the secretory pathway to control cytokine secretion and facilitate formation of the VAC for efficient infectious virus production. PMID- 24629343 TI - Gut microbiota promote hematopoiesis to control bacterial infection. AB - The commensal microbiota impacts specific immune cell populations and their functions at peripheral sites, such as gut mucosal tissues. However, it remains unknown whether gut microbiota control immunity through regulation of hematopoiesis at primary immune sites. We reveal that germ-free mice display reduced proportions and differentiation potential of specific myeloid cell progenitors of both yolk sac and bone marrow origin. Homeostatic innate immune defects may lead to impaired early responses to pathogens. Indeed, following systemic infection with Listeria monocytogenes, germ-free and oral-antibiotic treated mice display increased pathogen burden and acute death. Recolonization of germ-free mice with a complex microbiota restores defects in myelopoiesis and resistance to Listeria. These findings reveal that gut bacteria direct innate immune cell development via promoting hematopoiesis, contributing to our appreciation of the deep evolutionary connection between mammals and their microbiota. PMID- 24629345 TI - Demand-specific work ability, poor health and working conditions in middle-aged full-time employees. AB - We investigated the prevalence of reduced demand-specific work ability, its association with age, gender, education, poor health, and working conditions, and the interaction between poor health and working conditions regarding reduced demand-specific work ability. We used cross-sectional questionnaire data from 3381 full-time employees responding to questions about vocational education, job demands and social support (working conditions), musculoskeletal pain (MSP) and major depression (MD) (poor health) and seven questions about difficulty managing different job demands (reduced demand-specific work ability). Reduced demand specific work ability varied from 9% to 19% among the 46-year old and from 11% to 21% among the 56-year old. Age was associated with two, gender with four, and education with all measures of reduced demand-specific work ability. MSP was associated with four and MD was associated with six measures of reduced demand specific work ability. We found no interaction between working conditions and poor health regarding reduced demand-specific work ability. PMID- 24629344 TI - The treatment-naive microbiome in new-onset Crohn's disease. AB - Inflammatory bowel diseases (IBDs), including Crohn's disease (CD), are genetically linked to host pathways that implicate an underlying role for aberrant immune responses to intestinal microbiota. However, patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies. Using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases, we studied the microbiome in the largest pediatric CD cohort to date. An axis defined by an increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status. Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD. Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal associated microbiome offers unique potential for convenient and early diagnosis of CD. PMID- 24629346 TI - Reliability and validity of the Home Care STAT (Safety Task Assessment Tool). AB - Home care workers are a priority population for ergonomic assessment and intervention, but research on caregivers' exposures to hazards is limited. The current project evaluated the reliability and validity of an ergonomic self assessment tool called Home Care STAT (Safety Task Assessment Tool). Participants (N = 23) completed a background survey followed by 10-14 days of self-monitoring with the STAT. Results showed that the most frequent task was house cleaning, and that participants regularly performed dangerous manual client moving and transferring tasks. Researcher in-home observations of 14 workers (duration <= 2 h) demonstrated that workers' self-assessments were moderately reliable. Correlational and multi-level analyses of daily self-assessment data revealed that several task exposures were significantly related to daily fatigue and/or pain. Other associations have implications for Total Worker HealthTM; for example, daily stress was positively associated with both pain and consumption of high calorie snacks. Findings support the STAT as a reliable and potentially valid tool for measuring home care workers' exposures to physically demanding tasks. PMID- 24629348 TI - Cytomegalovirus seroprevalence in women with bad obstetric history in Kirkuk, Iraq. AB - The human cytomegalovirus (CMV) is a major cause of congenital infections. A case control descriptive study was conducted in Kirkuk, Iraq to determine the seroprevalence of CMV in women with bad obstetric history (BOH) compared to women with a normal previous pregnancy. The CMV IgG and IgM seroprevalence was higher in women with BOH. The CMV IgG seroprevalence was significantly influenced by pregnancy, age, residence and level of education. In addition, the current CMV infection was significantly associated with pregnancy, age, residence and education. Large families (crowding index >3) exhibited higher seroprevalence for CMV IgM (8.3%) and IgG (98.3%), but odd ratio (OR) showed no significant association between family size and seropositivity. The CMV IgG seropositivity was higher in working women (100%) compared to housewives (95.4%). However, the CMV IgM (current infection) was 6.8% in housewives and was not detected in any working women (0%). The OR exhibited no significant association between occupation and both IgM and IgG levels. PMID- 24629347 TI - Different paths to pathogenesis. AB - In a recent issue of Cell Host & Microbe, Elsen and colleagues identify a novel hemolysin in a highly virulent Pseudomonas aeruginosa strain that lacks a type III secretion system. Their analysis provides another example of how individual strains of P. aeruginosa utilize different virulence mechanisms to cause severe infections. PMID- 24629349 TI - A qualitative study of the causes of improper segregation of infectious waste at Nemazee Hospital, Shiraz, Iran. AB - BACKGROUND AND OBJECTIVES: Medical waste management is a major concern for healthcare facilities. One important element is the segregation of infectious waste from domestic, non-infectious waste. The aim of this qualitative study was to identify factors that negatively affect proper segregation at Nemazee Hospital, which is affiliated with Shiraz University of Medical Sciences. METHODS: Study data came from focus groups involving hospital workers. Participants expressed their opinions regarding barriers to proper segregation of medical wastes. The participants gave their permission to have their comments recorded. Data analyses were based on a grounded theory approach. RESULTS: The results indicated that managerial weakness was an important factor in suboptimal disposal of medical waste. It appears that hospital authorities should pay better attention to educational planning, organizational resources and supervision. Together, these considerations should help reduce waste-management errors. The results also suggest that healthcare worker training needs improvement. In general, patients and their companions, as well as the local population, did not appear to have sufficient knowledge concerning disposal of infectious medical waste. CONCLUSIONS: Hospital authorities should conduct a broad review of medical waste management, including improved employee training. This step should have a positive effect on local health, as well as the environment. Improvement is also needed in the infection prevention performance of hospital healthcare workers. This approach should reduce additional production of infectious waste and costs associated with healthcare. PMID- 24629350 TI - Multimodal imaging in cerebral gliomas and its neuropathological correlation. AB - INTRODUCTION: Concerning the preoperative clinical diagnostic work-up of glioma patients, tumor heterogeneity challenges the oncological therapy. The current study assesses the performance of a multimodal imaging approach to differentiate between areas in malignant gliomas and to investigate the extent to which such a combinatorial imaging approach might predict the underlying histology. METHODS: Prior to surgical resection, patients harboring intracranial gliomas underwent MRIs (MR-S, PWI) and (18)F-FET-PETs. Intratumoral and peritumoral biopsy targets were defined, by MRI only, by FET-PET only, and by MRI and FET-PET combined, and biopsied prior to surgical resection and which then received separate histopathological examinations. RESULTS: In total, 38 tissue samples were acquired (seven glioblastomas, one anaplastic astrocytoma, one anaplastic oligoastrocytoma, one diffuse astrocytoma, and one oligoastrocytoma) and underwent histopathological analysis. The highest mean values of Mib1 and CD31 were found in the target point "T' defined by MRI and FET-PET combined. A significant correlation between NAA/Cr and PET tracer uptake (-0.845, p<0.05) as well as Cho/Cr ratio and cell density (0.742, p<0.05) and NAA/Cr ratio and MIB-1 (-0761, p<0.05) was disclosed for this target point, though not for target points defined by MRI and FET-PET alone. CONCLUSION: Multimodal-imaging-guided stereotactic biopsy correlated more with histological malignancy indices, such as cell density and MIB-1 labeling, than targets that were based solely on the highest amino acid uptake or contrast enhancement on MRI. The results of our study indicate that a combined PET-MR multimodal imaging approach bears potential benefits in detecting glioma heterogeneity. PMID- 24629351 TI - Role of cardiac sympathetic nerves in blood pressure regulation. AB - Stellate ganglionectomy (SGx) was used to assess the contribution of cardiac sympathetic nerves to neurogenic hypertension in deoxycorticosterone (DOCA)-salt treated rats. Experiments were conducted in two substrains of Sprague-Dawley (SD) rats since previous studies reported bradycardia in Charles River-SD (CR-SD) rats and tachycardia in SASCO-SD (SA-SD) rats with DOCA treatment suggesting different underlying neural mechanisms. Uninephrectomized male rats underwent SGx or SHAM surgery and were instrumented for telemetric monitoring of mean arterial pressure (MAP) and heart rate (HR). After recovery, 0.9% saline solution and DOCA (50mg) were administered. Baseline MAP (Days 0-5 average) after SGx in CR-SD rats (96+/ 2mmHg; n=7) was not significantly different (p=0.08) than CR-SD SHAM rats (103+/ 3mmHg; n=9); however, there was a significantly lower HR during the baseline period (377+/-7 vs. 432+/-7bpm, p<0.05) in SGx rats. In SA-SD rats baseline MAP was not different between SGx and SHAM rats and HR was lower in SGx rats (428+/-8 vs. 371+/-5bpm, p<0.05). After DOCA treatment in both substrains, MAP and HR were elevated similarly in SHAM and SGx groups showing minimal impact in both groups of SGx on hypertension development. However, overall MAP in SA-SD SHAM rats reached a significantly higher level (155+/-10mmHg vs 135+/-5mmHg, p<0.05) than that observed in CR-SD SHAM rats demonstrating that the magnitude of hypertensive response to DOCA-salt treatment varies between substrains. In conclusion, removal of cardiac sympathetic nerves did not alter the development or maintenance of DOCA-salt hypertension in SD rats. PMID- 24629352 TI - Further evidence for a role of S100B in mood disorders: a human gene expression mega-analysis. PMID- 24629353 TI - Methotrexate in psoriatic arthritis. PMID- 24629354 TI - Percussion circuits and brain function--a hypothesis. AB - It is proposed that percussion reactions take place in cells of the sensory organs and the brain. The percussion pulses produced by such reactions are the basis of the recording of information and images generated by the five sensory organs. Also proposed and described are the mechanisms by which this information and these images can be recalled for use in the present time. PMID- 24629355 TI - Sympathetic nerve innervation in cervical posterior longitudinal ligament as a potential causative factor in cervical spondylosis with sympathetic symptoms and preliminary evidence. AB - Sympathetic symptoms associated with cervical disorders, such as vertigo, headache, dizziness, etc., are common clinical disorders bewildering both clinicians and patients. In our clinical practice we observed that sympathetic symptoms associated with cervical disorders were apparently relieved in some patients after undergoing routine anterior cervical decompression and fusion plus posterior longitudinal ligament (PLL) resection. This study was designed to investigate the sympathetic nerve innervations in the cervical PLL and its potential correlation with cervical sympathetic symptoms such as vertigo. METHOD: In animal research, cervical PLLs of 9 adult rabbits were harvested and stained with sucrose-phosphate-glyoxylic acid (SPG), which is a specific fluorescence staining method for sympathetic postganglionic fibers. In human research, cervical PLL of 8 patients of cervical spondylosis with sympathetic symptoms were harvested during surgery and stained with SPG. All sections were observed under fluorescence microscope. Sympathetic symptoms were evaluated using the sympathetic symptom 20-point score preoperatively and at 1 week, 2-month, and 6 month postoperatively. RESULTS: In rabbit specimens, a large number of sympathetic postganglionic fibers were distributed in the cervical PLL of every segment. The density of sympathetic fibers distributed in the intervertebral portion of PLL was more than that in the vertebral portion. Compared with deep layer section, the nerve fibers in the superficial PLL layer section were thicker and more densely populated. Existence of sympathetic postganglionic fibers was also confirmed in human specimens. Those nerve fibers were mostly short and isolated in areatus form, with non-interwoven branches. The mean sympathetic symptoms score decreased significantly from 6.6 +/- 2.6 before surgery to 2.0 +/- 1.9 at 6 months postoperatively after anterior cervical decompression and fusion with PLL removed. CONCLUSION: According to the experimental result and clinical practice, we hypothesized that sympathetic nerve fibers distributed in PLL may represent a pathologic basis of stimulation induced by cervical vertebral degenerative changes and thus are susceptible to being a potential causative factor in cervical spondylosis with sympathetic symptoms. PMID- 24629356 TI - Expanding upon the 'extreme male brain' theory of autism as a common link between other major risk factors: a hypothesis. AB - On average, males have a stronger preference for physical systems and machines over interpersonal interactions; they have lower average levels of cognitive empathy or social cognition than females; and they have higher rates of 'extreme' intelligence when it comes to abstract concepts such as those found in mathematics and sciences. All three traits are also commonly associated with individuals with an autism spectrum disorder or ASD; clearly, it is not coincidental that incidence rates of autism are reportedly four times higher in males than in females. The common link between the majority of risk factors assessed in this review (including technological advancements, advanced parental age, socioeconomic status, and genetic predispositions towards ASDs in families of scientists and engineers) can be traced to a specific hormone, testosterone. It was established that traits which are typically associated with males are also typically associated with ASDs as well as individuals with antisocial personality disorder, or APD. The key distinction between individuals who are considered to be 'autistic' as opposed to those who are considered 'sociopathic' lies in the difference between their empathy deficits: whereas those who are 'autistic' are said to lack cognitive empathy (the ability to identify and understand the thoughts and feelings of others and to respond to these with appropriate emotions), those who are 'sociopathic' are said to lack emotional empathy (which is responsible for inhibiting acts of physical aggression or violence). This would explain why autistic individuals can have elevated testosterone levels without becoming physically aggressive. PMID- 24629357 TI - EPR spectroscopy as a predictive tool for the assessment of marginal donor livers perfused on a normothermic ex vivo perfusion circuit. AB - Liver transplantation is a highly successful treatment for end-stage liver disease. While liver transplantation is often the only effective treatment for cirrhosis there is a critical shortage of donor organs, leading to death of many potential recipients on the waiting list. Marginal liver grafts are increasingly being used in an attempt to increase the number of donor livers utilized for transplantation. Marginal donor livers often have complications and worse outcomes for recipients receiving these types of transplant. The ability to predict the outcome with the use of marginal grafts is difficult and often imprecise leading decreased use of potentially suitable grafts. The development and maturation of normothermic ex vivo perfusion as a platform for the assessment of donor organs presents an opportunity to increase the number of usable donor livers available for transplantation. Furthermore, direct measurement of reactive oxygen species (ROS) present in the donor liver on an ex vivo perfusion circuit by electron paramagnetic resonance (EPR) spectroscopy would allow for precise real-time quantification of donor organ injury. The combination normothermic ex vivo liver perfusion with EPR spectroscopy could therefore present a powerful platform to increase the number of donor organs utilized for transplantation. PMID- 24629358 TI - Role of human papillomavirus in cutaneous squamous cell carcinoma: a meta analysis. AB - BACKGROUND: The role of human papillomavirus (HPV) in cutaneous squamous cell carcinoma (cuSCC) is not well defined, with past studies showing conflicting results. OBJECTIVE: We sought to determine if there is a significant association between HPV and cuSCC and whether cuSCC from immunosuppressed patients are more likely to carry HPV than cuSCC from immunocompetent patients. METHODS: We performed a systematic review and abstracted data from articles that included: skin samples by biopsy, HPV detection by polymerase chain reaction, and a minimum of 10 cases and 10 controls. Pooled effect size and 95% confidence intervals were calculated using random effects meta-analysis using the inverse variance method. RESULTS: cuSCC were more likely to carry HPV than normal-appearing skin (pooled effect size [ES] 3.43, 95% confidence interval 1.97-5.98, P < .0001) in all patients. An increase in HPV prevalence was found in tumors from immunosuppressed patients compared with immunocompetent patients (pooled ES 3.01, 95% confidence interval 2.00-4.52, P < .0001). LIMITATIONS: The greatest limitation is the heterogeneity of the studies included. The association of higher HPV prevalence in squamous cell carcinoma compared with normal-appearing skin does not imply causality. CONCLUSION: These results contribute to evidence that HPV is associated with cuSCC. Higher HPV burden in tumors from immunosuppressed patients compared with immunocompetent patients may have therapeutic implications. PMID- 24629359 TI - Simple onycholysis: a diagnosis of exclusion. PMID- 24629360 TI - Reply: To PMID 23957979. PMID- 24629361 TI - Electrosurgery: part I. Basics and principles. AB - The term electrosurgery (also called radiofrequency surgery) refers to the passage of high-frequency alternating electrical current through the tissue in order to achieve a specific surgical effect. Although the mechanism behind electrosurgery is not completely understood, heat production and thermal tissue damage is responsible for at least the majority--if not all--of the tissue effects in electrosurgery. Adjacent to the active electrode, tissue resistance to the passage of current converts electrical energy to heat. The only variable that determines the final tissue effects of a current is the depth and the rate at which heat is produced. Electrocoagulation occurs when tissue is heated below the boiling point and undergoes thermal denaturation. An additional slow increase in temperature leads to vaporization of the water content in the coagulated tissue and tissue drying, a process called desiccation. A sudden increase in tissue temperature above the boiling point causes rapid explosive vaporization of the water content in the tissue adjacent to the electrode, which leads to tissue fragmentation and cutting. PMID- 24629362 TI - Electrosurgery: part II. Technology, applications, and safety of electrosurgical devices. AB - Electrosurgical currents can be delivered to tissue in monopolar or bipolar and monoterminal or biterminal modes, with the primary difference between these modes being their safety profiles. A monopolar electrosurgical circuit includes an active electrode and a dispersive (return) electrode, while there are 2 active electrodes in bipolar mode. In monoterminal mode, there is an active electrode, but there is no dispersive electrode connected to the patient's body and instead the earth acts as the return electrode. Biterminal mode uses a dispersive electrode connected to the patient's body, has a higher maximum power, and can be safer than monoterminal mode in certain situations. Electrosurgical units have different technologies for controlling the output power and for providing safety. A thorough understanding of these technologies helps with a better selection of the appropriate surgical generator and modes. PMID- 24629365 TI - Amelanotic melanoma mimicking cutaneous epitheliomas. PMID- 24629366 TI - Atypical pigmented acral lesion proven to be fungal using reflectance confocal microscopy. PMID- 24629367 TI - Dermoscopic and confocal microscopy patterns of vulvar mucosal melanotic macules. PMID- 24629368 TI - Successful treatment of multifocal intracerebral and spinal hemangiomas with propranolol. PMID- 24629369 TI - Syringocystadenoma papilliferum developing over hyperkeratosis of the nipple in a pregnant woman. PMID- 24629370 TI - Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma. PMID- 24629371 TI - Vancomycin-associated neutrophilic dermatitis histologically mimicking Cryptococcus. PMID- 24629372 TI - Compassionate use of vismodegib and adjuvant radiotherapy in the treatment of multiple locally advanced and inoperable basal cell carcinomas and squamous cell carcinomas of the skin. PMID- 24629373 TI - Improvement of Darier disease with diclofenac sodium 3% gel. PMID- 24629374 TI - Lichen striatus associated with etanercept treatment of rheumatoid arthritis. PMID- 24629375 TI - Linking the distribution of (210)Po and (210)Pb with plankton community along Line P, Northeast Subarctic Pacific. AB - Depth profiles of (210)Po and (210)Pb activity and phytoplankton and zooplankton abundance were collected during two cruises along the Canadian time-series Line P in the Northeast Subarctic Pacific (ranging from 48o39 N to 50o00 N and 126o40 W to 145o00 W) in August 2010 and February 2011 to evaluate connections between the planktonic community and distributions of these radionuclides in the upper 500 m of the water column. Statistical analysis indicates that (210)Po is more effectively removed from the surface ocean when large (>0.1 mg ind(-1) dry wt) zooplankton dominate, and is less effectively scavenged when the picoplankton Synechococcus is present at high concentrations (>1 * 10(5) cells ml(-1)). While the zooplankton field data are consistent with previous lab studies and field observations, the phytoplankton results seem to conflict with recent evidence that small cells may contribute significantly to export in other oligotrophic regions. Differences in ecosystem mechanisms between the Subarctic Pacific and other oligotrophic systems that limit the contribution of small cells to sinking flux remain to be identified. PMID- 24629376 TI - PSA, CA19-9 and CEA tumor markers in blood serum of inhabitants of Ramsar, Iran, Heidary et al., Journal of Environmental Radioactivity. PMID- 24629377 TI - Structure and function of soil microbial community in artificially planted Sonneratia apetala and S. caseolaris forests at different stand ages in Shenzhen Bay, China. AB - The present study examined the relationships between soil characteristics, microbial community structure and function in the forests artificially planted with exotic Sonneratia apetala at stand ages of 1-, 2-, 7-, 10- and 14-years and Sonneratia caseolaris of 1-, 4-, 7-, 10- and 14-years in Futian National Nature Reserve, Shenzhen Bay, China. The 7-years old forests of both Sonneratia species reached peak growth and had the highest content of nitrogen and phosphorus, enzymatic activities, including dehydrogenase, cellulase, phosphatase, urease and beta-glucosidase, except arylsulphatase which increased continuously with stand ages. The microbial community structure reflected by phospholipid fatty acid (PLFA) profiles also reached the maximum value in the 7-years old forests and soil bacterial PLFAs in both forests were significantly higher than fungal PLFAs. The canonical correlation analysis revealed that differences in microbial structural variables were significantly correlated to the differences in their functional variables, and the highest correlation was found between the soil enzymatic activities and the content of carbon and nitrogen. PMID- 24629378 TI - Impact of laver treatment practices on the geoenvironmental properties of sediments in the Ariake Sea. AB - Since the 1970s, the catch of Tairagi and Agemaki shellfish that inhabit the shallow sediments of the Ariake Sea of Japan has fallen dramatically. This is partly accounted for by the Isahaya land reclamation dike project and by the increasingly frequent local red tides. A recent survey of local fisherman suggested that the decline in the shellfish harvest may also be due to the practice of laver treatment in the tidal flats of the Ariake Sea. We carried out field and laboratory investigations to determine whether the practice changes the geoenvironmental properties of the fine-grained sediments in the tidal flats. There were notable changes in the salt concentration, pH, and sulfide content between the sediments exposed to a laver treating agent and those without laver treatment. Based on these differences, we identified potential mechanisms by which the laver treating agent was transported into the sediments and influenced the sulfide levels. PMID- 24629379 TI - Marine debris in bottom trawl catches and their effects on the selectivity grids in the north eastern Mediterranean. AB - In this study composition of marine debris and their blocking potential on the selectivity grid systems deployed on demersal trawls were investigated in the north eastern Mediterranean. For this, a total of 132 hauls were examined in two fishing season between 20 September 2010 and 19 February 2012. Results showed that plastic items were the most abundant debris (73% in terms of weight) and they were followed by metals (10%). Because of plastics and packing debris, it is highly probable that grids may have been blocked in 85% of trawl hauls. The bathymetric and geographical variability in the quantity of debris were evaluated, and concluded that particularly in some areas where direction of currents and bottom topography favor deposition, such devices may easily be rendered ineffective by the plastics and packing debris in particular. To solve this problem, several solution proposals are submitted. PMID- 24629380 TI - Contrasting recovery of shallow and deep water seagrass communities following climate associated losses in tropical north Queensland, Australia. AB - Tropical seagrass decline and recovery from severe storm impacts was assessed via quarterly measurements of seagrass biomass, species composition and experimental investigations of recovery in north Queensland. Shallow and deep seagrass meadows suffered major declines. Significant recovery in the two years following loss only occurred at deeper sites. Halophila spp. in deep water areas had a high capacity for recovery through the availability of seed banks. In contrast, the shallow species did not recover quickly from experimental disturbance, had poor seed reserves and relied on asexual propagation. The potential for shallow species to recover rapidly from widespread losses was limited as seed banks were limited or non-existent. Understanding inter- and intra-specific differences in seagrass recovery and how this interacts with location is critical to predict the consequences of climate events to tropical seagrasses. This is especially important as more frequent severe storms are predicted as a consequence of climate change. PMID- 24629382 TI - [Infections in the elderly]. PMID- 24629381 TI - Identification and selection of Environmental Performance Indicators for sustainable port development. AB - In this paper an identification and selection of Environmental Performance Indicators (EPIs) in port areas has been conducted. A comprehensive inventory of existing EPIs in use in the seaport sector has been identified for monitoring performance of operational (e.g. dust, noise, dredging, and waste), managerial (e.g. certification, compliance, and complaints) and environmental condition (e.g. air, water, sediment and ecosystems). These indicators have been filtered against specific criteria and have been assessed and evaluated by port stakeholders in order to obtain a final set of indicators suitable to be implemented at EU level. A user friendly tool has been developed specifically to assist port authorities in calculating and reporting the proposed indicators. This study has drawn on major research projects to blend academic research with input from marine professionals in order to identify, select, evaluate and validate EPIs that are acceptable and feasible to the sector, and practicable in their application and implementation. PMID- 24629383 TI - [When senescence hits the immune system]. AB - Ageing is associated with a reshaping of the immune system characterised by decreased adaptive immunity and systemic low-grade inflammation. These changes are associated with mortality in elderly cohorts and not only important in the defence to infectious diseases but also associated with almost all age-associated chronic diseases such as atherosclerosis, type 2 diabetes and dementia as well as their related risk factors. This review discusses underlying molecular and cellular mechanisms and possible intervention strategy today and in the future. PMID- 24629384 TI - [Elderly patients suffer more from side effects and resistant microorganisms]. AB - Antibiotic treatment of elderly patients implies special problems because of higher probability of reduced renal or other organ function, and interactions with other medications. Elderly patients are more often previously hospitalised and treated with antibiotics or live in health-care institutions, and may be colonised with resistant microorganisms. It is crucial to sample for microbiological diagnostics before therapy. Adverse effects of antibiotics are seen more frequently with increasing age. Otherwise, the effect of antibiotics and durations of therapy is independent of patient age. PMID- 24629385 TI - [Fever of unknown origin in the elderly is a diagnostic challenge]. AB - Elderly individuals often have different causes of fever of unknown origin compared to young persons. While infections dominate in the young, system diseases like temporal arteritis and polymyalgia rheumatica, malignancy and drug fever are common causes in the elderly. The symptoms may be blunted with lack of fever. Co-morbidities may complicate, dominate, and confuse the clinical impression. In the diagnostic work-up it is important to consider other co morbidities and overall frailty. Patients should be informed and their wishes taken into account in the early phase of planning diagnostic work-up and treatment. PMID- 24629387 TI - [Lung infections are frequent in elderly persons]. AB - There are over 20,000 hospital admissions for pneumonia annually in Denmark. The incidence of pneumonia increases with age, functional impairment and co morbidity. In fact, 60% of admissions occur among persons 65 years or older. The public health burden is expected to increase because this population in Denmark and elsewhere is growing and by 2015 it is estimated to have increased by 15%. The aetiology and empirical antimicrobial therapy is not affected by age per se, but aetiology is influenced by co-morbidity, particularly chronic lung disease. Prophylactic measures include immunization, smoking cessation, mobilization and oral hygiene. PMID- 24629386 TI - [Evidence and guidelines for influenza and pneumococcal vaccines for the elderly]. AB - Influenza and pneumococcal disease are major causes of morbidity and mortality in the elderly. In most European countries dual vaccination of persons aged > 65 years is recommended, but the evidence supporting these recommendations is limited. Inadequate immune response in elderly hampers efficacy. Immunogenicity of the influenza vaccine may be improved by adding an adjuvant. Pneumococcal vaccination of children provides herd immunity, but may also result in expansion of non-vaccine strains. Better vaccines with documentation of efficacy in the elderly are needed for both diseases. PMID- 24629388 TI - [The frequencies of both urinary tract infection and asymptomatic bacteriuria increase with age]. AB - Urinary tract infection is common in the elderly, and the prevalence increases with age due to pathological changes in the urinary tract and common use of bladder catheter. The increasing incidence of asymptomatic bacteriuria, together with fewer classical dysuria symptoms complicates the diagnosis in the elderly. There is also an increasing prevalence of complicated urinary tract infection including septicaemia. Due to an increase in antibiotic resistance urine culture should precede the choice of antibiotic treatment. Treatment duration is seven days; 14 days in patients with pyelonephritis. Adverse effects are notably higher in the elderly. PMID- 24629389 TI - [The HIV population is aging]. AB - The HIV population is aging due to increased life expectancy among HIV patients on antiretroviral therapy. 37% of Danish HIV patients are now older than 50 years. Older age has implications for all stages of HIV care. Older patients are at higher risk of delayed HIV diagnosis and thereby less favourable prognosis. Factors related directly to HIV infection, lifestyle-related factors and co infections contribute to increased prevalence of co-morbidity in older HIV patients, and medical treatments of co-morbidity together with three or more antiviral drugs increase the risk of polypharmacy. PMID- 24629390 TI - [Elderly patients are at high risk from hospital-acquired infection]. AB - Hospital-acquired infections cause considerable morbidity and mortality in elderly patients and burden the individual patient as well as the economy of society. Although these infections are linked to biological factors in elderly patients, there is a potential for increased prevention efforts. Changes in antibiotic policy and organisational tasks can reduce the spread of drug resistant bacteria causing serious nosocomial infections. Transmission of pathogens from hospitals to nursing homes and vice versa poses a particular challenge when dealing with elderly colonized or infected patients. PMID- 24629392 TI - [Uncombable hair syndrome]. PMID- 24629393 TI - Insight into Tor2, a budding yeast microdomain protein. AB - The plasma membrane of eukaryotic organisms is compartmentalized into microdomains. The budding yeast Saccharomyces cerevisiae presents three laterally distinct microdomains: membrane compartment containing Can1 (MCC), membrane compartment containing Pma1 (MCP), and membrane compartment containing Tor2 (MCT). Tor2 and its corresponding protein complex, target of rapamycin complex 2 (TORC2), has been of particular interest in recent years. Tor2, the main organizer of TORC2, is a highly conserved kinase that has proved to be an important regulator of multiple cellular functions including cell growth, actin polymerization, endocytosis, and sphingolipid synthesis. Despite significant advancements, the full understanding of the Tor2 signaling networks is incomplete. Here we review the most compelling evidences for the function and physiological significance of Tor2, as well as discuss possible implications and explanations for observed phenomena. PMID- 24629394 TI - Hemangioblastomas in the elderly: epidemiology and clinical characteristics. AB - Intracranial hemangioblastomas are benign vascular tumors. The peak age of incidence is between 20 to 50 years. Hemangioblastomas rarely occur in patients over the age of 65. To our knowledge there is no review of the prevalence and clinical features in an elderly population. We reviewed our 12 year experience with intracranial hemangioblastomas, and characterized the clinical features of hemangioblastomas in patients over the age of 65. We present a 72-year-old man with a cerebellar mass initially thought to be a metastasis as an illustrative case. We reviewed our pathology database and identified all patients with a histopathologically confirmed diagnosis of hemangioblastoma over the last 12 years in a large tertiary adult hospital; all patients were over the age of 18. Of all cases of hemangioblastoma in the last 12 years, six of 77 (7.7%) occurred in patients over the age of 65. All were cerebellar in location, and none were associated with von-Hippel Lindau disease. Hemangioblastomas are uncommon, but not rare, in patients over the age of 65, and should be included in the differential diagnosis of patients presenting with gait ataxia and a cerebellar lesion in this age group. PMID- 24629395 TI - Initial response to antiepileptic drugs in patients with newly diagnosed epilepsy. AB - This study aimed to identify factors predicting the response to antiepileptic drugs in patients with newly diagnosed epilepsy. We prospectively studied 176 patients with newly diagnosed epilepsy. Patients were included if they had a history of two or more clinically definite unprovoked seizures, or had a definite epileptic focus on MRI or epileptiform discharges on electroencephalography if they had suffered only one seizure. The primary endpoint was seizure freedom during the initial 6 months of antiepileptic drug treatment. The secondary endpoint was the time to the first seizure during the maintenance period of antiepileptic drug treatment. A total of 100 patients were included, and seizure freedom for 6 months was achieved in 73 patients. The response to antiepileptic drugs was significantly lower in patients with early age at seizure onset (? 16 versus >16 years old, odds ratio=4; 95% confidence interval [CI] 1.5-12.9; relative risk=1.4; 95% CI 1.1-1.8). In addition, the time to the first seizure during the maintenance period was significantly earlier in patients with age at seizure onset ? 16 years compared with those with age at seizure onset >16 years on the Kaplan-Meier survival analysis (p=0.011). Early age at seizure onset is an important factor influencing the response to antiepileptic drugs in patients with newly diagnosed epilepsy. PMID- 24629396 TI - Association between Helicobacter pylori infection and dementia. AB - Dementia is the severe loss of global cognitive ability in a previously healthy person. This study examined the relationship between Helicobacter pylori infection (HP-I) and non-Alzheimer's dementia (non-AD) using a nationwide population-based dataset. The International Classification of Diseases, Ninth Revision (ICD-9) codes for dementia were used to define dementia patients; in addition, we examined the association of dementia with other comorbidities. Patients aged >=40years with newly diagnosed HP-I (ICD-9 code 041.86) during 1998 2010 were identified as the HP-I cohort. The comparison cohort consisted of people aged >=40years without HP-I (non-HP-I) randomly selected from the database at a ratio of 1:4 in the same time period. The controls were frequency matched according to the age (every 5years), sex, and index year of patients in the HP-I cohort. Follow-up was performed for all patients until the date of dementia diagnosis (ICD-9 codes 290.0-290.4, 294.1, 331.0-331.2), date of withdrawal from the Taiwanese National Health Insurance program, date of death, or until December 31 2010. Compared with patients without HP-I, HP-I patients were 1.60-fold (95% confidence interval [CI] 1.32-1.95) more likely to develop non-AD. There was no statistical association between HP-I and AD. The adjusted hazard ratio of dementia increased from 1.48 (95% CI 1.22-1.79) for patients who had HP-I once to 2.19 (95% CI 1.13-4.25) for patients who had HP-I two or more times. Our study revealed that HP-I may be a critical risk factor for the development of non-AD. Further investigation, including clinical trials, to examine the microbe-dementia connection may provide further proof of the association between HP-I and dementia. PMID- 24629397 TI - Profile of prothrombotic factors in Indian children with ischemic stroke. AB - This study was undertaken in view of paucity of data regarding the profile of prothrombotic factors in children with ischemic stroke. Sixty-four children with ischemic stroke were prospectively evaluated for prothrombotic factors over a 2 year period. The blood samples were analyzed for protein C (PC), protein S (PS), activated protein C resistance (APCR), factor V Leiden (FVL), anti-thrombin-III (AT-III), lipoprotein (a) [Lp(a)], lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL) immunoglobulin (Ig) M and IgG, homocysteine, and methylenetetrahydrofolate reductase (MTHFR) at least 3 months after the onset of stroke. At least one prothrombotic factor was identified in 45.3% children (29/64). These included hyperhomocysteinemia (11/64), PC deficiency (9/64), aCL (8/64), PS deficiency (5/64), APCR (3/64), AT-III deficiency (2/64) and LA (1/64). Multiple factors were coexistent in 17.2% (11/64). The prevalence of PC deficiency, PS deficiency and co-existence of multiple abnormalities observed were similar to the published literature. Elevated Lp(a) and APCR were less prevalent. FVL and MTHFR were not seen in any of the study children. Forty-five percent of children had at least one prothrombotic abnormality. Hyperhomocysteinemia, PC deficiency, aCL and PS deficiency were the most frequent prothrombotic abnormalities. PMID- 24629398 TI - Behavioral comorbidity in children and adolescents with epilepsy. AB - This cross sectional study assessed the prevalence of behavioral comorbidity and its association with epilepsy-related factors in children and adolescents with epilepsy. One hundred consecutive patients with active epilepsy, aged 6-16 years, were screened for behavioral comorbidity using the Child Behavior Checklist and those who qualified as having behavioral comorbidity were compared with those who did not have it. Behavioral comorbidity was found in 43 of 100 participants. Being treated with antiepileptic drug polytherapy (odds ratio 6.3, 95% confidence interval 1.4-17.3, p=0.01) independently predicted behavioral comorbidity in the patients studied. The demonstrated high frequency of behavioral comorbidity in children with epilepsy suggests that pediatricians and pediatric neurologists should be sensitive to this fact in order to identify and manage behavioral comorbidity in children with epilepsy. PMID- 24629399 TI - Regulation of expression of relaxin-3 and its receptor RXFP3 in the brain of diet induced obese rats. AB - An animal model closely related to human obesity is diet-induced obesity in Sprague-Dawley rats. These rats placed on a high-energy (HE) diet show wide distribution in body weight gain with a subset of animals developing diet-induced obesity (DIO) and the remaining animals showing a diet-resistant (DR) phenotype. Once obesity is established, DIO rats strongly defend their increased body weight against caloric restriction. There is evidence that neuropeptide relaxin-3 is involved in food intake regulation, but the levels of expression of relaxin-3 and its receptor have not been yet demonstrated in the DIO model. The present study investigated the brain expression of relaxin-3 and its cognate receptor RXFP3 in DIO and DR rats maintained on an HE diet since weaning. Expression of relaxin-3 and RXFP3 mRNAs was assessed by in situ hybridization in ad libitum, food deprived (12 h) and refed (1 h) feeding states. The levels of expression of relaxin-3 in the medial portion of the nucleus incertus (NI) were higher in the DIO rats compared to the DR rats in the ad libitum-fed state. Food deprivation increased the levels of expression of relaxin-3 in the medial NI in DR but not DIO rats. The stronger expression of relaxin-3 in the ad libitum-fed state in the DIO rats was accompanied by low expression of the RXFP3 receptor in the paraventricular hypothalamic nucleus (PVN), supraoptic nucleus, central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Refeeding increased expression of RXFP3 in the paraventricular thalamic nucleus, parvocellular PVN, CeA, NI, and NTS in the DIO rats. These results provide evidence that DIO rats show a constitutive increase in relaxin-3 expression in the medial NI and that refeeding after food deprivation may enhance the orexigenic effects of relaxin-3 in DIO rats by rapid upregulation of the expression of RXFP3 in the specific brain regions involved in food intake regulation. PMID- 24629401 TI - Excessive pulse pressure response to standing in community population with orthostatic systolic hypertension. AB - The postural change of pulse pressure (PP) in the persons with orthostatic hypertension (OHT) is unclear. This study included 2849 (65.0 +/- 9.3 years) community participants. Blood pressures (BPs) in supine and standing positions were measured. The differences between upright and supine BP and PP were recorded as DeltaBP and DeltaPP. The criteria for OHT was DeltaBP >=10 mm Hg, for orthostatic hypotension (OH) was <=-10 mm Hg and for orthostatic normotension (ONT) was -9 to 9 mm Hg. Fasting blood lipids and glucose were measured. The supine SBP of the sOHT group were similar to that of sONT group (140.9 +/- 20.2 mm Hg vs 138.2 +/- 19.7 mm Hg), but significantly lower than that of sOH group (151.9 +/- 19.2 mm Hg; P < .05). Their PPs were 65.3 +/- 15.9, 62.8 +/- 14.7, and 71.1 +/- 15.1 mm Hg, respectively, and with the similar group difference like SBP. When the position changed from supine to standing, the sOHT group showed PP rise, while sOH and sONT groups showed PP reduction (3.8 +/- 7.1 mm Hg vs -17.0 +/- 8.5 mm Hg and -5.8 +/- 6.6 mm Hg; both P < .05). Thus, the standing PP in the sOHT group was significantly higher than in the sONT (69.1 +/- 18.0 mm Hg vs 57.0 +/- 15.8 mm Hg; P < .05) and in the sOH (54.2 +/- 15.2 mm Hg; P < .05) groups. The postural PP profile varies with the postural responses of SBP. The sOHT group has obviously increased PP and significantly higher standing PP compared with the sONT group. PMID- 24629403 TI - Emerging drugs of abuse. PMID- 24629400 TI - Baseline predictors of central aortic blood pressure: a PEAR substudy. AB - Elevated central systolic blood pressure (BP) increases the risk of cardiovascular events and appears superior to peripheral BP for long term risk prediction. The objective of this study was to identify demographic and clinical factors associated with central pressures in patients with uncomplicated hypertension. We prospectively examined peripheral BP, central aortic BP, and arterial wall properties and wave reflection in 57 subjects with uncomplicated essential hypertension in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study. Significant predictors of central SBP included height, smoking status, heart rate (HR), and peripheral systolic BP (SBP), while central diastolic BP (DBP) was explained by peripheral DBP and HR. These variables accounted for nearly all of the variability in central SBP and central DBP (R(2) = 0.94 and R(2) = 0.98, respectively). Central pulse pressure variability was largely explained by gender, ex-smoking status, HR, peripheral SBP, and peripheral DBP (R(2) = 0.94). Central augmented pressure had a direct relationship with smoking status, peripheral SBP, and duration of hypertension, whereas it was indirectly related to height, HR, and peripheral DBP. Easily obtainable demographic and clinical factors are associated with central pressures in essential hypertensive persons. These relationships should be considered in future studies to improve assessment of BP to reduce cardiovascular risk and mortality. PMID- 24629404 TI - Asthma treatment decisions by pediatric residents do not consistently conform to guidelines or improve with level of training. AB - OBJECTIVE: To compare asthma treatment decisions by pediatric residents to current asthma guidelines and to learn whether treatment decisions vary by postgraduate year in training. METHODS: We conducted a Web-based survey of residents from 10 training programs through the Continuity Research Network of the Academic Pediatric Association (CORNET). Surveys included 6 vignettes of patients receiving low-dose inhaled steroids with guideline- and non-guideline based indicators of asthma status and 1 stable patient on high-intensity medication. RESULTS: There were 369 resident respondents (65% response rate), 26% postgraduate year (PGY) 1, 38% PGY2, and 36% PGY3+. Seventy-five percent of each resident group reported seeing fewer than 1 asthma patient per continuity clinic session. A majority of residents made appropriate treatment recommendations in 2 of 4 vignettes of guideline-based indicators of asthma status: first, 97% overall stepping up treatment for mild persistent asthma; and second, 52% overall stepping down treatment for a patient with well-controlled asthma on high intensity medications. Inconsistent with guideline recommendations, 82% of residents overall did not step down treatment for a patient with well-controlled asthma receiving low-intensity therapy; 75% of residents did not step up treatment for a patient with a recent hospitalization for asthma. Of the 3 vignettes evaluating non-guideline-based indicators of asthma status, a majority of residents (60%) stepped up treatment for parental reports of worse asthma, while a minority did so for a parental report of being bothered by their child's asthma (27%) or when wheezing was reported at physical examination (43%). There were no statistically significant differences for any of the comparisons by year in training. CONCLUSIONS: Pediatric residents' management of asthma is consistent with national guidelines in some cases but not in others. There were no differences in the outpatient asthma management decisions between residents by years in training. Educational efforts should be focused on strategies to facilitate pediatric resident adherence to national asthma guideline recommendations for outpatient asthma management. PMID- 24629405 TI - Reliability of a rating scale for assessing alignment of the posterior facet after surgical repair of joint depression fractures of the calcaneus. AB - Radiographs are frequently used to classify joint depression calcaneal fractures and assess the degree of repair of such injuries. To associate the degree of repair with clinical outcomes such as foot-related quality of life and subjective patient satisfaction, it would be useful to have a valid measuring instrument that has been shown to reliably categorize the alignment of the posterior facet of the calcaneus. To be considered valid, the measurement must have inter-rater and intrarater reliability. In an effort to demonstrate the validity of a coronal plane computed tomographic measurement for categorizing the alignment of the posterior facet after repair of joint depression fractures of the calcaneus, we measured the inter-rater and intrarater reliability of the classification system. PMID- 24629406 TI - Brain derived neurotrophic factor in the retina of the teleost N. furzeri. AB - BDNF plays an important role in the development and maintenance of visual circuitries in the retina and brain visual centers. In adulthood, BDNF signaling is involved in neural protection and regeneration of retina. In this survey, we investigated the expression of BDNF in the retina of adult Nothobranchius furzeri, a teleost fish employed for age research. After describing the retina of N. furzeri and confirming that the structure is organized in layers as in all vertebrates, we have studied the localization of BDNF mRNA and protein throughout the retinal layers. BDNF mRNA is detectable in all layers, whereas the protein is lacking in the photoreceptors. The occurrence of BDNF provides new insights on its role in the retina, particularly in view of age-related disease of retina. PMID- 24629408 TI - Longitudinal assessment of neuropathy in type 1 diabetes using novel ophthalmic markers (LANDMark): study design and baseline characteristics. AB - AIMS: Corneal nerve morphology and corneal sensation threshold have recently been explored as potential surrogate markers for the evaluation of diabetic neuropathy. We present the baseline findings of the 'Longitudinal Assessment of Neuropathy in type 1 Diabetes using novel ophthalmic Markers'(LANDMark) study. METHODS: The LANDMark study is a 4-year, two-site, natural history study of three participant groups: type 1 diabetes with neuropathy (T1W), type 1 diabetes without neuropathy (T1WO) and control participants without diabetes or neuropathy. All participants undergo a detailed annual assessment of neuropathy including corneal nerve parameters measured using corneal confocal microscopy and corneal sensitivity measured using non-contact corneal aesthesiometry. RESULTS: 76 T1W, 166 T1WO and 154 control participants were enrolled into the study. Corneal sensation threshold was significantly higher (i.e., sensitivity was lower) in T1W (1.0+/-1.1mbars) than T1WO (0.7+/-0.7mbars) and controls (0.6+/ 0.4mbars) (p<0.001), with no difference between T1WO and controls. Corneal nerve fibre length was lower in T1W (14.0+/-6.4mm/mm(2)) compared to T1WO (19.1+/ 5.8mm/mm(2)) and controls (23.2+/-6.3mm/mm(2)) (p<0.001). Corneal nerve fibre length was lower in T1WO compared to controls. CONCLUSIONS: The LANDMark baseline findings confirm a reduction in corneal sensitivity only in Type 1 patients with neuropathy. However, corneal nerve fibre length is reduced in Type 1 patients without neuropathy with an even greater deficit in Type 1 patients with neuropathy. PMID- 24629409 TI - Association between socioeconomic status, type 2 diabetes and its chronic complications in Argentina. AB - AIM: To compare the socioeconomic status (SES) of people with type 2 diabetes (T2DM) in Argentina (Cordoba) with and without major chronic complications of diabetes, with that recorded in persons without diabetes matched by age and gender. METHODS: For this descriptive and analytic case-control study, potential candidates were identified from the electronic records of one institution of the Social Security System of the city of Cordoba. We identified and recruited 387 persons each with T2DM with or without chronic complications and 774 gender- and age-matched persons without T2DM (recruitment rate, 83%). Data were obtained by telephone interviews and supplemented with data from the institution's records. Group comparisons were performed with parametric or non-parametric tests as appropriate. We used ordinary least squares to regress household income and the difference between income and household expenses on diabetes status, age, sex, education and body mass index. RESULTS: Persons with T2DM, particularly those with complications, reported fewer years of general education (13.6+/-4.2 years vs. 12.2+/-4.4 years), a lower percentage of full time jobs (43.0% vs. 26.9%), lower salaries and monthly household income among those with full-time jobs (> 5000 ARG$: 52.6% vs. 24.5%), and a higher propensity to spend more money than they earned (expenditure/income ratio>=1: 10.2% vs. 16.0%). The percentage of unmarried people was also higher among people with type 2 diabetes (7.0% vs. 10.9%). CONCLUSION: T2DM and the development of its complications are each positively associated with lower SES and greater economic distress in Argentina. PMID- 24629410 TI - Hemoglobin A1c predicts heart failure hospitalization independent of baseline cardiac function or B-type natriuretic peptide level. AB - AIMS: Diabetes is a major risk factor for heart failure (HF). We examined whether baseline HbA1c level predicts HF incidence independent of other HF risk factors, including baseline cardiac structural and functional abnormalities. METHODS: In patients with type 2 diabetes, multivariable Cox regression models were constructed to examine the independent association between baseline HbA1c and future HF hospitalization. RESULTS: In 608 subjects (mean age, 66.5 years; men, 68%; mean HbA1c, 9.1% (76 mmol/mol)), 92 were hospitalized for HF during a median follow-up of 6 years. For a 1% (11 mmol/mol) increase in baseline HbA1c, the hazard ratio for HF was 1.23 (95% confidence interval, 1.1-1.7, p<0.001) with adjustment for age, sex, body mass index, blood pressure and plasma B-type natriuretic peptide (BNP) level. The effect of HbA1c on HF was independent of baseline left ventricular (LV) ejection fraction, the ratio of peak early to late diastolic filling velocity, and prevalent/incident coronary heart disease (CHD), and was more evident in patients with enlarged LV, decreased systolic function, prevalent CHD, or prevalent HF. CONCLUSION: In patients with type 2 diabetes, HbA1c significantly predicts future HF hospitalization independent of baseline BNP level or echocardiographic parameters. PMID- 24629411 TI - The glycemic status of diabetes in an urban area of Cambodia. AB - Recently the Korea Diabetes Association participated in the 'Cambodia-Korea Twinning Project' to help Cambodia establish its own modernized diabetes center and to raise awareness of the seriousness of diabetes. Here we report the status of diabetes in an urban area of Cambodia as obtained through this project. PMID- 24629412 TI - Decreased sucrose preference in patients with type 2 diabetes mellitus. AB - AIMS: Increased sugar consumption may adversely affect glycemic control in patients with diabetes. Although patients with diabetes are generally thought to prefer sweet tastes, few data are available on the sucrose preference in these individuals. The aim of the present study was to evaluate sucrose preference in patients with type 2 diabetes in comparison with subjects without diabetes. METHODS: Sucrose preference was assessed in 200 subjects (100 type 2 diabetes patients and 100 age-, sex- and body mass index (BMI)-matched control subjects). Sucrose preference was evaluated together with sucrose perception (i.e., sucrose sensitivity). Clinical and biochemical factors affecting sucrose taste were also analyzed. RESULTS: Participants with type 2 diabetes preferred lower sucrose concentrations compared with control subjects (p=0.001), although they had a less sensitive palate for sucrose compared with subjects without diabetes (p=0.012). Individual sucrose preference demonstrated a negative relationship with sensitivity to sucrose in control subjects. Notably, this relationship between sucrose preference and sensitivity was completely absent in participants with type 2 diabetes. Male patients with diabetes demonstrated a higher sucrose preference compared with female patients. There were no significant correlations between sucrose preference and glycemic control, duration of diabetes, or anti diabetic medications. CONCLUSIONS: Participants with type 2 diabetes demonstrate a lower preference for sweet tastes than control subjects despite their decreased perception of sucrose. Reduced sucrose preference is not associated with better glycemic control in individuals with diabetes. PMID- 24629414 TI - [European Day of cardiac arrest]. PMID- 24629413 TI - Controlled oxidation of aliphatic CH bonds in metallo-monooxygenases: mechanistic insights derived from studies on deuterated and fluorinated hydrocarbons. AB - The control over the regio- and/or stereo-selective aliphatic CH oxidation by metalloenzymes is of great interest to scientists. Typically, these enzymes invoke host-guest chemistry to sequester the substrates within the protein pockets, exploiting sizes, shapes and specific interactions such as hydrogen bonding, electrostatic forces and/or van der Waals interactions to control the substrate specificity, regio-specificity and stereo-selectivity. Over the years, we have developed a series of deuterated and fluorinated variants of these hydrocarbon substrates as probes to gain insights into the controlled CH oxidations of hydrocarbons facilitated by these enzymes. In this review, we illustrate the application of these designed probes in the study of three monooxygenases: (i) the particulate methane monooxygenase (pMMO) from Methylococcus capsulatus (Bath), which oxidizes straight-chain C1-C5 alkanes and alkenes to form their corresponding 2-alcohols and epoxides, respectively; (ii) the recombinant alkane hydroxylase (AlkB) from Pseudomonas putida GPo1, which oxidizes the primary CH bonds of C5-C12 linear alkanes; and (iii) the recombinant cytochrome P450 from Bacillus megaterium, which oxidizes C12-C20 fatty acids at the omega-1, omega-2 or omega-3 CH positions. PMID- 24629415 TI - [Research into the education of asthmatic patients: the squaring of the circle]. PMID- 24629416 TI - "Candidatus Haloectosymbiotes riaformosensis" (Halobacteriaceae), an archaeal ectosymbiont of the hypersaline ciliate Platynematum salinarum. AB - The novel ciliate Platynematum salinarum (Scuticociliatia) was isolated only recently from a thalassohaline solar saltern pond (12%) in Portugal. Scanning electron microscopy showed numerous bacterial-shaped cells covering the complete surface of the ciliate. The rod-shaped epibionts were identified and characterized following the "Full-Cycle rRNA Approach". The almost full-length 16S rRNA gene sequence was obtained using archaeal-specific primers and two species-specific probes were designed for fluorescence in situ hybridization. The 16S rRNA gene sequence of the epibiotic cells showed 87% sequence identity with the type strain sequence of the closest characterized species Halolamina pelagica. Phylogenetic reconstructions affiliated the novel organism to the genus Halolamina (Halobacteria, Archaea). Attempts to isolate the epibionts failed and, therefore, growth experiments incorporating the antibiotic anisomycin were conducted in order to investigate the potential symbiotic relationship between P. salinarum and the epibionts. The results suggested an obligate symbiosis between the two organisms and revealed the first symbiotic representative of the Halobacteria. Based on the phylogenetic analyses and growth experiments we propose the classification of this novel organism in a new genus, with the taxon name "Candidatus Haloectosymbiotes riaformosensis". PMID- 24629417 TI - A comparison of the validity of two indirect utility instruments as measures of postoperative recovery. AB - BACKGROUND: Cost-effectiveness analyses of surgical interventions require valid measures of postoperative recovery. The objective of this study was to compare the validity of two indirect utility instruments, the Short Form 6D (SF-6D) and EuroQol 5D (EQ-5D), as measures of postoperative recovery. MATERIALS AND METHODS: A prospective cohort of patients undergoing elective colorectal resection at two university-affiliated institutions from October 2012-October 2013 completed the SF-6D and EQ-5D (including the EQ-visual analog scale [EQ-VAS]) at baseline (before surgery), and at 4 and 8 wk after surgery. Responsiveness and construct validity were assessed through a priori hypotheses. RESULTS: A total of 165 patients were included. The SF-6D was the most responsive to the expected postoperative changes at 4 and 8 wk compared with the EQ-5D and the EQ-VAS. The 4 wk SF-6D, EQ-5D, and EQ-VAS discriminated between patients with and without complications after controlling for confounders with adjusted mean differences of -0.070 (95% confidence interval [CI] -0.126 to -0.015), -0.133 (95% CI -0.231, 0.030), and -7.91 (95% CI -14.77, -1.04), respectively. Mean SF-6D and EQ-5D values were significantly different from the US population norms at all time points, but the magnitude of change was highest for the SF-6D. The strength of correlation between all three instruments was moderate at all time points (r=0.550-0.684, all P<0.05). CONCLUSIONS: The SF-6D preference-based health index appears to be a more valid measure of postoperative recovery than the EQ-5D and EQ-VAS in surgical cost-effectiveness analyses. PMID- 24629418 TI - CHADS2 score predicts atrial fibrillation following cardiac surgery. AB - BACKGROUND: Atrial fibrillation (AF) following cardiac surgery portends higher morbidity and increased health expenditure. Although many anatomic and patient risk factors have been identified, a simple clinical scoring system to identify high-risk patients is lacking. The CHADS2 score is widely used to predict the risk of stroke in patients with AF. We assessed the utility of this scoring algorithm in predicting the development of de novo postoperative atrial fibrillation (POAF) in cardiac surgery patients. MATERIAL AND METHODS: A total of 2120 patients from 2008 to 2013 were identified for inclusion in our analysis. CHADS2 scores were calculated, and patients grouped into low- (0), intermediate- (1) and high-risk (>=2) categories. A multivariate regression model was developed to account for known risk factors of AF. RESULTS: Of the 2120 patients, 344 (16.2%) patients developed de novo POAF during their primary hospitalization. Mean CHADS2 scores for POAF patients and no POAF patients were 2.1 +/- 1.2 and 1.7 +/- 1.3 (P < 0.0001), respectively. CHADS2 score was a significant predictor of AF on multivariate regression analysis (adjusted odds ratio, 1.26; 95% confidence interval, 1.14-1.40). As CHADS2 score increased from 0 to 6, the probability of POAF increased from 11.1% to 32.7% (P < 0.0001). Compared with the low-risk group, the intermediate-risk and high-risk groups had a 1.73- and 2.58 fold increase in odds of developing POAF, respectively (P < 0.02 and P < 0.0001). CONCLUSIONS: CHADS2 score is a powerful and convenient predictor of developing POAF. We recommend its utilization in identifying high-risk patients that may benefit from pharmacologic prophylaxis. PMID- 24629419 TI - A randomized controlled trial assessing the effect of prescribed patient position changes during colonoscope withdrawal on adenoma detection. AB - BACKGROUND: High-quality colonoscope withdrawal technique is associated with a higher adenoma detection rate. Position change is routinely used in barium enema and CT colonography to facilitate adequate distension of the colon and promote movement of fluid from the segment of the colon being assessed. OBJECTIVE: To determine whether prescribed position changes during colonoscope withdrawal affect the adenoma detection rate compared with the usual care per endoscopist. DESIGN: Prospective, randomized, controlled trial. SETTING: Tertiary-care, university-affiliated hospital. PATIENTS: Patients referred for outpatient colonoscopy between July 2011 and July 2012 were evaluated for eligibility. Inclusion criteria were outpatient status and age >=40 years. Exclusion criteria were (1) complete colonoscopy within 1 year before the procedure, (2) inability to provide informed consent, (3) incomplete colonoscopy to the cecum, (4) previous bowel resection, (5) inflammatory bowel disease, (6) colonic polyposis syndrome, (7) inadequate bowel preparation, and (8) musculoskeletal disorder or other mobility issues limiting effective patient position changes during colonoscopy. INTERVENTIONS: Prescribed position changes during colonoscope withdrawal. MAIN OUTCOME MEASUREMENTS: Polyp detection rate (PDR) and adenoma detection rate (ADR). RESULTS: A total of 776 patients were enrolled, with 388 in the dynamic group. There was no difference in PDR (odds ratio [OR] 0.99; P = .93) or ADR (OR 1.17; P = .28). Colonoscope withdrawal time was longer in the dynamic group (median time 466.5 vs 422.5 seconds; P < .0001). LIMITATIONS: Single-center study. Indication for procedure not controlled. Lack of standardized bowel preparation and blinding. CONCLUSION: Prescribed position changes during colonoscope withdrawal do not affect polyp/adenoma detection compared with the usual practice when the baseline ADR is above the recommended standard. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01395173.). PMID- 24629420 TI - Reflections on needle-knife papillotomy (with videos). PMID- 24629421 TI - Choledochoscopic surveillance in a patient with hepaticolithiasis. PMID- 24629422 TI - Boston Bowel Preparation Scale scores provide a standardized definition of adequate for describing bowel cleanliness. AB - BACKGROUND: Establishing a threshold of bowel cleanliness below which colonoscopies should be repeated at accelerated intervals is important, yet there are no standardized definitions for an adequate preparation. OBJECTIVE: To determine whether Boston Bowel Preparation Scale (BBPS) scores could serve as a standard definition of adequacy. DESIGN: Cross-sectional observational analysis of colonoscopy data from 36 adult GI endoscopy practices and prospective survey showing 4 standardized colonoscopy videos with varying degrees of bowel cleanliness. SETTING: The Clinical Outcomes Research Initiative. PATIENTS: Average-risk patients attending screening colonoscopy. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Recommended follow-up intervals among average-risk, screening colonoscopies without polyps stratified by BBPS scores. RESULTS: We evaluated 2516 negative screening colonoscopies performed by 74 endoscopists. If the BBPS score was >=2 in all 3 segments (N = 2295), follow-up was recommended in 10 years in 90% of cases. Examinations with total BBPS scores of 3 to 5 (N = 167) had variable recommendations. Follow-up within 1 year was recommended for 96% of examinations with total BBPS scores of 0 to 2 (N = 26). Similar results were noted among 167 participants in a video survey with pre established BBPS scores. LIMITATIONS: Retrospective study. CONCLUSION: BBPS scores correlate with endoscopist behavior regarding follow-up intervals for colonoscopy. A total BBPS score >=6 and/or all segment scores >=2 provides a standardized definition of adequate for 10-year follow-up, whereas total scores <=2 indicate that a procedure should be repeated within 1 year. Future work should focus on finding consensus for management of examinations with total scores of 3 to 5. PMID- 24629423 TI - Evaluation of the curative and preventive efficacy of a single oral administration of afoxolaner against cat flea Ctenocephalides felis infestations on dogs. AB - The efficacy of orally administered afoxolaner for treatment and prevention of repeated infestations with adult Ctenocephalides felis on dogs was evaluated in two studies after administration of a beef-flavored soft chew. In each study, 32 dogs were divided randomly into four equal groups. Dogs in Groups 1 and 3 were not treated and served as controls. Dogs in Groups 2 and 4 were treated on Day 0 with a combination of chewable tablets to be as close as possible to the minimum therapeutic dose of 2.5mg/kg. All animals were infested experimentally with unfed C. felis (100 +/- 5) on Days -1, 7, 14, 21, 28 and 35. Flea killing efficacy was evaluated in both studies while, efficacy against flea egg production was assessed in Study 1. Live fleas were counted at 12 (Groups 1 and 2) and 24h (Groups 3 and 4), after treatment or after weekly infestations. In Study 1, flea eggs were collected and counted at either 12 or 24h after each flea infestation on Days 7, 14, 21, 28 and 35. The results of both studies demonstrate the long lasting and rapid efficacy of afoxolaner against C. felis, when administered as a single oral dose to dogs. For flea counts conducted 24h after treatment or infestation, efficacy was 100% for all time points up to Day 36 in both studies, except for one time point (99.9% on Day 22) for Study 2. For flea counts performed 12h after treatment or infestation, efficacy was >= 95.2% until Day 21 in both studies. Efficacy at 12h was >= 93.0% on Day 35 in Study 1 and >= 89.7% on Day 35 in Study 2. The treated groups had significantly fewer fleas than untreated control dogs in both studies for all flea counts (p=0.003 Study 1, p=0.0006 Study 2). In Study 1, for all egg counts performed at or beyond Day 7, efficacy in egg reduction was >99% for all time points between Days 7 and 35. PMID- 24629424 TI - Evaluation of the efficacy of afoxolaner against two European dog tick species: Dermacentor reticulatus and Ixodes ricinus. AB - The acaricidal efficacy of a novel oral formulation of afoxolaner (NEXGARD((r)), Merial) against two European tick species was assessed in dogs experimentally infested with Ixodes ricinus and Dermacentor reticulatus. Three studies, each characterized by a negative controlled randomized block design, were conducted with a total of 52 beagle or mongrel dogs of both sexes. Starting 2 days before treatment, each dog was infested weekly with approximately 50 ticks. The number of live ticks was counted at 48 h post-treatment (Day 2) as well as 48 h following each infestation on Days 9, 16, 23, and 30. Afoxolaner, administered at an average dose of 2.7 mg/kg bodyweight (range 2.5-2.9 mg/kg), rapidly eliminated the pre-existing tick infestations with over 99% acaricidal efficacy and controlled the weekly re-infestations for up to 30 days post treatment with over 96% efficacy on both tick species. Afoxolaner provides excellent acaricidal efficacy against these two major European tick species using the oral route of administration. PMID- 24629425 TI - Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato. AB - Two studies were conducted to confirm that a single oral dose of the novel insecticide/acaricide afoxolaner is efficacious against existing infestations of Rhipicephalus sanguineus sensu lato in dogs and can control re-infestation for up to 35 days. Each study utilized 16 purpose bred adult dogs using a controlled randomized block design. One or two days prior to treatment, all dogs were infested with 50 unfed adult ticks. On Day 0 one group was treated with an oral chewable formulation of afoxolaner at a dose as close as possible to the minimum dose of 2.5mg/kg. Weekly re-infestations with 50 adult unfed ticks were repeated for five weeks. Forty-eight hours after treatment and after each re-infestation, the number of remaining live ticks on each dog was counted. Treatment with afoxolaner resulted in efficacies of 98.8-100% within 48 h on existing tick infestations, while the efficacy against new tick infestations was >95.7% over five weeks. PMID- 24629426 TI - Efficacy of afoxolaner against Dermacentor variabilis ticks in dogs. AB - Efficacy of afoxolaner, a novel isoxazoline insecticide/acaricide, against Dermacentor variabilis ticks was confirmed in two laboratory studies. Each study utilized a controlled, randomized block design. One day prior to treatment, beagle dogs were infested with 50 unfed adult ticks. Repeat infestations were performed weekly for four weeks. The number of live ticks remaining on each dog was determined 48 h after treatment and after each subsequent infestation. A single oral treatment with a dose approaching the minimum effective dose of afoxolaner (2.5mg/kg) eliminated the pre-existing infestations by D. variabilis ticks and controlled weekly re-infestations with 99.7-100% efficacy up to Day 23 and >97% efficacy at Day 30. PMID- 24629427 TI - Cytological and molecular detection of Leishmania infantum in different tissues of clinically normal and sick cats. AB - Natural infection of domestic cats by Leishmania infantum (synonym: L. chagasi) has been demonstrated in several European, Latin American, and Asian countries, and the estimated prevalence of infection, based mainly on blood PCR, ranges from 0.3% up to 60.6%. In this study we aimed to: (a) estimate the prevalence of the infection by L. infantum in clinically normal cats (group A; n=50) and in cats with various clinical signs (group B; n=50), living in an endemic region, by both cytological examination of four different tissues (lymph node, skin, bone marrow, and conjunctiva) and by PCR in four different tissues (blood, skin biopsies, bone marrow, and conjunctiva); (b) compare the diagnostic sensitivity of the above methods and evaluate for possible associations between their results; and (c) investigate the possible associations between infection by L. infantum and signalment, living conditions, season of sampling, and health status of the cats. The prevalence of the infection in the study population was 41% and did not differ (P=0.839) between group A (42%) and B (40%) cats. Lymph node, skin, bone marrow and conjunctiva cytology was always negative. Therefore, the diagnosis of the infection was based only on PCR in blood, skin biopsy, bone marrow and conjunctiva, which was positive in 13%, 18.2%, 16% and 3.1% of the cats, respectively. PCR was positive in only one of the four tissues in 80.5% of the infected cats. The results differed (P=0.014) among the four tissues and were less frequently positive in conjunctiva compared to skin biopsies and bone marrow (P=0.007 for both comparisons), thus highlighting the need for multiple tissue PCR testing in order to minimize false-negative results. More PCR-positive cats were found when sampling was performed during the period of sandfly activity (odds ratio: 2.44; P=0.022). Also, in group B cats, the likelihood of PCR positivity was higher (odds ratio: 3.93; P=0.042) among those presenting at least one systemic clinical sign that had been previously reported in cats with leishmaniosis. PMID- 24629428 TI - High levels of anti-Phlebotomus perniciosus saliva antibodies in different vertebrate hosts from the re-emerging leishmaniosis focus in Madrid, Spain. AB - From July 2009 to date, a leishmaniosis outbreak has occurred in the south-west of the Madrid region (Spain) and has already accounted for more than 450 human cases in an area that comprises a population of approximately 500,000. The causative agent is Leishmania infantum and the main vector in the area is Phlebotomus perniciosus. Although canine leishmaniosis prevalence in the focus is not higher than the average in the Madrid region, a wild reservoir - the hare - has been implicated. In this study, we examined the exposure of Leishmania reservoirs in the area: dogs, hares, and wild rabbits to sand fly bites using the detection of specific IgG antibodies against P. perniciosus salivary gland homogenate or recombinant salivary proteins. Hares collected in a green park adjacent to the focus (n=59) showed positive exposure to P. perniciosus bites in comparison to hares from a non-endemic area (Czech Republic, n=18). A significant positive correlation was found between IgG response to yellow protein rSP03B and salivary gland homogenate (r=0.902) and between apyrase rSP01B and salivary gland homogenate (r=0.710). Wild rabbits captured in the study area (n=21) presented higher anti-saliva antibody levels than negative control sera and their IgG response against recombinant salivary proteins were positively correlated with salivary gland homogenate (rSP03B: r=0.710; rSP01B: r=0.666). All sera of dogs from the focus (n=34) showed higher anti-saliva IgG levels than that of non exposed dogs. Moreover, dogs protected against sand fly bites through the use of topical insecticides and sleeping indoors showed significantly lower antibody levels than the non-protected ones. Antibody response to all three recombinant salivary proteins tested showed positive correlation with salivary gland extract (rSP03B: r=0.858; rSP01: r=0.864; and rSP01B: r=0.861). Data confirmed the exposure of hares, rabbits and dogs to P. perniciosus bites in the context of an outbreak of human leishmaniosis in Spain, highlighting their involvement in Leishmania transmission by supporting their role as potential reservoirs. This novel methodology represents a promising tool for further epidemiological studies that would help to design better strategies for the control of leishmaniosis in this area and other foci. PMID- 24629429 TI - Evaluation of the efficacy of afoxolaner against Haemaphysalis longicornis on dogs. AB - A controlled study to assess the acaricidal efficacy of afoxolaner in dogs after a single oral administration was conducted against Haemaphysalis longicornis ticks. The study was characterized by a negative controlled randomized block design and included sixteen beagle dogs of both sexes. Starting two days before treatment, each dog was infested weekly with 50 ticks over 4 weeks. The number of live ticks was determined 48 h after treatment and then 48 h after each infestation. The mean dose of afoxolaner received by dogs was 3.0mg/kg (range: 2.5-3.1mg/kg). Afoxolaner rapidly eliminated pre-existing tick infestations (100% ticks killed within 48 h of treatment) and controlled weekly re-infestations (91.9% prophylactic efficacy at Day 30). PMID- 24629430 TI - NEXGARD(r). Afoxolaner, a new oral insecticide-acaricide to control fleas and ticks in dogs. Editorial. PMID- 24629432 TI - [Unique article number rapid publication in Ugeskrift for Laeger]. PMID- 24629431 TI - Safety evaluation of orally administered afoxolaner in 8-week-old dogs. AB - The safety profile of afoxolaner, a new isoxazoline molecule, was evaluated following the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1*, 3* or 5* the maximum exposure dose (6.3mg/kg) in 8-week-old Beagle dogs. Thirty-two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Treatments were administered at three, one-month dose intervals (Days 0, 28 and 56) followed by three, 2-week dose intervals (Days 84, 98 and 112). The study ended at Day 126. The groups were: Group 1: non-treated control; Group 2: afoxolaner chews administered at a dosage of at least 6.3mg/kg (1*); Group 3: afoxolaner chews administered at a dosage of at least 18.9 mg/kg (3*); and Group 4: afoxolaner chews administered at a dosage of at least 31.5mg/kg (5*). All dogs were examined for general health twice a day beginning on at least Day-14. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner plasma concentrations, were performed throughout the study. On Day 126, 2 weeks following the last treatment, all dogs were humanely euthanized prior to the conduction of a full necropsy with tissue collection. No afoxolaner related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically or statistically significant health abnormalities related to the administration of afoxolaner were observed. Vomiting and diarrhea were observed sporadically across all groups including the controls. The kinetics of afoxolaner plasma concentrations was linear following 6 doses of 6.3, 18.9 and 31.5mg/kg and dose proportionality was demonstrated. There were no statistical differences (p<0.05) between samples taken on Days 55 and 83 when compared to Day 27. Based upon the results of this study, afoxolaner was shown to be safe when administered repeatedly in a soft chewable formulation at up to 5* the maximum exposure dose in dogs as young as 8 weeks of age. PMID- 24629434 TI - [ethal neglect]. PMID- 24629433 TI - [Cooperation, integration and consistency improves patient care]. PMID- 24629435 TI - [It is possible for people suffering from mental illness to change their lifestyle]. AB - A significant share of the excess mortality among people suffering from mental illness is due to unhealthy lifestyles. Obesity, smoking, unhealthy diets and sedentary behaviour is twice as frequent among people with mental illness, but the willingness to improve lifestyle is as high as in healthy people. Based on a review of the literature we conclude that it is possible for people with mental illness to change their lifestyle, but they encounter a number of barriers to lifestyle changes, including their symptoms, adverse drug effects and their life situations. PMID- 24629436 TI - [Cancer from the exocrine pancreas]. AB - Improving the prognosis for patients with cancer from the exocrine pancreas (PC) represents a challenge for health-care systems in the Western world. Vague and non-specific symptoms combined with rapid deterioration of the patients' condition often make diagnosis difficult. Multimodality therapy with a combination of surgery followed by adjuvant chemotherapy has improved the long term survival of patients. Recent data suggest improved efficacy of aggressive chemotherapy. Multidisciplinary team management and research are essential in order to further improve the outcome of patients with PC. PMID- 24629437 TI - [Dealing with surgical complications after bariatric gastric bypass surgery]. AB - The subject of this article is surgical complications to Roux-en-Y-gastric bypass and how to deal with them. The article addresses doctors, who are on duty in hospitals without bariatric surgery and who often deal with this patient category in the acute situation. Managing complications is challenging due to both the patient's physiognomy and the wide-ranged change in anatomy. The article gives a review of the literature and hands-on-recommendations for treating anastomotic leak, post-operative bleeding, internal herniation, bowel obstruction and biliary complications. PMID- 24629438 TI - [Clinical assessment cannot predict if children are infected with Mycoplasma pneumoniae]. AB - This meta-analysis was carried out to detect if clinical signs can predict infection with Mycoplasma pneumoniae in children. The only significant finding was that absence of wheezing was associated with M. pneumoniae-infection. The analysis does not justify changes in the recommendation regarding treatment of pneumonia in children. Empiric therapy with macrolides can only be recommended if the patient does not tolerate betalactam. PMID- 24629439 TI - [No contamination of instruments on the trolley during elective arthroplasty]. AB - Infection following arthroplasty is a very serious complication as it has major impact on morbidity and mortality. This study set out to examine if leaving the instruments on the trolley would result in contamination from airborne pathogens during elective hip and knee arthroplasty. We conclude that instruments placed in a laminar airflow field do get contaminated, but further studies with a larger sample size are needed to verify the results. PMID- 24629441 TI - Technical note: How to spare the pronator quadratus during MIPO of distal radius fractures by using a mini-volar plate. AB - Few surgical approaches have been described that spare the pronator quadratus (PQ) during the treatment of distal radius fractures. The PQ supplies blood to the distal radial epiphysis, helps stabilize the distal radio-ulnar joint, and contributes 21% of pronation strength. Sparing the PQ should result in faster bone union and shorter recovery time. To achieve these goals, we currently use a minimally-invasive volar procedure using a specially-designed short plate (APTUS Wrist 2.5 XS, Medartis((c))). A 20mm incision is made over the fracture line as described by Henry. The PQ is dissected and then detached from the volar side of the radius. Forceps are used to slide the plate under the muscle. The screws are locked after carefully elevating the distal edge of the PQ. A preliminary study of distal radius fracture fixation by this technique was performed in 31 patients. The scar was 26mm in length and the duration of surgery was 34minutes on average. Patients wore a removable brace for 15 days, and passive wrist motion without loading was allowed during the first week. Functional recovery was faster than seen in previously published series. An average Quick DASH score of 10 was achieved by the 10th post-operative week. Although there are no contraindications to this technique, the quality of the reduction is more important than the scar size and desire to spare the PQ. Never hesitate to convert the incision to a classical Henry approach if technical difficulties arise. Our technique seems best suited to patients with high functional demands. It is currently being evaluated in a prospective series. PMID- 24629442 TI - Opioid overdose: when good drugs break bad. PMID- 24629443 TI - Epidemiology of emergency department visits for opioid overdose: a population based study. AB - OBJECTIVES: To evaluate the rate of emergency department (ED) visits for opioid overdose and to examine whether frequent ED visits for opioid overdose are associated with more hospitalizations, near-fatal events, and health care spending. PATIENTS AND METHODS: Retrospective cohort study of adults with at least 1 ED visit for opioid overdose between January 1, 2010, and December 31, 2011, derived from population-based data of State Emergency Department Databases and State Inpatient Databases for 2 large and diverse states: California and Florida. Main outcome measures were hospitalizations for opioid overdose, near fatal events (overdose involving mechanical ventilation), and hospital charges during the year after the first ED visit. RESULTS: The analytic cohort comprised 19,831 unique patients with 21,609 ED visits for opioid overdose. During a 1-year period, 7% (95% CI, 7%-7%; n=1389 patients) of the patients had frequent (2 or more) ED visits, accounting for 15% (95% CI, 14%-15%; n=3167) of all opioid overdose ED visits. Middle age, male sex, public insurance, lower household income, and comorbidities (such as chronic pulmonary disease and neurological diseases) were associated with frequent ED visits (all P<.01). Overall, 53% (95% CI, 52%-54%; n=11,412) of the ED visits for opioid overdose resulted in hospitalizations; patients with frequent ED visits for opioid overdose had a higher likelihood of hospitalization (adjusted odds ratio, 3.98; 95% CI, 3.38 4.69). In addition, 10.0% (95% CI, 10%-10%; n=2161) of the ED visits led to near fatal events; patients with frequent ED visits had a higher likelihood of a near fatal event (adjusted odds ratio, 2.27; 95% CI, 1.96-2.66). Total charges in Florida were $208 million (95% CI, $200-$219 million). CONCLUSION: In this population-based cohort, we found that frequent ED visits for opioid overdose were associated with a higher likelihood of future hospitalizations and near fatal events. PMID- 24629444 TI - Predictors of an academic career on radiology residency applications. AB - RATIONALE AND OBJECTIVES: To evaluate radiology residency applications to determine if any variables are predictive of a future academic radiology career. MATERIALS AND METHODS: Application materials from 336 radiology residency graduates between 1993 and 2010 from the Department of Radiology, Duke University and between 1990 and 2010 from the Department of Radiology, Stanford University were retrospectively reviewed. The institutional review boards approved this Health Insurance Portability and Accountability Act-compliant study with a waiver of informed consent. Biographical (gender, age at application, advanced degrees, prior career), undergraduate school (school, degree, research experience, publications), and medical school (school, research experience, manuscript publications, Alpha Omega Alpha membership, clerkship grades, United States Medical Licensing Examination Step 1 and 2 scores, personal statement and letter of recommendation reference to academics, couples match status) data were recorded. Listing in the Association of American Medical Colleges Faculty Online Directory and postgraduation publications were used to determine academic status. RESULTS: There were 72 (21%) radiologists in an academic career and 264 (79%) in a nonacademic career. Variables associated with an academic career were elite undergraduate school (P = .003), undergraduate school publications (P = .018), additional advanced degrees (P = .027), elite medical school (P = .006), a research year in medical school (P < .001), and medical school publications (P < .001). A multivariate cross-validation analysis showed that these variables are jointly predictive of an academic career (P < .001). CONCLUSIONS: Undergraduate and medical school rankings and publications, as well as a medical school research year and an additional advanced degree, are associated with an academic career. Radiology residency selection committees should consider these factors in the context of the residency application if they wish to recruit future academic radiologists. PMID- 24629445 TI - [Pathophysiological hypothesis regarding the role of nicotinamide in the genesis of niacin-induced macular edema]. PMID- 24629446 TI - [Results of fractionated targeted proton beam therapy in the treatment of primary optic nerve sheath meningioma]. AB - INTRODUCTION: Optic nerve sheath meningioma (ONSM) is a common benign neoplasm arising from the arachnoid tissue encapsulating the optic nerve and affects mainly middle aged women. It is a slow-growing tumor for which there is still no consensus on treatment. PURPOSE: To evaluate the safety and efficacy of fractionated targeted proton beam therapy (PBT) in the treatment of ONSM and to define its role in the treatment of these tumors. METHODS AND MATERIALS: We performed a retrospective analysis of 15 patients (13 women and 2 men), mean age 41.8 years, presenting with primary ONSM, followed at the Fondation Ophtalmologique Adolphe de Rothschild (Paris) between September 2006 and August 2013. After a multidisciplinary consultation, all were treated with PBT at a total dose of 52.2 Gy Eco, in fractions of 1.8 Gy Eco, at the Institut Curie (Paris). Patients underwent standardized follow-up including ophthalmologic examinations, visual field testing and imaging every 6 months. Study parameters were post-treatment visual acuity, tumor size on MRI, and treatment side effects RESULTS: We separated the patients into 3 distinct groups: patients treated by PBT after an observation period (4/15), patients treated by PBT after primary surgery (5/15) and patients treated by PBT as primary treatment (6/15). Visual acuity improved in 3 cases, deteriorated in 1 and remained stable in 11 cases. Tumor size on MRI remained stable in 100 % of cases following PBT. No serious adverse effects were recorded after a mean follow-up of 22.4 months (8-79 months). CONCLUSION: Our experience confirms the efficacy and the safety of proton beam therapy in patients with ONSM. PBT presents a promising alternative to surgery and conventional radiotherapy in the treatment of the MGNO. It seems to be effective in controlling tumor size and stabilizing visual function, at the cost of very low toxicity. Additional studies are needed to accurately determine the decision-making criteria and the ideal timing of this treatment. PMID- 24629447 TI - [Anterior dislocation of the lens]. PMID- 24629448 TI - Synthetic approaches to the 2012 new drugs. AB - New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011. PMID- 24629449 TI - Computer-aided identification of novel 3,5-substituted rhodanine derivatives with activity against Staphylococcus aureus DNA gyrase. AB - Methicillin resistant Staphylococcus aureus (MRSA) is among the major drug resistant bacteria that persist in both the community and clinical settings due to resistance to commonly used antimicrobials. This continues to fuel the need for novel compounds that are active against this organism. For this purpose we have targeted the type IIA bacterial topoisomerase, DNA gyrase, an essential enzyme involved in bacterial replication, through the ATP-dependent supercoiling of DNA. The virtual screening tool Shape Signatures was applied to screen a large database for agents with shape similar to Novobiocin, a known gyrase B inhibitor. The binding energetics of the top hits from this initial screen were further validated by molecular docking. Compounds with the highest score on available crystal structure of homologous DNA gyrase from Thermus thermophilus were selected. From this initial set of compounds, several rhodanine-substituted derivatives had the highest antimicrobial activity against S. aureus, as determined by minimal inhibitory concentration assays, with Novobiocin as the positive control. Further activity validation of the rhodanine compounds through biochemical assays confirmed their inhibition of both the supercoiling and the ATPase activity of DNA gyrase. Subsequent docking and molecular dynamics on the crystal structure of DNA gyrase from S. aureus when it became available, provides further rationalization of the observed biochemical activity and understanding of the receptor-ligand interactions. A regression model for MIC prediction against S. aureus is generated based on the current molecules studied as well as other rhodanines derivatives found in the literature. PMID- 24629450 TI - Design, synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents. AB - A new series of pyrano chalcone derivatives containing indole moiety (3-42, 49a 49r) were synthesized and evaluated for their antiproliferative activities. Among all the compounds, compound 49b with a propionyloxy group at the 4-position of the left phenyl ring and N-methyl-5-indoly on the right ring displayed the most potent cytotoxic activity against all tested cancer cell lines including multidrug resistant phenotype, which inhibits cancer cell growth with IC50 values ranging from 0.22 to 1.80MUM. Furthermore, 49b significantly induced cell cycle arrest in G2/M phase and inhibited the polymerization of tubulin. Molecular docking analysis demonstrated the interaction of 49b at the colchicine binding site of tubulin. In experiments in vivo, 49b exerted potent anticancer activity in HepG2 human liver carcinoma in BALB/c nude mice. These results indicated these compounds are promising inhibitors of tubulin polymerization for the potential treatment of cancer. PMID- 24629452 TI - About "Jayaratne YS, Deutsch CK, Zwahlen RA. A 3-dimensional anthropometric analysis of the orolabial region in Chinese young adults" [Br J Oral Maxillofac Surg 2013;51:908-12]. PMID- 24629451 TI - Effect of diazepam on temporomandibular joints in rats with increased occlusal vertical dimension. AB - Anxiolytic agents, mainly benzodiazepines, have been used to treat symptomatic disorders of the temporomandibular joint (TMJ). Our aim was to evaluate the effect of diazepam on the TMJ of rats with increased occlusal vertical dimension (iOVD). Forty male rats were randomly assigned to 4 groups: control rats were given sham iOVD plus saline solution daily for 7 days. The first experimental group was given sham iOVD plus diazepam 2.5mg/kg/intramuscularly daily for 7 days (diazepam alone group); the second had iOVD induced in molars for 7 days plus saline daily for 7 days (iOVD alone group); and the third had iOVD induced in molars for 7 days plus diazepam 2.5mg/kg/intramuscularly daily for 7 days (iOVD plus diazepam group). At the end of each experiment the animals were killed and their bilateral TMJs were removed, randomly stained with haematoxylin and eosin and sirius-red, and immunoassayed. The thickness of condylar cartilage and of fibrous, proliferating, mature, and hypertrophic layers, number of collagen fibres, and the articular area were measured. Proinflammatory cytokines (interleukin (IL)-1alpha, IL-1beta, IL-6, and tumour necrosis factor (TNF)-alpha) were also measured. ANOVA and Tukey's tests or the Kruskal-Wallis test were used to compare data among groups (alpha=5%). Condylar cartilage was thicker in the control group than in the other groups, the diazepam alone group being thicker than the other 2 experimental groups. There were fewer collagen fibres in the 2 groups given diazepam than in the other 2 groups, and there were no significant differences in the area of cartilage among groups. The controls had lower concentrations of all cytokines (p<0.05) than the 3 experimental groups, except for IL-6. Both iOVD groups had higher concentrations of IL-1alpha, IL-1beta, and IL-6 than the diazepam alone group. Diazepam alone was associated with increased concentrations of all cytokines except IL-6. We conclude that both iOVD and diazepam induced significant changes in rats' articular cartilage. PMID- 24629453 TI - Intermaxillary splint and positioning stents to guide mandibular reconstruction. PMID- 24629455 TI - Comparative biomechanical study on three miniplates osteosynthesis systems for stabilisation of low condylar fractures of the mandible. AB - Open reduction and fixation of low condylar fractures of the mandible can be achieved by many osteosynthesis systems that differ in size, shape, and site of placement according to the surgical approach. We investigated the maximum load and rigidity of 4 osteosynthesis systems: the standard double 4-hole straight miniplates, the inverted y-miniplate (with and without self-drilling screws), and the TriLock Delta condyle trauma plate. The standard double 4-hole straight miniplate osteosynthesis achieved the best fixation and resistance in view of a mean (SD) maximum load of 539.8 (100.2)N, followed by the inverted y-miniplate with the self-drilling screws (246.5 (23.8)N), the inverted y-miniplate with standard screws (242.4 (27.2)N), and finally the TriLock Delta plate (167.4 (39.2)N). Analysis of the slope of the force-displacement diagram from 80N to 100N in each group showed that the TriLock Delta miniplate had the highest values for rigidity (17.3 (5.1)N/MUm), followed by the inverted y-miniplate groups with self-drilling screws (14.1 (6.4)N/MUm), and with standard screws (12.6 (2.5)N/MUm). The double 4-hole straight miniplate osteosynthesis had the lowest rigidity (8.7 1.4)N/MUm). Despite the significant difference in the maximum load between the double 4-hole miniplates and other investigated osteosynthesis patterns, all groups had sufficient load for the fixation of low condylar fractures of the mandible when postoperative bite forces and the slowly increasing voluntary clenching during healing were considered. PMID- 24629454 TI - Perforator flaps--how many perforators are necessary to keep a flap alive? AB - Perforator flaps are becoming increasingly important in reconstructive microsurgery because of their reduced donor-site morbidity. However, one drawback is partial necrosis caused by vasospasm or inconsistency of delicate perforator vessels. In this study we have evaluated the number and capacity of perforator vessels with respect to the size of a flap, and the influence of vascular endothelial growth factor (VEGF) on the capacity of perforators in a standard animal model. We realised an epigastric perforator flap 4cm*7cm in 36 rats. In 3 control groups (n=6 in each), flaps were raised based on 4, 2, or 1 perforator vessel(s), while all other perforators as well as the epigastric vessels were ligated. In three study groups (n=6 in each), set up in the same way as the control groups, we also injected a single dose of VEGF into the wound area. After one week, all areas of necrosis were assessed planimetrically. We also evaluated the wounds by laser Doppler flowmetry preoperatively and after one week, and by histological and immunohistochemical examination. An increased number of perforators, together with VEGF, was associated with a significant reduction in the areas of necrosis. This observation was particularly true in flaps based on only one perforator. The inclusion of additional perforators has a more important role in the success of a flap than theoretical models suggest. Proangiogenetic factors may improve the viability of perforator flaps. PMID- 24629456 TI - Changes in the calibre of the upper airway and the surrounding structures after maxillomandibular advancement for obstructive sleep apnoea. AB - Maxillomandibular advancement (MMA) is effective in the treatment of obstructive sleep apnoea. We aimed to assess changes in the calibre of the upper airway, facial skeleton, and surrounding structural position after MMA and their association with improvement in symptoms. Sixteen consecutive adults with moderate-to-severe apnoea were treated by primary MMA. Polysomnography and computed tomography (CT) of the head and neck were done before and at least 6 months after MMA. The calibre of the upper airway, the facial skeleton, and the surrounding structures were measured with image analysis software. After MMA, patients had a significant reduction in their apnoea-hypopnoea index (31.2 (18.8)number of events (n)/hour (h)). The mean (SD) volume of the airway increased significantly in the velopharynx (p<0.01), oropharynx (p=0.001), and hypopharynx (p<0.001) (by 2.3 (2.4), 2.1 (2.6), and 1.7 (1.1)cm(3), respectively) and the length of the airway was significantly decreased (by 3.1 (3.5)mm p<0.01). The soft palate (p<0.001), tongue (p<0.001), and hyoid (p=0.001) moved significantly anteriorly (by 4.4 (2.0), 7.5 (2.8), and 5.7 (5.0)mm, respectively), and these movements were related to the MMA (r=0.6-0.8). The improvement in the apnoea-hypopnoea index was associated with both maxillary advancement and anterior movements of the soft palate and hyoid (r=0.6-0.7). The results of this study suggest that MMA increases the volume in the upper airway and reduces its length. Improvement in obstructive sleep apnoea is associated with the extent of the anterior movements of the maxilla, soft palate, and hyoid. PMID- 24629458 TI - Outcomes of modified Dega acetabuloplasty in acetabular dysplasia related to developmental dislocation of the hip. AB - Developmental dislocation of the hip (DDH) is frequently, even after reduction, associated with residual acetabular dysplasia. Various surgical techniques are used to correct this, one of which is Dega acetabuloplasty. This osteotomy technique has, however, rarely been assessed in this particular indication. The present study therefore sought to describe the technical details, report clinical and radiological results, and present limitations. HYPOTHESIS: Unlike reorientation osteotomy in children, Dega acetabuloplasty does not lead to a high rate of acetabular retroversion at the end of growth. PATIENTS AND METHODS: Sixteen Dega acetabuloplasties in 15 patients were assessed on joint range of motion, limp, lower limb length discrepancy and impaired everyday activity, pre operatively and at end of follow-up. Hips were classified following Wicart et al. (2003). Radiologic assessment comprised Wiberg angle and acetabular index, pre- and post-operatively and at follow-up. Acetabular retroversion was analyzed by crossover sign, and hips were classified following Severin. RESULTS: Median age at surgery was 3 years (range, 1.1-12.2 years) and 10 years (6.4-17.8) at end of follow-up. At end of follow-up, all hips were pain-free and classified as Wicart A, and all activities were allowed. Radiologically, hips were classified as Severin I, II or IV, in 11 (68.5%), 4 (25%) and 1 (6.5%) cases respectively. Wiberg angle rose from a mean 3.3 degrees (-30 degrees to 30 degrees ) to 23 degrees (10 degrees to 38 degrees ) and acetabular index fell from a mean 31 degrees (25 degrees to 45 degrees ) to 20 degrees (5 degrees to 30 degrees ) with surgery, and both continued to improve over follow-up: 26 degrees (12-45 degrees ) and 13 degrees (3-24 degrees ) respectively (P<0.05). Acetabular retroversion was found in 2 of the 10 hips with Y cartilage fusion. DISCUSSION: Modified Dega acetabuloplasty was effective in correcting acetabular dysplasia in DDH. Functional and radiological results were good, with a low rate of acetabular retroversion (2/10), unlike with other techniques. LEVEL OF EVIDENCE: Level IV. Therapeutic study. PMID- 24629457 TI - C1-C2 stabilization by Harms arthrodesis: indications, technique, complications and outcomes in a prospective 26-case series. AB - INTRODUCTION: C1-C2 arthrodesis is a surgical challenge due to the proximity of neurovascular structures (vertebral arteries and spinal cord) and the wide range of motion of the joint, hampering bone fusion. A variety of techniques have been successively recommended to reduce anatomic risk and improve results in terms of biomechanical stability and fusion rates. Recently, Harms described a new technique using polyaxial screws in the C1 lateral masses and C2 pedicles. MATERIAL AND METHOD: The present study reports our experience in a consecutive series of 26 patients operated on by C1-C2 arthrodesis using the Goel and Harms technique, and details technical aspects step by step. Routine systematic immediate postoperative CT and 6-month CT controlled screw positioning and assessed fusion. Follow-up was at least 1 year, except in 2 cases (10 months). RESULTS: Twenty-six patients with a mean age of 57 years were included. Indications comprised: C2 non-union (n=11), C1-C2 fracture and/or dislocation (n=11), inflammatory pathology (n=2) and tumoral pathology (n=2). The results showed the technique to be reliable (no neurovascular complications and 85% of screws with perfect positioning) and an excellent rate of fusion (100% at 6 months). CONCLUSION: Anatomic and biomechanical considerations, combined with the present clinical and radiological outcomes, indicate that Goel and Harms fusion is to be considered the first-line attitude of choice for posterior C1-C2 arthrodesis. LEVEL OF EVIDENCE: Level IV prospective study. PMID- 24629460 TI - Chinese biobanks: present and future. AB - As the demands of scientific research and application for specimens increase rapidly, biobanks in China have been springing up over the recent years. This paper summarizes Chinese biobanks through investigation and survey on operative, managerial, ethical conditions and challenges of biobanks. At present, hospitals and research institutes in China set up and operate most of the biobanks, collecting human specimens to support clinical and scientific research. With the development of bio-industry and arrival of the big data era, biobanks need not only collect and store human and non-human specimens but also to manage the big data associated with these specimens. PMID- 24629459 TI - Allometric growth in juvenile marine turtles: possible role as an antipredator adaptation. AB - Female marine turtles produce hundreds of offspring during their lifetime but few survive because small turtles have limited defenses and are vulnerable to many predators. Little is known about how small turtles improve their survival probabilities with growth though it is assumed that they do. We reared green turtles (Chelonia mydas) and loggerheads (Caretta caretta) from hatchlings to 13 weeks of age and documented that they grew wider faster than they grew longer. This pattern of allometric growth might enable small turtles to more quickly achieve protection from gape-limited predators, such as the dolphinfish (Coryphaena hippurus). As a test of that hypothesis, we measured how dolphinfish gape increased with length, reviewed the literature to determine how dolphinfish populations were size/age structured in nearby waters, and then determined the probability that a small turtle would encounter a fish large enough to consume it if it grew by allometry vs. by isometry (in which case it retained its hatchling proportions). Allometric growth more quickly reduced the probability of a lethal encounter than did isometric growth. On that basis, we suggest that allometry during early ontogeny may have evolved because it provides a survival benefit for small turtles. PMID- 24629461 TI - [Ugeskrift for Laegers publishing strategy changes after new year]. PMID- 24629462 TI - [Coffee: the panacea of the present]. AB - The effects of coffee on the human body have been recognized through centuries and have now become the subject of systematic research. Coffee contains many biologically active substances, but the content of these is influenced by the method of brewing the coffee and the addition of milk. This review focuses on less well-known but rather more amusing facts regarding the effects of coffee and concludes that coffee drinking is beneficial as regards mental and physical capacity and mortality. These effects are highly desirable for doctors in clinical duty, and for that reason, attempts should be made to increase the intake of coffee in this population. PMID- 24629463 TI - [Participation in dinner at a medical conference reduces vascular age and is recommended]. AB - A total of 60 attendees at a medical conference had their peripheral and central blood pressure measured before and after the conference dinner. While heart rate increased, all measurements of peripheral and central blood pressure showed lower values after dinner. Furthermore, attendees' central vascular age was reduced by 13 years after dinner when augmentation index was evaluated in relation to age. Although 13% experienced postprandial hypotension, the present study motivates attendance at medical conference dinners due to the health implications of lowered blood pressure. PMID- 24629464 TI - [The effect of alcohol and fatty foods on the P-alanine aminotransferase level in rheumatoid- and psoriatic arthritis patients]. AB - INTRODUCTION: The P-alanine aminotransferase level (P-ALAT) is used as a biomarker for drug-induced liver toxicity in rheumatic patients treated with methrotrexate and leflunomide. A rumour at Kong Christian X's Gigthospital states that P-ALAT analysed in the beginning of January should be taken with a pinch of salt due to an increased intake of fatty foods and alcohol through Christmas. MATERIAL AND METHODS: In a retrospective study of P-ALAT, performed on 133 patients diagnosed with either rheumatoid- or psoriatic arthritis (median age 62 years) the change in P-ALAT over Christmas was recorded along with medical treatment and disease activity. A total of 88 patients were included, while 45 were excluded due to disease activity or change of drug-dosage. RESULTS: P-ALAT increased significantly through Christmas. Treatment with methotrexate or leflunomide was not a significant explanatory variable but age was. Lower age predicted higher P-ALAT increase over Christmas. The changes in P-ALAT did not lead to changes in medical treatment. CONCLUSION: A statistical significant increase of P-ALAT was detected. This might be due to exaggerated consumption of fatty food and alcohol during Christmas or less likely due to heavy dancing around the Christmas tree. The increase of P-ALAT during Christmas is of no clinical significance. Although the rumor is true, there is no need for worries. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24629465 TI - [Sex-induced air embolism in women]. AB - Death as a result of air embolism has been reported following sexual activity such as vaginal insufflation or coitus a tergo. It is a very uncommon cause of death, however, during pregnancy and puerperium the risk increases due to non collapsible veins at the placental site. Air embolism should be suspected in all sudden female deaths related to sexual activity in order to initiate appropriate treatment to minimize maternal and fetal morbidity and mortality. PMID- 24629466 TI - [Santa Claus is perceived as reliable and friendly: results of the Danish Christmas 2013 survey]. AB - INTRODUCTION: Several studies have indicated that the population in general perceives doctors as reliable. In the present study perceptions of reliability and kindness attributed to another socially significant archetype, Santa Claus, have been comparatively examined in relation to the doctor. MATERIALS AND METHODS: In all, 52 randomly chosen participants were shown a film, where a narrator dressed either as Santa Claus or as a doctor tells an identical story. Structured interviews were then used to assess the subjects' perceptions of reliability and kindness in relation to the narrator's appearance. RESULTS: We found a strong inclination for Santa Claus being perceived as friendlier than the doctor (p = 0.053). However, there was no significant difference in the perception of reliability between Santa Claus and the doctor (p = 0.524). CONCLUSION: The positive associations attributed to Santa Claus probably cause that he is perceived friendlier than the doctor who may be associated with more serious and unpleasant memories of illness and suffering. Surprisingly, and despite him being an imaginary person, Santa Claus was assessed as being as reliable as the doctor. PMID- 24629467 TI - [A button battery in the ear as cause of acute hearing loss and confusion in an elderly patient]. AB - A 95-year-old memory-impaired man presented with acute hearing loss and confusion. A head CT showed a metallic foreign body (a button battery from a hearing aid) in the left external auditory canal. Damage caused by batteries, immediate treatment and incidence of batteries as foreign bodies in the elderly are discussed. PMID- 24629468 TI - [The sweet Christmas rash]. AB - Christmas tree hypersensitivity is a rare condition, which has so far obtained scarce attention in the medical literature. We present two clinical cases of hypersensitivity associated with Christmas tree exposure, a 51-year-old woman with allergic contact dermatitis and a 41-year-old man with allergic rhinitis. The female patient had a positive patch test reaction to colophony, and the male patient had a positive skin prick test reaction to alternaria mould. Both were successfully advised to avoid prolonged exposure to Christmas trees and buy artificial trees for Christmas. PMID- 24629469 TI - [Fall during dancing can lead to urinary bladder rupture]. AB - The definition of dancing is body movements performed to music. It is hard to imagine any festive occasion without music and dancing. It is also a great exercise which helps you to stay in shape. As with any other form of sports, dancing can lead to injury. In this case report it is described how a fall during dancing resulted in urinary bladder rupture. This type of injury under these circumstances has never been described before in the literature. PMID- 24629470 TI - [Not all dietary supplements are biodegradable]. AB - A 65-year-old man had for some time noticed rounded elements in his faeces. It was examined for parasites, which were, however, not detected. A specimen was then sent to a department of pathology. The specimen consisted of a rounded and collapsed process, 12 mm in diameter. It was quite thin-walled and hollow; the wall itself was tough and not elastic and classified as non-biological material. It was concluded that it was probably a capsule of medicine, dietary supplements, oil or a similar substance. The patient had eaten fish oil in capsules, and they had apparently not been biodegradable. PMID- 24629471 TI - [Traumas to the scrotum or penis can be caused by "ordinary objects"]. AB - In boys, most traumas to the scrotum result from sports or straddle injuries and do typically not inflict serious injury. Due to the small size and mobility of the prepubertal testicles, testicular injuries from penetrating trauma are less common in this age group. Penetrating scrotal injury, which poses a significant threat to testicular viability, is more prevalent among adolescents and young men. We describe two unusual genital injuries; one in childhood and the other in adulthood. PMID- 24629472 TI - [The geese who flew home for Christmas]. AB - Gray geese of the bar-headed type (Anser indicus synonym: Eulabeia indica) perform trans-Himalayan migratory flight at extreme altitude. The physiological mechanisms include hyperventilation of cold air, increased lung diffusion capacity, proton gradients, high muscular temperature, amino acid mutation in haemoglobin and cytochrome oxidase, re-location of mitochondria, and extreme shifts in the oxy-haemoglobin dissociation curve due to Bohr- and temperature effects. The second annual migration takes place in late autumn, and the bar headed geese come home in due time before Christmas. PMID- 24629473 TI - [Burn from cellular phone]. PMID- 24629474 TI - [One should not believe everything the eye sees]. PMID- 24629475 TI - [Spanish FRAX((r)): pathing the way through walking]. PMID- 24629476 TI - Plasma S100A12 is associated with functional outcome after ischemic stroke: Research for Biomarkers in Ischemic Stroke. AB - BACKGROUND: Ischemic stroke is accompanied by an inflammatory response, which exacerbates brain injury and deteriorates functional outcome. S100A12 is expressed abundantly in granulocytes, and has been implicated to play an important role on inflammatory reactions in various disease states. We aimed to determine the association between plasma S100A12 levels and a functional outcome in patients with acute ischemic stroke. METHODS: We prospectively included 171 patients with acute ischemic stroke within 24h after onset in this study. Plasma samples were collected for the measurement of S100A12 levels. Poor functional outcome was defined as a modified Rankin Scale of 2-6 at day 90 after stroke onset. RESULTS: Of 171 patients, 74 (43.3%) had a poor functional outcome at day 90 after stroke onset. Plasma S100A12 levels on admission were significantly higher in patients with a poor functional outcome (2.1 [1.2-5.1] ng/mL, median [interquartile]) than in those with a favorable outcome (1.1 [0.5-2.0] ng/mL; p<0.001). Multivariate analysis showed that the highest quartile of plasma S100A12 levels on admission showed a significantly higher risk for a poor functional outcome (odds ratio, 4.01; 95% confidence interval, 1.09-16.10; p=0.03) than the lowest quartile. CONCLUSIONS: High plasma S100A12 levels on admission are associated with a poor functional outcome in patients with acute ischemic stroke. PMID- 24629477 TI - The effect of topiramate and lamotrigine on rat bone mass, structure and metabolism. AB - There is only limited data concerning the effect of the newer antiepileptic drugs on bone. The objective of this study was to determine the effect of topiramate (TPM) and lamotrigine (LTG) monotherapy on bone mineral density (BMD), mineral content (BMC), bone markers, body composition and bone mechanical strength in the orchidectomized (ORX) rat model. 24 orchidectomized Wistar rats were divided into control and test groups, 8 rats in each group. The control rats received standard laboratory diet (SLD) while rats in the test group were fed with SLD enriched with LTG or TPM for 12 weeks. Dual energy X-ray absorptiometry was used to measure bone mineral density. The concentrations of bone metabolism markers were assayed in bone homogenate. In addition, both femurs were measured and used for biomechanical testing. Compared to the control group, both test groups had significantly lower weight, fat mass, whole body and femur BMD, BMC and reduced mechanical strength of bone. All of these changes were more pronounced in rats exposed to LTG. In conclusion, both LTG and TPM significantly reduce BMD and body weight and impair mechanical strength of bone. A question arises as to the degree of dependence of the effect on the dose. Further studies are warranted to establish whether LTG and TPM may have a clinically significant effect on BMD exclusively in the model of gonadectomized rats, or whether the effect applies also in the model of gonadally intact animals, and in the respective human models. PMID- 24629478 TI - Body mass index and dietary intervention: implications for prognosis of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is an adult onset, neurodegenerative disease that is characterized by the loss of upper (corticospinal) and lower motor neurons. ALS is a multifactorial disease whereby a combination of genetic and environmental factors may contribute to disease pathogenesis. While the majority of studies indicate that the underlying causes for ALS pathology may be due to multiple defects at the cellular level, factors that have recently been identified to be associated with survival could lead to the development of beneficial interventions. In ALS, a higher pre-morbid body mass index (BMI) and the maintenance of BMI and nutritional state is associated with improved outcome. This review will focus on the associations between body composition and adiposity relative to disease duration and risk, and will discuss current evidence that supports the benefits of improving energy balance, and the maintenance of body mass through nutritional intervention in ALS. PMID- 24629479 TI - Protective behavioral strategies mediate problem-focused coping and alcohol use in college students. AB - OBJECTIVE: Protective behavioral strategies have emerged as a construct protective against alcohol use. The current study examines the theoretical associations among general coping styles, protective behavioral strategies, drinking to cope motives, and alcohol use in college students. METHOD: Analyses of fully latent variables were conducted using structural equation modeling in a sample of 327 college students. RESULTS: Protective behavioral strategies partially mediated the association between problem-focused coping and alcohol use. Behaviorally oriented problem-focused coping strategies accounted for the positive relationship between problem-focused coping and protective behavioral strategies whereas cognitively oriented problem-focused coping strategies were associated with less use of protective behavioral strategies and increased alcohol use. CONCLUSIONS: This is the first study to find that protective behavioral strategies are more likely to be used by college students who endorse using a problem-focused coping style, especially if they tend to use behaviorally oriented problem-focused coping strategies. These findings extend the literature on protective behavioral strategies and indicate that students less likely to use problem-focused coping skills to deal with stress in general may need additional interventions to increase their use of protective behavioral strategies. PMID- 24629480 TI - Behavioral cessation treatment of waterpipe smoking: The first pilot randomized controlled trial. AB - BACKGROUND: Waterpipe use has increased dramatically in the Middle East and other parts of the world. Many users exhibit signs of dependence, including withdrawal and difficulty quitting, but there is no evidence base to guide cessation efforts. METHODS: We developed a behavioral cessation program for willing-to-quit waterpipe users, and evaluated its feasibility and efficacy in a pilot, two arm, parallel group, randomized, open label trial in Aleppo, Syria. Fifty adults who smoked waterpipe >=3 times per week in the last year, did not smoke cigarettes, and were interested in quitting were randomized to receive either brief (1 in person session and 3 phone calls) or intensive (3 in-person sessions and 5 phone calls) behavioral cessation treatment delivered by a trained physician in a clinical setting. The primary efficacy end point of the developed interventions was prolonged abstinence at three months post-quit day, assessed by self-report and exhaled carbon monoxide levels of <10 ppm. Secondary end points were 7 day point-prevalent abstinence and adherence to treatment. RESULTS: Thirty percent of participants were fully adherent to treatment, which did not vary by treatment group. The proportions of participants in the brief and intensive interventions with prolonged abstinence at the 3-month assessment were 30.4% and 44.4%, respectively. Previous success in quitting (OR=3.57; 95% CI=1.03-12.43) predicted cessation. Higher baseline readiness to quit, more confidence in quitting, and being unemployed predicted a better adherence to treatment (all p-values <0.05). CONCLUSIONS: Brief behavioral cessation treatment for waterpipe users appears to be feasible and effective. PMID- 24629481 TI - Childhood trauma and suicide risk in a sample of young individuals aged 14-35 years in southern Brazil. AB - Suicide is among the main causes of death of people aged between 15 and 44 years old. Childhood trauma is an important risk factor for suicide. Hence, the objective of this study was to verify the relationship between childhood trauma and current suicide risk (suicidal behavior and ideation) in individuals aged 14 35 years, in the city of Pelotas, Brazil. This is a cross-sectional, population based study. Sample selection was performed by clusters. Suicide risk was evaluated using the Mini International Neuropsychiatric Interview (MINI) and Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Moreover, the participants responded to a questionnaire concerning socioeconomic status, work, and substance use. The sample was composed of 1,380 individuals. The prevalence of suicide risk was 11.5%. The prevalence figures of childhood trauma were 15.2% (emotional neglect), 13.5% (physical neglect), 7.6% (sexual abuse), 10.1% (physical abuse), and 13.8% (emotional abuse). Suicide risk was associated (p<.001) with gender, work, alcohol abuse, tobacco use, and all types of childhood trauma. The odds of suicide risk were higher in women (OR=1.8), people who were not currently working (OR=2.3), individuals who presented alcohol abuse (OR=2.6), and among tobacco smokers (OR=3.4). Moreover, suicide risk was increased in all types of trauma: emotional neglect (OR=3.7), physical neglect (OR=2.8), sexual abuse (OR=3.4), physical abuse (OR=3.1), and emotional abuse (OR=6.6). Thus, preventing early trauma may reduce suicide risk in young individuals. PMID- 24629482 TI - Comorbidity of PTSD in anxiety and depressive disorders: prevalence and shared risk factors. AB - The present study aims to assess comorbidity of posttraumatic stress disorder (PTSD) in anxiety and depressive disorders and to determine whether childhood trauma types and other putative independent risk factors for comorbid PTSD are unique to PTSD or shared with anxiety and depressive disorders. The sample of 2402 adults aged 18-65 included healthy controls, persons with a prior history of affective disorders, and persons with a current affective disorder. These individuals were assessed at baseline (T0) and 2 (T2) and 4 years (T4) later. At each wave, DSM-IV-TR based anxiety and depressive disorder, neuroticism, extraversion, and symptom severity were assessed. Childhood trauma was measured at T0 with an interview and at T4 with a questionnaire, and PTSD was measured with a standardized interview at T4. Prevalence of 5-year recency PTSD among anxiety and depressive disorders was 9.2%, and comorbidity, in particular with major depression, was high (84.4%). Comorbidity was associated with female gender, all types of childhood trauma, neuroticism, (low) extraversion, and symptom severity. Multivariable significant risk factors (i.e., female gender and child sexual and physical abuse) were shared among anxiety and depressive disorders. Our results support a shared vulnerability model for comorbidity of anxiety and depressive disorders with PTSD. Routine assessment of PTSD in patients with anxiety and depressive disorders seems warranted. PMID- 24629483 TI - The clinical impact of deficiency in DNA non-homologous end-joining. AB - DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency - (S)CID - due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology. PMID- 24629484 TI - Single-molecule views of MutS on mismatched DNA. AB - Base-pair mismatches that occur during DNA replication or recombination can reduce genetic stability or conversely increase genetic diversity. The genetics and biophysical mechanism of mismatch repair (MMR) has been extensively studied since its discovery nearly 50 years ago. MMR is a strand-specific excision resynthesis reaction that is initiated by MutS homolog (MSH) binding to the mismatched nucleotides. The MSH mismatch-binding signal is then transmitted to the immediate downstream MutL homolog (MLH/PMS) MMR components and ultimately to a distant strand scission site where excision begins. The mechanism of signal transmission has been controversial for decades. We have utilized single molecule Forster Resonance Energy Transfer (smFRET), Fluorescence Tracking (smFT) and Polarization Total Internal Reflection Fluorescence (smP-TIRF) to examine the interactions and dynamic behaviors of single Thermus aquaticus MutS (TaqMutS) particles on mismatched DNA. We determined that TaqMutS forms an incipient clamp to search for a mismatch in ~1 s intervals by 1-dimensional (1D) thermal fluctuation-driven rotational diffusion while in continuous contact with the helical duplex DNA. When MutS encounters a mismatch it lingers for ~3 s to exchange bound ADP for ATP (ADP->ATP exchange). ATP binding by TaqMutS induces an extremely stable clamp conformation (~10 min) that slides off the mismatch and moves along the adjacent duplex DNA driven simply by 1D thermal diffusion. The ATP-bound sliding clamps rotate freely while in discontinuous contact with the DNA. The visualization of a train of MSH proteins suggests that dissociation of ATP-bound sliding clamps from the mismatch permits multiple mismatch-dependent loading events. These direct observations have provided critical clues into understanding the molecular mechanism of MSH proteins during MMR. PMID- 24629485 TI - Studying the organization of DNA repair by single-cell and single-molecule imaging. AB - DNA repair safeguards the genome against a diversity of DNA damaging agents. Although the mechanisms of many repair proteins have been examined separately in vitro, far less is known about the coordinated function of the whole repair machinery in vivo. Furthermore, single-cell studies indicate that DNA damage responses generate substantial variation in repair activities across cells. This review focuses on fluorescence imaging methods that offer a quantitative description of DNA repair in single cells by measuring protein concentrations, diffusion characteristics, localizations, interactions, and enzymatic rates. Emerging single-molecule and super-resolution microscopy methods now permit direct visualization of individual proteins and DNA repair events in vivo. We expect much can be learned about the organization of DNA repair by linking cell heterogeneity to mechanistic observations at the molecular level. PMID- 24629487 TI - Expression profiles for 14-3-3 zeta and CCL20 in pancreatic cancer and chronic pancreatitis. AB - BACKGROUND: Pancreatic cancer (PCA) has a dismal prognosis because it is often diagnosed at an advanced stage. The overall survival rate is <5% after five years. Chronic pancreatitis (CP) is one of the most important risk factors for PCA. A major difficulty is to distinguish between CP and PCA at both clinical and morphologic level. The aim of this study was to assess the impact of the expression profiles for 14-3-3 zeta and CCL20 to histologically discriminate between PCA and CP. METHODS: In PCA (n=138) and CP (n=36) tissue samples, the expression of 14-3-3 zeta and CCL20 was examined by immunohistochemistry. Associations between expression profiles of 14-3-3 zeta and CCL20 expression in PCA, CP as well as MANT (matched adjacent normal tissue) (n=138) and clinicopathologic variables were analyzed. RESULTS: The expression of CCL20 and 14-3-3 zeta was significantly higher in PCA than in CP and MANT. For CP compared to MANT, no significant differences were observed for expression profiles of both 14-3-3 zeta and CCL20. CONCLUSION: CCL20 and 14-3-3 zeta are molecules that play a putative role during tumorgenesis in pancreas, and may therefore be new parameters for histological diagnosis and discrimination between PCA and CP. PMID- 24629488 TI - A modified point count method as a practical approach to assess the tumor volume and the percent gland involvement by prostate carcinoma. AB - This study reports a modified point-count method for quantifying the extent of carcinoma in prostatectomy specimens (n=143), as adapted from Billis et al. (2003) [3]. The prostates were studied as follows: the basal/apical margins were sampled using the cone method. The remainder of the gland was divided into 12 quadrant-shaped regions that were sampled using two slices. Eight equidistant points were marked directly on the coverslip over each fragment. The points inside the tumoral areas were counted and expressed as both the percentage of prostate gland involvement by carcinoma (PGI) and the tumor volume (TV). A significant correlation between the preoperative PSA levels and each of the three quantitative estimations were observed, with improved correlations with the PGI and TV values obtained using the point-count method (viz. number of slices involved (NSI) (r=0.32), PGI (r=0.39) and TV (r=0.44)). With the data sets stratified into three categories, all three methods correlated with multiple parameters, including Gleason scores >=7, primary Gleason scores >=4, perineural/angiolymphatic invasion, extraprostatic extension, seminal vesicle invasion and positive margins. All three quantitative methods were associated with morphologic features of tumor progression. The results obtained using this modified point-count method correlate more strongly with preoperative PSA levels. PMID- 24629489 TI - KRAS mutational analysis in ductal adenocarcinoma of the pancreas and its clinical significance. AB - Mutations of KRAS are detectable in 70-90% of pancreatic duct adenocarcinomas (PDAC), using direct sequencing. We used a highly sensitive molecular method in order to investigate: (a) the frequency and prognostic significance of different KRAS mutations and, (b) whether the presence of KRAS mutations in histologically negative resection margins of PDAC could explain local tumor recurrence after surgery. Twenty-seven patients with histologic diagnosis of PDAC, radical pancreaticoduodenectomy and histologically-negative margins were evaluated. KRAS mutations were searched for mutant-enriched PCR in tumor and negative resection margins. KRAS mutations were detected in 85.2% of the cases; the most frequent mutation was G12D (48.1%). Shorter OS was found in patients with G12D (25 months; 95% CI, 20.5-29.5), vs patients with other mutations (31.5 months; 95% CI, 25.6 37.1) (N.S.). KRAS mutation in histologically-negative margins was detected in one patient who died of locoregional recurrence; six patients had tumor recurrence but no mutations in surgical margins. The high frequency of KRAS mutations suggests a search for KRAS status to improve the diagnosis in suspected cases; the G12D mutation could be related to poor prognosis, but without statistical significance. No correlation was found between the frequency of cancer recurrence and KRAS mutations in surgical margins. PMID- 24629490 TI - Anatomical details of neurogenic heterotopic ossification anterior to the ankylotic hip. AB - Neurogenic heterotopic ossification (NHO) is a common complication in patients with spinal cord injury (SCI) and traumatic brain injury (TBI). Although there are many reports regarding the etiology, pathophysiology, and medical management, few studies elaborate the anatomical details of NHO, which leads to ankylosis of the hip joint. A prospective study on surgical resection of NHO in patients with hip ankylosis was conducted. Radiography and magnetic resonance imaging (MRI) were used to assess the relationship of the NHO block with the blood vessels, peripheral nerve, and surrounding muscles and bones. The anatomical relationships were also assessed and documented during the surgical procedures. NHO, which is anterior to the hip and causes hip ankylosis, settles into tissue planes without involving the tissue itself and does not disrupt the femoral neurovascular structures. The NHO bone block can then fuse to the cortex of adjacent bone. During resection, the normal bony contour should be exposed as a marker to guide the resection in order to avoid iatrogenic fracture. PMID- 24629491 TI - Transfemoral aortic valve implantation for severe aortic stenosis in a patient with dextrocardia situs inversus. AB - Transcatheter aortic valve implantation (TAVR) has grown rapidly over the past 10 years. Device and delivery catheter systems have evolved to facilitate the procedure and reduce the risk of associated complications, including those related to vascular access. It is important to understand the utility of the TAVR equipment in patients with more challenging anatomy to select the most appropriate technique for this complex procedure. We report the first case, to our knowledge, of a patient with dextrocardia situs inversus and previous coronary artery bypass grafting who underwent TAVR from the femoral route using the Edwards SAPIEN XT Novaflex+ Transfemoral System (Edwards Lifesciences, Irvine, CA). PMID- 24629492 TI - Perivalvular approach to percutaneous coronary intervention after transcatheter aortic valve replacement. PMID- 24629493 TI - Renal denervation for drug-resistant hypertension: suffering its original sin, seeking redemption. PMID- 24629494 TI - The prognostic significance of Gleason scores in metastatic prostate cancer. AB - PURPOSE: Although the majority of metastatic prostate cancer (mPCa) will arise from tumors with Gleason scores (GS) of 8 to 10 existing tumor grade analyses for mPCa have been almost uniformly limited to comparisons of <=7 vs. >=8. In this analysis, we comprehensively evaluate the GS as a prognostic factor for mPCa in the era of the updated Gleason grading system. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with mPCa, GS 6 to 10, diagnosed from 2006 to 2008. GS and primary-secondary Gleason pattern variations were analyzed for overall survival and prostate cancer-specific survival (PCSS). RESULTS: A total of 4,654 patients were evaluable. At 4 years, the overall survival rates were 51%, 45%, 34%, 25%, and 15% and PCSS rates were 69%, 57%, 44%, 33%, and 21% for GS 6, 7, 8, 9, and 10, respectively. Survival differences for GS 7 vs. 8, 8 vs. 9, and 9 vs. 10 were highly significant on both univariate and multivariate analyses accounting for age, prostate-specific antigen level, and T stage (all P<0.001). Gleason pattern 5 was an independent prognostic factor, both overall for patients with GS 6 to 10 and on primary secondary Gleason pattern comparisons within the GS 8 (4+4 vs. 3+5 and 5+3) and GS 9 (4+5 vs. 5+4) subgroups. No survival differences were observed between 3+4 vs. 4+3. Overall, lower prostate-specific antigen level, younger age, and lower GS were associated with improved survival, with GS being the strongest prognostic factor for PCSS. CONCLUSIONS: In this large population-based cohort, stratified survival outcomes were observed for GS 6 to 10, with sequential comparisons of GS 7 to 10, and the presence and extent of Gleason pattern 5 representing independent prognostic factors in the metastatic setting. PMID- 24629495 TI - Chromosome 9p deletions are an independent predictor of tumor progression following nephrectomy in patients with localized clear cell renal cell carcinoma. AB - OBJECTIVES: Chromosome 9p deletions have been observed in 14% to 36% of patients with clear cell renal cell carcinoma (ccRCC) and are associated with advanced stage tumors. We evaluated whether chromosome 9p deletions are an independent predictor of worse outcomes in patients with localized ccRCC. MATERIALS AND METHODS: In this retrospective study, tumor samples from 94 patients with ccRCC NX-0 M0 who underwent radical nephrectomy or conservative renal surgery were analyzed using a fluorescence in situ hybridization technique. RESULTS: The median follow-up period was 11.7 years, and 9p deletions were identified in 15% of cases. The cancer-specific survival rate estimated at 5 and 10 years was 99% and 96%, respectively, for patients without such chromosomal losses and 71% and 57% in patients with a loss of 9p (P<0.001). Chromosome 9p deletions were an independent prognostic factor in a multivariate analysis, increasing the risk of death due to disease by 28-fold (95% CI: 5-155, P<0.001). In patients with a low risk of progression, i.e., a low Stage, Size, Grade, and Necrosis score (0-2), low risk according to the University of California at Los Angeles Integrated Staging System, and low risk according to the pathological triad used at University of Sao Paulo, tumors with 9p deletions were significantly associated with a poorer cancer-specific survival at 10 years: 70%, 67%, and 67% vs. 98%, 97%, and 98%, respectively, in patients without 9p deletions. CONCLUSION: Chromosome 9p deletions independently establish a poorer prognosis for patients with localized ccRCC, providing further relevant clinical information that may improve the predictive ability of the main prognostic systems currently in use. PMID- 24629496 TI - Dermatological exposure to coal tar and bladder cancer risk: a case-control study. AB - OBJECTIVE: Coal tar ointments are used as treatment of various skin diseases, especially psoriasis and eczema. These ointments contain several carcinogenic polycyclic aromatic hydrocarbons. Metabolites of these polycyclic aromatic hydrocarbons are excreted in the urine and therefore, dermatological use of coal tar may be associated with an increased risk of bladder cancer. The objective of this study was to evaluate the association between dermatological use of coal tar ointments and bladder cancer. MATERIAL AND METHODS: A population-based case control study was conducted including 1,387 cases diagnosed with bladder cancer and 5,182 population controls. Information on the use of coal tar, history of skin disease, and known risk factors for bladder cancer was obtained through postal questionnaires. Logistic regression analyses were performed to estimate the risk of bladder cancer after coal tar treatment, adjusted for age, gender, smoking status, duration of smoking, and intensity of smoking. RESULTS: The use of coal tar ointments was approximately equal among cases and controls (3.8% vs. 3.0%, respectively). Dermatological application of coal tar was not significantly associated with bladder cancer (adjusted odds ratio = 1.37, 95% CI: 0.93-2.01). An inverse association between bladder cancer and a history of skin disease was observed (adjusted odds ratio = 0.74, 95% CI: 0.61-0.90). CONCLUSION: This is the first study with a specific aim to study the association between the use of coal tar preparations and bladder cancer. The results suggest that there is no reason for safety concerns with respect to the risk of bladder cancer after the use of coal tar preparations in dermatological practice. PMID- 24629497 TI - Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: a registry-based analysis. AB - OBJECTIVES: The aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: A national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs. RESULTS: Median progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013. CONCLUSION: PFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy. PMID- 24629498 TI - NLR is predictive of upstaging at the time of radical cystectomy for patients with urothelial carcinoma of the bladder. AB - OBJECTIVE: To evaluate the ability of preoperative neutrophil-lymphocyte ratio (NLR) to predict pathologic upstaging and nonorgan-confined (NOC) (>=pT3) disease. METHODS AND MATERIALS: After institutional review board approval, the records of consecutive patients undergoing radical cystectomy (RC) for urothelial carcinoma from 2002 to 2012 at the University of Wisconsin Hospital were reviewed. A total of 102 patients with NLR within 100 days of surgery were eligible for analysis. The primary outcome was difference in stage from preoperative assessment to time of RC. Differences in preoperative NLR between groups were evaluated with an unequal variance t test. A univariate analysis assessed whether NLR, preoperative stage, grade, associated lymphovascular invasion, preoperative hydronephrosis, gender, previous pelvic radiotherapy, previous intravesical bladder cancer treatments, or nodal stage were related to upstaging. Multivariate analyses were performed to evaluate the relationship of NLR to upstaging and relative organ-confined (<=pT2) and NOC disease. RESULTS: Of 390 consecutive patients undergoing RC, 102 patients met study criteria. Overall, 55 (53.9%) patients were upstaged, 25 (25.5%) were unchanged, and 21 (20.6%) were downstaged. Fifty-one patients (50%) were upstaged to more advanced disease (>=pT3). NLR and preoperative hydronephrosis were significantly related to pathologic tumor staging. NLR, preoperative hydronephrosis, and preoperative tumor stage were significantly related to upstaging to NOC disease. Patients who were upstaged to>=pT3 demonstrated statistically significant greater NLRs (4.33+/ 0.87) compared with patients who remained at<=pT2 stage (2.66+/-0.29) (P<0.001). CONCLUSIONS: Preoperative NLR is a simple measurement that can be used to identify high-risk patients who may be upstaged at the time of RC and may benefit from neoadjuvant chemotherapy. PMID- 24629499 TI - Underutilization of local salvage therapy after radiation therapy for prostate cancer. AB - OBJECTIVE: To evaluate the rates at which patients are offered and receive local salvage therapy (LST) after failure of primary radiotherapy for localized prostate cancer, as it is the only potentially curative treatment for localized recurrence but appears to be underutilized when compared with androgen deprivation therapy (ADT) or observation. MATERIALS AND METHODS: Patients with localized prostate cancer who received primary radiotherapy with curative intent between 1999 and 2000 were identified in the British Columbia Tumour Registry. Exclusion criteria included patient age >72 years, prostate-specific antigen>40 ng/ml, and clinical stage T4 at diagnosis. Data on clinicopathologic features, primary therapy, prostate-specific antigen kinetics, and salvage therapy were collected retrospectively. Radiation failure was defined as biochemical recurrence according to the Phoenix criteria or by initiation of salvage therapy. RESULTS: Of 1,782 patients treated in the study period, 1,067 met inclusion criteria. Of these, 257 failed radiation therapy. Radiation therapy failure was managed with observation (>12 mo) in 126 patients and ADT in 119. Of the observed patients, 66 subsequently received ADT. Five patients (1.8%) received LST (3 radical prostatectomy and 2 brachytherapy). CONCLUSIONS: Only 2% of patients relapsing after radiation therapy for localized prostate cancer received LST. Although the benefits of LST are unproven, these findings reveal a possible underutilization of LST and indicate a need for enhanced collaboration between specialties to optimize care of this challenging cohort. PMID- 24629500 TI - Race and sex disparities in the treatment of older patients with T1a renal cell carcinoma: a comorbidity-controlled competing-risks model. AB - OBJECTIVES: Recognizing population-level disparities for the treatment of patients with renal cell carcinoma (RCC) would inform clinical practice and health policy. Few studies, reporting conflicting results, have investigated race and sex disparities specifically among patients with small renal masses. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results-Medicare database (1995-2007) was queried for patients with localized T1a RCC undergoing radical nephrectomy, partial nephrectomy (PN), or deferred therapy (DT). Demographics, comorbidity, and treatment approach were assessed. Multivariable logistic regression models evaluated predictors of DT and then PN among those receiving surgery. Cox proportional hazards model evaluated survival differences for whites vs. blacks and women vs. men. RESULTS: A total of 6,092 white and 617 black patients with T1a RCC met the inclusion criteria. Blacks were twice as likely to defer therapy compared with whites (odds ratio = 1.95, 95% CI: 1.52-2.51) and had worse overall survival (hazard ratio = 1.36, 95% CI: 1.19-1.56). However, cancer specific survival (CSS) was similar (P = 0.429). The greatest discrepancy was among healthy (Charlson comorbidity index<=1) blacks who had a much higher rate of DT compared with their white counterparts. Women were found to have decreased use of PN compared with men (odds ratio = 0.84, 95% CI: 0.74-0.96) and better CSS (hazard ratio = 0.74, 95% CI: 0.58-0.94), but there were no differences by race. CONCLUSIONS: The differential use of DT by race instead of purely by age and comorbidity is concerning but has not led to a significant difference in CSS. Women are less likely to undergo PN compared with men, but they also have a notably improved CSS. PMID- 24629501 TI - Asking questions during breast cancer consultations: does being alone or being accompanied make a difference? AB - PURPOSE: Companions often accompany patients to cancer consultations. The number of questions asked by patients and companions is an indicator of their active participation. The present study aims to provide first descriptive evidence on the characteristics of unaccompanied and accompanied Italian breast cancer patients that attend the first consultation after surgery and to analyse companions contribution to the type and quantity of questions asked during the consultation. METHOD: Seventy consultations of female patients with breast cancer were audio taped. Questions were transcribed and coded by content. Companion's questions were also classified in terms of function. Socio-demographic and clinical data, patients' role preference and confidence in decision making measures were gathered for each patient. Post consultation satisfaction with decision and the perceived level of shared decision making were collected either for the patient and the companion. RESULTS: 69% of patients were accompanied, usually by one close family member, either husband or adult child. Non employed or retired patients and those with a preference for passive role in decision making were more likely to be accompanied. Unaccompanied patients and accompanied patients had comparable levels of anxiety, emotional distress and depression and were equally active in asking questions. These levels were far greater than those reported for other cancer patients in the literature. Companions did not increase significantly the number of questions per consultation. CONCLUSION: Accompanied and non accompanied patients differed more in socio-demographic than clinical characteristics. Companions sustained the patient and shared information without reducing the level of patient involvement. PMID- 24629502 TI - Patient views on smoking, lung cancer, and stigma: a focus group perspective. AB - PURPOSE: Patients with lung cancer, the leading cause of cancer death, are shown to have high levels of psychological distress and poorer quality of life as compared to patients with other cancer types. The purpose of this paper is to describe patient focus group discussions about the lung cancer experience in relation to perceived stigmatization, smoking behaviors, and illness causes; and to discuss implications of these findings relative to the role of the nurse as a patient advocate. METHODS AND SAMPLE: Eleven adult lung cancer patients participated in audio taped focus group sessions. Discussion questions probed patient perceptions of lung cancer challenges and adaptation issues. RESULTS: Six primary themes from the qualitative analysis included: 1) societal attitudes; 2) institutional practices and experiences; 3) negative thoughts and emotions such as guilt, self-blame and self-deprecation, regret, and anger; 4) actual stigmatization experiences; 5) smoking cessation: personal choices versus addiction; and 6) causal attributions. CONCLUSIONS: Patients with lung cancer uniquely experience an added burden from developing an illness that the public recognizes is directly associated with smoking behaviors. Stigmatization and smoking related concerns are of high importance. Oncology nurses must be at the forefront in ensuring that patients with lung cancer do not experience additional burden from perceptions that they somehow deserve and need to defend why they have the illness that they are facing. PMID- 24629503 TI - Adapting Champion's Breast Cancer Fear Scale to colorectal cancer: psychometric testing in a sample of older Chinese adults. AB - PURPOSE: Colorectal cancer (CRC) is the most common type of cancer in both men and women, and older adults are more susceptible to this disease. Previous studies suggest that cancer fear may be a key predictor of participation in cancer screening. Yet there is a lack of validated measuring tools of fear relating to CRC for the Chinese older adult population. This study aims to test the psychometric properties of the Chinese version of the Colorectal Cancer Fear Scale (CRCFS), adapting from the Champion's Breast Cancer Fear Scale. METHODS: The CRCFS was developed by altering the wording 'breast cancer' to 'colorectal cancer'. Interviewer-administered surveys were carried out with a convenience sample of 250 community-dwelling adults aged at least 60 years old without a history of cancer. A subsample of 40 participants completed the scale again at one-month. RESULTS: Confirmatory factor analysis revealed that the one-factor model provided excellent fits to the overall data, and two randomly split samples. Cronbach's alpha of the scale was 0.95 and test-retest reliability was 0.52. Positive and significant correlations of CRC Cancer Fear with CRC-related susceptibility, severity and barriers were observed. A non-linear relationship with benefits was found. CONCLUSIONS: The findings provide support for the psychometric properties of a Chinese version of the Champion Cancer Fear with an adaption to CRC in a sample of community dwelling older Chinese adults. The scale provides a useful tool to assess CRC-related fear, which interventions should address in order to improve screening rates among older Chinese adults. PMID- 24629504 TI - Effects of an educational intervention for managing fatigue in women with early stage breast cancer. AB - PURPOSE: This randomized controlled trial of outpatients with breast cancer (stage I or II) evaluated the effects of a 3-week educational intervention on patient levels of fatigue. METHODS: Norwegian outpatients were randomized into an intervention group (n = 79) and a control group (n = 81). Women with fatigue (>2.5 on a 0-10 numeric rating scale, NRS) completed the Fatigue Questionnaire (FQ) and the Lee Fatigue Scale (LFS) at baseline (after treatment) (T1), immediately after intervention (T2) and 3 months after intervention (T3). RESULTS: The mean fatigue score (NRS) at study entry was 6.1 (SD 1.7) and 36% (n = 57) had a score >=7. There were no statistically significant differences between the fatigue measures of women in the intervention and control group at T2 or T3 in the overall sample after the intervention. Using an NRS cut-off of 5, there was a borderline difference for women who scored <5 for chronic fatigue on FQ (p = 0.062) and a significant difference for energy on LFS (p = 0.042) where the women in the intervention group had less fatigue. Using an NRS cut-off score of 6, there was a borderline difference for women who scored <6 for fatigue on FQ (p = 0.062) and a significant difference for energy on LFS (p = 0.021) where women in the intervention group had more energy than those in the control group. CONCLUSIONS: Further research is needed to identify psycho-educational interventions to reduce levels of fatigue and to tailor an intervention based on the level of fatigue. Fatigue measurements should be chosen more carefully. PMID- 24629505 TI - Children's participation in shared decision-making: children, adolescents, parents and healthcare professionals' perspectives and experiences. AB - PURPOSE OF THE RESEARCH: Despite decision-making featuring throughout the trajectory of cancer care, children's participation in decision-making remains an area much under-researched and complicated by conflicting opinions. This study explored children's participation in shared decision-making (SDM) from multiple perspectives from one haematology/oncology unit in Ireland. METHODS AND SAMPLE: Qualitative research design was used to explore participants' experiences of children's decision-making. Interviews were conducted with children(1) aged 7-16 years (n = 20), their parents (n = 22) and healthcare professionals (n = 40). Data were managed with the aid of NVivo (version 8). KEY RESULTS: Parents and children's roles in decision-making were significantly influenced by the seriousness of the illness. Cancer is a life-threatening illness and so the treatment 'had to be done'. Children were not involved in major decisions (treatment decisions) as refusal was not an option. They were generally involved in minor decisions (choices about care delivery) with the purpose of gaining their cooperation, making treatment more palatable, giving back a sense of control and building trusting relationships. These choices were termed 'small' decisions that would not compromise the child's welfare. Some adolescents were aware that choices were not 'real' decisions since they were not allowed to refuse and expressed feelings of frustration. CONCLUSIONS: Healthcare professionals and parents controlled the process of SDM and the children's accounts revealed that they held a minimal role. Children appeared content that adults held responsibility for the major treatment decisions. However, they desired and valued receiving information, voicing their preferences and choosing how treatments were administered to them. PMID- 24629506 TI - Patients' perception of information after completion of adjuvant radiotherapy for breast cancer. AB - PURPOSE OF THE RESEARCH: The aims of the present study were to examine patients' perceptions of received information and satisfaction with information after completion of adjuvant radiotherapy (RT) for breast cancer. Associations between satisfaction with information and health related quality of life (HRQoL), and clinical variables were also studied. METHODS AND SAMPLE: A total of 93 consecutive women planned for adjuvant RT were asked to complete two questionnaires (EORTC QLQ-C30 and QLQ-INFO25) in connection with their last treatment. KEY RESULTS: A total of 88 patients (95%) responded. The mean values for the information subscale scores, on a 0 to 100 point scale (QLQ-INFO25) regarding "the treatments" and "the disease" were 46 and 53 respectively. A total of 48% of the patients expressed a wish for more information. Patients treated with chemotherapy previous to RT reported statistically significant lower levels of information about "the disease". Age was statistically significant related to satisfaction with received information. Younger women were less satisfied with the information received, and a higher proportion wanted more information (55%), as well among women treated with chemotherapy previous to RT (63%). Patients satisfied with information scored significantly higher on global health status and emotional functioning and reported less fatigue. Positive associations were found between "satisfaction with information" and HRQoL. CONCLUSIONS: Improvements of information to breast cancer patients during their treatments are needed. The results also underline the need for patient-centred information in general and that extra attention should be paid to younger women and patients undergoing combined treatment. PMID- 24629507 TI - Modest increase in risk of acute coronary syndrome associated with morphine use in cancer patients: a population-based nested case-control study. AB - BACKGROUND: Morphine is widely used for pain management in cancer patients. Use of heroin, a morphine derivative, is a risk factor for acute coronary syndrome (ACS). OBJECTIVE: This study investigates the risk of ACS associated with morphine use by comparing the incidence of ACS in cancer patients treated with and without morphine. METHODS: This is a population-based nested case-control study using the Longitudinal Health Insurance Database 2000 in Taiwan. In total, 31,384 patients on the database were diagnosed with cancer without prior history of ACS during 1998-2010. In this cohort, 499 patients subsequently developed ACS and 30,885 patients did not. The 499 patients were designated as the ACS group; controls were selected from the remaining 30,885 patients and matched 3:1 to each case for age, sex, year of cancer diagnosis, and index year. Logistic regression was used to estimate the odds ratios and 95% confidence intervals, and the multivariable model was applied to control for age, sex, and Charlson comorbidity score. RESULTS: Cancer patients who received morphine had a 32% higher risk of developing ACS than non-morphine users. This increase in risk was significant when evaluating the overall cancer patients, but non-significant when evaluating any specific cancer type. The risk of ACS increased significantly with increasing morphine dosage (to >=65 mg/y). CONCLUSION: Morphine treatment is associated with a modest increase in risk of ACS in patients with malignancy, but this association displays low significance in specific cancer types. PMID- 24629508 TI - Safety aspects of gadofosveset in clinical practice--analysis of acute and long term complications. AB - PURPOSE: The purpose of this retrospective study was to systematically search for acute adverse reactions and long-term complications in all patients that had been administered gadofosveset at our hospital. MATERIALS AND METHODS: We identified 67 gadofosveset administrations during 2006-2009 in 62 patients from 8 to 84years of age. Radiological information system (RIS) and clinical patient records were analyzed for suspected acute adverse reactions and long-term complications including nephrogenic systemic fibrosis (NSF). The gadofosveset doses ranged between 0.024 and 0.060mmol/kg bodyweight with a mean dose of 0.031-mmol/kg bodyweight. Follow-up time of the patients ranged from less than 1year up to 4years with a mean follow-up time of 2.1years. RESULTS: No acute adverse events or technical failures related to the contrast medium were recorded in the RIS. No dermatological and nephrological diseases related to the gadofosveset administration were found in the clinical patient records. Four patients died during follow-up without any apparent relation to the gadofosveset exposure. CONCLUSIONS: Based on our clinical material we conclude that gadofosveset is safe for a mixed patient population with no acute adverse events or any indications of long-term complications during the follow-up time up to four years. PMID- 24629509 TI - Measuring steady-state cerebral vasomotor reactivity using non-triggered phase contrast magnetic resonance imaging. AB - To investigate cVMR by using CO2-based hypercapnic challenge and blood flow monitoring employing non-triggered phase contrast (PC) magnetic resonance imaging. Six healthy volunteers (6 male; mean age: 29 years) participated this study after providing institutionally approved consent. This study used non triggered PC imaging to increase temporal resolution of dynamic blood flow measurements, allowing real-time monitoring of the hypercapnic challenge response. Results suggest that vasomotor reactivity measured by non-triggered PC imaging is positively associated with the concentration of inhaled CO2. This study concludes that CO2 challenge combined with non-triggered PC flow imaging is potentially useful to provide diagnostic information for patients with cerebrovascular disease. PMID- 24629510 TI - Fractional amplitude of low-frequency fluctuation changes in monkeys with spinal cord injury: a resting-state fMRI study. AB - PURPOSE: Although functional magnetic resonance imaging (fMRI) has revealed that spinal cord injury (SCI) causes anomalous changes in task-induced brain activation, its effect during the resting state remains unclear. The aim of this study is to explore the changes of the brain resting-state function in non-human primates with unilateral SCI. MATERIALS AND METHODS: Eleven adult female rhesus monkeys were subjected to resting-state fMRI: five with unilateral thoracic SCI and six healthy monkeys, to obtain the fractional amplitude of low-frequency fluctuations (fALFF) of the blood oxygenation level-dependent (BOLD) contrast signal to determine the influence of SCI on the cerebral resting-state function. RESULTS: The SCI-induced fALFF vary significantly in several encephalic regions, including the left cerebellum, the left thalamus, the right lateral geniculate nucleus, the right superior parietal lobule, and the posterior cingulate gyrus. CONCLUSION: Analysis of the resting-state fMRI provides evidence of abnormal spontaneous brain activations in primates with SCI, which may help us understand the pathophysiologic mechanisms underlying the changes in neural plasticity in the central nervous system after SCI. PMID- 24629511 TI - Efficacy of magnetic resonance diffusion tensor imaging and three-dimensional fiber tractography in the detection of clinical manifestations of central nervous system lupus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease frequently associated with neuropsychiatric manifestations. No follow-up case report has characterized white matter alterations in patients with neuropsychiatric lupus erythematosus (NPSLE) before and after treatment. In this study, a 16-year-old NPSLE patient with severe neuropsychological symptoms was treated with steroid pulse therapy, and was scanned with conventional magnetic resonance (MR) and diffusion tensor imaging (DTI) at onset and 17months after treatment. Conventional MR images showed diffuse brain atrophy and focal vasogenic edema in the putamen, but they did not reveal abnormalities in the corpus callosum. Region-of-interest analysis of DTI images showed that fractional anisotropy and fiber tracts increased significantly, while axial diffusivity, radial, and mean diffusivity decreased significantly in the corpus callosum after treatment. The results indicated that the vasogenic edema was present in the corpus callosum at onset and was significantly reduced after treatment. These changes were generally compatible with the patient's clinical manifestations. Hence, we concluded that MR-DTI and fiber tractography are helpful to reveal the relationship between white matter alterations and neurological dysfunctions in NPSLE patients. PMID- 24629512 TI - Hyperpolarized (3)He diffusion MRI and histology of secreted frizzled related protein-1 (SFRP1) deficient lungs in a Murine model. AB - Secreted frizzled related protein-1 (SFRP1) plays a key role in many diverse processes, including embryogenesis, tissue repair, bone formation, and tumor genesis. Previous studies have shown the effects of the SFRP1 gene on lung development using the SFRP1 knockout mouse model via histological and physiological studies. In this study, the feasibility of ADC (acquired via HP (3)He) to detect altered lung structure in the SFRP1 knockout (SFRP1(-/-)) mice was investigated, and compared to analysis by histology. This study consisted of two groups, the wild-type (WT) mice and the knockout (KO) mice with n=6 mice for each group. (3)He ADC MRI and histology were performed on all of the animals. The global Lm values of WT and KO mice were 35.0+/-0.8MUm and 38.4+/-3.8MUm, respectively, which translated to an increase of 9.58% in the Lm of KO mice. The mean global ADCs for the WT and KO mice were 0.12+/-0.01cm(2)/s and 0.13+/ 0.01cm(2)/s, respectively, which equated to a relative increase of 8.0% in the KO mice compared to the WT mice. In the sub-analysis of the anterior, medial and posterior lung regions, Lm increased by 10.50%, 6.66% and 11.84% in the KO mice, respectively, whereas the differences in ADC between the two groups in the anterior, medial, and posterior regions were 7.3%, 8.3%, and 4.6%, respectively. These results suggest that HP MRI measurements can be used as a suitable substitute for histology to obtain valuable information about lung geometry non invasively. This technique is also advantageous as regional measurements can be performed, which can identify lung destruction more precisely. Most importantly, this approach extends far beyond the specific pathology analyzed in this study, as it can be applied to many other pathological conditions in the lung tissue, as well to many other embryonic studies. PMID- 24629513 TI - Semiquantitative perfusion combined with diffusion-weighted MR imaging in pre operative evaluation of endometrial carcinoma: results in a group of 57 patients. AB - PURPOSE: To evaluate the semiquantitative DCE and quantitative DWI parameters in endometrial cancer, in order to assess the presence of neoplastic tissue and normal myometrium and to ascertain a potential relationship with tumor grade. METHODS AND MATERIALS: A total of 57 patients with biopsy-proven endometrial adenocarcinoma who underwent MR imaging examination for staging purposes were retrospectively evaluated. Imaging protocol included multiplanar T1- and T2 weighted TSE, DCE T1-weighted (THRIVE; 0, 30, 90 and 120seconds after intravenous injection of gadolinium) and DWIBS sequences (b values=0 and 1000mm(2)/s). Color perfusion and ADC maps were automatically generated on dedicated software. Relative enhancement (RE, %), maximum enhancement (ME, %), maximum relative enhancement (MRE, %), time to peak (TTP, s) and mean apparent diffusion coefficient (ADC) were calculated by manually drawing a region of interest (ROI) both on the neoplastic tissue and the normal myometrium. Histopathology was used as reference standard. RESULTS: Histopathological analysis confirmed the presence of endometrial carcinoma in all patients. Neoplastic tissue demonstrated significantly lower (P<0.001) values of RE (%) 63.92+/-35.68; ME (%) 864.91+/ 429.54 and MRE (%) 75.97+/-38.26 as compared to normal myometrium (RE (%) 151.43+/-55.99; ME (%) 1800.73+/-721.32; MRE (%) 158.28+/-54.05). TTP was significantly higher (P<0.05) in tumor lesion (385.51+/-1630.27 vs 195.44+/ 78.69). Mean ADC value of neoplastic tissue (775.09+/-?220.73*10(-3)mm(2)/s) was significantly lower (P<0.05) than in myometrium (1602.37+/-378.54*10(-3)mm(2)/s). The analysis of perfusion and diffusion parameters classified according to tumor grades, showed a statistically significant difference only for RE (P=0.043) and ME (P=0.007). CONCLUSIONS: Perfusion parameters and mean ADC differ significantly between endometrial cancer and normal myometrium, potentially reflecting the different microscopical features of cellularity and vascularity; however a significant relationship with tumor grade was not found in our series. PMID- 24629515 TI - An investigation of motion correction algorithms for pediatric spinal cord DTI in healthy subjects and patients with spinal cord injury. AB - Patient and physiological motion can cause artifacts in DTI of the spinal cord which can impact image quality and diffusion indices. The purpose of this investigation was to determine a reliable motion correction method for pediatric spinal cord DTI and show effects of motion correction on DTI parameters in healthy subjects and patients with spinal cord injury. Ten healthy subjects and ten subjects with spinal cord injury were scanned using a 3T scanner. Images were acquired with an inner field-of-view DTI sequence covering cervical spine levels C1 to C7. Images were corrected for motion using two types of transformation (rigid and affine) and three cost functions. Corrected images and transformations were examined qualitatively and quantitatively using in-house developed code. Fractional anisotropy (FA) and mean diffusivity (MD) indices were calculated and tested for statistical significance pre- and post- motion correction. Images corrected using rigid methods showed improvements in image quality, while affine methods frequently showed residual distortions in corrected images. Blinded evaluation of pre and post correction images showed significant improvement in cord homogeneity and edge conspicuity in corrected images (p<0.0001). The average FA changes were statistically significant (p<0.0001) in the spinal cord injury group, while healthy subjects showed less FA change and were not significant. In both healthy subjects and subjects with spinal cord injury, quantitative and qualitative analysis showed the rigid scaled-least-squares registration technique to be the most reliable and effective in improving image quality. PMID- 24629514 TI - Real-time monitoring of ischemic and contralateral brain pO2 during stroke by variable length multisite resonators. AB - PURPOSE: Electron paramagnetic resonance (EPR) oximetry using variable length multi-probe implantable resonator (IR), was used to investigate the temporal changes in the ischemic and contralateral brain pO2 during stroke in rats. MATERIAL AND METHODS: The EPR signal to noise ratio (S/N) of the IR with four sensor loops at a depth of up to 11 mm were compared with direct implantation of lithium phthalocyanine (LiPc, oximetry probe) deposits in vitro. These IRs were used to follow the temporal changes in pO2 at two sites in each hemisphere during ischemia induced by left middle cerebral artery occlusion (MCAO) in rats breathing 30% O2 or 100% O2. RESULTS: The S/N ratios of the IRs were significantly greater than the LiPc deposits. A similar pO2 at two sites in each hemisphere prior to the onset of ischemia was observed in rats breathing 30% O2. However, a significant decline in the pO2 of the left cortex and striatum occurred during ischemia, but no change in the pO2 of the contralateral brain was observed. A significant increase in the pO2 of only the contralateral non ischemic brain was observed in the rats breathing 100% O2. No significant difference in the infarct volume was evident between the animals breathing 30% O2 or 100% O2 during ischemia. CONCLUSIONS: EPR oximetry with IRs can repeatedly assess temporal changes in the brain pO2 at four sites simultaneously during stroke. This oximetry approach can be used to test and develop interventions to rescue ischemic tissue by modulating cerebral pO2 during stroke. PMID- 24629516 TI - Manganese-enhanced magnetic resonance imaging investigation of the interferon alpha model of depression in rats. AB - Therapeutic effects of interferon-alpha (IFN-alpha) are known to be associated with CNS toxicity in humans, and in particular with depression symptoms. Animal models of IFN-alpha-induced depression (sickness behaviour) have been developed in rodents using various preparations, dosing schedules or routes of administrations. In this work, Manganese Enhanced MRI (MEMRI) has been applied to investigate an experimental model of sickness behaviour induced by administration of IFN-alpha in rats. IFN-alpha (3.10(5) U/kg), or vehicle, was daily administered i.p., for 7days in rats (n=20 IFN-alpha treated and n=20 controls). After treatment, animals were assigned to behavioural (n=10 treated, n=10 control) or MRI (n=10 treated and n=10 control) studies. Animals assigned to the MRI study received two repeated i.p. injections of MnCl2, before image acquisition. Images were acquired at 4.7T using T1 mapping for determination of Mn concentration in brain. After co-registration of T1 maps to a digital brain atlas, differences between brains of treated and untreated animals were assessed pixel-to-pixel by statistical analysis. Behavioural tests showed alterations in freezing and struggling parameters, as expected in an experimental model of sickness behaviour. MRI showed a well defined brain region, mainly contained in the visual cortex, in which Mn uptake was significantly lower in treated than in control animals, indicating probably altered functionality. No significant difference was detected in other brain regions. In addition, a statistically significant decrease in the volume of the pituitary gland, paralleled by a slight increase in its Mn content, was detected in treated animals. MEMRI provides both morphological and functional information in the brain of small laboratory animals and can constitute a valuable tool in the investigation of experimental models of psychiatric diseases. PMID- 24629517 TI - Correlation imaging with arbitrary sampling trajectories. AB - The presented work aims to develop a generalized linear approach to image reconstruction with arbitrary sampling trajectories for high-speed MRI. This approach is based on a previously developed image reconstruction framework, "correlation imaging". In the presented work, correlation imaging with arbitrary sampling trajectories is implemented in a multi-dimensional hybrid space that is formed from the physical sampling space and a virtually defined space. By introducing an undersampling trajectory with both uniformity and randomness in the hybrid space, correlation imaging may take advantage of multiple image reconstruction mechanisms including coil sensitivity encoding, data sparsity and information sharing. This hybrid-space implementation is demonstrated in multi slice 2D imaging, multi-scan imaging, and radial dynamic imaging. Since more information is used in image reconstruction, it is found that hybrid-space correlation imaging outperforms several conventional techniques. The presented approach will benefit clinical MRI by enabling correlation imaging to be used to accelerate multi-scan clinical protocols that need different sampling trajectories in different scans. PMID- 24629518 TI - Cutaneous extranodal natural killer/T-cell lymphoma: a comparative clinicohistopathologic and survival outcome analysis of 45 cases according to the primary tumor site. AB - BACKGROUND: Differences in survival outcomes and prognostic factors of cutaneous extranodal natural killer/T-cell lymphoma (ENKTL) depending on primary tumor site are currently unknown. OBJECTIVE: We sought to analyze the clinicopathological features and survival outcomes of cutaneous ENKTL according to primary tumor site. METHODS: In all, 45 patients with cutaneous ENKTL were classified with: (1) primary cutaneous ENKTL, or (2) nasal ENKTL with cutaneous involvement. Clinicopathologic features, survival outcomes, and prognostic factors were analyzed using patient's medical records. Survival outcomes were analyzed using the Kaplan-Meier method and compared using the log rank test. The Student t test, Fisher exact test, and linear by linear association test were used to analyze clinicopathologic differences between groups. RESULTS: Clinical manifestations of cutaneous ENKTL included solitary or multiple subcutaneous nodules and cellulitis or abscess-like lesions. Primary cutaneous ENKTL demonstrated a less aggressive clinical course and better survival outcomes. The extent of cutaneous lesions demonstrated a significant effect on the prognosis of primary cutaneous ENKTL, but not on nasal ENKTL with cutaneous involvement. The presence of nasal lesions in primary cutaneous ENKTL was associated with poor prognosis. LIMITATIONS: This study used a retrospective design and included a small sample size. CONCLUSION: Although the clinicopathological features were similar regardless of subgroup, survival outcomes and prognostic factors differed depending on the primary tumor site of cutaneous ENKTL. PMID- 24629519 TI - Experimental and computational studies on the femoral fracture risk for advanced core decompression. AB - BACKGROUND: Two questions are often addressed by orthopedists relating to core decompression procedure: 1) Is the core decompression procedure associated with a considerable lack of structural support of the bone? and 2) Is there an optimal region for the surgical entrance point for which the fracture risk would be lowest? As bioresorbable bone substitutes become more and more common and core decompression has been described in combination with them, the current study takes this into account. METHODS: Finite element model of a femur treated by core decompression with bone substitute was simulated and analyzed. In-vitro compression testing of femora was used to confirm finite element results. FINDINGS: The results showed that for core decompression with standard drilling in combination with artificial bone substitute refilling, daily activities (normal walking and walking downstairs) are not risky for femoral fracture. The femoral fracture risk increased successively when the entrance point is located further distal. The critical value of the deviation of the entrance point to a more distal part is about 20mm. INTERPRETATION: The study findings demonstrate that optimal entrance point should locate on the proximal subtrochanteric region in order to reduce the subtrochanteric fracture risk. Furthermore the consistent results of finite element and in-vitro testing imply that the simulations are sufficient. PMID- 24629520 TI - Site-specific ionisation edge fine-structure of Rutile in the electron microscope. AB - Combined Bloch-wave and density functional theory simulations are performed to investigate the effects of different channelling conditions on the fine-structure of electron energy-loss spectra. The simulated spectra compare well with experiments. Furthermore, we demonstrate that using this technique, the site specific investigation of atomic orbitals is possible. This opens new possibilities for chemical analyses. PMID- 24629521 TI - Papillary renal cell carcinoma: current progress and future directions. AB - Papillary renal cell carcinoma (pRCC) represents the second most common histologic variant of kidney cancer. It exhibits a different molecular signature than clear-cell carcinoma and is typically not associated with mutations in the VHL (von Hippel-Lindau) tumor suppressor gene. pRCC is less responsive to modern drugs introduced in the management of kidney cancer in the past decade. In this article, the heredity and biology of 2 main variants of pRCC are outlined. New targets that are being explored in the treatment of this disease are discussed, with particular emphasis on inhibition of mesenchymal epithelial transition (MET) and epidermal growth factor receptor (EGFR) pathways. We discuss preclinical data providing rationale for the combination of MET and EGFR inhibitors and review recently completed and ongoing clinical trials that attempt to expand our therapeutic options for this important subset of kidney cancer. PMID- 24629522 TI - A case of pneumonia caused by Legionella pneumophila serogroup 12 and treated successfully with imipenem. AB - The patient was an 83-year-old man hospitalized for Haemophilus influenzae pneumonia, who developed recurrent pneumonia after improvement of the initial episode. Legionella pneumophila serogroup 12 was isolated from the sputum, accompanied by increased serum antibody titers to L. pneumophila serogroup 12. Therefore, the patient was diagnosed as having Legionella pneumonia caused by L. pneumophila serogroup 12. Case reports of pneumonia caused by L. pneumophila serogroup 12 are rare, and the case described herein is the first report of clinical isolation of this organism in Japan. When the genotype was determined by the protocol of The European Working Group for Legionella Infections (Sequence Based Typing [SBT] for epidemiological typing of L. pneumophila, Version 3.1), the sequence type was ST68. Imipenem/cilastatin therapy was found to be effective for the treatment of Legionella pneumonia in this patient. PMID- 24629523 TI - Diversity of the ectoines biosynthesis genes in the salt tolerant Streptomyces and evidence for inductive effect of ectoines on their accumulation. AB - Streptomyces commonly produce ectoines as compatible solutes to prevent osmotic stresses. Fine structure of the genes producing ectoine (ectC) and hydroxyectoine (ectD) enzymes in Streptomyces rimosus C-2012 as a slightly halophilic bacterium is reported in this study. Deduced amino acid sequences of ectC and ectD genes from strain C-2012 and some other related species were compared and 72-90% and 13 81% identities were detected for ectC and ectD, respectively. High similarity of ectC between closely or distantly related Streptomyces to the strain C-2012 may indicate horizontal transfer of this gene. However, phylogenetic relationships of ectD were correlated with phylogenetic affiliation of the strains. It suggests that the ability of Streptomyces to produce hydroxyectoine has been the result of a vertical transfer event. HPLC analysis showed that strain C-2012 was able to produce ectoine and hydroxyectoine both in the presence and absence of external salinity (up to 0.45 M NaCl). Accordingly, reverse transcription quantitative PCR (RT-qPCR) showed that ectABCD operon in this strain is positively affected by salt. Also, inductive effect of the salt was increased when it was applied with 1 mM of ectoines. Transcription level of ectC was increased 2.7- and 2.9-fold in the medium supplied with salt and ectoine and salt and hydroxyectoine, respectively. The effect of salinity with or without ectoines was more on ectD transcription level than that of ectC. In S. rimosus under salt stress, ectoine and hydroxyectoine biosynthesis primarily depends on the stimulation of ectABCD operon transcription. However, drastic accumulation of ectoine and hydroxyectoine without increase in ectC and ectD transcripts was observed in the medium supplied with salt and ectoines and that suggest there might be additional posttranscriptional level of control. Increases in ratio of some intracellular free amino acids in salt stressed to unstressed conditions were observed in cells grown with ectoines. Our results suggest the possibility of a supplementary role of ectoines to improve structure and function of the cells in stressful environments as well as their important role as osmoprotectants. PMID- 24629524 TI - Multiple approaches to characterize the microbial community in a thermophilic anaerobic digester running on swine manure: a case study. AB - In this study, the first survey of microbial community in thermophilic anaerobic digester using swine manure as sole feedstock was performed by multiple approaches including denaturing gradient gel electrophoresis (DGGE), clone library and pyrosequencing techniques. The integrated analysis of 21 DGGE bands, 126 clones and 8506 pyrosequencing read sequences revealed that Clostridia from the phylum Firmicutes account for the most dominant Bacteria. In addition, our analysis also identified additional taxa that were missed by the previous researches, including members of the bacterial phyla Synergistetes, Planctomycetes, Armatimonadetes, Chloroflexi and Nitrospira which might also play a role in thermophilic anaerobic digester. Most archaeal 16S rRNA sequences could be assigned to the order Methanobacteriales instead of Methanomicrobiales comparing to previous studies. In addition, this study reported that the member of Methanothermobacter genus was firstly found in thermophilic anaerobic digester. PMID- 24629525 TI - Differential contribution of the proline and glutamine pathways to glutamate biosynthesis and nitrogen assimilation in yeast lacking glutamate dehydrogenase. AB - In Saccharomyces cerevisiae, the glutamate dehydrogenase (GDH) enzymes play a pivotal role in glutamate biosynthesis and nitrogen assimilation. It has been proposed that, in GDH-deficient yeast, either the proline utilization (PUT) or the glutamine synthetase-glutamate synthase (GS/GOGAT) pathway serves as the alternative pathway for glutamate production and nitrogen assimilation to the exclusion of the other. Using a gdh-null mutant (gdh1Delta2Delta3Delta), this ambiguity was addressed using a combination of growth studies and pathway specific enzyme assays on a variety of nitrogen sources (ammonia, glutamine, proline and urea). The GDH-null mutant was viable on all nitrogen sources tested, confirming that alternate pathways for nitrogen assimilation exist in the gdh null strain. Enzyme assays point to GS/GOGAT as the primary alternative pathway on the preferred nitrogen sources ammonia and glutamine, whereas growth on proline required both the PUT and GS/GOGAT pathways. In contrast, growth on glucose-urea media elicited a decrease in GOGAT activity along with an increase in activity of the PUT pathway specific enzyme Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH). Together, these results suggest the alternative pathway for nitrogen assimilation in strains lacking the preferred GDH-dependent route is nitrogen source dependent and that neither GS/GOGAT nor PUT serves as the sole compensatory pathway. PMID- 24629528 TI - [Can anastomotic leaks after oesophageal resections be avoided?]. PMID- 24629527 TI - Are EORTC risk tables suitable for Chinese patients with non-muscle-invasive bladder cancer? AB - OBJECTIVE: To evaluate the applicability of using EORTC risk tables in Chinese patients with non-muscle-invasive bladder cancer. MATERIAL AND METHODS: Between October 2000 and July 2009, 301 patients with NMIBC who underwent transurethral resection of the bladder tumor (TURBT) at our hospital were followed up. The probability of recurrence and progression at 1 year and 5 years post-operatively was calculated along with the 95% confidence intervals. We then compared the actual probabilities in our center to those obtained through the application of the EORTC risk tables. RESULTS: Median patient age was 67 years (range, 21-92 years), and the median follow-up duration was 46 months (range, 2-151 months). The probability of recurrence at 1 year ranged from 2% to 58%, and the probability of progression ranged from less than 1.2% to 30%. At 5 years, the probability of recurrence ranged from 12% to 85%, and the probability of progression ranged from less than 2.9% to 50%. An overlapping of the confidence intervals of the probability between our series and the EORTC group is detected. CONCLUSIONS: Although the immediate instillation of intravesical chemotherapy may reduce the risk of recurrence, EORTC risk tables could predict recurrence and progression in Chinese patients with non-muscle-invasive bladder cancer. PMID- 24629529 TI - [There is a need for evidence-based management in health care]. PMID- 24629526 TI - Explaining additional genetic variation in complex traits. AB - Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits, discovering >6000 variants associated with >500 quantitative traits and common complex diseases in humans. The associations identified so far represent only a fraction of those that influence phenotype, because there are likely to be many variants across the entire frequency spectrum, each of which influences multiple traits, with only a small average contribution to the phenotypic variance. This presents a considerable challenge to further dissection of the remaining unexplained genetic variance within populations, which limits our ability to predict disease risk, identify new drug targets, improve and maintain food sources, and understand natural diversity. This challenge will be met within the current framework through larger sample size, better phenotyping, including recording of nongenetic risk factors, focused study designs, and an integration of multiple sources of phenotypic and genetic information. The current evidence supports the application of quantitative genetic approaches, and we argue that one should retain simpler theories until simplicity can be traded for greater explanatory power. PMID- 24629530 TI - [Quality management is associated with high quality services in health care]. AB - In these years, quality management has been the focus in order to meet high quality services for the patients in Danish health care. This article provides information on quality management and quality improvement and it evaluates its effectiveness in achieving better organizational structures, processes and results in Danish health-care organizations. Our findings generally support that quality management is associated with high quality services in health care. PMID- 24629531 TI - [A Cochrane meta-analysis regarding procalcitonin is in accordance with international goals for the use of antibiotics]. AB - Antimicrobial resistance towards antibiotics is an increasing issue for the international society. A Cochrane meta-analysis regarding procalcitonin (PCT) as guidance for initiating and discontinuation of antibiotic treatment in respiratory tract infections in a total of 4,221 patients in various care settings has shown promising results for guiding treatment with a PCT cut-off of 0.25 ng/ml, although more research is needed to clarify possible risks to the approach, especially in intensive care units. PMID- 24629532 TI - [Stevens-Johnson syndrome and toxic epidermal necrolysis]. AB - Stevens-Johnson syndrome and toxic epidermal necrolysis are acute mucocutaneous diseases primarily due to drug intake. The diseases are characterised by the separation of epidermis from dermis which can be life-threatening. Mortality is often caused by sepsis and multiple organ failure. The most common drugs involved are antibiotics, antiepileptic medicine, allopurinol and nonsteroidal anti inflammatory drugs. Besides withdrawing the suspected drug the treatment is mainly symptomatic. A number of systemic treatments have been suggested including systemic corticosteroids, intravenous immunoglobulins, cyclosporine, granulocyte colony stimulating factor and tumour necrosis factor-alpha inhibitors although they remain controversial. PMID- 24629533 TI - [Specialised early rehabilitation of brain injury performed in an intensive care setting]. AB - In Denmark, early rehabilitation of acquired head injuries is centralised in two centres, each covering half the country as uptake area. The Regional Hospital Hammel Neurocenter (HN), which covers the western half of Denmark, traditionally receives patients for rehabilitation after discharge from the intensive care unit (ICU). In collaboration with the Regional Hospital in Silkeborg HN now offers early rehabilitation in Silkeborg's ICU setting to patients with acquired brain injury. This preliminary study discusses whether the collaboration facilitates rehabilitation at an earlier state than previously. PMID- 24629534 TI - [Left-sided appendicitis due to intestinal malrotation]. AB - Left-sided appendicitis due to malrotation is a rare condition with an atypical presentation. We report a history of a 31-year-old man who had four days of right sided abdominal pain, moving across lower abdomen and tenderness in both right and left side on examination. A computed tomography revealed intestinal malrotation and inflammation of the appendix, which was placed from a caecum in left fossa to across the abdominal midline. Appendix was removed and the patient recovered uneventfully. Presentations, diagnostic procedures and operation techniques are discussed. PMID- 24629535 TI - [Acute, severe pancreatitis in a 13-year-old girl]. AB - Acute pancreatitis is uncommon in children and the spectrum of etiologies is broader than in adults. Here we describe a case of acute, severe gallstone pancreatitis in an obese, 13-year-old girl presenting with upper abdominal pain and markedly elevated levels of amylase and transaminases. Abdominal ultrasound showed cholelithiasis and dilatation of the common bile duct; and an endoscopic retrograde cholangiopancreatography with papillotomy was performed. The girl was discharged for elective laparoscopic cholecystectomy. PMID- 24629536 TI - A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype. AB - BACKGROUND: While dopamine signaling in the nucleus accumbens (NAc) plays a well established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self administration under conditions known to produce either a nonaddicted or an addicted phenotype. METHODS: Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 MUg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended access self-administration. RESULTS: Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group. CONCLUSIONS: These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed. PMID- 24629538 TI - Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. AB - BACKGROUND: Inflammation might play a role in the development of several psychiatric diseases. However, the origins of processes that mediate inflammation are unknown. We previously reported increased intestinal permeability, elevated blood lipopolysaccharide levels, and low-grade systemic inflammation associated with psychological symptoms of alcohol dependence in alcohol-dependent subjects. In this study, we tested inflammatory responses of peripheral blood mononuclear cells (PBMCs) to gut-derived bacterial products during detoxification and the relationship to alcohol craving. METHODS: In 63 actively drinking noncirrhotic alcohol-dependent subjects, testing was performed at the beginning (day 2) and end (day 18) of alcohol detoxification and compared with testing in 14 healthy subjects. Activation of various intracellular signaling pathways by gut-derived bacterial products was analyzed by quantitative polymerase chain reaction, Western blotting, and DNA binding assays (for transcription factors). Toll-like receptor activation was assessed by cell cultures. RESULTS: In addition to lipopolysaccharides, we showed that peptidoglycans may also cross the gut barrier to reach the systemic circulation. Both activate their respective Toll-like receptors in peripheral blood mononuclear cells. Chronic alcohol consumption inhibited the nuclear factor kappa B proinflammatory cytokine pathway but activated the mitogen-activated protein kinase/activator protein 1 pathway, together with the inflammasome complex. This activity resulted in increased messenger RNA and plasma levels of interleukin (IL)-8, IL-1beta, and IL-18. Activated proinflammatory pathways, in particular, IL-8 and IL-1beta, were positively correlated with alcohol consumption and alcohol-craving scores. Short term alcohol withdrawal was associated with the recovery of lipopolysaccharide dependent receptors but not peptidoglycan-dependent receptors. CONCLUSIONS: Lipopolysaccharides and peptidoglycans from the gut microbiota stimulate specific inflammatory pathways in peripheral blood mononuclear cells that are correlated with alcohol craving. PMID- 24629537 TI - Default mode network mechanisms of transcranial magnetic stimulation in depression. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response. METHODS: We used resting state functional magnetic resonance imaging to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a 5-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared with a cohort of 35 healthy control subjects. RESULTS: Before treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. Transcranial magnetic stimulation normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. Transcranial magnetic stimulation also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement. CONCLUSIONS: Transcranial magnetic stimulation selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response. PMID- 24629539 TI - Pre-schoolchildren with autism spectrum disorders are rarely macrocephalic: a population study. AB - Numerous clinical studies over the past decades have concluded that there is an association between autism spectrum disorders (ASD) and large head size. Lately, some studies have reported conflicting results. The present study was conducted with a view to assess the presence of macrocephaly in a community-representative group of pre-school children with ASD. The prevalence of ASD in this general population was 0.8%. Thirty-three children (5 girls, 28 boys) recruited after general population screening for ASD, and diagnosed with ASD (two-thirds not globally delayed) were assessed as regards growth parameters; height, weight, and head circumference (HC), at birth and at comprehensive medical-psychiatric diagnostic examinations at a mean age of 3 years. Macrocephaly in the present study was defined as HC above the 97th percentile, and >= 2 SD above recorded length/height. Only one of the 33 children (3%) had macrocephaly which is similar to the general population prevalence. Another 9% had a big but proportional head. None of the children were microcephalic. In this community-based study we found no evidence to support a strong link between a large head size and ASD. Conclusions must be guarded because of the relatively small number of ASD cases included. PMID- 24629540 TI - Building words on actions: verb enactment and verb recognition in children with specific language impairment. AB - Recent studies have shown that language processing is grounded in actions. Multiple independent research findings indicate that children with specific language impairment (SLI) show subtle difficulties beyond the language domain. Uncertainties remain on possible association between body-mediated, non linguistic expression of verbs and early manifestation of SLI during verb acquisition. The present study was conducted to determine whether verb production through non-linguistic modalities is impaired in children with SLI. Children with SLI (mean age 41 months) and typically developing children (mean age 40 months) were asked to recognize target verbs while viewing video clips showing the action associated with the verb (verb-recognition task) and to enact the action corresponding to the verb (verb-enacting task). Children with SLI performed more poorly than control children in both tasks. The present study demonstrates that early language impairment emerges at the bodily level. These findings are consistent with the embodied theories of cognition and underscore the role of action-based representations during language development. PMID- 24629541 TI - Commonly studied comorbid psychopathologies among persons with autism spectrum disorder. AB - The study of comorbid psychopathology among persons with autism spectrum disorder (ASD) is picking up steam. The purpose of this paper was to review and describe important characteristics of existing studies. Among the current crop of papers, depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD) have been frequently evaluated. Groups studied have most frequently been children. Persons with ASD and normal intelligence quotient (IQ) scores have been studied more often than individuals with ASD and intellectual disability. Additional characteristics are discussed, and the implications of these data for future developments in the field are reviewed. PMID- 24629542 TI - Accelerometer use during field-based physical activity research in children and adolescents with intellectual disabilities: a systematic review. AB - Many methodological questions and issues surround the use of accelerometers as a measure of physical activity during field-based research. To ensure overall research quality and the accuracy of results, methodological decisions should be based on study research questions. This paper aims to systematically review accelerometer use during field-based research in children and adolescents with intellectual disabilities. Medline, Embase, Cochrane Library, Web of Knowledge, PsycINFO, PubMed, and a thesis database (up to May 2013) were searched to identify relevant articles. Articles which used accelerometry-based monitors, quantified activity levels, and included ambulatory children and adolescents (<= 18 years) with intellectual disabilities were included. Based on best practice guidelines, a form was developed to extract data based on 17 research components of accelerometer use. The search identified 429 articles. Ten full-text articles met the criteria and were included in the review. Many shortcomings in accelerometer use were identified, with the percentage of review criteria met ranging from 12% to 47%. Various methods of accelerometer use were reported, with most use decisions not based on population-specific research. However, a lack of measurement research, e.g., calibration/validation, for children and adolescents with intellectual disabilities is limiting the ability of field-based researchers to make to the most appropriate accelerometer use decisions. The methods of accelerometer use employed can have significant effects on the quality and validity of results produced, which researchers should be more aware of. To allow informed use decisions, there should be a greater focus on measurement research related to children and adolescents with intellectual disabilities. PMID- 24629543 TI - A pilot study of the effects of RightStart instruction on early numeracy skills of children with specific language impairment. AB - This pilot study investigated the effects of an early numeracy program, RightStart Mathematics (RS), on Finnish kindergartners with specific language impairment (SLI). The study applied a pre-test-instruction-post-test design. The children with SLI (n=9, Mage=82.11 months) received RS instruction two to three times a week for 40 min over seven months, which replaced their business-as-usual mathematics instruction. Mathematical skill development among children with SLI was examined at the individual and group levels, and compared to the performance of normal language-achieving age peers (n=32, Mage=74.16 months) who received business-as-usual kindergarten mathematics instruction. The children with SLI began kindergarten with significantly weaker early numeracy skills compared to their peers. Immediately after the instruction phase, there was no significant difference between the groups in counting skills. In Grade 1, the children with SLI performed similarly to their peers in addition and subtraction skills (accuracy) and multi-digit number comparison, but showed weaker skills in arithmetical reasoning and in matching spoken and printed multi-digit numbers. Our pilot study showed encouraging signs that the early numeracy skills of children with SLI can be improved successfully in a kindergarten small-classroom setting with systematic instruction emphasizing visualization. PMID- 24629544 TI - Psychometric properties and normative data of the French developmental behavior checklist - adult version. AB - The main aim of this study was to generate psychometric data for the French translation of the Developmental Behavior Checklist - Adult version (DBC-A). In addition, the score distributions were examined by using components of mean-based scores. The DBC-A was administered to 580 adults with intellectual disability recruited in the French-speaking regions of Switzerland and Belgium. A confirmatory factor analysis was performed to evaluate the adjustment of the collected data to the original six-factor model; the internal consistency of the factors was analyzed with Cronbach's alpha. The Reiss Screen for Maladaptive Behavior was used to evaluate the concurrent validity of the instrument. Psychopathology prevalence was also explored. The original factor structure of the DBC-A was replicated, with the internal consistency of the factors ranging from respectable to very good according to the alpha values. When the "screening" cut-off of the DBC-A was used, the DBC-A highlighted a psychopathology prevalence of 38%, which was close to the frequency provided by the Reiss Screen (36%). These results show the robustness of the DBC-A's psychometric properties. Thus, we recommend the use of this instrument to assess and screen psychopathology among French-speaking adults with intellectual disability. PMID- 24629546 TI - Heterogeneity in TV fast food advertisement exposure in South Korea. AB - OBJECTIVES: To assess TV fast food ad exposure in South Korea. METHODS: We assessed time trends of targeted ratings (licensed from Nielsen Media Research Korea) by household income and education during 2004-2010. RESULTS: Lower income groups saw more fast food TV ads during the study period. Exposure decreased in all income groups with a bigger income gap in 2010 than in 2004. The relative exposure to local fried chicken franchise TV ads surged from one fifth in 2004 to half of all TV fast food ads seen in 2010 in all socioeconomic status (SES). CONCLUSIONS: Future studies should assess the link between TV fast ood ad exposure, an important contextual factor for individual food choices, and actual consumption. PMID- 24629545 TI - Shelter proximity and affect among homeless smokers making a quit attempt. AB - OBJECTIVES: To explore the associations between shelter proximity and real-time affect during a specific smoking quit attempt among 22 homeless adults. METHODS: Affect was measured via 485 smartphone-based Ecological Momentary Assessments randomly administered during the weeks immediately before and after the quit day, and proximity to the shelter was measured via GPS. Adjusted linear mixed model regressions examined associations between shelter proximity and affect. RESULTS: Closer proximity to the shelter was associated with greater negative affect only during the post-quit attempt week (p = .008). All participants relapsed to smoking by one week post-quit attempt. CONCLUSIONS: Among homeless smokers trying to quit, the shelter may be associated with unexpected negative affect/stress. Potential intervention applications are suggested. PMID- 24629547 TI - Alternative tobacco use among college students: who is at highest risk? AB - OBJECTIVE: To examines smoking status, substance use, sociodemographics, and psychosocial characteristics in relation to alternative tobacco use among college students. METHODS: Current tobacco use (cigarettes, cigar-like products, hookah, chew, snus) and correlates (sociodemographics, sensation-seeking, attitudes toward tobacco and smokers, social factors) were assessed among students aged 18 25 at 6 Southeastern US colleges using an online survey. RESULTS: Those who were younger, male, black, cigarette and marijuana users, and demonstrating at-risk psychosocial factors were at increased risk of alternative tobacco product use (p < .001). Among current smokers, never daily nondaily smokers were 3 times as likely as former daily non-daily smokers and daily smokers to use alternative tobacco products (p < .001). CONCLUSIONS: Important risk factors for alternative tobacco use included important sociodemographic and psychosocial characteristics. PMID- 24629548 TI - Religion and health in African Americans: the role of religious coping. AB - OBJECTIVES: To test a model of the religion-health connection to determine whether religious coping plays a mediating role in health behaviors in a national sample of African Americans. METHODS: Participants completed a telephone survey (N = 2370) assessing religious involvement, religious coping, health behaviors, and demographics. RESULTS: Religious beliefs were associated with greater vegetable consumption, which may be due to the role of positive and negative religious coping. Negative religious coping played a role in the relationship between religious beliefs and alcohol consumption. There was no evidence of mediation for fruit consumption, alcohol use in the past 30 days, or smoking. CONCLUSIONS: Findings have implications for theory and health promotion activities for African Americans. PMID- 24629549 TI - School characteristics and physical activity among grade 1-4 students. AB - OBJECTIVES: To examine school and student characteristics associated with physical activity in grade 1 to 4 students. METHODS: Multi-level logistic regression examined factors associated with being moderately and highly active. RESULTS: A student was more likely to be moderately or highly active if he/she attended a school that provides student access to facilities and equipment outside of school hours. Male students were more likely to be moderately or highly active and overweight or obese students were less likely to be moderately or highly active. CONCLUSIONS: Research should evaluate if implementing a school policy that provides student access to facilities and equipment outside of school hours is effective in promoting physical activity in grade 1 to 4 students. PMID- 24629550 TI - Obesogenic and youth oriented restaurant marketing in public housing neighborhoods. AB - OBJECTIVES: To compare restaurant marketing by restaurant and neighborhood type. METHODS: All restaurants (61=fast food, FF; 72=table service, TS) within an 800 meter radius of 13 public housing developments (HD) and 4 comparison neighborhoods were audited using the Restaurant Assessment Tool(c)2010. HD neighborhoods were lower income and higher minority than comparison neighborhoods with similar density and street connectivity. RESULTS: Restaurants in HD neighborhoods had fewer healthy entrees than comparison neighborhoods. FF restaurants had cheaper beverages and more children's meals, supersize drinks, free prize with purchase, super-size items, special characters, and more items geared to driving than TS restaurants. CONCLUSIONS: Residents of lower socioeconomic neighborhoods may be differentially exposed to unhealthy food options. PMID- 24629551 TI - Undiagnosed prediabetes among food insecure adults. AB - OBJECTIVES: To identify sub-populations at risk for diabetes based on having prediabetes. Although food insecurity has been linked to diabetes, to our knowledge, no studies have examined whether food insecure individuals are more likely than fully food secure individuals to have undiagnosed prediabetes. METHODS: This study was based on a cross-sectional analysis of 6577 adults in the 2005-08 National Health and Nutrition Examination Survey. USDA's Food Security Survey Module, self-reported prediabetes status and clinical measures were examined. RESULTS: Whereas men who were food insecure were more likely than fully food secure men to have undiagnosed prediabetes, no association was observed among women. CONCLUSION: Prediabetes screening appears warranted for food insecure men. PMID- 24629552 TI - Providers role in colonoscopy screening for colorectal cancer. AB - OBJECTIVES: To examine predictors of provider recommendations for colorectal cancer (CRC). METHODS: We examined proportions of patients without prior screening for colonoscopy and their willingness to get a colonoscopy if recommended by a healthcare provider. RESULTS: The rate of CRC screening with a colonoscopy within the recommended guidelines was 35%; provider recommendation rate for colonoscopy screening was 34.9%; and never-screened patients would receive a colonoscopy 78% when recommended by a provider. Provider recommendation was the best predictor for receiving a screening colonoscopy (OR 4.19; 95% CI, 1.91-9.22, p < .01). CONCLUSIONS: Physician recommendation for colonoscopy is the most effective strategy to promote screening colonoscopy in the US, but only one third of eligible patients recall such counseling. PMID- 24629553 TI - Associations of subjective social status with nondaily and daily smoking. AB - OBJECTIVES: To explore associations between subjective social status (SSS) and smoking level among 2274 adult current smokers. METHODS: Associations were investigated using a covariate-adjusted proportional odds cumulative logit model. Moderation (via race/ethnicity or sex) and mediation (via depressive symptoms, social/emotional support, or life satisfaction) were explored in additional models. RESULTS: Higher SSS was associated with greater likelihood of nondaily versus light daily or moderate/ heavy daily smoking (p = .017). Life satisfaction partially mediated the association of SSS and smoking level (p = .003). CONCLUSIONS: Higher SSS was associated with greater likelihood of nondaily relative to light daily or moderate to heavy smoking, potentially via greater life satisfaction. Additional studies are needed to confirm these findings. PMID- 24629554 TI - Self-reported activity and accelerometry in 2 behavior-maintenance trials. AB - OBJECTIVES: To compare between accelerometry (MVPA-A) and self-reported activity (MVPA-SR) in activity-maintenance (Keep Active Minnesota; KAM) and weight loss maintenance (Keep It Off; KIO) trials. METHODS: Linear regression estimated moderation of study, treatment, or time on MVPA-A and MVPA-SR associations. RESULTS: MVPA-A was similar between studies (KAM 119 minutes, KIO 112 minutes, p = .555), whereas MVPA-SR differed significantly (KAM 350 minutes, KIO 87 minutes, p < .0001). Only study moderated correlation between MVPA-A and MVPA-SR. MVPA-SR better predicted MVPA-A in KIO relative to KAM (p = .023). CONCLUSIONS: Results suggest that self-presentation bias may influence validity of self-report in intervention studies with activity as a primary outcome. Researchers should select self-report to assess activity dimensions that objective measures capture poorly. PMID- 24629555 TI - Nicotine blood levels and short-term smoking reduction with an electronic nicotine delivery system. AB - OBJECTIVES: To evaluate nicotine delivery from the NJOY(r) King Bold Electronic Nicotine Delivery System (ENDS) and its short-term potential for smoking reduction or cessation. METHODS: One week of ad libitum use was followed by measurements of plasma nicotine, heart rate, and craving and withdrawal after 12 hours of nicotine abstinence in 25 adult smokers not interested in quitting. RESULTS: After 5 minutes of use, blood nicotine levels increased by a mean of 3.5 ng/mL (p < .001), heart rate increased, and craving was reduced by 55%. Cigarettes per day were reduced by 39% during the test week, and perceptions of use for reduction or cessation were positive. CONCLUSIONS: The NJOY(r) King Bold ENDS delivers nicotine and led to short-term smoking reduction. PMID- 24629556 TI - Impact of role models and policy exposure on support for tobacco control policies in Hangzhou, China. AB - OBJECTIVES: To examine how expectations of role models concerning smoking and exposure to tobacco control policies are associated with people's support for smoking bans. METHODS: Face-to-face interviews were conducted using multistage sampling. Employed structural equation modeling to examine the relationships and multi-group analysis to compare cross-group difference between smokers and non smokers. RESULTS: Expectations of role models were found to be significantly associated with support for FCTC policies related to smoking. Policy exposure indirectly relates to policy support. Cross-group differences between smokers and non-smokers were not significant. CONCLUSION: Expectations of role models are strong predictors of support for FCTC tobacco control policy among Chinese urban residents; policy exposure is associated with policy support indirectly through the influence of expectations of role models. Policymakers should utilize social roles to promote tobacco control measures. PMID- 24629557 TI - Beliefs, experience, and interest in pharmacotherapy among smokers with HIV. AB - OBJECTIVES: To examine beliefs, prior use, and interest in using pharmacotherapy among people living with HIV/AIDS (PLWHA). METHODS: Cross-sectional survey of smokers in a midwestern HIV clinic. RESULTS: The sample (N = 146) included 69% men, 82% African Americans, 45% were in precontemplation for quitting, and 46% were interested in using pharmacotherapy. Primary reasons for non-use included cost and a belief that they would be able to quit on their own. Physician assistance was the strongest correlate of prior use. Perceived benefits and self efficacy were the strongest correlates of willingness to use pharmacotherapy. CONCLUSIONS: Future interventions should address misconceptions, perceived benefits, and self-efficacy for using cessation aids. Physicians should offer pharmacotherapy to all smokers. PMID- 24629558 TI - Daily hassles' role in health seeking behavior among low-income populations. AB - OBJECTIVES: To adapt a daily hassles measure for a low-income population and assess the relationship between hassles and health seeking behavior. METHODS: The mixed methods approach used cognitive interviews (N = 23) to inform an adapted measure of daily hassles. The adapted scale was then tested via surveys (N = 144) in community health centers; multivariate logistic regression models were used to assess relationships among variables. RESULTS: Hassle concerning having enough money for emergencies (76.5%) and worrying about personal health (68.8%) were among the most common. Increased health-related hassles were associated with an increased likelihood to delay needed care. CONCLUSIONS: Findings suggest daily hassles are unique among low-income populations and should be considered in health behavior interventions. PMID- 24629560 TI - Primiparous outcomes and future pregnancy health behaviors. AB - OBJECTIVE: To examine the impact of repeat, G2, and outcomes of first, G1, (previous livebirth, PLB, or stillbirth, PSB) pregnancies on health-compromising behaviors (HCB). METHODS: Retrospective cohort study of 137,374 pregnancies in Kansas City, MO, 1990 through 2009, using birth certificate database. RESULTS: Overall HCB rate was 17% and increased with G2 and PSB (G1=12% v G2-PLB=21% v G2 PSB=29%, p < .001). Compared to G2-PLB, the odds of HCB increased for G2-PSB (OR=1.42; 95%CI 1.10, 1.82) and decreased for G1 (0.54; 0.52, 0.56). CONCLUSION: Women are more likely to engage in HCB during their second pregnancy, especially those who lose their first pregnancy. This finding is evidence for promoting effective inter-conception health care at post-partum and primary care visits. PMID- 24629559 TI - Lessons learned from small store programs to increase healthy food access. AB - OBJECTIVES: To document implementation challenges and opportunities associated with small store interventions. METHODS: Case study analysis of small store interventions conducted in 4 regions of the US. We systematically generated matrices to compare and contrast lessons learned to advance implementation science. RESULTS: Seven thematic areas were identified including: establishing relationships with stores, store owner and customer relationships, selection of intervention approaches, stocking healthier foods, evaluation, maintenance of changes, and dissemination. CONCLUSIONS: This information provides guidance to researchers and practitioners wishing to design, implement, and evaluate small store interventions. PMID- 24629561 TI - Glycoprotein 130 polymorphism predicts soluble glycoprotein 130 levels. AB - OBJECTIVE: Interleukin-6 (IL-6) is a key cytokine in inflammatory diseases. It exerts its biological function via binding to a homodimer of its signal transducer glycoprotein 130 (gp130). Soluble gp130 (sgp130) is the natural inhibitor of IL-6 trans-signalling. The aim of this study was to test a possible influence of the gp130 genotype on sgp130 serum levels. MATERIAL AND METHODS: In two separate populations, subjects were genotyped for the gp130 polymorphism G148C. Sgp130, IL-6 and soluble interleukin-6 receptor (sIL-6R) levels were measured. The OSLO population consisted of 546 male subjects at high risk for CAD. The VIENNA population consisted of 299 male subjects with angiographically proven CAD. RESULTS: In the OSLO population, 124 (22.7%) subjects were hetero- or homozygote for the rare C allele. Individuals carrying the polymorphism had significantly higher levels of sgp130. In a multivariate linear regression model this association remained significant (adjusted p=0.001). In the VIENNA population, 48 (16.1%) subjects were hetero- or homozygote for the rare C allele. Consistent with the former study, sgp130 levels were significantly higher in carriers of the polymorphism compared to wildtype carriers (adjusted p=0.038). In the VIENNA population, sgp130 levels were significantly higher in diabetic patients. In the OSLO population, sgp130 was higher in patients with increased body mass index and in smokers (p<0.05). CONCLUSIONS: Sgp130 serum levels are significantly higher in subjects carrying the gp130 polymorphism G148C compared to wildtype carriers. This finding proposes a possible genetical influence on sgp130 levels which may alter individual coping mechanisms in inflammatory diseases. PMID- 24629562 TI - Obesity-associated mechanisms of hepatocarcinogenesis. AB - Obesity has been recognized as a key component of the metabolic syndrome, a cluster of risk factors associated with diabetes and cardiovascular morbidity. In addition, obesity has been linked to higher frequency of cancers in a variety of tissues including the liver. Liver cancer most often occurs as hepatocellular carcinoma (HCC) complicating cirrhosis due to chronic viral infection or toxic injury and remains the third leading cause of cancer death in the world. However, HCC is increasingly diagnosed among individuals with obesity and related disorders. As these metabolic conditions have become globally prevalent, they coexist with well-established risk factors of HCC and create a unique challenge for the liver as a chronically diseased organ. Obesity-associated HCC has recently been attributed to molecular mechanisms such as chronic inflammation due to adipose tissue remodeling and pro-inflammatory adipokine secretion, ectopic lipid accumulation and lipotoxicity, altered gut microbiota, and disrupted senescence in stellate cells, as well as insulin resistance leading to increased levels of insulin and insulin-like growth factors. These mechanisms synergize with those occurring in chronic liver disease resulting from other etiologies and accelerate the development of HCC before or after the onset of cirrhosis. Increasingly common interactions between oncogenic pathways linked to obesity and chronic liver disease may explain why HCC is one of the few malignancies with rising incidence in developed countries. Better understanding of this complex process will improve our strategies of cancer prevention, prediction, and surveillance. PMID- 24629563 TI - Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation. AB - OBJECTIVE: Resveratrol (RSV) regulates NAD bioavailability and sirtuin-related metabolism, which relates to aging, metabolic syndrome and non-alcoholic fatty liver disease. The purpose of this study was to investigate the effects of resveratrol on hepatic metaflammation in a rodent model of high-fat (HF) diet induced obesity (DIO). MATERIALS/METHODS: DIO was induced in a subset of mice given an HF diet (45% kcal fat). After 6weeks of HF diet feeding, RSV was delivered via an osmotic pump for 4weeks. The experimental groups were as follows: 1) lean control fed with a standard diet, 2) HF diet-induced obese control, and 3) HF_RSV (8mg/kg/day). After 4weeks of each treatment, blood and liver tissues were collected and the indices of glucose control, serum and liver triglyceride (TG), sirtuin pathway, inflammation, and NOD-like receptor family, pryin domain containing 3 (NLRP3) inflammasome were analyzed. RESULTS: Body weight and food intake were not altered by administering resveratrol. Glucose control was impaired, and serum and liver TG levels were increased by the HF diet. Hepatic inflammation was aggravated in mice fed with the HF diet, as shown by the increased levels of the pro-inflammatory markers interleukin-1 (IL-1), IL 6 and tumor necrosis factor-alpha in the liver. However, resveratrol administration significantly improved glucose control, and serum and liver TG contents. Also, resveratrol treatment reduced the levels of the pro-inflammatory markers. These improvements were accompanied by alterations in sirtuin pathway and NLRP3 inflammasome activation. CONCLUSION: These results demonstrate that resveratrol ameliorates hepatic metaflammation, accompanied by alterations in NLRP3 inflammasome. PMID- 24629564 TI - Gypenosides might have neuroprotective and immunomodulatory effects on optic neuritis. AB - Optic neuritis is a common disease in young adults, inducing apoptosis of retinal ganglion cells, which leads to varying degree of visual function damages, even blindness. As the standard treatment, methylprednisolone pulse therapy can only promote the recovery of visual acuity but not prevent retinal ganglion cell degeneration. It cannot help improve the ultimate visual outcome. Both inflammatory response and endogenous oxidative stress play crucial roles in the progression of optic neuritis. The combination of immunomodulatory and antioxidant is expected to improve the prognosis of the disease by preventing the apoptosis of retinal ganglion cells. Triterpenoids (oleanolic acid derived) were reported to have the dual capacity of simultaneously repressing production of pro inflammatory mediators and exerting neuroprotective effects through induction of anti-oxidant genes in experimental optic neuritis. Gypenosides with an aglycone mainly of dammarane-type tetracyclic triterpenoids, also has the dual capacity of immune regulation and antioxidation. Both gypenosides and oleanolic acid were reported to have similar roles in hepatoprotection. Beside, gypenosides were reported to have the capacity of modulating the activation of immune cells and the expression of cytokines. In addition, gypenosides showed neuroprotective effect against oxidative injury in dopaminergic neurons and mouse model of Parkinson's disease. Accordingly, we propose that gypenosides have potential neuroprotective and immunomodulatory effects on optic neuritis through antioxidation and immune regulation. The application of gypenosides might prevent the apoptosis of retinal ganglion cells and improve the ultimate visual outcome in patients with optic neuritis. PMID- 24629565 TI - Probable posttraumatic stress disorder in a sample of urban jail detainees. AB - This study examined the nature and extent of probable posttraumatic stress disorder (PTSD) among men in a substance abuse treatment program in a large urban jail. Specifically, it explored the prevalence of probable PTSD and other psychiatric problems among jail detainees, the types of trauma detainees experienced during different phases of their lives, and how those experiences might have contributed to the development of probable PTSD. Results showed that psychiatric problems were quite serious; nearly one-quarter of the sample reported previous psychiatric hospitalization, and nearly 10% were being currently treated with psychiatric medication. In addition, 21% of the sample met the criteria for probable PTSD, a rate five times greater than that in the general population. The current study suggests that the presence of probable PTSD among male detainees should be incorporated into the creation and implementation of jail-based behavioral healthcare services, including screening, assessment, and clinical interventions. Furthermore, in-custody drug treatment programs should adopt trauma-informed strategies for all program participants as the expected standard of care. PMID- 24629566 TI - Mental health at the intersections: the impact of complex needs on police contact and custody for Indigenous Australian men. AB - Indigenous Australians experience significant social risk, vulnerability and disadvantage. Nowhere is this more starkly demonstrated than in the levels of contact that Indigenous Australians have with the criminal justice system, particularly the police. Utilizing a linked dataset of extant criminal justice, human and health service administrative data in New South Wales (NSW) Australia, this paper explores patterns of police contact and custody for a cohort of Indigenous males with complex needs. Four significant factors are identified that alone or in combination appear to impact on the frequency with which these men experience police contact and custody, including young age at first police contact, experiencing out of home care as a child, alcohol misuse, and limited locational mobility. Whilst it might be expected that the presence of mental ill health and/or cognitive disability would be a key predictor of the frequency and intensity of police contact and custody, the findings suggest rather that the presence of multiple disadvantages beginning in the early years and compounding throughout individuals' lives, in which mental illness may or may not be a factor, is more significant than the presence of any one diagnosis in precipitating police contact and custody for this group. PMID- 24629567 TI - Attitudes toward hiring applicants with mental illness and criminal justice involvement: the impact of education and experience. AB - Individuals with mental health diagnoses, as well as those involved in the criminal justice system, experience a number of barriers in the recovery and reintegration progress, including access to stable, prosocial employment opportunities. Employment for these populations is important for establishing financial security, reducing unstructured leisure time, increasing self-worth, and improving interpersonal skills. However, research has demonstrated that individuals with psychiatric and/or criminal backgrounds may experience stigmatizing attitudes from employers that impede their ability to find adequate work. This study aimed to evaluate stigmatizing beliefs toward hypothetical applicants who indicated a mental health history, a criminal history, or both, as well as the effectiveness of psychoeducation in reducing stigma. Participants consisted of 465 individuals recruited from a large university who completed a series of online questions about a given applicant. Results of this study varied somewhat across measures of employability, but were largely consistent with extant research suggesting that mental illness and criminal justice involvement serve as deterrents when making hiring decisions. Overall, psychoeducation appeared to reduce stigma for hiring decisions when the applicant presented with a criminal history. Unfortunately, similar findings were not revealed when applicants presented with a psychiatric or a psychiatric and criminal history. Implications and limitations of these findings are presented, along with suggestions for future research. PMID- 24629568 TI - Beyond police crisis intervention: moving "upstream" to manage cases and places of behavioral health vulnerability. AB - Law enforcement officers continue to serve on the front lines as mental health interventionists, and as such have been subject to a wave of "first generation" reform designed to enhance their crisis response capabilities. Yet, this focus on crisis intervention has not answered recent calls to move "upstream" and bolster early intervention in the name of long-term recovery. This paper reports on findings from an action research project in Philadelphia aimed at exploring opportunities for enhanced upstream engagement. Study methods include spatial analyses of police mental health transportations from an eight year period (2004 2011) and qualitative data from twenty-three "framing conversations" with partners and other stakeholders, seven focus groups with police and outreach workers, five key informant interviews as well as document reviews of the service delivery system in Philadelphia. Recommendations include the need to move beyond a focus on what police can do to a wider conception of city agencies and business stakeholders who can influence vulnerable people and vulnerable spaces of the city. We argue for the need to develop shared principles and rules of engagement that clarify roles and stipulate how best to enlist city resources in a range of circumstances. Since issues of mental health, substance use and disorder are so tightly coupled, we stress the importance of establishing a data-driven approach to crime and disorder reduction in areas of the city we term "hotspots of vulnerability". In line with a recovery philosophy, such an approach should reduce opportunities for anti-social behavior among the "dually labeled" in ways consistent with "procedural justice". Furthermore, crime and disorder data flowing from police and security to behavioral health analysts could contribute to a more focused case management of "repeat utilizers" across the two systems. Our central argument is that a twin emphasis on "case management" and "place management" may provide the pillars needed to move upstream and strengthen interventions along a continuum of engagement. PMID- 24629569 TI - Rapamycin limits the growth of established experimental abdominal aortic aneurysms. AB - OBJECTIVES: Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease affecting 4-8% of men older than 60 years. No pharmacologic strategies limit disease progression, aneurysm rupture, or aneurysm-related death. We examined the ability of rapamycin to limit the progression of established experimental AAAs. METHODS: AAAs were created in 10-12-week-old male C57BL/6J mice via the porcine pancreatic elastase (PPE) infusion method. Beginning 4 days after PPE infusion, mice were treated with rapamycin (5 mg/kg/day) or an equal volume of vehicle for 10 days. AAA progression was monitored by serial ultrasound examination. Aortae were harvested for histological analyses at sacrifice. RESULTS: Three days after PPE infusion, prior to vehicle or rapamycin treatment, aneurysms were enlarging at an equal rate between groups. In the rapamycin group, treatment reduced aortic enlargement by 38%, and 53% at 3 and 10 days, respectively. On histological analysis, medial elastin and smooth muscle cell populations were relatively preserved in the rapamycin group. Rapamycin treatment also reduced mural macrophage density and neoangiogenesis. CONCLUSION: Rapamycin limits the progression of established experimental aneurysms, increasing the translational potential of mechanistic target of rapamycin-related AAA inhibition strategies. PMID- 24629570 TI - [Intraoperative choledochoscopy usefulness in the treatment of difficult biliary stones]. AB - BACKGROUND: Choledocholithiasis presents in 5-10% of the patients with biliary lithiasis. Numerous treatment algorithms have been considered for this disease, however, up to 10% of these therapeutic procedures may fail. Intraoperative choledochoscopy has become a useful tool in the treatment of patients with difficult-to-manage choledocholithiasis. OBJECTIVES: To determine the usefulness of intraoperative choledochoscopy in the laparoendoscopic treatment of difficult stones that was carried out in our service. PATIENTS AND METHODS: A cross sectional study was conducted. The case records were reviewed of the patients that underwent intraoperative choledochoscopy during biliary tree exploration plus laparoscopic choledochoduodenal anastomosis within the time frame of March 1, 2011 and May 31, 2012, at the Hospital General Dr. Manuel Gea Gonzalez. Transabdominal choledochoscopies were performed with active stone extraction when necessary, followed by peroral choledochoscopies through the recently formed bilioenteric anastomosis. The data were analyzed with descriptive statistics and measures of central tendency. RESULTS: The mean age was 71 years, 57% of the patients were women, and the ASA III score predominated. Active extraction of stones with 7 to 35mm diameters was carried out in 4 of the cases and the absence of stones in the biliary tract was corroborated in all the patients. The mean surgery duration was 18 minutes (range: 4 to 45min). CONCLUSIONS: Choledochoscopy is a safe and effective minimally invasive procedure for the definitive treatment of difficult stones. PMID- 24629571 TI - [Anorectal leiomyoma: a case report and literature review]. PMID- 24629572 TI - Trends in physical stature across socioeconomic groups of Chilean boys, 1880 1997. AB - This paper studies the trends in height-by-age across socioeconomic groups of Chilean boys aged 5-18 born between 1880 and 1997, by performing a meta-analysis of 38 studies reporting height-by-age published since 1898. We estimate the trends using quantile regressions and by analyzing detailed height data from five selected studies. Both methods yield an average decennial increase in height of 1 1.1cm, and 0.9 and 1.2-1.3 cm for boys of upper and lower socioeconomic status (SES), respectively. SES differences in heights of 9-11 cm are observed up to the late 1940s. However, boys born after the 1930s exhibit substantial convergence in height between socioeconomic groups, driven by an increase in height of middle and lower SES boys of 1.5 and 1.4-2 cm per decade, respectively. As a result, SES differences in height decreased to 5 cm in 1990s. Since these changes occurred in a context of moderate economic growth and persistent income inequality, we argue that our findings are associated with the emergence and expansion of social policies in Chile since the 1940s, which delivered steady improvements in health, nutrition and living conditions. PMID- 24629573 TI - Antiphospholipid antibodies in critically ill patients with cancer: a prospective cohort study. AB - PURPOSE: The purpose of this study is to evaluate the prevalence and the prognostic impact of antiphospholipid antibodies (aPL) in critically ill cancer patients. METHODS: This is a prospective cohort study in adult patients admitted to the intensive care unit for more than 48 hours at a cancer center. Clinical and laboratory data including coagulation parameters were obtained. Cox proportional hazard models were used to identify predictors of 6-month mortality. RESULTS: Ninety-five (solid tumor, 79%; hematologic malignancies, 21%) patients were included, and aPL were identified in 74% of them. Median Simplified Acute Physiology Score 3 and Sequential Organ Failure Assessment scores were 51 (37-65) and 5 (2-8) points, respectively. The most frequent aPL were lupus anticoagulant (61%) and anti-beta2 glicoprotein I (32%). Vascular complications occurred in 18% of patients and were comparable between aPL+ and aPL- patients. Sepsis and need for renal replacement therapy were more frequent in aPL+ patients. Hospital and 6 month mortality rates were 44% and 56%, respectively. Higher Sequential Organ Failure Assessment scores (each point) (hazard ratios [HR]=2.83 [95% confidence interval, 1.59-5.00]), medical admissions (HR=2.66 [1.34-5.27]), and d-dimer more than 500 ng/dL (HR=1.89 (1.04-3.44]) were independently associated with mortality. After adjusting for these covariates, aPL status was not associated with outcomes (HR=1.22 [0.60-2.47]). CONCLUSIONS: Lupus anticoagulants were frequent in critically ill cancer patients. However, they were not associated with medium-term survival in these patients. PMID- 24629575 TI - Effects of etomidate on vasopressor use in patients with sepsis or severe sepsis: a propensity-matched analysis. AB - PURPOSE: The safety of single-bolus etomidate to facilitate intubation in septic patients is controversial due to its potential to suppress adrenal steroidogenesis. The purpose of this study was to evaluate the effects of etomidate on the development of shock when used as an induction agent to facilitate intubation in septic patients. METHODS: A multicenter, retrospective, propensity-matched cohort study comparing patients with sepsis or severe sepsis who either received etomidate or did not receive etomidate for intubation was conducted. The primary outcome was the difference in the need for vasopressor support within 72 hours after intubation. Secondary outcomes included the use of multiple vasopressors, intensive care unit length of stay, and in-hospital mortality. RESULTS: A total of 411 patients were analyzed. Eighty-three patients were matched by propensity score. There was no difference in the matched cohort in regards to vasopressor use within 72 hours of intubation (odds ratio, 0.95; 95% confidence interval, 0.52-1.76; P=.88). Furthermore, there were no significant differences observed with regard to secondary outcomes, including in hospital mortality (P=.76). CONCLUSIONS: The use of etomidate for intubation in septic patients did not increase vasopressor requirements within 72 hours after intubation. PMID- 24629574 TI - Barriers and facilitators of thromboprophylaxis for medical-surgical intensive care unit patients: a multicenter survey. AB - BACKGROUND: The objective of this study was to identify the self-reported barriers to and facilitators of prescribing low-molecular-weight heparin (LMWH) thromboprophylaxis in the intensive care unit (ICU). METHODS: We conducted an interviewer-administered survey of 4 individuals per ICU (the ICU director, a bedside pharmacist, a thromboprophylaxis research coordinator, and physician site investigator) regarding LMWH thromboprophylaxis for medical-surgical patients in 27 ICUs in Canada and the United States. Items were generated by the research team and adapted from previous surveys, audits, qualitative studies, and quality improvement research. Respondents rated the barriers to LMWH use, facilitators (effectiveness, affordability, and acceptability thereof), and perceptions regarding LMWH use. RESULTS: Respondents had 14.5 (SD, 7.7) years of ICU experience (response rate, 99%). The 5 most common barriers in descending order were as follows: drug acquisition cost, fear of bleeding, lack of resident education, concern about bioaccumulation in renal failure, and habit. The top 5 rated facilitators were preprinted orders, education, daily reminders, audit and feedback, and local quality improvement committee endorsement. Centers using preprinted orders (mean difference [P<.01]) and computerized physician order entry (P<.01) compared with those centers not using those tools reported higher affordability for these 2 facilitators. Compared with physicians and pharmacists, research coordinators considered ICU-specific audit and feedback of thromboprophylaxis rates to be a more effective, acceptable, and affordable facilitator (odds ratio, 6.67; 95% confidence interval, 1.97-22.53; P<.01). Facilitator acceptability ratings were similar within centers but differed across centers (P<=.01). CONCLUSIONS: This multicenter survey found several barriers to use of LMWH including cost, concern about bleeding, and lack of resident knowledge of effectiveness. The diversity of reported facilitators suggests that large scale programs may address generic barriers but also need site-specific interprofessional knowledge translation activities. PMID- 24629576 TI - Conservative management of femoroacetabular impingement (FAI) in the long distance runner. AB - Femoroacetabular impingement (FAI) is one cause of anterior hip pain that may occur in a long distance runner. By definition FAI is due to bony abutment of the femoral neck and the acetabulum. This occurs primarily with end-ranges of hip flexion and adduction. An understanding of running mechanics and performing a thorough examination will help the clinician provide an appropriate intervention for these athletes. A course of conservative treatment that includes patient education, manual therapy and strengthening should be tried prior to surgical management. PMID- 24629577 TI - Diagnostic value of adenosine deaminase in ascites for tuberculosis ascites: a meta-analysis. AB - The diagnosis of tuberculosis (TB) ascites using standard diagnostic tools is difficult. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of adenosine deaminase (ADA) levels in ascites for diagnosing TB ascites. A systematic review was performed of English language publications prior to April 2013. Sensitivity, specificity, and other measures of the accuracy of ADA for the diagnosis of TB ascites using ascites fluid were summarized using a random-effects model or a fixed-effects model. Receiver operating characteristic curves were used to summarize overall test performance. Seventeen studies involving 1797 subjects were eligible for the analysis. The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the area under cure of overall analysis were: 0.93, 0.94, 13.55, 0.11, 169.83, and 0.976, respectively; the results of sensitivity analysis of studies that used Giusti method were 0.94, 0.94, 12.99, 0.08, 183.18, and 0.977, respectively. Our results suggest that ADA in the ascites can be a sensitive and specific target and a critical criterion for the diagnosis of TB ascites. PMID- 24629578 TI - Suppressive therapy using azithromycin in 2 rare cases of recurrent staphylococcal infections. AB - Recurrent staphylococcal skin and soft tissue infections may recur despite decontamination and multiple courses of antibiotic therapy and may dramatically impair the patient's quality of life. We report successful use of long-term azithromycin prophylaxis in a recurrent laryngitis and a scalp folliculitis due to methicillin-susceptible Staphylococcus aureus. PMID- 24629579 TI - Separation of suspensions and emulsions via ultrasonic standing waves - a review. AB - Ultrasonic standing waves (USW) separation is an established technology for micro scale applications due to the excellent control to manipulate particles acoustically achieved when combining high frequency ultrasound with laminar flow in microchannels, allowing the development of numerous applications. Larger scale systems (pilot to industrial) are emerging; however, scaling up such processes are technologically very challenging. This paper reviews the physical principles that govern acoustic particle/droplet separation and the mathematical modeling techniques developed to understand, predict, and design acoustic separation processes. A further focus in this review is on acoustic streaming, which represents one of the major challenges in scaling up USW separation processes. The manuscript concludes by providing a brief overview of the state of the art of the technology applied in large scale systems with potential applications in the dairy and oil industries. PMID- 24629580 TI - Synthesis of TiO2/WO3 nanoparticles via sonochemical approach for the photocatalytic degradation of methylene blue under visible light illumination. AB - Through an ultrasound assisted method, TiO2/WO3 nanoparticles were synthesized at room temperature. The XRD pattern of as-prepared TiO2/WO3 nanoparticles matches well with that of pure monoclinic WO3 and rutile TiO2 nanoparticles. TEM images show that the prepared TiO2/WO3 nanoparticles consist of mixed square and hexagonal shape particles about 8-12nm in diameter. The photocatalytic activity of TiO2/WO3 nanoparticles was tested for the degradation of a wastewater containing methylene blue (MB) under visible light illumination. The TiO2/WO3 nanoparticles exhibits a higher degradation rate constant (6.72*10(-4)s(-1)) than bare TiO2 nanoparticles (1.72*10(-4)s(-1)) under similar experimental conditions. PMID- 24629581 TI - Effects of ultrasound and temperature on copper electro reduction in Deep Eutectic Solvents (DES). AB - This paper concerns a preliminary study for a new copper recovery process from ionic solvent. The aim of this work is to study the reduction of copper in Deep Eutectic Solvent (choline chloride-ethylene glycol) and to compare the influence of temperature and the ultrasound effects on kinetic parameters. Solutions were prepared by dissolution of chloride copper salt CuCl2 (to obtain Copper in oxidation degree II) or CuCl (to obtain Copper in oxidation degree I) and by leaching metallic copper directly in DES. The spectrophotometry UV-visible analysis of the leached solution showed that the copper soluble form obtained is at oxidation degree I (Copper I). Both cyclic voltammetry and linear voltammetry were performed in the three solutions at three temperatures (25, 50 and 80 degrees C) and under ultrasonic conditions (F=20kHz, PT=5.8W) to calculate the mass transfer diffusion coefficient kD and the standard rate coefficient k degrees . These parameters are used to determine that copper reduction is carried out via a mixed kinetic-diffusion control process. Temperature and ultrasound have the same effect on mass transfer for reduction of Cu(II)/Cu(I). On the other hand, temperature is more beneficial than ultrasound for mass transfer of Cu(I)/Cu. Standard rate constant improvement due to temperature increase is of the same order as that obtained with ultrasound. But, by combining higher temperature and ultrasound (F=20kHz, PT=5.6W at 50 degrees C), reduction limiting current is increased by a factor of 10 compared to initial conditions (T=25 degrees C, silent), because ultrasonic stirring is more efficient in lower viscosity fluid. These values can be considered as key-parameters in the design of copper recovery in global processes using ultrasound. PMID- 24629582 TI - An emerging reactor technology for chemical synthesis: surface acoustic wave assisted closed-vessel Suzuki coupling reactions. AB - In this paper we demonstrate the use of an energy-efficient surface acoustic wave (SAW) device for driving closed-vessel SAW-assisted (CVSAW), ligand-free Suzuki couplings in aqueous media. The reactions were carried out on a mmolar scale with low to ultra-low catalyst loadings. The reactions were driven by heating resulting from the penetration of acoustic energy derived from RF Raleigh waves generated by a piezoelectric chip via a renewable fluid coupling layer. The yields were uniformly high and the reactions could be executed without added ligand and in water. In terms of energy density this new technology was determined to be roughly as efficient as microwaves and superior to ultrasound. PMID- 24629583 TI - Sonochemical synthesis of carbon supported Sn nanoparticles and its electrochemical application. AB - A sonochemical approach was employed to prepare Vulcan carbon XC-72R supported by Sn nanoparticles at room temperature in the presence of ethylene glycol. The reduction of metallic Sn ion and ethylene glycol takes place and in turn the glycolate ion as formed acts as a stabilizing agent. Transmission electron microscope, X-ray diffraction, and X-ray photoelectron spectroscopy have illustrated that the metallic Sn nanoparticles are successfully embedded on the carbon. The significantly observed reduction over potential for oxygen reduction reaction displays a higher catalytic activity of carbon supported by Sn nanoparticles due to the large surface area of the modified electrode. PMID- 24629584 TI - A commentary on "maternal work and children's diet, activity, and obesity". PMID- 24629585 TI - Magnetic resonance imaging-detected inner ear hemorrhage as a potential cause of sudden sensorineural hearing loss. AB - PURPOSE: The aim of this study is to assess the value of magnetic resonance imaging in identifying the etiology of sudden sensorineural hearing loss, and to correlate the high signals in the labyrinth with clinical features to identify if inner ear hemorrhage could be implicated. MATERIALS AND METHODS: In this retrospective study, inner ear magnetic resonance imaging was given to 112 patients with sudden sensorineural hearing loss in the First Affiliated Hospital of Sun Yat-sen University from 2011 to 2012. The clinical features of patients with high signals in the labyrinth on magnetic resonance imaging were analyzed. RESULTS: Abnormal magnetic resonance images were identified in 13 (11.6%) patients. Retrocochlear pathology was found in six patients, including two cases of lacunar infarction, one case of multiple ischemias in the brainstem and bilateral centrum semiovale, two cases of acoustic neuroma, and one case of inner ear hemangioma. There were seven cases showing high signals in the labyrinth on unenhanced T1-weighted and fluid-attenuated inversion recovery images. Clinical features of these seven patients were characterized by irreversible profound hearing impairment and vestibular dysfunction. These findings were consistent with the hypothesis that their symptoms were caused by an inner ear hemorrhage. CONCLUSION: The results indicate the importance of magnetic resonance imaging in sudden sensorineural hearing loss in patients. Moreover, patients with vestibular dysfunction and sudden profound hearing loss may have an inner ear hemorrhage evident by interpreting clinical and magnetic resonance imaging results. PMID- 24629586 TI - Improving outcomes by combining septoplasty with primary external dacryocystorhinostomy. AB - PURPOSE: External dacryocystorhinostomy (EXT-DCR) is the gold standard in the treatment of acquired nasolacrimal duct obstruction. Intranasal pathology can compromise the success of primary and revision external dacryocystorhinostomy EXT DCR procedures. Nasal septal deviations resulting in unfavorable anatomy are an identified cause of DCR failures. In this study, we examine the causes of failure in our patient population and propose that concomitant treatment of septal deviations at the time of primary EXT-DCR can decrease the rate of revision surgery. MATERIALS AND METHODS: Retrospective review of patients who had undergone an EXT-DCR. RESULTS: Over a five year period, 12 EXT-DCR failures were identified and 8 were directly attributable to nasal septal deviations. Revision surgery was successful in all 8 cases after correction of the nasal septal deviation. A second cohort of patients was identified who had undergone primary EXT-DCR and septoplasty concomitantly. Eight consecutive patients underwent the combined procedure for a total of 10 EXT-DCR and 8 septoplasties. The only failure was due to a common canalicular obstruction (90% success rate for the combined approach). CONCLUSIONS: As a result of our findings, we believe that treating nasal septal deviation at the time of the initial surgery can help minimize the need for revision surgery. PMID- 24629587 TI - Transoral negative-pressure catheter drainage of a retropharyngeal and mediastinal abscess. AB - PURPOSE: A retropharyngeal abscess (RPA) is an extremely rare entity in adults that has a tendency to spread vertically and cause a mediastinal abscess. Traditionally, immediate aggressive drainage is recommended via a transcervical or transthoracic approach for the treatment of a retropharyngeal abscess with mediastinal extension. Here, we present a case of a retropharyngeal and mediastinal abscess using a transoral negative-pressure catheter drainage approach. PATIENTS AND METHODS: A 24-year-old woman was admitted with a 4-day history of severe sore throat and painful swallowing. Computed tomography identified a retropharyngeal abscess extending to the upper posterior mediastinum. We performed transoral negative-pressure catheter drainage. RESULTS: The postoperative course was uneventful. The patient reported a rapid improvement in symptoms and had a good tolerance of the catheters in the nasal cavity. At 2 years postoperatively, physical examinations revealed no recurrence or surgical complications. CONCLUSIONS: Transoral negative-pressure catheter drainage is a minimally invasive operation for the treatment of RPA in adults with or without a mediastinal abscess. This method could be recommended as an alternative approach in such cases. PMID- 24629588 TI - Experiences in the treatment of patients with multiple head and neck paragangliomas. AB - PURPOSE: To analyze treatment results in the multidisciplinary management of patients with multiple head and neck paragangliomas (HNPs). METHODS: Retrospective analysis including all patients with multiple HNPs (VP, vagal paraganglioma; JTP, jugulotympanic paraganglioma; CBT, carotid body tumor) treated between 2000 and 2013 at a tertiary referral center. RESULTS: Ten patients (three men, seven women) had 25 HNPs (two VPs, eight JTPs, and 15 CBTs). The age range at diagnosis was 31-71 years (mean 40.9 years, median 37 years). Nine tumors (four CBTs, three JTPs, two VPs) were treated only with stereotactic radiotherapy (SRT; 50.4-56Gy, mean 55.3Gy) or in one case intensity-modulated radiotherapy (60 Gy). Nine tumors were treated with surgery alone (eight CBTs, one JTP) and three JTPs with subtotal surgery combined with adjuvant SRT. A "wait and scan" strategy was used in three cases (two CBTs, one JTP). The mean follow up period was 4.3 years (range 0.1-13 years, median 4 years). The rate of tumor control with surgery and/or SRT was 100% (21/21). One patient with a wait-and scan strategy for CBT had slow asymptomatic progression during a 13-year follow up. CONCLUSIONS: The treatment results in this series of patients with multiple HNPs show that a very high rate of long-term tumor control with low morbidity can be achieved using tailored and individualized approaches. All of the different treatment strategies available should be discussed with the patient. In particular, the treatment should involve a multidisciplinary team of experts in the fields of nuclear medicine, genetics, pathology, radiology, radio-oncology, and surgery. PMID- 24629589 TI - An experimental study of pain upon stimulation of the nasal and sinus cavities. AB - OBJECTIVE: To map different areas of pain sensitivity and to determine the existence and/or pattern of referred pain from upon stimulating the sinonasal cavity. STUDY DESIGN: Experimental human study. METHODS: Mechanical and electrical stimulations to various anatomical structures and areas of the nasal and sinus cavities were conducted on nine volunteers. Intensity, location and character of pain were recorded in all subjects. RESULTS: The postero-superior (cephalic) aspect of the nasal cavity, primarily the anterior face of the sphenoid sinus and the superior turbinate, were the most sensitive sites, and the antero-inferior (caudal) region was the least sensitive. Referred pain to the head and face was reported by several subjects. CONCLUSION: Topographical differences in pain sensitivity exist in the sinonasal cavity. The phenomenon of referred pain from the nasal cavity was demonstrated. PMID- 24629590 TI - Tolerance of brown bear spermatozoa to conditions of pre-freezing cooling rate and equilibration time. AB - Specific protocols for the cryopreservation of endangered Cantabrian brown bear spermatozoa are critical to create a genetic resource bank. The aim of this study was to assess the effect of cooling rates and equilibration time before freezing on post-thawed brown bear spermatozoa quality. Electroejaculates from 11 mature bears were extended to 100 * 10(6) spermatozoa/mL in a TES-Tris-Fructose-based extender, cryopreserved following performance of the respective cooling/equilibration protocol each sample was assigned to, and stored at -196 degrees C for further assessment. Before freezing, after thawing, and after 1 hour's incubation post-thawing at 37 degrees C (thermal stress test), the quality of the samples was assessed for motility by computer-assisted semen analysis, and for viability (SYBR-14/propidium iodide), acrosomal status (peanut agglutinin-fluorescein isothiocyanate /propidium iodide), and sperm chromatin stability (SCSA) by flow cytometry. In experiment 1, three cooling rates (0.25 degrees C/min, 1 degrees C/min, and 4 degrees C/min) to 5 degrees C were assessed. After thawing, total motility (%TM) was higher and percentage of damaged acrosomes (%dACR) was lower (P < 0.05) for 0.25 degrees C/min than for 4 degrees C/min. The thermal stress test data indicated equally poor quality (P < 0.05) for the 4 degrees C/min cooled samples in viability (%VIAB), %dACR, %TM, and progressive motility (%PM). In experiment 2, the effect of a pre-freezing equilibration period at 5 degrees C for 1 hour (cooling at 0.25 degrees C/min) was evaluated. Samples kept at 5 degrees C for 1 hour showed higher (P < 0.05) values than the nonequilibrated ones for both thawing (%dACR) and thermal stress test (%VIAB, %TM, and %PM). In experiment 3, samples stored without cooling and equilibration (direct freezing) were compared with the samples cooled at 0.25 degrees C/min and equilibrated for 1 hour (control freezing). Using thermal stress test, we observed that direct freezing causes damage in viability, acrosomal status, and motility of spermatozoa compared with the control group (P < 0.05). In conclusion, our results suggest that slow cooling rates to 5 degrees C and at least 1 hour equilibration time are necessary for the effective cryopreservation of brown bear sperm. PMID- 24629591 TI - Aminopeptidase activity in seminal plasma and effect of dilution rate on rabbit reproductive performance after insemination with an extender supplemented with buserelin acetate. AB - Ovulation induction in artificially inseminated rabbits by adding GnRH synthetic analogues in the seminal doses is a welfare-orientated method to induce ovulation in rabbits and could have some advantages in field practice. This study was conducted to determine the effect of male genotype on the aminopeptidase activity in rabbit seminal plasma and the effects of dilution rate of semen on availability and reproductive performance when buserelin acetate is added to the seminal dose. To study the aminopeptidase activity, 12 mature bucks belonging to a paternal line and 12 from a maternal line were used. The bucks from the paternal line were used to study the effect of dilution rate on the availability of buserelin acetate after 2 hours of dilution and on the reproductive performance of the doses after artificial insemination of 389 commercial crossbreed does. Aminopeptidase activity in seminal plasma is dependent on the male genotype. The paternal line resulted 27% more aminopeptidase activity than the maternal line (P < 0.05). On the other hand, semen diluted 1:20 exhibited a marked increase in the availability of buserelin acetate and the fertility in this group was significantly higher than females from dilution rate 1:5 group, which showed similar results to that of the negative control group (does inseminated with semen diluted 1:20 in non-GnRH-supplemented extender). We conclude that the bioavailability of buserelin acetate when added to the seminal dose appears to be determined by the activity of the existing aminopeptidases and is consequently affected by the dilution rate used to prepare the artificial insemination doses. PMID- 24629592 TI - Heparan sulfate glycosaminoglycans modulate migration and survival in zebrafish primordial germ cells. AB - Early in embryonic development, primordial germ cells (PGCs) are specified and migrate from the site of their origin to where the gonad develops, following a specific route. Heparan sulfate glycosaminoglycans (HS-GAGs) are ubiquitous in extracellular matrix and the cell surface and have long been speculated to play a role during the migration of PGCs. In line with this speculation, whole-mount immunohistochemistry revealed the existence of HS-GAGs in the vicinity of migrating PGCs in early zebrafish embryos. To examine the roles of HS-GAGs during PGC migration, zebrafish heparanase 1 (hpse1), which degrades HS-GAGs, was cloned and overexpressed specifically in PGCs. The guidance signal for the migration of PGCs was disrupted with the overexpression of hpse1, as cluster formation and marginal localization at the blastoderm were significantly perturbed at 6 hours postfertilization. Furthermore, the number of PGCs was significantly decreased with the lack of vicinal HS-GAGs, as observed in the whole-mount in situ hybridization and quantitative PCR of the PGC marker gene vasa. Terminal deoxynucleotidyl transferase dUTP nick-end labeling indicated significantly increased apoptosis in PGCs overexpressing hpse1, suggesting that HS-GAGs contribute to the maintenance of PGC survival. In conclusion, HS-GAGs play multifaceted roles in PGCs during migration and are required both for guidance signals and multiplication of PGCs. PMID- 24629593 TI - Epithelial cadherin is present in bovine oviduct epithelial cells and gametes, and is involved in fertilization-related events. AB - Fertilization is a calcium-dependent process that involves sequential cell-cell adhesion events of spermatozoa with oviduct epithelial cells (OECs) and with cumulus-oocyte complexes (COCs). Epithelial cadherin (E-cadherin) participates in calcium-dependent somatic cell adhesion; the adaptor protein beta-catenin binds to the E-cadherin cytoplasmic domain and links the adhesion protein to the cytoskeleton. The study was conducted to immunodetect E-cadherin and beta-catenin in bovine gametes and oviduct (tissue sections and OEC monolayers), and to assess E-cadherin participation in fertilization-related events. Epithelial cadherin was found in spermatozoa, oocytes, cumulus cells, and OEC. In acrosome-intact noncapacitated spermatozoa, E-cadherin was mainly localized in the apical ridge and acrosomal cap (E1-pattern; 84 +/- 9%; mean +/- standard deviation of the mean). After sperm treatment with heparin to promote capacitation, the percentage of cells with E1-pattern (56 +/- 12%) significantly decreased; concomitantly, the percentage of spermatozoa depicting an E-cadherin staining pattern similar to E1 pattern but showing a signal loss in the acrosomal cap (E2-pattern: 40 +/- 11%) increased. After l-alpha-lysophosphatidylcholine-induced acrosome reaction, E cadherin signal was mainly localized in the inner acrosomal membrane (E3-pattern: 67 +/- 22%). In IVM COC, E-cadherin was immunodetected in the plasma membrane of cumulus cells and oocytes, but was absent in the polar body. The 120 KDa mature protein form was found in protein extracts from spermatozoa, oocytes, cumulus cells, and OEC. beta-Catenin distribution followed E-cadherin's in all cells evaluated. Epithelial cadherin participation in cell-cell interaction was evaluated using specific blocking monoclonal antibody DECMA-1. Sperm incubation with DECMA-1 impaired sperm-OEC binding (the number of sperm bound to OEC: DECMA 1 = 6.7 +/- 6.1 vs. control = 29.6 +/- 20.1; P < 0.001), fertilization with COC (% fertilized COC: DECMA-1 = 68.8 +/- 10.4 vs. control = 90.7 +/- 3.1; P < 0.05) or denuded oocytes (% fertilized oocytes: DECMA-1 = 57.0 +/- 15.2 vs. control = 89.2 +/- 9.8; P < 0.05) and binding to the oolemma (the number of sperm bound to oolemma: DECMA-1 = 2.2 +/- 1.1 vs. control = 11.1 +/- 4.8; P < 0.05). This study describes, for the first time, the presence of E-cadherin in bovine spermatozoa, COC, and OEC, and shows evidence of its participation in sperm interaction with the oviduct and the oocyte during fertilization. PMID- 24629594 TI - Development of methods for cryopreservation of rooster sperm from the endangered breed "Gallina Valenciana de Chulilla" using low glycerol concentrations. AB - Glycerol (11%; v:v) is the cryoprotectant most often used for the cryopreservation of rooster sperm. However, chicken breeds differ in the resistance of their sperm to the cryopreservation process and endangered or local breeds usually present low fertilizing ability when conventional sperm cryopreservation protocols are used. The objective of this study was to optimize the protocol for the cryopreservation of the sperm from the endangered breed "Gallina Valenciana de Chulilla". For this purpose, 10 pools of semen from 43 roosters of this breed were cryopreserved using 8%, 7%, 6%, or 4% glycerol, and the sperm quality was determined immediately after thawing and in the insemination doses. Lohmann Brown Classic laying hens (n = 40) were used for the insemination trials. The sperm quality after cryopreservation progressively decreased as the glycerol concentration was reduced (P < 0.01); samples frozen using 4% glycerol exhibited the lowest quality (38% total motile sperm and 49% live sperm), and samples frozen using 8% glycerol exhibited the highest quality (67% total motile sperm and 66% live sperm). These differences were also observed after the glycerol was removed (P < 0.01). However, the sperm fertilizing ability was similar for all the treatments (23%-30% fertilized eggs), and increased as the glycerol concentration decreased. In conclusion, semen from roosters frozen using 4% glycerol exhibited lower sperm quality but similar fertilizing ability compared with samples processed using higher glycerol concentrations. These results may provide useful information for developing cryopreservation protocols for other breeds. PMID- 24629595 TI - Development rate and gene expression of IVP bovine embryos cocultured with bovine oviduct epithelial cells at early or late stage of preimplantation development. AB - The use of somatic cells for coculture with embryos has been amply investigated to study embryo maternal interactions. The use of bovine oviduct epithelial cells (BOEC) has been shown to improve the blastocyst rate and quality, affecting their gene expression profile. In this study, we evaluated different timings of BOEC coculture for the development of in-vitro-produced embryos and their effects on blastocysts rate and mRNA abundance of some genes that are important for embryo development. Our results confirmed the positive effects of BOEC on early development of bovine embryos. The presence of the cells during the first four days or during the last four days of development was enough to produce the full BOEC effect. When the presence of BOEC was restricted to the four first days, the kinetics of blastocyst development was accelerated, with significantly more blastocysts at Days 6 and 7 than when the cells were present all along the culture or only during the last four days. Older cells used at early stage were not active anymore. Using young cells at late stage did not improve the cell effect, compared with the older ones. Therefore, the lower effect of BOEC at late stage, compared with early period, may not be explained by cell aging. In addition, the presence of BOEC, at early or late stages, induced changes in the embryos expression profile of genes known to be related to embryo quality, suggesting reduced apoptosis and increased capacity to struggle against oxidative stress after coculture. In conclusion, we confirmed the effect of BOEC on the rate and quality of bovine IVP embryos development. We found for the first time that the presence of BOEC during the four first days of the 8-days development is enough to produce these effects. These first four days represent the period of the presence of the embryos in the oviduct in vivo, highlighting the physiological relevance of this in vitro model of coculture. In addition, we found that the presence of BOEC at early stages of development induced modification of transcription profile in the blastocyst, four days later, suggesting an epigenetic regulation induced by BOEC in growing embryos. PMID- 24629596 TI - Five-year experience with setup and implementation of an integrated database system for clinical documentation and research. AB - In radiation oncology, where treatment concepts are elaborated in interdisciplinary collaborations, handling distributed, large heterogeneous amounts of data efficiently is very important, yet challenging, for an optimal treatment of the patient as well as for research itself. This becomes a strong focus, as we step into the era of modern personalized medicine, relying on various quantitative data information, thus involving the active contribution of multiple medical specialties. Hence, combining patient data from all involved information systems is inevitable for analyses. Therefore, we introduced a documentation and data management system integrated in the clinical environment for electronic data capture. We discuss our concept and five-year experience of a precise electronic documentation system, with special focus on the challenges we encountered. We specify how such a system can be designed and implemented to plan, tailor and conduct (multicenter) clinical trials, ultimately reaching the best clinical performance, and enhancing interdisciplinary and clinical research. PMID- 24629597 TI - Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats. AB - The present study was designed to evaluate the antihyperglycemic potential of tangeretin on the activities of key enzymes of carbohydrate and glycogen metabolism in control and streptozotocin induced diabetic rats. The daily oral administration of tangeretin (100mg/kg body weight) to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, glycosylated hemoglobin (HbA1c) and increase in the levels of insulin and hemoglobin. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver of diabetic rats were significantly reverted to near normal levels by the administration of tangeretin. Further, tangeretin administration to diabetic rats improved hepatic glycogen content suggesting the antihyperglycemic potential of tangeretin in diabetic rats. The effect produced by tangeretin on various parameters was comparable to that of glibenclamide - a standard oral hypoglycemic drug. Thus, these results show that tangeretin modulates the activities of hepatic enzymes via enhanced secretion of insulin and decreases the blood glucose in streptozotocin induced diabetic rats by its antioxidant potential. PMID- 24629598 TI - Essential oil composition of Senecio graciliflorus DC: comparative analysis of different parts and evaluation of antioxidant and cytotoxic activities. AB - The essential oil of different parts of Senecio graciliflorus DC was obtained by hydrodistillation and analysed by GC-FID and GC-MS for the first time. A total of 17, 20, 19 and 17 constituents were identified comprising 99.90, 95.50, 98.93 and 95.96% of the essential oil of flower, leaf, stem and root parts of Senecio graciliflorus respectively. Monoterpene hydrocarbons predominated in the essential oil with 85.28% in flower, 57.53% in leaf, 67.74% in stem and 64.98% in root oil. alpha-pinene, cis-ocimene, 1,2,3-trimethylcyclohexane and beta-pinene were the major constituents of the essential oil. The flower essential oil exhibited a strong antioxidant potential displaying IC50 values of 21.6+/-0.6 and 26.0+/-1.0MUg/ml in DPPH and hydroxyl radical assays respectively. On the other hand the essential oil of flower and root displayed highest cytotoxicity against lung (A-549) cancer cell lines (IC50=19.1+/-0.9 and 21.3+/-1.1MUg/ml respectively. This study which represents the first report of the essential oil composition and bioevaluation of Senecio graciliflorus, can serve as a new source of cytotoxic and antioxidant activity. PMID- 24629599 TI - Suppression of adipocyte hypertrophy by polymethoxyflavonoids isolated from Kaempferia parviflora. AB - We previously demonstrated that ethyl acetate extracts of Kaempferia parviflora Wall. Ex Baker (KPE) improve insulin resistance in TSOD mice and showed that its components induce differentiation and adipogenesis in 3T3-L1 preadipocytes. The present study was undertaken to examine whether KPE and its isolated twelve components suppress further lipid accumulation in 3T3-L1 mature adipocytes. KPE reduced intracellular triglycerides in mature adipocytes, as did two of its components, 3,5,7,3',4'-pentamethoxyflavone and 5,7,4'-trimethoxyflavone. Shrinkage of lipid droplets in mature adipocytes was observed, and mRNA expression levels of adipose tissue triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) were up-regulated by these two polymethoxyflavonoids (PMFs). Furthermore, the protein expression level of ATGL and the release level of glycerol into the cell culture medium increased. In contrast, the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, troglitazone, did not decrease intracellular triglycerides in mature adipocytes, and the mRNA expression level of PPARgamma was not up-regulated in mature adipocytes treated with the two active PMFs. Therefore, suppression of lipid accumulation in mature adipocytes is unlikely to be enhanced by transcriptional activation of PPARgamma. These results suggest that KPE and its active components enhance lipolysis in mature adipocytes by activation of ATGL and HSL independent of PPARgamma transcription, thus preventing adipocyte hypertrophy. On the other hand, the full hydroxylated flavonoid quercetin did not show the suppressive effects of lipid accumulation in mature adipocyte in the same conditions. Consequently, methoxy groups in the flavones are important for the activity. PMID- 24629600 TI - In vitro inhibition of herpes simplex virus type 1 replication by Mentha suaveolens essential oil and its main component piperitenone oxide. AB - Several essential oils exert in vitro activity against bacteria and viruses and, among these latter, herpes simplex virus type 1 (HSV-1) is known to develop resistance to commonly used antiviral agents. Thus, the effects of the essential oil derived from Mentha suaveolens (EOMS) and its active principle piperitenone oxide (PEO) were tested in in vitro experimental model of infection with HSV-1. The 50% inhibitory concentration (IC50) was determined at 5.1MUg/ml and 1.4MUg/ml for EOMS and PEO, respectively. Australian tea tree oil (TTO) was used as control, revealing an IC50 of 13.2MUg/ml. Moreover, a synergistic action against HSV-1 was observed when each oil was added in combination with acyclovir. In order to find out the mechanism of action, EOMS, PEO and TTO were added to the cells at different times during the virus life-cycle. Results obtained by yield reduction assay indicated that the antiviral activity of both compounds was principally due to an effect after viral adsorption. Indeed, no reduction of virus yield was observed when cells were treated during viral adsorption or pre treated before viral infection. In particular, PEO exerted a strong inhibitory effect by interfering with a late step of HSV-1 life-cycle. HSV-1 infection is known to induce a pro-oxidative state with depletion of the main intracellular antioxidant glutathione and this redox change in the cell is important for viral replication. Interestingly, the treatment with PEO corrected this deficit, thus suggesting that the compound could interfere with some redox-sensitive cellular pathways exploited for viral replication. Overall our data suggest that both EOMS and PEO could be considered good candidates for novel anti-HSV-1 strategies, and need further exploration to better characterize the targets underlying their inhibition. PMID- 24629601 TI - [Oncology and other specialities Centre of the Georges-Pompidou European hospital: a model of unifying pneumology and oncology network]. PMID- 24629602 TI - De novo transcriptomic profile in the gonadal tissues of the intertidal whelk Reishia clavigera. AB - The intertidal whelk Reishia clavigera (formerly named as Thais clavigera) is one of the most sensitive species to organotin-associated imposex. However, the limited information on mRNA transcriptome of the species has restricted the molecular investigation on such endocrine disruption. By means of Illumina sequencing, we obtained a global de novo transcriptome from the gonadal tissues of both male and female R. clavigera, with 197,324 assembled transcripts and 151,684 condensed non-redundant transcripts. Blast hit results from the NCBI's non-redundant molluscan database showed that 28,948 transcripts were successfully annotated with significant matches at an e-value of ?1e(-6). Among them, 1108 transcripts were assigned a well-defined gene ontology term. As the first transcriptomic study on the gonadal tissues of R. clavigera, this study has enhanced the information of mRNA transcriptome on this species and will thus facilitate mechanistic studies of chemical contaminants (e.g., organotins) on this common biomonitor species. PMID- 24629603 TI - [Upcoming requirements on sharing of research data]. PMID- 24629604 TI - [Quality in the dialogue with the patient: Make it measurable!]. PMID- 24629605 TI - [Measuring health literacy can improve communication in health care]. AB - A tool for measuring health literacy is desirable when tailoring health care services to individual patients. Existing tools measure the functional aspects of health literacy whereas newly developed tools have a broader scope and measure people's knowledge, motivation and competences to access, understand, appraise and apply health information. Two novel, international health literacy questionnaires have been translated and are being validated in a Danish context. The final questionnaires may assist Danish health professionals in shaping communication with patients and reduce health disparities. PMID- 24629606 TI - [Need for more research in patients' health literacy]. AB - This paper introduces the concept of health literacy to the Danish health field by sharing the definition, conceptual model and matrix from the European Health Literacy Survey (HLS-EU). The general results of the HLS-EU are presented to show how health literacy can be measured, and how limited health literacy is a challenge for various European countries. The fact that the term health literacy is not easily translated into Danish might be a barrier for its wider use and dissemination. However, this should not be an excuse for lack of attention or action in Danish health services. PMID- 24629607 TI - [The use of video as preparation for the objective structured clinical examination in medicine and surgery]. AB - The objective structured clinical examination (OSCE) is a tool for measuring the dimensions of clinical competences. OSCE differs from traditional oral or written examination and results should not be influenced by lack of knowledge of the testing type. We prepared a video describing the practical aspects. On a Likert scale from 1 to 7 our video was rated 4 (interquartile range (IQR): 4-6). An informatory lecture was rated 4 (IQR: 3-5) and a rehearsal OSCE was rated 6 (IQR: 5-7). Video use peaked in the days up to OSCE. Accessibility should be improved by reaching out using the appropriate tools. We encourage the use of video for preparation to new examination types. PMID- 24629608 TI - [Use of magnetic resonance imaging]. AB - Magnetic resonance imaging (MRI) is one of the four imaging modalities used in radiology. In contrast to computed tomography (CT), it does not use radiation. MRI is still developing and the diagnostic capabilities are growing. There are many indications for MRI and in some fields it has replaced CT. With few exceptions MRI is used mainly for elective examinations, and because of the new techniques like diffusion and perfusion MRI in cancer imaging the use is increasing both with regard to work-up and follow-up. For non-malignant lesions MRI is increasingly used thanks to its great soft-tissue contrast capabilities. PMID- 24629609 TI - [Genetic screening for mutations enables early diagnosis of pituitary adenomas]. AB - Mutations in the aryl hydrocarbon receptor interaction protein gene (AIP) occur in familial pituitary adenomas as an autosomal dominant inheritance with a 15-30% penetrance. The AIP mutation-associated pituitary adenomas are generally large, the onset of disease is early and treatment failure frequent. Genetic screening is also offered in Denmark and enables the detection of mutation carriers, and thus early diagnosis and treatment. Mutations have been recorded among Danish patients and their families. PMID- 24629610 TI - [Dopamin agonist treatment and fibrotic heart valve disease in hyperprolactinaemia patients]. AB - Treatment with dopamin agonists, particularly cabergoline, is the primary and preferred therapy for prolactinomas and symptomatic hyperprolactinaemia due to its effectiveness and tolerability. However, an association has been demonstrated between fibrotic heart valve disease and high-dose dopamin agonist use in patients with Parkinson's disease in several echocardiographic studies. Such observations have prompted a number of studies of valvular function in cabergoline-treated hyperprolactinaemia patients. These studies have failed to show an increased prevalence of clinically significant valvular regurgitation. PMID- 24629611 TI - [Acromegaly masked by symptomatic hyperprolactinaemia]. AB - A 48-year-old woman presented with galactorrhoea, moderate hyperprolactinaemia (0.97 IU/l) and a pituitary macroadenoma (10 * 7 * 6 mm). Over a period of six years the patient had developed overt acromegalic features and was subsequently diagnosed with acromegaly while treated with dopamine receptor agonist. Acromegaly should always be considered in patients presenting with hyperprolactinaemia and a pituitary adenoma. PMID- 24629612 TI - [Tropical sprue as a differential diagnosis to coeliac disease in a patient on immunosuppressive medication]. AB - A Danish woman who was on immunosuppressive medication due to a previous liver transplantation travelled to Indonesia for three weeks. After returning she developed nonfebrile severe, watery diarrhoea, dehydration and malnutrition. A thorough examination revealed small intestine changes, which were compatible with coeliac disease. However, the HLA-type and the serology did not support this diagnosis. Treatment for tropical sprue was initiated, resulting in complete remission. Tropical sprue is suggested to be an infectious disease. It is usually seen in people with prolonged stay in tropical areas, but this patient's medication may have predisposed her. PMID- 24629613 TI - [ABC ahead of rewarming in the treatment of accidental hypothermia]. AB - The treatment of accidental hypothermia is still controversial and is missing detailed evidence-based guidelines. Current knowledge suggests that advanced trauma life support principles must be prioritized ahead of rewarming. In case of cardiac arrest, initiation of extracorporeal circulation before rewarming and prolongation of hypothermia at 33 degrees C to reduce reperfusion injury and cerebral hyperthermia is recommended but is not as yet implemented as standard treatment. We propose a simplified clinical approach to on-site triage of hypothermia: 1. Awake below 35 degrees C (Glasgow Coma Scale > 8). 2. Unconscious below 32 degrees C. 3. Absent respiration and circulation below 32 degrees C. PMID- 24629614 TI - [Experience with the training of non-technical skills on a course for surgical trainees]. AB - This paper describes the introduction of the training of non-technical skills on a mandatory course for surgical trainees. The training consisted of an introduction to non-technical skills in a plenum session and was followed by a full-scale simulation with debriefing in which participants reflected on their actions. Evaluations showed that > 90% of the participants found that the subject was relevant for their further training and some requested more simulation training. The course hereby addresses several of the Danish seven roles of a fully trained specialist doctor. PMID- 24629615 TI - [Bullous erythema multiforme major]. PMID- 24629616 TI - Tick infestation and prophylaxis of dogs in northeastern Germany: a prospective study. AB - Ticks transmit various important pathogens to humans and animals, and dogs are frequently exposed to tick infestation. The objective of this study was to examine tick infestation and the characteristics of tick prophylaxis of dogs in the Berlin/Brandenburg area. A total of 441 dogs (392 owners) was examined from March 2010 to April 2011. The dog owners participated in the study for a period of 1-13 months (10.33+/-2.85; median 11.00). The prevalences of a total of 1728 ticks collected from 251 (57%) of these dogs were: 46.0% Ixodes ricinus, 45.1% Dermacentor reticulatus, 8.8% Ixodes hexagonus, and 0.1% Rhipicephalus sanguineus. The ticks were 75.2% adult females and 24.4% adult males, and 0.4% were nymphs. The average prevalence of apparent infestation of tick-positive dogs was 0.78 ticks/month (median 0.38). Tick infestation was highest in October (5.9+/-5.8 ticks/dog) and lowest in December (1+/-0 tick/dog). The highest frequency of infestation was observed during May (117 dogs). The number of ticks found on dogs by owners on a single day varied from one to 70 (median 1). The scutal index indicated that more than 60% of I. ricinus and more than 40% of D. reticulatus had been removed after they had fed for more than 2 days. The heads, necks, chests, and limbs of the dogs were the most common attachment sites. Data for tick prophylaxis with substances licensed for dogs by the Medicinal Products Act (MPA) were available for 124 dogs; a total of 1195 ticks was obtained from these dogs. About two-thirds of the ticks were collected from dogs that were treated incorrectly (n=96) or were not treated (n=60). One third of the ticks were collected from dogs (n=96) that had been treated correctly. Dog-specific characteristics such as length of coat (p=0.011) and body size (p=0.040) played significant roles in tick infestation. PMID- 24629617 TI - Assessment of the reliability of standard automated perimetry in regions of glaucomatous damage. AB - PURPOSE: Visual field testing uses high-contrast stimuli in areas of severe visual field loss. However, retinal ganglion cells saturate with high-contrast stimuli, suggesting that the probability of detecting perimetric stimuli may not increase indefinitely as contrast increases. Driven by this concept, this study examines the lower limit of perimetric sensitivity for reliable testing by standard automated perimetry. DESIGN: Evaluation of a diagnostic test. PARTICIPANTS: A total of 34 participants with moderate to severe glaucoma; mean deviation at their last clinic visit averaged -10.90 dB (range, -20.94 to -3.38 dB). A total of 75 of the 136 locations tested had a perimetric sensitivity of <= 19 dB. METHODS: Frequency-of-seeing curves were constructed at 4 nonadjacent visual field locations by the Method of Constant Stimuli (MOCS), using 35 stimulus presentations at each of 7 contrasts. Locations were chosen a priori and included at least 2 with glaucomatous damage but a sensitivity of >= 6 dB. Cumulative Gaussian curves were fit to the data, first assuming a 5% false negative rate and subsequently allowing the asymptotic maximum response probability to be a free parameter. MAIN OUTCOME MEASURES: The strength of the relation (R(2)) between perimetric sensitivity (mean of last 2 clinic visits) and MOCS sensitivity (from the experiment) for all locations with perimetric sensitivity within +/- 4 dB of each selected value, at 0.5 dB intervals. RESULTS: Bins centered at sensitivities >= 19 dB always had R(2) >0.1. All bins centered at sensitivities <= 15 dB had R(2) <0.1, an indication that sensitivities are unreliable. No consistent conclusions could be drawn between 15 and 19 dB. At 57 of the 81 locations with perimetric sensitivity <19 dB, including 49 of the 63 locations <= 15 dB, the fitted asymptotic maximum response probability was <80%, consistent with the hypothesis of response saturation. At 29 of these locations the asymptotic maximum was <50%, and so contrast sensitivity (50% response rate) is undefined. CONCLUSIONS: Clinical visual field testing may be unreliable when visual field locations have sensitivity below approximately 15 to 19 dB because of a reduction in the asymptotic maximum response probability. Researchers and clinicians may have difficulty detecting worsening sensitivity in these visual field locations, and this difficulty may occur commonly in patients with glaucoma with moderate to severe glaucomatous visual field loss. PMID- 24629618 TI - Relationship between retinal microstructures on optical coherence tomography and microperimetry in age-related macular degeneration. AB - PURPOSE: To determine the relationship between structural parameters of the outer retina on spectral-domain optical coherence tomography (SD-OCT) and microperimetric retinal sensitivity in early stages of age-related macular degeneration (AMD). DESIGN: Prospective, observational study. PARTICIPANTS: Seventy-five eyes of 75 participants with early stages of AMD (drusen >= 125 MUm, with/without pigmentary abnormalities) and 25 control participants of a similar age. METHODS: Participants underwent microperimetry testing and high-resolution SD-OCT scans. Structural parameters at 5 central points (0 degrees , 1 degrees , and 2.33 degrees nasal and temporal to the fovea along the horizontal axis) corresponding to areas tested by microperimetry were compared. Structural parameters included outer segment (OS) length, thickness and elevation of the retinal pigment epithelium (RPE) band, grading of the inner-segment ellipsoid (ISe) band integrity, and presence of hyperreflective foci (HF). MAIN OUTCOME MEASURES: Relationship between structural parameters and retinal sensitivity. RESULTS: Retinal sensitivity was significantly correlated with RPE elevation (P<0.001), ISe grading (P<0.001), and presence of HF (P <= 0.018) at all test points, but not with OS length (P >= 0.093) or RPE thickness (P >= 0.125). However, multiple linear regression analyses revealed that only ISe grading (P <= 0.011) and RPE elevation (P <= 0.030) remained significantly associated with retinal sensitivity at all points. By using a simple linear model incorporating ISe grading and RPE elevation to predict values of retinal sensitivity, the 95% limits of agreement between the predicted and the actual value was +/- 3.83 dB. CONCLUSIONS: The integrity of the ISe band and drusen-associated RPE elevation are significant independent predictors of microperimetric retinal sensitivity. Our findings imply that these 2 structural parameters may be surrogate markers of retinal function in the early stages of AMD. PMID- 24629620 TI - Implementation of a new fuzzy vector control of induction motor. AB - The aim of this paper is to present a new approach to control an induction motor using type-1 fuzzy logic. The induction motor has a nonlinear model, uncertain and strongly coupled. The vector control technique, which is based on the inverse model of the induction motors, solves the coupling problem. Unfortunately, in practice this is not checked because of model uncertainties. Indeed, the presence of the uncertainties led us to use human expertise such as the fuzzy logic techniques. In order to maintain the decoupling and to overcome the problem of the sensitivity to the parametric variations, the field-oriented control is replaced by a new block control. The simulation results show that the both control schemes provide in their basic configuration, comparable performances regarding the decoupling. However, the fuzzy vector control provides the insensitivity to the parametric variations compared to the classical one. The fuzzy vector control scheme is successfully implemented in real-time using a digital signal processor board dSPACE 1104. The efficiency of this technique is verified as well as experimentally at different dynamic operating conditions such as sudden loads change, parameter variations, speed changes, etc. The fuzzy vector control is found to be a best control for application in an induction motor. PMID- 24629621 TI - On performance analysis of ADRC for a class of MIMO lower-triangular nonlinear uncertain systems. AB - This paper designs the active disturbance rejection control (ADRC) to achieve desired performance for a class of MIMO lower-triangular nonlinear systems with large uncertainties under un-matched condition. We develop the ADRC with a set of extended state observers, and prove that the closed-loop system can achieve satisfied dynamic performance. The theoretical results illustrate the relationship between the bound of the concerned error and the bandwidth of extend state observers. PMID- 24629619 TI - Rates of retinal nerve fiber layer thinning in glaucoma suspect eyes. AB - PURPOSE: To compare the rates of retinal nerve fiber layer (RNFL) loss in patients suspected of having glaucoma who developed visual field damage (VFD) with those who did not develop VFD and to determine whether the rate of RNFL loss can be used to predict the development of VFD. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Glaucoma suspects, defined as having glaucomatous optic neuropathy or ocular hypertension (intraocular pressure, >21 mmHg) without repeatable VFD at baseline, from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. METHODS: Global and quadrant RNFL thickness (RNFLT) were measured with the Spectralis spectral-domain optical coherence tomography (SD-OCT; Spectralis HRA+OCT [Heidelberg Engineering, Heidelberg, Germany]). Visual field damage was defined as having 3 consecutive abnormal visual fields. The rate of RNFL loss in eyes developing VFD was compared to eyes not developing VFD using multivariate linear mixed-effects models. A joint longitudinal survival model used the estimated RNFLT slope to predict the risk of developing VFD, while adjusting for potential confounding variables. MAIN OUTCOME MEASURES: The rate of RNFL thinning and the probability of developing VFD. RESULTS: Four hundred fifty-four eyes of 294 glaucoma suspects were included. The average number of SD-OCT examinations was 4.6 (range, 2-9), with median follow-up of 2.2 years (0.4-4.1 years). Forty eyes (8.8%) developed VFD. The estimated mean rate of global RNFL loss was significantly faster in eyes that developed VFD compared with eyes that did not develop VFD (-2.02 MUm/year vs. 0.82 MUm/year; P<0.001). The joint longitudinal survival model showed that each 1 MUm/year faster rate of global RNFL loss corresponded to a 2.05-times higher risk of developing VFD (hazard ratio, 2.05; 95% confidence interval, 1.14-3.71; P = 0.017). CONCLUSIONS: The rate of global RNFL loss was more than twice as fast in eyes that developed VFD compared with eyes that did not develop VFD. A joint longitudinal survival model showed that a 1-MUm/year faster rate of RNFLT loss corresponded to a 2.05-times higher risk of developing VFD. These results suggest that measuring the rate of SD-OCT RNFL loss may be a useful tool to help identify patients who are at a high risk of developing visual field loss. PMID- 24629622 TI - Alternatives approaches to the sub-occipital transtentorial route for pineal tumors: How and when I do it? AB - Deeply located beneath the corpus callosum and surrounding by crucial veins, the pineal and tectal structures still challenge the surgeon. Either anterior or posterior, many surgical approaches have been developed to reach the pineal region. Most popular are likely the posterior sub-occipital or occipito-parietal transtentorial routes. Others, primarily transcallosal or supracerebellar, may be indicated depending of the extension of the tumors while the transcortical routes (frontal, parietal or atrial) have been almost given up. Our purpose in this article is give a practical overview of how to do and what are the respective indications of all these alternatives approaches developed for pineal tumors. PMID- 24629623 TI - Load-transfer analysis after insertion of cementless anatomical femoral stem using pre- and post-operative CT images based patient-specific finite element analysis. AB - Periprosthetic bone remodeling is commonly seen after total hip arthroplasty, but the remodeling pattern differs among patients even in those implanted with the same stem. Remodeling occurs mainly because of the difference in load transmitted from the stem to the femur. In this study, we evaluated the load-transfer pattern in eight female patients implanted with an anatomical stem on an individual basis by patient-specific finite element analysis that is based on pre- and postoperative computed tomography images. Load transfer was evaluated using interface stress between the stem and bone. One of eight patients demonstrated proximal dominant load transfer, while the other patients demonstrated a distal dominant pattern. The results of our biomechanical simulations reveal the differences in load-transfer pattern after surgery among patients with the same anatomical stem. PMID- 24629624 TI - Development of a balanced experimental-computational approach to understanding the mechanics of proximal femur fractures. AB - The majority of people who sustain hip fractures after a fall to the side would not have been identified using current screening techniques such as areal bone mineral density. Identifying them, however, is essential so that appropriate pharmacological or lifestyle interventions can be implemented. A protocol, demonstrated on a single specimen, is introduced, comprising the following components; in vitro biofidelic drop tower testing of a proximal femur; high speed image analysis through digital image correlation; detailed accounting of the energy present during the drop tower test; organ level finite element simulations of the drop tower test; micro level finite element simulations of critical volumes of interest in the trabecular bone. Fracture in the femoral specimen initiated in the superior part of the neck. Measured fracture load was 3760N, compared to 4871N predicted based on the finite element analysis. Digital image correlation showed compressive surface strains as high as 7.1% prior to fracture. Voxel level results were consistent with high-speed video data and helped identify hidden local structural weaknesses. We found using a drop tower test protocol that a femoral neck fracture can be created with a fall velocity and energy representative of a sideways fall from standing. Additionally, we found that the nested explicit finite element method used allowed us to identify local structural weaknesses associated with femur fracture initiation. PMID- 24629625 TI - Generating finite element models of the knee: How accurately can we determine ligament attachment sites from MRI scans? AB - In this study, we evaluated the intra- and inter-observer variability when determining the insertion and origin sites of knee ligaments on MRI scan images. We collected data of five observers with different backgrounds, who determined the ligament attachment sites in an MRI scan of a right knee of a 66-year-old male cadaver donor. We evaluated the intra- and inter-observer differences between the ligament attachment center points, and also determined the differences relative to a physical measurement performed on the same cadaver. The largest mean intra- and inter-observer differences were 4.30mm (ACL origin) and 16.81mm (superficial MCL insertion), respectively. Relative to the physical measurement, the largest intra- and inter-observer differences were 31.84mm (superficial MCL insertion) and 23.39mm (deep MCL insertion), respectively. The results indicate that, dependent on the location, a significant variation can occur when identifying the attachment site of the knee ligaments. This finding is of particular importance when creating computational models based on MRI data, as the variations in attachment sites may have a considerable effect on the biomechanical behavior of the human knee joint. PMID- 24629626 TI - A micro-optical system for endoscopy based on mechanical compensation paradigm using miniature piezo-actuation. AB - The goal of the study was to investigate the feasibility of a novel miniaturized optical system for endoscopy. Fostering the mechanical compensation paradigm, the modeled optical system, composed by 14 lenses, separated in 4 different sets, had a total length of 15.55mm, an effective focal length ranging from 1.5 to 4.5mm with a zoom factor of about 2.8*, and an angular field of view up to 56 degrees . Predicted maximum lens travel was less than 3.5mm. The consistency of the image plane height across the magnification range testified the zoom capability. The maximum predicted achromatic astigmatism, transverse spherical aberration, longitudinal spherical aberration and relative distortion were less than or equal to 25MUm, 15MUm, 35MUm and 12%, respectively. Tests on tolerances showed that the manufacturing and opto-mechanics mounting are critical as little deviations from design dramatically decrease the optical performances. However, recent micro fabrication technology can guarantee tolerances close to nominal design. A closed loop actuation unit, devoted to move the zoom and the focus lens sets, was implemented adopting miniaturized squiggle piezo-motors and magnetic position encoders based on Hall effect. Performance results, using a prototypical test board, showed a positioning accuracy of less than 5MUm along a lens travel path of 4.0mm, which was in agreement with the lens set motion features predicted by the analysis. In conclusion, this study demonstrated the feasibility of the optical design and the viability of the actuation approach while tolerances must be carefully taken into account. PMID- 24629627 TI - The Betel Quid Dependence Scale: replication and extension in a Guamanian sample. AB - BACKGROUND: Betel quid is the fourth most commonly consumed psychoactive substance in the world. The Betel Quid Dependence Scale (BQDS) is the first instrument designed specifically to measure betel quid dependence. The three factor structure of the BQDS consists of "physical and psychological urgent need," "increasing dose," and "maladaptive use." The BQDS initially was validated in a sample of male prisoner ex-chewers in Taiwan. OBJECTIVE: To replicate and extend the original validation research on the BQDS in a sample of male and female current betel quid chewers in Guam. METHODS: A survey containing the BQDS was administered to 300 current betel quid chewers in Guam. Participants were compensated for their time with a gift card worth $25. RESULTS: Confirmatory factor analysis revealed an adequate fit with the hypothesized three-factor measurement model. ANOVAs and structural equations modeling revealed that betel quid dependence is associated with the inclusion of tobacco in the quid, number of chews per day, years of chewing, and education. CONCLUSIONS: The BQDS is valid for current English-speaking male and female chewers in Guam. Overall levels of betel quid dependence were high, and most chewers included tobacco in their betel quid. The results suggest that levels of dependence for betel quid are similar to those observed for nicotine dependence. Future research should explore other important psychological and behavioral aspects of betel quid chewing such as health risk perceptions and motivation to quit chewing. PMID- 24629629 TI - Circumstances and toxicology of sudden or unnatural deaths involving alprazolam. AB - BACKGROUND: There has been a great deal of clinical concern regarding alprazolam abuse. This paper reported on alprazolam positive cases of sudden or unnatural deaths presenting to the New South Wales Department of Forensic Medicine (DOFM), 1/1/1997-31/12/2012. METHODS: Case series. RESULTS: 412 cases were identified. There was a large increase in the annual number of cases, from 3 in 1997 to 86 in 2012. By 2012, 4.5% of all DOFM case presentations involved alprazolam. The mean age was 41.3 years, and 66.5% were male. Circumstances of death were: accidental drug toxicity (57.0%), deliberate drug toxicity (10.4%), suicide by means other than drug overdose (12.6%), disease (10.0%), accident (5.1%), homicide (2.4%). The major factor driving the increase in cases was accidental drug toxicity involving alprazolam, rising from 0 in 1997 to 58 in 2012. A history of drug/alcohol problems was noted in 80.4%, and 56.6% were injecting drug users. The median alprazolam concentration was 0.08 mg/L (range 0.005-2.10mg/L), with 37.4% of cases having concentrations of >= 0.1 mg/L. In 94.9% of cases, drugs other than alprazolam and its metabolites were present, including all accidental overdoses. The most commonly detected drugs were opioids (64.6%), other benzodiazepines (44.4%) and alcohol (34.5%). A third (31.8%) of cases were HCV positive. CONCLUSIONS: Cases involving alprazolam increased markedly, driven mostly by toxicity deaths amongst people with known drug and alcohol problems. Caution in prescribing alprazolam would appear appropriate, particularly to those with known drug dependence. PMID- 24629628 TI - Racial differences in the validity of self-reported drug use among men who have sex with men in Atlanta, GA. AB - BACKGROUND: Men who have sex with men (MSM), particularly young black MSM, are disproportionately affected in the United States' HIV epidemic. Drug use may contribute to these disparities, yet previous studies have failed to provide evidence of elevated use among black MSM, relying exclusively on self-reported usage. This study uses biological assays to validate self-reports of drug use and explore the potential for misclassification to distort findings on racial patterns of use in this population. METHODS: From an Atlanta-based cohort study of 454 black and 349 white MSM from 2010 to 2012, participants' self-reported drug use was compared to urine drug screening findings. The sensitivity of self report was calculated as the proportion reporting recent usage among those who screened positive. Multivariable regression models were constructed to examine racial patterns in self-report, urine-detection, and self-report sensitivity of marijuana and cocaine usage, adjusted for socio-demographic factors. RESULTS: In analyses that adjusted for age, education, income, sexual orientation, and history of arrest, black MSM were less likely to report recent use of marijuana (P<0.001) and cocaine (P=0.02), but equally likely to screen positive for either drug. This discrepancy between self-reported and urine-detected drug use was explained by significantly lower sensitivity of self-report for black participants (P<0.001 for marijuana, P<0.05 for cocaine). CONCLUSIONS: The contribution of individual drug-related risk behaviors to the HIV disparities between black and white MSM should be revisited with methods that validate self reports of illegal drug use. PMID- 24629630 TI - Long-term effects of exposure to methamphetamine in adolescent rats. AB - BACKGROUND: Flexible cognition is a set of processes mediated by the prefrontal cortex (PFC), an area of the brain that continues to develop during adolescence and into adulthood. Adult rodents exhibit impairments specific to reversal learning across various dosing regimens of methamphetamine (mAMPH). For adolescent rodents, ongoing PFC development can be assessed by discrimination reversal learning, a task dependent on frontostriatal integrity. The task may also index an increased vulnerability for mAMPH sampling in adulthood. METHODS: The purpose of the present study was to investigate the long-term effects of escalating, adolescent mAMPH exposure on reversal learning, a PFC-dependent task (Experiment 1) and the likelihood of later sampling of mAMPH in adulthood (Experiment 2). RESULTS: Unlike previous research in adult-treated rats, our results show more generalized learning impairments after adolescent mAMPH exposure to include both attenuated visual discrimination as well as reversal learning. Additionally, we found that rats pre-exposed to mAMPH during adolescence consumed significantly more drug in adulthood. Intake of mAMPH was positively correlated with this learning. Taken together, these findings show that even modest exposure to mAMPH during adolescence may induce general learning impairments in adulthood, and an enduring sensitivity to the effects of mAMPH. PMID- 24629631 TI - Treatment of crack-cocaine dependence with topiramate: a randomized controlled feasibility trial in The Netherlands. AB - BACKGROUND: Crack-cocaine dependence is a complex disorder with limited treatment options. Topiramate is one of the promising medications with reported reductions in cocaine use and craving in former studies. The present study evaluated the acceptance and effectiveness of topiramate as an add-on to cognitive behavioral therapy (CBT) in crack-cocaine dependent patients. METHODS: Seventy-four crack cocaine dependent outpatients participated in an open-label, randomized feasibility trial. They were randomized to receive either 12-week CBT plus topiramate (200mg/day) or 12-week CBT only. The primary outcome measure was treatment retention. Secondary outcomes included medication adherence, safety, cocaine and other substance use, health, social functioning, and patient satisfaction. RESULTS: Adherence to topiramate treatment was low. In the intent to-treat analyses, topiramate neither improved treatment retention nor reduced cocaine and other substance use. Post hoc, exploratory analyses suggested a moderation effect of comorbid opioid dependence, with a significant effect of topiramate on cocaine use reduction only in crack-cocaine dependent patients with comorbid opioid dependence. CONCLUSIONS: Topiramate was safe and well-tolerated in this sample of crack-cocaine dependent patients, but efficacy was not supported probably due to low acceptance of the treatment. Given the equivocal results of previous studies and the negative findings in our study, the potential of topiramate in the treatment of cocaine dependence seems limited. PMID- 24629632 TI - Should anyone be riding to glory on the now-descending limb of the crack-cocaine epidemic curve in the United States? AB - BACKGROUND: Many pre-clinical and clinical researchers do not appreciate the recent decline in United States (US) population-level incidence of crack-cocaine smoking. At present, no more than about 200 young people start using crack cocaine each day. Ten years ago, the corresponding estimated daily rate was 1000. This short communication looks into these trends, surrounding evidence on this important public health topic, and checks whether duration-reducing treatment interventions might be responsible, versus selected alternatives. METHODS: Via analyses of standardized computer-assisted self-interview data from the US National Surveys on Drug Use and Health (NSDUH, 2002-2011; n>500,000), we evaluated change in incidence estimates, perceived difficulty to acquire crack, risk of using cocaine, treatment entries, and persistence once crack use has started. RESULTS: We draw attention to a marked overall decline in year-specific incidence rates for crack-cocaine smoking from 2002 to 2011, especially 2007 2011. There is some variation in estimates of difficulty to acquire crack (p<0.001) and observed risk of using cocaine among 'at risk' susceptibles (p<0.001), but no appreciable shifts in duration of crack smoking among active users (p>0.05) or in proportion of crack users receiving treatment (p>0.05). CONCLUSIONS: Changing epidemiology of crack-cocaine smoking may rest largely on reductions in newly incident use with no major direct effects due to US cocaine treatment, incarceration, or interdiction. Concurrently, we see quite modest declines in survey-based estimates of cocaine-attributed perceived risk and cocaine availability. As such, we posit that no specific US agency should claim it is 'riding to glory' on the descending limb of this epidemic curve. PMID- 24629633 TI - Pharmacokinetics and dose response of anti-TB drugs in rat infection model of tuberculosis. AB - Robust and physiologically relevant infection models are required to investigate pharmacokinetic-pharmacodynamic (PK/PD) correlations for anti-tuberculosis agents at preclinical discovery. We have validated an inhalation-based rat infection model of tuberculosis harbouring mycobacteria in a replicating state, that is suitable for investigating pharmacokinetics and drug action of anti-tubercular agents. A reproducible and actively replicating lung infection was established in Wistar rats by inhalation of a series of graded inocula of Mycobacterium tuberculosis. Following an initial instillation of ~10(5) log10 CFU/lung, M. tuberculosis grew logarithmically for the first 3 weeks, and then entered into a chronic phase with no net increase in pulmonary bacterial loads. Dose response of front-line anti-TB drugs was investigated following pharmacokinetic measurements in the plasma of infected rats. Rifampicin, Isoniazid, and Ethambutol dosed per orally exhibited bactericidality and good dose response with maximal effect of 5.66, 4.66, and 4.80 log10 CFU reductions in the lungs, respectively. In contrast, Pyrazinamide was merely bacteriostatic with 1.92 log10 CFU/lung reduction and did not reduce the bacterial burden beyond the initial bacterial loads present at beginning of treatment in spite of high Pyrazinamide blood levels. Rat infection model with actively replicating bacilli provides a physiologically distinct and pharmacologically relevant model that can be exploited to distinguish investigational compounds in to bacteriostatic or bactericidal scaffolds. We propose that this rat infection model though need more drug substance, can be used in early discovery settings to investigate pharmacology of novel anti-tubercular agents for the treatment of active pulmonary tuberculosis. PMID- 24629634 TI - Programmed death-1 receptor suppresses gamma-IFN producing NKT cells in human tuberculosis. AB - IFN-gamma biased Th1 effector immune response is crucial for containment of Mycobacterium tuberculosis infection. Various T cell subsets with regulatory function dictate the generation of Th1 like cells. NKT cells are a specialized T cell subset known to be activated early in immune response and control T cell response via release of immunoregulatory cytokines like IFN-gamma, IL-4 and IL 10. M. tuberculosis, with abundance of its cell wall lipids may potently activate NKT cells resulting in cytokine production and PD-1 expression. In this study, among 49 treatment naive active pulmonary tuberculosis patients, we found a higher percentage of PD1(+) NKT cells correlating with sputum bacillary load. Furthermore, blocking PD-1 increased the number of IFN-gamma producing NKT cells by inhibiting their apoptosis. Moreover, peripheral frequency of NKT cells declined with therapy suggesting their role in host T cell response. In this study, we concluded that PD-1 preferentially induces apoptosis of IFN-gamma producing NKT cells while sparing NKT cells that produce IL-4. Such a polarized NKT cell function may impose a Th2 bias on the ensuing effector T cell response leading to inefficient clearance of M. tuberculosis. Inhibiting PD-1 may therefore alter the T cell response in favor of the host by rescuing type 1 NKT cells from apoptosis and boosting Th1 effector T cell functions against M. tuberculosis. PMID- 24629635 TI - Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis. AB - BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Ralpha, HSP70, Galectin-8, alpha2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study. PMID- 24629636 TI - ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: a comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features. AB - BACKGROUND: To have a comprehensive investigation of the clinicopathologic, histologic and cytologic features of fusion-positive lung adenocarcinomas. METHODS: Quantitative real-time reverse transcriptase PCR (qRT-PCR) and reverse transcriptase PCR (RT-PCR) were simultaneously performed to screen ALK, ROS1 and RET fusions in resected tumor samples from 1139 Chinese lung adenocarcinoma patients, with validation of positive results using fluorescent in situ hybridization. Clinicopathologic characteristics, predominant histologic subtype and cytomorphology were assessed in fusion-positive lung adenocarcinomas and compared to those harboring EGFR, KRAS, HER2 or BRAF mutations. RESULTS: There were 58 (5.1%) ALK fusions, 11 (1.0%) ROS1 fusions and 15 (1.3%) RET fusions. Tumors with ROS1 fusions had significantly larger diameter than ROS1 fusion negative tumors (P = 0.007), whereas all the 15 tumors harboring RET fusions were <= 3 cm in diameter (P = 0.001). The three fusion genes were all more prevalent in solid-predominant adenocarcinoma. Compared to fusion-negative lung adenocarcinomas, tumors harboring a fusion gene had significantly higher prevalence of extracellular mucin (P < 0.001), cribriform pattern (P < 0.001), signet ring cells (P < 0.001) and hepatoid cytology (P < 0.001). No significant difference in relapse-free survival (P = 0.147) and overall survival (P = 0.444) was observed between fusion-positive and fusion-negative patients. CONCLUSIONS: This study showed fusion-positive lung adenocarcinomas had identifiable common and fusion-pattern specific clinicopathologic, histologic and cytologic features, offering implications for fusion genes screening. PMID- 24629637 TI - Tumor, node and metastasis classification of lung cancer--M1a versus M1b- analysis of M descriptors and other prognostic factors. AB - INTRODUCTION: The current edition of the tumor, node and metastasis (TNM) classification of lung cancer (LC) divides the presence of metastasis (M1) into two categories: M1a and M1b, depending on its anatomical location. To assess this new classification, the survival and the M descriptors of LC patients with metastatic disease registered by the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery II (GCCB-S-II), were analyzed. METHODS: Non-small cell lung cancer (NSCLC) patients, with M1a or M1b disease, included in the GCCB-S-II, from April 2009 to December 2010, staged in accordance with the prospective staging project protocol of the International Association for the Study of Lung Cancer (IASLC), and with complete TNM staging and follow-up data, were studied. The overall survival associated with each M1 category and each M descriptor, besides other prognostic factors (sex, age, performance status [PS] and others) were analyzed by univariate and multivariate models. RESULTS: 640 NSCLC patients (195 M1a and 445 M1b) were included. M1b tumors had significantly worse survival than M1a tumors (p < 0.001). The prognostic value of M1 category was independent from other prognostic variables such as PS, weight loss, and others. The number of metastatic sites (isolated versus multiple) and the number of lesions (single versus multiple) in patients with isolated metastasis showed prognostic value, especially in those with brain metastasis. CONCLUSION: The current division of the M1 category into two subsets (M1a and M1b) is warranted by their prognostic significance. The number of metastatic sites and the number of lesions in patients with isolated metastasis should be taken into account, because they also have prognostic relevance. PMID- 24629638 TI - Impact of cigarette smoking on response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in lung adenocarcinoma with activating EGFR mutations. AB - OBJECTIVES: The aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations. METHODS: We retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol. RESULTS: Of 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with < 30 pack-years, and 14.9% were smokers with >= 30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with >= 30 pack-years were significantly lower than never-smokers and smokers with < 30 pack-years (DCR, 78.8% vs. 93.1%, p = 0.016; ORR, 45.5% vs. 62.4%, p = 0.020). Smokers with >= 30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p = 0.001) and smokers with < 30 pack years (6.4 vs. 11.4 months, p = 0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p = 0.003). There was no survival difference between smokers with < 30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage >= 30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15-3.05; p = 0.012). CONCLUSIONS: Cigarette smoking dosage of >= 30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations. PMID- 24629639 TI - ApoptomiRs expression modulated by BCR-ABL is linked to CML progression and imatinib resistance. AB - BACKGROUND: Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of Philadelphia chromosome (Ph) leading to expression of a BCR-ABL1 fusion oncogene. The BCR-ABL protein has a constitutive tyrosine kinase activity which is responsible for CML pathogenesis by promoting cell apoptosis resistance; however, the cellular and molecular mechanisms associated with BCR-ABL expression and apoptosis impairment in CML leukemic cells have not been fully elucidated. METHODS: This study evaluated apoptomiRs and their predicted apoptotic genes in BCR-ABL(+) cells from patients in different phases of CML treated with tyrosine kinase inhibitor (TKI) according to their imatinib (IM) response by qPCR. Phosphotyrosine and c-ABL expressions in HL 60.BCR-ABL cells treated with TKI were done by Western blot. RESULTS: We found that dasatinib (DAS) modulated miR-let-7d, miR-let-7e, miR-15a, miR-16, miR-21, miR-130a and miR-142-3p expressions while IM modulated miR-15a and miR-130a levels. miR-16, miR-130a and miR-145 expressions were modulated by nilotinib (NIL). We observed higher miR-15a, miR-130b and miR-145; and lower miR-16, miR 26a and miR-146a expressions in CML-CP in comparison with controls. CML-AP patients showed low miR-let-7d, miR-15a, miR-16, miR-29c, miR-142-3p, miR-145, and miR-146a levels in comparison with CML-CP. We noted that the miR-26a, miR 29c, miR-130b and miR-146a expressions were downregulated in IM resistant patients in comparison with IM responsive patients. CONCLUSIONS: This study showed the modulation of apoptomiRs by BCR-ABL kinase activity and the deregulation of apoptomiRs and their predicted apoptotic target genes in different CML phases and after treatment with TK inhibitors. ApoptomiRs may be involved in the BCR-ABL(+) cell apoptosis regulation. PMID- 24629640 TI - Efficacy of anti-reflux surgery on refractory laryngopharyngeal reflux disease in professional voice users: a pilot study. AB - OBJECTIVES: Laryngopharyngeal reflux (LPR) is a pervasive disorder that may cause hoarseness, throat clearing, and other symptoms. These symptoms are particularly problematic in professional voice users. Proton pump inhibitors (PPIs) are the mainstay of current medical management for LPR but may be insufficient in managing some patients' symptoms. Laparoscopic Nissen fundoplication (LNF) is well established for treatment of gastroesophageal reflux disease with a high success rate, but its role in the treatment of LPR remains uncertain. This study was designed to investigate the effectiveness of anti-reflux surgery in managing disease refractory to medical reflux therapy (twice of more per day PPIs). STUDY DESIGN: Retrospective medical record review. METHODS: This study examined 25 professional voice users, age ranging from 14 to 75 years, diagnosed with refractory LPR treated twice daily or more with PPIs. Reflux finding scores (RFS) were graded by blinded raters and compared for initial, preoperative, postoperative, and final visits. Twenty-four-hour pH-impedance study scores were obtained pre- and postoperatively. RESULTS: Sixty percent of patients were on no reflux medications postoperatively and an additional 24% were on less medication. RFS was not significantly different between pre- and postoperative evaluations with good inter- and intrarater reliability; postoperative examinations occurred on less or no pharmaceutical reflux treatment. Twenty-four-hour pH-impedance testing revealed significant reductions in reflux and a nearly significant reduction in total acid. Ninety percent of positive symptom indices preoperatively were negative postoperatively. Seventy-six percent of patients on BID dosing of PPIs and 86% of those receiving super-high-dose PPI administration who underwent LNF were satisfied with the results for their LPR disease. CONCLUSION: LNF should be considered as a treatment option for professional voice users with LPR with symptoms refractory to standard or super-high-dose medical management. LNF may decrease or eliminate the need for postoperative PPI usage. The RFS may not be sensitive enough to monitor changes in LPR severity. Patients, especially those on super-high-dose medication administration, are satisfied with the improvement in LPR symptoms after anti-reflux surgery. PMID- 24629642 TI - Sexual dimorphism in the histologic organization of the muscle fibers in human tongue. AB - Tongue movements are critical for speech, swallowing, and respiration; and tongue dysfunction could lead to dysarthria, dysphagia, and obstructive sleep apnea, respectively. Our current understanding of the contributions of specific tongue muscles (TOs) to precise movement patterns is limited. Likewise, there is still little information regarding the orientation of histologic muscle fibers of the tongue in humans, especially between men and women. Thus, the aim of this study was to compare the histologic organization in the tongue of men and women. Ten tongues were studied in human specimens obtained from necropsies (five men and five women). The muscles were analyzed using histology, and the morphometric parameters were measured using Image Pro-Plus Software (Image Pro-Plus 6.0; Media Cybernetics, Silver Spring, MD). Slices were obtained from the anterior, median, and posterior parts of the tongue. We classified and estimated the percentages of transverse (T), oblique (O), and longitudinal (L) fibers in the tongue. To quantify the percentage of fibers in each category in the tongue, the shape coefficient (Shape Z) was estimated. Statistical differences were found between the orientation of the muscle fibers of men and women only for the middle region of the tongue. The middle region of the tongue in women compared with men has a smaller difference in the variation of the percentage of fibers T (P=0.0004), O (P=0.0006), and L (P=0.0013). These morphologic findings are probably related to physiological differences. PMID- 24629641 TI - Using active shape modeling based on MRI to study morphologic and pitch-related functional changes affecting vocal structures and the airway. AB - OBJECTIVE: The shape of the vocal tract and associated structures (eg, tongue and velum) is complicated and varies according to development and function. This variability challenges interpretation of voice experiments. Quantifying differences between shapes and understanding how vocal structures move in relation to each other is difficult using traditional linear and angle measurements. With statistical shape models, shape can be characterized in terms of independent modes of variation. Here, we build an active shape model (ASM) to assess morphologic and pitch-related functional changes affecting vocal structures and the airway. METHOD: Using a cross-sectional study design, we obtained six midsagittal magnetic resonance images from 10 healthy adults (five men and five women) at rest, while breathing out, and while listening to, and humming low and high notes. Eighty landmark points were chosen to define the shape of interest and an ASM was built using these (60) images. Principal component analysis was used to identify independent modes of variation, and statistical analysis was performed using one-way repeated-measures analysis of variance. RESULTS: Twenty modes of variation were identified with modes 1 and 2 accounting for half the total variance. Modes 1 and 9 were significantly associated with humming low and high notes (P < 0.001) and showed coordinated changes affecting the cervical spine, vocal structures, and airway. Mode 2 highlighted wide structural variations between subjects. CONCLUSION: This study highlights the potential of active shape modeling to advance understanding of factors underlying morphologic and pitch-related functional variations affecting vocal structures and the airway in health and disease. PMID- 24629643 TI - Reported vocal habits of first-year undergraduate musical theater majors in a preprofessional training program: a 10-year retrospective study. AB - OBJECTIVE: Collegiate-level musical theater performance students are a specialized group of vocal performers, who rely on frequent and optimal voice use for their academic advancement and ultimate livelihood. The purpose of this study was to gather information to develop a greater understanding of vocal health and practice patterns of incoming collegiate-level musical theater performers. STUDY DESIGN: Data obtained from questionnaires completed by freshman musical theater majors were retrospectively analyzed to gather information about baseline vocal habits of the participants. METHODS: Results of a questionnaire were obtained from incoming freshman musical theater students at the Cincinnati Conservatory of Music over a period of 10 years (2002-2011). One hundred eighty-eight participants (female = 90) (male = 98) with an average age of 18.28 years (standard deviation = 0.726) were included. RESULTS: Results specifying participants' self-reported vocal training and practice habits, vocal health and hygiene practices, and current vocal symptoms or contributing factors to potential voice problems are provided. CONCLUSIONS: Data obtained from the participants revealed that the potential for vocal problems exists in this group of performers, as over half of the subjects reported at least one current negative vocal symptom. The findings from this study provide information that may be useful for individuals who are involved in the training of vocal performers. PMID- 24629644 TI - Facial bone vibration in resonant voice production. AB - PURPOSE: This study investigated whether resonant voice training would enhance facial bone vibration during resonant voice production. METHODS: Twelve normal healthy participants undertook four sessions of resonant voice training, each lasted for 30 minutes. Piezoelectric accelerometer was used to measure the vibratory level on the face (nasal bridge and upper lip) and the perilaryngeal area during the production of nasal consonant /m/ and vowels /a/, /i/, and /u/ before and after the resonant voice training. The extents of vibration of these four sounds among these three sites were compared. RESULTS: Significant increase in facial bone vibration following resonant voice training was found. The nasal bridge showed a significantly larger magnitude of increase when compared with that at the upper lip. Different sounds were also found to facilitate different magnitude of facial bone vibration. Greater magnitude of facial bone vibration was found with the phonation of /m/, /i/, and /u/ when compared with the phonation of /a/. CONCLUSION: Resonant voice training facilitated an increase in facial bone vibration, more so at the nasal bridge area than around the upper lip. This is hypothesized to contribute to the improved resonant voice production. Sounds that involve relatively restricted oropharyngeal cavities facilitated a greater extent of facial bone vibration during resonant voice production. PMID- 24629645 TI - Does the presence or location of graphic markers affect untrained listeners' ratings of severity of dysphonia? AB - OBJECTIVE: To determine the effect of presence and location of severity labels for different types of visual analog scales (VAS) on overall severity (OS) ratings in dysphonic speech. STUDY DESIGN: Experimental, between group comparisons. METHODS: Dysphonic and normal voice samples from male and female speakers were presented to inexperienced listeners for judgments of OS. To rate samples, listeners used an undifferentiated 100-mm VAS labeled at the extremes, a VAS with nonlinearly distributed labels as in the "beta" version of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), or a VAS with symmetrically distributed labels as in the "official" version of the CAPE-V. RESULTS: Overall, mean OS ratings did not differ significantly across scale types, although ratings using the nonlinearly marked VAS were generally lower than those from other scales. This effect was significant for female speakers whose samples tended toward moderate OS. The ratings distribution, when compiled into 10-mm bins, differed significantly by scale type, with users of the nonlinearly marked scales skewing their ratings toward normal. CONCLUSIONS: The presence and placement of labels on VAS did not significantly affect OS ratings overall, but values were significantly lower when rating female voices with the nonlinearly labeled VAS. Results indicate that professionals should specify the scale type used for rating OS and use scales consistently when comparing voices. PMID- 24629647 TI - The effect of in vitro fertilization treatment on women's voice. AB - OBJECTIVES: To examine the effect of in vitro fertilization (IVF) treatment on acoustic properties of women's voice. STUDY DESIGN: Prospective case series. METHODS: Ten women undergoing IVF treatment participated in the study. All participants were recorded repeatedly in three successive sessions, before and during treatment, in addition to collecting hormonal assays, endometrial thickness measurements, and follicular growth data. Recordings were performed while sustaining an isolated vowel repeatedly and during a reading task. Acoustic analyses included a limited set of fundamental frequency (F0) measures, as well as frequency- and amplitude perturbation measures. Repeated-measure analyses of variance were performed to test for the treatment effect, and the correlations between the acoustic measures and the hormonal as well as endometrial thickness data were examined. RESULTS: A significant reduction in the two F0 measures and in the amplitude perturbation measure was found throughout the treatment (P<0.05). Before treatment, a negative correlation was found between F0 and estrogen levels. After treatment, however, a negative correlation was found between F0 and endometrial thickness. CONCLUSION: An association was found between IVF treatment and specific voice properties. In addition, the possibility of a ceiling effect for the influence of estrogens on female vocal folds was introduced. PMID- 24629648 TI - Suture lateralization in patients with bilateral vocal fold paralysis. AB - OBJECTIVES: To introduce a simplified suture lateralization (SL) technique to treat patients with bilateral vocal fold paralysis (BVFP). STUDY DESIGN: A retrospective study of surgical procedures by manual chart review. METHODS: The proposed endoscopic SL procedure was used for 20 patients operated on for BVFP between 2007 and 2013, with three attempts to remove a tracheostomy tube and 17 attempts to resolve the dyspnea. An adjustment procedure was also used to correct any excessive lateralization according to the individual's clinical symptoms, such as intolerable aspiration after SL in elderly patients and excessive breathiness of voice in socially active patients. St George's respiratory questionnaire was used to subjectively evaluate the efficacy of lateralization of vocal folds. Pulmonary function test with flow-volume loop was used to objectively evaluate the improvement of BVFP-related upper airway obstruction after surgery. Phonatory ability tests were also used to evaluate the degree of deterioration of voice quality. RESULT: Twenty patients underwent 22 episodes of SL. Two adjustment procedures were performed to correct excessive breathiness of voice or intolerable aspiration. Respiration was adequate in all 19 patients without artificial airways. Voice quality was socially acceptable in 19 of the patients and even equal to preoperative voice quality in 14 of them. Temporary mild aspiration occurred in 18 patients only in the first few days after the procedure. One decannulation failure and refusing adjustment procedure occurred in one elderly patient. All the patients were followed up for surgical outcomes for at least 9 and 33 months on average. CONCLUSION: SL is a simple, reversible, and minimally invasive reconstructive procedure for patients with BVFP. Our study supported its applicability for selected patients. PMID- 24629646 TI - Measurement of glottal cycle characteristics between children and adults: physiological variations. AB - OBJECTIVES: The aim of this study was to quantify phases of the vibratory cycle using measurements of glottal cycle quotients and glottal cycle derivatives, in typically developing prepubertal children and young adults with the use of high speed digital imaging (HSDI). METHODS: Vocal fold vibrations were recorded from 27 children (age range 5-9 years) and 35 adults (age range 21-45 years), with HSDI at 4000 frames per second for sustained phonation. Glottal area waveform measures of Open Quotient, Closing Quotient, Speed Index (SI), Rate Quotient, and Asymmetry Quotient (AsyQ) were computed. Glottal cycle derivatives of Amplitude Quotient (AQ) and Maximum Area Declination Rate (MADR) were also computed. Group differences (adult females, adult males, and children) were statistically investigated for mean and standard deviation values of the glottal cycle quotients and glottal cycle derivatives. RESULTS: Children exhibited higher values of SI and AsyQ and lower values of MADR compared with adult males. Children exhibited the highest mean value and lowest variability in AQ compared with adult males and females. Adult males showed lower values of SI, AsyQ, AQ, and higher values of MADR compared with adult females. CONCLUSIONS: Glottal cycle vibratory motion in children is functionally different compared with adult males and females, suggesting the need for development of children specific norms for both normal and disordered voice qualities. PMID- 24629649 TI - General practitioners' views on using a prescribing substitution application (ScriptSwitch((r))). AB - BACKGROUND: General practitioners (GPs) are increasingly pressured to prescribe cost-effectively, due to rising prescribing expenditure and limited budgets. A computerised prescribing substitution application (ScriptSwitch((r))) provides 'pop-ups' of cost-saving drug switches at the point of prescribing. It has been used by some United Kingdom local health commissioning organisations as part of a medicines management strategy. OBJECTIVE: To explore GPs' views on using this prescribing substitution application in their day-to-day clinical practice. METHODS: Qualitative study employing face-to-face semi-structured interviews, undertaken with a convenience sample of eight GPs across five practices within one local health commissioning area in the North of England. Interviews were audio-recorded, transcribed verbatim and thematically analysed. RESULTS: Six themes were identified including: (1) GPs' acceptance, (2) the application's impact, (3) external control, (4) disruption to workflow, (5) GP willingness to switch and (6) patient willingness to switch. CONCLUSIONS: Clinician, patient and organisational factors were identified which were assumed by GPs to affect the engagement with the application. Despite general acceptance of the application to enhance cost-effective prescribing, its impact was perceived to be limited within the context of existing cost-effective prescribing initiatives. The application's perceived lack of 'learning'-e.g. offering the same switch despite the prescriber repeatedly declining this-devalued users' confidence in it. With patients varying in amenability and acceptance to drug switches, GPs appear to experience tension between considering individual patient choice and wider practice population prescribing priorities. Giving GPs more control in adapting the application to their own local prescribing priorities may enhance its success. PMID- 24629650 TI - Getting on with your computer is associated with job satisfaction in primary care: entrants to primary care should be assessed for their competency with electronic patient record systems. AB - Job satisfaction in primary care is associated with getting on with your computer. Many primary care professionals spend longer interacting with their computer than anything else in their day. However, the computer often makes demands rather than be an aid or supporter that has learned its user's preferences. The use of electronic patient record (EPR) systems is underrepresented in the assessment of entrants to primary care, and in definitions of the core competencies of a family physician/general practitioner. We call for this to be put right: for the use of the EPR to support direct patient care and clinical governance to be given greater prominence in training and assessment. In parallel, policy makers should ensure that the EPR system use is orientated to ensuring patients receive evidence-based care, and EPR system suppliers should explore how their systems might better support their clinician users, in particular learning their preferences. PMID- 24629651 TI - Comparison of howRU and EQ-5D measures of health-related quality of life in an outpatient clinic. AB - This paper reports on a head-to-head study of howRU and EQ-5D on patients with cardiovascular disease. howRU is a short generic measure of health-related quality of life comprising 39 words, designed for routine use, which we compare with EQ-5D (230 words). Patients attending a clinic completed both instruments. Completed data were available for 116 patients, 51% female, mean age 56 and SD 20. howRU is shorter, has better readability statistics, a higher completion rate, a wider range of states used and a smaller ceiling effect than EQ-5D. The correlations of howRU with EQ-5D are similar to those of EQ-5D with other validated instruments. PMID- 24629652 TI - Satisfaction with electronic health records is associated with job satisfaction among primary care physicians. AB - OBJECTIVE: To evaluate the association between electronic health record (EHR) satisfaction and job satisfaction in primary care physicians (PCPs). METHOD: Cross-sectional survey of PCPs at 825 primary care practices in North Carolina. RESULTS: Surveys were returned from 283 individuals across 214 practices (26% response rate for practices), of whom 122 were physicians with EHRs and no missing information. We found that for each point increase in EHR satisfaction, job satisfaction increased by ~0.36 points both in an unadjusted and an adjusted model (beta 0.359 unadjusted, 0.361 adjusted; p < 0.001 for both models). CONCLUSION: We found that EHR satisfaction was associated with job satisfaction in a cross-sectional survey of PCPs. Our conclusions are limited by suboptimum survey response rate, but if confirmed may have substantial implications for how EHR vendors develop their product to support the needs of PCPs. PMID- 24629653 TI - The impact of interoperability of electronic health records on ambulatory physician practices: a discrete-event simulation study. AB - BACKGROUND: The effect of health information technology (HIT) on efficiency and workload among clinical and nonclinical staff has been debated, with conflicting evidence about whether electronic health records (EHRs) increase or decrease effort. None of this paper to date, however, examines the effect of interoperability quantitatively using discrete event simulation techniques. OBJECTIVE: To estimate the impact of EHR systems with various levels of interoperability on day-to-day tasks and operations of ambulatory physician offices. METHODS: Interviews and observations were used to collect workflow data from 12 adult primary and specialty practices. A discrete event simulation model was constructed to represent patient flows and clinical and administrative tasks of physicians and staff members. RESULTS: High levels of EHR interoperability were associated with reduced time spent by providers on four tasks: preparing lab reports, requesting lab orders, prescribing medications, and writing referrals. The implementation of an EHR was associated with less time spent by administrators but more time spent by physicians, compared with time spent at paper-based practices. In addition, the presence of EHRs and of interoperability did not significantly affect the time usage of registered nurses or the total visit time and waiting time of patients. CONCLUSION: This paper suggests that the impact of using HIT on clinical and nonclinical staff work efficiency varies, however, overall it appears to improve time efficiency more for administrators than for physicians and nurses. PMID- 24629654 TI - Effects of exam room EHR use on doctor-patient communication: a systematic literature review. AB - BACKGROUND: High levels of funding have been invested in health information technologies, especially electronic health records (EHRs), in an effect to coordinate and organize patient health data. However, the effect of EHRs in the exam room on doctor-patient communication has not been sufficiently explored. Objective The purpose of this systematic review was to determine how physician use of EHRs in medical consultations affects doctor-patient communication, both in terms of patient perceptions and actual physician behaviours. METHOD: The reviewer conducted a comprehensive online database search in March 2013 of EMBASE, MEDLINE, and SCOPUS, using a combination of synonyms of the terms "patient", "doctor", "communication", and "EHR" or "computing". For inclusion in this review, articles had to be published in English, take place in an outpatient setting and demonstrate an empirical investigation into whether EHR affects doctor-patient communication. The reviewer then analysed 13 articles that met the inclusion criteria. RESULTS: Studies showed EHR use encouraged biomedical questioning of the patient, and encouraged patient-led questioning and doctor-led information provision. EHR-related behaviours such as keyboarding and screen gaze impaired relationships with patients, by reducing eye contact, rapport, and provision of emotional support. EHRs negatively affected physician-led patient centred communication. Computer use may have amplified existing physician behaviours regarding medical record use. CONCLUSION: We noted both positive and negative effects of EHR use. This review highlights the need for increased EHR specific communication training to mitigate adverse effects and for continued acknowledgement of patient perspectives. PMID- 24629655 TI - "Effects of exam room EHR use on doctor-patient communication: a systematic literature review" - triadic and other key terms may have identified additional literature. PMID- 24629656 TI - Using the information value method in a geographic information system and remote sensing for malaria mapping: a case study from India. AB - BACKGROUND: This paper explores the scope of malaria-susceptibility modelling to predict malaria occurrence in an area. OBJECTIVE: An attempt has been made in Varanasi district, India, to evaluate the status of malaria disease and to develop a model by which malaria-prone zones could be predicted using five classes of relative malaria susceptibility, i.e.very low, low, moderate, high and very high categories. The information value (Info Val) method was used to assess malaria occurrence and various time-were used as the independent variables. A geographical information system (GIS) is employed to investigate associations between such variables and distribution of different mosquitoes responsible for malaria transmission. Accurate prediction of risk depends on a number of variables, such as land use, NDVI, climatic factors, population, distance to health centres, ponds, streams and roads etc., all of which have an influence on malaria transmission or reporting. Climatic factors, particularly rainfall, temperature and relative humidity, are known to have a major influence on the biology of mosquitoes. To produce a malaria-susceptibility map using this method, weightings are calculated for various classes in each group. The groups are then superimposed to prepare a Malaria Susceptibility Index (MSI) map. RESULTS: We found that 3.87% of the malaria cases were found in areas with a low malaria susceptibility level predicted from the model, whereas 39.86% and 26.29% of malaria cases were found in predicted high and very high susceptibility level areas, respectively. CONCLUSIONS: Malaria susceptibility modelled using a GIS may have a role in predicting the risks of malaria and enable public health interventions to be better targeted. PMID- 24629657 TI - Development of a web-based pharmaceutical care plan to facilitate collaboration between healthcare providers and patients. AB - BACKGROUND: In medication therapy management there is a need for a tool to document medication reviews and pharmaceutical care plans (PCPs) as well as facilitate collaboration and sharing of patient data between different healthcare providers. Currently, pharmacists and general practitioners (GPs) have their own computer systems and patient files. To facilitate collaboration between different healthcare providers and to exchange patient data we developed a paper-based tool. As a result the structured collection of all relevant information for a clinical medication review was more protocol driven. The tool also enabled to plan interventions and follow-up activities: the PCP. The PCP was piloted among three GPs and six community pharmacists. Interviews with all healthcare providers concluded the PCP was found a very useful tool to collect and share patient data. A disadvantage was the time spent to collect all information. We therefore developed our PCP into a web-based tool: the web-based PCP (W-PCP). OBJECTIVES: Development of a W-PCP to (1) provide healthcare providers with information from pharmacist- and GP computer systems and (2) facilitate collaboration between healthcare providers and patients. Development and Application: W-PCP facilitates uploading and sharing of patient data among health care professionals and collaboration between professionals and patients on performing treatment plans. The W-PCP is a stand-alone application developed by cocreation using a generic software platform that provides developmental speed and flexibility. METHOD: The W-PCP was used in three research lines, two in primary care and one in a hospital setting. Outcomes measures were defined as satisfaction about efficiency and effectiveness during data sharing and documentation in providing care and conducting medication reviews using the W-PCP. First experiences concerning the use of W-PCP in a primary care setting were collected by a questionnaire and interviews with pharmacists and GPs using the W-PCP. RESULTS: A questionnaire about first experiences with the W-PCP was sent to 38 healthcare providers. 17 healthcare providers returned the questionnaire (response 44.7%). The use of W PCP resulted in positive experiences from participating healthcare providers. One of the needs expressed is to have the W-PCP application integrated in the current pharmacy and GP computer systems. All experiences, needs, and ideas for improvement of the current application were collected. On the basis of experiences and requirements collected, the application will be further developed. CONCLUSIONS: The W-PCP application can potentially support successful collaboration between different healthcare providers and patients, which is important for medication therapy management. With this application, a successful collaboration between different healthcare providers and patients could be achieved. PMID- 24629658 TI - Myofibroblastoma of the breast with smooth muscle differentiation showing deletion of 13q14 region: report of a case. AB - Breast myofibroblastomas are rare benign mesenchymal tumors belonging to the group of stromal breast tumors composed of spindle-shaped cells and characterized by a broad morphologic spectrum. Among the different morphologic variants described, breast MFBs can show smooth muscle cell differentiation in very rare cases. In terms of the genetic abnormalities found in this type of tumor, a deletion of chromosome 13q14 was recently confirmed by FISH in some cases of mammary MFB. In this paper, we report an unusual case of MFB with smooth muscle differentiation showing a deletion of chromosome 13q14. PMID- 24629659 TI - Congenital cystic neck masses: embryology and imaging appearances, with clinicopathological correlation. AB - Congenital cystic masses of the neck are uncommon and can present in any age group. Diagnosis of these lesions can be sometimes challenging. Many of these have characteristic locations and imaging findings. The most common of all congenital cystic neck masses is the thyroglossal duct cyst. The other congenital cystic neck masses are branchial cleft cyst, cystic hygroma (lymphangioma), cervical thymic and bronchogenic cysts, and the floor of the mouth lesions including dermoid and epidermoid cysts. In this review, we illustrate the common congenital cystic neck masses including embryology, clinical findings, imaging features, and histopathological findings. PMID- 24629660 TI - Abdominal and pelvic tumors with musculoskeletal histology. AB - This article is a case-based review of the broad spectrum of tumors with musculoskeletal histology that can arise in the abdomen or pelvis and involve the soft tissues, muscle, and bone. In this article, pathology-proven cases are presented with a focus on radiographic, computed tomography, magnetic resonance imaging, and positron emission tomography-computed tomography findings. The imaging features that differentiate tumors with musculoskeletal histology from more common abdominal tumors are discussed. Representative cases include malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, hemangiopericytoma, desmoplastic fibroma, neurofibrosarcoma, osteosarcoma, intimal sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, teratoma, and chordoma. A variety of tumors with musculoskeletal histology can arise in the abdomen and pelvis. In some cases, unique imaging characteristics allow a confident diagnosis, whereas other cases have a more nonspecific appearance. Recognition of imaging features that suggest a musculoskeletal tumor including direct extension from a bone or neural foramen, the presence of cartilaginous or osseous matrix, or macroscopic fat would allow the radiologist to suggest the proper diagnosis. Recognizing imaging characteristics of tumors with musculoskeletal histology is important clinically as management and prognosis differ from that of more common abdominal tumors. PMID- 24629661 TI - Complications of sporadic, hereditary, and acquired renal cysts: cross-sectional imaging findings. AB - Commonly encountered in the general adult and elderly population, in most cases simple renal cysts are confidently diagnosed on imaging studies and do not require further workup or treatment. However, large or growing renal cysts sometimes cause symptoms or signs such as hypertension, palpable mass, flank or abdominal pain, obstructive uropathy, and hematuria, which may indicate the need for minimally invasive percutaneous or laparoscopic treatment. Furthermore, severe complications such as cystic hemorrhage, rupture, or superinfection may occur, particularly in patients with polycystic renal disorders, either hereditary (namely adult polycystic kidney diseases) or acquired in chronic renal failure. This pictorial essay reviews and discusses the cross-sectional imaging appearances of symptomatic and complicated sporadic, hereditary, and acquired renal cysts. Early cross-sectional imaging with multidetector computed tomography or magnetic resonance imaging or both, including contrast enhancement unless contraindicated by renal dysfunction, is warranted to investigate clinical and laboratory signs suggesting retroperitoneal hemorrhage or infection in patients with pre-existent renal cysts, particularly if large, multiple, or hereditary. PMID- 24629662 TI - Eponyms in cardiothoracic radiology: Part I. Neoplasms. AB - Eponyms serve the purpose of honoring individuals who have made important observations and discoveries. As with other fields of medicine, eponyms are frequently encountered in radiology, particularly in chest radiology. However, inappropriate use of an eponym may lead to potentially dangerous miscommunication. Moreover, an eponym may honor the incorrect person or a person who falls into disrepute. Despite their limitations, eponyms are still widespread in medical literature. Furthermore, in some circumstances, more than one individual may have contributed to the description or discovery of a particular anatomical structure or disease, whereas in others, an eponym may have been incorrectly applied initially and propagated for years in medical literature. Nevertheless, radiologic eponyms are a means of honoring those who have made lasting contributions to the field of radiology, and familiarity with these eponyms is critical for proper reporting and accurate communication. In addition, the acquisition of some historical knowledge about those whose names are associated with various structures or pathologic conditions conveys a sense of humanity in the field of medicine. In this article, the first of a multipart series, the authors discuss a number of chest radiology eponyms as they relate to neoplasms, including relevant clinical and imaging features, as well biographic information of the respective eponym's namesake. PMID- 24629663 TI - Sll0939 is induced by Slr0967 in the cyanobacterium Synechocystis sp. PCC6803 and is essential for growth under various stress conditions. AB - In this study, the genes expressed in response to low pH stress were identified in the unicellular cyanobacterium Synechocystis sp. PCC 6803 using DNA microarrays. The expression of slr0967 and sll0939 constantly increased throughout 4-h acid stress conditions. Overexpression of these two genes under the control of the trc promoter induced the cells to become tolerant to acid stress. The Deltaslr0967 and Deltasll0939 mutant cells exhibited sensitivity to osmotic and salt stress, whereas the trc mutants of these genes exhibited tolerance to these types of stress. Microarray analysis of the Deltaslr0967 mutant under acid stress conditions showed that expression of the high light inducible protein ssr2595 (HliB) and the two-component response regulator slr1214 (rre15) were out of regulation due to gene inactivation, whereas they were upregulated by acid stress in the wild-type cells. Microarray analysis and real time quantitative reverse transcription-polymerase chain reaction analysis showed that the expression of sll0939 was significantly repressed in the slr0967 deletion mutant. These results suggest that sll0939 is directly involved in the low pH tolerance of Synechocystis sp. PCC 6803 and that slr0967 may be essential for the induction of acid stress-responsive genes. PMID- 24629665 TI - Evaluating implementation of the emergency severity index in a Belgian hospital. AB - INTRODUCTION: Triage aims to categorize patients based on their clinical need and the available departmental resources. To accomplish this goal, one needs to ensure that the implemented triage system is reliable and that staff use it correctly. Therefore this study assessed the ability of Belgium nurses to apply the Emergency Severity Index (ESI), version 4, to hypothetical case scenarios after an educational intervention. METHODS: An ESI educational intervention was implemented in accordance with the ESI manual. Using paper case scenarios, nurses' interrater agreement was assessed by comparing triage nurse ESI levels with the reference answers noted in the implementation manual. Interrater agreement was measured by the percentage of agreement and Cohen's kappa coefficient using different weighting schemes. RESULTS: Overall, 77.5% of the scenario cases were coded according the ESI guidelines, resulting in a good interrater agreement (kappa = 0.72, linear weighted kappa = 0.84, quadratic weighted kappa = 0.92, and triage-weighted scheme = 0.79). Interrater agreement varied when evaluating each ESI level separately. Undertriage was more common than overtriage. The highest misclassification range (37.8%) occurred in ESI level 2 scenarios, with 99.2% of the misclassifications being undertriaged. DISCUSSION: Implementation of the ESI into a novel setting guided by a locally developed training program resulted in suboptimal interrater agreement. Existing weighted kappa schemes overestimated the interrater agreement between the triage nurse-assigned ESI level and the reference standard. By providing an aggregated measure of agreement, which allows partial agreement, clinically significant misclassification was masked by a misleading "good" interrater agreement. PMID- 24629664 TI - Monitoring thylakoid ultrastructural changes in vivo using small-angle neutron scattering. AB - The light reactions of oxygenic photosynthesis take place in the thylakoid membranes, flattened vesicles, which contain the two photosystems and also embed the cytochrome b6f complex and the ATP synthase. In general, the thylakoid membranes are assembled into multilamellar membrane systems, which warrant an optimal light capturing efficiency. In nature, they show astounding variations, primarily due to large variations in their protein composition, which is controlled by multilevel regulatory mechanisms during long-term acclimation and short-term adaptation processes and also influenced by biotic or abiotic stresses - indicating a substantial degree of flexibility in the membrane ultrastructure. The better understanding of the dynamic features of this membrane system requires the use of non-invasive techniques, such as small angle neutron scattering (SANS), which is capable of providing accurate, statistically and spatially averaged information on the repeat distances of periodically organized thylakoid membranes under physiologically relevant conditions with time resolutions of seconds and minutes. In this review, after a short section on the basic properties of neutrons, we outline the fundamental principles of SANS measurements, its strengths and weaknesses in comparison to complementary structure investigation techniques. Then we overview recent results on isolated plant thylakoid membranes, and on living cyanobacterial and algal cells as well as on whole leaves. Special attention is paid to light-induced reversible ultrastructural changes in vivo, which, in cyanobacterial and diatom cells, were uncovered with the aid of SANS measurements; we also discuss the role of membrane reorganizations in light adaptation and photoprotection mechanisms. PMID- 24629666 TI - Adopt the 2014-2015 targeted best practices for medication safety. PMID- 24629667 TI - Neurodegenerative dementias: connecting psychiatry and neurology through a shared neurobiology. PMID- 24629669 TI - Network dysfunction in Alzheimer's disease and frontotemporal dementia: implications for psychiatry. AB - Structural and functional connectivity methods are changing how researchers conceptualize and explore neuropsychiatric disease. Here, we summarize emerging evidence of large-scale network dysfunction in Alzheimer's disease and behavioral variant frontotemporal dementia, focusing on the divergent impact these disorders have on the default mode network and the salience network. We update a working model for understanding the functions of these networks within a broader anatomical context and highlight the relevance of this model for understanding psychiatric illness. Finally, we look ahead to persistent challenges in the application of network-based imaging methods to patients with Alzheimer's disease, behavioral variant frontotemporal dementia, and other neuropsychiatric conditions. Recent advances and persistent needs are discussed, with an eye toward anticipating the hurdles that must be overcome for a network-based framework to clarify the biology of psychiatric illness and aid in the drug discovery process. PMID- 24629668 TI - Dementia in a dish. AB - Neurodegenerative disorders of aging represent a growing public health concern. In the United States alone, there are now >5 million patients with Alzheimer's disease (AD), the most common form of dementia. No therapeutic approaches are available that alter the relentless course of AD or other dementias of aging. A major hurdle to the development of effective therapeutics has been the lack of predictive model systems in which to develop and validate candidate therapies. Animal model studies based on the analysis of transgenic mice that overexpress rare familial AD-associated mutant genes have been informative about mechanisms of familial disease, but they have not proven predictive for drug development. New approaches to disease modeling are of particular interest. Methods such as epigenetic reprogramming of patient skin fibroblasts to human induced pluripotent stem cells, which can be differentiated into patient-derived neuron subtypes, have generated significant excitement because of their potential to model more accurately aspects of human neurodegeneration. Studies focused on the generation of human neuron models of AD and frontotemporal dementia have pointed to pathologic pathways and potential therapeutic venues. This article discusses the promise and potential pitfalls of modeling of dementia disorders based on somatic cell reprogramming. PMID- 24629670 TI - Differential metal content and gene expression in rat left ventricular hypertrophy due to hypertension and hyperactivity. AB - The spontaneously hypertensive rat (SHR) has been studied extensively as a model of left ventricular hypertrophy (LVH) and associated cardiac dysfunction due to hypertension (HT). The SHR also possesses a hyperactive trait (HA). Crossbreeding SHR with Wistar-Kyoto (WKY) control rats, which are nonHT and nonHA, followed by selected inbreeding produced two additional homozygous strains: WKHT and WKHA, in which the traits of HT and HA, respectively, are expressed separately. WKHT, WKHA and SHR all display LVH, but only the SHR exhibits cardiac dysfunction. We hypothesized that cardiac dysfunction in the SHR is uniquely characterized by calcium overload. We measured total cardiac Ca, Cu, Fe, K, Mg and Zn in the four strains. We found elevated Ca and depressed Cu, Mg and Zn with HT, but not unique to SHR. We surmise that HT promotes aberrant regulation of cardiac Ca(2+), Cu(2+), Mg(2+) and Zn(2+), which does not necessarily result in cardiac dysfunction. Interestingly, Cu was elevated in HA strains compared to nonHA counterparts. We then analyzed gene expression as mRNA of Cu-containing proteins, most notably mitochondrial-Cox, Dbh, Lox, Loxl1, Loxl2, Sod1 and Tyr. The gene expression profiles of Lox, Loxl1, Loxl2 and Sod1 were found especially high in the WKHA, which if reflective of protein content could account for the high Cu content in the WKHA. The mRNA of other genes, notably Mb, Fxyd1, Maoa and Maob were also examined. We found that Maoa gene expression and monoamine oxidase-A (MAO-A) protein content were low in the SHR compared to the other strains. The finding that MAO-A protein is low in the SHR and normal in the WKHT and WKHA strains is most consistent with the idea that MAO-A protects against the development of cardiac dysfunction in LVH but not against LVH in these rats. PMID- 24629671 TI - A novel concept to derive iodine status of human populations from frequency distribution properties of a hair iodine concentration. AB - Today, human iodine deficiency is next to iron the most common nutritional deficiency in developed European and underdeveloped third world countries, respectively. A current biological indicator of iodine status is urinary iodine that reflects the very recent iodine exposure, whereas some long term indicator of iodine status remains to be identified. We analyzed hair iodine in a prospective, observational, cross-sectional, and exploratory study involving 870 apparently healthy Croatians (270 men and 600 women). Hair iodine was analyzed with the inductively coupled plasma mass spectrometry (ICP MS). Population (n870) hair iodine (IH) respective median was 0.499MUgg(-1) (0.482 and 0.508MUgg(-1)) for men and women, respectively, suggesting no sex related difference. We studied the hair iodine uptake by the logistic sigmoid saturation curve of the median derivatives to assess iodine deficiency, adequacy and excess. We estimated the overt iodine deficiency to occur when hair iodine concentration is below 0.15MUgg(-1). Then there was a saturation range interval of about 0.15-2.0MUgg( 1) (r(2)=0.994). Eventually, the sigmoid curve became saturated at about 2.0MUgg( 1) and upward, suggesting excessive iodine exposure. Hair appears to be a valuable and robust long term biological indicator tissue for assessing the iodine body status. We propose adequate iodine status to correspond with the hair iodine (IH) uptake saturation of 0.565-0.739MUgg(-1) (55-65%). PMID- 24629672 TI - Differential aggregation properties of alpha-synuclein isoforms. AB - Pathologic aggregation of alpha-synuclein is a central process in the pathogenesis of Parkinson's disease. The alpha-synuclein gene (SNCA) encodes at least 4 different alpha-synuclein isoforms through alternative splicing (SNCA140, SNCA126, SNCA112, SNCA98). Differential expression of alpha-synuclein isoforms has been shown in Lewy body diseases. In contrast to the canonical alpha synuclein isoform of 140 amino acid residues (SNCA140), which has been investigated in detail, little is known about the properties of the 3 alternative isoforms. We have investigated the aggregation properties of all 4 isoforms in cultured cells and analyzed fibril-formation of 3 isoforms (SNCA140, SNCA126, and SNCA98) in vitro by electron microscopy. Each of the 3 alternative isoforms aggregates significantly less than the canonical isoform SNCA140. Electron microscopy showed that SNCA140 formed the well-known relatively straight fibrils while SNCA126 formed shorter fibrils, which were arranged in parallel fibril bundles and SNCA98 formed annular structures. Expression analysis of alpha synuclein isoforms in different human brain regions demonstrated low expression levels of the alternative isoforms in comparison to the canonical SNCA140 isoform. These findings demonstrate that alpha-synuclein isoforms differ qualitatively and quantitatively in their aggregation properties. The biological consequences of these findings remain to be explored in vitro and in vivo. PMID- 24629673 TI - Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles. AB - Several studies have highlighted the frequency of sleep disturbances in Alzheimer's disease (AD). However, whether they are secondary to the disease or per se increase its risk remains to be fully investigated. The aim of the current investigation was to study the effect of sleep deprivation (SD) on the development of AD phenotype in a transgenic mouse model with plaques and tangles, the 3xTg mice. We evaluated the functional and biological consequences on 3xTg mice that underwent 4 hours sleep restrain per day for 8 weeks. Compared with controls, behavioral assessment showed that SD-treated mice had a significant decline in their learning and memory. Although no differences were detected in the levels of soluble amyloid-beta peptides, the same animals displayed a decrease in tau phosphorylation, which associated with a significant increase in its insoluble fraction. In addition, we observed that SD resulted in lower levels of postsynaptic density protein 95 and increased glial fibrillary acidic protein levels. Finally, although total levels of the transcription factor cellular response element binding protein were unchanged, its phosphorylated form was significantly diminished in brains of sleep-deprived mice when compared with controls. Our study underlines the importance of SD as a chronic stressor, which by modulating biochemical processes influences the development of memory impairments and AD neuropathologies. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD in individuals bearing this risk factor. PMID- 24629674 TI - Neuroprotective effects of mesenchymal stem cells through autophagy modulation in a parkinsonian model. AB - Autophagy is a major degradation pathway for abnormal aggregated proteins and organelles that cause various neurodegenerative diseases. Current evidence suggests a central role for autophagy in pathogenesis of Parkinson's disease, and that dysfunction in the autophagic system may lead to alpha-synuclein accumulation. In the present study, we investigated whether mesenchymal stem cells (MSCs) would enhance autophagy and thus exert a neuroprotective effect through the modulation of alpha-synuclein in parkinsonian models. In MPP(+) treated neuronal cells, coculture with MSCs increased cellular viability, attenuated expression of alpha-synuclein, and enhanced the number of LC3-II positive autophagosomes compared with cells treated with MPP(+) only. In an MPTP treated animal model of Parkinson's disease, MSC administration significantly increased final maturation of late autophagic vacuoles, fusion with lysosomes. Moreover, MSC administration significantly reduced the level of alpha-synuclein in dopaminergic neurons, which was elevated in MPTP-treated mice. These results suggest that MSC treatment significantly enhances autophagolysosome formation and may modulate alpha-synuclein expression in parkinsonian models, which may lead to increased neuronal survival in the presence of neurotoxins. PMID- 24629675 TI - [A good working environment in health care benefits the patients]. PMID- 24629676 TI - [Use the influence and take responsibility for the work environment]. PMID- 24629677 TI - [Violence against health personnel]. AB - Health personnel are at risk of threats and violence, especially when young and inexperienced. Also, working in emergency departments, psychiatric wards, and eldercare bears a risk. The phenomenon is reported from all over the world and may originate in intoxication, confusion or frustration during long waiting hours and uncertainty of treatment and prognosis. Experiences of threats and violence result in decreased well-being, anger, helplessness and thoughts about change of workplace or quitting the job. Training in communication and teamwork may prevent threats and violence. PMID- 24629678 TI - [Stress and burnout increase among general practitioners in Denmark]. AB - Burnout is characterized by emotional exhaustion, depersonalization and reduced personal accomplishment. In agreement with international studies, Danish figures have revealed an increase in prevalence of severe burnout from 2.8% in 2004 to 5.3% in 2012. There is only little research on the consequences for the burned out general practitioner (GP) and his patients as well as on appropriate intervention strategies. Even though burnout appears to be caused by a combination of personality factors and environmental conditions, the literature has one-sidedly focused on the resilience of the individual GP. PMID- 24629679 TI - [Doctors' use of their Network of Colleagues]. AB - For more than twenty years a dynamic group of doctors has on a voluntary basis been on call for their colleagues experiencing crisis reactions related to work and personal life. Consultancies are anonymous; only a few data are registered in order to gather insight into the reasons for seeking assistance. The majority of contacts now seem to be work-related stress, conflicts with colleagues, family problems, illness and abuse. Patient claims and a bad press are not as frequent as they used to be. PMID- 24629680 TI - [Uncertain if physicians' shift work causes patient harm]. AB - The role of physicians' shift work in adverse events causing patient harm is not clear. However, extended shifts reduce psychomotor performance and cognition in daytime after a 24-hour shift. The incidence and preventability of adverse events in Denmark are comparable to other Western countries, despite the fact that Danish physicians do not work extended hours. The role of physicians' shift work in adverse events causing patient harm remains controversial and further research is needed. PMID- 24629681 TI - [Shift work and risk of cancer and coronary heart diseases]. AB - Shift and night work are among the most frequent occupational exposures. Such work schedules involve exposure to light-at-night, which may reduce normal nocturnal melatonin production, create circadian rhythm disruption, sleep deprivation and unhealthy lifestyle. There is strong experimental evidence that light-at-night and circadian disruption may increase the risk of cancer and coronary heart diseases. There is emerging, but limited epidemiologic evidence that night shift work may increase breast cancer and certain cardiovascular diseases. PMID- 24629682 TI - [Working environment and educational environment are two sides of the same coin]. AB - Educational environment is of major importance for job satisfaction and it consists of several components including curriculum and values of the organization. Educational climate is the environment, as the individual physicians perceive it. Motivation is important for job satisfaction as well as for learning. Autonomy, responsibility, supervision, feedback are all important factors influencing motivation and learning. These factors must be supported through appropriate organization of work in hospital departments and in general practice. PMID- 24629683 TI - [Presentation, diagnosis and management of swallowed foreign bodies]. AB - Foreign body ingestion occurs commonly. In 80-90% of cases, the ingested foreign body passes uneventfully through the gastrointestinal tract; endoscopy is performed in 20% of cases, and surgery in less than 1%. Complications usually occur when the ingested foreign body is sharp, large, a button battery or multiple magnets. We present a potential algorithm for the management of swallowed foreign bodies. Most patients can be treated conservatively by observation alone, but often it is convenient to proceed to endoscopic retrieval. Surgery is reserved for complicated cases. PMID- 24629684 TI - [Cowden syndrome can be a challenging diagnosis]. AB - Cowden syndrome is a rare autosomal dominant overgrowth syndrome with a predisposition to cancer. The overgrowth and cancer may occur in many different tissues, which makes it a challenge to recognize it, but due to the high risk of cancer early diagnosis is important. We present the Danish screening guidelines for patients with Cowden syndrome. PMID- 24629685 TI - [Cowden syndrome diagnosed in patients with macrocephaly]. AB - Cowden syndrome is a rare autosomal dominant syndrome with a predisposition to cancer. We present a case of Cowden syndrome in a mother and her son, who were diagnosed with palmoplantar hyperkeratosis, macrocephaly and goitre. Early diagnosis is a challenge as the patients present with a variety of symptoms, but it is important because of the risk of cancer. PMID- 24629686 TI - [Cold panniculitis]. PMID- 24629687 TI - Zenker's pharyngo-esophageal diverticulum: diverticulectomy and diverticulopexy. PMID- 24629688 TI - Day-care for breast cancer: ambulatory surgery and intra-operative radiation. Techniques and preliminary results of the Centre Val-d'Aurelle--Montpellier. AB - One-day breast carcinoma treatment is defined as association of ambulatory surgery and intra-operative irradiation. Selection and rigorous process of patients is the key to success. The surgical technique is not changed by the radiotherapy. Patient's satisfaction index is very high. Financial loss should not be a hurdle to its implementation. PMID- 24629689 TI - Step-by-step nerve-preserving mesorectal excision in the female. PMID- 24629690 TI - [Effect of a hypocaloric diet in the oxidative stress in obese subjects without prescription of exercise and antioxidants]. AB - BACKGROUND AND OBJECTIVE: Obesity is characterized by a generalized increase of adipose tissue, high production of adipocytokines and presence of oxidative systemic stress. The objective of this study was to evaluate the changes generated in the oxidative stress and anthropometric parameters in obese subjects by the prescription of a hypocaloric diet in combination with moderate aerobic exercise and supplementation with antioxidants. PATIENTS AND METHODS: Oxidative damage was determined in the plasma from 30 normal weight and 30 obese subjects. Three groups of treatment were established: Hypocaloric diet (HD), HD plus moderate aerobic exercise (HDE) and HDE plus antioxidants (DHEA). Biomarkers of oxidative stress (thiobarbituric acid reactive substances [TBARS], carbonyl groups, dityrosine) and anthropometric parameters were determined. RESULTS: Higher values of biomarkers of oxidative damage were observed in obese (TBARS 13.74 +/- 1.2 MUM; carbonyl groups 0.89 +/- 0.04 nmol of osazone/mg of protein; dityrosine 478.9 +/- 27.4 RFU/mg of protein) in comparison to normal weight subjects (TBARS 7.08 +/- 0.8 MUM; carbonyl groups 0.65 +/- 0.04 nmol of osazone/mg of protein; dityrosine 126.3 +/- 12.6 RFU/mg of protein), thus showing the presence of an oxidative damage. The prescription of HD decreased the oxidative damage and anthropometric parameters in the obese subjects. We did not observe additional benefit effects on these determinations with HDE or HDEA treatments. CONCLUSIONS: We demonstrated that an HD decreases the oxidative damage in obese subjects. Oxidative stress is an important factor in the development of comorbidity in obesity. Therefore, the prescription of a HD could be a key issue in the treatment of the disease. PMID- 24629691 TI - [Side effects of drugs on the oral cavity]. AB - Although drugs are the most powerful therapeutic tools we have for improving the quality of life of the population, their use is not free of adverse effects. Today there are many polymedicated patients, and it is difficult to find the cause of their adverse effects that increase exponentially when more than 4 drugs are combined. There are a large number of drugs that can result in numerous adverse effects in the oral cavity. The most common are xerostomia, altered taste, gingival enlargement and mucositis caused by cancer treatment. We also review other disorders of the salivary glands, oral mucosal changes, pigmentations, halitosis, osteonecrosis, opportunistic infections and bleeding diathesis. PMID- 24629692 TI - [Clinical usefulness of the determination of fibroblast growth factor 23 in the evaluation of patients with osteomalacia]. AB - BACKGROUND AND OBJECTIVE: The aim of the present study was to analyze the usefulness of the determination of fibroblast growth factor 23 (FGF23), a regulatory hormone of phosphate metabolism, in the evaluation of patients with osteomalacia of different causes. PATIENTS AND METHOD: Seventeen patients with osteomalacia were included: 12 hypophosphatemic osteomalacia (by several causes), 4 vitamin D-deficiency osteomalacia and one with hypophosphatasia. Plasma C terminal FGF23 was determined in all patients. RESULTS: FGF23 levels were increased in 6/12 (50%) of patients with hypophosphatemic osteomalacia (2 X linked, one autosomal dominant, one related HIV therapy and 2 not elucidated). No patient with vitamin D-deficiency osteomalacia or hypophosphatasia presented increased FGF23 levels. CONCLUSION: The determination of FGF23 could be useful in the evaluation of the different types of hypophosphatemic osteomalacia and also in the identification of their associated etiopathogenic mechanisms. Thus, depending on the cause, 50% of the patients with hypophosphatemic osteomalacia showed increased FGF23 values, whereas in vitamin D-deficiency osteomalacia and in hypophosphatasia FGF23 levels were normal. PMID- 24629693 TI - [Dementia and diabetes: casual or causal relationship?]. AB - Several studies have reported the existence of an epidemiological association between diabetes mellitus (DM) and dementia. Although this association is more evident for vascular dementia, it is also described in Alzheimer's disease (AD). In this review we evaluate the different hypotheses that may explain the association between DM and dementia. We can consider the existence of a diabetes type 3 as the situation that occurs when hyperinsulinemia in response to insulin resistance leads to a decrease of the brain insulin and a poor regulation of insulin-degrading enzyme; thus, beta-amyloid accumulates, among other mechanisms, by the decline of its degradation by insulin-degrading enzyme. Consequently, AD may be related, at least in part, to a brain insulin resistance. There are several studies that prove the concept that a better metabolic control, especially in not very old people, is associated with an increased cognitive performance. It is not known whether the use of any specific drug for the treatment of DM is better than any other. It is important for physicians responsible for the metabolic control of diabetic patients to know this possible association, and to explore cognition in the control visits of patients with DM. PMID- 24629694 TI - [Vitamin D, metabolic syndrome and diabetes mellitus]. PMID- 24629695 TI - [Diagnostic performance of surface electrocardiogram in early detection of chagasic cardiomyopathy]. AB - BARCKGROUND AND OBJECTIVE: Contrast-enhanced cardiac magnetic resonance imaging (CMR) allows early detection of myocardial involvement by Trypanosoma cruzi infection. The aim of our study was to assess the diagnostic performance of the surface electrocardiogram (ECG) in the early detection of Chagas' cardiomyopathy (CCM) compared with CMR. METHODS: We included 43 asymptomatic patients (30 women, 42 +/- 9.8 years), diagnosed of Chagas disease. The sample was divided into 2 groups according to the presence (n=17) or absence (n=26) of electrocardiographic abnormalities. All patients underwent CMR and late gadolinium enhancement (LGE) was used as a marker of early myocardial involvement. RESULTS: Six (14%) patients had a LGE significantly higher in the group who had electrocardiographic abnormalities (29 vs. 4%, P<.05). With CMR as the method of reference, the ECG had a sensitivity of 83% and a negative predictive value of 96% to detect CCM. CONCLUSION: ECG is a useful, inexpensive and globally available tool for the screening of CCM in asymptomatic patients but with proven myocardial involvement in CMR. PMID- 24629696 TI - Photodynamic action of methylene blue in osteosarcoma cells in vitro. AB - BACKGROUND: Osteosarcoma is a common malignant bone tumor which threatens the life of young people worldwide. To explore alternative strategy for combating osteosarcoma, a light-emitting diode (LED) that activates methylene blue (MB) was used in the present study to investigate cell death of osteosarcoma-derived UMR106 cells. MATERIALS AND METHODS: Photocytotoxicity in UMR106 cells was investigated 24h after photodynamic activation of MB using sulforhodamine B (SRB) assay and light microscopy. Apoptosis induction was observed 24h after photodynamic treatment using a confocal laser scanning microscopy (CLSM) with Hoechst 33342 staining. The change in mitochondrial membrane potential (MMP) was analyzed using a flow cytometry with rhodamine 123 staining. RESULTS: MB under red light irradiation caused a drug-concentration (0-100MUM) and light-dose (0 32J/cm(2)) dependent cytotoxicity in UMR106 cells. The SRB assay and light microscopy observed a significant decrease in the number of UMR106 cells attached to the bottom of culture well after LED light-activated MB (100MUM, 32J/cm(2)). Nuclear shrinkage, chromatin condensation and fragmentation were found in the treated cells by nuclear staining. In addition, flow cytometry showed that the MMP in UMR106 cells was rapidly reduced by photo-activated MB (100MUM, 32J/cm(2)). CONCLUSION: Photodynamic action of MB under LED irradiation could remarkably kill osteosarcoma cells and induce cell apoptosis as well as MMP collapse. PMID- 24629697 TI - A novel photodynamic therapy for drug-resistant prostate cancer cells using porphyrus envelope as a novel photosensitizer. AB - BACKGROUND: In the clinic, it is often very difficult to treat drug-resistant advanced prostate cancer by conventional treatments. Photodynamic therapy (PDT) is a minimally invasive treatment that takes advantage of photochemical reactions between a photosensitizer and light. On the basis of several of its key characteristics, PDT is considered to be a promising novel method for treating drug-resistant prostate cancer. OBJECTIVES: For effective treatment of drug resistant prostate cancer, we developed a novel agent termed porphyrus envelope, which was produced from PpIX lipid and hemagglutinating virus of Japan envelope (HVJ-E). MATERIALS AND METHODS: We inserted PpIX lipid into HVJ-E by centrifugation, and used the resultant porphyrus envelope in PDT of two drug resistant prostate cancer cell lines, PC-3 and PC-3-DR. RESULTS: Porphyrus envelope enhanced uptake of PpIX, and cytotoxicity of PDT, relative to free PpIX lipid or PpIX induced by 5-ALA. CONCLUSION: PDT using porphyrus envelope has potential as a method for treating drug-resistant prostate cancer. PMID- 24629698 TI - Correlation of deregulated like-acetylglucosaminyl transferase and aberrant alpha dystroglycan expression with human tongue cancer metastasis. AB - PURPOSE: The present study examined the correlation of alpha-dystroglycan (alpha DG) expression and like-acetylglucosaminyl transferase (LARGE) with metastasis of human tongue cancer. MATERIALS AND METHODS: Fifty human tongue cancer tissues and 2 tongue squamous cell carcinoma cell lines (CAL27 and SCC4) were involved. Immunohistochemistry was used to detect the expression of alpha-DG and LARGE. Methylation-specific polymerase chain reaction was performed to assess the methylation status of the LARGE gene promoter. CAL27 and SCC4 cells were transfected with exogenous LARGE and treated with 5-aza-2'-deoxycytidine (Aza dC), respectively. Glycol sites of alpha-DG were detected by western blotting. In addition, the laminin overlay assay, cell adhesion assay, and invasion assay were performed. RESULTS: Immunohistochemical results showed that decreased expression of VIA4-1 and IIH6 (antibodies that recognize the glycol sites of alpha-DG) were correlated with the lymph node metastasis of tongue cancer (n = 50; P = .016 and .025, respectively). Decreased LARGE expression and hypermethylation of the LARGE gene promoter were correlated with lymph node metastasis and alpha-DG glycosylation in human tongue cancer (n = 50; P = .043 and .015 respectively). In addition, LARGE overexpression and Aza-dC treatment actively led to restoration of functional alpha-DG expression, elevation of laminin binding, and decrease of migratory ability in cancer cells. CONCLUSION: The results suggested that absent alpha-DG expression and LARGE deregulation were closely associated with nodal metastasis of tongue cancer. Aberrant alpha-DG expression and glycosylation were attributed at least in part to the abnormal epigenetic modification of LARGE, especially the hypermethylation of its promoter. PMID- 24629700 TI - Management of a pneumopericardium due to penetrating trauma. AB - INTRODUCTION: A pneumopericardium presenting after penetrating chest trauma is a rare event. The surgical management of this clinical problem has not been clearly defined. The aim of this study was to document the mode of presentation and to suggest a protocol for management. PATIENT AND METHODS: A review of a prospectively collected cardiac database of patients presenting to Groote Schuur Hospital Trauma Centre between October 2001 and February 2009 with a pneumopericardium on chest X-ray after penetrating trauma. RESULTS: There were 27 patients with a pneumopericardium (mean age 25 years, range 17-36). The mechanism of injury was a stab wound to the chest in 26 patients and a single patient with multiple low velocity gunshot wounds. Six patients (22%) were unstable and required emergency surgery. One of these patients presented with a tension pneumopericardium. Twenty-one patients were initially stable. Two of these (10%) patients later developed a tension pneumopericardium within 24-h and were taken to theatre. The remaining 19 patients were managed with a subxiphoid pericardial window (SPW) at between 24 and 48h post admission. Ten of these 19 patients (52%) were positive for a haemopericardium. Only 4 of the 19 underwent a sternotomy and only two of these had cardiac injuries that had sealed. There were no deaths in this series. CONCLUSION: Patients with a penetrating chest injury with a pneumopericardium who are unstable require emergency surgery. A delayed tension pneumopericardium developed in 10% of patients who were initially stable. It is our recommendation that all stable patients with a pneumopericardium after penetrating chest trauma should undergo a SPW. A sternotomy is not required in stable patients. PMID- 24629699 TI - Synthesis, photophysical studies and 1O2 generation of carboxylate-terminated zinc phthalocyanine dendrimers. AB - Highly water-soluble dendrimers have been prepared consisting of a central zinc phthalocyanine moiety and dendritic wedges with terminal carboxylate groups. The biggest polyelectrolyte comprises 32 negative charges at the dendrimer surface. The photophysical studies reveal a strong correlation between the degree of dendritic environment, the extent of aggregation, and the ability to generate singlet oxygen in aqueous media. Compared to dendrimers having an axial derivatization the functionalization on the outer rim also significantly improves the phthalocyanine's ability to photosensitize singlet oxygen. PMID- 24629701 TI - Use of AUDIT-C as a tool to identify hazardous alcohol consumption in admitted trauma patients. AB - INTRODUCTION: Alcohol use is an important contributor to injuries. Simple bedside tools to identify trauma patients with potentially harmful drinking may assist in brief intervention efforts in clinical practice. The objective of the study was to determine and compare the accuracy of alcohol use disorders identification test (AUDIT) and an abbreviated version of this test, in the detection of hazardous drinking. METHODS: A cross-sectional study of a convenience sample of admitted trauma patients at a single Australian major trauma centre. Eligible patients completed the AUDIT. AUDIT survey responses were scored in two ways, using the full form scale and secondly an abbreviated (AUDIT C) scale which uses only the first 3 questions. AUDIT and AUDIT-C scores were then evaluated with respect to the primary study measure; the detection of hazardous alcohol consumption based on a full alcohol consumption history. Sensitivities for each relevant score were calculated and receiver operator characteristic (ROC) curve analysis was used to determine test accuracy. RESULTS: During the study period, 523 trauma admissions were identified and of these 146 (28%) were screened. The optimum cut off scores for AUDIT and AUDIT-C were 8 and 5 respectively corresponding to sensitivities of 88% and 91% and both tests had excellent overall accuracy for the detection of hazardous alcohol consumption. There was no significant difference between AUDIT-C and AUDIT performance (p=0.395) (AUDIT-C AUROC 0.96 95%CI 0.93, 0.99). CONCLUSION: AUDIT-C appears to be a potentially useful screening tool for use trauma centres, but that further research with larger samples is required. PMID- 24629702 TI - A novel technique for accurate Poller (blocking) screw placement. AB - Achieving good results with intramedullary nailing of oblique long bone fractures at the metaphyseal-diaphyseal junction can be difficult. There is a strong tendency for axial displacement and an association with characteristic malalignment of the short fragment. Poller or blocking screws have been shown to be effective in aiding fracture reduction. While several papers describe methods for screw placement, these are confusing to understand, difficult to follow in clinical practice and not always applicable. Here we describe a new, simple, reproducible and easy to use method for ensuring accurate Poller screw placement, in order to maximise the benefits of their use and achieve good overall results. PMID- 24629703 TI - Angular malalignment as cause of limitation of forearm rotation: an analysis of prospectively collected data of both-bone forearm fractures in children. AB - INTRODUCTION: Although limitation of pronation/supination following both-bone forearm fractures in children is often attributed to an angular malunion, no clinical study has compared pronation/supination and angular malalignment of the same child by analysis of prospectively collected clinical data. AIM: The purpose of this trial is to explore whether limitation of pronation/supination can be predicted by the degree of angular malalignment in children who sustained a both bone forearm fracture. METHODS: In four Dutch hospitals, children aged <=16 years with a both-bone forearm fracture were prospectively followed up consecutive children for 6-9 months. At the final follow-up, pronation/supination and angular malunion on radiographs were determined. RESULTS: Between January 2006 and August 2010, a total of 410 children were prospectively followed up, of which 393 children were included for analysis in this study. The mean age of the children was 8.0 (+/-3.5) years, of which 63% were male and 40% fractured their dominant arm. The mean time to final examination was 219 (+/-51) days. Children with a metaphyseal both-bone fracture of the distal forearm with an angular malalignment of <=15 degrees had a 9-13% chance of developing a clinically relevant limitation (i.e., <50 degrees of pronation and/or supination), while children with an angular malalignment of >=16 degrees had a 60% chance. Children with diaphyseal both-bone forearm fractures with <=5 degrees of angular malalignment had a 13% chance of developing a clinically relevant limitation, which showed no significant increase with a further increase of angular malalignment. CONCLUSIONS: Children who sustained a both-bone forearm fracture localised in the distal metaphysis have a higher chance of developing a clinically relevant limitation of forearm rotation in case of a more severe angular malalignment, while children with a diaphyseal both-bone forearm fracture had a moderate chance of limitation, irrespective of the severity of the angular malalignment. PMID- 24629704 TI - The outcomes of peritendon tissue free-grafted on the tendon surface. AB - OBJECTIVE: The objective of this study is to observe the gross and histological changes of free-grafted peritendon tissue. METHODS: The incisions were made in the bilateral Achilles tendon sites in six healthy rabbits weighing 2.0-2.5kg. The peritendon tissue flaps of about 2.0cm*0.5cm size were harvested and free grafted into the contralateral donor sites. After 3 weeks, three animals were sacrificed, and after 6 weeks the remaining three animals were sacrificed. The peritendon tissue specimens were sampled for gross observation and histological observation. RESULTS: Gross observation after 3 weeks: the peritendon tissue became thick, there was tissue proliferation, and the deep surface was smooth. Histological observation after 3 weeks: inflammatory cells in the peritendon tissue were observed, many fibroblasts proliferated in the superficial surface, and some neovascularization was observed. Tissue growth could be seen in the suture site. Gross observation after 6 weeks: the peritendon tissue looked thick and the deep surface was smooth. Histological observation after 6 weeks: inflammatory cells in the peritendon tissue were significantly reduced and there were still more fibroblasts in the tissues. Neovascularization was obvious and the suture site was firmly healed. No signs of necrosis were found at the two time points, and the structure of the free-grafted peritendon tissue was almost the same as the structure of the peripheral tissue. CONCLUSION: The peritendon tissue can survive well after being free-grafted into the tendon surface and the structure shows no obvious changes. PMID- 24629705 TI - Volume of chronic subdural haematoma: is it one of the radiographic factors related to recurrence? AB - BACKGROUND: Recurrence of chronic subdural haematoma (CSDH) is a significant issue in neurosurgical practice, and to distinguish individuals at high risk is important. In this study, we aim to clarify the relationship between quantitative haematoma volume and recurrence of CSDH. METHODS: For this two-year retrospective study, 94 patients with CSDH were enrolled and all underwent burr-hole craniostomy with closed-system drainage. The volume of haematoma before surgery was quantitatively analysed by computed tomography (CT) of the brain. The patients were subdivided into 2 groups based on whether recurrence of CSDH was present or not. We investigated the intergroup differences in the volume of haematoma and other radiographic parameters. RESULTS: Recurrence of CSDH was identified in 13 of 94 patients (14%). Univariable analysis of CT features revealed significant differences in the volume of haematoma, bilateral cerebral convexity, and layering of the haematoma. To adjust for the confounding effect, these 3 parameters were entered into multivariable logistic regression analysis. Ultimately, neither the volume of haematoma (p=0.449) or bilateral cerebral convexity (p=0.123) was relevant in this model. Only the presence of layering of the haematoma was independently associated with recurrence of CSDH (p=0.009). CONCLUSION: The volume of CSDH is not related to recurrence in patients undergoing burr-hole craniostomy with closed-system drainage. Layering of the haematoma was the only independent risk factor on CT images for recurrence of CSDH in our series. PMID- 24629706 TI - Psychosocial care for seriously injured children and their families: a qualitative study among emergency department nurses and physicians. AB - BACKGROUND: Approximately one in five children who sustain a serious injury develops persistent stress symptoms. Emergency Department nurses and physicians have a pivotal role in psychosocial care for seriously injured children. However, little is known about staff's views on this role. OBJECTIVE: Our aim was to investigate Emergency Department staff's views on psychosocial care for seriously injured children. METHODS: We conducted semi-structured interviews with 20 nurses and physicians working in an Australian Paediatric Emergency Department. We used purposive sampling to obtain a variety of views. The interviews were transcribed verbatim and major themes were derived in line with the summative analysis method. We also mapped participants' strategies for child and family support on the eight principles of Psychological First Aid (PFA). RESULTS: Five overarching themes emerged: (1) staff find psychosocial issues important but focus on physical care; (2) staff are aware of individual differences but have contrasting views on vulnerability; (3) parents have a central role; (4) staff use a variety of psychosocial strategies to support children, based on instinct and experience but not training; and (5) staff have individually different wishes regarding staff- and self-care. Staff elaborated most on strategies related to the PFA elements 'contact and engagement', 'stabilization', 'connection with social supports' and least on 'informing about coping'. CONCLUSIONS: The strong notion of individual differences in views suggests a need for training in psychosocial care for injured children and their families. In addition, further research on paediatric traumatic stress and psychosocial care in the ED will help to overcome the current paucity of the literature. Finally, a system of peer support may accommodate wishes regarding staff care. PMID- 24629708 TI - Is this the beginning of the marathon for cartilage regeneration in osteoarthritis? PMID- 24629707 TI - Femoral malrotation after intramedullary nailing in obese versus non-obese patients. AB - OBJECTIVE: Intramedullary nailing (IMN) of obese patients with femoral fractures can be difficult due to soft tissue considerations and overall body habitus. Complications including malrotation can occur and have significant impact on postoperative function. The purpose of this study was to evaluate femoral rotation after intramedullary nailing of obese and non-obese patients to see if there was a difference in rotation, complications and any risk factors for malrotation. MATERIALS AND METHODS: Between 2000 and 2009, 417 consecutive patients with femur fractures treated with IM nail at Level I trauma and tertiary referral center. Of these, 335 with postoperative computed tomography (CT) scanogram of the bilateral lower extremities were included in this study. Baseline demographic, perioperative and postoperative femoral version calculations were included in the dataset. Statistical analysis included chi squared test for categorical data, t-test for continuous data, and univariate and multivariate regression analysis. Significance was set at p<0.05. RESULTS: Of the 417 patients with femur fractures between 2000 and 2009, 335 met criteria for this study. There were 111 patients with a BMI <25, 129 with BMI 25-29.9, and 95 patients with a BMI >30. When BMI was categorised into 3 groups (<25, 25-29.9, or 30+), none of these groups were predictive of version in univariate or multivariate regressions. Among only obese patients (BMI 30+), BMI of 35+ was not a significant predictor of version when compared to BMI 30-34.9. There were no significant differences in femoral version based on entry point (antegrade vs. retrograde) in any BMI category. There were also no significant difference between groups of patients with a DFV of >15 (p=0.212). CONCLUSIONS: Based on this study, BMI did not have an effect on postoperative difference in femoral version. In fact, in our multivariate regression analysis, BMI of over 30 was actually predictive of significantly lower difference in femoral version. While other studies have documented the intraoperative difficulties encountered with obese patients with femur fractures, the outcome of femoral rotation is not affected by an increasing BMI. PMID- 24629709 TI - Non-enzymatic dissociation of human mesenchymal stromal cells improves chemokine dependent migration and maintains immunosuppressive function. AB - BACKGROUND AIMS: Human bone marrow-derived mesenchymal stromal cells (MSC) can suppress inflammation; therefore their therapeutic potential is being explored in clinical trials. Poor engraftment of infused MSC limits their therapeutic utility; this may be caused by MSC processing before infusion, in particular the method of their detachment from culture. METHODS: Enzymatic methods of detaching MSC (Accutase and TrypLE) were compared with non-enzymatic methods (Cell Dissociation Buffer [CDB], ethylenediamine tetra-acetic acid and scraping) for their effect on MSC viability, chemokine receptor expression, multi-potency, immunomodulation and chemokine-dependent migration. RESULTS: TrypLE detachment preserved MSC viability and tri-lineage potential compared with non-enzymatic methods; however, this resulted in near complete loss of surface chemokine receptor expression. Of the non-enzymatic methods, CDB detachment preserved the highest viability while retaining significant tri-lineage differentiation potential. Once re-plated, CDB-detached MSC regained their original morphology and reached confluence, unlike with the use of other non-enzymatic methods. Viability was significantly reduced with the use of ethylenediamine tetra-acetic acid and further reduced with the use of cell scraping. Addition of 1% serum during CDB detachment led to higher MSC numbers entering autophagy and increased MSC recovery after re-plating. TrypLE and CDB-detached MSC suppressed CD3(+)CD4(+)CD25(-) T-cell proliferation, although TrypLE-detached MSC exhibited superior suppression at 1:20 ratio. CDB detachment retained surface chemokine receptor expression and consequently increased migration to CCL22, CXCL12 and CCL4, in contrast with TrypLE-detached MSC. CONCLUSIONS: This study demonstrates that non-enzymatic detachment of MSC with the use of CDB minimizes the negative impact on cell viability, multipotency and immunomodulation while retaining chemokine-dependent migration, which may be of importance in MSC delivery and engraftment in sites of injury. PMID- 24629710 TI - The road not taken: social vs. private comparisons in Asperger's syndrome and high functioning autism. AB - Evaluation of the outcomes of our decisions may instigate comparisons of our actual outcome with those of others (social comparisons) or comparisons with alternative outcomes of choices not made (private comparisons). Previous research has suggested a deficit in attention to social information among individuals with autism spectrum disorders. As social comparison involves the processing of social information, here we investigated the orientation towards and sensitivity to social vs. private comparisons in individuals with autism spectrum disorders. We compared the sensitivity to social vs. private comparisons among individuals diagnosed with Asperger's Syndrome (AS) or High Functioning Autism, using a task that entailed monetary rewards. Results showed that while individuals with AS generally demonstrate comparable sensitivity to absolute and relative rewards, they show less sensitivity to social comparison as compared to controls. Furthermore, they are characterized by a higher sensitivity to private rather than social comparison. These results suggest that low sensitivity to social comparisons is an important factor to consider in autism spectrum disorders. PMID- 24629711 TI - Abnormal dynamics of language in schizophrenia. AB - Language could be conceptualized as a dynamic system that includes multiple interactive levels (sub-lexical, lexical, sentence, and discourse) and components (phonology, semantics, and syntax). In schizophrenia, abnormalities are observed at all language elements (levels and components) but the dynamic between these elements remains unclear. We hypothesize that the dynamics between language elements in schizophrenia is abnormal and explore how this dynamic is altered. We, first, investigated language elements with comparable procedures in patients and healthy controls. Second, using measures of reaction time, we performed multiple linear regression analyses to evaluate the inter-relationships among language elements and the effect of group on these relationships. Patients significantly differed from controls with respect to sub-lexical/lexical, lexical/sentence, and sentence/discourse regression coefficients. The intercepts of the regression slopes increased in the same order above (from lower to higher levels) in patients but not in controls. Regression coefficients between syntax and both sentence level and discourse level semantics did not differentiate patients from controls. This study indicates that the dynamics between language elements is abnormal in schizophrenia. In patients, top-down flow of linguistic information might be reduced, and the relationship between phonology and semantics but not between syntax and semantics appears to be altered. PMID- 24629712 TI - Clinical differences between cocaine-induced psychotic disorder and psychotic symptoms in cocaine-dependent patients. AB - The aim of this study is to compare the clinical characteristics of three groups of patients in treatment for cocaine dependence: patients without any psychotic symptoms (NS), patients with transient psychotic symptoms (PS) and patients with cocaine-induced psychotic disorder (CIPD). An observational and retrospective study of 150 cocaine-dependent patients undergoing treatment in the Drug Unit of the Psychiatry Department of University Hospital Vall d'Hebron in Barcelona (Spain) using these three groups, NS, PS and CIPD, was performed. All patients were evaluated with the PRISM interview. ANOVA, chi2 tests and multivariate multinomial regression analysis were used to perform statistical analyses. Seven patients with a primary psychotic disorder were discharged. Forty-six patients (32.1%) did not report any psychotic symptoms. Ninety-seven patients (67.9%) presented with a history of any cocaine-induced psychotic symptom and were considered as the cocaine-induced psychotic (CIP) group. Among them, 39 (27.3%) were included in the PS group and 58 (40.6%) were included in the CIPD group. A history of imprisonment was found significantly more frequently in the PS group than in the NS group. The distribution of age at onset of dependence, lifetime cannabis abuse or dependence and imprisonment were significantly different between the NS and CIPD groups. We conclude that in cocaine-dependent patients, clinicians should be advised about the risk of development of psychotic symptoms. The presence of some psychotic symptoms could increase the potential risks of disturbing behaviours. PMID- 24629713 TI - Commentary to 'Practice changes in childhood surgery for ambiguous genitalia?'. PMID- 24629714 TI - Ambivalent childbearing motivations: predicting condom use by urban, African American, female youth. AB - STUDY OBJECTIVE: To describe a model of how interactions between positive and negative childbearing motivations affect the use of condoms for contraceptive purposes and test hypotheses based on that model. DESIGN: Psychological and behavioral data were collected during a study that sampled randomly selected census block groups. SETTING: Respondents were household residents of Baltimore City, Maryland, between 2004 and 2007. PARTICIPANTS: English-speaking, sexually active African-American women between the ages of 15 and 24 who had completed a reliable and valid measure of both positive and negative childbearing motivations. MAIN OUTCOME MEASURES: Regularity of condom use during the past 90 days and contraceptive method at last sex. RESULTS: The results of regression analyses with the total sample confirm that antinatal childbearing motivations predicted more regular condom use and that ambivalent, pronatal, and indifferent childbearing motivations acting together each predicted less regular condom use. The results with a subgroup using condom and not hormonal contraception confirmed that ambivalent childbearing motivation alone predicted less regular condom use. CONCLUSIONS: Our findings demonstrate how positive and negative childbearing motivations interact to create a dynamic effect on contraceptive behavior that transcends the effect of either positive or negative motivation acting alone. We conclude that the dynamics of these motivational interactions have important implications for further research on contraceptive decision-making, for augmenting the understanding of caretakers and providers, and for the formation of new policies that focus on the prevention of unplanned pregnancy among youth. PMID- 24629715 TI - Giant vulvar lipoma in an adolescent girl: a case study and literature review. AB - A rare case of a giant vulvar lipoma that developed in an adolescent is presented. A review of the world literature of 15 cases that occurred prior to adulthood confirmed that they tend to occur on the right side of the vulva. PMID- 24629716 TI - Pregnancy intentions among expectant adolescent couples. AB - STUDY OBJECTIVE: To examine the self-reported pregnancy intentions of the male partners of expectant adolescent mothers, the accuracy of adolescent mothers' perceptions of their partner's pregnancy intentions, and the concordance between young mothers' and fathers' pregnancy intentions. DESIGN: This cross-sectional pilot study collected interview data from expectant adolescent mothers and their male partners. SETTING: Data were collected in participants' homes. PARTICIPANTS: 35 expectant couples were interviewed separately. Most participants were African American (89% of mothers, 74% of fathers). 69% of mothers were 17-18 years old, and half of the fathers were >=19. MAIN OUTCOME MEASURES: Parents responded to survey questions adapted from the Center for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System Questionnaire. RESULTS: 44% of fathers reported wanting their partner to get pregnant. Another 15% were ambivalent. A kappa statistic of 0.12 (P = .33) indicated very little "accuracy" of mothers' perceptions of their partners' pregnancy intentions. Further, there was low concordance between the pregnancy intentions of mothers and fathers. Young fathers who wanted or were ambivalent about pregnancy were significantly more likely to use no contraception or withdrawal. CONCLUSION: For a notable number of minority couples, adolescent mothers do not have an accurate perception of their partners' pregnancy intentions and use contraceptive methods that are not within their control. These findings indicate that teen pregnancy prevention interventions must target young males in addition to females and sexually active adolescents should be encouraged to discuss pregnancy intentions with each other. PMID- 24629717 TI - Loss of morphine reward and dependence in mice lacking G protein-coupled receptor kinase 5. AB - BACKGROUND: The clinical benefits of opioid drugs are counteracted by the development of tolerance and addiction. We provide in vivo evidence for the involvement of G protein-coupled receptor kinases (GRKs) in opioid dependence in addition to their roles in agonist-selective mu-opioid receptor (MOR) phosphorylation. METHODS: In vivo MOR phosphorylation was examined by immunoprecipitation and nanoflow liquid chromatography-tandem mass spectrometry analysis. Using the hot-plate and conditioned place preference test, we investigated opioid-related antinociception and reward effects in mice lacking GRK3 or GRK5. RESULTS: Etonitazene and fentanyl stimulated the in vivo phosphorylation of multiple carboxyl-terminal phosphate acceptor sites, including threonine 370, serine 375, and threonine 379, which was predominantly mediated by GRK3. By contrast, morphine promoted a selective phosphorylation of serine 375 that was predominantly mediated by GRK5. In contrast to GRK3 knockout mice, GRK5 knockout mice exhibited reduced antinociceptive responses after morphine administration and developed morphine tolerance similar to wild-type mice but fewer signs of physical dependence. Also, morphine was ineffective in inducing conditioned place preference in GRK5 knockout mice, whereas cocaine conditioned place preference was retained. However, the reward properties of morphine were evident in knock-in mice expressing a phosphorylation-deficient S375A mutation of the MOR. CONCLUSIONS: These findings show for the first time that MOR phosphorylation is regulated by agonist-selective recruitment of distinct GRK isoforms that influence different opioid-related behaviors. Modulation of GRK5 function could serve as a new approach for preventing addiction to opioids, while maintaining the analgesic properties of opioid drugs at an effective level. PMID- 24629718 TI - The effects of mindfulness eating and yoga exercise on blood sugar levels of pregnant women with gestational diabetes mellitus. AB - AIM: This randomized controlled trial was carried out to investigate the effect of mindfulness eating and yoga exercise on blood sugar levels among pregnant Thai women with GDM. BACKGROUND: Interventions promoting achievement of good glycemic control result in desired pregnancy outcomes. Little is known about the health benefits of mindfulness eating and yoga exercise on blood sugar levels among pregnant with GDM. METHODS: A randomized controlled trial was carried out. Main outcome measures were capillary fasting plasma glucose, 2-h postprandial blood glucose, and hemoglobin A1c. RESULTS: The intervention group showed significantly reduced fasting plasma glucose, 2-h postprandial blood glucose, and glycosylated hemoglobin (HbA1c) in the intervention group (p<0.05). CONCLUSIONS: Mindfulness eating and yoga exercise had health benefits on glycemic control in pregnant women with GDM. It should be recommended in clinical and community health services. PMID- 24629719 TI - What is punctuated equilibrium? What is macroevolution? A response to Pennell et al. PMID- 24629720 TI - Artificial environments and the study of 'adaptive' personalities. AB - Research on the adaptive nature of animal personality is blooming. We detail here the common practice of conducting such studies in the laboratory, inherent shortcomings of this approach when addressing ecological or evolutionary questions, and alternative strategies that might be applied to firmly place personality research in evolutionary biology. PMID- 24629721 TI - Tropical grassy biomes: misunderstood, neglected, and under threat. AB - Tropical grassy biomes (TGBs) are globally extensive, provide critical ecosystem services, and influence the earth-atmosphere system. Yet, globally applied biome definitions ignore vegetation characteristics that are critical to their functioning and evolutionary history. Hence, TGB identification is inconsistent and misinterprets the ecological processes governing vegetation structure, with cascading negative consequences for biodiversity. Here, we discuss threats linked to the definition of TGB, the Clean Development Mechanism (CDM) and Reducing Emissions from Deforestation and Forest Degradation schemes (REDD+), and enhanced atmospheric CO2, which may facilitate future state shifts. TGB degradation is insidious and less visible than in forested biomes. With human reliance on TGBs and their propensity for woody change, ecology and evolutionary history are fundamental to not only the identification of TGBs, but also their management for future persistence. PMID- 24629722 TI - [Prophylaxis for stress ulcer bleeding in the intensive care unit]. AB - BACKGROUND: The critically ill patient can develop gastric erosions and, on occasion, stress ulcers with severe gastrointestinal bleeding that can be fatal. AIMS: The purpose of this review was to provide current information on the pathophysiology, risk factors, and prophylaxis of digestive tract bleeding from stress ulcers in the intensive care unit. METHODS: We identified articles through a PubMed search, covering the years 1970 to 2013. The most relevant articles were selected using the search phrases "stress ulcer", "stress ulcer bleeding prophylaxis", and "stress-related mucosal bleeding" in combination with "intensive care unit". RESULTS: The incidence of clinically significant bleeding has decreased dramatically since 1980. The most important risk factors are respiratory failure and coagulopathy. Proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) are used in stress ulcer bleeding prophylaxis. Both drugs have been shown to be superior to placebo in reducing the risk for gastrointestinal bleeding and PPIs are at least as effective as H2RAs. Early enteral feeding has been shown to reduce the risk for stress ulcer bleeding, albeit in retrospective studies. CONCLUSIONS: Admittance to the intensive care unit in itself does not justify prophylaxis. PPIs are at least as effective as H2RAs. We should individualize the treatment of each patient in the intensive care unit, determining risk and evaluating the need to begin prophylaxis. PMID- 24629723 TI - [Panenteric melanosis secondary to melanoma of the rectum: a case report]. PMID- 24629724 TI - ["Neurochirurgie": the confidence pact]. PMID- 24629725 TI - [Health care circuit for patients with soft tissue sarcomas of the extremities. A tortuous and slow road to referral units]. AB - OBJECTIVE: To analyse the waiting periods elapsed since soft tissue sarcomas become symptomatic until their specific treatment in our unit, and to determine new strategies for the improvement of referral circuits. MATERIAL AND METHODS: This is an ambispective observational study of a cohort of 61 patients, with previously untreated soft tissue sarcomas, obtained from our Musculoskeletal Tumors Database. Several variables related to the patient, tumour, and health care circuit were analysed, as well as the different periods between the initial symptoms of the disease and the first consultation in our unit. The significance level was alpha=0.05. RESULTS: The mean size of the sarcomas was 11.3 cm. Thirty six patients (59%) followed the usual circuit of the National Health System in Spain. The time elapsed since the disease became symptomatic until the first medical consultation was greater than 9.5 months, and nearly another 8.5 months to the consultation in our specific unit. Statistically significant relationships were found between the independent and dependent variables. DISCUSSION: The study shows that the care of patients with soft tissue sarcomas in our environment is far away from the times of care in our neighbouring countries. CONCLUSIONS: It is essential to make the population and health professionals aware of this disease, as well as to remember that there is a referral circuit that must be used. PMID- 24629726 TI - Editorial overview: Lymphocyte development. PMID- 24629727 TI - Editorial overview: Tumour immunology: New frontiers in cancer immunotherapy. PMID- 24629728 TI - The costs of action: Comment on "Action semantics: A unifying conceptual framework for the selective use of multimodal and modality-specific object knowledge" by Michiel van Elk, Hein van Schie and Harold Bekkering. PMID- 24629729 TI - One way, but diverse methods for fungi and yeast transformation: Comment on "Physical methods for genetic transformation of fungi and yeast" by Rivera et al. PMID- 24629730 TI - [Inclusion of the elderly in clinical trials: a need and an obligation]. PMID- 24629731 TI - [Increased complement levels in cryoglobulinemia as a marker of chronic lymphocytic leukemia progression in a nonagenarian patient]. PMID- 24629732 TI - [Drug prescription profile in patients with advanced chronic diseases]. AB - OBJECTIVES: To analyze the prescription profile and the factors associated with multiple medications (polypharmacy) and non-adherence in patients with advanced chronic diseases. MATERIAL AND METHODS: Longitudinal cross-sectional study including 41 Spanish hospitals (PALIAR project). Polypharmacy was defined as a prescribed treatment with five or more drugs, and excessive polypharmacy when the number was ten or more. The adherence was evaluated using a questionnaire completed by the patients or their caregivers. Description of drug prescription profile and analysis was performed on the risk factors associated with multiple medications and non-adherence. RESULTS: The study included 1847 patients, and 1778 (96.2%) completed the questionnaire. Mean age was 78.74+/-10 years. Antihypertensives (82.6%), gastroprotectives (73.8%), anti platelets/anticoagulants (70.3%), and psychotropic drugs (51.8%) were the most frequently prescribed drugs. Prevalence of polypharmacy/excessive polypharmacy was 86.2%/31.3%, with a mean of 8+/-3.5 drugs per patient. Errors in treatment compliance were detected in 48.2% of patients, but 38.5% and 9.6% referred to an occasional or almost daily failure, respectively. Factors associated with non adherence were: to be a patient with multiple diseases, cognitive impairment, three or more 3 hospital admissions in the last three months, and having polypharmacy. Factors associated with polypharmacy were: to be a patient with multiple diseases, an ECOG score <3, age <85 years, and 3 or more hospital admissions. Factors associated with excessive polypharmacy were: to be a patient with multiple diseases and previous frequent hospital admissions. CONCLUSIONS: The prevalence of polypharmacy in patients with advanced chronic diseases is high, and mistakes in treatment compliance are frequent. Further studies with better defined objectives and more specific therapeutic limits are needed. PMID- 24629734 TI - Reduced polymerization stress of MAPO-containing resin composites with increased curing speed, degree of conversion and mechanical properties. AB - OBJECTIVES: The degree and rate of photopolymerization in resin-based dental composites will significantly affect polymer network formation and resultant material properties that may determine their clinical success. This study investigates the mechanical properties, the generation of stress from polymerization, tooth cusp deflection and marginal integrity of experimental resin composites that contain different photoinitiators. METHODS: Experimental light-activated resin composites (60vol% particulate filled in 50/50mass% bis GMA/TEGDMA) were formulated using a monoacylphosphine oxide (MAPO) photoinitiator and compared with a conventional camphoroquinone (CQ)-based system. Similar radiant exposure was used (18Jcm(-2)) for polymerization of each material although the curing protocol was varied (400mWcm(-2) for 45s, 1500mWcm(-2) for 12s and 3000mWcm(-2) for 6s). Degree and rate of polymerization was calculated in real-time by near infrared spectroscopy and the generation of stress throughout polymerization measured using a cantilever beam method. Flexural strength and modulus were acquired by three-point bend tests. Standardized cavities in extract pre-molar teeth were restored with each material, the total cuspal deflection measured and post-placement marginal integrity between the tooth and restoration recorded. RESULTS: Generally, MAPO- exhibited a significantly higher degree of conversion (72+/-0.8 to 82+/-0.5%) compared with CQ-based materials (39+/-0.7 to 65+/-1.6%) regardless of curing protocol (p<0.05) and MAPO-based materials exhibited less difference in conversion between curing protocols. CQ-based materials exhibited between ~85 and 95% of the maximum rate of polymerization at <15% conversion, whereas MAPO-based RBCs did not approach the maximum rate until >50% conversion. Higher irradiance polymerization had a significant deleterious effect on the mechanical properties of CQ-based materials (p<0.05) whereas MAPO based materials exhibited increased strength and modulus and were less affected by the curing method. Total cuspal deflection in restored extracted teeth was higher for CQ- compared with MAPO-based materials cured at the lowest irradiance curing protocol (12.9+/-4.0 and 8.3+/-1.5MUm) and similar at 3000mWcm(-1) for 6s (10.1+/-3.5 and 9.0+/-1.5MUm). A significant decrease in marginal integrity was observed for CQ-based RBCs cured at high irradiance for short exposure time compared with that of the MAPO-based RBC cured using a similar protocol (p=0.037). SIGNIFICANCE: Polymer network formation dictates the final properties of the set composite and the use MAPO photoinitiators may provide an effective restorative material that exhibits higher curing speeds, increased degree of conversion, strength and modulus without compromise in terms of polymerization stress and marginal integrity between tooth and restoration. PMID- 24629733 TI - Psychiatric symptoms in boys with fragile X syndrome: a comparison with nonsyndromic autism spectrum disorder. AB - In the present study, we examined the profile of psychiatric symptoms in boys with fragile X syndrome (FXS) using a parent report instrument. In addition, by comparing boys with FXS to boys with nonsyndromic autism spectrum disorder (ASD) utilizing multiple matching strategies, we examined between-group differences in the types of psychiatric symptoms observed and in the strength of their concurrent associations. Across all matching strategies, symptoms of manic/hyperactive behaviors and general anxiety were more frequently reported for boys with FXS than for boys with nonsyndromic ASD. Results also indicated a positive association between social avoidance and general anxiety in FXS that was stronger than that observed in nonsyndromic ASD across all matching strategies. Theoretical and treatment implications are discussed. PMID- 24629735 TI - Rheological properties of resin composites according to variations in composition and temperature. AB - OBJECTIVE: To study the effect of compositional variables and temperature (25 degrees C and 37 degrees C) on the rheological properties of contemporary resin composites. METHODS: Fourteen commercial resin composites with different resin matrices of Bis-GMA and TEGDMA, different filler loading (41-65, v/v) and particle sizes (ranging 5nm to 20MUm) were studied using a parallel plate rheometer. Shear sweep measurements were made to determine each composite's viscosity over the angular frequency range of omega=10(-4)-10(2)rad/s. Data were analyzed using one way ANOVA, Bonferroni post hoc and t-independent tests (p<0.05). RESULTS: All composites exhibited viscosity reducing with shear rate (pseudoplasticity). Viscosity averages were calculated over the shear rate range. These viscosities increased as the percentage of filler loading (by volume) increased ranging between 0.05-349.33kPas at 25 degrees C and 0.03-132.00kPas at 37 degrees C. Filtek Supreme XTE exhibited the highest viscosity at both temperatures (p<0.05). Filtek Bulk Fill on the other hand, showed the lowest viscosity at both temperatures (p<0.05). Viscosity significantly decreased with the increase in the temperatures for all materials (p<0.05). The reduction ranged from 40.8% (for Venus Diamond Flow) to 92.2% (for Spectrum TPH3). SIGNIFICANCES: There was a considerable variation in the resin composite viscosities measured at 25 degrees C as an average value for shear-rate sweep. The factor between the least and highest viscosities was about 7000. The formulation differences that led to such a great variation were primarily: (i) volume fraction of fillers and (ii) particle size, the latter influencing total particle surface area. Rheological properties such as viscosity are key parameters influencing perceived differences in handling behavior of resin composites. PMID- 24629736 TI - Intranasal glucocorticosteroids - not only in allergic rhinitis In the 40th anniversary of intranasal glucocorticosteroids' introduction. AB - It has been 40 years since Niels Mygind's publication in British Medical Journal on intranasal application of beclomethasone dipropionate aerosol in allergic rhinitis (AR). Since then a new era in treatment of allergic and nonallergic upper airway diseases began. This publication presents current concepts on application of intranasal glucocorticosteroids (inGCS) in treatment of upper airway diseases and in particular of AR and rhinosinusitis. Nonquestionable advantage of inGCS is their strong anti-inflammatory local action with little impact on general health responsible for few and benign side effects. Main way of action of glucocorticosteroids is connected with binding to the intracellular glucocorticosteroid receptor and its impact on nuclear cytoplasmic transcriptional factors. Glucocorticosteroids suppress gene expression of factors responsible for generating and supporting inflammatory processes, proinflammatory cytokines and chemokines production, and adhesive molecules expression. It appears that glucocorticosteroids have also other mechanisms of action, non involving intracellular receptors, leading to inhibition of early and late phase of allergic reaction. At the moment the following glucocorticosteroids are registered in Poland: beclomethasone, budesonide, fluticasone propionate, fluticasone furoate, and mometasone furoate. Furoates earn special attention as their lateral furoate ester chain makes the molecules highly lipophilic, and hence easily absorbed by nasal mucous membranes, epithelium and cell membrane phospholipids. This minimizes their general action and maximizes local action. According to current state of knowledge topical glucocorticosteroids are used in the following upper airway diseases with different inflammatory mechanisms: AR, non-AR, particularly NARES, acute rhinosinusitis, chronic rhinosinusitis with and without nasal polyps, adenoid hypertrophy and rhinitis in bronchial asthma. PMID- 24629737 TI - [Treatment of lip cancer, material from the Department of Otolaryngology and Laryngological Oncology, Medical College of Bydgoszcz, Nicolaus Copernicus University, Torun]. AB - The subject of this study is methods and results of treatment of 21 cases of lip cancer between 2007 and 2012, which included 15 men and 6 women, aged 48-63. In 18 cases it was squamous cell carcinoma, in other 3 basocellulare carcinoma. Of the hospitalized patients the following clinical stages were found: T1 - five, T2 - five, T3 - seven, T4 - four. We operated with several techniques, we performed: V-incision and surgery according to the Webster - one patient, Rutkowski - four, Estlander - four, Karpandzic - three; in the treatment of cancer of upper lip the frontal flap was used. Fourteen patients underwent selective or modified lymph node operation. Five patients appeared local recurrence, 3 of them died due to metastases to multiply organs. Six operated patients did not continue oncological treatment, their subsequent fate is unknown. The remaining 10 patients remained under observation. The results indicate the need of extensive resection of the limph node in case of recurrence and the necessity of implementing selective or radical nodal surgery in the early stages of cancer. PMID- 24629738 TI - [Quality of life patients with sudden sensorineural hearing loss]. AB - AIM: The aim of this study was the assessment of the quality of life of patients suffering from SSNHL and treated in the Otolaryngology Ward of Regional Specialized Hospital in Slupsk between 2001 and 2010, who were interviewed at least one year after the end of treatment. MATERIAL AND METHODS: A test examination was carried out in the period between 1 September 2011 and 31 March 2012 in the group of patients previously treated for SSNHL in the Otolaryngology Ward of Regional Specialized Hospital in Slupsk. Sixty-one patients responded to an invitation in writing. Quality of life was measured using following questionnaires: WHOQOL-Bref and Cantril's ladder (questionnaire). RESULTS: A test carried out using a Cantril's questionnaire showed that the respondents assessed their quality of life as higher before they fell ill, compared to the period directly after they fell ill, in hope of improvement of their well being, although this hope was not as high as it was before they fell ill. These differences were statistically significant. As it was indicated by WHOQOL-Bref questionnaire, the condition did not influence the quality of life of the patients, however the patients reported a higher quality of life, when compared to the patients who did not observe hearing improvement (these differences were noticeable but considered statistically insignificant). CONCLUSIONS: The indicated ambiguous influence of the treatment of patients suffering from SSNHL on their quality of life demonstrates the need to continue such research. PMID- 24629739 TI - Expression of Toll-like receptors on peripheral blood white cells in acute otitis media. AB - OBJECTIVE: From 10 to 15% of children suffer from recurrent acute otitis media (AOM). An association between polymorphism in TLRs and their co-receptor CD14 with otitis media proneness has been described in children. Moreover, the experiments on animal models have shown that TLRs and their signaling molecules are critical for timely resolution of bacterial otitis. AIM: The aim of this study was to determine the expression of TLR1, TLR2 and TLR4 on lymphocytes, monocytes and granulocytes in peripheral blood in children with recurrent or persistent AOM. METHODS: The study was performed on a group of 25 children hospitalized for recurrent AOM, failures of previous treatments and/or acute mastoiditis. The results were compared to the control group of healthy children at the same age. The expression of TLRs on peripheral blood white cells was measured by flow cytometric analysis. The results were expressed as mean fluorescence intensity (MFI). The statistical analysis was performed using the Mann-Whitney U test. RESULTS: The highest expression of TLR was found on monocytes, the lowest on lymphocytes in both groups of children (AOM and the control one). The expression of TLR1 was the lowest and expression of TLR4 was the highest on all examined cells. The expression of all examined TLRs on monocytes was significantly higher in the AOM group. CONCLUSIONS: Peripheral blood monocytes are characterized by increased expression of TLRs in the course of recurrent AOM. PMID- 24629741 TI - [The importance of Halmagyi-Curthoys test in standard otoneurological diagnosis of patients with vestibular disorders]. AB - THE AIM: This given work is dedicated to examine the correlation of results of the ambulant screening vHIT test conducted by applying ICS Impulse device, with results of standard appliance otoneurological videonystagmography (VNG) testing. Comparison of given results will provide assessment of vHIT test effectiveness for otoneurological diagnosis of patients suffering giddiness or any other equilibrium system disorder. REFERENCE AND METHOD: Diagnosis was reached with 20 patients suffering vestibular disorders with no specific ailment location. From overall VNG test there was a caloric testing extracted, containing assessment of canal paresis and directional preponderance. Numerical values of these parameters were compared to vHIT test result - the indicator of "gain" eye-ball movement imaging head move, to be specific. RESULTS: Conducted examinations did not reveal any significant correlation between VNG and vHIT parameters however it is need to be emphasized here, that most of the considered cases were not affected but any defect of vestibular canal receptor. Nevertheless, unsettled values of "gain" indicator may signify that vHIT regardless of ailments location is defected. CONCLUSION: vHIT test with its quantitative analysis may in the future become indicator of auricular disorders. PMID- 24629740 TI - Unilateral pathological lesions of paranasal sinuses removed by endoscopic surgery. AB - INTRODUCTION: The aim of this study was to analyze the incidence and nature of unilateral pathological lesions of paranasal sinuses in patients who had endoscopic sinus surgery performed in ENT. MATERIALS AND METHODS: In the years 2006-2011 endoscopic sinus surgery for unilateral pathological lesions of paranasal sinuses was performed in 1847 patients (838 women and 1009 men). The enrollment of patients was based on the findings of otolaryngological clinical and subjective examinations, assessment of the paranasal sinuses on three dimensional CT scans, and laboratory examinations. Based on the analysis of medical history data, including gender, age, the type of surgical procedure performed, and histopathological findings the cases were finally analyzed. RESULTS: Pathological lesions of the paranasal sinuses were localized on the left side in 132 (57%) patients, and on the right side in 100 (43%) patients. Of the 232 patients with unilateral pathological changes, 41.8% subjects underwent endoscopic sinus surgery for polypotic changes in the ethmoid and maxillary sinuses; 28.4% for the maxillary sinus; 10.8% for the ethmoid, maxillary and frontal sinuses; and 8.6% patients for all paranasal sinuses on one side. The number of operations of only one sinus was considerably lower: sphenoid sinus, 4.7%; ethmoid sinus, 2.2%; and frontal sinus, 1.7% patients. The histopathological analysis of unilateral pathological lesions removed by endoscopic surgery showed chronic paranasal sinusitis with polyps in 56.5% patients; chronic paranasal sinusitis in 22.8% patients; and maxillary sinus cyst was confirmed in 11.6% patients. In 5.1% patients inverted papilloma was diagnosed and in 2.2% patients the presence of osteoma was found. CONCLUSIONS: Unilateral paranasal pathological lesions, leaving aside rather typical maxillary sinus cysts, require a particularly thorough pre-operative diagnosis and a precise histopathological assessment. PMID- 24629742 TI - Neurofibroma of sinus maxillae. AB - Neurofibroma is a benign tumour composed from Schwann cells. Localization in sinus maxillea is very rare. Authors presenting case which was treatment in Maxillo-Facial Surgery Clinic in Wroclaw. PMID- 24629743 TI - [Acute isolated sphenoid sinusitis - report of 4 cases]. AB - INTRODUCTION: Isolated acute sphenoid sinusitis is an uncommon sinus infection, frequently misdiagnosed and not usually considered in the differential diagnosis of acute severe headache, with the potential of serious neurologic complications. AIM: Describe four patients with acute sphenoid sinusitis who presented with acute onset of severe headache and consider the role of medical or surgical management. Two patients do not required surgical intervention and medical treatment was sufficient. One patient had sphenoidotomy due to meningitis. One patient was performed surgical intervention after fail of medical therapy. Acute isolated sphenoid sinusitis appears to be difficult to diagnose. It is important to be aware of acute sphenoid sinusitis in the setting of new onset severe headache, when imaging studies are unrevealing for intracranial pathology. Medical therapy focused on infection, inflammation, and obstruction may be adequate for resolution, but surgical intervention may be required in certain situations. PMID- 24629745 TI - [Robotic Surgery--improves the surgical treatment?]. PMID- 24629744 TI - Monitoring the response to treatment of acute heart failure patients by ultrasonographic inferior vena cava collapsibility index. AB - OBJECTIVE: Our aim was to determine if N-terminal pro-brain natriuretic peptide (NT-proBNP) or sonographic measurements of inferior vena caval (IVC) diameters and collapsibility index (IVC-CI) have a role in the monitoring of acute heart failure (AHF) therapy. METHODS: Inferior vena caval diameters of 50 healthy people (control group) were measured to determine the normal values of the IVC parameters. We then prospectively enrolled patients who were admitted to the emergency department (ED) with a primary diagnosis of AHF. At presentation, IVC diameters were measured during expiration and inspiration, and blood was drawn for NT-proBNP. We repeated the measurement of the IVC parameters and collected a second blood sample 12 hours after the therapy was administered. The data were analyzed in SPSS 15.0 (IBM, Armonk, NY) using the Student t test and Mann-Whitney U test. RESULTS: A total of 97 subjects were enrolled: 47 in the patient group and 50 in the control group. The mean IVC during expiration was 2.10 +/- 0.37 cm before and 1.57 +/- 0.24 cm after the therapy (P < .001). The mean IVC during inspiration was 1.63 +/- 0.40 cm before and 0.90 +/- 0.26 cm after the therapy (P < .001). The mean IVC-CI rose from 22.80% +/- 10.97% to 43.09% +/- 13.63% (P < .001). After the therapy, there was no difference between the IVC-CI of the patients and controls (P = .246). There was no significant change in the mean NT proBNP levels after the therapy. CONCLUSION: Inferior vena caval collapsibility index may be helpful in monitoring AHF patients' responses to therapy in the ED. PMID- 24629746 TI - [Statin therapy and the development of diabetes mellitus]. PMID- 24629747 TI - [The current and future use of robot-assisted surgery for gastro-oesophageal cancer]. AB - Minimally invasive oesophagectomy and gastrectomy are increasingly used procedures due to the known advantages, e.g. shorter hospital stay, less post operative pain and quicker recovery. The technical disadvantages of laparoscopy and thoracoscopy are, however, limited degrees of freedom and ergonomic discomfort for the surgeons, but these drawbacks are expected to be reduced by robot-assisted surgery with its seven degrees of freedom, 3D vision, tremor filtering and improved ergonomics. The purpose of the review is to describe the current and future use of robot-assisted surgery for gastro-oesophageal cancer. PMID- 24629748 TI - [Pathophysiological aspects of the diabetogenic effect of statins]. AB - Statins are potent inhibitors of cholesterol biosynthesis. Statins are beneficial in the primary and secondary prevention of coronary heart disease. Recent studies indicate that there is an association between statin use and the development of new-onset diabetes mellitus. This article reviews the patophysiological mechanisms by different statins to explain this association. PMID- 24629749 TI - [Statin treatment causes an increased risk of type 2 diabetes]. AB - Statins are important in the prevention of cardiovascular (CV) disease. However, they are associated with new-onset diabetes in a dose-dependent manner, particularly when the patient is already in risk of contracting diabetes. Meta analyses estimate that the risk is increased by 9%. In absolute terms one major CV event can be prevented per 155 patients treated with statins per year compared to one new case of diabetes per 498 patients treated per year. However, this new evidence should not affect the guidelines, where the goal of LDL-cholesterol concentration is < 1,8 mmol/l in patients with high CV risk. PMID- 24629750 TI - [Discontinuation syndrome after SSRI antidepressants]. AB - Discontinuation symptoms are described for almost all major groups of antidepressants. Crucial differences between discontinuation symptoms and symptoms after withdrawal of benzodiazepines are pointed out. Furthermore, it is important to discern from relapse of depression in order to manage the symptoms in primary care where the use of selective serotonin re-uptake inhibitors (SSRI) is substantial. In this paper we inform of the key symptoms after SSRI, present tools for understanding and recognizing the condition and suggest initiatives to manage it rationally. PMID- 24629751 TI - [Selective serotonin reuptake inhibitors and pregnancy]. AB - Selective serotonin reuptake inhibitors (SSRI) is the most common pharmacological treatment for depression during pregnancy. In recent years it has been under suspicion of causing spontaneous abortion, cardiac malformation, preterm birth, low birthweight, persistent pulmonary hypertension and neonatal withdrawal syndrome in the newborn exposed to SSRI. But the risks of SSRI side effects are low compared to background population. Non-pharmacological treatment methods should also be considered while treating pregnant women with depression. This paper describes the present state of knowledge about the potential complications associated with the use of SSRI during pregnancy and points at treatment recommendations to the physician. PMID- 24629752 TI - [Bladder pain and urinary tract symptoms as a consequence of ketamine abuse]. AB - A recent study has shown that ketamine has become popular among Danish clubgoers. The drug can induce psychedelic effects but it also has serious urological side effects, such as frequency and urgency in relation to voiding as well as pain from the bladder and haematuria. Ketamine can also induce histological bladder changes. Mild changes are reversible on cessation of ketamine abuse but long-term abuse can cause fibrosis of the bladder and may necessitate cystectomy. Therefore, physicians should ask young patients with bladder symptoms of unknown pathology about ketamine abuse. PMID- 24629753 TI - [Ketamine-induced urinary symptoms]. AB - Ketamine is gaining popularity among Danish drug users. We present the first three reports of ketamine-induced urinary symptoms in Denmark. The patients were 22-27 years old and were all referred to urological departments due to microscopic or macroscopic haematuria. In addition, all three patients reported pain from the penis and the gut, respectively. No specific pathology was found and all patients admitted to ketamine abuse. The cases illustrate that Danish physicians must be aware of potential side effects to ketamine abuse. PMID- 24629754 TI - [Uncertain evidence for effect of medication reviews of the prescriptions for elderly patients]. AB - Elderly patients are often prescribed several drugs, which might increase the risk of drug-related harms and the risk of not using the drugs as prescribed, both of which can result in increased costs. The literature supports the conclusions in a newly published Cocranereview on four randomized controlled trials (RCT) showing that it is uncertain whether medication reviews reduce mortality or hospital readmissions, but medication reviews seem to reduce emergency department contacts. However, further RCT are needed before implementing medication reviews. PMID- 24629755 TI - [Implementation of new guidelines for management of prelabour rupture of membranes did not have the desired effect]. AB - Many resources are used in developing guidelines for the treatment and handling of different diseases and clinical situations. It is important to evaluate the effect of these guidelines; are they being followed and do they have the desired impact on patient care? This report describes a quality control evaluation of whether the implementation of a new PROM (prelabour rupture of membranes) management guideline at Department Y at the Aarhus University Hospital had the wanted effect on the length of labour, use of prophylactic antibiotics, frequency of neonatal admission and neonatal infection. PMID- 24629756 TI - [HIV-positive individuals still have shorter life-expectancy than the general population]. AB - Despite more than 15 years of available highly active anti-retroviral therapy treatment, HIV-positive individuals still have a two-third shorter life expectancy in comparison with the general population. Six studies of individuals with HIV (n = 235,854) were analysed with 7,898 deaths, of which 90% had a known cause. 42% were still due to AIDS, followed by liver-related deaths (12%), non AIDS cancer (12%), cardiovascular disease (10%), suicide/overdose/accidents (8%), non-AIDS infection (7%) and other non-AIDS causes (11%). Recognising the causes of death among HIV-positive individuals may aid in reducing mortality. PMID- 24629757 TI - Antibiotics in respiratory tract infections in hospital pediatric emergency departments. AB - BACKGROUND: Respiratory tract infections are one of the most frequent problems in pediatric clinics and generate an elevated prescription of antibiotics. The aim of this study was to find out the standard of care practice about antibiotic use in these infections in a pediatric emergency department and to evaluate compliance with clinical guidelines. METHODS: A pediatric emergency department database was reviewed from July 2005 to October 2007 under the category "respiratory infection", including variables such as age, antibiotic prescription and compliance with current clinical recommendations. RESULTS: Out of the 23,114 reviewed reports, 32.7% (7,567) were upper respiratory tract infections (URTI) (cold, acute otitis media [AOM], sinusitis and tonsillopharyngitis) or lower respiratory tract infections (LRTI) (laryngitis, bronchitis, bronchiolitis and pneumonia). Children under the age of 2 were the most represented age group. Amongst URTI, rhinopharyngitis was the most frequent infection, while bronchitis was the most frequent among LRTI. Antibiotic therapy (mainly amoxicillin) was prescribed in 30.8% of URTI (5.7% rhinopharyngitis, 96.5% AOM, and 36.7% tonsillopharyngitis) and in 12.4% of LRTI. CONCLUSIONS: The percentage of respiratory tract infections was similar to previous studies and the antibiotic prescriptions followed current guidelines, except for cases diagnosed with AOM. Prescription compliance and clinical course of the cases should be monitored. PMID- 24629758 TI - Influence of migration on tuberculosis in a semi-urban area. AB - AIMS: To describe the epidemiology of tuberculosis and analyzing the differences among native and immigrant patients in Area III of the Region of Murcia. METHODS: Cohort study of tuberculosis cases reported to the Epidemiological Surveillance Service from 2004 to 2009. Data collection was performed through the System of Notification Diseases, reviewing clinical files and epidemiological surveys. RESULTS: One hundred sixty two cases were detected; 110 (67.9%) were immigrants, whose incidence rates ranged from 43.4 to 101.2 cases per 100,000 inhabitants. Ecuador (42.7%), Bolivia (30%) and Morocco (18.2%) were the main nationalities. Immigrants were younger than Spanish population (P<.001). The overall diagnostic delay was 50.5 days: 59.5 in Spanish and 47 in foreigners. Moroccans had higher proportions of extrapulmonary TB (P=.02). Mainly, immigrant population took treatment with four drugs (P<.001). Natives had better treatment adherence (P=.04). Spanish cases tuberculosis were associated with smoking (P<.001), the same as alcohol consumption (P=.01) and injection drug use (P<.001), nevertheless in the foreign-born population the most relevant risk factor was overcrowding (P<.001). CONCLUSIONS: The incidence tuberculosis rates are higher among immigrant population, whose the main risk factor is overcrowding. In contrast, Spanish cases are associated with toxic substances consumption and increasing age. PMID- 24629759 TI - Diffuse interstitial lung disease as a first manifestation of Waldenstrom's macroglobulinemia: case report and review of the literature. AB - Waldenstrom's macroglobulinemia (WM) is a lymphoid malignancy characterized by infiltration, mainly of the bone marrow and lymph nodes, by small mature lymphocytes showing plasmacytoid differentiation, associated with an IgM monoclonal band, and, in general, a low degree of aggressiveness. We present the first case reported in the Spanish literature of interstitial lung disease presenting as MW and we review the literature. PMID- 24629760 TI - Cervical bronchogenic cyst in adults. Case report and literature review. PMID- 24629761 TI - Positive positron emission tomography/computed tomography scan and multiple pulmonary nodules: an unusual diagnosis. PMID- 24629762 TI - Pulmonary arteriovenous malformations and embolic complications in patients with hereditary hemorrhagic telangiectasia. AB - Patients with hereditary hemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformation (PAVM) face higher risk of embolic complications. It is not clear whether poor outcomes are related to PAVM severity or pulmonary symptoms. Furthermore, there is currently no available data on HHT patients in Argentina. We conducted a cross sectional study in a teaching hospital in Buenos Aires, Argentina. We describe baseline characteristics of HHT and compare the prevalence of embolic complications in patients with significant PAVM compared to patients without significant PAVM. One hundred and eight consecutive patients were included. Significant PAVM was defined as: contrast echocardiography grade 2 or greater; bilateral PAVM or feeding artery bigger than 3mm; or previous PAVM treatment. Primary composite outcome was defined as: cerebrovascular accident, cerebral abscess or peripheral embolism. 20% of participants had embolic complications, the most frequent one was stroke. Embolic complications were associated with significant PAVM and respiratory symptoms. PMID- 24629763 TI - Geriatric assessment and prognostic factors of mortality in very elderly patients with community-acquired pneumonia. AB - INTRODUCTION: To assess the relationship between the parameters obtained in the geriatric assessment and mortality in elderly people with community-acquired pneumonia in an acute care geriatric unit. METHODS: Four hundred fifty-six patients (>=75years). VARIABLES: age, sex, referral source, background, consciousness level, heart rate, breathing rate, blood pressure, laboratory data, pleural effusion, multilobar infiltrates, functional status (activities of daily living) prior to admission [Lawton index (LI), Barthel index (BIp)] prior to and at admission (BIa), cognitive status [Pfeiffer test (PT)], comorbidity [Charlson index (ChI)] and nutrition (total protein, albumin). RESULTS: A hundred ten patients died (24.2%) during hospitalization. These patients were older (86.6+/ 6.4 vs 85.1+/-6.4, P<.04), had more comorbidity (ChI 2.35+/-1.61 vs 2.08+/-1.38; P<.083), worse functional impairment [(LI: 0.49+/-1.15 vs 1.45+/-2.32, P<.001) (BIp: 34.6+/-32.9 vs 54.0+/-34.1, P<.001) (BIa: 5.79+/-12.5 vs 20.5+/-22.9, P<.001)], a higher percentage of functional loss at admission (85.9+/-23.2 vs 66.4+/-28.6; P<.0001), worse cognitive impairment (PT: 7.20+/-3.73 vs 5.10+/ 3.69, P<.001) and malnutrition (albumin 2.67+/-0.54 vs 2.99+/-0.49, P<.001). Mortality was higher with impaired consciousness [49.2% (P<.01)], tachypnea [33.3% (P<.01)], tachycardia [44.4% (P<.002), high urea levels [31.8 (P<.001)], anemia [44.7% (P<.02)], pleural effusion [42.9% (P<.002)], and multilobar infiltrates [43.2% (P<.001)]. In the multivariate analysis, variables associated with mortality were: age >=90years [OR: 3.11 (95%CI: 1.31 to 7.36)], impaired consciousness [3.19 (1.66 to 6.15)], hematocrit <30% [2.87 (1.19 to 6.94)], pleural effusion [3.77 (1.69 to 8.39)] and multilobar infiltrates [2.76 (1.48 to 5.16)]. Female sex and a preserved functional status prior (LI>=5) and during admission (BIa>=40) were protective of mortality [0.40 (0.22 to 0.70), 0.09 (0.01 to 0.81) and 0.11 (0.02 to 0.51)]. CONCLUSIONS: Geriatric assessment parameters and routine clinical variables were associated with mortality. PMID- 24629764 TI - Generation by self re-fusion of bovine3 * murine2 heterohybridomas secreting virus-neutralizing bovine monoclonal antibodies to bovine herpesvirus 1 glycoproteins gB, gC, and gD. AB - Seventy-eight heterohybridomas (HH) stably secreting bovine monoclonal antibodies (BomAb) to Bovine herpesvirus 1 (BHV1) were produced by fusing lymph node cells from a BHV1 hyperimmunized calf with 3 types of non-secreting fusion partners. Seven were generated through fusion with the murine * murine (murine(2)) hybridoma SP2/0, 3 through fusion with bovine-murine(2) HH previously generated using cells from the same calf, and 68 through fusion with bovine(2)-murine(2) HH previously generated by sequential fusions using cells from the same calf. The chromosome number of example HH increased with increasing numbers of input fusions. A variety of indirect fluorescent antibody assay patterns was observed using the BomAb, suggesting diverse antigen specificity. Three bovine(3) murine(2) HH secreted IgG1 BomAb neutralizing BHV1 without complement, and were chosen for further characterization. SDS-PAGE of detergent-solubilized BHV1 proteins bound to the 3 neutralizing BomAb demonstrated their individual specificities for BHV1 envelope glycoproteins gB, gC, and gD, the major neutralization targets for BHV1. The 3 HH stably secreted the BomAb in culture for over one year, and pilot-scale production of the BomAb was accomplished by in vivo and in vitro methods. A cocktail of the 3 BomAb was administered intravenously (i.v.) to a 6-month-old calf and its serum neutralization activity decreased with a half-life consistent with non-immune clearance, suggesting that BomAb may be useful for passive immune treatment of disease in cattle. Rabbits were passively protected by i.v. injection with each of the anti-gB and anti-gD BomAb when challenged i.v. with BHV1 24h later. Self re-fusion was shown to be advantageous for efficiently producing HH stably secreting host monoclonal antibodies. The BomAb described should prove useful in studies of the host immune response to BHV1, as reagents, and as sources of bovine immunoglobulin sequences. PMID- 24629765 TI - A study for characterization of IgE-mediated cutaneous immediate and late-phase reactions in non-allergic domestic cats. AB - Immunoglobulin-E (IgE) mediated reactions can be induced by intradermal injection of anti-IgE antibodies in both humans and dogs. These reactions grossly and histologically mimic changes seen in naturally occurring allergic dermatitis in these species. Similar studies have not been conducted in the cat. Purified polyclonal rabbit-origin IgG specific for canine IgE (anti-IgE) and rabbit immunoglobulin G (IgG) were injected intradermally in 7 non-allergic laboratory colony cats. Wheal measurements were obtained and biopsies collected before injection and at injection sites after 20 min, 6, 24, and 48 h. Injection of anti IgE induced an immediate wheal response which was significantly larger than that seen after injection of rabbit IgG. Anti-IgE injected skin was also significantly thicker than IgG-injected skin. This corresponded with a significant increase in number of visibly degranulated mast cells in anti-IgE samples when compared to IgG samples. Injection of anti-IgE was associated with the rapid recruitment of inflammatory cells to the injected dermis. The number of inflammatory cells and mononuclear cells were significantly elevated after the injection of anti-IgE when compared to IgG-injected skin. Both eosinophils and neutrophils were significantly increased in anti-IgE samples relative to IgG, although neutrophils were only transiently increased. The high eosinophil and relatively low neutrophil cell counts in these samples were consistent with previously documented histologic features of naturally occurring feline allergic skin disease. Immunohistochemistry identified a significantly overall increased CD1a(+) cells after the intradermal injection of anti-IgE when compared to IgG and non-injected skin. CD3(+), CD8(+) and CD4(+) were also significantly increased overall in anti-IgE injected skin relative to IgG injected skin. These data document the gross and cellular response to injection of anti-IgE in the skin of healthy, non-allergic cats and support a possible role for IgE in the development of feline allergic dermatitis. PMID- 24629766 TI - Inhibitory effects of alpha-cyperone on adherence and invasion of avian pathogenic Escherichia coli O78 to chicken type II pneumocytes. AB - Avian pathogenic Escherichia coli (APEC) are extra-intestinal pathogenic E. coli, and usually cause avian septicemia through breaching the blood-gas barrier. Type II pneumocytes play an important role of maintaining the function of the blood gas barrier. However, the mechanism of APEC injuring type II pneumocytes remains unclear. alpha-cyperone can inhibit lung cell injury induced by Staphylococcus aureus. In order to explore whether alpha-cyperone regulates the adherence and invasion of APEC-O78 to chicken type II pneumocytes, we successfully cultured chicken type II pneumocytes. The results showed that alpha-cyperone significantly decreased the adherence of APEC-O78 to chicken type II pneumocytes. In addition, alpha-cyperone inhibited actin cytoskeleton polymerization induced by APEC-O78 through down regulating the expression of Nck-2, Cdc42 and Rac1. These results provide new evidence for the prevention of colibacillosis in chicken. PMID- 24629767 TI - Modulation of microRNAs in two genetically disparate chicken lines showing different necrotic enteritis disease susceptibility. AB - MicroRNAs (miRNA) play a critical role in post-transcriptional regulation by influencing the 3'-UTR of target genes. Using two inbred White Leghorn chicken lines, line 6.3 and line 7.2 showing Marek's disease-resistant and -susceptible phenotypes, respectively, we used small RNA high-throughput sequencing (HTS) to investigate whether miRNAs are differently expressed in these two chicken lines after inducing necrotic enteritis (NE). The 12 miRNAs, selected from the most down-regulated or up-regulated miRNAs following NE induction, were confirmed by their expressions in real-time PCR. Among these miRNAs, miR-215, miR-217, miR 194, miR-200a, miR-200b, miR-216a, miR-216b, and miR-429 were highly expressed in intestine derived from line 7.2, whereas, miR-1782 and miR-499 were down regulated. In spleen, miR-34b and miR-1684 were the most up-regulated miRNAs in line 6.3. Notably, five out of six target genes, CXCR5, BCL2, GJA1, TCF12, and TAB3 were differentially expressed between line 6.3 and line 7.2, and showed suppression in the MD-susceptible chicken line. Their expression levels were conversely correlated with those of miRNA obtained from both HTS and quantitative real-time PCR. These results suggest that some miRNAs are differentially altered in response to NE and they modulate the expression of their target genes in the two inbred lines. Collectively, HTS analysis of intestinal miRNAs from NE afflicted inbred chickens showing different disease phenotypes led to the identification of host immunity genes regulated by miRNA. Future studies of the function of these miRNAs and their target genes in the host will lead to enhanced understanding of molecular mechanisms controlling host-pathogen interaction in NE. PMID- 24629768 TI - Dual purpose with dual benefit research models in veterinary and biomedical research. PMID- 24629769 TI - Rare tumors of the rectum. Narrative review. AB - Most rectal neoplasms are adenocarcinomas, but there is a small percentage of tumors which are of other histological cell lines such as neuroendocrine tumors, sarcomas, lymphomas and squamous cell carcinomas, which have special characteristics and different treatments. We have reviewed these rare tumors of the rectum from a clinical and surgical point of view. PMID- 24629770 TI - Recurrent pancreatitis in a 16-year-old patient. PMID- 24629771 TI - Bighorn sheep * domestic sheep hybrids survive Mannheimia haemolytica challenge in the absence of vaccination. AB - Bighorn sheep (BHS, Ovis canadensis) are much more susceptible than domestic sheep (DS, Ovis aries) to pneumonia caused by leukotoxin (Lkt)-producing members of the Family Pasteurellaceae, particularly Mannheimia haemolytica and Bibersteinia trehalosi. Leukotoxin is widely accepted as the critical virulence factor of these bacteria since Lkt-negative mutants do not cause death of BHS. Typically, DS carry Lkt-positive M. haemolytica and/or B. trehalosi as commensal bacteria in their nasopharynx. In contrast, most BHS do not carry Lkt-positive M. haemolytica or B. trehalosi, or carry Lkt-negative strains in their nasopharynx. In previous studies, we demonstrated that unimmunized DS resist M. haemolytica challenge while BHS succumb to it. We hypothesized that Lkt-neutralizing antibodies, induced by Lkt-positive M. haemolytica and/or B. trehalosi innately carried by DS in their nasopharynx, render them less susceptible to infection by these bacteria. In this study we developed BHS*DS F1 hybrids by artificial insemination of domestic ewes with BHS semen. F1 hybrids were fertile, and produced F2 hybrids and back-crosses. The F1, F2, and back-crosses were raised together with domestic ewes. All these animals acquired Lkt-positive M. haemolytica and/or B. trehalosi, and developed high titers of Lkt-neutralizing antibodies in the absence of vaccination. Furthermore, all of these animals resisted challenge with lethal dose of M. haemolytica. These results suggest that lack of previous exposure to Lkt is at least partially responsible for fatal pneumonia in BHS when they acquire Lkt-positive M. haemolytica and/or B. trehalosi from DS when the two species commingle. PMID- 24629772 TI - Enterobacter cloacae with a novel variant of ACT AmpC beta-lactamase originating from glaucous gull (Larus hyperboreus) in Svalbard. AB - We aimed at Escherichia coli and Enterobacter cloacae isolates resistant to cephalosporins and fluoroquinolones and Salmonella isolates in wild birds in Arctic Svalbard, Norway. Cloacal swabs of little auks (Alle alle, n=215) and samples of faeces of glaucous gulls (Larus hyperboreus, n=15) were examined. Inducible production of AmpC enzyme was detected in E. cloacae KW218 isolate. Sequence analysis of the 1146 bp PCR product of the ampC gene from this isolate revealed 99% sequence homology with the blaACT-14 and blaACT-5 AmpC beta lactamase genes. Four, respectively six of the identified single nucleotide polymorphisms generated amino acid substitutions in the amino acid chain. As the ampC sequence polymorphism in the investigated E. cloacae strain was identified as unique, we revealed a novel variant of the ampC beta-lactamase gene blaACT-23. PMID- 24629773 TI - Emergence of AmpC-producing Escherichia coli in the broiler production chain in a country with a low antimicrobial usage profile. AB - The aim of this study was to estimate the prevalence of cephalosporin-resistant Escherichia coli at the different levels of the Norwegian broiler production pyramid and identify the mechanisms responsible for the resistance phenotype. Samples from all levels of the broiler production pyramid and retail chicken meat (fillets) were included (n=649). The occurrence of cephalosporin-resistant E. coli at the different production levels ranged from 8 to 43%. All these isolates had an AmpC-phenotype, and the majority carried the blaCMY-2 gene. In addition, a few isolates with up-regulated chromosomal ampC were identified. The results show that Norway has a relatively high prevalence of cephalosporin-resistant E. coli in the broiler production chain in spite of a very low consumption of antimicrobial agents. Cephalosporins have not been used in the Norwegian broiler production, and it has been hypothesised that import of breeding animals and hatching eggs may be the source of these resistant bacteria. We demonstrate that these bacteria are disseminated in the production pyramid despite the lack of selection pressure from antimicrobial agents. PMID- 24629774 TI - Effects of fluoroquinolone treatment and group housing of pigs on the selection and spread of fluoroquinolone-resistant Campylobacter. AB - There are concerns that the use of fluoroquinolones (FQs) and group housing of food animals may contribute to the development of bacterial FQ resistance. Here, we studied the effects of administering FQ to pigs on the selection of FQ resistant Campylobacter. Fifteen pigs were randomly allocated to either a group treated with FQs (enrofloxacin or norfloxacin), or an untreated control group. The number of FQ-resistant Campylobacter in feces was determined using appropriate selective agar containing enrofloxacin. FQ-resistant Campylobacter from samples of both groups were observed on days 3 and 4. These bacteria persisted for up to 21 days after treatment was discontinued. To evaluate the effect of group housing on the transmission of FQ-resistant Campylobacter, five pigs infected with FQ-sensitive Campylobacter pigs and one pig infected with FQ resistant Campylobacter were housed together. On day 3, FQ-resistant Campylobacter were isolated from all six pigs. Moreover, FQ-resistant Campylobacter were isolated from environmental samples from the pen. These results indicate that the treatment of pigs with FQs selects for and spreads FQ resistant Campylobacter among the pen. Therefore, responsible and prudent use of FQs at pig farms is required to prevent the emergence and transmission of FQ resistant Campylobacter. PMID- 24629775 TI - The ecological importance of the Staphylococcus sciuri species group as a reservoir for resistance and virulence genes. AB - The Staphylococcus sciuri species group includes five species that are most often presented as commensal animal-associated bacteria. The species of this group are Staphylococcus sciuri (with three subspecies), Staphylococcus lentus, Staphylococcus vitulinus, Staphylococcus fleurettii and Staphylococcus stepanovicii. Members of these group are commonly found in a broad range of habitats including animals, humans and the environment. However, those species have been isolated also from infections, both in veterinary and human medicine. Members of this group have been shown to be pathogenic, though infections caused by these species are infrequent. Furthermore, members of the S. sciuri species group have also been found to carry multiple virulence and resistance genes. Indeed, genes implicated in biofilm formation or coding for toxins responsible of toxic shock syndrome and multi-resistance, similar to those carried by Staphylococcus aureus, were detected. This group may thereby represent a reservoir for other bacteria. Despite its recognized abundance as commensal bacteria and its possible role as reservoir of virulence and resistance genes for other staphylococci, the S. sciuri species group is often considered harmless and, as such, not as well documented as, for example, S. aureus. More investigation into the role of the S. sciuri species group as commensal and pathogenic bacteria is required to fully assess its medical and veterinary importance. PMID- 24629776 TI - Comparative prevalence and characterization of ESBL-producing Enterobacteriaceae in dominant versus subdominant enteric flora in veal calves at slaughterhouse, France. AB - Food-producing animals have become a growing reservoir of Extended-Spectrum Beta Lactamase (ESBL)-producing bacteria. In cattle, veal calves are exposed to high amounts of antibiotics but ESBL prevalence data are still limited compared to other food sectors such as poultry production. Based on the investigation of 491 veal calves from different slaughtering batches at 12 abattoirs, this study shows a prevalence of 29.4% of ESBL producers in the faecal flora of veal calves in France in 2012. A variety of blaCTX-M genes was found, reflecting possible diverse pathways of dissemination in cattle. Another major conclusion is the comparison of the ESBL prevalence in the dominant versus sub-dominant Escherichia coli population of the same calves (1% and 29.4%, respectively). Also, the ESBL E. coli clones in the sub-dominant flora mostly differed from the non-ESBL dominant E. coli clones of the same calves. Of note, the distribution of blaCTX-M genes and E. coli phylogroups were similar to the ones previously found in ESBL E. coli clones from diseased calves. The hypothesis that ESBL genes may distribute more abundantly in certain backgrounds of E. coli was also discussed. In all, as recently reported in the Netherlands, these results strongly suggest a recent increase in the prevalence of ESBL carriage in French veal calves, which should be considered one of the major ESBL reservoirs in food animals. PMID- 24629777 TI - An emerging public health problem: acquired carbapenemase-producing microorganisms are present in food-producing animals, their environment, companion animals and wild birds. AB - Worldwide, the emergence and global spread of microorganisms with acquired carbapenemases is of great concern. The reservoirs for such organisms are increasing, not only in hospitals, but also in the community and environment. A new and important development is the presence of such organisms in livestock, companion animals and wildlife. During the last three years, carbapenemase producing Escherichia coli, Salmonella spp. (VIM-1 producers) and Acinetobacter spp. (producing OXA-23 and NDM-1) in livestock animals (poultry, cattle and swine) and their environment have been reported. In addition, the isolation of NDM-1-producing E. coli, OXA-48 in E. coli and Klebsiella pneumoniae or OXA-23 in Acinetobacter spp. from companion animals (cats, dogs or horses) has also been observed. Other reports have described the presence of NDM-1-producing Salmonella isolated from wild birds, as well as OXA-23-like-producing Acinetobacter baumannii in ectoparasites. However, until now carbapenemase producers from foods have not been detected. For humans in contrast carbapenem-producing Salmonella isolates are increasingly reported. The real prevalence of carbapenemase-encoding genes in zoonotic bacteria or commensals from animals is unknown. Consequently, there is a need for intensified surveillance on the occurrence of carbapenemase producing bacteria in the food chain and other animal sources in order to assist in the formulation of measures to prevent their potential spread. PMID- 24629778 TI - Molecular characterization of antibiotic resistance in Pseudomonas and Aeromonas isolates from catfish of the Mekong Delta, Vietnam. AB - A collection of 116 motile Pseudomonas spp. and 92 Aeromonas spp. isolated from 15 Vietnamese intensive catfish farms was analyzed to examine the molecular antibiotic resistance characteristics and the transferability of resistance markers within and between species. High levels of resistance to ampicillin, trimethoprim/sulfamethoxazole, nalidixic acid, chloramphenicol, and nitrofurantoin were observed. The percentage of multiple drug resistance of Pseudomonas spp. and Aeromonas spp. isolates was 96.6% and 61.9%, respectively. The multiple antibiotic resistance (MAR) index mean values of 0.457 and 0.293 of Pseudomonas and Aeromonas isolates, respectively, indicated that these isolates were exposed to high risk sources of contamination where antibiotics were commonly used. Approximately 33% of Pseudomonas spp. and 28% of Aeromonas spp. isolates from catfish contained class 1 integrons, but no class 2 integrons were detected. Several common resistance genes including aadA, dfrA and catB were harbored in class 1 integrons. Large plasmids (>55 kb) were frequently detected in 50% and 71.4% of the plasmids extracted from Pseudomonas and Aeromonas isolates, respectively. Conjugation and transformation experiments demonstrated the successful transfer of all or part of the resistance phenotypes of catfish isolates to the recipient strains, including laboratory strains and strains isolated from this study. These results highlight the likely role of catfish bacteria as a reservoir of antibiotic resistant, Gram-negative bacteria harboring a pool of mobile genetic elements that can readily be transferred intra- and interspecies. To our knowledge, this is the first report on molecular characterization of antibiotic resistance of bacteria isolated from catfish in Vietnam. PMID- 24629779 TI - DIVA vaccine properties of the live chimeric pestivirus strain CP7_E2gif. AB - Live modified vaccines to protect against classical swine fever virus (CSFV), based on chimeric pestiviruses, have been developed to enable serological Differentiation of Infected from Vaccinated Animals (DIVA). In this context, the chimeric virus CP7_E2gif vaccine candidate is unique as it does not include any CSFV components. In the present study, the DIVA vaccine properties of CP7_E2gif were evaluated in comparison to the conventional live attenuated Riemser C-strain vaccine. Sera and tonsil samples obtained from pigs immunised with these two vaccines were analysed. No viral RNA was found in serum after vaccination with CP7_E2gif, whereas some serum samples from C-strain vaccinated animals were positive. In both vaccinated groups, individual viral RNA-positive tonsil samples were detected in animals euthanised between 7 and 21 days post vaccination. Furthermore, serum samples from these animals, together with archival samples from pigs vaccinated with CP7_E2gif and subsequently CSFV challenged, were analysed for specific antibodies using ELISAs and for homologous neutralising antibodies. In animals vaccinated with CP7_E2gif, neutralising antibodies were detected from day 10. However, the sera remained negative for anti-CSFV E2 specific antibodies whereas pigs vaccinated with C-strain seroconverted against CSFV by 14 days after vaccination, as determined by a CSFV-E2 specific blocking ELISA. One week after subsequent CSFV challenge, a strong anti-CSFV E2 reaction was detected in CP7_E2gif vaccinated pigs and anti-E(rns) antibodies were detected from 10 days after infection. In conclusion, CP7_E2gif has the potential to be used as a DIVA vaccine in combination with detection of anti-CSFV E2 specific antibodies. PMID- 24629780 TI - Cross-border activities and association with current methamphetamine use among Chinese injection drug users (IDUs) in a China-Myanmar border region. AB - BACKGROUND: Methamphetamine has become one of the most widely used illicit substances in the world. We measured the prevalence and identified the correlates of methamphetamine use amongst current injection drug users (IDUs) in a China Myanmar border region. METHODS: A cross-sectional survey including interviews and serological testing was conducted in 2012. Chinese IDUs who had injected within the past six months and aged >= 18 years were recruited using respondent-driven sampling (RDS). Logistic regression indentified factors associated with current methamphetamine use. RESULTS: Among 370 IDUs recruited, prevalence of lifetime and current methamphetamine use was 84.2% and 75.2% respectively. Amongst 293 current users, 18.1% ever purchased methamphetamine from Myanmar while 8.9% ever used it there during the past 6 months. IDUs who had cross-border activities, including purchasing drugs (AOR: 1.20; 95% CI: 1.10, 1.31) and visiting family/friends, doing business or odd jobs in Myanmar (AOR: 1.13; 95% CI: 1.02, 1.24) were more likely to use methamphetamine in the past six months. Other factors independently associated with current methamphetamine use included being younger (aged <= 25 years, AOR: 1.24; 95% CI: 1.09, 1.41), being syphilis positive (AOR: 1.17; 95% CI: 1.03, 1.33), having used previously self-used needle/syringe (AOR: 1.20; 95% CI: 1.08, 1.34) and recently received prevention services (AOR: 1.15; 95% CI: 1.04, 1.28). CONCLUSION: Methamphetamine has become another major drug of use and poses the serious concern among injecting drug users living in the China/Myanmar border region. The bi-national cooperation is urgently needed to develop targeted effective intervention strategies. PMID- 24629781 TI - Prospective risk factors for traumatic event reexposure in community syringe exchange participants. AB - BACKGROUND: Traumatic event reexposure in injecting drug users is associated with increased drug use and potential for psychiatric symptoms. This is the first study to examine fixed and time-varying factors that are prospectively associated with new traumatic event reexposure in injecting drug users. METHODS: Injecting drug users registered in a syringe exchange program were enrolled in a 16-month parent study comparing strategies to increase drug abuse treatment enrollment. Participants (N=162) completed baseline measures of demographics, psychiatric treatment history, and lifetime traumatic event exposure. Monthly follow-ups assessed past-month traumatic event exposure, days of heroin and cocaine use, criminal activity, and drug abuse treatment participation. Generalized estimating equations models tested the influence of fixed baseline and time-varying factors on traumatic event reexposure in the same month, the following month, and two months later. RESULTS: Significant fixed risk factors for traumatic event reexposure include female gender and past psychiatric treatment. In addition, each past traumatic event exposure was associated with an increased likelihood of reexposure. After accounting for all other factors, each day of cocaine use was associated with a small but persistent increased risk of traumatic event reexposure. Reexposure to a traumatic event in the prior month more than doubled the risk of subsequent reexposure. CONCLUSIONS: Injecting drug users experience a pattern in which drug use is associated with increased risk of subsequent traumatic event reexposure, and traumatic event reexposure is associated with further drug use and continued reexposure. Implications for addressing these concerns in injecting drug users are presented. PMID- 24629782 TI - Comparison of toxicity associated with nonmedical use of benzodiazepines with buprenorphine or methadone. AB - BACKGROUND: Polysubstance use is prevalent in individuals using buprenorphine or methadone nonmedically, with benzodiazepines being a common co-ingestant. The objective of this study was to compare the severity of buprenorphine and methadone toxicity with concomitant use of benzodiazepines. METHODS: A retrospective analysis of buprenorphine and methadone cases from November 1, 2002 to December 31, 2010 reported to the American Association of Poison Control Centers' National Poison Data System (NPDS) was conducted. INCLUSION CRITERIA: age >= 18 years, nonmedical use of methadone with benzodiazepines (methadone-BZD) or buprenorphine with benzodiazepines (BUP-BZD), and case followed to a documented outcome. Cases with co-ingestants other than benzodiazepines were excluded. Clinical effects, treatments, disposition and final medical outcomes were evaluated. RESULTS: There were 692 methadone-BZD cases and 72 BUP-BZD cases. Clinical effects in methadone-BZD and BUP-BZD groups were lethargy (71.1%, 59.7%), respiratory depression (29.0%, 15.3%), coma (22.4%, 5.6%), respiratory arrest (4.5%, 0), hypotension (11.8%, 2.8%) and cardiac arrest (1.9%, 0), respectively. Patients in the methadone-BZD group were four-times more likely to receive naloxone (60.4% vs 15.3%) or be intubated (16.3% vs 4.2%) than in the BUP BZD group. Hospitalization rates were highest for methadone-BZD patients with 67.3% receiving medical admissions compared to 43.3% of BUP-BZD patients. Outcomes were more serious for methadone-BZD cases (p<0.0001); while there were no BUP-BZD deaths, exposure to methadone-BZD yielded 16 deaths. CONCLUSIONS: Nonmedical use of benzodiazepines with methadone is associated with higher hospitalization rates, greater ICU utilization rates and considerably worse medical outcomes when compared to nonmedical use of benzodiazepines with buprenorphine. PMID- 24629783 TI - Complement C1q and C2 polymorphisms are not risk factors for SLE in Indian Tamils. AB - INTRODUCTION: Complement system is an important effector component of the innate immune system. More than 30 plasma proteins undergo a cascade of enzymatic reactions to produce effector molecules to clear infectious microbes, immune complexes, post apoptotic cellular debris and thus participate in prevention of autoimmunity. Absolute deficiency of individual complement components and selective deficiency of classical pathway complement components are reported to be associated with severe infections and a high risk for lupus like syndromes. Genetic defects in gene encoding for complement components were reported to be associated with complement deficiency. This study was carried out to investigate whether C1q and C2 polymorphisms are risk factors for SLE in south Indian Tamils. MATERIALS AND METHODS: Three hundred SLE patients fulfilling ACR criteria for SLE and 460 age and sex similar ethnicity matched individuals were included as patients and healthy controls respectively. The genomic DNA obtained from both the groups was screened for two polymorphisms including a C/T transition in exon 2 of C1qA (rs121909581) by PCR-RFLP and a 28bp deletion in sixth exon of C2 gene by PCR. RESULTS: C1q exon 2 C/T polymorphism analysis revealed that homozygous CC was the most common genotype in patients and controls. A single SLE patient was found to have heterozygous variant (CT). None of the patients or healthy controls were found to have 28bp deletion variant of C2 gene. CONCLUSION: The C/T polymorphism in exon 2 of C1qA and a 28bp deletion in sixth exon of C2 gene were found to be rare in south Indian Tamil SLE patients. They do not appear to be susceptibility factors for SLE in Indian Tamils. PMID- 24629784 TI - Expression of PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) in human urinary bladder transitional cell carcinoma. AB - The objective of this study was to evaluate the expression pattern of PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) and its clinical significance in human bladder cancer (BC). We detected PBK/TOPK mRNA overexpression in BC and human normal testis tissues using RT-PCR. Using qRT-PCR revealed a higher expression of PBK/TOPK in BC tissues than their adjacent noncancerous tissues (ANCTs) (p<0.0001). Cytoplasmic expression of PBK/TOPK protein was found to be positive in 64.6% (42 of 65) BC patients. Expression of PBK/TOPK protein was found to be significantly higher in muscle-invasive bladder cancer (MIBC) than in non-muscle-invasive bladder cancer (NMIBC) (86.1% vs. 37.9%, p<0.001). The immunohistochemical (IHC) expression of PBK/TOPK was found to be significantly (p<0.001) associated with the stage of disease. Study findings suggest that the PBK/TOPK mRNA/protein expression is specific to human BC and might be used as a novel target for development of cancer immunotherapy and diagnostic biomarker. PMID- 24629785 TI - Prenatal diagnostic testing among women referred for advanced maternal age in Beijing, 2001-2012. AB - OBJECTIVE: To determine the proportion of women with advanced maternal age (AMA) undergoing amniocentesis and assess the recommended indication of 35 years or older in China. METHODS: Data were retrospectively evaluated from 9641 patients who underwent diagnostic prenatal amniocentesis in Beijing, China, between January 2001 and December 2012. Maternal age, indication for testing, and karyotype data were collected. Patients referred for AMA were stratified in 2 ways: 35-37 years, 38-40 years, and 41 years or older; and indication of AMA alone or combined with other screening. Outcomes and safety performance were compared among the groups. RESULTS: From 2001 to 2012, the annual rate of amniocentesis and the proportion of AMA-related indications increased (P < 0.01). Overall, 82 abnormalities were detected. In the AMA group, the spontaneous abortion rate was 0.5% (22/4748). The positive predictive value (PPV) of AMA alone was 0.5% for women aged 35-37 years. Only among women aged 41 years or older was the PPV of AMA alone better than that of AMA plus other indications (2.3% vs 1.5%, respectively). CONCLUSION: The PPV of 35 years or older did not offset the risk of spontaneous abortion. AMA alone should not be used as an indication for amniocentesis especially among women aged 35-40 years. PMID- 24629786 TI - Anemia in pregnancy in Abakaliki, South East Nigeria. PMID- 24629787 TI - Surgical outcome following treatment of obstetric vesicovaginal fistula among HIV positive and HIV-negative patients in Cameroon. PMID- 24629788 TI - Audit of cesarean delivery in Burkina Faso. AB - OBJECTIVE: To assess the level and determinants of unnecessary cesarean delivery. METHODS: In a retrospective study, the medical charts were reviewed for 300 low risk women who underwent intrapartum cesarean delivery at 10 referral hospitals in Burkina Faso between May 2009 and April 2010. In this context, cesarean deliveries were delegated to clinical officers who have less training than doctors. RESULTS: Among the 300 study patients, 223 women (74.3%) were referred from primary healthcare facilities. The reason for referral was not medically justified for 35 women. Cesarean was performed by a gynecologist-obstetrician (46.0%), a trained doctor (35.0%), or a clinical officer (19.0%). Acute fetal distress and fetopelvic disproportion were the main indications recorded for intrapartum cesarean delivery. These diagnoses were not confirmed by an obstetrician-gynecologist in 12.0% of cases. Clinical officers were associated with a higher risk of unnecessary cesarean delivery compared with gynecologist obstetricians by multivariate analysis (odds ratio, 4.46; 95% confidence interval, 1.44-13.77; P = 0.009). CONCLUSION: Verification of cesarean indications by highly qualified personnel (i.e. second opinion), in-service training, and supervision of health workers in primary healthcare facilities might improve the performance of the referral system and help to reduce unnecessary cesarean deliveries in Burkina Faso. PMID- 24629789 TI - The "Spot Sign" secondary to a ruptured lenticulostriate artery aneurysm. AB - The "Spot Sign" is a well-recognized radiographic predictor for hematoma expansion in patients with intracerebral hemorrhages. Although the exact underlying pathophysiology is unknown, it is generally assumed to be the site of blood vessel rupture and contrast extravasation. We report a case of an 81-year old man who presented with right basal ganglia hemorrhage and the "Spot Sign" on computed tomography angiography. Conventional angiography subsequently revealed a lenticulostriate artery aneurysm within the hematoma, which was treated with surgical clipping. This case demonstrates that rare entities such as lenticulostriate aneurysms must be kept in the differential diagnoses in order to optimize patient management and improve clinical outcome. PMID- 24629790 TI - Prevalence and risk of cancer of incidental uptake in prostate identified by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography. AB - OBJECTIVE: The objective was to investigate the prevalence of incidental fluorine 18 fluorodeoxyglucose (FDG) uptake in positron emission tomography/computed tomography. METHODS: A total of 11,239 male nonprostate disease patients were included retrospectively. RESULTS: The prevalence of incidental prostate FDG uptake was approximately 1.8%. Among 198 incidental lesions, 100 patients had further examinations; 20 lesions were confirmed to be malignant, while 80 lesions were benign. After logistic regression analysis, age, site, and the maximum standard uptake value were the potent predictors for differentiation of malignant prostate lesions. CONCLUSION: When focal FDG uptake in the peripheral zone of prostate is detected, especially in elderly men, further clinical evaluation is recommended. PMID- 24629791 TI - Imaging of invasive thymoma in the costophrenic recess presenting as thickening of arcuate ligaments of the diaphragm. AB - Imaging findings in a patient with invasive thymoma in the costophrenic recess are presented, in whom computed tomography (CT) and MRI revealed lateral arcuate ligament thickening. Increased fluoro-deoxy-glucose (FDG) uptake on subsequent positron emission tomography (PET)/CT was helpful in suggesting the correct diagnosis. A second patient with much more obvious invasive thymoma occurring in the costophrenic recess is presented for comparison. It is a well-known fact that thymic malignancies can metastasize to the pleura even years after resection. Rarely, they may present as focal thickening of the diaphragmatic lateral arcuate ligament. PMID- 24629792 TI - Solid-pseudopapillary tumor of the pancreas: MR imaging findings in 21 patients. AB - PURPOSE: Solid-pseudopapillary tumor (SPT) of the pancreas is a rare, low-grade malignancy, which mostly occurs in adolescent and young adult females. The goal of this study was to retrospectively analyze the magnetic resonance (MR) imaging presentation of SPT of the pancreas. METHODS: We retrospectively reviewed the preoperative MR imaging examinations and the medical, surgical and histopathological records of 21 patients who underwent surgery for SPT of the pancreas. MR imaging included T1-weighted, T2-weighted, and gadolinium chelate enhanced MR imaging. In addition, 10 patients had diffusion-weighted (DW) MR imaging. MR examinations were retrospectively reviewed for location, size, morphological features and signal intensity of the tumors. RESULTS: Nineteen women and 2 men (median age, 23 years; range, 14-59) were included. Seven patients (7/21; 33%) presented with abdominal symptoms. The median largest tumor diameter was 53mm (range, 32-141 mm). SPTs were located in the pancreatic head, body, and tail in 9 (9/21; 43%), 5 (5/21; 24%) and 7 (7/21, 33%) patients, respectively. All patients (21/21; 100%) had a single SPT. SPTs were more frequently oval (12/21; 57%), predominantly solid (12/21; 57%), fully encapsulated (16/21; 76%), larger than 30 mm (21/21; 100%), hypointense on T1 weighted MR images (21/21, 100%), hyperintense on T2-weighted MR images (21/21; 100%) and with an enhancing capsule after gadolinium-chelate administration (21/21; 100%). CONCLUSIONS: There is trend of appearance for SPT of the pancreas on MR imaging but that variations may be observed in a number of cases. SPT uniformly presents as a single, well-demarcated and encapsulated pancreatic mass. PMID- 24629793 TI - Visualization of periprostatic nerve fibers before and after radical prostatectomy using diffusion tensor magnetic resonance imaging with tractography. AB - PURPOSE: The purpose was to evaluate whether the diffusion tensor imaging (DTI) technique can visualize changes in the numbers of periprostatic nerve fibers before and after nerve-sparing and non-nerve-sparing prostatectomy. METHOD: Fifty two prostate cancer patients underwent 3-T magnetic resonance imaging including DTI before and after prostatectomy. RESULTS: After non-nerve-sparing prostatectomy, the numbers of tracts were significantly decreased at base (218.8+/-198.8 vs. 60.5+/-88.7), midgland (124.1+/-134.5 vs. 32.5+/-45.7), and apex (103.1+/-127.4 vs. 29.1+/-57.1). However, after nerve-sparing prostatectomy, the numbers of tracts were not changed significantly at base (170.5+/-139.7 vs. 127.7+/-146.0), midgland (134.3+/-140.8 vs. 83.7+/-58.3), and apex (64.1+/-68.4 vs. 62.3+/-61.9). CONCLUSION: DTI technique may be feasible for visualization of periprostatic nerve fibers. PMID- 24629794 TI - Transcatheter embolization for massive hemoptysis from an intralobar pulmonary sequestration: a case report. AB - Pulmonary sequestration is rarely presented as massive hemoptysis and is conventionally treated by a surgical procedure. Here, we report a case of a 25 year-old man who presented with massive hemoptysis that rapidly developed into a hypovolemic shock. Multidetector computed tomographic angiography showed active contrast extravasation from the aberrant systemic artery originating from the lower descending thoracic aorta. Immediate transcatheter embolization of the aberrant systemic artery was performed successfully. Emergent transcatheter embolization can be an effective method for the management of pulmonary sequestration with life threatening massive hemoptysis. PMID- 24629796 TI - Twenty years of the International Society for Cellular Therapies: the past, present and future of cellular therapy clinical development. PMID- 24629798 TI - Significance of distraction osteogenesis of the craniomaxillofacial skeleton - a clinical review after 10 years of experience with the technique. AB - INTRODUCTION: Distraction osteogenesis (DO) has been applied to the field of craniomaxillofacial surgery for more than two decades. Although relevant factors for successful distraction osteogenesis are well known there are ongoing controversies about indications and limitations of the method and there is still a lack of evidence based data. Since 2003 the principle of gradual lengthening has been applied to patients affected by different types of skeletal craniomaxillofacial deficiency within individualized treatment protocols at the Campus Virchow Klinikum - Charite Universitatsmedizin Berlin - by the same surgical team. The records of these patients were reviewed in order to assess the significance of the technique within the spectrum of a craniomaxillofacial department. During 10 years DO has been applied in 80 patients representing less than 1% of all patients that have been treated since 2003. Review of the protocols showed a heterogeneous group with a wide variance of parameters, the age ranging from 21/2 to 51 years. Internal distraction devices were used in all cases and individually selected with respect to optimal stability during active distraction and consolidation phase. Although distraction related complications occurred the majority of procedures ended up with the favoured result and skeletal stability. However additional reconstructive surgery was required despite successful distraction in the majority of patients. Although DO has a low significance with respect to overall patient counts the method is a powerful tool within individual therapeutic concepts for the surgical correction of craniofacial anomalies that are characterized by skeletal deficiencies and should be seen as addendum to other surgical options. Predictable and stable results can be expected if the basic principles of the method are regarded. PMID- 24629797 TI - Immunotherapy: opportunities, risks and future perspectives. AB - This review is intended to reflect upon the current status and perspectives of cell-based immunotherapy at a time when the promise of extensive pre-clinical research has been translated into encouraging clinical responses. However, some of these have also been complicated by significant adverse reactions. As the field moves towards definitive late stage trials, with a growing interest from pharmaceutical companies, we realize that novel cell therapy strategies pose questions that are familiar to traditional drug development, along with new considerations due to the potential of T cells to persist long term and to expand after adoptive transfer. These questions address the safety of the product, the efficacy, the mode of action, and the anticipation of risks. From different perspectives, we intend to address exciting opportunities and safety concerns in current concepts of cellular immunotherapy. PMID- 24629799 TI - Olfactory performance in spinocerebellar ataxia type 7 patients. AB - A large body of evidence has shown olfactory deficits in many neurodegenerative diseases. However, the nature of the olfactory impairment remains poorly understood partly because the majority of studies have only explored smell identification capabilities. The purpose of the present study was twofold. First we wanted to test if patients with spinocerebellar ataxia type 7 (SCA7), a progressive neurodegenerative disorder characterized by cerebellar ataxia and visual loss, also have olfactory deficits. Secondly, we wanted to test the nature of the olfactory deficits by testing not only the identification level but also olfactory threshold and discrimination. Based on the olfactory dysfunction found in different neurodegenerative diseases and functional neuroimaging data showing cerebellar activation during olfaction, we hypothesized that SCA7 patients would show an olfactory impairment. To test this hypothesis we studied twenty-eight genetically confirmed SCA7 patients and twenty-seven matched controls using the Sniffing Sticks Test and the University of Pennsylvania Smell Identification Test (UPSIT). The results show that SCA7 patients' ability to discriminate and identify odors is significantly impaired, although their odor detection thresholds were at normal levels. These results suggest that SCA7 neurological damage affects olfactory perception but spares the patients' olfactory sensory capabilities. PMID- 24629800 TI - Substantia nigra echogenicity and imaging of striatal dopamine transporters in Parkinson's disease: a cross-sectional study. AB - Approximately 10% of patients with a presumed diagnosis of Parkinson's disease (PD) remain misdiagnosed despite recent advances in neuroimaging. The current study addresses the use of transcranial sonography and single-photon emission computed tomography (SPECT) using (99m)Tc-TRODAT-1 to evaluate the echogenicity of the substantia nigra (SN) and the density of striatal presynaptic dopamine transporters, respectively, in a sample of 20 PD patients (13 males and 7 females) and 9 healthy subjects. The median age of the PD patients was 62 years. The median age at disease onset was 56 years, and the median disease duration was 5 years. The SN echogenic area was larger in PD patients than healthy subjects. The cut-off value of 0.22 cm(2) for the SN echogenic area was associated with 100% sensitivity and 78% specificity for the diagnosis of PD. Striatal and putaminal (99m)Tc-TRODAT-1 binding was lower in PD patients than healthy subjects. The cut-off value of 0.90 for the striatal (99m)Tc-TRODAT-1 binding was associated with 100% sensitivity and an 89% specificity for the diagnosis of PD, and the cut-off value of 0.76 for putaminal (99m)Tc-TRODAT-1 binding was associated with an 85% sensitivity and an 89% specificity. The size of the SN echogenic area did not correlate with the degree of striatal (99m)Tc-TRODAT-1 binding in PD patients. In conclusion, both SN hyperechogenicity and decreased striatal or putaminal (99m)Tc-TRODAT-1 binding constitute surrogate markers for differentiating PD patients from healthy individuals with a slightly higher diagnostic specificity of (99m)Tc-TRODAT-1 SPECT. PMID- 24629801 TI - Neurological manifestations of dengue. PMID- 24629802 TI - Hepatitis A vaccination in patients with rheumatic diseases and drug-induced immunosuppression. PMID- 24629803 TI - Production of prostaglandins in transgenic Arabidopsis thaliana. AB - Plants do not naturally produce the very-long-chain polyunsaturated fatty acids that are the precursors of prostaglandins, but in previous studies Arabidopsis thaliana had been transformed sequentially with genes encoding a Delta(9) elongase and a Delta(8)-desaturase to produce dihomo-gamma-linolenic acid (DGLA) and eicosatetraenoic acid (ETA), and subsequently with a gene encoding a Delta(5) desaturase to produce arachidonic acid (AA) and eicosapentaenoic acid (EPA). Transformation of A. thaliana with the first two genes consolidated on a single binary vector yielded transformants producing high levels of DGLA, and these plants were further transformed with mouse prostaglandin H synthase (PGH) genes to produce prostaglandins. Mouse PGHS-1 and PGHS-2 cDNAs were amplified for expression as three isoforms: PGHS-1 (complete coding sequence with signal peptide), PGHS-1-Ma (mature PGHS-1 sequence, without signal peptide) and PGHS-2 (complete coding sequence with signal peptide). PGHS-1 transformants showed the highest activity, followed by PGHS-2 transformants, whereas removal of the signal peptide resulted in almost complete loss of PGHS-1 activity. In order to produce a physiologically active prostaglandin, the Trypanosoma brucei prostaglandin F synthase gene was combined with the mouse PGHS-1 gene and the Mortierella alpina Delta(5)-desaturase on a binary vector. Transformation of DGLA-producing A. thaliana with this construct yielded transformants that successfully produced prostaglandin F. PMID- 24629804 TI - Effects of overexpression of AaWRKY1 on artemisinin biosynthesis in transgenic Artemisia annua plants. AB - The effective anti-malarial medicine artemisinin is costly because of the low content in Artemisia annua. Genetic engineering of A. annua is one of the most promising approaches to improve the yield of artemisinin. In this work, the transcription factor AaWRKY1, which is thought to be involved in the regulation of artemisinin biosynthesis, was cloned from A. annua var. Chongqing and overexpressed using the CaMV35S promoter or the trichome-specific CYP71AV1 promoter in stably transformed A. annua plants. The transcript level of AaWRKY1 was increased more than one hundred times under the CaMV35S promoter and about 40 times under the CYP71AV1 promoter. The overexpressed AaWRKY1 activated the transcription of CYP71AV1 and moreover the trichome-specific overexpression of AaWRKY1 improved the transcription of CYP71AV1 much more effectively than the constitutive overexpression of AaWRKY1, i.e. up to 33 times as compared to the wild-type plant. However the transcription levels of FDS, ADS, and DBR2 did not change significantly in transgenic plants. The significantly up-regulated CYP71AV1 promoted artemisinin biosynthesis, i.e. up to about 1.8 times as compared to the wild-type plant. It is demonstrated that trichome-specific overexpression of AaWRKY1 can significantly activate the transcription of CYP71AV1 and the up-regulated CYP71AV1 promotes artemisinin biosynthesis. PMID- 24629805 TI - Stress-dependent regulation of 13-lipoxygenases and 13-hydroperoxide lyase in olive fruit mesocarp. AB - The effect of different environmental stresses on the expression and enzyme activity levels of 13-lipoxygenases (13-LOX) and 13-hydroperoxide lyase (13-HPL) and on the volatile compounds synthesized by their sequential action has been studied in the mesocarp tissue of olive fruit from the Picual and Arbequina cultivars. The results showed that temperature, light, wounding and water regime regulate olive 13-LOXs and 13-HPL genes at transcriptional level. Low temperature and wounding brought about an increase in LOX and HPL enzyme activities. A very slight increase in the total content of six straight-chain carbons (C6) volatile compounds was also observed in the case of low temperature and wounding treatments. The physiological roles of 13-LOXs and 13-HPL in the olive fruit stress response are discussed. PMID- 24629806 TI - [Eating disorders and primary care: the challenge of new technologies]. PMID- 24629807 TI - Treatment of lateral pelvic nodes metastases from rectal cancer: the future prospective. AB - One feature of rectal cancer that remains controversial is the significance of lateral lymph node, because TME does not remove these nodes. We discussed the brief history of lateral nodes dissection and some problems in performing the extended surgery.In Japan, an ongoing prospective multicenter randomized trial comparing TME alone and TME with clearance of lateral node is progress. In the West, MERCURY study showed 11.7% of patients with rectal cancer had MRI identified suspicious pelvic side wall nodes. Judging from incidence and prognosis, pelvic side wall nodes in the west are almost similar meaning as lateral nodes in Japan. There is long-standing controversy as to whether lateral lymph nodes metastasis represent systemic or localized disease. Though there has been reports suggesting effect of RT on lateral nodes metastases, the question remains whether preoperative CRT can fully sterilize lateral nodes deposits. Is it appropriate inspection assuming that positive CRM and bowel perforation is major cause of local recurrence after abdominoperineal resection? Some reports say that lateral node metastasis is major cause of local recurrence.We must share following views that the east and the west should join forces to improve selection criteria for lateral node dissection and neoadjuvant treatment to prevent overtreatment, and ultimately aim to improve quality of life and oncological outcome for patients with low rectal cancer. PMID- 24629808 TI - Laparoscopic, three-port and SILS cholecystectomy: a retrospective study. AB - INTRODUCTION: The aim of this study was to compare the results of classic laparoscopic, three-port and SILS cholecystectomy. MATERIALS AND METHODS: We conducted a retrospective study of data collected between January 2010 and December 2012 pertaining to 159 selected patients with symptomatic gallstones. 57 underwent laparoscopic cholecystectomy, 51 three-port cholecystectomy and 48 SILS cholecystectomy. We then compared the groups with respect to mean operating time, intraoperative complications, postoperative pain, duration of hospitalization and final aesthetic result. RESULTS: The mean operating time was significantly higher in the SILS cholecystectomy group (93 minutes) than in the other two groups. There were no intraoperative complications. There were no significant differences in the duration of hospitalization among the three groups. Patients in the SILS cholecystectomy group reported significantly less pain 3, 6 and 12 hours after surgery. The aesthetic results at 1 and 6 months' follow-up were also decidedly better. CONCLUSIONS: On the basis of this study, SILS cholecystectomy is a feasible, safe procedure. In any case, it should be used in selected patients only and carried out by a dedicated team with strong experience in laparoscopy. The main advantages of this technique are a reduction in post-operative pain and improved aesthetic result, at the price, however, of its greater technical difficulty and longer operating times. Future studies are in any case necessary to evaluate any other benefits of this method. PMID- 24629809 TI - Breast-conserving surgery after neoadjuvant chemotherapy in patients with locally advanced cancer. Preliminary results. AB - Neoadjuvant chemotherapy (NACT) in locally advanced breast tumors may allow an adequate control of the disease impossible with surgery alone. Moreover, NACT increases the chance of breast-conserving surgery. Between 2008 and 2012, we treated with NACT 83 patients with locally advanced breast cancer. We report the preliminary results evaluating the impact of NACT on the type of surgery. PMID- 24629810 TI - Toxic multinodular goitre. Personal case histories and literature review. AB - The authors reviewed their own case histories of surgical thyreopathy over the last 20 years in order to establish how many multinodular goitre (MNG) patients developed hyperthyroidism during the follow-up period. In agreement with the findings reported in literature, the authors observed that 220 out of 1117 patients with MNG developed hyperthyroidism caused by the appearance of hyperfunctioning nodules after 6-18 years from the initial diagnosis of MNG. PMID- 24629811 TI - Prostatic abscess after transrectal ultrasound-guided prostate biopsy. Case report. AB - Prostatic abscess (PA) is an uncommon complication after transrectal ultrasonography-guided prostate biopsy with possible heavy outcome too. In this case report (a 68-year-old patient) prostatic abscess presents non specific symptoms: dysuria, supra-pubic pain, urinary frequency, fever 36.0 degrees C (96.8 degrees F). Full blood count, serum urea, electrolytes, liver function test and serum amylase were all normal. There was no growth in his urine culture. Diagnosis is based on digital rectal examination and transrectal ultrasonography. With transrectal ultrasonography (TRUS) we observed a hypoechoic area that contained inhomogeneus material. Color and power Doppler sonography showed a hypovascular fluid collection surrounded by perilesional increased parenchymal flow. TRUS-guided aspiration was performed with an 18 Gauge Chiba needle and the pathogen identified was Escherichia Coli. TRUS of the prostate 1 month later showed complete resolution of the PA and patient remained free of any lower urinary tract symptoms. PMID- 24629812 TI - Renal artery embolization in a gross kidney neoplasm. Case report. AB - AIM: To demonstrate the utility of the renal artery embolization (RAE) in the dissection of gross neoplasms and the reduction in blood loss and operative time. CASE REPORT: We report a case of a gross left renal neoplasm (with the diameter of about 12 cm) in a 45 years old Caucasian female who underwent to renal artery embolization 24 hours before left nephroureterectomy. This procedure has determined a reduction in operative times (about 90 minutes) because of the ligature of the renal vein was facilitated. Intraoperative blood loss was of about 100 ml and the patient didn't need of blood transfusions; the abdominal drain was removed in third postoperative day (daily drained serous fluid was about 20 ml). The patient was discharged 7 days later. CONCLUSION: RAE facilitates the dissection of gross neoplasms (diameter> than 10 cm), so causing a reduction in intraoperative blood loss and in blood transfusion. The operative times are lower because the ligature of the renal vein is less difficult and the dissection is facilitated for the presence of tissue oedema. The disadvantages are the incomplete hembolyzation, coil migration, hematomes, post-infarction syndrome (nausea, vomit, abdominal pain, leucocytosis, hyperpyrexia, hematoma); other risks include the possibility of pulmonary embolism, intestinal infarction and infections. Its reduced utilization could be due to the lack of randomized prospective studies showing its potential benefits. PMID- 24629813 TI - Primary sclerosing cholangitis in patient with celiac disease complicated by cholecystic empyema and acute pancreatitis. AB - BACKGROUND: The association of celiac disease and sclerosing cholangitis is a well known, although unusual, pathologic feature of autoimmunity. METHODS: A 64 year old patient presenting with sub-acute cholangitis and pancreatitis, treated with cholecystectomy and endoscopic sphincterotomy. The post-operative course, complicated by cholestatic jaundice, and subsequent clinical complications are described, showing how the diagnosis of sclerosing cholangitis was outlined after the Endoscopic Retrograde Cholangio-Pancreatography (ERCP) and confirmed by liver biopsy. Long term treatment with Ursodeoxycholic acid has gradually normalized bilirubin values, while cholestasis enzymes are gradually decreasing. After 18 months bleeding from oesophageal varices ensued, which was controlled through endoscopic ligation. CONCLUSIONS: The diagnosis of primary sclerosing cholangitis should be taken into account when cholangitis is associated with other immunity derangements and segmentary dilatations of the intra-hepatic bile ducts, but no dilatation of the main bile duct is noticed at imaging or endoscopy. Recovery of hepatic function should be always attempted before bringing the patient to surgery, in order to avoid postoperative hepatic decompensation. PMID- 24629814 TI - Circumscribed myositis ossificans of the masseter muscle: report of a case. AB - Myositis Ossificans (MO) is an unusual pathological entity still largely unknown, characterized by dystrophic calcification leading to heterotopic ossification of intramuscular connective tissue. The masticatory muscles are exceptionally involved. Four distinct types of myositis ossificans have been described: MO Progressiva, which is a genetic disorder involving several muscular groups; MO Circumscripta, limited to a single muscle and generally due to calcification of an intramuscular haematoma following severe trauma and progressive ossification; MO Pseudo-malignant limited to soft tissue and not associated to any trauma; MO associated to paraplegia. A case of circumscribed myositis ossificans of the masseter muscle in a 62 years-old woman is reported. PMID- 24629815 TI - Distal embolization of Edwards SAPIEN prosthesis during transcatheter aortic valve implantation. AB - AIM: Transcatheter aortic valve implantation (TAVI) is considered an alternative therapy in high risk patients with severe aortic stenosis. Despite this, such a minimally invasive procedure is not free from complications. CASE REPORT: An 86 year-old woman underwent a 26-mm SAPIEN TAVI for aortic valve stenosis. Procedure was complicated by valve embolization into the ascending aorta likely due to a sub-optimal positioning of prosthesis during its deployment. Patient was treated by surgical removal of stent-valve and conventional valve replacement. Patient was discharged from hospital 7 days after surgery. At six months follow-up she was asymptomatic and the valve had a good competence with a mean transaortic gradient of 8 mmHg. CONCLUSIONS: After TAVI prosthesis embolization, conversion to conventional surgical treatment is imperative and can be associated with excellent outcome. PMID- 24629816 TI - Transcutaneous insertion of the Chitwood(r) clamp in case of minimally invasive cardiac surgery. Personal experience. AB - We describe a simple trick consisting of an insertion of a trans-thoracic Chitwood(r) clamp (Scanlan International, Inc, St Paul, MN, USA) through a small skin incision (<1cm), via the second intercostal space along the anterior axillary line, in case of minimally invasive mitral surgery, through right thoracotomy. This trick has been used in more than 100 patients and no complication or discomfort have been reported so far. PMID- 24629817 TI - Adult bowel intussusception: presentation, location, etiology, diagnosis and treatment. AB - Bowel intussusception is rare in adults but common in children. Almost 90% of adult intussusceptions are secondary to a pathologic condition and the clinical picture can be very aspecific and challenging. In this review we discuss the symptoms, location, etiology, characteristics, diagnostic methods and treatment strategies of this rare and enigmatic clinical entity in adults. We have to highlight the high index of suspicion that is necessary for the operating surgeon, when dealing with acute, subacute or chronic abdominal pain in adults, because any misinterpretation may result in unfavorable outcomes. PMID- 24629818 TI - Severe necrotic and septic pancreatitis. Indications to endoscopic, surgical, and nutritional therapy. AB - Severe acute pancreatitis (SAP) management has changed over the last fifteen years, and from too aggressive behaviour, we moved to a cautious one. In every case, we can appreciate defect of extremist conceptual position. We reviewed our strategy on disease treatment, and we analyzed treatment of single cases. We collected 4 SAP cases from January 2009 to January 2010. All patients were septic, and we adopted the same approach for all of them, avoiding surgery without peritoneal infection. In all patients we placed jejumostomy and, after cleaning of septic site, we started immediate enteral nutrition (EN). Antibiotic therapy against Gram+, Gram- and antifugal drug had been started. No one died and all patients were back to an active life even if social costs are considerably high especially due to very long hospital stay. PMID- 24629821 TI - Spontaneous intrahepatic portocaval shunt in a patient undergoing liver transplantation. PMID- 24629820 TI - Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms. AB - BACKGROUND: The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier. METHODS: Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestatic rats, or bile acid treatment, in the presence of a Rac1 inhibitor. RESULTS: Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability. CONCLUSIONS: These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions. PMID- 24629822 TI - The association between Cytotoxic T lymphocyte associated antigen-4, Fas, tumour necrosis factor-alpha gene polymorphisms and autoimmune hepatitis: a meta analysis. AB - BACKGROUND: Several previous studies have assessed the association of Cytotoxic T Lymphocyte Associated Antigen-4, Fas, and Tumour Necrosis Factor-alpha gene polymorphisms with autoimmune hepatitis risk, but the results were inconsistent and inconclusive. We performed a meta-analysis to better evaluate these associations. METHODS: PubMed, EMBASE and MEDLINE were searched in all languages. Overall odd ratios with 95% confidence intervals were calculated to assess the strength of associations using a fixed-effects or random-effects models. RESULTS: 15 relevant studies were identified. No significant association was found between CTLA-4+49A/G and AH. TNF-alpha-308A/G was significantly associated with autoimmune hepatitis risk. Individuals with the "A" allele had a 67% increased risk of autoimmune hepatitis (odds ratio=1.67, 95% confidence interval 1.11 2.52). The genotype "AA" was a potential predisposing factor for autoimmune hepatitis, when compared with the genotype "GG" and "AG+GG" (odds ratio=2.71, 95% confidence interval 1.12-6.57; odds ratio=2.14, 95% confidence interval 1.30 3.52). Besides, no significant association was found between the Fas-670G/A and TNF-alpha-238A/G polymorphisms and autoimmune hepatitis risk using any model. CONCLUSION: The meta-analysis identified the TNF-alpha-308 "A" allele as a predisposing factor for autoimmune hepatitis, whereas the genotype "GG" was a protective factor. This study did not find a significant association between CTLA 4+49A/G, Fas-670G/A, TNF-alpha-238A/G and susceptibility to autoimmune hepatitis. PMID- 24629823 TI - Effects of fentanyl administration before induction of anesthesia and placement of the Laryngeal Mask Airway: a randomized, placebo-controlled trial. AB - STUDY OBJECTIVE: To assess the effects of fentanyl administered before induction of anesthesia on movement and airway responses during desflurane anesthesia via the Laryngeal Mask Airway (LMA). DESIGN: Randomized, double-blinded, controlled trial. STUDY SETTING: Tertiary-care academic center. PATIENTS: 100 adult, ASA physical status 1, 2, and 3 patients undergoing ambulatory surgery. INTERVENTIONS: Patients were administered fentanyl 1 MUg/kg (n=51) or saline (n=49) 3 to 5 minutes before induction with propofol 2-2.5 mg/kg intravenously (IV), followed by LMA placement. Anesthesia was maintained with desflurane titrated to a bispectral index (BIS) of 50-60 and 50% nitrous oxide in oxygen, and fentanyl 25 MUg boluses were titrated to respiratory rate. MEASUREMENTS: Apnea occurrence and duration of manual ventilation, as well as frequency and severity of movement, coughing, breath holding, and laryngospasm were recorded. MAIN RESULTS: Two patients in each group were excluded from analysis. The fentanyl pretreatment group had a higher frequency of apnea (94% vs 64%; P=0.0003) and longer duration of manual ventilation (3 [interquartile range (IQR), 1.5-5] min vs 1 [0-1.5] min; P<0.0001) at induction. In contrast, the fentanyl pretreatment group had a lower frequency of movements (16% vs 51%;P=0.0001). The rates of intraoperative breath holding (6.1% vs 8.5%) and laryngospasm (2% vs 4.3%) in the two groups were similar. All subjects experiencing laryngospasm were smokers. Adjusting for smoking status did not affect the differences noted in apnea, duration of manual ventilation, or movement between groups; however, coughing occurrence was statistically higher in the placebo group (P=0.043). CONCLUSIONS: Preinduction fentanyl increased the frequency of apnea at induction and duration of manual ventilation, but reduced the frequency of movements. In addition, it reduced intraoperative coughing in smokers. PMID- 24629824 TI - Primary care practice characteristics associated with the quality of care received by patients with depression and comorbid chronic conditions. AB - OBJECTIVE: This study aimed to identify primary care practice characteristics associated with the quality of depression care in patients with comorbid chronic medical and/or psychiatric conditions. METHOD: Using data from cross-sectional organizational and patient surveys conducted within 61 primary care clinics in Quebec, Canada, the relationships between primary care practice characteristics, comorbidity profile, and the recognition and minimally adequate treatment of depression were assessed using multilevel logistic regression analysis with 824 adults with past-year depression and comorbid chronic conditions. RESULTS: Likelihood of depression recognition was higher in clinics where accessibility of mental health professionals was not viewed to be a major barrier to depression care [odds ratio (OR)=1.61; 95% confidence interval (CI) 1.13-2.30]. Four practice characteristics were associated with minimal treatment adequacy: greater use of treatment algorithms for depression (OR=1.77; 95% CI=1.18-2.65), high value given to teamwork (OR=2.48; 95% CI=1.40-4.38), having at least one general practitioner at the clinic devote significant time in practice to mental health (OR=1.54; 95% CI=1.07-2.21) and low perceived barriers to depression care due to inadequate payment models (OR=2.12; 95% CI=1.30-3.46). CONCLUSIONS: Several primary care practice characteristics significantly influence the quality of care provided to patients with depression and comorbid chronic conditions and should be targeted in quality improvement efforts. PMID- 24629825 TI - Influence of asthma on sleep disordered breathing in children: a systematic review. AB - The objective of this study was to perform a systematic review for the association between asthma and sleep disordered breathing (SDB) in children. We performed an electronic search in Medline, Embase, CINAHL, LILACS and Cochrane databases. Study selection criteria: children <18 y of age with diagnosis of asthma and SDB. PRIMARY OUTCOMES: odds ratios (OR) and 95% confidence intervals [95%CI] of asthma for SDB were calculated. There were n = 968 citations identified, of them n = 17 studies were selected, which included n = 45 155 (53% males) children. All included studies defined asthma and SDB based on questionnaires, and only two performed a sleep study for diagnosing obstructive sleep apnea. Mean age was 8.6 +/- 2.5 y. SDB was significantly more frequent in children with asthma compared with non-asthmatics: 23.9% vs 16.7% respectively, p < 0.0001. Children with asthma had a significantly higher risk for SDB: OR 1.9 [1.7; 2.2]. This systematic review showed evidence of a significant association between asthma and SDB in children. Asthma seems to be a significant risk factor for developing SDB. However, the minority of the studies based the diagnosis of SDB on polysomnography, considered the current gold standard for SDB. The physiological and temporal relationships between both conditions should be addressed in future cohort studies. PMID- 24629826 TI - The evidence base of sleep restriction therapy for treating insomnia disorder. AB - Sleep restriction therapy is routinely used within cognitive behavioral therapy to treat chronic insomnia. However, the efficacy for sleep restriction therapy as a standalone intervention has yet to be comprehensively reviewed. This review evaluates the evidence for the use of sleep restriction therapy in the treatment of chronic insomnia. The literature was searched using web-based databases, finding 1344 studies. Twenty-one were accessed in full (1323 were deemed irrelevant to this review). Nine were considered relevant and evaluated in relation to study design using a standardized study checklist and levels of evidence. Four trials met adequate methodological strength to examine the efficacy of therapy for chronic insomnia. Weighted effect sizes for self-reported sleep diary measures of sleep onset latency, wake time after sleep onset, and sleep efficiency were moderate-to-large after therapy. Total sleep time indicated a small improvement. Standalone sleep restriction therapy is efficacious for the treatment of chronic insomnia for sleep diary continuity variables. Studies are insufficient to evaluate the full impact on objective sleep variables. Measures of daytime functioning in response to therapy are lacking. Variability in the sleep restriction therapy implementation methods precludes any strong conclusions regarding the true impact of therapy. A future research agenda is outlined. PMID- 24629827 TI - Ontogeny of dreaming: a review of empirical studies. AB - The examination of children's sleep-related mental experiences presents many significant challenges for researchers investigating the developmental trajectories of human dreaming. In contrast to the well-explored developmental patterns of human sleep, data from dream research are strikingly divergent with highly ambiguous results and conclusions, even though there is plenty of indirect evidence suggesting parallel patterns of development between neural maturation and dreaming. Thus results from studies of children's dreaming are of essential importance not only to enlighten us on the nature and role of dreaming but to also add to our knowledge of consciousness and cognitive and emotional development. This review summarizes research results related to the ontogeny of dreaming: we critically reconsider the field, systematically compare the findings based on different methodologies, and highlight the advantages and disadvantages of methods, arguing in favor of methodological pluralism. Since most contradictory results emerge in connection with descriptive as well as content related characteristics of young children's dreams, we emphasize the importance of carefully selected dream collection methods. In contrast nightmare-related studies yield surprisingly convergent results, thus providing strong basis for inferences about the connections between dreaming and cognitive emotional functioning. Potential directions for dream research are discussed, aiming to explore the as yet unraveled correlations between the maturation of neural organization, sleep architecture and dreaming patterns. PMID- 24629828 TI - The complexities of defining optimal sleep: empirical and theoretical considerations with a special emphasis on children. AB - The main aim of this paper is to consider relevant theoretical and empirical factors defining optimal sleep, and assess the relative importance of each in developing a working definition for, or guidelines about, optimal sleep, particularly in children. We consider whether optimal sleep is an issue of sleep quantity or of sleep quality. Sleep quantity is discussed in terms of duration, timing, variability and dose-response relationships. Sleep quality is explored in relation to continuity, sleepiness, sleep architecture and daytime behaviour. Potential limitations of sleep research in children are discussed, specifically the loss of research precision inherent in sleep deprivation protocols involving children. We discuss which outcomes are the most important to measure. We consider the notion that insufficient sleep may be a totally subjective finding, is impacted by the age of the reporter, driven by socio-cultural patterns and sleep-wake habits, and that, in some individuals, the driver for insufficient sleep can be viewed in terms of a cost-benefit relationship, curtailing sleep in order to perform better while awake. We conclude that defining optimal sleep is complex. The only method of capturing this elusive concept may be by somnotypology, taking into account duration, quality, age, gender, race, culture, the task at hand, and an individual's position in both sleep-alert and morningness-eveningness continuums. At the experimental level, a unified approach by researchers to establish standardized protocols to evaluate optimal sleep across paediatric age groups is required. PMID- 24629829 TI - Eight-years failure of subthalamic stimulation rescued by globus pallidus implant. AB - BACKGROUND: Deep brain stimulation is the surgical procedure of choice in patients with Parkinson's disease. The subthalamic nucleus and the globus pallidus interna are the two most common targets used to treat Parkinson's disease. METHODS: We describe three patients with previous effective subthalamic deep brain stimulation in whom globus pallidus interna deep brain stimulation was performed as "rescue" surgery, 8 years after the original operation. RESULTS: Two years after globus pallidus surgery the reduction of dystonia and dyskinesias led to an improvement of motor symptoms. In two patients, painful dystonias disappeared and motor fluctuations markedly improved. One patient achieved an improvement in freezing. CONCLUSION: After 24 months of follow up, our observations suggest that globus pallidus deep brain stimulation, can improve motor fluctuations, dyskinesia and axial symptoms. PMID- 24629830 TI - Supraorbital stimulation does not induce an antidepressant-like response in rats. AB - BACKGROUND: Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. OBJECTIVE: To show that supraorbital stimulation is effective in preclinical models. METHODS: Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. RESULTS: Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. CONCLUSIONS: Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials. PMID- 24629832 TI - Response to repetitive transcranial magnetic stimulation induced seizures in an adolescent patient with major depression: a case report. PMID- 24629831 TI - Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. AB - Transcranial focused ultrasound (FUS) and microbubble contrast agent, applied at parameters known to transiently increase blood-brain barrier permeability, were tested for the potential to stimulate hippocampal neurogenesis. In adult mice, FUS treatment significantly increased the number of proliferating cells and newborn neurons in the dentate gyrus of the dorsal hippocampus. This provides evidence that FUS with microbubbles can stimulate hippocampal neurogenesis, a process involved in learning and memory and affected in neurological disorders, such as Alzheimer's disease. PMID- 24629833 TI - Author's response. PMID- 24629834 TI - A health literacy pilot intervention to improve medication adherence using Meducation(r) technology. AB - OBJECTIVE: To determine whether antihypertensive medication adherence could improve using a Meducation(r) technology health literacy intervention. METHODS: We conducted a six-month feasibility study among patients with cardiovascular disease (CVD) risk factors receiving care from hospital-based primary care clinics. All patients received a personalized Meducation(r) calendar listing CVD related medications. We evaluated changes in medication adherence and clinical outcomes at six months. RESULTS: There was a 42% enrollment rate (n=23). Forty percent had low health literacy, defined as less than 9th grade reading level. At three months, self-reported medication adherence improved. At six months, medication possession ratio improved 3.2%. Also, at six months there were decreases in patients' average systolic blood pressure (0.5 mmHg), diastolic blood pressure (1.5 mmHg), and body weight (3.6 pounds) (p>0.05). CONCLUSIONS: A health literacy intervention may be a feasible mechanism to improve cardiovascular-related medication adherence and outcomes. PRACTICE IMPLICATIONS: Health literacy interventions may improve adherence while requiring relatively few resources to implement. PMID- 24629835 TI - Optimizing lay counsellor services for chronic care in South Africa: a qualitative systematic review. AB - OBJECTIVE: To conduct a qualitative systematic review on the use of lay counsellors in South Africa to provide lessons on optimizing their use for psychological and behavioural change counselling for chronic long-term care in scare-resource contexts. METHOD: A qualitative systematic review of the literature on lay counsellor services in South Africa. RESULTS: Twenty-nine studies met the inclusion criteria. Five randomized control trials and two cohort studies reported that lay counsellors can provide behaviour change counselling with good outcomes. One multi-centre cohort study provided promising evidence of improved anti-retroviral treatment adherence and one non-randomized controlled study provided promising results for counselling for depression. Six studies found low fidelity of lay counsellor-delivered interventions in routine care. Reasons for low fidelity include poor role definition, inconsistent remuneration, lack of standardized training, and poor supervision and logistical support. CONCLUSION: Within resource-constrained settings, adjunct behaviour change and psychological services provided by lay counsellors can be harnessed to promote chronic care at primary health care level. PRACTICE IMPLICATIONS: Optimizing lay counsellor services requires interventions at an organizational level that provide a clear role definition and scope of practice; in-service training and formal supervision; and sensitization of health managers to the importance and logistical requirements of counselling. PMID- 24629836 TI - Effect of cognitive dysfunction on the relationship between age and health literacy. AB - OBJECTIVE: Age is generally an inverse predictor of health literacy. However, the role of cognitive dysfunction among older adults in this relationship is not understood. METHODS: We conducted a cross-sectional survey of 446 adult patients in a large urban academic level one trauma center, assessing health literacy and cognitive dysfunction. RESULTS: Removing older patients (60 years of age and older) who screened positive for cognitive dysfunction attenuated the relationship between age and health literacy (r=-0.16, p=0.001 vs. r=-0.35, p<0.0001). Older patients screening positive for cognitive dysfunction had significantly lower health literacy than older patients screening negative and patients less than 60 years; health literacy scores did not generally differ significantly between the latter groups. CONCLUSION: Much of the relationship between age and health literacy was driven by cognitive dysfunction among a subset of older adults. PRACTICE IMPLICATIONS: Our findings suggest that older patients with cognitive dysfunction have the greatest need for health literacy interventions. PMID- 24629837 TI - Brief report: how adolescent personality moderates the effect of love history on the young adulthood romantic relationship quality? AB - This study examined the effect of previous romantic relationship involvement on later romantic relationship quality and tested whether adolescents' personality type (i.e., overcontrollers, undercontrollers, resilients) moderated this link. We answered our research questions in a sample of 320 Dutch participants (213 girls) who had a romantic relationship when they were 21 years old. At 12 years of age, their personality types were identified. At 21 years of age, participants reported their current romantic relationship quality (i.e., commitment, exploration, and reconsideration) and indicated the number of romantic relationships they had before. No main effects of the number of romantic relationships on current romantic relationship quality were found. There were significant interaction effects between personality types and the number of romantic relationships on romantic relationship quality. With more romantic relationship experiences, undercontrollers committed less to and explored less in their current romantic relationship. No such link was found for resilients and overcontrollers. PMID- 24629838 TI - Expression of stress ligands of the immunoreceptor NKG2D in melanoma: regulation and clinical significance. AB - Tumor cells, in particular melanoma cells, can be detected as abnormal self by cytotoxic lymphocytes of the innate and adaptive immune system. Of major importance in this process is the activating lymphocyte receptor NKG2D that in humans binds to MIC and ULBP surface molecules on tumor cells. Expression of NKG2D ligands (NKG2DL) is an early event in malignant transformation, induced by stress-associated and oncogene-driven pathways. Thus NKG2DL expression is considered as an innate barrier against tumor development. However, tumor cells can overcome this barrier by shedding of NKG2DL. Ligand shedding leads to elevated levels of soluble ligands in sera of tumor patients that in case of melanoma are of strong prognostic relevance. Here we review important aspects of NKG2DL expression and regulation in tumor cells with a focus on melanoma, and discuss their clinical relevance and potential in immunotherapy. PMID- 24629839 TI - Requirements for and consequences of Rac-dependent protrusion. AB - Small GTPases of the Rac subfamily exert multiple functions, the most prominent of which includes stimulation of dynamic actin rearrangements at the cell periphery. Frequently, these actin reorganizations cause the protrusion of leaflets of plasma membrane, so-called lamellipodia, which remain anchored at flat surfaces during forward protrusion of migrating cells, or develop into ruffles when lifting up- and backwards. Ruffling membranes are also engaged in fluid and particle uptake during pino- and phagocytosis, respectively. In recent work, we sought to clarify the precise role of Rac GTPases in actin-based protrusion, using a gene disruption approach. Furthermore, we aimed at dissecting the function of its downstream target Arp2/3 complex employing its instantaneous inhibition during simultaneous Rac activation. These complementary approaches allow comparison of the consequences of Rac versus Arp2/3 complex loss of function at the cell periphery, and help to formulate a working hypothesis for how the actin network in lamellipodia is initiated and maintained. PMID- 24629840 TI - Role of BAFF/BAFF-R axis in B-cell non-Hodgkin lymphoma. AB - B-cell activating factor (BAFF), as a member of the tumor necrosis factor (TNF) ligand family, plays important roles in B-cell homeostasis, tolerance, and malignancy. BAFF binds to three receptors of TNF, TACI, BCMA and BAFF-receptor (BAFF-R). In particular, the BAFF/BAFF-R pathway is crucial to the survival and growth of mature normal and malignant B-cells. BAFF is displayed on the cell surface or is released in a soluble form after cleavage from the plasma membrane. BAFF-R as the main BAFF receptor is expressed mainly on B-cells. Aberrant BAFF expression was found in malignant B-cells from B-cell non-Hodgkin lymphoma (B NHL) patients, which protects these cells from spontaneous or drug-induced apoptosis and stimulated NF-kappaB activation via autocrine and/or paracrine pathways. However, the mechanisms involved in the gene expression and regulation of BAFF or BAFF-R has not been elucidated. More importantly, the design of reagents able to counteract BAFF/BAFF-R pathways may be of therapeutic value for B-NHL. Results of ongoing clinical trials with BAFF or BAFF-R antagonists are eagerly awaited. PMID- 24629841 TI - Applications of positron emission tomography in neuro-oncology: a clinical approach. AB - The field of neuro-oncology is concerned with some of the most challenging and difficult to treat conditions in medicine. Despite modern therapies patients diagnosed with primary brain tumours often have a poor prognosis. Imaging can play an important role in evaluating the disease status of such patients. In addition to the structural information derived from MRI and CT scans, positron emission tomography (PET) provides important quantitative metabolic assessment of brain tumours. This review describes the use of PET with radiolabelled glucose and amino acid analogues to aid in the diagnosis of tumours, differentiate between recurrent tumour and radiation necrosis and guide biopsy or treatment. [(18)F]Fluorodeoxyglucose (FDG) is the tracer that has been used most widely because it has a 2 h half life and can be transported to imaging centres remote from the cyclotron and radiochemistry facilities which synthesise the tracers. The high uptake of FDG in normal grey matter however limits its use in some low grade tumours which may not be visualised. [(11)C] methionine (MET) is an amino acid tracer with low accumulation in normal brain which can detect low grade gliomas, but its short 20 min half life has limited its use to imaging sites with their own cyclotron. The emergence of new fluorinated amino acid tracers like [(18)F]Fluoroethyl-l-tyrosine (FET) will likely increase the availability and utility of PET for patients with primary brain tumours. PET can, further, characterise brain tumours by investigating other metabolic processes such as DNA synthesis or thymidine kinase activity, phospholipid membrane biosynthesis, hypoxia, receptor binding and oxygen metabolism and blood flow, which will be important in the future assessment of targeted therapy. PMID- 24629842 TI - High HIV incidence in the postpartum period sustains vertical transmission in settings with generalized epidemics: a cohort study in Southern Mozambique. AB - INTRODUCTION: Acute infection with HIV in the postpartum period results in a high risk of vertical transmission through breastfeeding. A study was done to determine the HIV incidence rate and associated risk factors among postpartum women in Southern Mozambique, where HIV prevalence among pregnant women is 21%. METHODS: A prospective cohort study was conducted in six rural health facilities in Gaza and Maputo provinces from March 2008 to July 2011. A total of 1221 women who were HIV-negative on testing at delivery or within two months postpartum were recruited and followed until 18 months postpartum. HIV testing, collection of dried blood spot samples and administration of a structured questionnaire to women were performed every three months. Infant testing by DNA-PCR was done as soon as possible after identification of a new infection in women. HIV incidence was estimated, and potential risk factors at baseline were compared using Poisson regression. RESULTS: Data from 957 women were analyzed with follow-up after the enrolment visit, with a median follow-up of 18.2 months. The HIV incidence in postpartum women is estimated at 3.20/100 women-years (95% CI: 2.30-4.46), with the highest rate among 18- to 19-year-olds (4.92 per 100 women-years; 95% CI: 2.65-9.15). Of the new infections, 14 (34%) were identified during the first six months postpartum, 11 (27%) between 6 and 12 months and 16 (39%) between 12 and 18 months postpartum. Risk factors for incident HIV infection include young age, low number of children, higher education level of the woman's partner and having had sex with someone other than one's partner. The vertical transmission was 21% (95% CI: 5-36) among newly infected women. CONCLUSIONS: Incidence of HIV is high among breastfeeding women in Southern Mozambique, contributing to increasing numbers of HIV-infected infants. Comprehensive primary prevention strategies targeting women of reproductive age, particularly pregnant and postpartum women and their partners, will be crucial for the elimination of paediatric AIDS in Africa. PMID- 24629843 TI - Challenges with couples, serodiscordance and HIV disclosure: healthcare provider perspectives on delivering safer conception services for HIV-affected couples, South Africa. AB - INTRODUCTION: Safer conception interventions should ideally involve both members of an HIV-affected couple. With serodiscordant couples, healthcare providers will need to manage periconception risk behaviour as well tailor safer conception strategies according to available resources and the HIV status of each partner. Prior to widespread implementation of safer conception services, it is crucial to better understand provider perspectives regarding provision of care since they will be pivotal to the successful delivery of safer conception. This paper reports on findings from a qualitative study exploring the viewpoints and experiences of doctors, nurses, and lay counsellors on safer conception care in a rural and in an urban setting in Durban, South Africa. METHODS: We conducted six semistructured individual interviews per site (a total of 12 interviews) as well as a focus group discussion at each clinic site (a total of 13 additional participants). All interviews were coded in Atlas.ti using a grounded theory approach to develop codes and to identify core themes and subthemes in the data. RESULTS: Managing the clinical and relationship complexities related to serodiscordant couples wishing to conceive was flagged as a concern by all categories of health providers. Providers added that, in the HIV clinical setting, they often found it difficult to balance their professional priorities, to maintain the health of their clients, and to ensure that partners were not exposed to unnecessary risk, while still supporting their clients' desires to have a child. Many providers expressed concern over issues related to disclosure of HIV status between partners, particularly when managing couples where one partner was not aware of the other's status and expressed the desire for a child. Provider experiences were that female clients most often sought out care, and it was difficult to reach the male partner to include him in the consultation. CONCLUSIONS: Providers require support in dealing with HIV disclosure issues and in becoming more confident in dealing with couples and serodiscordance. Prior to implementing safer conception programmes, focused training is needed for healthcare professionals to address some of the ethical and relationship issues that are critical in the context of safer conception care. PMID- 24629844 TI - Impact of supervised drug consumption services on access to and engagement with care at a palliative and supportive care facility for people living with HIV/AIDS: a qualitative study. AB - INTRODUCTION: Improvements in the availability and effectiveness of highly active antiretroviral therapy (HAART) have prolonged the lives of people living with HIV/AIDS. However, mortality rates have remained high among populations that encounter barriers to accessing and adhering to HAART, notably people who use drugs. This population consequently has a high burden of illness and complex palliative and supportive care needs, but is often unable to access these services due to anti-drug policies and discrimination. In Vancouver, Canada, the Dr. Peter Centre (DPC), which operates a 24-bed residential HIV/AIDS care facility, has sought to improve access to palliative and supportive care services by adopting a comprehensive harm reduction strategy, including supervised injection services. We undertook this study to explore how the integration of comprehensive harm reduction services into this setting shapes access to and engagement with care. METHODS: Qualitative interviews were conducted with 13 DPC residents between November 2010 and August 2011. Interviews made use of a semistructured interview guide which facilitated discussion regarding how the DPC Residence's model of care (a) shaped healthcare access, (b) influenced healthcare interactions and (c) impacted drug use practices and overall health. Interview transcripts were analysed thematically. RESULTS: Participant accounts highlight how the harm reduction policy altered the structural-environmental context of healthcare services and thus mediated access to palliative and supportive care services. Furthermore, this approach fostered an atmosphere in which drug use could be discussed without the risk of punitive action, and thus increased openness between residents and staff. Finally, participants reported that the environmental supports provided by the DPC Residence decreased drug-related risks and improved health outcomes, including HAART adherence and survival. CONCLUSIONS: This study highlights how adopting comprehensive harm reduction services can serve to improve access and equity in palliative and supportive care for drug-using populations. PMID- 24629846 TI - Women, culture and the HIV epidemic in MENA. PMID- 24629845 TI - Adolescent HIV disclosure in Zambia: barriers, facilitators and outcomes. AB - INTRODUCTION: As adolescents living with HIV gain autonomy over their self-care and begin to engage in sexual relationships, their experiences of being informed about their HIV status and of telling others about their HIV status may affect their ability to cope with having the disease. METHODS: In 2010, we conducted a qualitative study among adolescents aged 10-19 living with HIV in Zambia, and with their parents and health care providers. Through interviews and focus group discussions, we explored the disclosure of HIV status to adolescents living with HIV; adolescents' disclosure of their status to others; and the impact of both forms of disclosure on adolescents. RESULTS: Our study identified three main barriers to disclosure of HIV status: local norms that deter parents from communicating with their children about sexuality; fear of HIV stigma; and an underlying presumption that adolescents would not understand the consequences of a HIV diagnosis on their lives and relationships. With regard to adolescents' disclosure of their HIV status to their sexual partners, our study identified fear of rejection as a common barrier. In rare cases, open family conversations about HIV helped adolescents come to terms with a HIV diagnosis. Findings indicated that disclosure had various outcomes at the individual and interpersonal levels. At the individual level, some adolescents described being anxious, depressed and blaming themselves after being told they had HIV. At the interpersonal level, disclosure created opportunities for adolescents to access adherence support and other forms of psychosocial support from family members and peers. At the same time, it occasionally strained adolescents' sexual relationships, although it did not always lead to rejection. CONCLUSIONS: There is a need for public health interventions that guide adolescents living with HIV, their parents and families through the disclosure process. Such interventions should help parents to assess and understand the evolving cognitive capacity and maturity of their adolescents in order to determine the appropriate time to inform them of their HIV-positive status. Such interventions should also mitigate the risk of HIV stigma, as well as local norms that may prevent discussions of sexuality within families. Adolescents who have been informed of their HIV status should be provided with on-going support to prevent disclosure from negatively affecting their psychological and sexual wellbeing. Further research is needed to explore the potential role of trusted family members in contributing to the disclosure process. PMID- 24629847 TI - Inclusion of adolescent girls in HIV prevention research - an imperative for an AIDS-free generation. PMID- 24629848 TI - The effect of in-hospital developmental care on neonatal morbidity, growth and development of preterm Taiwanese infants: a randomized controlled trial. PMID- 24629849 TI - Comparison of the outcomes of three surgical treatments for end-stage temporomandibular joint disease. AB - The aim of this study was to determine whether there are any differences between condylectomy, rib grafts, and prosthetic joints (Biomet TMJ stock prosthesis) with regard to outcomes for patients with end-stage temporomandibular joint (TMJ) disease. Fifty-six of a total 127 patients who presented with category 5 end stage TMJ disease over 3 years (2010-2013) agreed to participate in this retrospective, comparative, cohort study. Patients were divided into four groups: preoperative (n=16), condylectomy (n=8), rib graft (n=16), and prosthetic joint (n=16). They were assessed for major postoperative complications (i.e., return to theatre) and maximum range of mandibular motion, and all completed a specific quality of life (QOL) questionnaire. Whilst the condylectomy group demonstrated the best mandibular range of motion (P<0.01), rib graft patients were more likely to experience complications (43.8%) necessitating a return to theatre. The prosthesis group recorded the best mean aggregate QOL score, but the difference compared to the rib graft and condylectomy groups was not statistically significant. The results of this study suggest that for dentate patients, prosthetic joints are highly dependable with no returns to theatre and favourable QOL outcomes. For edentulous patients, condylectomies alone also appear to work well. Future TMJ prosthetic designs should focus on improving mandibular range of motion, as the current stock prosthesis allows only a restricted range, no better than that achieved with rib graft (P>0.05) and far less than that achieved with condylectomy (P<0.01). PMID- 24629850 TI - The choice of multiple myeloma induction therapy affects the frequency and severity of oral mucositis after melphalan-based autologous stem cell transplantation. AB - INTRODUCTION/BACKGROUND: Mucositis is a common complication of high-dose melphalan (HDM) used before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Mucositis rates are influenced by previous chemotherapy (CT) exposure. We examined the effect of induction therapy before ASCT on ASCT mucositis rates. PATIENTS AND METHODS: Patients undergoing first 200 mg/m(2) HDM ASCT were assessed. Those receiving < 200 mg/m(2), or those with previous ASCT were excluded. Patients were evaluated depending on type of induction therapy (CT, immunomodulatory drug [IMiD], or proteasome inhibitor [PI]) before ASCT. A case record review was performed and data collected on response to induction, rates of Grade 3/4 mucositis, and days of total parenteral nutrition (TPN) or parenteral opiate analgesia. RESULTS: One hundred twenty-eight patients with ASCT were assessed. Induction therapy was CT- (n = 62), IMiD- (n = 51), or PI-based (n = 15) therapy. Patient characteristics were overall similar, including median age, MM stage, and CD34(+) cell dose. IMiD-based therapy patients had lower rates of mucositis (33% vs. 53%; P = .03) and less opiate requirements (10% vs. 31%; P = .02) compared with those treated with CT. Rates of mucositis and opiate use in the PI group were not different to the CT cohorts (33% vs. 53%; P = .6 and 13% vs. 31%; P = .13), likely due to concurrent anthracycline exposure. TPN usage was similar (CT, 42%; IMiD, 35%; and PI, 20%), as was neutropenia duration and antibiotic usage. CONCLUSION: Patients treated with IMiD-based regimens before HDM ASCT had significantly lower rates of mucositis than those treated with CT based therapy. There were too few patients who received PI therapy to evaluate the effect. PMID- 24629851 TI - Single-agent lenalidomide is effective in the treatment of a heavily pretreated and refractory angioimmunoblastic T-cell lymphoma patient. PMID- 24629856 TI - Paediatric thyroid disease. Preface. PMID- 24629852 TI - What determines therapeutic choices for elderly patients with DLBCL? Clinical findings of a multicenter study in Portugal. AB - BACKGROUND: Age is a negative prognostic factor in lymphomas, and elderly patients are often undertreated because of toxicity concerns. The pattern of treatment in elderly patients with diffuse large B-cell lymphoma (DLBCL) in Portugal has not been previously described. PATIENTS AND METHODS: We conducted a multicenter retrospective study including 378 elderly patients with DLBCL receiving alkylating agent-containing regimens between 2003 and 2010. We compared the outcome of patients aged 60 to 79 years with patients > 79 years and analyzed the second group according to treatment. RESULTS: R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) was prescribed in only 60% of patients and was prescribed significantly less in patients > 79 years, despite no significant differences being found in comorbidities between the 2 age groups. Similarly, dose reductions frequently were instituted because of chronologic age and not always because of toxicity. When different regimens were compared, multivariate analysis showed an independent beneficial effect of R-CHOP in treatment outcomes. Additionally, treatment with anthracyclines and rituximab predicted a better progression-free survival (PFS) and time to progression (TTP) in patients > 79 years. CONCLUSION: This was the first characterization of the clinical care of elderly Portuguese patients with DLBCL. We showed that R-CHOP is effective even in patients > 79 years, emphasizing that treatment decisions based on age alone can compromise treatment efficacy and outcome in fit patients. PMID- 24629857 TI - Genetics of normal and abnormal thyroid development in humans. AB - The most frequent cause of congenital hypothyroidism is thyroid dysgenesis. Thyroid dysgenesis summarizes a spectrum of developmental abnormalities of the embryonic thyroid ranging from complete absence of the thyroid gland (athyreosis), to a normally located but too small thyroid (hypoplasia), or an abnormally located thyroid gland (ectopy). Although considered a sporadic disease, distinct genetic forms of isolated or syndromic thyroid dysgenesis have been described in recent years. However, genetics of thyroid dysgenesis (TD) are mostly not following simple Mendelian patterns, and beside monogenic, multigenic and epigenetic mechanisms need to be considered. The review will highlight the molecular mechanisms of thyroid organogenesis, clinical and genetic features of the different monogenetic forms of thyroid dysgenesis, the aspects relevant for diagnosis and counseling of affected families and current research strategies to get more insight into the non-Medelian mechanisms of normal and abnormal thyroid development. PMID- 24629858 TI - Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects. AB - DEHAL1 (also named IYD) is the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone. Failure of this enzyme leads to the iodotyrosine deiodinase deficiency (ITDD), characterized by hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations. A handful of mutations in the DEHAL1 gene have been identified as the molecular basis for the ITDD. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, and psychomotor deficits were present in some affected individuals. This is probably due to the lack of biochemical expression of the disease at the beginning of life, which causes ITDD being undetected in screening programs for congenital hypothyroidism, as currently performed. This worrying feature calls for efforts to improve pre clinical detection of iodotyrosine deiodinase deficiency during the neonatal time. Such a challenge poses questions of patho-physiological (natural history of the disease, environmental factors influencing its expression) epidemiological (prevalence of ITDD) and technical nature (development of optimal methodology for safe detection of pre-clinical ITDD), which will be addressed in this review. PMID- 24629859 TI - Fetal thyroidology. AB - Advances in prenatal imaging techniques and in fetal hormonology now allow for identification of disorders of thyroid function in the fetus. These can potentially be treated in utero by giving drugs to the mother. This review shows the feasibility of in utero treatment of fetal thyroid disorders, either indirectly by treating the mother or by giving the necessary drugs directly to the fetus. For goitrous fetal hypothyroidism leading to hydramnios, repeated intra-amniotic injections of thyroxine have been reported to decrease the size of the fetal thyroid. Experience with such procedures is limited but positive. The risk that direct in utero treatment of the fetus may provoke premature labor or cause infection should be carefully evaluated. In women with Graves' disease, autoimmune fetal hyperthyroidism can generally be treated in a noninvasive way by optimizing treatment of the mother, such as by increasing the dose of antithyroid drugs. Follow-up of the efficacy and the possible long-term consequences of medical interventions to normalize thyroid function of the fetus are of great importance. Specialized care of the fetus should be provided by skilled teams with extensive experience in prenatal care. PMID- 24629860 TI - Screening for congenital hypothyroidism: a worldwide view of strategies. AB - Detection by newborn screening (NBS) and treatment of babies with congenital hypothyroidism (CH) has largely eliminated the intellectual disability caused by this disorder. Lowering of the screening TSH cutoff and changes in birth demographics have been associated with an approximate doubling of the incidence of CH, from 1:3500 to 1:1714. The additional cases detected by lowering of the TSH cutoff tend to have milder hypothyroidism, with imaging often demonstrating a eutopic, "gland in-situ", and some cases turn out to have transient CH. Based on our search for current screening programs, approximately 71 percent of babies worldwide are not born in an area with an established NBS program, despite the existence of screening for over five decades in developed countries. Thus, the majority of babies with CH worldwide are not detected and treated early, such that the economic burden of retardation owing to CH remains a significant public health challenge. PMID- 24629862 TI - Imaging the thyroid in children. AB - Color Doppler Ultrasounds (CDU) and Thyroid Scanning (TS) have much improved in recent years and offer a likely diagnosis of the disorder and its main subtypes. This especially applies when diagnosing permanent or transient causes of congenital hypothyroidism (CH), where dual imaging has proven to be more informative than single scanning. Though both isotopes have acceptable performances, the use of (123)I appears more advisable, since it more accurately identifies the various aetiologies of CH and probably has better dosimetric characteristics than (99m)Tc. Detailed dual imaging patterns are presented in connection with most of the underlying mechanisms explaining CH, thyroid dysgenesis (75%) and dyshormonogenesis (20%). Imaging of thyroid autoimmunity, of immunogenic thyrotoxicosis and of thyroid autonomy, is helped by CDU but most often requires a quantified (123)I-TS (molecular imaging). We finally show the interest of CDU to sort suspicious nodule and present the new TIRADS scoring system. PMID- 24629861 TI - Inherited defects in thyroid hormone cell-membrane transport and metabolism. AB - The description of two novel human defects in the last ten years has uncovered new aspects of thyroid hormone physiology with regard to cell-membrane transport and intracellular metabolism. Mutations in the X-linked monocarboxylate transporter 8 (MCT8) gene result in an invalidating neurodevelopmental phenotype in males and pathognomonic thyroid functions tests with high T3, low rT3, low or low normal T4, and normal or slightly high TSH. Recessive mutations in the selenocysteine insertion sequence binding protein 2 (SBP2) gene present a variable clinical phenotype depending on the severity of the defect and its consequences on the selenoprotein hierarchy. Most characteristic is the thyroid phenotype of low serum T3, high T4, high rT3, and slightly elevated TSH levels. Herein we review all known cases of MCT8 and SBP2 deficiency and describe each disease in terms of the clinical, biochemical, genetic, and therapeutic aspects. PMID- 24629863 TI - Impact of mild thyroid hormone deficiency in pregnancy on cognitive function in children: lessons from the Generation R Study. AB - Animal models and epidemiological studies suggest that mild maternal thyroid hormone deficiency in early gestation has adverse consequences on the cognitive abilities of the children. However, methodological problems, lack of a consistent definition for mild thyroid hormone deficiency, and short follow-up of the children reduce the confidence in the conclusion of existing studies. In this review, we summarize the main findings of a series of studies performed in Generation R, a population-based birth cohort in Rotterdam, the Netherlands. In this iodine sufficient region, we aimed to investigate the relation between mild maternal thyroid hormone deficiency in early gestation and children's verbal and nonverbal cognitive function and executive function. We discuss the main findings of these studies, present recommendations for clinicians and formulate suggestions for future research. PMID- 24629864 TI - Graves' disease in children. AB - Graves' disease is an autoimmune disorder resulting from thyrotropin receptor stimulation by autoantibodies. It may occur at any age during childhood, but its frequency increases with age, peaking during adolescence. Symptoms and signs are often recognizable and proportional to the increase in serum free thyroid hormone levels. Antithyroid drug treatment with methimazole (or carbimazole) is recommended for initial treatment, but relapse rates are high, with remission achieved in only 30% of children after a first course of treatment for about two years. More prolonged medical treatment may increase the remission rate to up to 50%. Alternative treatments, such as radioactive iodine or thyroidectomy, are considered in cases of relapse, lack of compliance or antithyroid drug toxicity. Relapse risk decreases with increasing duration of the first course of antithyroid drug treatment. The identification of other predictive factors, such as severe biochemical hyperthyroidism at diagnosis, young age and the absence of other autoimmune conditions, has made it possible to stratify patients according to the risk of relapse, leading to improvements in patient management, by facilitating the identification of patients requiring long-term antithyroid drug treatment or early alternative therapy. PMID- 24629865 TI - Thyroid nodules. AB - According to the literature, thyroid nodules (TNs) are quite rare in the first two decades of life and are predominantly non-cancerous, although cancerous TNs are more common in the first two decades of life than in adults. Therefore, it is important for clinicians to distinguish benign from malignant lesions preoperatively because the latter require a total thyroidectomy with or without neck lymph node dissection. A careful work-up and a fine-needle aspiration biopsy (FNAB) are mandatory to improve the preoperative diagnosis. High-resolution thyroid ultrasound and real-time elastosonography are adjuvant presurgical tools in selecting patients for surgery, particularly those with indeterminate or non diagnostic cytology. Elevated thyroid-stimulating hormone (TSH) level in a patient with a thyroid nodule is a new laboratory predictor of thyroid cancer risk. The majority of thyroid carcinomas derive from the follicular cell, whereas medullary thyroid carcinoma (MTC) derives from calcitonin-producing cells. Patients with MTC are screened for germ-line RET mutations to detect carriers and identify family members for prophylactic or therapeutic thyroidectomy. PMID- 24629866 TI - The identification of factors contributing to self-reported anomalies in civil aviation. AB - The main objective of this study was to analyze anomalies voluntarily reported by pilots in civil aviation sector and identify factors leading to such anomalies. Experimental data were obtained from the NASA aviation safety reporting system (ASRS) database. These data contained a range of text records spanning 30 years of civilian aviation, both commercial (airline operations) and general aviation (private aircraft). Narrative data as well as categorical data were used. The associations between incident contributing factors and self-reported anomalies were investigated using data mining and correspondence analysis. The results revealed that a broadly defined human factors category and weather conditions were the main contributors to self-reported civil aviation anomalies. New associations between identified factors and reported anomaly conditions were also reported. PMID- 24629867 TI - Investigated serious occupational accidents in the Netherlands, 1998-2009. AB - Since 2003, a project has been underway to analyse the most serious occupational accidents in The Netherlands. All the serious occupational accidents investigated by the Dutch Labour Inspectorate for the 12 years of 1998-2009 inclusive have been entered into a database, a total of 20 030 investigations. This database uses a model of safety barriers supported by barrier tasks and management delivery systems such that, when combined with sector and year information, trends in the data can be analysed for their underlying causes. The trend analyses show that while the number of victims of serious reportable accidents is significantly decreasing, this is due to specific sectors, hazards and underlying causes. The significant results could not easily be directly associated with any specific regulation or action undertaken in The Netherlands although there have been many different approaches to reducing accidents during the period analysed, which could be contributing to the effect. PMID- 24629868 TI - The impact of occupational load carriage on carrier mobility: a critical review of the literature. AB - Military personnel and firefighters are required to carry occupational loads and complete tasks in hostile and unpredictable environments where a lack of mobility may risk lives. This review critically examines the literature investigating the impacts of load carriage on the mobility of these specialist personnel. Several literature databases, reference lists, and subject matter experts were employed to identify relevant studies. Studies meeting the inclusion criteria were critiqued using the Downs and Black protocol. Inter-rater agreement was determined by Cohen's kappa. Twelve original research studies, which included male and female participants from military and firefighting occupations, were critiqued (kappa = .81). A review of these papers found that as the carried load weight increased, carrier mobility during aerobic tasks (like road marching) and anaerobic tasks (like obstacle course negotiation) decreased. As such, it can be concluded that the load carried by some specialist personnel may increase their occupational risk by reducing their mobility. PMID- 24629869 TI - Friction between footwear and floor covered with solid particles under dry and wet conditions. AB - Solid particles on the floor, both dry and wet, are common but their effects on the friction on the floor were seldom discussed in the literature. In this study, friction measurements were conducted to test the effects of particle size of solid contaminants on the friction coefficient on the floor under footwear, floor, and surface conditions. The results supported the hypothesis that particle size of solids affected the friction coefficient and the effects depended on footwear, floor, and surface conditions. On dry surfaces, solid particles resulted in friction loss when the Neolite footwear pad was used. On the other hand, solid particles provided additional friction when measured with the ethylene vinyl acetate (EVA) footwear pad. On wet surfaces, introducing solid particles made the floors more slip-resistant and such effects depended on particle size. This study provides information for better understanding of the mechanism of slipping when solid contaminants are present. PMID- 24629870 TI - The effect of a physical activity program on decreasing physical disability indicated by musculoskeletal pain and related symptoms among workers: a pilot study. AB - The aim of this study was to verify the effect of a physical activity (PA) program on musculoskeletal pain and related symptoms in different body regions among workers. METHODS: The intervention study lasted 6 months. The training sessions were given during work time. The intervention group (TOI) (n = 39) participated in 10-15 min of physical exercise training 3 times a week and focused on stretching exercises and general strength. The reference group (TOR) (n = 31) were asked to continue their daily activities. Musculoskeletal pain was assessed with the standardized Nordic questionnaires for analyzing musculoskeletal symptoms. Evaluations were performed at baseline and at the end of the intervention. RESULTS: After the intervention, the TOI obtained some significant results regarding a decrease in the intensity of pain in some of the body regions evaluated, such as elbow (p = .03) and dorsal region (p = .015). In comparing the TOR and TOI after the 6 months of the PA program, we can verify that in the elbow and in the thigh/hip regions, the pain intensity decreased significantly; additionally, there is some evidence to suggest statistically significant results in the neck region (p = .063). CONCLUSION: Our intervention seems to have reduced musculoskeletal pain and related symptoms in factory workers. PMID- 24629871 TI - Flexion and extension angles of resting fingers and wrist. AB - This study determined flexion and extension angles of resting fingers and wrist in terms of forearm posture (neutral, pronation and supination) and shoulder flexion (0 degrees , 45 degrees , 90 degrees and 135 degrees ). The participants participated in 12 angle measurements for 16 finger joints and wrist. The finger joints flexed more in supination than in neutral posture and pronation and the thumb flexed more than the other fingers because of the gravity and skin tension. This phenomenon became more apparent as the shoulder flexed. The carpometacarpal joint had the largest flexion angle in the thumb joints, whereas the proximal interphalangeal joints had the largest flexion angles in the other finger joints. The resting posture of the wrist extended of ~16 degrees in any forearm postures when the shoulder was at 0 degrees . The results of this study could be useful for rehabilitation tool and product designs. PMID- 24629872 TI - Stereovision safety system for identifying workers' presence: results of tests. AB - This article presents the results of extensive tests of a stereovision safety system performed using real and artificial images. A vision based protective device (VBPD) analyses images from 2 cameras to calculate the position of a worker and moving parts of a machine (e.g., an industrial robot's arm). Experiments show that the stereovision safety system works properly in real time even when subjected to rapid changes in illumination level. Experiments performed with a functional model of an industrial robot indicate that this safety system can be used to detect dangerous situations at workstations equipped with a robot, in human-robot co- operation. Computer-generated artificial images of a workplace simplify and accelerate testing procedures, and make it possible to compare the effectiveness of VBPDs and other protective devices at no additional cost. PMID- 24629873 TI - Factors influencing unsafe behaviors and accidents on construction sites: a review. AB - OBJECTIVE: Construction is a hazardous occupation due to the unique nature of activities involved and the repetitiveness of several field behaviors. The aim of this methodological and theoretical review is to explore the empirical factors influencing unsafe behaviors and accidents on construction sites. METHODS: In this work, results and findings from 56 related previous studies were investigated. These studies were categorized based on their design, type, methods of data collection, analytical methods, variables, and key findings. A qualitative content analysis procedure was used to extract variables, themes, and factors. In addition, all studies were reviewed to determine the quality rating and to evaluate the strength of provided evidence. RESULTS: The content analysis identified 8 main categories: (a) society, (b) organization, (c) project management, (d) supervision, (e) contractor, (f) site condition, (g) work group, and (h) individual characteristics. The review highlighted the importance of more distal factors, e.g., society and organization, and project management, that may contribute to reducing the likelihood of unsafe behaviors and accidents through the promotion of site condition and individual features (as proximal factors). CONCLUSION: Further research is necessary to provide a better understanding of the links between unsafe behavior theories and empirical findings, challenge theoretical assumptions, develop new applied theories, and make stronger recommendations. PMID- 24629874 TI - Assessing the interplay between the shoulders and low back during manual patient handling techniques in a nursing setting. AB - The purpose of this research was to quantify shoulder demands during freestyle manual patient handling (MPH) tasks and determine whether approaches intended to prevent low back injury increased shoulder demands. Twenty females completed 5 MPH tasks found commonly in hospital settings before and after a training session using current workplace MPH guidelines. Most normalized muscle activity indices and ratings of perceived exertion decreased following training at both the low back and shoulders, but were more pronounced at the low back. There was little evidence to suggest that mechanical demands were transferred from the low back to the shoulders following the training session. The study generally supports continued use of the recommended MPH techniques, but indicates that several tasks generate high muscular demands and should be avoided if possible. PMID- 24629875 TI - The relationship between shift work schedules and spillover in a sample of nurses. AB - The aim of the present study was to estimate spillover effects between the work and the family sphere in a sample of nurses (N = 2058). Hierarchical regression analyses investigated whether shift work schedules were associated with negative or positive spillover, both from family to work and vice versa, controlling for demographic factors, job demands and decision latitude. With daytime work as a reference group, all types of shift work (day and evening shift, night shift only and rotating 3 shift) were associated with higher negative work-to-family spillover. Night work was associated with significantly less negative family-to work spillover. None of the different shift work schedules were related to any type of positive spillover. The results indicate that working outside of daytime hours is less compatible with workers' family lives, compared to working ordinary day shifts. On the other hand, working night shifts only was associated with reduced negative family-to-work spillover. PMID- 24629876 TI - Development of PAOT tool kit for work improvements in clinical nursing. AB - The aim of this study was to develop an action checklist for educational training of clinical nurses. The study used qualitative and quantitative methods. Questionnaire items were extracted through in-depth interviews and a questionnaire survey. PASW version 19 and AMOS version 19 were used for data analyses. Reliability and validity were tested with both exploratory and confirmative factor analysis. The levels of the indicators related to goodness-of fit were acceptable. Thus, a model kit of work improvements in clinical nursing was developed. It comprises 5 domains (16 action points): health promotion (5 action points), work management (3 action points), ergonomic work methods (3 action points), managerial policies and mutual support among staff members (3 action points), and welfare in the work area (2 action points). PMID- 24629877 TI - Combined effects of physical demands and shift working on low back disorders among nursing personnel. AB - The aim of this study was to investigate the synergistic effects of physical demands and shift working on low back disorders (LBDs) among nursing personnel. The study used 2 questionnaires: a self-administered questionnaire composed of parts of Nordic musculoskeletal questionnaire to assess LBDs and job content questionnaire to assess physical demands. The participants were divided into 4 groups: from group 1 (low physical demands day workers) to group 4 (high physical demands shift workers). In regression analysis, high physical demands were associated with the prevalence of LBDs independently (OR 4.4, 95% CI [2.40, 8.00] and p < .05), but there was no association between shift working and LBDs (p > .05). Odds ratio in high physical demands shift workers was 9.33 compared to the reference group (p < .001). Calculated synergistic index was 7.37. Simultaneous impacts of shift working and high physical demands may increase the prevalence of LBDs among nursing personnel. PMID- 24629878 TI - Application of a screening method in assessing occupational safety and health of computer workstations. AB - Employers and workers need concrete guidance to plan and implement changes in the ergonomics of computer workstations. The Nappara method is a screening tool for identifying problems requiring further assessment and corrective actions. The aim of this study was to assess the work of occupational safety and health (OSH) government inspectors who used Nappara as part of their OSH enforcement inspections (430 assessments) related to computer work. The modifications in workstation ergonomics involved mainly adjustments to the screen, mouse, keyboard, forearm supports, and chair. One output of the assessment is an index indicating the percentage of compliance items. This method can be considered as exposure assessment and ergonomics intervention used as a benchmark for the level of ergonomics. Future research can examine whether the effectiveness of participatory ergonomics interventions should be investigated with Nappara. PMID- 24629879 TI - Occupational cognitive failures and safety performance in the workplace. AB - Introduction. The majority of industrial accidents occur because of human errors. Human error has different causes, however, in all cases cognitive abilities and limitations of human play an important role. Occupational cognitive failures are cognitively-based human errors that occur at work. The aim of this study was to examine the relationship between occupational cognitive failures and safety consequences. Method. Personnel of a large industrial company in Iran filled out an occupational cognitive failure questionnaire (OCFQ) and answered questions on accidents. Univariate and multiple logistic regression analysis were used to determine the relationship between cognitive failures and safety consequences. Results. According to developed regression models, personnel with a high rate of cognitive failure, in comparison to low rate, have a high risk of minor injury involvement (OR 5.1, 95% CI [2.62, 10.3]); similar results were for major injury and near miss. Discussion. The results of this study revealed usefulness of the OCFQ as a tool of predicting safety- related consequences and planning preventive actions. PMID- 24629880 TI - Workplace hazards and prevention options from a nonrandom sample of retail trade businesses. AB - Employer commitment is a key factor in an effective safety program, yet limited research has focused on the safety priorities of retail store managers. To address this, the U.S. National Institute for Occupational Safety and Health recruited 4 experienced ergonomists, who met and interviewed 9 retailers in different parts of the eastern USA. The reports from the 9 interviews were used to document the hazards facing retailers and the interventions they attempted. Those interviewed were managers/owners of establishments that ranged from a small bakery with 11 employees to a supermarket with 85 or more employees. The main hazards across all establishments included overexertion, contact-with-objects, and falls-to-the-same-level. We also compared the retailers' perceptions of safety hazards with injuries from actual hazards as supplied by the U.S. Bureau of Labor Statistics. This report provides insight into the retailers' perceptions of safety hazards as well as their commitment to the prevention of workplace injuries. PMID- 24629881 TI - Horizontal career changes as an alternative to premature exit from work. AB - Certain workplaces are called jobs with limited tenure. Due to physical or psychosocial risk factors, often coupled with qualification mismatches, workers cannot grow old in them. That may lead to premature exit into retirement, to a period of drawing a work incapacity pension or to a long spell of unemployment. A horizontal career change, which enables the worker to move on to a less burdening workplace while preserving social status, is a possible solution. The objective of the "Horizontal career change-a new job opportunity for older employees" project is to develop a model of career changes for workers employed in jobs with limited tenure and to implement it in the form of an information- and communication technology-based tool. Possible applications range from individual career planning, through institutionalized vocational reintegration, to personnel development in small and medium-sized enterprises. PMID- 24629882 TI - Experimental study on gender differences in hands and sequence of force application on grip and hand-grip control. AB - The purpose of this study was to examine how gender of young adults in Taiwan affected the ability of their hands to apply force regarding the use of the left or right hand and the varying sequences of force application. Maximal voluntary contraction of grip (MVCg ) and hand-grip control (HGC 50% ) of 200 participants was measured. The study discovered that gender showed significant differences in the scale of MVC g, whereas there were no significant differences in HGC 50% . Left hand versus right hand resulted in significant differences in the scale of MVC g, whereas there were no significant differences in the scale of HGC 50% . The 5 levels of the sequence of force application showed no significant differences in either MVC g or HGC 50% . The interactive effects of the 3 factors (gender, hand, and sequence of force application) showed no significant differences. The results of the study can serve as a reference in designing tools. PMID- 24629883 TI - Green and gold--the colours of modern research publishing. PMID- 24629884 TI - Continued drug use during methadone treatment in China: a retrospective analysis of 19,026 service users. AB - This study examined nation-wide data from China to assess client outcomes after 6 months of methadone treatment. Data on 19,026 clients enrolled between April 2008 and March 2010 were reviewed for changes in HIV-risk behaviours and emergence of new HIV cases. Multivariable logistic regression was used to identify factors associated with illicit drug use while in MMT. Clients reported reduced drug use and related risk behaviours and improved social functioning. There were 24 newly identified cases of HIV. Continued drug use was associated with low attendance (OR=5.98, 95% CI=4.69-7.63), frequently seeing drug using friends (OR=3.72 for daily vs. never, 95% CI=3.18-4.34) and having a difficult family relationship (OR=2.03 for difficult vs. good, 95% CI=1.63-2.52). Methadone dose was not associated with continued drug use while in treatment. The Chinese MMT programme appears to be having a positive influence on those clients who remain in treatment, but needs to explore strategies to increase accessibility. PMID- 24629885 TI - Substance use recovery outcomes among a cohort of youth participating in a mobile based texting aftercare pilot program. AB - Project ESQYIR (Educating & Supporting Inquisitive Youth in Recovery) is a pilot study examining the feasibility of a 12-week mobile-based aftercare intervention for youth (ages 12 to 24) transitioning out of community-based substance abuse treatment programs. From January 2012 through July 2013, a total of 80 youth were recruited from outpatient and residential treatment programs, geographically dispersed throughout Los Angeles County, California. Results revealed that youth who participated in the texting mobile pilot intervention were significantly less likely to relapse to their primary compared to the aftercare as usual control condition (OR=0.52, p=0.002) over time (from baseline throughout the 12-week aftercare pilot program to a 90-day follow-up). Participants in the texting aftercare pilot program also reported significantly less substance use problem severity (beta=-0.46, p=0.03) and were more likely to participate in extracurricular recovery behaviors (beta=1.63, p=0.03) compared to participants in the standard aftercare group. Collectively, findings from this pilot aftercare study suggest that mobile texting could provide a feasible way to engage youth in recovery after substance abuse treatment to aid with reducing relapse and promoting lifestyle behavior change. PMID- 24629886 TI - Impulsivity as a vulnerability factor for poor addiction treatment outcomes: a review of neurocognitive findings among individuals with substance use disorders. AB - With the current review, we explore the hypothesis that individual differences in neurocognitive aspects of impulsivity (i.e., cognitive and motor disinhibition, delay discounting and impulsive decision-making) among individuals with a substance use disorder are linked to unfavorable addiction treatment outcomes, including high drop-out rates and difficulties in achieving and maintaining abstinence. A systematic review of the literature was carried out using PubMed, PsycINFO and Web of Knowledge searches. Twenty-five unique empirical papers were identified and findings were considered in relation to the different impulsivity dimensions. Although conceptual/methodological heterogeneity and lack of replication are key limitations of studies in this area, findings speak for a prominent role of cognitive disinhibition, delay discounting and impulsive decision-making in the ability to successfully achieve and maintain abstinence during and following addiction treatment. In contrast, indices of motor disinhibition appear to be unrelated to abstinence levels. Whereas the relationship between impulsivity and treatment retention needs to be examined more extensively, preliminary evidence suggests that impulsive/risky decision making is unrelated to premature treatment drop-out among individuals with a substance use disorder. The reviewed findings are discussed in terms of their clinical implications. PMID- 24629888 TI - Is the leaf bundle sheath a "smart flux valve" for K+ nutrition? AB - Evidence has started to accumulate that the bundle sheath regulates the passage of water, minerals and metabolites between the mesophyll and the conducting vessels of xylem and phloem within the leaf veins which it envelops. Although potassium (K(+)) nutrition has been studied for several decades, and much is known about the uptake and recirculation of K(+) within the plant, the potential regulatory role of bundle sheath with regard to K(+) fluxes has just begun to be addressed. Here we have collected some facts and ideas about these processes. PMID- 24629887 TI - Test-retest reliability of a self-administered Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in primary care patients. AB - The time required to conduct drug and alcohol screening has been a major barrier to its implementation in mainstream healthcare settings. Because patient self administered tools are potentially more efficient, we translated the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) into an audio guided computer assisted self interview (ACASI) format. This study reports on the test retest reliability of the ACASI ASSIST in an adult primary care population. Adult primary care patients completed the ACASI ASSIST, in English or Spanish, twice within a 1-4 week period. Among the 101 participants, there were no significant differences between test administrations in detecting moderate to high risk use for tobacco, alcohol, or any other drug class. Substance risk scores from the two administrations had excellent concordance (90-98%) and high correlation (ICC 0.90 0.97) for tobacco, alcohol, and drugs. The ACASI ASSIST has good test-retest reliability, and warrants additional study to evaluate its validity for detecting unhealthy substance use. PMID- 24629889 TI - [Effect of biliary obstruction on lipoprotein(a) concentration]. AB - OBJECTIVES: This study was appointed to determine the correlation between the concentration of lipoprotein(a) [Lp(a)], apolipoproteins and lipids with biochemical parameters of liver function in a group of patients with reversible cholestasis. We have also determined the concentration of these parameters once solved the biliary obstruction process. MATERIAL AND METHODS: Eighteen adults over 17 years with extrahepatic cholestasis were included in the study on a prospective basis, and we determined in them biochemical liver function parameters and lipoprotein metabolism parameters, particularly Lp(a) before and after unblocking. RESULTS: The concentration of Lp(a) prior to desobstruction was inverse and statistically significantly correlated with the concentration of gamma glutamyl transpeptidase (correlation coefficient [r] = -0.757, P = .018). The concentration of Lp(a) (median = 2.66 mg/dL, interquartile range = 5,62) showed a statistically significant increase (median = 9.72 mg/dL, interquartile range = 28.76, P < .001), once the unblocking was performed. Concentrations of total cholesterol and triglycerides had a statistically significant decrease, and HDL cholesterol and apolipoprotein A-1 showed a statistically significant increase once the unblocking was carried out. CONCLUSIONS: The concentration of Lp(a) is decreased during cholestasis, although there is a significant simultaneous hypercholesterolemia. Cholestasis has a causal role in lowering Lp(a), because the unblocking of bile duct recovers Lp(a) concentration. Our study supports the concept that bile acids exert a controlling effect on the synthesis of Lp(a) and open a mechanism for the treatment of hyper Lp(a). PMID- 24629890 TI - Deep sequencing reveals myeloma cells in peripheral blood in majority of multiple myeloma patients. AB - INTRODUCTION: The evaluation of myeloma cells in multiple myeloma (MM) patients has generally been limited to the assessment of bone marrow involvement because of the sensitivity limitations of traditional minimal-residual-disease-detection methods. MATERIALS AND METHODS: We developed a sequencing-based method to identify myeloma cells in bone marrow (BM) and peripheral blood (PB) samples, based on their unique immunoglobulin gene rearrangements, that can detect cancer clones at levels well below 1 in 1 million leukocytes (0.0001%). In this multisite study, we used this sequencing method to determine the fraction of patients with myeloma cells in their PB at diagnosis and posttreatment time points. RESULTS: Using this sequencing approach, we detected myeloma cells in the PB in the vast majority of MM patients (44/46, 96%). We demonstrated a clear correlation (R(2) = 0.57) between myeloma clone levels in paired BM and PB samples, and noted that PB clone levels were approximately 100-fold lower than levels in BM samples. The sequencing assay demonstrated a clear sensitivity advantage in the BM compartment and at least equivalent sensitivity in the PB compared with that of monoclonal-protein results. CONCLUSION: This study highlights the promise of a blood-based, sequencing minimal-residual-disease assay that can be used to measure MM disease burden at different time points and various disease stages. PMID- 24629891 TI - Case report: benign gastric ulcer erosion leading to a gastropericardial fistula in a patient with no known risk factors. AB - A 53-year-old homeless male presented to the emergency department with sudden onset chest pain and was found to have a large pneumopericardium on chest X-ray. The patient had no history of surgery, hiatal hernia, or ulcer disease. A contrast-enhanced computed tomography scan demonstrated the pneumopericardium and raised concern for possible gastropericardial fistula from a benign gastric ulcer. An esophagogastroduodenoscopy confirmed the fistula, as did surgery, and intraoperatively vegetable particular matter was removed from the anatomic space continuous with the pericardium. PMID- 24629892 TI - CD44 in canine leukemia: analysis of mRNA and protein expression in peripheral blood. AB - Hyaluronan receptor CD44 mediates interaction between cells and extracellular matrix. The expression of standard form and its variants is dysregulated in human leukemias and is associated with metastasis and prognosis. The aim of this work is the evaluation of CD44 mRNA and protein expression in canine leukemia. Peripheral blood from 20 acute leukemias (AL) (10 acute lymphoblastic, 6 acute myeloid and 4 acute undifferentiated leukemias), 21 chronic lymphocytic leukemias (CLL) and thirteen healthy dogs were collected. The mRNA expression of all CD44 variants presenting exons 1-5 and/or 16-20 (CD44_ex1-5 and CD44_ex16-20) and CD44 protein were determined by real-time RT-PCR and flow cytometry, using the mean fluorescent index (MFI), respectively. CD44 MFI was significantly higher in leukemic samples compared to controls and a higher expression was found in AL in respect with CLL. No significant differences were found when considering different phenotypic subtypes of AL and CLL. CD44_ex1-5 mRNA expression was significantly higher in AL compared to controls, whereas there was no difference in CLL compared to controls and AL. CD44_es16-20 showed the same trend, but without differences among groups. The high CD44 expression found in canine leukemias could be considered a step toward the definition of their molecular features. PMID- 24629893 TI - NK cell self tolerance, responsiveness and missing self recognition. AB - Natural killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NK cells is regulated by the integration of signals deriving from activating and inhibitory receptors expressed on their surface. However, different NK cells respond differently to the same stimulus, be it target cells or agents that crosslink activating receptors. The processes that determine the level of NK cell responsiveness have been referred to collectively as NK cell education. NK cell education plays an important role in steady state conditions, where potentially auto-reactive NK cells are rendered tolerant to the surrounding environment. According to the "tuning" concept, the responsiveness of each NK cell is quantitatively adjusted to ensure self tolerance while at the same time ensuring useful reactivity against potential threats. MHC-specific inhibitory receptors displayed by NK cells play a major role in tuning NK cell responsiveness, but recent studies indicate that signaling from activating receptors is also important, suggesting that the critical determinant is an integrated signal from both types of receptors. An important and still unresolved question is whether NK cell education involves interactions with a specific cell population in the environment. Whether hematopoietic and/or non-hematopoietic cells play a role is still under debate. Recent results demonstrated that NK cell tuning exhibits plasticity in steady state conditions, meaning that it can be re set if the MHC environment changes. Other evidence suggests, however, that inflammatory conditions accompanying infections may favor high responsiveness, indicating that inflammatory agents can over-ride the natural tendency of NK cells to adjust to the steady state environment. These findings raise many questions such as whether viruses and tumor cells manipulate NK cell responsiveness to evade immune-recognition. As knowledge of the underlying processes grows, the possibility of modulating NK cell responsiveness for therapeutic purposes is becoming increasingly attractive, and is now under serious investigation in clinical studies. PMID- 24629894 TI - Morphine increases hippocampal viral load and suppresses frontal lobe CCL5 expression in the LP-BM5 AIDS model. AB - Chronic opiate abuse accelerates the development of cognitive deficits in human immunodeficiency virus (HIV)-1 patients. To investigate morphine's effects on viral infection of the central nervous system, we applied chronic morphine treatment to the LP-BM5 murine acquired immunodeficiency syndrome (MAIDS) model. LP-BM5 infection induces proinflammatory cytokine/chemokine production, correlating to increased blood-brain barrier permeability. Morphine treatment significantly increased LP-BM5 viral load in the hippocampus, but not in the frontal lobe. Morphine reduced the chemokine CCL5 to non-infected levels in the frontal lobe, but not in the hippocampus. These data indicate a region-specific mechanism for morphine's effects on virally-induced neurocognitive deficits. PMID- 24629895 TI - Risk of major bleeding and the standard doses of dabigatran. PMID- 24629896 TI - Good two-year outcome for parents whose infants were admitted to a neonatal intensive care unit. AB - OBJECTIVE: To evaluate the psychological functioning in parents whose infants were admitted to a neonatal intensive care unit (NICU) over the first 2 years of the infant's life. METHODS: Prospective 2-year follow-up study of a random selection of NICU and control families. At baseline, 9 months, and 2 years, all parents received a clinical interview. Infants underwent a pediatric examination and Bayley II neurodevelopmental assessment at 2 years. Psychological distress is defined as having one or more of the following criteria: any psychiatric diagnosis on the Mini-International Neuropsychiatric Interview at 2 years; Edinburgh Post Natal Depression Scale score more than 12.5 at 2 years; Hospital Anxiety and Depression Scale score more than 11.0 at 2 years, receiving treatment with antidepressants/psychotherapy/counselling over the previous 15 months. RESULTS: Overall, 300 families of infants admitted to a NICU and 120 control families were approached to take part in the study. There was no difference in psychological distress in NICU parents (30.8%) vs control parents (28.2%). In fathers, there was no relationship between psychological distress and infant development measured using the Bayley II. In mothers, there was a relationship between psychological distress and the child's mental development, which was most significant in infants with severe developmental delay. CONCLUSIONS: There are no significant long-term negative psychological effects on parents whose infants were admitted to a NICU. Should interventions for parents be offered, they should focus on mothers whose infants are likely to have significant mental health development problems whether or not their infant is admitted to a NICU. PMID- 24629897 TI - Goserelin-induced depression in a man with prostate cancer. PMID- 24629898 TI - Metabolic syndrome and elevated C-reactive protein levels in elderly patients with newly diagnosed depression. AB - BACKGROUND: Depression and metabolic syndrome (MeS) are prevalent in elderly people and are associated with adverse outcomes, especially cardiovascular disease. Increased C-reactive protein (CRP) levels are a risk factor for depression and chronic medical disorders, such as cardiovascular disease and MeS. OBJECTIVE: The aim of this study was to evaluate the risk of MeS and CRP levels in elderly (>60y) patients with newly-diagnosed major depressive disorder. METHODS: We enrolled 30 subjects with newly diagnosed depression and 30 age- and sex-matched controls who presented for a health examination at Asan Medical Center, Seoul, Korea. Sociodemographic, MeS components, and CRP were measured before starting treatment with antidepressants. RESULTS: There were no significant differences in sociodemographic characteristics or lifestyle factors between depressive and healthy control patients. The newly-diagnosed depression group showed a significantly increased risk of MeS (odds ratio = 4.75, 95% CI: 1.58-14.25) compared with the control group. Of the 5 MeS components examined, only waist circumference was significantly different between the 2 groups (odds ratio = 4.33, 95% CI: 1.20-15.61). Elevated CRP levels were significantly associated with an increased risk for depression (odds ratio = 4.57, 95% 1.45 14.39). CONCLUSIONS: The risks of MeS and elevated CRP levels are higher in elderly patients with depression than in normal subjects. Physicians need to be alert to these cardiovascular risk factors when diagnosing and prescribing antidepressants for depression in the elderly. Clinical investigators are encouraged to assess markers of inflammation and review detailed information on risk factors such as waist circumference for MeS in patients with depression. PMID- 24629899 TI - Cytokine and chemokine mRNA expression profiles in BALF cells isolated from pigs single infected or co-infected with swine influenza virus and Bordetella bronchiseptica. AB - Pigs serve as a valuable animal experimental model for several respiratory pathogens, including Swine Influenza Virus (SIV) and Bordetella bronchiseptica (Bbr). To investigate the effect of SIV and Bbr coinfection on cytokine and viral RNA expression, we performed a study in which pigs were inoculated with SIV, Bbr or both pathogens (SIV/Bbr). Our results indicate that Bbr infection alters SIV clearance. Pulmonary lesions in the SIV/Bbr group were more severe when compared to SIV or Bbr groups and Bbr did not cause significant lesions. Broncho-alveolar lavage fluid (BALF) was examined for inflammatory mediators by qPCR. Interferon (IFN)-alpha, interleukin IL-8, IL-1 peaked in BALF at 2 DPI, while the virus titres and severity of clinical signs were maximal at the same time. Despite its increased expression in co-infected pigs, interferon-alpha did not enhance SIV clearance, since the viral replication was detected at the same day as the highest IFN levels. The mRNA levels for IFN-alpha, IL-1beta and IL-8 were significantly higher in BALF of co-infected pigs and correlated with enhanced viral RNA titers in lungs, trachea and nasal swabs. Transcription of mRNA for IL 1beta was stable in SIV and SIV/Bbr groups throughout all the study. In Bbr group, the levels of mRNAs for IL-1beta were significantly higher at 2, 4 and 9 DPI. The mean levels of mRNAs for TNF-alpha were lower than the levels of other chemokines and cytokines in all infected groups. Transcript levels of IL-10 and IL-4 did not increase at each time points. Overall, SIV replication was increased by Bbr presence and the enhanced production of pro-inflammatory mediators could contribute to the exacerbated pulmonary lesions. PMID- 24629900 TI - Ornamental fish as a source of plasmid-mediated quinolone resistance genes and antibiotic resistance plasmids. AB - Growing ornamental fish industry is associated with public health concerns including extensive antibiotic use accompanied by increasing antibiotic resistance. The aim of this study was to analyze Aeromonas isolates from imported tropical ornamental fish and coldwater koi carps bred in the Czech Republic to assess the potential risk of ornamental fish as a source of plasmid-mediated quinolone resistance genes (PMQR) and antibiotic resistance plasmids. A collection of Aeromonas spp. with reduced susceptibility to ciprofloxacin (MIC >= 0.05 mg/L) was selected for the detection of PMQR genes. Isolates harbouring PMQR genes were further analyzed for the additional antibiotic resistance, integron content, clonality, biofilm production and transferability of PMQR genes by conjugation and transformation. Comparative analysis of plasmids carrying PMQR genes was performed. Fifteen (19%, n=80) isolates from koi carps and 18 (24%, n=76) isolates from imported ornamental fish were positive for qnrS2, aac(6')-Ib cr or qnrB17 genes. PMQR-positive isolates from imported ornamental fish showed higher MIC levels to quinolones, multiresistance and diverse content of antibiotic resistance genes and integrons compared to the isolates from the carps. Related IncU plasmids harbouring qnrS2 and aac(6')-Ib-cr genes were found in Aeromonas spp. from imported ornamental fish and koi carps from various geographical areas. Ornamental fish may represent a potential source of multiresistant bacteria and mobile genetic elements for the environment and for humans. PMID- 24629901 TI - The identification, typing, and antimicrobial susceptibility of Pseudomonas aeruginosa isolated from mink with hemorrhagic pneumonia. AB - The biological characteristics and molecular epidemiology of Pseudomonas aeruginosa associated with mink hemorrhagic pneumonia from Shandong province of eastern China were determined in this study. From 2010 to 2011, 30 mink P. aeruginosa isolates were identified from lung, fecal and feed samples of clinical cases and subjected to serotyping, antimicrobial susceptibility testing and pulsed-field gel electrophoresis (PFGE) using SpeI. The P. aeruginosa isolates belonged to four serotypes-21 of type G, four of type I, three of type M, one of type B, and one non-typable strain. The strains were divided into four large groups as determined by PFGE. Isolates from the group 2 were highly homologous and were obtained from the same region as an epidemic. All of the isolates were sensitive to piperacillin, piperacillin/tazobactam, ceftazidime, cefepime, imipenem, amikacin, gentamicin and tobramycin and resistant to ampicillin, cefuroxime and cefuroxime axetil. A high frequency of resistance was found to ampicillin/sulbactam, cefazolin, cefotetan, ceftriaxone, nitrofurantoin, and trimethoprim/sulfamethoxazole (96.7%). Resistance to ticarcillin/clavulanic acid, ciprofloxacin and levofloxacin was less common (13.3%). There was no relationship between antibiotic resistance and serotype distribution of the isolates. The epidemic serotype of P. aeruginosa from the mink hemorrhagic pneumonia in Shandong province was type G, which was a clone of commonly found in this province. These findings reveal the genetic similarities and antimicrobial susceptibility profiles of P. aeruginosa from clinical cases of mink hemorrhagic pneumonia and will facilitate the prevention and control of the disease in Shandong province of China. PMID- 24629902 TI - Novel Bartonella infection in northern and southern sea otters (Enhydra lutris kenyoni and Enhydra lutris nereis). AB - Since 2002, vegetative valvular endocarditis (VVE), septicemia and meningoencephalitis have contributed to an Unusual Mortality Event (UME) of northern sea otters in southcentral Alaska. Streptococcal organisms were commonly isolated from vegetative lesions and organs from these sea otters. Bartonella infection has also been associated with bacteremia and VVE in terrestrial mammals, but little is known regarding its pathogenic significance in marine mammals. Our study evaluated whether Streptococcus bovis/equinus (SB/E) and Bartonella infections were associated with UME-related disease characterized by VVE and septicemia in Alaskan sea otter carcasses recovered 2004-2008. These bacteria were also evaluated in southern sea otters in California. Streptococcus bovis/equinus were cultured from 45% (23/51) of northern sea otter heart valves, and biochemical testing and sequencing identified these isolates as Streptococcus infantarius subsp. coli. One-third of sea otter hearts were co-infected with Bartonella spp. Our analysis demonstrated that SB/E was strongly associated with UME-related disease in northern sea otters (P<0.001). While Bartonella infection was also detected in 45% (23/51) and 10% (3/30) of heart valves of northern and southern sea otters examined, respectively, it was not associated with disease. Phylogenetic analysis of the Bartonella ITS region allowed detection of two Bartonella species, one novel species closely related to Bartonella spp. JM-1, B. washoensis and Candidatus B. volans and another molecularly identical to B. henselae. Our findings help to elucidate the role of pathogens in northern sea otter mortalities during this UME and suggested that Bartonella spp. is common in sea otters from Alaska and California. PMID- 24629903 TI - [Has the use of antipyretics been modified after the introduction of different concentrations of ibuprofen into the market?]. AB - INTRODUCTION: Due to the emergence of new pharmaceutical presentations of ibuprofen (40 mg/ml), an analysis was made on the use of antipyretics in pediatric outpatient in Spain. PATIENTS AND METHODS: A cross-sectional, observational, descriptive study was carried out on a sample of children under 14 years old with treated febrile syndrome, seen in the Emergency Room of the Hospital General Universitario de Valencia from November 2012 to January 2013. RESULTS: Of the 217 children included, 144 were treated with paracetamol or ibuprofen, 69 received both drugs, and one received paracetamol and metamizol. There were 58.7% of exposures to paracetamol and 40.9% to ibuprofen. The parents decided the use of antipyretics in 63.2% of cases. In 98 exposures the dose was different from that authorized in the labeling of the drug (off-label use). Ibuprofen was used off-label in 40.2% of cases, mostly by underdosing (35.9%). Paracetamol was used off-label in 29.8% of cases, predominantly overdose (26.8%), with the difference being statistically significant. No significant differences were observed in the off-label use in either monotherapy or combined use. There were also no differences when antipyretics prescribed by doctors or given directly by parents were evaluated separately. CONCLUSIONS: The majority of children with treated febrile syndrome seen in the Emergency Room were receiving antipyretic drugs after a parental decision. Paracetamol is the most commonly used drug and one in three children received it simultaneously with ibuprofen. The antipyretics were used off label in one-third of the cases. Off label use of ibuprofen is increasing, and is probably due to the existence of different pharmaceutical presentations. PMID- 24629904 TI - [Has the presence of parents during invasive procedures in the emergency department increased in the last few years?]. AB - INTRODUCTION: In the recent years, parents are playing an important role in Pediatric Emergency Department (PED), and wish to be present when invasive procedures (IP) are performed. OBJECTIVES: 1) To compare the presence of parents during IP in PED in Spain between 2008 and 2012. 2) To compare the arguments to restrict the presence and problems arising from this, and 3) To determine whether the views of health personnel have changed on this subject. METHODOLOGY: A descriptive multicenter comparative study was conducted in 2008 and 2012. A total of 42 questionaires were sent by email to PED managers, with the responding hospitals being included in the 2 periods of the study. RESULTS: A total of 22 hospitals participated in the study. The presence of parents in the PED increased between 2008 and 2012 for all IP, significantly in the blood test and urine catheterization. In 2012, managers state that children are not so nervous, and anxiety of the parents and staff fear of a poorer performance, as an argument to restrict family presence. There were few problems during the 2 periods, with the poor behavior of the children decreasing. According to managers, the opinion of health personnel has not changed in the last four years. CONCLUSIONS: The presence of parents during the IP in the PED has increased in the last four years, although the presence is low for more invasive procedures. Managers argue the presence of fewer behavior problems to restrict family presence. The opinion of the staff has not changed in the last four years, although more studies are required on this issue. PMID- 24629906 TI - [Benign massive lymphadenopathy: Rosai-Dorfman disease]. PMID- 24629905 TI - [Aplastic crisis due to parvovirus B19 and Epstein-Barr virus in a patient with hereditary spherocytosis]. AB - Anemic syndrome in childhood requires a diagnosis and urgent treatment guided by systematic protocols that can avoid unnecessary additional testing. The case of a 4 year-old girl with fatigue and intermittent fever of 7 days duration, accompanied by abdominal pain is presented. She had regular general health status, with mucocutaneous jaundice, a grade III/VI/iv murmur, and painful abdomen with hepatosplenomegaly. The blood analysis showed a hypo-regenerative anemia with increased LDH and indirect bilirubin. The Coombs Test was negative, with spherocytes being observed in the peripheral blood smear. The IgM and IgG were positive for parvovirus B19 IgM and Epstein Barr virus, leading to the diagnosis of aplastic crisis in a patient with hereditary spherocytosis. No specific treatment was required. Under the suspicion of anemic syndrome in emergencies, the ABCDE sequence must be followed. Through the history, physical examination and basic laboratory tests, an initial diagnostic approach can be made. Specific etiological tests should be based on this first study. PMID- 24629907 TI - Variables associated with the use of complete oral calorie supplements in children with feeding problems. AB - OBJECTIVE: To examine child and parent variables associated with complete oral calorie supplement use among children with feeding problems. DESIGN: Correlational examination of data from patient intake surveys. SETTING: Hospital based feeding program. PARTICIPANTS: Participants included 281 parents of children referred to a hospital-based feeding clinic, including 114 who received supplements (70.2% boys; mean age, 60.1 months) and 167 who did not receive (79.6% boys; mean age, 67.5 months). VARIABLES MEASURED: Children's age, gender, weight status, diagnostic category (no special needs, autism, or other special needs), supplement intake, oral motor problems, child mealtime behavior (using the Child Eating Behavior Questionnaire), parent feeding practices (using the Parent Mealtime Action Scale), and diet variety for child and parent. ANALYSIS: Chi-square analyses compared children who did and did not receive supplements for their percentage of gender, diagnostic, and weight status categories; t tests or Mann-Whitney U tests compared children who did and did not receive supplements, for age, oral motor problems, children's mealtime behavior, parent feeding practices, and diet variety. RESULTS: Compared with children who did not receive nutritional supplements, those who did were younger (P < .01) and more underweight (P < .001), and showed less Food Responsiveness (P < .001), less Food Enjoyment (P < .001), more Food Satiety (P < .001, and more Slow Eating (P < .001), and their parents were more likely to use Insistence on Eating (P < .001). CONCLUSIONS: Whereas supplement use was related to underweight, 78.2% of children receiving them were normal weight or overweight, which suggests that supplements are being used to address mealtime selective eating. The use of supplements should be considered carefully because they do not appear to increase diet variety and may increase the chance of overweight over time. PMID- 24629908 TI - The "benefits" of the mini-extracorporeal circulation in the minimal invasive cardiac surgery era. AB - Mini-extracorporeal circulation (MECC) constitutes a novel miniaturized cardiopulmonary bypass (CPB) circuit, heparin-coated and primed with aprotinin. Its membrane oxygenation is similar to conventional cardio-pulmonary bypass (CCPB), but it is a completely closed-volume system due to the lack of the venous reservoir which has been removed. In a mini circuit, the reservoir is the patient himself. Consequently, air entering the venous cannula is avoided. Nevertheless, the capabilities of MECC have been expanded either by the inclusion of a suction device that is only activated on direct contact with liquid in some circuits or by postoperative autotransfusion of the wrecked erythrocytes by a separate suction device with a cell-saver. Although the tubing diameter is similar between the two systems, the tubing length of the MECC is around half that of the CCPB, resulting in the restriction of priming volume. As a consequence, a higher hematocrit thus a limited need for perioperative blood transfusion is achieved due to less hemodilution. In addition, the inflammatory response is also diminished as a result of less artificial surface area interacting with blood. Finally, a lower dose of heparin is required prior to MECC than prior to CCPB. PMID- 24629909 TI - The caffeoylquinic acid-rich Pandanus tectorius fruit extract increases insulin sensitivity and regulates hepatic glucose and lipid metabolism in diabetic db/db mice. AB - Caffeoylquinic acids (CQAs) are widely distributed in various foods. While some CQAs have been shown to possess antihyperglycemic activities, whether it is beneficial for diabetes patients to ingest CQA-rich foods has still to be known. In this work, the antihyperglycemic and antihyperlipidemic effects of CQA-rich Pandanus tectorius fruit extract (PTF) was investigated in diabetic db/db mice. Treatment with PTF (200 mg/kg) significantly decreased body weight and fasting glucose level, alleviated hyperinsulinism and hyperlipidemia and declined glucose area under the curve in oral glucose tolerance test and insulin tolerance test. The elevated levels of serum proinflammatory cytokines and islet hypertrophy in db/db mice were remarkably attenuated by PTF treatment. Biochemical analysis showed that administration of PTF significantly stimulated the phosphorylation of AMP-activated protein kinase (AMPK) and Akt substract of 160 kDa (AS160), and enhanced the expression and translocation of glucose transporter type 4 (GLUT4) in skeletal muscles. It also increased the activity of hexokinase, decreased the expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase and switched the transcription of several key lipid metabolic genes in the liver, which, in turn, improved hepatic glucose and lipid profiles as determined by nuclear magnetic resonance-based metabolomics. Overall, the CQA-rich PTF is beneficial for the treatment of diabetes. It may alleviate hyperglycemia and dyslipidemia via activation of AMPK-AS160-GLUT4 pathway in skeletal muscles and inhibition of gluconeogenesis and lipogenesis in the liver. PMID- 24629910 TI - Metallothionein prevents cardiac pathological changes in diabetes by modulating nitration and inactivation of cardiac ATP synthase. AB - Mitochondrial ATP production is the main energy source for the cell. Diabetes reduces the efficient generation of ATP, possibly due to the inactivation of ATP synthase. However, the exact mechanism by which diabetes induces inactivation of ATP synthase remains unknown, as well as whether such inactivation has a role in the development of pathological abnormalities of the diabetic heart. To address these issues, we used cardiac metallothionein-transgenic (MT-TG) and wild-type (WT) mice with streptozotocin-induced diabetes, since we have demonstrated previously that diabetes-induced cardiac damage and remodeling were found in WT diabetic mice, but not in MT-TG diabetic mice. Immunohistochemical and biochemical assays were used to compare pathological and biochemical changes of the heart between MT-TG and WT diabetic mice, and a proteomic assay to evaluate ATP synthase expression and tyrosine nitration, with its activity. LC/MS analysis revealed that diabetes increased tyrosine nitration of the ATP synthase alpha subunit at Tyr(271), Tyr(311), and Tyr(476), and the beta subunit at Tyr(269) and Tyr(508), and also significantly reduced ATP synthase activity by ~32%. These changes were not observed in MT-TG diabetic mice. Furthermore, parallel experiments with induced expression of cardiac MT by zinc supplementation in diabetic mice produced similar effects. These results suggest that MT can preserve ATP synthase activity in streptozotocin-induced diabetes, probably through the inhibition of ATP synthase nitration. PMID- 24629911 TI - Reduction of the body burden of PCBs and DDE by dietary intervention in a randomized trial. AB - Serum polychlorinated biphenyls (PCBs) in Anniston, AL, residents have been associated with hypertension and diabetes. There have been no systematic interventions to reduce PCB body burdens in Anniston or other populations. Our objective was to determine the efficacy of 15 g/day of dietary olestra to reduce PCBs in Anniston residents. Blood PCBs and 1,1-bis-(4-chlorophenyl)-2,2 dichloroethene were measured at baseline and 4-month intervals in a double-blind, placebo-controlled, 1-year trial. Participants with elevated serum PCBs were randomized into two groups of 14 and received potato crisps made with olestra or vegetable oil (VO). Elimination rates during the study period were compared with 5-year prestudy rates. Eleven participants in the olestra group and 12 in the VO group completed the study. Except for one participant in the VO group, reasons for dropout were unrelated to treatments. The elimination rate of 37 non-coplanar PCB congeners during the 1-year trial was faster during olestra consumption compared to the pretrial period (-0.0829 +/- 0.0357 and -0.00864 +/- 0.0116 year( 1), respectively; P=.04), but not during VO consumption (-0.0413 +/- 0.0408 and 0.0283 +/- 0.0096 year(-1), respectively; P=.27). The concentration of PCBs in two olestra group participants decreased by 27% and 25% during the trial. There was no significant time by group interaction in change from baseline. However, group main effects for total PCBs and PCB 153 were of borderline significance. This pilot study has demonstrated that olestra can safely reduce body burdens of PCBs and supports a larger intervention trial that may also determine whether reduction in PCBs will reduce the risk of hypertension and diabetes. PMID- 24629912 TI - Chronic coffee consumption in the diet-induced obese rat: impact on gut microbiota and serum metabolomics. AB - Epidemiological data confirms a strong negative association between regular coffee consumption and the prevalence of type 2 diabetes. Coffee is initially absorbed in the stomach and small intestine but is further fermented in the colon by gut microbiota. The bioavailability, production and biological activity of coffee polyphenols is modulated, in part, by gut microbiota. The purpose of this study was to determine if chronic coffee consumption could mitigate negative gut microbiota and metabolomic profile changes induced by a high-fat diet. Male Sprague-Dawley rats were randomized to chow (12% kcal fat) or high-fat (60% kcal fat) diet. Each group was further divided into water or caffeinated coffee for 10 weeks. Coffee consumption in high-fat-fed rats was associated with decreased body weight, adiposity, liver triglycerides and energy intake. Despite a more favorable body composition, rats displayed profound systemic insulin resistance, likely due to caffeine. Coffee consumption attenuated the increase in Firmicutes (F)-to-Bacteroidetes (B) ratio and Clostridium Cluster XI normally associated with high-fat feeding but also resulted in augmented levels of Enterobacteria. In the serum metabolome, coffee had a distinct impact, increasing levels of aromatic and circulating short-chain fatty acids while lowering levels of branched-chain amino acids. In summary, coffee consumption is able to alter gut microbiota in high-fat-fed rats although the role of these changes in reducing diabetes risk is unclear given the increased insulin resistance observed with coffee in this study. PMID- 24629913 TI - Folic acid stimulation of neural stem cell proliferation is associated with altered methylation profile of PI3K/Akt/CREB. AB - Proliferation of neural stem cells (NSCs) is required for development and repair in the nervous system. NSC amplification in vitro is a necessary step towards using NSC transplantation therapy to treat neurodegenerative diseases. Folic acid (FA) has been shown to act through DNA methyltransferase to stimulate NSC proliferation. To elucidate the underlying mechanism, the effect of FA on the methylation profiles in neonatal rat NSCs was assessed by methylated DNA immunoprecipitation (MeDIP) and methylated DNA immunoprecipitation-DNA microarray (MeDIP-Chip). Differentially methylated regions (DMRs) were determined by quantitative differentially methylated regions analysis, and genes carrying at least three DMRs were selected for pathway analysis. Gene network analysis revealed links with steroid biosynthesis, fatty acid elongation and the PI3K/Akt/CREB, neuroactive ligand-receptor interaction, Jak-STAT and MAPK signaling pathways. Moreover, Akt3 acted as a hub in the network, in which 14 differentially methylated genes converged to the PI3K/Akt/CREB signaling pathway. These findings indicate that FA stimulates NSC proliferation by modifying DNA methylation levels in the PI3K/Akt/CREB pathway. PMID- 24629914 TI - Single-port thoracoscopic access for a mediastinal ectopic goiter. PMID- 24629915 TI - Ultrasound findings associated to gallbladder carcinoma. AB - OBJECTIVE: This article reviews the most relevant ultrasound findings associated with gallbladder cancer. MATERIAL AND METHOD: A descriptive and retrospective study was made of clinical features and imaging studies in patients subjected to surgery for gallbladder neoplasm in the Reina Sofia General University Hospital (Murcia) during the time period 2000-2011. RESULTS: A total of 15 cases of gallbladder cancer were found during the study period, 9 of whom were women. The mean age was 77 years (range 61-96). Pain was the principal complaint. The patients had cholelithiasis in 13 cases, smoking in 2 cases, and obesity in 3 cases. The ultrasound showed gallbladder wall thickening (>4mm) in 8 cases, intraluminal mass in 4, scleroatrophic gallbladder in 2, and mass replacing the gallbladder in one. Only in 4 cases was the suspicion of gallbladder carcinoma established preoperatively. According to the pTNM staging, 4 patients were carcinoma in situ (Tis), one case T1a, 6 cases T2, 3 cases T3 and one case T4. In 7 cases, the only evidence was the preoperative ultrasound, and in 8 the study was completed with an abdominal CT. CONCLUSION: Early diagnosis of gallbladder cancer is rare. The ultrasound diagnostic approach is difficult; only a localized thickening coexisting with gallstones seems to be significant, and requires a biopsy. The image of a mass and a stone occupying the gallbladder is associated with later stages of the disease. PMID- 24629916 TI - Giant abdominal mass of undetermined origin: Should the diagnosis of chromophobe carcinoma be considered? PMID- 24629917 TI - Outpatient laparoscopic cholecystectomy and pain control: a series of 100 cases. AB - INTRODUCTION: We present our experience of 100 consecutive cases that underwent ambulatory cholecystectomy using a standard protocol of anesthesia and surgery. PATIENTS AND METHOD: Prospective study of 100 consecutive patients assessed in the surgery outpatient clinic in Torrevieja Hospital (September 2008-september 2009). Both anesthetic and surgical techniques were protocolized, standardized. The protocol included the use of intraperitoneal and parietal anesthesia. RESULTS: One hundred patients were included. Average age was 53 years and average surgical time was 29+/-12 min. Day-case surgery rate was 96%. Postoperative pain (VAS scale) was less than 4 in all cases. Six patients complained of nausea that eased with the administration of ev metoclopramide. Average length of stay in the day-case surgery unit was 7.4h (maximum 9.6, minimum 7). Morbidity and mortality rates were 0%. No re-admission was registered and conversion rate was 0%. Postoperative follow-up was 100%. A total of 97% of the cases were fully satisfied with the procedure. CONCLUSION: Ambulatory laparoscopic cholecystectomy is a feasible and safe technique. Postoperative pain has classically been the reason to not perform day-case surgery, but we achieved an excellent control by the combined use of local anesthetics and warm intraperitoneal saline solution. PMID- 24629918 TI - Trichophagia and trichobezoar. PMID- 24629919 TI - Conservative "in situ" treatment of pneumoperitoneum. PMID- 24629920 TI - Glove port cholecystectomy. PMID- 24629921 TI - A young woman with a pancreatic head cystic neoplasm. PMID- 24629922 TI - Low doses of haloperidol combined with ondansetron are not effective for prophylaxis of postoperative nausea and vomiting in susceptible patients. AB - BACKGROUND: In this observational study we reviewed the efficacy and side effects of different antiemetic combinations used in our hospital for postoperative nausea and vomiting (PONV) prophylaxis in high-risk women undergoing highly emetogenic surgery. METHODS: After reviewing retrospectively the medical records of patients undergoing highly emetogenic elective surgeries under general anaesthesia, we selected 368 women whose Apfel risk score was >= 3 and receiving a combination of 2 antiemetics for PONV prophylaxis. We analysed the incidence of PONV at 2, 6, 12 and 24h after surgery, antiemetic rescue requirements, pattern of occurrence of PONV, side effects and level of sedation were also assessed. The main goal was complete response defined as no PONV within 24h after surgery. RESULTS: Ondansetron 4mg i.v. plus dexamethasone 8mg i.v. (O&Dex), haloperidol 1mg i.v. (O&Hal1), haloperidol 2mg i.v. (O&Hal2) or droperidol 1.25mg i.v. (O&Dro) were the combinations most frequently used. The complete response was better in groups O&Dex: 68.5% (CI: 58-78), O&Hal2: 64.1% (CI: 53-74) and O&Dro 63% (CI: 52-73) than in group O&Hal1: 41.3% (CI: 31-52) (p<0,01). Peak incidence of PONV occurred within the 2-6h period. The incidence of side effects was higher in group O&Hal2. CONCLUSION: In high risk patients for PONV who underwent highly emetogenic surgeries, the efficacy of low-dose haloperidol (1mg) in combination is limited. Higher doses (2mg) are more effective but its use is associated with a high incidence of side effects. PMID- 24629923 TI - Surgical repair of a false bile-duct passage after percutaneous transhepatic cholangiography in a patient with biliary stenosis after cholecystectomy. PMID- 24629924 TI - Marfan syndrome and pneumothorax. PMID- 24629925 TI - Cystic dystrophy of the duodenal wall: from diagnostic uncertainty to pathological confirmation. PMID- 24629926 TI - RAC1 single nucleotide polymorphisms in Crohn's disease. PMID- 24629927 TI - Accuracy of stool antigen test for the diagnosis of Helicobacter pylori infection in children: a meta-analysis. AB - INTRODUCTION: Helicobacter pylori (H. pylori) is regarded as a major pathogen in gastrointestinal diseases and the infection rate is still at a high level in children. Therefore, the diagnosis is of great clinical importance. The objective was to perform a meta-analysis on H. pylori stool antigen test (SAT) for the diagnosis of the infection in children. METHODS: Published information on the sensitivity and specificity of stool antigen test in each study was collected to assess the accuracy of the test for the diagnosis of H. pylori infection. Forty five eligible studies were selected for analysis. Data on the publication year, H. pylori prevalence, eradication rate and gold standard of each study were summarized. RESULT: Forty-five studies, including 5931 patients, evaluated the accurancy of H. pylori SAT. Pooled sensitivity, specificity, LR+ and LR- were: 92.1%, 94.1%, 17.01, 0.085, respectively. Subgroup analyses were conducted to evaluate the sensitivity and specificity of H. pylori SAT in different situations and found that sensitivity and specificity were significantly higher when monoclonal H. pylori SAT and two or more reference methods were used. CONCLUSIONS: Detection of H. pylori antigen in stools with ELISA monoclonal antibodies is a non-invasive efficient test for the diagnosis of infection in children. However, the available one-step and polyclonal SAT tests are still unreliable. PMID- 24629928 TI - Elastic properties of organ of Corti tissues from point-stiffness measurement and inverse analysis. AB - We describe a method to use point-stiffness (PtSt) measurements, i.e., indentation measurements, to obtain elastic moduli of different organ of Corti (OC) tissues. A detailed finite element (FE) model of the OC is used to account for geometric effects in the indentation measurements. We also present a sensitivity analysis, performed within a Bayesian estimation framework, that can be used to improve experimental design. The sensitivity analysis shows that the basilar membrane (BM) PtSt is most sensitive to changes in the BM properties and to changes in the pillar cells (PC) properties. This result suggests that the BM and the PC dominate the macromechanics of the OC. The most likely values of the Young's modulus predicted for the middle turn for the BM arcuate, BM pectinate, and the PC are found to be 935 KPa (range 640-1360 KPa), 300 KPa (range 190-460 KPa), and 3 GPa (range 1-9 GPa), respectively. PMID- 24629929 TI - Thyroid-stimulating hormone maintains bone mass and strength by suppressing osteoclast differentiation. AB - It has been suggested that pituitary hormone might be associated with bone metabolism. To investigate the role of thyroid-stimulating hormone (TSH) in bone metabolism, we designed the present study as follows. After weaning, TSH receptor (TSHR) null mice (Tshr(-/-)) were randomly divided into a thyroxine treatment group (n=10) or non-treatment group (n=10); the treatment group received a dose of desiccated thyroid extract at 100 ppm daily for 5 weeks. Age-matched wild-type (Tshr(+/+), n=10) and heterozygote mice (Tshr(+/-), n=10) served as controls. After 5 weeks, the animals were sacrificed, and the femurs were collected for histomorphometrical and biomechanical analyses. In addition, the effect of TSH on osteoclastogenesis was examined in the RAW264.7 osteoclast cell line. We found that compared with Tshr(+/+) mice, Tshr(-/-) and Tshr(+/-) mice had lower bone strength. The histomorphometric results showed that trabecular bone volume, osteoid surface, osteoid thickness and osteoblast surface were significantly decreased, whereas the osteoclast surface was significantly increased in both Tshr(-/-) and Tshr(+/-) mice compared with Tshr(+/+) mice. Bone resorption and formation in Tshr(-/-) mice were further enhanced by thyroxine replacement. bTSH inhibited osteoclast differentiation in vitro, as demonstrated by reduced development of TRAP-positive cells and down-regulation of differentiation markers, including tartrate-resistant acid phosphatase, matrix metallo-proteinase 9 and cathepsin K in RAW264.7 cells. Our results confirm that TSH increased bone volume and improved bone microarchitecture and strength at least partly by inhibiting osteoclastogenesis. PMID- 24629930 TI - Molecularly imprinted polymer microspheres for optical measurement of ultra trace nonfluorescent cyhalothrin in honey. AB - In this study, we first present a general protocol for making fluorescent molecularly imprinted polymer microspheres via precipitation polymerisation. We first prepared the fluorescent molecularly imprinted polymer microspheres upon copolymerisation of acrylamide with a small quantity of allyl fluorescein in the presence of cyhalothrin to form recognition sites without doping. The as synthesised microspheres exhibited spherical shape, high fluorescence intensity and highly selective recognition. Under optical conditions, polymer microspheres were successfully applied to selectively and sensitively detect cyhalothrin, and a linear relationship could be obtained covering the lower concentration range of 0-1.0nM with a correlation coefficient of 0.9936 described by the Stern-Volmer equation. A lower limit of detection was found to be 0.004nM. The results of practical detection suggested that the developed method was satisfactory for determination of cyhalothrin in honey samples. This study therefore demonstrated the potential of molecularly imprinted polymers for detection of cyhalothrin in food. PMID- 24629931 TI - Microwave-assisted acid hydrolysis to produce xylooligosaccharides from sugarcane bagasse hemicelluloses. AB - Hemicelluloses from sugarcane bagasse were subjected to microwave-assisted acid hydrolysis at mild temperature to produce xylooligosaccharides (XOS). The hydrolysis was performed with dilute H2SO4 at 90 degrees C and the influence of acid concentration (0.1-0.3M) and reaction time (20-40min) on the XOS production was ascertained with response surface methodology based on central composite design. The fitted models of XOS and xylose yields were in good agreement with the experimental results. Compared to hydrolysis time, acid concentration was a more significant coefficient in the production of XOS. A well-defined degree of polymerisation of XOS and the monomer in the hydrolysates were quantified. No sugar-degraded byproduct was detected. The maximum XOS yield of 290.2mgg(-1) was achieved by hydrolysis with 0.24M H2SO4 for 31min. The results indicated that the yields of xylose and the byproducts can be controlled by the acid concentration and reaction time in microwave-assisted acid hydrolysis. PMID- 24629932 TI - Heat-induced aggregation and sulphydryl/disulphide reaction products of soy protein with different sulphydryl contents. AB - In this study, soy proteins were reduced with 0.1-10mM dithiothreitol (DTT) to obtain an increasing number of sulphydryl groups (SH) with a similar particle size. Aggregation was promoted by increasing the degree of reduction when heated (100 degrees C, 30min), resulting in larger sized aggregates (from 40 to 70nm) and a higher viscosity of the aggregate dispersion. The disulphide bond (SS) content decreased and the less SS linked polymer, which was composed of acidic (A) polypeptide of glycinin, basic (B) polypeptides of glycinin, and a small amount of alpha' and alpha subunits of beta-conglycinin, was formed with increasing reduction degree, suggesting that SH/SS polymerisation was not the driving force for aggregation. The larger aggregates with increasing degrees of reduction were composed of more B of glycinin and beta of beta-conglycinin, suggesting that the A and the small amount of alpha' and alpha in the SS linked polymer have an inhibiting effect on protein aggregates formation. PMID- 24629933 TI - Polymer incompatibility as a potential tool for polyphenol recovery from olive mill wastewater. AB - Experiments were designed and preformed in consideration of polymer type (proteins, i.e. caseinate and ovalbumin, and polysaccharides, i.e. alginate and methylcellulose), charge character and polysaccharide concentrations, intended to understand how the polymer properties determine both phase separation and polyphenol partitioning from olive mill wastewater (OMW). The highest yield of polyphenols (YBP=92.9%) was achieved in an aqueous two-phase system (ATPS) using an ovalbumin-methylcellulose system (OMCS) in comparison to ATPS with caseinate alginate system (CAS; YBP=85.8%) or caseinate methylcellulose system (CMCS; YBP=74%). The performance of CMCS for the ATPS partitioning of polyphenols in OMW was found to depend on the addition of salt (sodium chloride). The use of centrifugation as assistive technology appears to be necessary for the polyphenol partitioning in ATPS using OMCS. In contrast to these polymer systems, CAS caused a rapid ATPS without resorting to centrifugation and salt, mainly because of strong electrostatic repulsion between alginate and caseinate. In this regard, CAS in phase-separated OMW obtained a partition coefficient of protein (KP1) of 0.04, a tie-line length (TLL) of 10.47% (w/w) and a phase volume ratio (VR) of 0.7. Thus, ATPS based on CAS represent an efficient and environmentally friendly concept in recovery of polyphenols from OMW. The spray drying of the caseinate polyphenol-rich phase from CAS could become a dry intermediate product with potential use in the food and non-food industry. PMID- 24629934 TI - Characterisation of the hydrolytic specificity of Aspergillus niger derived prolyl endoproteinase on bovine beta-casein and determination of ACE inhibitory activity. AB - The hydrolytic specificity of Aspergillus niger prolyl endoproteinase (An-PEP) on purified beta-casein (beta-CN) was assessed. This analysis confirmed cleavage at the C-terminal side of Pro residues. An-PEP also had the ability to cleave at the C-terminal side of Ala, Glu, Gly, Ser, Lys and Leu. Incubation of purified beta CN with An-PEP resulted in the generation of highly potent angiotensin converting enzyme (ACE) inhibitory hydrolysates. The most potent hydrolysate was obtained after 24h incubation (ACE IC50=16.41+/-6.06MUg/mL). Fourteen beta-CN derived C terminal Pro-containing di-, tri, and tetrapeptides which were predicted in silico to be released following An-PEP hydrolysis or which were detected by ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) in the 24h hydrolysate were synthesised and characterised for their ACE inhibitory activity. The most potent inhibitory peptides were Ile-Gln-Ala (beta-CN f187-189) and Val Glu-Pro (beta-CN f116-118) having ACE IC50 values of 32.9+/-9.2 and 63.7+/ 12.0MUM, respectively. The hydrolysates generated appear to have the most potent ACE IC50 values reported for a food derived hydrolysate to date. PMID- 24629935 TI - Carotenoid stability in fruits, vegetables and working standards - effect of storage temperature and time. AB - The effects of freezing and storage temperature on the mass fraction of alpha- and beta-carotene, beta-cryptoxanthin, lutein, lycopene and zeaxanthin in minimally processed fresh food products, were evaluated after sample preparation, extraction and saponification (only when strictly necessary). Effects of freezing and long-term stability were studied at two temperatures, -20 and -70 degrees C, using high performance liquid chromatography (reversed phase columns, UV-Vis diode array detector) at time points during storage; measurement uncertainty was included in the evaluation. Stability of working standard solutions was also examined. Freezing did not affect the carotenoid mass fraction under the conditions studied. Carotenoids in orange, cherry, peach, apple, and kale were stable (except alpha-carotene and zeaxanthin in peach) for 13, 9.7, 5.7, 2.5 and 7.5months, respectively. For these food sample matrices, no significant difference between the freezing/storage at -20 and -70 degrees C was observed. Standard solutions (0.05-5MUg/mL) were stable for at least 6months at -70 degrees C, except lycopene which at 0.05MUg/mL was apparently stable only for six weeks. PMID- 24629936 TI - Evaluating belinjau (Gnetum gnemon L.) seed flour quality as a base for development of novel food products and food formulations. AB - Belinjau (Gnetum gnemon L.) seed flour was evaluated for nutritional composition, antioxidant activity and functional properties. Seed flour was found to be rich in protein (19.0g/100g), crude fibre (8.66g/100g), carbohydrates (64.1%), total dietary fibre (14.5%) and encompassed adequate amounts of essential amino acids, fatty acids and minerals. Antioxidant compounds such as total phenols (15.1 and 12.6mgGAE/100g), tannins (35.6 and 16.1mgCE/100g) and flavonoids (709 and 81.6mgCEQ/100g) were higher in ethanolic extracts over aqueous extracts, respectively. Inhibition of DPPH was high in ethanol extracts (48.9%) compared to aqueous extracts (19.7%), whereas aqueous extracts showed a higher FRAP value compared to ethanol extracts (0.98 and 0.61mmolFe(II)/100g, respectively). Results on functional properties revealed acceptable water and oil absorption capacities (5.51 and 1.98g/g, respectively), emulsion capacity and stability (15.3% and 6.90%, respectively), and foaming capacity (5.78%). FTIR spectral analysis showed seed flour to encompass major functional groups such as: amines, amides, amino acids, polysaccharides, carboxylic acids, esters and lipids. As belinjau seed flour possesses a rich nutraceutical value, it has high potential to be used as a basic raw material to develop new low cost nutritious functional foods. PMID- 24629937 TI - Effect of storage under extremely low oxygen on the volatile composition of 'Royal Gala' apples. AB - The aim of this work was to assess the profile of volatile compounds in 'Royal Gala' apples stored under controlled atmosphere (CA), with O(2) levels ranging from 1.0kPa to as low as 0.5kPa during 8months (0.5 degrees C), followed by 7days of shelf-life at 20 degrees C. Volatile compounds were collected via solid-phase microextraction (HS-SPME) and analysed by gas chromatography. Straight and branched-chain esters exhibited a distinct pattern. The emission of straight chain esters decreased under extremely low O(2) (0.5kPa), while branched-chain esters were not significantly affected in such condition. 2-Methyl-butyl acetate, a significant contributor to the 'Royal Gala' aroma, was higher in intermediate O(2) concentration, suggesting that lowering the O(2) levels down to 0.7kPa does not negatively affect the volatile composition of 'Royal Gala' apples, as compared to the standard CA (1.0kPa O(2)). The remaining volatile compounds were not strongly affected by storing fruits under extremely low O(2). PMID- 24629938 TI - Isomerization and increase in the antioxidant properties of lycopene from Momordica cochinchinensis (gac) by moderate heat treatment with UV-Vis spectra as a marker. AB - Momordica cochinchinensis (gac) is a plant rich in lycopene. This pigment tends to solubilize in oil and get damaged during extraction. The impact of heating on cis-isomerization of oil-free lycopene in hexane was studied at 50 and 80 degrees C during 240min with UV-Vis spectrometry, DAD-HPLC and TEAC test. The initial all trans-form isomerized to the 13-cis isomer more rapidly at 80 degrees C. After this treatment, 16% of the lycopene compounds were in the 9-cis-form. This isomer triggered an increase in the antioxidant properties which was detectable from concentrations above 9% and resulted in a change from 2.4 to 3.7MUmol Trolox equivalent. It is thus possible to increase the bioactivity of lycopene samples by controlling heating. The evolution of ratios calculated from the global UV-Vis spectrum was representative of cis-isomerization and spectrometry can thus be a simple way to evaluate the state of isomerization of lycopene solutions. PMID- 24629939 TI - The combination of atomic force microscopy and sugar analysis to evaluate alkali soluble Canna edulis Ker pectin. AB - Alkali-soluble pectin, which has been extracted from Canna edulis Ker, was characterized by single sugar determination and atomic force microscopy (AFM). The results indicated that the amounts of four predominant sugars including arabinose (Ara), glucose (Glc), galactose (Gal) and galacturonic acid (GalA) significantly decreased during the process of mild acid hydrolysis. The decreasing rates of these four sugars followed a sequential order of Ara>Gal>Glc>GalA. The homogalacturonan (HG) chain present in pectin, and the quantity of branched material is greater than the sample containing the main neutral sugars. The results indicated that the neutral sugar and HG side chains are attached to pectin as part of the rhamnogalacturonan I (RGI) complex. Moreover, hydrolysis leads to the reduction of mean lengths of backbone and branch, as well as the number/weight-average molecular weight. Meanwhile, the amount of short chain fractions increased during hydrolysis. Furthermore, the decrease of the polymerization degree of alkali-soluble C. edulis pectin as a function of the hydrolysis time could be described by a first-order exponential decay function. PMID- 24629940 TI - Effect of bottling and storage on the migration of plastic constituents in Spanish bottled waters. AB - Bottled water is packaged in either glass or, to a large extent, in plastic bottles with metallic or plastic caps of different material, shape and colour. Plastic materials are made of one or more monomers and several additives that can eventually migrate into water, either during bottle manufacturing, water filling or storage. The main objective of the present study was to carry out a comprehensive assessment of the quality of the Spanish bottled water market in terms of (i) migration of plastic components or additives during bottling and during storage and (ii) evaluation of the effect of the packaging material and bottle format on the migration potential. The compounds investigated were 5 phthalates, diethylhexyl adipate, alkylphenols and bisphenol A. A set of 362 bottled water samples corresponding to 131 natural mineral waters and spring waters sources and 3 treated waters of several commercial brands were analysed immediately after bottling and after one-year storage (a total of 724 samples). Target compounds were detected in 5.6% of the data values, with diethyl hexyl phthalate and bisphenol A being the most ubiquitous compounds detected. The total daily intake was estimated and a comparison with reference values was indicated. PMID- 24629941 TI - Determination of caffeic acid in wine using PEDOT film modified electrode. AB - A novel method using PEDOT (poly(3,4-ethylenedioxy) thiophene) modified electrode was developed for the determination of caffeic acid (CA) in wine. Cyclic voltammetry (CV) with the additions standard method was used to quantify the analyte at PEDOT modified electrodes. PEDOT films were electrodeposited on Platinum electrode (Pt) in aqueous medium by galvanostatic method using sodium poly(styrene-4-sulfonate) (PSS) as electrolyte and surfactant. CV allows detecting the analyte over a wide concentration range (10.0nmoll(-1)-6.5mmoll( 1)). The electrochemical method proposed showed good statistical and analytical parameters as linearity range, LOD, LOQ and sensitivity. PMID- 24629942 TI - Strawberry intake increases blood fluid, erythrocyte and mononuclear cell defenses against oxidative challenge. AB - The health promoting effects of a regular consumption of strawberries deserve attention, and a direct or indirect antioxidant role of strawberry bioactive compounds is among the most probable mechanisms underlying their beneficial properties. In the present study, we evaluated the overall effects of a 2-week daily consumption of strawberries on plasma antioxidant status, membrane lipid susceptibility to ex vivo-induced oxidation, and erythrocyte and mononuclear cell resistance to oxidative damage in apparently healthy volunteers. After strawberry intake, a moderate increase in fasting plasma antioxidant capacity and vitamin C was observed, together with a significant increase in the lag phase preceding plasma lipid oxidation. A significantly enhanced resistance to oxidative hemolysis was confirmed in red blood cells, while no significant changes were found in the extent of their membrane lipid peroxidation. For the first time, increased intake of strawberries for only 2weeks was shown to be sufficient to attenuate mononuclear cell mortality after ex vivo exposure to a single acuteoxidative challenge, but the analysis of DNA oxidative damage gave conflicting results. These findings suggest that a regular consumption of strawberries may enhance body defences against oxidative challenges. PMID- 24629943 TI - Stability of catechins in green tea nutraceutical products: application of solid phase extraction-thin layer chromatography densitometry. AB - Epigallocatechin gallate (EGCG) is a powerful antioxidant and commonly used nutraceutical. Accelerated stability of EGCG in tablet formulations was investigated. LLE and SPE were employed for sample clean-up and enrichment of EGCG over caffeine. Samples were analysed after spiking with fixed concentration of gallic acid (GA), in order to verify reproducibility of analysis. A TLC densitometric assay was developed and validated for determination of % loss EGCG. EGCG, GA and caffeine were resolved with Rf values 0.54, 0.69 and 0.80, respectively. LC-MS/MS was used to verify identity and purity of the EGCG band. Determination was carried out over a concentration range of 0.50-5.00MUg/band and 0.20-2.40MUg/band for GA and caffeine, respectively. Results showed significant reduction in EGCG content after one, three and six months: 24.00%, 28.00% and 52.00% respectively. Results continue to demonstrate that stability of nutraceutical products should be investigated in-depth using industry-oriented protocols before granting marketing authorisation. PMID- 24629944 TI - Hydrogen-rich water delays postharvest ripening and senescence of kiwifruit. AB - The effect of hydrogen-rich water (HRW) on prolonging the shelf life of kiwifruit and possible underlying mechanisms were assessed. Our results revealed that HRW (30%, 80%, and 100%) displayed different effects in inhibiting the rot of kiwifruit. Among these treatments, 80% HRW had the most significant effect by decreasing the rot incidence and preserving the firmness of kiwifruit. This conclusion was supported by the fact that 80% HRW treatment could effectively alleviate pectin solubilization and reduce the activities of cell wall-degrading enzymes. On the other hand, HRW treatment was able to reduce the respiration intensity, increase the activity of superoxide dismutase, decrease lipid peroxidation level, and maintain the radical (DPPH,O2(-),andOH)-scavenging activity of kiwifruit. Moreover, the inner membrane of mitochondria exhibited higher integrity. Thus, our results demonstrate that HRW treatment could delay fruit ripening and senescence during storage by regulating the antioxidant defence. PMID- 24629945 TI - Comparative antioxidant activity appraisal of traditional Sudanese kisra prepared from two sorghum cultivars. AB - The effect of fermentation and heating on the antioxidant activity of the fermented and fermented baked (kisra) dough prepared from two Sorghum cultivars (Tabat and Wad Ahmed) was evaluated. Kisra prepared from Tabat cultivar showed higher DPPH (1,1-diphenyl-2-picrylhydrazyl radical) scavenging and ferric reducing/antioxidant power (FRAP) than that of the Wad Ahmed cultivar. Baking improves the DPPH and FRAP of the kisra prepared from two cultivars. Baking caused a variable effect on the total phenol, tannins and flavonoids content across different periods of fermentation where an increase was mainly observed for samples subjected to longer periods of fermentation. A positive high correlation between the total phenol and antioxidant activity, using the DPPH and FRAP assays, was obtained for kisra prepared from both cultivars. The same observation was obtained for tannin content. In conclusion, fermentation and heating improve the antioxidant capacity of the sorghum grains from Tabat and Wad Ahmed cultivars. PMID- 24629946 TI - Droplet size and composition of nutraceutical nanoemulsions influences bioavailability of long chain fatty acids and Coenzyme Q10. AB - The influence of droplet size (d32=0.21, 0.70 or 2.2MUm) and oil digestibility (corn oil versus mineral oil) on the bioavailability of a model long chain fatty acid (heptadecanoic acid) and lipophilic nutraceutical (Coenzyme Q10) was investigated using a rat feeding study. Initially, we showed that small droplets were digested more rapidly than large droplets using a simulated small intestinal model (pH stat), which was attributed to the greater surface area of lipid exposed to intestinal juices. The pH stat model also confirmed that emulsified corn oil was digestible, whereas emulsified mineral oil was indigestible. A rat feeding study showed that the bioavailability of the fatty acid and lipophilic nutraceutical in small intestinal tissues was highest when they were encapsulated within digestible oil droplets with the smallest size. This study provides important information for development of nanoemulsion-based delivery systems that increase oral bioavailability of lipophilic nutraceuticals. PMID- 24629947 TI - Preparation of lutein-loaded particles for improving solubility and stability by Polyvinylpyrrolidone (PVP) as an emulsion-stabilizer. AB - Lutein, a non-provitamin A carotenoid, possesses multiple valuable physiological functions. Unfortunately, its application is limited due to its poor water solubility and instability under adverse conditions. To expand the applied range of lutein, we developed lutein-loaded particles and characterized by differential scanning calorimetry, X-ray powder diffraction and Fourier transformed infrared spectroscopy and investigated the encapsulation efficiency, aqueous saturation solubility and stability. The results showed that the lutein-loaded particles possessed high encapsulation efficiency (93.8+/-0.35%) and good water solubility (158MUg/ml). Compared with free lutein, the stability of the lutein-loaded particles against heat, light and oxygen was improved by 1.7 times, 3.3 times and 4.0 times, respectively. The results also indicated that lutein was embedded in PVP matrix in an amorphous state, and intermolecular hydrogen bonding was in existence between PVP, lutein and Tween 80, forming the main force assembling the lutein-loaded particles. PMID- 24629948 TI - Advances in structure-function relationships of tyrosinase from Agaricus bisporus - investigation on heat-induced conformational changes. AB - A combination of fluorescence spectroscopic measurements, inactivation kinetics and in silico prediction was used in the present study to investigate the heat induced behaviour of tyrosinase from Agaricus bisporus. The phase diagram indicated the existence of at least two distinct species induced by the temperature increase up to 75 degrees C. Regardless of calcium ion presence, the fluorescence intensity results suggest that tyrosinase tends to form aggregates after 10min at 75 degrees C. The quenching experiments using acrylamide and iodide demonstrate a more flexible conformation of tyrosinase at higher temperature. Detailed insights into tyrosinase structure after performing molecular dynamics simulations, suggest important structural rearrangements of the protein with the temperature increase. The copper coordinating His(94) residue was predicted to be involved in salt bridge formation with Glu(98), therefore causing significant alteration of the substrate binding site with increasing temperature. These significant changes in tyrosinase structure at temperatures over 60 degrees C might lead to enzyme inactivation. PMID- 24629949 TI - Effects of salts on physicochemical, microstructural and thermal properties of potato starch. AB - The objective of this study was to determine the effects of salts on the physicochemical, microstructural and thermal properties of potato starch. The salting-out ions were able to decrease the solubility, swelling power, transparency and particle size of potato starch significantly (p<0.05), while the salting-in ions increased these properties significantly (p<0.05). The microstructure of potato starch granules, observed by a light microscopy at 50 degrees C and 70 degrees C, was consistent with the above results. Differential scanning calorimetry (DSC) analysis demonstrated an increase in gelatinization temperature and enthalpy with the addition of salting-out ions, whereas there was a reverse trend for the addition of salting-in ions. The effects of anions on these properties of potato starch follow the order of SCN(-)>I(-)>NO3(-)>Br( )>Cl(-)>SO4(2-)>F(-), while effects of the cations follow the order of Li(+)>Na(+)>K(+), matching to the order of the Hofmeister series. PMID- 24629950 TI - Nanoencapsulation of an active peptidic fraction from sea bream scales collagen. AB - Sea bream scales were subjected to enzymatic hydrolysis with Esperase, and a peptide fraction with a molecular mass <3kDa (F3) was isolated by ultrafiltration. F3 was encapsulated in nanoliposomes made of partially purified phosphatidylcholine (PC). Concentrations of 3.1% and 1mg/ml for PC and F3, respectively, were established as the best entrapment protocol by response surface methodology. The liposomes entrapment efficiency and zeta potential were 74.6+/-0.9% and -40.8+/-0.67mV, respectively. The liposome size ranged from 66.2 to 214nm, with a mean diameter of 90.3nm and a polydispersity index of 0.25. The antioxidant activity and ACE inhibitory activity of the encapsulated peptide fraction (L-F3) remained constant after 8days at 4 degrees C. Encapsulation preserved the biological activities of F3, and could therefore be an alternative to improve the stability of these compounds when applied to a food product. PMID- 24629951 TI - Effect of enzyme additions on the oligosaccharide composition of Monastrell red wines from four different wine-growing origins in Spain. AB - The release of oligosaccharides during winemaking depends on the grape skin cell wall degradation, which can be facilitated by the use of enzymes. Oligosaccharide quantities and composition in wine could be influenced by the "terroir" effect. Monastrell wine was elaborated from grapes from four different "terroirs" (Canada Judio, Albatana, Chaparral-Bullas and Montealegre). Monastrell wines were also treated with beta-galactosidase enzyme addition and commercial enzyme addition. The results showed significant differences in the Monastrell wine oligosaccharide fractions, according to the geographical origin of grapes. A higher quantity of oligosaccharides was found for three out of four terroirs studied when commercial enzymes were added. The use of commercial enzyme modified the Arabinose/Galactose and the Rhamnose/Galacturonic acid ratios in Canada Judio and Albatana terroirs wines, and it modified the (Arabinose+Galactose)/Rhamnose ratio in Canada Judio, Albatana and Chaparral-Bullas terroirs wines. Therefore, the "terroir" impacts the effect of commercial enzyme treatment on wine oligosaccharide composition. PMID- 24629952 TI - Control of degreening in postharvest green sour citrus fruit by electrostatic atomized water particles. AB - The effect of electrostatic atomized water particles (EAWP) on degreening of green sour citrus fruit during storage was determined. Superoxide anion and hydroxyl radicals included in EAWP were present on the surface of the fruit peel after the treatment. Hydrogen peroxide was formed from EAWP in an aqueous solution, which could indicate that a hydroxyl radical of EAWP turns to hydrogen peroxide in the fruit flavedo as well as in the aqueous solution. EAWP treatment effectively suppressed the degreening of green yuzu and Nagato-yuzukichi fruits during storage at 20 degrees C. The enhancement in K+ ion leakage of both EAWP treated fruits reduced in comparison with the control. In spite of EAWP treatment, total peroxide level in both fruits showed almost no changes during storage, suggesting that hydrogen peroxide formed by EAWP treatment could stimulate the activation of hydrogen peroxide scavenging system and control degreening of these fruits during storage. PMID- 24629953 TI - Development and validation of RP-HPLC method for the quantitative estimation of alphas1-genetic variants in goat milk. AB - A high-performance liquid chromatographic (HPLC) method was developed and validated for separation and quantification of the most common genetic variants of alphas1-casein in goat's milk, to evaluate the effect of alphas1-casein polymorphisms on casein content. Chromatography was carried out by binary gradient technique on a reversed-phase C8 Zorbax column and the detection was made at a wavelength of 214nm. The procedure was developed using individual raw milk samples of Girgentana goats. For calibration experiments, pure genetic variants were extracted from individual milk samples of animals with known genotypes, considering that commercial standards for goat genetic variants were not available. The data obtained for Girgentana goat breed showed that A, B, F variants were alleles associated with a content of alphas1-casein in milk of 3.2+/-0.4, 5.4+/-0.5 and 0.7+/-0.1g/L, respectively, whereas N variant was a 'null' allele associated with the absence of alphas1-casein in milk. PMID- 24629954 TI - Concordance analysis between estimation methods of milk fatty acid content. AB - Considering the milk fatty acid influence on human health, the aim of this study was to compare gas chromatography (GC) and Fourier transform infrared (FTIR) spectroscopy for the determination of these compounds. Fatty acid content (g/100g of fat) were obtained by both methods and compared through Pearson's correlation, linear Bayesian regression, and the Bland-Altman method. Despite the high correlations between the measurements (r=0.60-0.92), the regression coefficient values indicated higher measures for palmitic acid, oleic acid, unsaturated and monounsaturated fatty acids and lower values for stearic acid, saturated and polyunsaturated fatty acids estimated by GC in comparison to FTIR results. This inequality was confirmed in the Bland-Altman test, with an average bias varying from -8.65 to 6.91g/100g of fat. However, the inclusion of 94% of the samples into the concordance limits suggested that the variability of the differences between the methods was constant throughout the range of measurement. Therefore, despite the inequality between the estimates, the methods displayed the same pattern of milk fat composition, allowing similar conclusions about the milk samples under evaluation. PMID- 24629955 TI - Delivery of green tea catechin and epigallocatechin gallate in liposomes incorporated into low-fat hard cheese. AB - The encapsulation of green tea catechin and epigallocatechin gallate (EGCG) in soy lecithin liposomes was examined at four concentrations (0%, 0.125%, 0.25% and 0.5% w/v), and inclusion in cheese at 0% and 0.25% w/v. The empty capsules had a mean diameter of 133nm and significantly (p<0.05) increased with the addition of catechin or EGCG. Electron microscopy revealed the lamellae and central core of the liposomes. Addition of antioxidants gave a significant (p<0.05) increase in the size of liposomes. Liposomes had surface potentials of -42.4 to -46.1mV with no significant difference between treatments, suggesting stable liposome systems. High efficiency (>70%) and yield (~80%) were achieved from the incorporation of catechin or EGCG inside the liposome structure. Addition of either antioxidant increased the liposome phase transition temperature (>50 degrees C). Nanocapsules containing these antioxidants were effectively retained within a low-fat hard cheese, presenting a simple and effective delivery vesicle for antioxidants. PMID- 24629956 TI - Rapid visual detection of phytase gene in genetically modified maize using loop mediated isothermal amplification method. AB - Transgenic maize plant expressing high phytase activity has been reported and approved by Chinese government in 2009. Here, we report a highly specific loop mediated isothermal amplification (LAMP) method to detect the phytase gene in the GMO maize. The LAMP reaction takes less than 20min and the amplification is visible without gel electrophoresis. The detection sensitivity of the LAMP method is about 30 copies of phytase genomic DNA, which is 33.3 times greater than the conventional PCR method with gel electrophoresis. The quantitative detection results showed that the LAMP method has a good linear correlation between the DNA copy number and the associated Tt values over a large dynamic range of template concentration from 6*10(1) to 6*10(7) copies, with a quantification limit of 60 copies. Therefore, the LAMP method is visual, faster, and more sensitive, and does not need special equipment compared to traditional PCR technique, which is very useful for field tests and fast screening of GMO feeds. PMID- 24629957 TI - A lipase based approach for studying the role of wheat lipids in bread making. AB - While endogenous wheat lipids exert a major effect on bread quality, little is known on the way they impact on bread loaf volume (LV). Here we altered wheat flour lipid composition during bread making using lipases in situ. Lipopan F, Lecitase Ultra, and surfactants increased LV to similar extents. The increases in bread LV as a result of these enzymes were related to decreased levels of galactolipids and phospholipids and concomitant increased 'lyso'-lipid as well as free fatty acid (FFA) levels. The FFA formed were transferred to the free lipid fraction, while the 'lyso'-lipids remained in the bound lipid fraction. For optimal gas cell stabilisation, an equilibrium between the lipid classes present and hence, the type of mesophase formed, is essential. Sufficient levels of lipids forming lamellar mesophases and lipids forming hexagonal I mesophases, which respectively form condensed monolayers or emulsify (deleterious) non-polar lipids in dough liquor, are needed. PMID- 24629958 TI - Cold-set whey protein microgels as pH modulated immobilisation matrices for charged bioactives. AB - The ability of cold-set whey protein microgels to function as pH-sensitive immobilisation matrices for bioactives was investigated. A pH dependent interaction was confirmed between the microgels and charged bioactives and this binding was impeded by the presence of competing ions in the solution, suggesting an electrostatic interaction. The use of a computer generated prediction model for the pH-dependent association of the microgels and further bioactives (including cationic and anionic peptides) was validated. The prediction model was efficient at determining the pH at which the maximum microgel-bioactive interaction occurred. This study highlights the capabilities of these food-grade whey based microgels as matrices that enable the immobilisation of a variety of bioactives by a charge interaction, and shows the potential for these matrices to function as smart delivery systems, in which uptake and release of bioactives is facilitated by environmental pH change. PMID- 24629959 TI - Assessment of the antioxidant and antiproliferative effects of sesquiterpenic compounds in in vitro Caco-2 cell models. AB - In this study, the antiradical and antiproliferative effects of the sesquiterpenic compounds trans, trans-farnesol, cis-nerolidol, alpha-humulene and guaiazulene, commonly found in plants and plant-derived foods and beverages, were evaluated. Chemical (DPPH and hydroxyl radicals) and biological (Caco-2 cells) models were used. Guaiazulene (IC50=0.73mM) showed higher scavenger capacity against DPPH, while trans, trans-farnesol (IC50=1.81mM) and cis-nerolidol (IC50=1.48mM) were more active towards hydroxyl radicals. All compounds, with the exception of alpha-humulene, were able to protect Caco-2 cells from oxidative stress induced by tert-butyl hydroperoxide. As antiproliferative agents, guaiazulene and cis-nerolidol were more effective than trans, trans-farnesol and alpha-humulene. The results obtained for the sesquiterpenic compounds by these in vitro assays opens a perspective for their promising use as antioxidants and antiproliferative agents. However, in vivo tests should be carried out in the future to confirm their safety and effectiveness. PMID- 24629960 TI - Antioxidant activity of fractions from oregano essential oils obtained by molecular distillation. AB - The objective of this study was to determine the antioxidant activity of fractions separated from oregano essential oil by short-path molecular distillation. Two residue (R1 and R2) and two distillate (D1 and D2) fractions were prepared by molecular distillation. The major components were: carvacrol, terpinen-4-ol and gamma-terpinene in R1 and R2; and gamma-terpinene, alpha terpineol and sabinene in D1 and D2. Free-radical scavenging activity was observed in all fractions and was highest in R2 (77.2%). D1 and D2 showed a smaller amount of volatile oxidation compounds produced from sunflower oil stored at 60 degrees C for 14days. The greatest antioxidant activity was observed in D1 and D2. The thermal stability of oregano essential oil and its fractions was also analysed. R1 and R2 presented an increased carvacrol concentration and thermal stability. The short-path molecular distillation fractions can be used to prepare fractions from oregano essential oil with a higher antioxidant activity. PMID- 24629961 TI - Protective ability of phenolics from white grape vinification by-products against structural damage of bovine serum albumin induced by glycation. AB - Grape skins recovered from white grape vinification processes were studied as possible anti-glycation agents. Total phenolics were characterised by the Folin Ciocalteu assay, proanthocyanidins by depolymerisation with n-butanol/HCl, flavonols by HPLC-DAD, reducing capacity by ferric ion reducing antioxidant power assay (FRAP) and anti-glycation activity by a bovine serum albumin (BSA)/fructose model system. Structural modifications of BSA were investigated by 2D isoelectric focusing sodium dodecyl sulfate polyacrylamide gel electrophoresis (IEF/SDS-PAGE) and fluorescence measurements. Both pI and Mr. of BSA were modified upon glycation reaction. These changes attributable to the involvement of free amino groups in Maillard-type reactions were inhibited by the white grape skin extracts. The anti-glycation activity ranged between 250 and 711mmol aminoguanidine Eq/kg. These results raise the interest in the potential health benefits of by-products of white grape vinification that could have a secondary use as an ingredient for new functional foods targeting wellbeing of diabetic and elderly people. PMID- 24629962 TI - Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin. AB - Curcumin has been shown to have a wide variety of biological activities for various human diseases including inflammation, diabetes and cancer. However, the poor oral bioavailability of curcumin poses a significant pharmacological barrier to its use therapeutically and/or as a functional food. Here we report the evaluation of the bioavailability and bio-efficacy of curcumin as an amorphous solid dispersion (ASD) in a matrix consisting of hydroxypropyl methyl cellulose (HPMC), lecithin and isomalt using hot melt extrusion for application in food products. Oral pharmacokinetic studies in rats showed that ASD curcumin was ~13 fold more bioavailable compared to unformulated curcumin. Evaluation of the anti inflammatory activity of ASD curcumin in vivo demonstrated enhanced bio-efficacy compared to unformulated curcumin at 10-fold lower dose. Thus ASD curcumin provides a more potent and efficacious formulation of curcumin which may also help in masking the colour, taste and smell which currently limit its application as a functional food ingredient. PMID- 24629963 TI - Effects of temperature during frozen storage on lipid deterioration of saithe (Pollachius virens) and hoki (Macruronus novaezelandiae) muscles. AB - Lipid deterioration of two lean fish species, saithe (Pollachius virens) and hoki (Macruronus novaezelandiae), during frozen storage at -20 and -30 degrees C (up to 18months) was studied. Lipid composition, lipid oxidation and hydrolysis, and sensory attributes were evaluated on both light and dark muscles of the fish species. Results showed significant lipid deterioration with extended storage time, but lower storage temperature showed significantly more preservative effects. A marked difference was observed between the composition of dark muscle of hoki and saithe. Polyunsaturated fatty acids were the predominant lipids in dark muscle of saithe, while monounsaturated fatty acids were predominant in dark muscle of hoki. Further, the hydrolytic activity differed greatly between dark muscle of hoki and saithe, with significantly lower activity observed in hoki. Present results indicate that both tertiary lipid oxidation and hydrolysis products are appropriate for assessing lipid deterioration of saithe and hoki light muscle during frozen storage. PMID- 24629964 TI - Modification of the structural and rheological properties of whey protein/gelatin mixtures through high pressure processing. AB - High pressure processing (HPP) can induce structure development in macromolecules which are distinct from those of conventional thermal treatments. Gelation properties of whey protein (5-20% w/w) upon 15min HPP at 600MPa and 5 or 30 degrees C (initial sample temperatures) were examined in the presence and absence of 5% w/w gelatin. The values of storage modulus (G') in pressure treated mixed gels were below those of their counterparts thermally treated at 80 degrees C. Mixed systems subjected to HPP in the solution state possessed higher G' than the mixed systems subjected to HPP in the form of gels. The cooling profile of G' in pressurised mixed solutions was similar to that of the gelatin solution, which indicates that HPP resulted in a high degree of gelatin continuity. Confocal images confirmed that gelatin was the continuous phase whilst whey protein aggregated in discontinuous inclusions within the pressurised mixed systems. PMID- 24629965 TI - Comparison between different types of carboxylmethylcellulose and other oenological additives used for white wine tartaric stabilization. AB - Carboxylmethylcellulose (CMC) is authorised to prevent wine tartaric instability. The effect of CMC structural characteristics on their effectiveness is not well understood. The main purpose of this study was to compare the impact of CMC's with different degrees of substitution and molecular weight, on tartaric stability, tartaric acid, mineral concentration, phenolic compounds, chromatic and sensory characteristics in white wines, and compare its effectiveness with other oenological additives. Mini-contact test showed that all CMC's and metatartaric acid stabilized the wines; however, some arabic gums and mannoproteins do not stabilized the wines. CMC's had no significant effect on tartaric acid, potassium, calcium and sensory attributes. Tartaric stabilization effectiveness depends on CMC's degree of substitution, but also on wine matrix, probably its initial potassium content. Results suggest that CMC is a good alternative to white wine tartaric stabilization; nevertheless deeper structure knowledge is necessary in order to choose the appropriate CMC for a given tartaric instability. PMID- 24629966 TI - Health benefits of wine: don't expect resveratrol too much. AB - Moderate consumption of red wine reduces the risk of heart disease and extends lifespan, which these healthy benefits are often attributed to its high antioxidant content. The relative contributions of wine polyphenols in healthy benefits were studied in this study. Among all wine polyphenols, caffeic acid was the richest one, while gallic acid showed the highest free radical scavenging activity. There was no significant difference between the prime red wine and the red wine adding 10-fold resveratrol on neuroprotective effects on SH-SY5Y cell line. The contribution percentage of resveratrol to the antioxidant activity of red wine was less than other tested polyphenols. It suggested that resveratrol may be negligible with respect to healthy benefits of red wine. PMID- 24629967 TI - Effect of probiotics on antioxidant and antimutagenic activities of crude peptide extract from yogurt. AB - Search for bioactive peptides is intensifying because of the risks associated with the use of synthetic therapeutics, thus peptide liberation by lactic acid bacteria and probiotics has received a great focus. However, proteolytic capacity of these bacteria is strain specific. The study was conducted to establish proteolytic activity of Lactobacillus acidophilus (ATCC(r) 4356TM), Lactobacillus casei (ATCC(r) 393TM) and Lactobacillus paracasei subsp. paracasei (ATCC(r) BAA52TM) in yogurt. Crude peptides were separated by high-speed centrifugation and tested for antioxidant and antimutagenic activities. The degree of proteolysis highly correlated with these bioactivities, and its value (11.91%) for samples containing all the cultures was double that of the control. Liberated peptides showed high radical scavenging activities with 1,1-diphenyl-2 picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), IC50 1.51 and 1.63mg/ml, respectively and strong antimutagenicity (26.35%). These probiotics enhanced the generation of bioactive peptides and could possibly be commercially applied in new products, or production of novel anticancer peptides. PMID- 24629968 TI - Effect of chemical elicitors on peppermint (Mentha piperita) plants and their impact on the metabolite profile and antioxidant capacity of resulting infusions. AB - Infusions are widely consumed all over the world and are a source of dietary antioxidants, which can be improved in plants using elicitors. The aim of this study was to evaluate the foliar application of salicylic acid (SA) (0.5, 1 and 2mM) or hydrogen peroxide (H2O2) (0.05, 0.1 and 0.5mM) on peppermint (Mentha piperita) plants and its effect on the metabolite profile and antioxidant capacity of resulting infusions. Whereas 2mM SA treatment improved plant growth parameters and metabolite profile (carbohydrates and amino acids), 0.5 and 1mM SA treatments increased phenolic compound concentration. Sinapic acid, rutin and naringin were detected only in SA treatments; antioxidant capacity was also improved. Regarding H2O2 treatments, no differences in plant growth parameters, metabolite profile or antioxidant capacity were found. Therefore, the application of SA to peppermint is recommended in order to improve bioactive compounds and the antioxidant capacity of infusions. PMID- 24629969 TI - Acetylation and carboxymethylation of the polysaccharide from Ganoderma atrum and their antioxidant and immunomodulating activities. AB - A water-soluble polysaccharide extracted from Ganoderma atrum was chemically modified to obtain its acetyled and carboxymethylated derivatives. The results of chemical analysis, Fourier-transform infrared and (13)C nuclear magnetic resonance spectroscopy showed that these modifications were successful, although the molecular weight of these derivatives decreased due to slight degradation during the reaction. The antioxidant and immunomodulating activities of these derivatives were then investigated to determine the structure-bioactivity relationship. Results showed that the acetyled derivative with appropriate degree of substitution and lower molecular weight exhibited stronger antioxidant abilities on scavenging DPPH radical, and inhibitory effects in beta-carotene linoleic acid systems compared with the native polysaccharide. In addition, it also enhanced the macrophage phagocytosis capacity and tumor necrosis factor alpha secretion, whereas the carboxymethylated derivative was shown to be slightly less effective. These results indicated that the type of substitution group and their degree of substitution play a decisive role in the bioactivities of the derivatives. PMID- 24629970 TI - Vegetable and fermented vegetable juices containing germinated seeds and sprouts of lentil and cowpea. AB - Health-promoting effects of vegetable juice (VJ) and fermented vegetable juice (FVJ) were determined. Both juices displayed antioxidant activity against DPPH radical, and ORAC values obtained for both juices were not statistically different. The alpha-glucosidase inhibitory activities of the VJ and FVJ were not different. However, alpha-amylase inhibitory effect of the VJ (IC50: 41MUM) was higher than that of FVJ (IC50: 149MUM) (p<0.05). In vitro bile acid-binding capacity of FVJ was about 4.30times higher than that of VJ (p<0.05). Although in vitro ACE inhibitory activity of VJ was below 50%, FVJ displayed ACE inhibition (80.2%) with an IC50 value of 50MUgprotein/ml. Even though ACE inhibitory activities of digested and undigested FVJ were similar, there was a 42-fold decrease in the IC50 value of FVJ after small intestinal digestion (p<0.05). FVJ, diluted by one half, displayed hemagglutinating activity whilst VJ did not display any hemagglutinating activity. PMID- 24629971 TI - Determination of polycyclic aromatic hydrocarbons [PAHs] in processed meat products using gas chromatography - flame ionization detector. AB - The concentrations of polycyclic aromatic hydrocarbons (PAHs) in smoked, grilled and boiled meats were determined using gas chromatography - flame ionization detector (GC-FID). PAHs in the processed meats were extracted in n-hexane after hydrolysis with methanolic KOH. Clean-up was achieved using solid phase extraction in neutral-Si/basic-Si/acidic-Si/neutral-Si frits. The fractions, benzo[k]fluoranthene (BkP), benzo[a]pyrene (BaP), indeno[123-cd]pyrene (IP) and benzo[ghi]perylene (BghiP) were separated and quantified using GC-FID. The method and instrument limits of detections were 0.1, 0.1, 0.2, 0.3MUg/kg and 0.5, 0.5, 1.0, 1.5MUg/kg, respectively, for BkP, BaP, IP and BghiP. The method's recovery and precision generally varied between 83.69% and 94.25% with relative standard deviation (RSD) of 3.18-15.60%; and 90.38-96.71% with relative standard deviation (RSD) of 1.82-12.87% respectively. The concentration of BkP, BaP, IP and BghiP in smoked, grilled and boiled meat samples were ranged 0.64-31.54MUg/kg, 0.07 7.04MUg/kg, 0.09-15.03, 0.51-46.67MUg/kg and 0.01-5.11MUg/kg, respectively. PMID- 24629972 TI - Potential of tara (Caesalpinia spinosa) gallotannins and hydrolysates as natural antibacterial compounds. AB - Gallotannins obtained from tara pod extracts (EE) and from the products of acid hydrolysis for 4 and 9h (HE-4 and HE-9) were characterised for their composition, antioxidant activity, antimicrobial activity (AA) and minimum inhibitory concentration (MIC). Results of AA and MIC showed that EE exerted the highest inhibitory activity against Staphylococcus aureus, followed by Pseudomonas fluorescens; and among these bacteria, the antibacterial potency was enhanced after EE hydrolysis only against S. aureus. The lowest minimum inhibitory concentration (MIC) value (0.13mg gallic acid equivalent (GAE)/ml) was exerted by HE-4 against S. aureus. These results indicate that tara gallotannins have the potential to inhibit pathogenic bacteria with potential application in foods as antimicrobials and their AA can be enhanced by acid hydrolysis. PMID- 24629973 TI - Antioxidant activity of bovine casein hydrolysates produced by Ficus carica L. derived proteinase. AB - A Ficus carica L. latex proteinase preparation was investigated for its ability to produce antioxidant hydrolysates/peptides from bovine casein (CN). The Oxygen Radical Absorbance Capacity (ORAC) values for NaCN and beta-CN hydrolysates ranged from 0.06 to 0.18, and from 0.51 to 1.19MUmol Trolox equivalents/mg freeze dried sample, respectively. Gel permeation HPLC showed that the beta-CN hydrolysate with a degree of hydrolysis of 21% had 65% of peptide material with a molecular mass <500Da. The RP-UPLC profiles also indicated that beta-CN was substantially hydrolysed during the early stages of hydrolysis. Analysis of the 4h beta-CN hydrolysate by LC-ESI-MS/MS allowed identification of 8 peptide sequences with potential antioxidant properties. PMID- 24629975 TI - Changes in resistant starch from two banana cultivars during postharvest storage. AB - Banana resistant starch samples were extracted and isolated from two banana cultivars (Musa AAA group, Cavendish subgroup and Musa ABB group, Pisang Awak subgroup) at seven ripening stages during postharvest storage. The structures of the resistant starch samples were analysed by light microscopy, polarising microscopy, scanning electron microscopy, X-ray diffraction, and infrared spectroscopy. Physicochemical properties (e.g., water-holding capacity, solubility, swelling power, transparency, starch-iodine absorption spectrum, and Brabender microviscoamylograph profile) were determined. The results revealed significant differences in microstructure and physicochemical characteristics among the banana resistant starch samples during different ripening stages. The results of this study provide valuable information for the potential applications of banana resistant starches. PMID- 24629974 TI - Degradation of cyanidin-3-rutinoside and formation of protocatechuic acid methyl ester in methanol solution by gamma irradiation. AB - Anthocyanins are naturally occurring phenolic compounds having broad biological activities including anti-mutagenesis and anti-carcinogenesis. We studied the effects and the degradation mechanisms of the most common type of anthocyanins, cyanidin-3-rutinoside (cya-3-rut), by using gamma ray. Cya-3-rut in methanol (1mg/ml) was exposed to gamma-rays from 1 to 10kGy. We found that the reddish colour of cya-3-rut in methanol disappeared gradually in a dose-dependent manner and effectively disappeared (>97%) at 10kGy of gamma ray. Concomitantly, a new phenolic compound was generated and identified as a protocatechuic acid methyl ester by liquid chromatography, (1)H, and (13)C NMR. The formation of protocatechuic acid methyl ester increased with increasing irradiation and the amount of protocatechuic acid methyl ester formed by decomposition of cya-3-rut (20MUg) at 10kGy of gamma ray was 1.95MUg. In addition, the radical-scavenging activities were not affected by gamma irradiation. PMID- 24629976 TI - Identification of volatile organic compounds generated from healthy and infected powdered chili using solvent-free solid injection coupled with GC/MS: application to adulteration. AB - To investigate adulteration in commercial chili powder, the volatile organic compounds of healthy and infected powdered chili pepper were characterized using a solvent-free solid injector (SFSI) coupled with gas chromatography/mass spectrometry (GC/MS). Except for one compound (capillary compound for blank), 43 compounds were identified in healthy and infected chili powder. Specifically, 31, 36, and 41 compounds were identified in healthy, medium-infected, and severely infected chili powder. Among these compounds, acetic acid (13.77%), propanal (2.477%), N-methylpyrrole (1.986%), and 2-methyl-propanal (1.768%) were leading volatiles in the healthy chili powder. In contrast, infected chili powder contained 9,12-octadecadienoic acid, ethyl ester (15.984%), acetic acid (11.249%), hexadecanoic acid, methyl ester (3.3%), N-methylpyrrole (3.221%), and 2-furanmethanol (2.629%) as major compounds. Trimethylamine and isosorbide were detected in both medium and severely infected chili, but not in healthy chili. This means that these compounds could be used as biomarkers to distinguish between healthy and infected chili. The proposed technique was applied to 12 commercial chili powders, and trimethylamine and isosorbide were detected in six samples. These results suggest that a contaminated chili that was added to a healthy one could be successfully identified by a combination of the SFSI and GC/MS. PMID- 24629977 TI - Raman spectroscopy in determination of horse meat content in the mixture with other meats. AB - A new method based on FT-Raman measurements that allows to determine the content of horse meat in its mixture with beef has been proposed. In the analysis of the Raman spectra of the meat mixtures, the integral intensity ratios of the 937/1003, 879/1003, 856/1003, 829/1003, and 480/1003cm(-1) pairs of bands have been determined the intensities of which were related to the reference intensity of the band at 1003cm(-1). The reasonable results that show good fitting between the spectroscopic parameters and chemical content of the studied samples have been obtained. The analytical equations between these parameters have been proposed. PMID- 24629978 TI - Nutritional and antioxidant contributions of Laurus nobilis L. leaves: would be more suitable a wild or a cultivated sample? AB - Medicinal and aromatic plants are used since ancient times in folk medicine and traditional food, but also in novel pharmaceutical preparations. The controversy lies in the use of cultivated and/or wild plants presenting both advantages and disadvantages in biological, ecological but also economic terms. Herein, cultivated and wild samples of Laurus nobilis L. were chemically characterized regarding nutritional value, free sugars, organic acids, fatty acids and tocopherols. Furthermore, the antioxidant activity (scavenging activity, reducing power and lipid peroxidation inhibition) and individual phenolic profile of L. nobilis extracts and infusions were evaluated. Data showed that the wild sample gave higher nutritional contribution related to a higher content of proteins, free sugars, organic acids, PUFA and tocopherols. It also gave better PUFA/SFA and n-6/n-3 ratios. Regarding antioxidant activity and phenolic compounds, it was the cultivated sample (mostly the infusion) that showed the highest values. The present study supports the arguments defending the use of wild and cultivated medicinal and aromatic plants as both present very interesting features, whether nutritional or antioxidant, that can be an assessed by their consumption. In vitro culture could be applied to L. nobilis as a production methodology that allows combination of the benefits of wild and cultivated samples. PMID- 24629979 TI - Melatonin content of pepper and tomato fruits: effects of cultivar and solar radiation. AB - We evaluated the effect of cultivar and solar radiation on the melatonin content of Capsicum annuum (pepper) and Solanum lycopersicum (tomato) fruits. The melatonin content of red pepper fruits ranged from 31 to 93ngg(-1) (dry weight). The melatonin content of tomato ranged from 7.5 to 250ngg(-1) (dry weight). We also studied the effect of ripeness on melatonin content and identified one group of pepper cultivars in which the melatonin content increased as the fruit ripened and another in which it decreased as the fruit ripened. Under shade conditions, the melatonin content in most of tomato cultivars tended to increase (up to 135%), whereas that of most pepper cultivars decreased (to 64%). Overall, the results also demonstrated that the melatonin content of the fruits was not related to carbon fluxes from leaves. PMID- 24629980 TI - Characteristics of compounds in hops using cyclic voltammetry, UV-VIS, FTIR and GC-MS analysis. AB - The article presents the antioxidant properties of the extracts of hop EI and EII, by the electrochemical methods on a platinum electrode and comparative analysis of the composition of the extracts of hops using UV-VIS, FTIR and GC-MS methods. The hops extract EI, was obtained from the waste of the hops cone. The hops extract EII, was obtained from the hops cone itself. Hops contain a wide range of polyphenolic compounds with antioxidant properties divided in various chemical classes. Flavonoids and other polyphenolic compounds contained in hops show antioxidant capacity because of the presence of hydroxyl groups in various configurations and numbers within their molecules. The electrochemical properties and antioxidant capacity of hop samples were determined to select the most effective antioxidant. Based on the cyclic and pulse voltammograms, it was observed that hop extract EI contains polyphenols that are oxidised at a less positive potential than extract EII, i.e., it shows better antioxidant capacity. From the analysis of the UV-VIS and FTIR spectra and the GC-MS analysis, it was observed that extract EI contains less phenyl compounds than EII. In addition to flavonoids, EII contains hop acids and chlorophyll. The solutions of hop extracts show very good antioxidant capacities; therefore, they can effectively inhibit or slow negative oxidation reactions and scavenge free radicals and reactive oxygen species (ROS). PMID- 24629981 TI - Determination of the bioactive compounds, antioxidant activity and chemical composition of Brazilian blackberry, red raspberry, strawberry, blueberry and sweet cherry fruits. AB - This study aimed to evaluate the chemical composition, identify the bioactive compounds and measure the antioxidant activity present in blackberry, red raspberry, strawberry, sweet cherry and blueberry fruits produced in the subtropical areas of Brazil and to verify that the chemical properties of these fruit are similar when compared to the temperate production zones. Compared with berries and cherries grown in temperate climates, the centesimal composition and physical chemical characteristics found in the Brazilian berries and cherries are in agreement with data from the literature. For the mineral composition, the analyzed fruits presented lower concentrations of P, K, Ca, Mg and Zn and higher levels of Fe. The values found for the bioactive compounds generally fit the ranges reported in the literature with minor differences. The greatest difference was found in relation to ascorbic acid, as all fruits analyzed showed levels well above those found in the literature. PMID- 24629982 TI - Chemical composition of seed oils in native Taiwanese Camellia species. AB - The aim of this study was to examine the fatty acid (FA) composition and levels in seeds of twelve native Camellia species collected in different populations of major producing regions in Taiwan. The constituents of FAs varied within and among populations. Oleic acid (OA) was found to be the predominant FA constituent in all species. Remarkably high levels of unsaturated OA and linoleic acid (LA), found in two populations of Camellia tenuiflora (CT), C. transarisanensis (CTA), and C. furfuracea (CFA), were similar to those reported for olive oil. The levels of saturated palmitic acid (PA) from most of the tested seed oils were less than 13%. Among the different fats, some FAs can be used as functional ingredients for topical applications. The seed oils of CT, CTA, and CFA possess chemical compounds that make them useful in health-oriented cooking due to their high OA and LA contents and low PA content. PMID- 24629983 TI - Influence of whey protein-beet pectin conjugate on the properties and digestibility of beta-carotene emulsion during in vitro digestion. AB - The impact of a whey protein isolate (WPI)-beet pectin (BP) conjugate (formed by dry-heating) on the physical properties and digestibilities of beta-carotene and carrier oil in oil-in-water emulsions was studied when they passed through a model gastrointestinal system. beta-Carotene emulsions were stabilized by WPI, unconjugated and conjugated WPI-BP, separately. The emulsions were then passed through an in vitro digestion model and the mean droplet size, droplet distribution, zeta-potential, free fatty acids and beta-carotene released were measured. The stability to droplet flocculation and coalescence during digestion was increased for the WPI-BP conjugate stabilized emulsion. Addition of BP onto the WPI stabilized emulsions could inhibit the releases of carrier oil (MCT) and beta-carotene. The releases of free fatty acids and beta-carotene did not differ greatly between the unconjugated and conjugated WPI-BP stabilized emulsions. These results have important implications for protein-polysaccharide stabilized emulsions and conjugates used for the protection and delivery of bioactive compounds. PMID- 24629984 TI - Sweet potato (Ipomoea batatas L.) leaves as nutritional and functional foods. AB - In this study, the nutritional compositions of leaves from 40 sweet potato (Ipomoea batatas L.) cultivars were assessed. The correlations between antioxidant activity and crude protein, crude fat, crude fiber, carbohydrate, and polyphenol contents were determined. The crude protein, crude fiber, crude fat, carbohydrate and ash contents ranged between 16.69-31.08, 9.15-14.26, 2.08-5.28, 42.03-61.36, and 7.39-14.66g/100gdryweight(DW), respectively. According to the index of nutritional quality, sweet potato leaves are good sources of protein, fiber, and minerals, especially K, P, Ca, Mg, Fe, Mn, and Cu. The correlation coefficient between antioxidant activity and total polyphenol content was the highest (0.76032, p<0.0001), indicating that polyphenols are important antioxidants in sweet potato leaves. Sweet potato leaves, which contain several nutrients and bioactive compounds, should be consumed as leafy vegetables in an attempt to reduce malnutrition, especially in developing countries. PMID- 24629985 TI - Determination of dicyandiamide in infant formula by stable isotope dilution hydrophilic interaction liquid chromatography with tandem mass spectrometry. AB - Dicyandiamide is a compound for reducing the negative effects of greenhouse gas emissions and nitrate leaching into waterways. In this study, the trace contamination of dicyandiamide in infant formula was analysed by stable isotope dilution hydrophilic interaction liquid chromatography with tandem mass spectrometry (HILIC-MS/MS). Dicyandiamide and a stable isotope internal standard were monitored by multiple reaction-monitoring with mass transitions: m/z 85 >68/43 and m/z 89->71/45 in the electrospray positive ion mode. For sample preparation of the infant formula, a diluted/filtered procedure was developed for this assay. The calculated LOD and LOQ values were 0.01 or 0.05ng/mL for the standard solution, respectively. The averaged recovery and precision were 110.8% and 7.4%, respectively. This assay was applied to monitor 23 infant formulas, and the dicyandiamide contamination in one sample was detected and quantified at 79.1+/-1.2ng/g (ppb) powder. We suggest that it is necessary to cautiously monitor the DCD in common products from international countries. PMID- 24629986 TI - Rapid and non-destructive determination of drip loss and pH distribution in farmed Atlantic salmon (Salmo salar) fillets using visible and near-infrared (Vis NIR) hyperspectral imaging. AB - Drip loss and pH are important indices in quality assessment of salmon products. This work was carried out for rapid and non-destructive determination of drip loss and pH distribution in salmon fillets using near-infrared (Vis-NIR) hyperspectral imaging. Hyperspectral images were acquired for salmon fillet samples and their spectral signatures in the 400-1700nm range were extracted. Partial least square regression (PLSR) was used to correlate the spectra with reference drip loss and pH values. Important wavelengths were selected using the regression coefficients method to develop new PLSR models, leading to a correlation coefficient of cross-validation (rCV) of 0.834 with root-mean-square errors by cross-validation (RMSECV) of 0.067 for drip loss and a rCV of 0.877 with RMSECV of 0.046 for pH, respectively. Distribution maps of drip loss and pH were generated based on the new PLSR models using image processing algorithms. The results showed that Vis-NIR hyperspectral imaging technique combined with PLSR calibration analysis offers an effective quantitative capability for determining the spatial distribution of drip loss and pH in salmon fillets. PMID- 24629987 TI - Physicochemical properties of natural actomyosin from threadfin bream (Nemipterus spp.) induced by high hydrostatic pressure. AB - Changes of physicochemical properties in natural actomyosin (NAM) from threadfin bream (Nemipterus spp.) induced by high hydrostatic pressure (200, 400, 600MPa for 10, 30, 50min) were studied. The increase in turbidity of NAM was coincidental with the decrease in protein solubility with increasing pressure and time, suggesting the formation of protein aggregates. SDS-PAGE showed that polymerisation and degradation of myosin heavy chain were induced by high pressure. Ca(2+)-ATPase activity of NAM treated by high pressure was lost, suggesting the denaturation of myosin and the dissociation of actomyosin complex. Surface hydrophobicity of NAM increased when the pressure and pressurization time increased, indicating that the exposed hydrophobic residues increased upon application of high pressure. Decrease in total sulfhydryl content and increase in surface-reactive sulfhydryl content of NAM samples were observed with the extension of pressurizing time, indicating the formation of disulphide bonds through oxidation of SH groups or disulphide interchanges. The above changes of physicochemical properties suggested conformational changes of NAM from muscle of threadfin bream induced by high hydrostatic pressure. PMID- 24629988 TI - Evaluation of the antioxidant and anti-osteoporosis activities of chemical constituents of the fruits of Prunus mume. AB - The present study investigated the antioxidant and anti-osteoporosis activities of phytochemicals in the fruits of Prunus mume. From the methanol extract, three new acylated sucroses, mumeoses P-R (1-3), were isolated together with 20 known compounds (4-23). Compounds 1-3 showed potent peroxyl radical-scavenging activities and 12-19 showed both potent peroxyl radical-scavenging and reducing activities. The anti-osteoporosis activity was evaluated using murine pre osteoblastic MC3T3-E1 cells and pre-osteoclastic RAW 264.7 cells. Compounds 2 and 3 (cis-trans isomers), 5, 7, 8, and 10 significantly stimulated the differentiation of pre-osteoblastic MC3T3-E1 cells to increase collagen synthesis or mineralization functions of osteoblasts, while compounds 5, 6, 9, 10, 12, 14 16, 18, 20, and 22 significantly suppressed tartrate-resistant acid phosphatase activity in receptor activator of nuclear factor-kappaB ligand-induced osteoclastic RAW 264.7 cells. These results indicated that the fruits of P. mume are an excellent source of antioxidant and anti-osteoporosis phytochemicals. PMID- 24629989 TI - Antiplatelet effects of clopidogrel dose adjustment (75 mg/d vs 150 mg/d) after carotid stenting. AB - OBJECTIVE: Clopidogrel plays a central role in the treatment of patients undergoing carotid artery stenting (CAS). The objective was to evaluate the effect of clopidogrel (75 mg/d) on platelet reactivity in responders and nonresponders and the antiplatelet effect of different doses of clopidogrel in patients with high on-treatment reactivity (OTR) after CAS. METHODS: Patients with high OTR (defined by VerifyNow (Accumetrics, San Diego, Calif) assay as >=230 P2Y12 reaction units [PRU]) were randomly assigned in a 1:1 ratio to group 1 (standard-dose clopidogrel therapy: 75 mg/d for 30 days) or group 2 (high-dose clopidogrel: 150 mg/d for 30 days). RESULTS: The study enrolled 214 patients. Of these, 115 (53.7%) were clopidogrel responders (group 0), and 99 (46.3%) had high OTR (clopidogrel nonresponders); of which, 50 were randomly assigned to group 1 and 49 to group 2. At baseline, the PRU value did not differ between group 1 (288.50 +/- 46) and group 2 (295.45 +/- 47.2; P = .308). Patients displayed reduced mean platelet reactivity levels at 30 days in group 1 (238.96 +/- 72.25; P < .001) and group 2 (201.85 +/- 77.8; P < .001). Although high-dose clopidogrel resulted in more intense platelet function inhibition, the differences between median 30-day PRU values (P = .483) and the percentage change of PRU (P = .442) for groups 1 and 2 were not significant. The incidences of transient ischemic attack, stroke, or death at up to 30 days after CAS in the high-OTR patients were similar between groups 1 and 2 (P = .481). CONCLUSIONS: Patients with high OTR undergoing CAS treated with standard-dose and double-dose clopidogrel had significantly reduced platelet reactivity after 30 days. The double dose did not result in statistically significantly greater reductions in reactivity compared with the standard dose. PMID- 24629990 TI - The current position of precuffed expanded polytetrafluoroethylene bypass grafts in peripheral vascular surgery. AB - OBJECTIVE: Long-term results of precuffed expanded polytetrafluoroethylene (ePTFE) grafts used for peripheral bypass surgery are lacking. The aim of this study was to obtain the long-term outcomes of precuffed ePTFE grafts compared with autologous saphenous vein (ASV) grafts used in patients with peripheral arterial disease (PAD). METHODS: A single-institution retrospective study of precuffed ePTFE and ASV graft performances in patients with PAD was undertaken between January 2004 and December 2012. Five-year primary patency, secondary patency, and limb salvage rates were determined by Kaplan-Meier analyses. RESULTS: A total of 467 bypass grafts were included in this study (169 precuffed ePTFE grafts and 298 ASV grafts). Secondary patency rates of ePTFE vs ASV at 1 and 5 years, respectively, were as follows: for 134 supragenicular femoropopliteal bypasses, 60% and 27% vs 89% and 85% (P < .05); for 190 infragenicular femoropopliteal bypasses, 40% and 25% vs 86% and 79% (P < .05); and for 84 femorocrural bypasses, 30% and 14% vs 50% and 50% (P < .05). Five-year limb salvage rates of ePTFE vs ASV for supragenicular femoropopliteal bypasses were 82% vs 94% (P = .16); for infragenicular femoropopliteal bypasses, 41% vs 92% (P < .05); and for femorocrural bypasses, 43% vs 64% (P = .06). CONCLUSIONS: ASV bypasses are still the first-choice conduit in peripheral bypass surgery performed in patients with PAD. Precuffed ePTFE bypasses are acceptable alternatives in the absence of adequate autologous vein. PMID- 24629991 TI - Reliability of hospital readmission rates in vascular surgery. AB - OBJECTIVE: The Center for Medicare and Medicaid Services recently began assessing financial penalties to hospitals with high readmission rates for a narrow set of medical conditions. Because these penalties will be extended to surgical conditions in the near future, we sought to determine whether readmissions are a reliable predictor of hospital performance with vascular surgery. METHODS: We examined 4 years of national Medicare claims data from 1576 hospitals on beneficiaries undergoing three common vascular procedures: open or endovascular abdominal aortic aneurysm repair (n = 81,520) or lower extremity arterial bypass (n = 57,190). First, we divided our population into two groups on the basis of operative date (2005-2006 and 2007-2008) and generated hospital risk- and reliability-adjusted readmission rates for each time period. We evaluated reliability through the use of the "test-retest" method; highly reliable measures will show little variation in rates over time. Specifically, we evaluated the year-to-year reliability of readmissions by calculating Spearman rank correlation and weighted kappa tests for readmission rates between the two time periods. RESULTS: The Spearman coefficient between 2005-2006 readmissions rankings and 2007-2008 readmissions rankings was 0.57 (P < .001) and weighted kappa was 0.42 (P < .001), indicating a moderate correlation. However, only 32% of the variation in hospital readmission rates in 2007-2008 was explained by readmissions during the 2 prior years. There were major reclassifications of hospital rankings between years, with 63% of hospitals migrating among performance quintiles between 2005-2006 and 2007-2008. CONCLUSIONS: Risk-adjusted readmission rates for vascular surgery vary substantially year to year; this implies that much of the observed variation in readmission rates is either random or caused by unmeasured factors and not caused by changes in hospital quality that may be captured by administrative data. PMID- 24629992 TI - 116E rotavirus vaccine development: a successful alliance. PMID- 24629993 TI - Team science and the creation of a novel rotavirus vaccine in India: a new framework for vaccine development. PMID- 24629995 TI - HIV infection predisposes skin to toxic epidermal necrolysis via depletion of skin-directed CD4+ T cells. AB - BACKGROUND: A greater incidence of adverse cutaneous drug eruptions, including toxic epidermal necrolysis (TEN), occurs among HIV-infected patients. OBJECTIVE: We sought to determine if immunophenotypical differences exist in the inflammatory infiltrates of TEN lesions from HIV-infected individuals versus noninfected individuals. METHODS: The inflammatory infiltrates in 12 cases of TEN from HIV-positive patients were characterized and compared with the infiltrates present in 12 cases of TEN from HIV-negative patients. RESULTS: TEN infiltrates consisted of CD3, CD4, and CD8 immunoreactive T lymphocytes in both the dermis and epidermis. HIV infection was associated with an 8-fold increase in the ratio of CD8(+) to CD4(+) T cells infiltrating the dermis (P = .006) and a decrease in the number of dermal CD4(+) cells (P = .044). There was also a significant decrease in the ratio of CD25(+) to CD4(+) cells in the epidermis of HIV-infected skin (P = .011). LIMITATIONS: This study is limited by small sample sizes. CONCLUSION: A decrease in the number of skin-directed CD4(+) cells and an increase in the ratio of CD8(+) to CD4(+) cells exists in TEN lesions among HIV infected individuals and likely contribute to an increased risk of developing drug reactions because of the loss of skin-protective CD4(+)CD25(+) regulatory T cells. PMID- 24629994 TI - Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. METHODS: We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (>=11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). FINDINGS: 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53.6% (95% CI 35.0-66.9; p=0.0013) and 56.4% (36.6 70.1; p<0.0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37-97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1.5 in the vaccine group and 3.2 in the placebo group, with an incidence rate ratio of 0.46 (95% CI 0.33-0.65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. INTERPRETATION: Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. FUNDING: Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India. PMID- 24629996 TI - Basal cell carcinomas of the ear are more aggressive than on other head and neck locations. AB - BACKGROUND: On pathology review, basal cell carcinomas (BCCs) on the ear more commonly present as aggressive subtypes. It is unclear if this histologic observation translates into more clinically aggressive tumors. OBJECTIVE: We sought to determine the clinical aggressiveness of ear BCCs compared with BCCs elsewhere on the head and neck. METHODS: We conducted a retrospective chart review of all BCCs treated at an academic center from 2005 through 2012. Subjects were divided into ear and non-ear groups. Subtypes classified as "aggressive" included morpheaform, infiltrative, micronodular, adenoid, metatypical, and mixed histology. RESULTS: Of the 7732 head and neck BCCs, 758 (9.8%) were on the ear. Ear BCCs presented as larger lesions (1.28 vs 0.98 cm(2)), required more Mohs layers (16.5% vs 10.7%), and produced a larger final defect (4.29 vs 3.49 cm(2)) than non-ear lesions. When comparing only aggressive subtypes, ear BCCs also presented as larger lesions (1.42 vs 1.23 cm(2)), more frequently required 3 or more layers for clearance (22.3% vs 14.2%), and produced a larger final defect (4.92 vs 4.21 cm(2)) than non-ear lesions. LIMITATIONS: Limitations include single-center design and lack of long-term follow-up. CONCLUSION: Ear BCCs appear to exhibit greater subclinical extension compared with non-ear head and neck BCCs. Therefore, the ear should be considered a high-risk location for BCCs. PMID- 24629997 TI - Melanoma depth in patients with an established dermatologist. AB - BACKGROUND: The impact of having an established dermatologist on melanoma depth at diagnosis is incompletely understood. OBJECTIVE: We sought to determine whether having had a previous dermatologic examination (an established dermatologist), the recency of the last examination, and the wait time for the dermatology appointment are associated with melanoma invasiveness and depth. METHODS: This was a retrospective cross-sectional study of 388 patients with primary melanoma at an academic dermatology department. RESULTS: Patients with an established dermatologist were more likely than patients without an established dermatologist to be given a diagnosis of melanoma in situ (103/162 [63.6%] vs 69/155 [44.5%], P = .001) and to have thinner invasive melanoma (0.48 [0.30-0.71] mm vs 0.61 [0.40-1.10] mm, respectively, P = .003). These trends were observed for patients with self-detected, but not dermatologist-detected, melanoma. Patient-detected melanomas made up 184/361 (51.0%) of all melanomas, 83/199 (41.7%) of in situ melanomas, and 101/162 (62.4%) invasive melanomas. Self detected melanomas were in situ in 36 of 61 (59.0%) patients with an established dermatologist versus 40 of 108 (37.0%) patients without an established dermatologist, P = .006. Neither time from last dermatologic examination nor wait time for an appointment was associated with melanoma invasiveness or depth. LIMITATIONS: Data are retrospective and from 1 large academic health care system. CONCLUSION: Education obtained at the dermatology appointment may improve early self-detection of melanoma, and having an established dermatologist may facilitate earlier evaluation of concerning lesions. PMID- 24629998 TI - The association of indoor tanning and melanoma in adults: systematic review and meta-analysis. AB - BACKGROUND: Tanning beds are associated with increased risk of melanoma. OBJECTIVE: We sought to update the evidence of the association of melanoma and indoor tanning focusing on frequency of use and exposure to newer tanning beds. METHODS: We searched Scopus, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature on August 14, 2013. We included all observational studies that included patients with melanoma who had indoor tanned. Odds ratios (OR) with 95% confidence intervals (CI) were extracted and combined using generic inverse variance methods assuming a random effects model. RESULTS: In all, 31 studies were included with data available on 14,956 melanoma cases and 233,106 controls. Compared with never using, the OR for melanoma associated with ever using indoor tanning beds was 1.16 (95% CI 1.05-1.28). Similar findings were identified in recent studies with enrollment occurring in the year 2000 onward (OR 1.22, 95% CI 1.03-1.45) and in subjects attending more than 10 tanning sessions (OR 1.34, 95% CI 1.05-1.71). LIMITATIONS: The quality of evidence contributing to review results ranges from poor to mediocre. CONCLUSION: Using tanning beds is associated with a subsequent melanoma diagnosis. Exposure from more than 10 tanning sessions is most strongly associated and there was no statistically significant difference in this association before and after 2000, suggesting that newer tanning technology is not safer than older models. PMID- 24629999 TI - Juvenile mycosis fungoides: cutaneous T-cell lymphoma with frequent follicular involvement. AB - BACKGROUND: The literature on mycosis fungoides (MF) in children/adolescents is sparse. OBJECTIVE: We sought to evaluate the characteristics of juvenile MF in a large cohort. METHODS: Data were collected on all patients with MF, aged 18 years or younger at the time of clinicopathologic diagnosis, who attended the Rabin Medical Center Dermatology Department, Petach Tikva, Israel, between 1994 and 2012 and were followed up prospectively. RESULTS: There were 50 patients (30 male; mean age 11.4 years at diagnosis); 18 (36%) had Fitzpatrick skin type IV or higher. All were given a diagnosis of early-stage disease (IA-IIA) except 1 (tumor stage, IIB). Eight had classic MF lesions only and 42 had other variants, alone or in combination; these were mainly hypopigmented MF (n = 29) and cases with subtle but clear clinicopathologic features of folliculotropic MF (FMF) (n = 18). Among the various skin-targeted therapies, psoralen plus ultraviolet A (systemic/bath) proved beneficial for FMF. During a follow-up period of 0.25 to 15 years (mean 4.5), 2 patients progressed from stage IA to IB or IIA. LIMITATIONS: Relatively short follow-up is a limitation. CONCLUSIONS: This case series shows that FMF is not uncommon in children and adolescents. It is characterized by more superficial clinical features and less heavy perifollicular lymphocytic infiltrates than adult FMF, and responds well to psoralen plus ultraviolet A. The prognosis of childhood FMF remains unclear. PMID- 24630000 TI - Characteristics of noninvoluting congenital hemangioma: a retrospective review. AB - BACKGROUND: Noninvoluting congenital hemangioma (NICH) is a distinct vascular tumor of infancy. OBJECTIVE: We describe the clinical characteristics, histopathology, imaging, and natural history of NICH and compare our findings with previous reports. METHODS: We conducted a retrospective review of charts and photographic databases from 2 vascular anomaly centers over a 15-year period. RESULTS: Thirty cases of NICH were identified. All patients had fully formed vascular lesions at birth that demonstrated a nonprogressive course. The trunk and lower extremities were preferred sites and there was a female predominance. Thirteen of 30 patients reported pain. Focal necrosis and scarring was seen in a minority. Doppler studies, when performed, confirmed high vascular flow. Microscopic evaluation of 4 excised lesions showed lobular areas of endothelial cell proliferation directly adjacent to ectatic malformed vessels. Immunohistochemical studies demonstrated absence of glucose transporter-1 protein expression in every case. Wilms tumor-1 positivity was observed in lobular areas. The larger vessels did not stain with Wilms tumor-1, but some displayed D2-40 positivity. LIMITATIONS: Patients were referred to university-based pediatric vascular anomaly centers, with potential bias toward more severe or extensive cases. CONCLUSIONS: This retrospective study highlights the unique clinical and histopathologic features of NICH. PMID- 24630002 TI - [Full understanding of occupational stress hazards and strengthening of prevention and management of occupational stress]. PMID- 24630001 TI - Duration of efficacy increases with the repetition of botulinum toxin A injections in primary palmar hyperhidrosis: a study of 28 patients. AB - BACKGROUND: Intradermal injections of botulinum toxin are effective but transitory in primary palmar hyperhidrosis. These injections are repeated when the symptoms recur. We do not know how the duration of efficacy changes when injections are repeated. OBJECTIVE: In this retrospective study, we aimed to investigate the change in the duration of efficacy of botulinum toxin A (Dysport, Ipsen, Boulogne-Billancourt, France) with the repetition of injections in patients with primary palmar hyperhidrosis. METHODS: From May 2001 to April 2012, 28 patients were treated with a dose of 250 U of botulinum toxin A per palm. We compared the duration of efficacy of the first and last toxin injections. RESULTS: The median duration of efficacy was 7 months for the first injection and 9.5 months for the last, the difference being statistically significant (P = .0002). LIMITATIONS: Study limitations include a relatively small number of patients treated at a single center and evaluated retrospectively. CONCLUSION: To our knowledge, this study is the first to report a significant increase in the duration of efficacy of botulinum toxin A injections with the repetition of injections in patients with primary palmar hyperhidrosis. The reasons for this effect may be linked to the mechanism of action of botulinum toxin, and may improve our understanding of its pharmacologic effects. PMID- 24630003 TI - [The relationship of occupational stress and the level of some hormone metabolites in urine]. AB - OBJECTIVE: To explore the possibility for 17-OHCS, 17-KS, VMA and HVA in urine as indicators of occupational stress identification and evaluation. METHODS: 225 policies were investigated by using convenience sampling and cluster sampling methods, occupational stressors, strains, buffer factors and individual factors were measured by questionnaires. The urine 17-OHCS, 17-KS, VMA and HVA level was tested by ELISA and high performance liquid chromatography method respectively. RESULTS: The urine 17-OHCS level of the groups with high coworker support and job control scores was lower than that of the groups with low score group (P < 0.05), the urine 17-OHCS level of the group with high negative affectivity score was higher than that of the group with low score group (P < 0.05). The urine 17-KS level of the group with high job security score was lower than that of the counterparts (P < 0.05). The urine VMA level of the group with high coworker support score was lower than that of the counterparts (P < 0.05). The urine HVA level of the group with high coping strategy score was lower than that of counterpart (P < 0.05). Logistic regression analysis revealed that the job control and respect were the protective factors of urine 17-OHCS level increase (OR = 0.353 and 0.352 respectively), but over-commitment, self-esteem and daily hassles were the risk factors of urine 17-OHCS with level increase (OR = 3.391, 2.439, and 2.584 respectively). The risk of urine 17-KS level increase for the groups high job control and job security scores were respectively 0.387, 0.356 times than that of the counterparts, the risk of urine VMA level increase for the group with high negative affectivity score was 2.643 times than that of the counterparts. CONCLUSION: The urine 17-OHCS, 17-KS and VMA level were potential indicators for occupational stress evaluation. PMID- 24630004 TI - [Relationship between occupational stress and mental health in offshore oil platform workers]. AB - OBJECTIVE: To investigate the relationship between occupational stress and mental health in offshore oil platform workers and to provide a scientific basis for protection of their mental health. METHODS: A total of 768 workers on offshore oil platform were surveyed with the Occupational Stress Inventory Revised Edition and Symptom Check List-90 (SCL-90). RESULTS: The total score of Occupational Role Questionnaire (ORQ) for the workers (160.27+/-24.63) was significantly lower than the national norm (166.52+/-27.01) (P < 0.01); the total score of Personal Strain Questionnaire (PSQ) (101.96+/-19.8) was significantly higher than the national norm (92.45+/-17.33) (P < 0.01). The total score of Personal Resource Questionnaire (PRQ) for the workers was not significantly different from the national norm (P > 0.05), but the items of recreation, social support, and rational/cognitive found significant difference (P < 0.05). The total score of SCL-90 was positively correlated with all items of ORQ and PSQ (P < 0.01) and negatively correlated with all items of PRQ (P < 0.01). The multiple stepwise regression analysis showed that current work seniority, education background, drinking, role overload, role insufficiency, role ambiguity, responsibility, physical environment, and rational/cognitive conduct impacted the score of SCL-90 (P < 0.05). CONCLUSION: The mental health of workers on offshore oil platform is related to occupational stress, and role overload, role ambiguity, physical environment, and rational/cognitive conduct, etc, are closely associated with the workers' mental health. PMID- 24630005 TI - [Relationship between emotion and plasma fibrinogen level in train drivers]. AB - OBJECTIVE: To investigate the relationship between emotion and plasma fibrinogen level in train crew. METHODS: A cross-sectional study was conducted in 350 male workers of passenger car, freight car, shunting locomotive for passenger service, and high-speed car from a locomotive depot. The factors involved in this study were as follows: common factors including educational level, physical exercise, smoking, drinking, and physical environment, emotional/characteristic factors including sleep quality, depression, and coping strategies, and working -related factors including effort -reward imbalance, working age, responsibility for people, responsibility for work, intragroup conflicts, and intergroup conflicts. Variables were measured with common rating scales at home and abroad. Plasma fibrinogen level was determined by immunological turbidimetry. The Spearman rank correlation test and multiple stepwise regression were used to analyse the influential factors for fibrinogen level. The original concentration of fibrinogen was subjected to logarithmic transformation in statistical analysis. RESULTS: The Spearman rank correlation test showed that plasma fibrinogen level was significantly correlated with age(r = 0.228, P = 0.001), working age(r = 0.231, P = 0.001), and emotion (r = -0.138, P = 0.016), but showed no significant relationship with other variables (P > 0.05). The multiple stepwise regression with fibrinogen level as a dependent variable was performed in four models. Model 1 showed that emotion and age were included in the regression after adjustment for common factors (P < 0.05). Model 2 also showed inclusion of emotion and age in the regression after adjustment for common factors and occupational stress factors (P < 0.05). Model 3 showed inclusion of emotion in the regression after adjustment for common factors, occupational stress factors, and psychological factors (P < 0.05). Model 4 showed inclusion of emotion and age after adjustment for common factors, occupational stress factors, psychological factors, and relief factors (P < 0.05). CONCLUSION: The emotion of train crew is correlated with plasma fibrinogen level. PMID- 24630006 TI - [Analysis of correlation between occupational stress and serum monoamine neurotransmitters in nurses]. AB - OBJECTIVE: To investigate the impact of occupational stress on serum monoamine neurotransmitters in nurses. METHODS: A total of 131 nurses were included as study subjects by stratified cluster sampling. The occupational health information collection system (based on the Internet of things) was used to measure occupational stress. Serum levels of monoamine neurotransmitters were also measured. RESULTS: Epinephrine (E) was negatively correlated with superior support (P < 0.05) and colleague support (P < 0.05). Negative correlation was also found between dopamine (DA) and job prospect (P < 0.05). Level of 5 hydroxytryptamine was negatively correlated with promotion opportunities (P < 0.05). Norepinephrine (NE), E, and DA were all negatively correlated with work satisfaction (P < 0.05) and positively correlated with daily stress (P < 0.01). NE and E were negatively correlated with sufficient confidence (P < 0.05) and positively correlated with physical complaints (P < 0.01). There was a negative correlation between NE and psychological satisfaction (P < 0.05). CONCLUSION: Occupational stress in nurses is correlated with serum monoamine neurotransmitters, and it may affect serum levels of monoamine neurotransmitters to a certain extent. PMID- 24630007 TI - [Effect of occupational stress on oxidation/antioxidant capacity in nurses]. AB - OBJECTIVE: To investigate the effect of occupational stress on the oxidation/antioxidant capacity in nurses. METHODS: A total of 131 nurses were included as study subjects. The occupational health information collection system (based on the Internet of things) was used for measurement of occupational stress. Levels of hydroxyl free radicals and antioxidant enzymes were determined. RESULTS: The serum level of superoxide dismutase (SOD) was the highest in nurses under the age of 30 and the lowest in those over 45 (P < 0.05). The serum levels of glutathione peroxidase (GSH-Px) and peroxidase (POD) were the highest in nurses of working age less than 5 years, followed by those of 5-15 years, and nurses with more than 25 years' working experience showed the lowest GSH-Px and POD levels (P < 0.05). Furthermore, nurses with a university (college) degree had a higher GSH-Px level and a lower POD level compared with those with junior and senior high school degrees (P < 0.05). Job prospects and job control were positive occupational stress factors for SOD. Job hazards were negative occupational stress factors for POD. Psychological satisfaction was negative occupational stress reaction for hydroxyl free radicals. Calmness was positive occupational stress reaction for SOD, and daily stress was a negative one. The positive occupational stress reactions for GSH-Px were psychological satisfaction and job satisfaction, and daily stress was negative reaction. CONCLUSION: Nurses with higher occupational stress have stronger oxidation and weaker antioxidant capacity, which intensifies oxidant-antioxidant imbalance and leads to oxidative stress damage. PMID- 24630008 TI - [Association between SNPs in DNMT1 and noise-induced hearing loss in Chinese Han population]. AB - OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in DNA methyltransferase 1 (DNMT1) (rs12984523, rs16999593, and rs2228612) and noise-induced hearing loss (NIHL) in Chinese Han population. METHODS: This case-control study consisted of 188 cases (case group) and 300 controls (control group) in the same working position, who were matched for age and gender. The cases had a binaural average high-frequency hearing threshold not less than 40 dB, and the controls had a binaural average high-frequency hearing threshold less than 40 dB. The genotypes at the three SNPs were determined by TaqMan probe. RESULTS: TT genotype at DNMT1 rs2228612 is a risk factor for NIHL (adjusted OR = 1.69, 95% CI: 1.14-2.52). CONCLUSION: The study of Chinese Han population suggested that DNMT1 rs2228612 is associated with susceptibility to NIHL. PMID- 24630009 TI - [Inhibitory effect of resveratrol on expression of IL-1beta in mesenchymal stem cells exposed to radiation]. AB - OBJECTIVE: To investigate the inhibitory effect of resveratrol on interleukin 1beta (IL-1beta) production in mesenchymal stem cells (MSCs) exposed to radiation and the action mechanism of resveratrol. METHODS: MSCs were divided into blank control group, radiation group, shRNA interference group, and resveratrol groups. The resveratrol groups were given different doses of resveratrol (50, 100, and 200 umol/L) before radiation. The secretion and expression of IL-1beta was measured by enzyme-linked immunosorbent assay, Western blot, and RT-PCR. RESULTS: Compared with the radiation group, the resveratrol groups had significantly decreased extracellular secretion of IL-1beta (t = 83.34, 24.48, and 12.52, P < 0.05 for all) and significantly decreased intracellular expression of IL-1beta protein and mRNA (t = 8.695, 14.77, and 13.9, P < 0.05 for all). Compared with those given 200 umol/L resveratrol alone before radiation, the MSCs treated by SIRT1 silencing and given 200 umol/L resveratrol before radiation had significantly increased extracellular secretion of IL-1beta (t = 18.57, P < 0.05) and significantly increased intracellular expression of IL-1beta protein and mRNA (t = 10.24, P < 0.05). CONCLUSION: Resveratrol can significantly inhibit the production of IL-1beta in MSCs exposed to radiation, and SIRT1 may play a key regulatory role in the process of inflammation induced by radiation. PMID- 24630010 TI - [Relationship between occupational stress and depression in migrant workers]. AB - OBJECTIVE: To investigate the relationship between occupational stress and depression in migrant workers. METHODS: Migrant workers in the textile industry were selected as subjects, and the self-made Occupational Stress Questionnaire and Self-rating Depression Scale were used to investigate the sex, age, seniority, educational level, and marital status of these subjects. Data analysis was performed by independent-samples t test, analysis of variance, Spearman rank correlation analysis, and stepwise multiple regression analysis. RESULTS: Sex, seniority, and educational level were not influential factors for depression scores. The lower age group had a higher moderate depression score than the higher age group; the unmarried group had a higher moderate depression score than the married group. Severe depression was negatively correlated with decision making power, psychological job demands, social support, and external pay-return, but positively correlated with skills and internal input; moderate depression was positively correlated with psychological job demands and external pay, but negatively correlated with other factors; mild depression was negatively correlated with all factors. The stepwise regression analysis showed that the influential factors for depression included, from major to minor, supervisor support, skills, internal input, and colleague support, according to the standardized regression coefficients; internal input was the contribution factor, and the remaining ones were negative factors. CONCLUSION: Among migrant workers, certain mental health problems exist, and occupational stress is associated with depression. PMID- 24630011 TI - [Investigation of capacities of occupational disease prevention and control institutions in Hunan Province, China]. PMID- 24630012 TI - [Investigation of occupational noise exposure and hearing loss in large automobile manufacturing enterprise during 2006-2010 in Guangzhou, China]. AB - OBJECTIVE: To analyze the relationship between occupational noise exposure and hearing loss among workers in large automobile manufacturing enterprise during 2006-2010 in Guangzhou, China. METHODS: A retrospective cohort study was conducted. The subjects were divided into noise exposure group and control group. Their hearing examination results and noise exposure levels in different workplaces were collected during 2006-2010, and the relationship between noise exposure in workplaces and hearing loss was analyzed. RESULTS: The incidence of hearing loss for the noise exposure group was 9.34%, versus 2.75% for the control group; the noise exposure group had a significantly higher risk of hearing loss than the control group (R = 3.378, 95%CI = 1.467~ 9.083). The noise intensity and over-limit rate were significantly higher in the stamping, welding, and general assembly workshops than in other workshops. The risk of hearing loss significantly increased with years of noise exposure in 80, 85, and 90 dB (A) groups (chi(2) = 6.377, P = 0.041; chi(2) = 8.570, P = 0.014; chi(2) = 7.037, P = 0.030). The risk of hearing loss also increased with noise intensity in all working age groups (chi(2) = 5.068, P = 0.024; chi(2) = 71.497, P < 0.01; chi(2) = 24.226, P < 0.01). CONCLUSION: Noise exposure increases the risk of noise induced hearing loss in workers. The incidence of hearing loss increases with the noise intensity in workplaces and years of noise exposure. The noise exposure level and incidence of hearing loss are higher in the stamping workshop than in other workshops. Controlling the noise intensity in automobile manufacturing enterprise may reduce the risk of hearing loss in workers. PMID- 24630013 TI - [Analysis of risk factors for contact dermatitis in pig farm workers]. AB - OBJECTIVE: To investigate the risk factors for contact dermatitis in pig farm workers. METHODS: The cross-sectional questionnaire survey and on-site survey were conducted in pig farms raising more than 50 pigs in a county of Fujian Province, China. The study subjects were grouped based on different factors. The incidence rate was compared between groups by statistical analysis. RESULTS: Of 302 subjects, 70 (23.18%) had contact dermatitis. There was a significant difference in the prevalence of contact dermatitis between the subjects in direct contact with commercially available pannage and those in indirect contact (chi(2) = 14.552, P < 0.01). Region, season, farm scale, brand of pannage, and allergic history were not influential factors for contact dermatitis (P > 0.05 for all). CONCLUSION: Direct contact with commercially available pannage is closely associated with contact dermatitis in pig farm workers. PMID- 24630014 TI - [Association of GSTM1 and GSTT1 polymorphisms with noise-induced hearing loss: a meta-analysis]. AB - OBJECTIVE: To evaluate the association of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms with noise-induced hearing loss. METHODS: The Cochrane library, PubMed, OVID, EMBASE, Springer, Wanfang Data, VIP, CNKI, and CBM were searched to collect case-control studies on GSTM1 or GSTT1 polymorphism and noise-induced hearing loss. The articles meeting the inclusion criteria were reviewed systematically, and the reported data were aggregated using Revman 5.0. RESULTS: Five studies were included in the meta analysis. The meta-analysis and subgroup analysis showed that the persons with GSTM1 null genotype had an increased risk of noise-induced hearing loss compared with those with GSTM1 wild genotype (OR = 1.37, 95%CI: 1.13~1.66); in the Chinese population, the risk of noise-induced hearing loss was higher in persons with GSTM1 null genotype than in those with GSTM1 wild genotype (OR = 1.5, 95%CI: 1.2~1.86); there was no significant difference in the risk of noise-induced hearing loss between persons with GSTT1 null and wild genotypes. CONCLUSION: GSTM1 polymorphism is related to noise-induced hearing loss, but GSTT1 polymorphism is unrelated to this condition. PMID- 24630015 TI - [Industry distribution of 1392 occupational hazard enterprises and their current status of occupational health management]. PMID- 24630016 TI - [Status of lead exposure and its impact on health of workers in an accumulator factory]. AB - OBJECTIVE: To identify the occupational hazard factors in an accumulator factory, to analyze the status of internal and external lead exposure and evaluate the impact of lead exposure on the health of workers in the accumulator industry, and to provide a theoretical basis for improved lead exposure criteria and technical support for the control of lead contamination in the accumulator industry. METHODS: An on-site investigation was carried out to monitor and evaluate the lead fume and dust in the workplaces of an accumulator factory, and occupational health examination was performed in all workers. RESULTS: The occupational hazard safeguards in the accumulator factory were unadvanced. The contamination of lead fume and dust was serious. The abnormal rate of blood lead was up to 79.80%, and many workers developed anemia and mild peripheral nerve disease. CONCLUSION: Lead contamination is serious in the accumulator factory, leading to poor health of workers. It is essential to take effective control measures, improve the working environment, provide occupational health education, increase workers' self protection awareness, and periodically conduct occupational hazard monitoring and health surveillance. The government must reinforce occupational health supervision of such enterprises. PMID- 24630017 TI - [Prevention and control of occupational hazards of trichloroethylene]. PMID- 24630018 TI - [Radiation exposure and health status in gastroenterologists]. PMID- 24630019 TI - [Clinical analysis of driver's hip fracture caused by trauma in high-speed driving]. PMID- 24630020 TI - [One case of acute arsenic poisoning by absorption through skin wound]. PMID- 24630021 TI - [Electric ophthalmia caused by metal halide lamp: a report of 26 cases]. PMID- 24630022 TI - [Determination of four biogenic amine metabolites in urine by high-performance liquid chromatography]. AB - OBJECTIVE: To establish a method for simultaneously determining vanilmandelic acid (VMA), 5-hydroxyindoleacetic (5-HIAA), 3, 4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in urine by high-performance liquid chromatography (HPLC). METHODS: After being filtered with a 0.45 um membrane syringe filter, the urinary samples were injected directly into the HPLC system using a C18 chromatographic column and a fluorescence detector. The excitation and emission wavelengths were chose as 280 nm and 315 nm, respectively, and the urinary samples were carried with a mobile phase of methanol-0.1 mol/L phosphate buffered solution (V/V = 20:80) at a flow rate of 1.0 ml/min and an injection volume of 20 ul. RESULTS: Using the method reported here, the correlation coefficients of VMA, 5-HIAA, DOPAC, and HVA were 0.9999, 0.9998, 0.9997, 0.9999, respectively, over linear ranges of 0-2.5, 0-2.0, 0-2.0, and 0-2.5 ug/ml, the minimum detectable concentrations were 0.006, 0.008, 0.012, and 0.0082 ug/ml, the average precisions were 4.2%, 3.7%, 4.9%, and 3.6%, and the recovery rates were 91%~102%, 93%~101%, 94%~101%, and 89%~ 102%. CONCLUSION: This determination method is simple, efficient, accurate, and sensitive for the simultaneous detection of VMA, 5-HIAA, DOPAC, and HVA in urine. PMID- 24630023 TI - [Determination of urinary 8-hydroxy-2'-deoxyguanosine, trans, trans-muconic acid, and S-phenylmercapturic acid by liquid chromatography-mass spectrometry]. AB - OBJECTIVE: To establish a method for simultaneously determining the urinary concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), trans, trans-muconic acid (tt-MA), and S-phenylmercapturic acid (S-PMA) in subjects exposed to benzene. METHODS: After being purified by a solid-phase extraction column, the urine samples were transferred to a liquid chromatography-mass spectrometry system, and the concentrations of 8-OHdG, tt-MA, and S-PMA were determined by external standard method. A C18 reversed-phase column was used as the chromatographic column, and methanol/acidic ammonium formate solution was used as the mobile phase for gradient elution. The mass spectrometer was operated in a multi reaction monitoring mode. RESULTS: For tt-MA, the calibration curves were linear in the range of 10-1000 ug/L, and the recovery rates were over 90% (relative standard deviation (RSD) < 3%) at spiked levels of 50 ug/L and 500 ug/L. For S PMA and 8-OHdG, the calibration curves were linear in the range of 1-100 ug/L, and the recovery rates were over 85% (RSD < 5%) at spiked levels of 5 ug/L and 50 ug/L. CONCLUSION: This determination method meets the requirement of Biological materials- METHODS: of monitoring-Guide of development (WS/T 68-1996) and can be used for simultaneous determination of 8-OHdG, tt-MA, and S-PMA in urine. PMID- 24630024 TI - [Method for determining 2, 4-D butylate in serum by gas chromatography]. AB - OBJECTIVE: To establish a method for determining 2, 4-D butylate in serum by gas chromatography (GC)and to provide a basis for the diagnosis and treatment of clinical poisoning. METHODS: Serum 2, 4-D butylate level was determined by the following steps: mixing serum (0.5 ml)with trichloromethane (2.0 ml), adequately shaking for extraction, standing for 5 min, centrifuging at 4 000 rpm for 10 min, blow-drying the trichloromethane layer with nitrogen, adding ethanol (50 ul)to a certain volume, adding the sample (1.0 ul), and performing GC with a hydrogen flame ionization detector. RESULTS: Serum 2, 4-D butylate level showed a linear relationship within 5~40 ug/ml, with a regression equation of y = 1 831.6.4x 899.4 (r = 0.999 2); the minimum detectable concentration was 1.0 ug/ml. The recovery rate was 88.7%~103.0% (relative standard deviation (RSD) 3.8%~5.0%). The intra-day RSD and inter-day RSD were 3.87-4.92% and 3.33%~5.34%, respectively. CONCLUSION: This determination method is simple, efficient, and accurate and provides a good means for rapid diagnosis and treatment of 2, 4-D butylate poisoning. PMID- 24630025 TI - [Ultraviolet spectrophotometry for determination of sulpiride in serum]. PMID- 24630026 TI - [Health hazards of polycyclic aromatic hydrocarbons and related health surveillance]. PMID- 24630027 TI - [Research progress in effect of electromagnetic radiation on mitochondrial function]. PMID- 24630028 TI - [Research progress in objective evaluation indices for occupational stress]. PMID- 24630029 TI - Letter to the Editor regarding "The Value of Resident Presentations at Scientific Meetings". PMID- 24630030 TI - Auditory performance and speech intelligibility of Mandarin-speaking children implanted before age 5. AB - OBJECTIVES: (1) To report the auditory performance and speech intelligibility of 84 Mandarin-speaking prelingually deaf children after using cochlear implants (CIs) for one, two, three, four, and five years to understand how many years of implant use were needed for them to reach a plateau-level performance; (2) to investigate the relation between subjective rating scales and objective measurements (i.e., speech perception tests); (3) to understand the effect of age at implantation on auditory and speech development. METHODS: Eighty-four children with CIs participated in this study. Their auditory performance and speech intelligibility were rated using the Categorical Auditory Performance (CAP) and the Speech Intelligibility Rating (SIR) scales, respectively. The evaluations were made before implantation and six months, one, two, three, four, and five years after implantation. At the fifth year after implantation, monosyllabic word, easy-sentence, and difficult-sentence perception tests were administered. RESULTS: The median CAP score reached a plateau at category 6 after three years of implant use. The median SIR arrived at the highest level after five years of use. With five years of CI experiences, 86% of the subjects understood conversation without lip-reading, and 58% were fully intelligible to all listeners. The three speech perception tests had a moderate-to-strong correlation with the CAP and SIR scores. The children implanted before the age of three years had significantly better CAP and monosyllabic word perception test scores. CONCLUSIONS: Five years of follow-up are needed for assessing the post implantation development of communication ability of prelingually deafened children. It is recommended that hearing-impaired children receive cochlear implantation at a younger age to acquire better auditory ability for developing language skills. Constant postoperative aural-verbal rehabilitation and speech and language therapy are most likely required for the patients to reach the highest level on the CAP and SIR scales. PMID- 24630031 TI - Autophagy facilitates the EGFR-TKI acquired resistance of non-small-cell lung cancer cells. PMID- 24630032 TI - Hemoglobin, iron, and vitamin B12 deficiencies and high blood homocysteine levels in patients with anti-thyroid autoantibodies. AB - BACKGROUND/PURPOSE: Autoimmune thyroiditis can be diagnosed by measuring patients' serum levels of thyroid stimulating hormone (TSH), anti-thyroglobulin antibody (TGA), and anti-thyroid microsomal antibody (TMA). This study evaluated whether there were hematinic deficiencies, high blood homocysteine levels, and serum gastric parietal cell antibody (GPCA) positivity in patients with TGA or TMA. METHODS: The blood hemoglobin (Hb), iron, vitamin B12, folic acid, homocysteine and TSH concentrations and the serum GPCA level in 190 TGA- or TMA positive patients were measured and compared with the corresponding levels in 190 age- and sex-matched healthy control subjects. RESULTS: We found that 31 (16.3%), 27 (14.2%), 12 (6.3%), and 2 (1.1%) TGA- or TMA-positive patients had deficiencies of Hb (Men<13g/dL, Women<12g/dL), iron (< 60MUg/dL), vitamin B12 (< 200pg/mL), and folic acid (< 4ng/mL), respectively. Moreover, 25 (13.2%) and 48 (25.3%) TGA- or TMA-positive patients had abnormally high blood homocysteine level and serum GPCA positivity, respectively. TGA- or TMA-positive patients had a significantly higher frequency of Hb (p<0.001), iron (p<0.001), or vitamin B12 deficiency (p=0.001), of abnormally elevated blood homocysteine level (p=0.001), or of serum GPCA positivity (p<0.001) than healthy control subjects. Of 190 TGA- or TMA-positive patients, 8 (4.2%) had lower serum TSH level (< 0.1MUIU/mL, suggestive of hyperthyroidism), 163 (85.8%) had serum TSH level within normal range (0.1-4.5MUIU/mL), and 19 (10%) had higher serum TSH level (>4.5MUIU/mL, suggestive of hypothyroidis). CONCLUSION: There are significant deficiencies of hemoglobin, iron, and vitamin B12, abnormally high blood homocysteine levels, and serum GPCA positivity in TGA- or TMA-positive patients. In addition, the majority (85.8%) of TGA- or TMA-positive patients had euthyroid and only a small portion (14.2%) of TGA- or TMA-positive patients had either hypothyroidism or hyperthyroidism. PMID- 24630033 TI - Clinical and video urodynamic characteristics of adult women with dysfunctional voiding. AB - BACKGROUND/PURPOSE: Dysfunctional voiding (DV) is an abnormality of bladder emptying in neurologically normal individuals where the external sphincter activity increases during voiding. This study investigated the clinical presentations and videourodynamic characteristics of adult women with DV. METHODS: A total of 1605 women with lower urinary tract symptoms (LUTS) were investigated with videourodynamic (VUD) studies from 1997 to 2010. The clinical urinary symptoms and VUD characteristics of DV were compared with a group of urodynamically normal controls. Antimuscarinic or alpha-blocker treatment according to the chief complaint of storage or voiding LUTS was respectively given. RESULTS: There were 168 women diagnosed with DV. Detrusor overactivity (DO) occurred in 69% of women with DV. Patients with DV had significantly lower cystometric bladder capacity, higher detrusor pressure, lower maximum flow rate, and larger post-void residual volume than the controls. A total of 114 (67.9%) patients had storage symptoms and 54 (32.1%) had voiding symptoms as their chief complaints among those with DV. Among them, urinary frequency (n = 69, 41.1%) was the most common chief complaint, followed by dysuria (n = 53, 32.1%), and urgency incontinence (n = 26, 15.5%). The incidence of urgency incontinence and dysuria were significantly greater than that in the control group, however, the incidence of frequency, urgency, or nocturia showed no significant difference between DV and control groups. The success rates were 41.2% (n = 47) for antimuscarinic therapy and 51.9% (n = 28) for alpha-blocker therapy in patients with storage and voiding LUTS, respectively (p = 0.366). CONCLUSION: DO and storage LUTS commonly occurred in women with DV, suggesting DO could be one of the etiology in the pathophysiology of DV. VUD studies yielded a high diagnostic rate for DV in women with LUTS. PMID- 24630034 TI - Clinical treatment outcomes for 40 patients with bisphosphonates-related osteonecrosis of the jaws. AB - BACKGROUND/PURPOSE: Bisphosphonates (BPs) are used to treat osteoporosis and bone metastases from malignancy. They may result in BPs-related osteonecrosis of the jaws (BRONJ) in a subset of patients receiving BPs. This study examined whether conservative or aggressive surgical approach could result in successful treatment of BRONJ lesions and assessed whether concomitant steroid administration or tobacco smoking habit might hinder the remission of BRONJ lesions. METHODS: The 40 BRONJ patients were evenly divided into four different groups. Group 1 contained 10 patients with concomitant corticosteroid medication but without smoking habit. Group 2 contained 10 patients with smoking habit but without concomitant corticosteroid medication. Groups 3 and 4 each consisted of 10 patients without concomitant corticosteroid medication and smoking habit. To avoid bias, each group contained equal number of patients with different stages of BRONJ. Patients in Groups 1, 2, and 3 received conservative treatment, including antibiotic coverage, antibacterial solution irrigation, and minor surgical debridement. Patients in Group 4 were treated with aggressive surgical excision of necrotic bone segment. RESULTS: The mean duration to achieve complete remission of BRONJ lesion was 19.7+/-0.6, 18.2+/-0.5, 13.0+/-1.0, and 7.6+/-1.1 months for patients in Groups 1, 2, 3 and 4, respectively. Student's t-test showed significant differences in the mean duration to achieve complete remission of BRONJ lesion between Groups 1 and 3, between Groups 2 and 3, between Groups 3 and 4, between Groups 1 and 4, and between Groups 2 and 4 (all p values < 0.001). CONCLUSION: Although both conservative and aggressive surgical approaches can result in successful treatment of BRONJ lesions, aggressive surgical treatment needs a shorter mean duration to achieve complete remission of BRONJ lesion than conservative treatment. Concomitant corticosteroid administration or tobacco smoking may prolong the duration for complete remission of BRONJ lesion. PMID- 24630035 TI - Meta-tetrahydroxyphenyl chlorine mediated photodynamic therapy inhibits the migration and invasion of a nasopharyngeal carcinoma KJ-1 cell line. AB - BACKGROUND/PURPOSE: Different photosensitizer-mediated photodynamic therapy (PDT) has different intracellular cytotoxic cascades. Previous reports showed that 5 aminolevulinic acid (5-ALA)-mediated PDT suppressed the migration and invasion of head and neck cancer cells. Unlike from 5-ALA, which mainly targets the mitochondria of cells, meta-tetrahydroxyphenyl chlorin (m-THPC) mainly accumulates in the endoplasmic reticulum and Golgi complex. Does m-THPC PDT inhibit the migration and invasion of cancer cells? METHODS: The effect of m-THPC PDT with a sublethal dose sufficient to kill around 20% of cells on the migration and invasion of a nasopharyngeal carcinoma KJ-1 cell line was studied by wound healing and Matrigel invasion assays. RESULTS: In the wound healing assay, the migration distance of KJ-1 cells decreased significantly from 0.71 +/- 0.02 mm in the control cells to 0.31 +/- 0.03 mm in the PDT-treated cells 24 hours after light treatment (p < 0.05) and the migration distance also decreased significantly from 1.02 +/- 0.07 mm in the control cells to 0.32 +/- 0.04 mm in the PDT-treated cells 48 hours after treatment (p < 0.05). In the Matrigel invasion assay, the number of the invaded KJ-1 cells in PDT treated group was also statistically significantly less than those without PDT treatment (p < 0.05). CONCLUSION: This study demonstrates that a sublethal dose of m-THPC PDT inhibits the migration and invasion of nasopharyngeal carcinoma cells in vitro. PMID- 24630036 TI - Likelihood ratios of multiple cutoff points of the Taipei City Developmental Checklist for Preschoolers, 2nd version. AB - BACKGROUND/PURPOSE: This study aimed to examine the reliability and clinical decision validities of the Taipei City Developmental Checklist for Preschoolers, 2nd version (the Taipei II, which was filled out by parents) and the screening procedures conducted in the medical setting. METHODS: Methodology research and case control study designs were adopted. A total of 310 dyads consisting of children who were developing typically and 196 dyads of children with developmental delays and age 5.5 to 35.5 months were recruited for validity test. Among them, 165 mothers filled out the questionnaire twice within 1 week to examine the test-retest reliability of the total score and individual items. Validity indexes of the single cutoff strategy and multiple cutoff strategies were analyzed. With two cutoff point strategies, the likelihood ratios (LR) of the three test results, positive, neutral, and negative, were calculated. RESULTS: The test-retest reliabilities of the total scores of the seven checklists of the Taipei II (rs = 0.54-0.89, p<0.05) and their individual items (agreement 92% to 100%) were acceptable, except for the 30-month checklist and three individual items. The positive LR (LR+) and negative LR (LR-) of the single cutoff strategy were acceptable with most LR+ more than 2, and all LR- less than 0.5. Most of the diagnostic odds ratios of single cutoff strategies were less than 50 and they did not meet the acceptable criteria. When multiple cutoff points were used, all of the LRs with positive test results were equal to infinity that met SpPin criteria, and all of the LRs with negative test results less than 0.5 had at least a small but important diagnostic impact. CONCLUSION: Taipei II with multiple cutoff points could give more useful clinical information than using a single cutoff point. The multiple likelihood ratios of Taipei II for children older than 3 years and in different cultural backgrounds need further study. PMID- 24630037 TI - Gingival and localized alveolar bone necrosis related to the use of arsenic trioxide paste--two case reports. AB - The leakage of arsenic trioxide paste from tooth fillings has been associated with widespread necrosis of the supporting periodontal tissues. This report describes two cases of arsenic trioxide paste-induced gingival and localized alveolar bone necrosis in the mandible, following the use of arsenic trioxide paste as a pulp-devitalized agent. The first case was a 54-year-old female complaining of a painful white patch on the gingival tissue of the left mandibular second molar (tooth #37) after treatment by a private dentist. She underwent completely debridement of all necrotic soft tissue with physical saline irrigation. The gingival tissue was gradually replaced with vascular tissue and completely healed after 7 weeks. The second case was a 30-year-old female complaining of severe pain and continuous gingival bleeding from the right maxillary first bicuspid (tooth #14) following treatment by a private dentist. She finally accepted debridement of the sequestrum and necrotic alveolar bone with decortication to induce active bleeding. A partial thickness gingival flap was made to cover the wound. Four weeks later, the supporting tissues had completely healed. Arsenic trioxide paste is a cytotoxic agent and may cause harmful adverse effects on adjacent periodontium and supporting hard tissue if leakage occurs, or it is used carelessly. There is no indication for the use of arsenic trioxide paste in modern dental practice. PMID- 24630038 TI - Rapid development of severe skin rash after adding valproic acid in a case of bipolar depression treated with low-dose lamotrigine. PMID- 24630039 TI - Successful treatment of primary immune thrombocytopenia in aged patients using clarithromycin. PMID- 24630040 TI - Sorting out the FACS: a devil in the details. PMID- 24630041 TI - Cadmium induces the differentiation of duck embryonic bone marrow cells into osteoclasts in vitro. AB - This study aimed to determine the in vitro effect of cadmium on the differentiation of duck embryonic bone marrow cells into osteoclasts. Bone marrow cells were harvested from 23-day old Gaoyou duck embryos and were cultured with either 50 nmol/L cadmium alone or different cadmium concentrations (0, 5, 10, 20 and 50 nmol/L) in combination with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). Tartrate resistant acid phosphatase (TRAP) staining, pit formation assay with bovine cortical bone slices, and co-staining with tetramethyl rhodamine isothiocyanate (TRITC)-conjugated phalloidin and Hoechst 33258 were performed to determine the number of TRAP-positive cells and bone resorption activity. Cadmium at a concentration ? 10 nmol/L in the presence of M-CSF and RANKL significantly increased in a concentration-dependent manner both the number of TRAP-positive cells (35-160%) and bone resorption activity (36-261%) (P<0.05). High cadmium concentrations in the presence of M-CSF and RANKL markedly promoted the formation of filamentous (F)-actin rings in differentiated osteoclasts. In conclusion, cadmium promotes in vitro the differentiation of duck embryonic osteoclasts in the presence of M-CSF and RANKL. PMID- 24630042 TI - Novel gonadal characteristics in an aged bovine freemartin. AB - The gonads from a five-year-old freemartin Holstein animal were subjected to morphological analysis and to immunohistochemistry using antibodies against developmental and functional markers. We demonstrate, for the first time, the retention of anti-mullerian hormone (AMH) producing intratubular cells (Sertoli cells) in the context of abundant steroidogenic interstitial cells, and structures consistent with clusters of luteal cells. This novel report describes the clinical, gross and histological findings accompanying this newly described gonadal immunophenotype, and its implication in the understanding of freemartin development. PMID- 24630043 TI - Corticosterone in ovo modifies aggressive behaviors and reproductive performances through alterations of the hypothalamic-pituitary-gonadal axis in the chicken. AB - Exposure to excess glucocorticoids during embryonic development affects offspring reproduction and suppresses the hypothalamic-pituitary-gonadal (HPG) axis in mammals. However, whether corticosterone (CORT) causes similar effects in the chicken remains unclear. In the present study, we injected low (0.2MUg) and high (1MUg) doses of CORT in ovo before incubation and detected changes in aggressive behavior, tonic immobility (TI), reproductive performances, and HPG axis gene expression in posthatch chickens of different ages. High dose of CORT suppressed growth rate from 3 weeks of age, increased the frequency of aggressive behaviors, which was associated with elevated plasma CORT concentration. High-dose CORT significantly (P<0.05) down-regulated arginine vasotocin (AVT), corticotropin releasing hormone (CRH), 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) and gonadotropin-releasing hormone 1 (GnRH1), while significantly (P<0.05) up regulated gonadotropin-inhibitory hormone (GnIH) and 11beta-HSD1 mRNA expression in the hypothalamus. Glucocorticoid receptor (GR) and 20-hydroxysteroid dehydrogenase (20-HSD) mRNA levels were not affected by CORT treatment. High-dose CORT significantly (P<0.05) reduced egg production and egg quality, which was associated with decreased ovary and oviduct weight. Moreover, CORT exposure significantly decreased (P<0.05) luteinizing hormone (LH) receptor and follicle stimulating hormone (FSH) receptor mRNA abundance in theca cells of ovarian follicles 1 (F1), F2 and F3. In addition, yolk CORT concentration was significantly higher in eggs laid by hens prenatally exposed to high-dose CORT. Our findings suggest that in ovo administration of CORT programs the aggressive behaviors and reproductive functions in the chicken through alterations of HPG axis. PMID- 24630044 TI - Seasonality of fecal androgen and glucocorticoid metabolite excretion in male goral (Naemorhedus griseus) in Thailand. AB - There is no information on the endocrinology of Chinese goral (Naemorhedus griseus), a high priority species for captive breeding and reintroduction in Thailand. This study characterized fecal androgen and glucocorticoid metabolites in male goral at Omkoi Wildlife Sanctuary to investigate seasonal relationships. Fecal samples were collected 3 days/week for 1 year from eight adult males. Mean androgen metabolite concentrations were greater (P<0.05) during the rainy season (289.82+/-9.18ng/g) and winter (224.09+/-11.97ng/g) compared to the summer (195.48+/-8.23ng/g), and were related to breeding activity. A similar pattern was observed for glucocorticoid concentrations (22.10+/-0.72ng/g compared to 21.98+/ 0.98ng/g compared to 15.30+/-0.48ng/g), respectively, and this resulted in a positive correlation between the two hormones (P<0.05). There also were positive correlations between fecal androgen metabolite concentrations and temperature (P<0.05) and day length (P<0.05). In summary, this is the first study to assess endocrine function in male goral, and results showed seasonal variation in testicular and adrenal steroidogenic function, with greater activity in the rainy season and winter. Given that resources for captive male goral are consistent throughout the year, reproduction may be regulated primarily by photoperiod in this species. PMID- 24630045 TI - The added clinical and economic value of diagnostic testing for epilepsy surgery. AB - The costs, benefits and risks associated with diagnostic imaging investigations for epilepsy surgery necessitate the identification of an optimal pathway in the pre-surgical workup. In order to assess the added value of additional investigations a full cost-effectiveness evaluation should be conducted, taking into account all of the life-time costs and benefits associated with undertaking additional investigations. This paper considers and applies the appropriate framework against which a full evaluation should be assessed. We conducted a systematic review to evaluate the progression of the literature through this framework, finding that only isolated elements of added value have been appropriately evaluated. The results from applying the full added value framework are also presented, identifying an optimal strategy for pre-surgical evaluation for temporal lobe epilepsy surgery. Our results suggest that additional FDG-PET and invasive EEG investigations after an initially discordant MRI and video-EEG appears cost-effective, and that the value of subsequent invasive-EEGs is closely linked to the maintenance of longer-term benefits after surgery. It is integral to the evaluation of imaging technologies in the work-up for epilepsy surgery that the impact of the use of these technologies on clinical decision-making, and on further treatment decisions, is considered fully when informing cost effectiveness. PMID- 24630046 TI - Regional brain perfusion changes during standard and microburst vagus nerve stimulation in dogs. AB - PURPOSE: Vagus nerve stimulation (VNS) is an effective adjunctive treatment for refractory epilepsy in humans, but its mechanism of action (MOA) and optimal stimulation parameters are still unknown. Functional neuroimaging studies could provide better insight into the brain structures involved in the activity of VNS, but have not yet been described in dogs. The aim of this study was to investigate the effect of acute VNS on the regional cerebral blood flow (rCBF) in dogs using micro-SPECT (MU-SPECT). Additionally, a novel stimulation paradigm (microburst VNS) was used and compared with standard VNS. METHODS: A VNS Therapy System was implanted in ten Beagle dogs. MU-SPECT was performed after sham, standard and microburst VNS in a randomized, cross-over study. Nineteen volumes of interest (VOIs) were semi-quantitatively analysed and perfusion indices (PIs) were calculated. Furthermore, a rostro-caudal gradient (R-C), an asymmetry index (AI) and a cortical-subcortical index (Co-SCo) were determined. The SPECT results after standard and microburst VNS were compared pairwise with sham stimulation. RESULTS: Acute standard VNS did not cause significant rCBF alterations. Acute microburst VNS caused a significant hypoperfusion in the left frontal lobe (P=0.023) and in the right parietal lobe (P=0.035). Both stimulation paradigms did not cause changes in R-C, AI nor Co-SCo. CONCLUSIONS: Microburst VNS is more potent than standard VNS to modulate the rCBF in the dog. Our results promote further research towards the antiepileptic effect of microburst VNS in dogs and humans. PMID- 24630047 TI - Short-term effect of levetiracetam monotherapy on haematological parameters in children with epilepsy: a prospective study. AB - Studies evaluating the effect of levetiracetam (LEV) on haematological parameters in patients with epilepsy are very limited. Clinical trials have also reported an unexplained increased incidence of pharyngitis and rhinitis in LEV-treated patients. The objective of this study was to evaluate prospectively the changes in haematological parameters in children treated with LEV monotherapy. White blood cell, neutrophils, lymphocytes, monocytes, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelets were measured in 22 children (13 females, mean age 6.70+/-4.23 years) with epilepsy, before and after 2 and 6 months of LEV monotherapy. Lymphocyte count was significantly decreased at 6 months (p=0.019) of treatment and this effect was not dose dependent. One child (4.5%) at 2 months and four children (18%) at 6 months of treatment had lymphocyte count below 10th percentile for age. There were no significant alterations in the other parameters evaluated during the study. LEV monotherapy may significantly decrease lymphocyte count at six months of treatment in children with epilepsy. Further prospective studies are needed to investigate the effect of LEV on haematological parameters and the possible association with the higher incidence of infections reported in children receiving LEV. PMID- 24630048 TI - Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine induced status epilepticus: edema or apoptosis? AB - Manganese-enhanced MRI (MEMRI) has been considered a surrogate marker of Ca(+2) influx into activated cells and tracer of neuronal active circuits. However, the induction of status epilepticus (SE) by kainic acid does not result in hippocampal MEMRI hypersignal, in spite of its high cell activity. Similarly, short durations of status (5 or 15min) induced by pilocarpine did not alter the hippocampal MEMRI, while 30 min of SE even reduced MEMRI signal Thus, this study was designed to investigate possible explanations for the absence or decrease of MEMRI signal after short periods of SE. We analyzed hippocampal caspase-3 activation (to evaluate apoptosis), T2 relaxometry (tissue water content) and aquaporin 4 expression (water-channel protein) of rats subjected to short periods of pilocarpine-induced SE. For the time periods studied here, apoptotic cell death did not contribute to the decrease of the hippocampal MEMRI signal. However, T2 relaxation was higher in the group of animals subjected to 30min of SE than in the other SE or control groups. This result is consistent with higher AQP-4 expression during the same time period. Based on apoptosis and tissue water content analysis, the low hippocampal MEMRI signal 30min after SE can potentially be attributed to local edema rather than to cell death. PMID- 24630049 TI - Regional brain volumes and cognition in childhood epilepsy: does size really matter? AB - PURPOSE: Recent studies have correlated neurocognitive function and regional brain volumes in children with epilepsy. We tested whether brain volume differences between children with and without epilepsy explained differences in neurocognitive function. METHODS: The study sample included 108 individuals with uncomplicated non-syndromic epilepsy (NSE) and 36 healthy age- and gender-matched controls. Participants received a standardized cognitive battery. Whole brain T1 weighted MRI was obtained and volumes analyzed with FreeSurfer (TM). KEY FINDINGS: Total brain volume (TBV) was significantly smaller in cases. After adjustment for TBV, cases had significantly larger regional grey matter volumes for total, frontal, parietal, and precentral cortex. Cases had poorer performance on neurocognitive indices of intelligence and variability of sustained attention. In cases, TBV showed small associations with intellectual indices of verbal and perceptual ability, working memory, and overall IQ. In controls, TBV showed medium associations with working memory and variability of sustained attention. In both groups, small associations were seen between some TBV-adjusted regional brain volumes and neurocognitive indices, but not in a consistent pattern. Brain volume differences did not account for cognitive differences between the groups. SIGNIFICANCE: Patients with uncomplicated NSE have smaller brains than controls but areas of relative grey matter enlargement. That this relative regional enlargement occurs in the context of poorer overall neurocognitive functioning suggests that it is not adaptive. However, the lack of consistent associations between case-control differences in brain volumes and cognitive functioning suggests that brain volumes have limited explanatory value for cognitive functioning in childhood epilepsy. PMID- 24630050 TI - Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence. AB - PURPOSE: To evaluate the efficacy and safety of stiripentol as add-on therapy in Japanese patients with Dravet syndrome treated with clobazam (CLB) and valproate (VPA). METHODS: In this open-label study, patients aged 1-30 years entered a 4 week baseline phase, followed by a 4-week stiripentol dose-adjustment and 12-week fixed-dose phase. The primary efficacy endpoint was responder rate (proportion of patients with a >=50% reduction from baseline phase in clonic or tonic-clonic seizure frequency over the last 4 weeks of fixed-dose treatment [target phase]). Safety and pharmacokinetics were also assessed. KEY FINDINGS: Of 27 patients screened in the baseline phase, 24 patients entered the dose-adjustment phase. All patients completed the study. Responder rate was 66.7% (16/24, 95% CI: 44.7 84.4%), and four patients became free from clonic or tonic-clonic seizures. The duration of clonic or tonic-clonic seizures was also significantly reduced in the target versus baseline phase. The most frequent adverse events were somnolence, anorexia, ataxia, nasopharyngitis and gamma-glutamyl transpeptidase increase, all of which were of mild-to-moderate severity. Stiripentol plasma concentration in the fixed-dose phase was 4-25 MUg/mL. After adding stiripentol to CLB and VPA, the minimum plasma concentrations of CLB and N-desmethyl-CLB (NCLB) increased and that of 4'-hydroxy-N-desmethyl-CLB(OH-NCLB) decreased, while those of VPA and bromide (optionally used) were not affected. SIGNIFICANCE: Add-on stiripentol to CLB and VPA was well tolerated and significantly decreased clonic or tonic-clonic seizures in patients with Dravet syndrome. PMID- 24630051 TI - A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). AB - Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6. These findings expand the clinical spectrum of the syndrome and indicate NHE6 dysfunction as a new cause of electrical status epilepticus during slow-wave sleep (ESES). PMID- 24630052 TI - Prediction of frequency-specific hearing threshold using chirp auditory brainstem response in infants with hearing losses. AB - OBJECTIVES: To investigate the clinical usefulness of the LS-chirp auditory brainstem response for estimation of behavioral thresholds in young children with mild to severe hearing losses. METHODS: 68 infants (136 ears) aged 6-12 months (mean age=9.2 months) with bilateral mild to severe hearing losses were studied at Children's Hospital of Fudan University. In all cases, the children were referred for LS-chirp ABR and visual reinforcement audiometric (VRA) measurements. The low-frequency band chirp (LF-chirp) thresholds (frequency band=0.1-0.85kHz) were compared to the average VRA thresholds (frequency band=0.25-0.5kHz), whereas the high-frequency band chirp (HF-chirp) thresholds (frequency band=1-10kHz) were compared to the average VRA thresholds (frequency band=1-4kHz) using statistical correlation coefficient values. RESULTS: The LS chirp ABR thresholds are very close to behavioral hearing levels. The mean differences between chirp-ABR and VRA thresholds were within 5dBHL for all measurements. The smallest mean threshold difference (<3dBHL) was obtained for the severe hearing loss group. The correlation coefficient values (r) were 0.97 at low-frequency and high-frequency bands. For each carrier frequency, the best correlations between chirp-ABR thresholds and VRA thresholds were obtained at VRA frequency of 0.25kHz/LF-chirp (r=0.98) and VRA frequency of 1kHz/HF-chirp (r=0.98). CONCLUSIONS: This study demonstrates the effectiveness using chirp-ABR predicted frequency-specific thresholds, especially of low and middle frequencies. LS-chirp ABR thresholds determined behavioral thresholds in patients with severe hearing losses were better than for mild hearing losses. The use of a chirp-ABR testing ensures higher sensitivity and accuracy than that of auditory stead-state evoked response (ASSR) for measuring frequency-specific thresholds in young children. PMID- 24630053 TI - Apriori feasibility testing of randomized clinical trial design in patients with cleft deformities and Class III malocclusion. AB - OBJECTIVES: To assess the feasibility of randomizing treatment (surgical vs. non surgical) for correction of a Class III malocclusion (underbite) resulting from an earlier repair of cleft lip and palate. MATERIALS AND METHODS: Surveys about willingness to accept randomized treatment during adolescence were mailed to the parents of cleft lip and palate patients under the care of Children's Hospital Los Angeles between 2005 and 2010. The inclusion criteria were patients with cleft lip and palate, Class III malocclusion due to maxillary deficiency, and absence of medical and cognitive contraindications to treatment. RESULTS: Out of 287 surveys, 82 (28%) were completed and returned; 47% of the subjects held a strong treatment preference (95% CI, 35-58%), while 30% were willing to accept randomization (95% CI, 20-41%). Seventy-eight percent would drop out of a randomized trial if dissatisfied with the assigned treatment (95% CI, 67-86%). The three most commonly cited reasons for being unwilling to accept random treatment assignment were 1) the desire for doctors to choose the best treatment, 2) the desire for parents to have input on treatment, and 3) the desire to correct the underbite as early as possible. CONCLUSION: Based on this study, parents and patients would be unwilling to accept a randomly assigned treatment and would not remain in an assigned group if treatment did not meet expectations. This highlight the limitations associated with randomization trials involving surgical modalities and provide justification for other research models (e.g., cohort studies) to compare two treatment options when randomization is not feasible. PMID- 24630054 TI - A radio-high-performance liquid chromatography dual-flow cell gamma-detection system for on-line radiochemical purity and labeling efficiency determination. AB - In this study, a method of determining radiochemical yield and radiochemical purity using radio-HPLC detection employing a dual-flow-cell system is evaluated. The dual-flow cell, consisting of a reference cell and an analytical cell, was constructed from two PEEK capillary coils to fit into the well of a NaI(Tl) detector. The radio-HPLC flow was directed from the injector to the reference cell allowing on-line detection of the total injected sample activity prior to entering the HPLC column. The radioactivity eluted from the column was then detected in the analytical cell. In this way, the sample will act as its own standard, a feature enabling on-line quantification of the processed radioactivity passing through the system. All data were acquired on-line via an analog signal from a rate meter using chromatographic software. The radiochemical yield and recovery could be simply and accurately determined by integration of the peak areas in the chromatogram obtained from the reference and analytical cells using an experimentally determined volume factor to correct for the effect of different cell volumes. PMID- 24630055 TI - Continuous processing of recombinant proteins: integration of refolding and purification using simulated moving bed size-exclusion chromatography with buffer recycling. AB - Continuous processing of recombinant proteins was accomplished by combining continuous matrix-assisted refolding and purification by tandem simulated moving bed (SMB) size-exclusion chromatography (SEC). Recombinant proteins, N(pro) fusion proteins from inclusion bodies were dissolved with NaOH and refolded in the SMB system with a closed-loop set-up with refolding buffer as the desorbent buffer and buffer recycling of the refolding buffer of the raffinate by tangential flow filtration. For further purification of the refolded proteins, a second SMB operation also based on SEC was added. The whole system could be operated isocratically with refolding buffer as the desorbent buffer, and buffer recycling could also be applied in the purification step. Thus, a significant reduction in buffer consumption was achieved. The system was evaluated with two proteins, the N(pro) fusion pep6His and N(pro) fusion MCP-1. Refolding solution, which contained residual N(pro) fusion peptide, the cleaved autoprotease N(pro), and the cleaved target peptide was used as feed solution. Full separation of the cleaved target peptide from residual proteins was achieved at a purity and recovery in the raffinate and extract, respectively, of approximately 100%. In addition, more than 99% of the refolding buffer of the raffinate was recycled. A comparison of throughput, productivity, and buffer consumption of the integrated continuous process with two batch processes demonstrated that up to 60-fold higher throughput, up to 180-fold higher productivity, and at least 28-fold lower buffer consumption can be obtained by the integrated continuous process, which compensates for the higher complexity. PMID- 24630056 TI - Investigation of liquid chromatography quadrupole time-of-flight mass spectrometry performance for identification and determination of hydroxylated stilbene antioxidants in wine. AB - The performance of liquid chromatography (LC) followed by quadrupole time-of flight (QTOF) mass spectrometry (MS) for the determination of hydroxylated stilbene compounds in red and white wine samples is assessed. When combined with a solid-phase extraction step, LC-QTOF-MS allowed the selective determination of five target compounds (trans- and cis-resveratrol, trans-piceatannol, trans piceid and trans-pterostilbene) attaining limits of quantification between 3 and 20ngmL(-1) and providing linear responses up to 4000ngmL(-1). Recoveries, established against standards prepared in methanol, varied between 93% and 115%. The distribution of the above species in wine is illustrated with the analysis of 15 samples. Trans-pterostilbene remained undetected in samples, whereas trans piceid and trans-resveratrol maximum concentrations exceed the 6000ngmL(-1) level. Values for trans-piceatannol and cis-resveratrol ranged from non detected to 600ngmL(-1), and from 11 to more than 3200ngmL(-1), respectively. Accurate MS and MS/MS scan spectra were used to investigate the existence of reduced (dihydro) and oxidized (dehydro) forms of resveratrol and picetannol in the processed samples. Dihydro derivatives appeared, as free compounds, in 100% (dihydro-piceatannol) and 40% (dihydro-resveratrol) of the samples. On the other hand, dehydro derivatives were noticed as conjugated (glycosylated) species, with detection frequencies of 100% and 47% for dehydro-glucosyl-resveratrol and dehydro-glucosyl-piceatannol, respectively. Above findings confirm the suitability of LC-QTOF-MS for the comprehensive study of hydroxylated stilbene antioxidants in wine samples. PMID- 24630057 TI - Rapid, high performance method for the determination of vitamin K(1), menaquinone 4 and vitamin K(1) 2,3-epoxide in human serum and plasma using liquid chromatography-hybrid quadrupole linear ion trap mass spectrometry. AB - Unlike the other fat-soluble vitamins, vitamin K circulates in the human bloodstream at very low levels because of a low intake in the diet. Mammals have developed an efficient recycling system, known as vitamin K-epoxide cycle, which involve quinone, hydroquinone and epoxide forms of the vitamin. Phylloquinone (K(1)) is the main homologue, while menaquinone-4 (MK-4) is both a member of the vitamin K(2) family and metabolite of K(1) in extra-hepatic tissues. Notwithstanding the recent advances, many aspects of the complex vitamin K physiology still remain to be investigated. Therefore, there is a critical need to develop more reliable analytical methods for determining the vitamin K and its metabolites in biological fluids and tissues. Nevertheless, relatively low concentrations, unavailability of some authentic standards and occurrence of interfering lipids make this a challenging task. The method proposed in the present paper can directly and accurately estimate K(1), K(1) 2,3-epoxide (K(1)O), and MK-4 in human serum and plasma at concentrations in the ng/L-MUg/L range, using labelled internal standards and a quadrupole linear ion trap instrument operated in multiple reaction monitoring (MRM) mode. High sensitivity was achieved by removing signal "endogenous suppressors" and making the composition of the non-aqueous mobile phase suitable to support the positive atmospheric pressure chemical ionization of the analytes. An excellent selectivity resulted from the combination of some factors: the MRM acquisition, the adoption of an identification point system, an extraction optimized to remove most of the lipids and a tandem-C18 column-system necessary to separate isobaric interferences from analytes. The method was validated according to the Food and Drug Administration (FDA) guidelines and its accuracy was assessed by analysing 9 samples from the Vitamin K External Quality Assessment Scheme (KEQAS). Its feasibility in evaluating vitamin K status in human serum was also tested by monitoring a group of six healthy subjects and a group of six patients under oral anticoagulant therapy (OAT). Warfarinised patients did not show deficiency of K1 but levels comparable with those of healthy people and an accumulation of K1O up to 3.760MUg/L. MK-4 was not detected in either of the two groups. PMID- 24630058 TI - Evaluation and application of static headspace-multicapillary column-gas chromatography-ion mobility spectrometry for complex sample analysis. AB - An evaluation of static headspace-multicapillary column-gas chromatography-ion mobility spectrometry (SHS-MCC-GC-IMS) has been undertaken to assess its applicability for the determination of 32 volatile compounds (VCs). The key experimental variables of sample incubation time and temperature have been evaluated alongside the MCC-GC variables of column polarity, syringe temperature, injection temperature, injection volume, column temperature and carrier gas flow rate coupled with the IMS variables of temperature and drift gas flow rate. This evaluation resulted in six sets of experimental variables being required to separate the 32 VCs. The optimum experimental variables for SHS-MCC-GC-IMS, the retention time and drift time operating parameters were determined; to normalise the operating parameters, the relative drift time and normalised reduced ion mobility for each VC were determined. In addition, a full theoretical explanation is provided on the formation of the monomer, dimer and trimer of a VC. The optimum operating condition for each VC calibration data was obtained alongside limit of detection (LOD) and limit of quantitation (LOQ) values. Typical detection limits ranged from 0.1ng bis(methylthio)methane, ethylbutanoate and (E) 2-nonenal to 472ng isovaleric acid with correlation coefficient (R(2)) data ranging from 0.9793 (for the dimer of octanal) through to 0.9990 (for isobutyric acid). Finally, the developed protocols were applied to the analysis of malodour in sock samples. Initial work involved spiking an inert matrix and sock samples with appropriate concentrations of eight VCs. The average recovery from the inert matrix was 101+/-18% (n=8), while recoveries from the sock samples were lower, that is, 54+/-30% (n=8) for sock type 1 and 78+/-24% (n=6) for sock type 2. Finally, SHS-MCC-GC-IMS was applied to sock malodour in a field trial based on 11 volunteers (mixed gender) over a 3-week period. By applying the SHS-MCC-GC-IMS database, four VCs were identified and quantified: ammonia, dimethyl disulphide, dimethyl trisulphide and butyric acid. A link was identified between the presence of high ammonia and dimethyl disulphide concentrations and a high malodour odour grading, that is, >= 6. Statistical analysis did not find any correlation between the occurrence of dimethyl disulphide and participant gender. PMID- 24630059 TI - An insulin monitoring device based on hyphenation between molecularly imprinted micro-solid phase extraction and complementary molecularly imprinted polymer sensor. AB - Molecularly imprinted micro-solid phase extraction fiber was developed by modifying molecularly imprinted polymer film on the surface of silica fiber exploring "grafting via surface attached monomer" (method I) and "grafting via sol-gel" (method II) approaches. The latter approach was found to be inferior to the former one in terms of the sensitivity of insulin detection [method I, LOD=0.009ngmL(-1); method II, LOD=0.064ngmL(-1), RSD=1.21%]. Notably, either of the techniques, molecularly imprinted micro-solid phase extraction or complementary sensor, was found to be incompetent to monitor the stringent level of insulin in the real samples. However, the combination of these techniques has been found quite suitable for achieving the high detection sensitivity of ultra trace insulin in human blood serum and Huminsulin injection, without any non specific (false-positives) contributions. The proposed hyphenated device could serve as a possible marker for risk of developing type 2 diabetes mellitus and diabetic coma due to insulin resistance in human beings. PMID- 24630060 TI - Two novel solvent system compositions for protected synthetic peptide purification by centrifugal partition chromatography. AB - Protected synthetic peptide intermediates are often hydrophobic and not soluble in most common solvents. They are thus difficult to purify by preparative reversed-phase high-performance liquid chromatography (RP-HPLC), usually used for industrial production. It is then challenging to develop alternative chromatographic purification processes. Support-free liquid-liquid chromatographic techniques, including both hydrostatic (centrifugal partition chromatography or CPC) and hydrodynamic (counter-current chromatography or CCC) devices, are mainly involved in phytochemical studies but have also been applied to synthetic peptide purification. In this framework, two new biphasic solvent system compositions covering a wide range of polarity were developed to overcome solubility problems mentioned above. The new systems composed of heptane/tetrahydrofuran/acetonitrile/dimethylsulfoxide/water and heptane/methyl tetrahydrofuran/N-methylpyrrolidone/water were efficiently used for the CPC purification of a 39-mer protected exenatide (Byetta(r)) and a 8-mer protected peptide intermediate of bivalirudin (Angiox(r)) synthesis. Phase compositions of the different biphasic solvent systems were determined by (1)H nuclear magnetic resonance. Physico-chemical properties including viscosity, density and interfacial tension of these biphasic systems are also described. PMID- 24630061 TI - Novel carbamoyl type quinine and quinidine based chiral anion exchangers implementing alkyne-azide cycloaddition immobilization chemistry. AB - The synthesis and chromatographic evaluation of a series of new Cinchona derived chiral weak anion exchangers is presented. Huisgen Cu(I) mediated alkyne-azide cycloaddition, so-called click chemistry, was used as an immobilization strategy. In this way it was possible to immobilize about 90% of offered selector via 1,2,3 triazole linker, which displays a more efficient way of binding the selector to modified silica compared to common radical mediated thiol-ene addition. Problems associated with potential radical scavenging properties of chiral selectors thereby could be circumvented. The evaluation of the synthesized chiral stationary phases regarding chromatographic behavior was carried out using polar organic mode mobile phase composition and a set of representative chiral organic acids. Different loading densities revealed an optimum selector density of about 310MUmol/g chiral stationary phase with respect to resolution and selectivity. A decrease of performance was observed for higher loading, indicating mutual spatial influence of selector units leading to sterical hindrance. In addition, we observed that the effect of free azide groups on retention is negligible and the overall chromatographic behavior is comparable to other Cinchona derived chiral stationary phases. PMID- 24630062 TI - New reversed-phase/anion-exchange/hydrophilic interaction mixed-mode stationary phase based on dendritic polymer-modified porous silica. AB - A novel dendritic polymer-modified silica (DPS) stationary phase was prepared by a divergent synthesis scheme starting from propylamine on silica by consecutive amine-epoxy reactions with 1,4-butanedioldiglycidyl ether and aniline. Both elemental analysis and infrared spectra data shows the successful growth of dendritic polymer on silica particles. The carbon and nitrogen contents increased with an increasing number of reaction cycles and achieved 25.2% and 2.1% (w/w) after 11 reaction cycles. The combination of a phenyl ring with a quaternary ammonium, or a tertiary amine at the branch point along with embedded polar functionalities (including ether and hydroxyl groups) in the branch, generated hydrophobic, electrostatic, as well as hydrophilic interactive domains. Depending on solute structure and mobile phase composition, the DPS stationary phase provided multiple retention mechanisms, including reversed phase (RP), anion exchange (AEX), and hydrophilic interactions. The RP capability achieved separation of polycyclic aromatic hydrocarbons. Basic, neutral and acidic molecules were well separated under RP/AEX mixed mode. Effective separation of small polar compounds (such as nucleobases and nucleosides) was also obtained under hydrophilic interaction liquid chromatography (HILIC) mode. PMID- 24630063 TI - iMatch2: compound identification using retention index for analysis of gas chromatography-mass spectrometry data. AB - We developed a method, iMatch2, for compound identification using retention indices (RI) in NIST11 library. Three-way ANOVA test and Kruskal-Wallis test respectively demonstrate that column class and temperature program type defined by the NIST library are the most dominant factors affecting the magnitude of retention index while the retention index data type does not cause significant difference. The developed linear regression transformation for merging retention indices with different data types, but the same column class and temperature program type, reduces the standard deviation of retention index up to 8%, compared to the simple union approach used in the original iMatch. As for outlier detection methods to remove retention indices having large difference with the remaining data of the same compound, Tietjen-Moore test and generalized extreme studentized deviate test are the strictest methods, while methods such as Dixon's test, Thompson tau approach, and Grubbs' test are more conservative. To improve the accuracy of retention index window, a concept of compound specific retention index window is introduced for compounds with a large number of retention indices in the NIST11 library, while the retention index window is calculated from empirical distributions for the compounds with a small number of retention indices. Analysis of the experimental data of a mixture of compound standards and the metabolite extract from mouse liver show significant improvement of retention index quality in the NIST11 library and the new data analysis methods. PMID- 24630064 TI - Core-shell molecularly imprinted polymer-based solid-phase microextraction fiber for ultra trace analysis of endosulfan I and II in real aqueous matrix through gas chromatography-micro electron capture detector. AB - In this study, core-shell molecularly imprinted polymer selective for endosulfan I and II was prepared by copolymerization of Fe3O4@SiO2-methacrylamide composites and N,N'-methylene-bis-acrylamide. The synthesized polymer was thoroughly characterized by FT-IR, TGA, and SEM. The adsorption properties of the MIP and NIP were demonstrated by equilibrium rebinding experiments, pseudo-second-order kinetic model, LF-isotherm and Scatchard analysis. The competitive recognition studies were performed with endosulfan I and II and structurally similar compounds: aldrin, dieldrin and heptachlor. The imprinting factors (IF) of endosulfan I and II were found to be 10.1 and 9.1, respectively, which were much higher than the imprinting factors (IF) of other cyclodienes. The imprinted polymer was then coated on stainless steel wire to develop an easy and simple laboratory made solid phase microextraction device for selective extraction of endosulfan I and II from water samples of environmental importance. Also the main parameters influencing coating of fiber and microextraction procedure were investigated and optimized using Plackett-Burman and Central Composite designs. The developed method was thoroughly validated for its linearity, selectivity, precision and accuracy. The developed MISPME method's linearity ranged from 7 to 5*10(3)ngl(-1) (R(2)=0.999) and from 10 to 5*10(3)ngl(-1) (R(2)=0.999) for endosulfan I and II, respectively. The limits of detection for endosulfan I and II were found to be 2ngl(-1) and 3ngl(-1), respectively. However, the limits of quantification for endosulfan I and II were 7ngl(-1) and 10ngl(-1), respectively. PMID- 24630065 TI - Development of a phenyl membrane chromatography-based process yielding pharmaceutical grade plasmid deoxyribonucleic acid for mammalian cells transfection. AB - Production of plasmid DNA pharmaceuticals requires fast, robust and cost effective methodologies able to deliver high amounts of the target molecule in short periods of time. Membrane adsorbers can be tailored and operated to suit such criteria. This study focuses on the impact of pDNA samples produced by a membrane chromatography-based purification methodology on the transfection efficiency of CHO cells. Chromatographies were performed with 5mL of plasmid containing clarified bacterial lysate each on a Sartorius(r) Phenyl 3mL spiral cartridge using a bind and elute mode to purify the GFP expressing pVAX1/GFP model plasmid. The developed methodology could deliver up to 285MUg pDNA samples per run that were virtually RNA free (over 99% removal) and chromatographic step yields of 85%. The purified samples had a reduced content of OC pDNA (~15% less in average). Additionally, robustness of the process was assessed up to nine chromatographic runs without noticing any relevant loss in chromatographic performance and transfection capabilities. The increase of productivity was also studied by increasing the flow rate 5 fold-a maximum productivity of 100MUg pDNA/(hmL-BV) was achieved. The pDNA samples produced led to transfection efficiencies that were comparable among all experiments-72% and within 4% relative standard deviation when samples were produced using a lower throughput. Transfection efficiencies obtained by the membrane process were comparable to a combined HIC/SEC bead-based purification process, with values ranging within 74 113% of the values obtained from the latter. PMID- 24630066 TI - Determination of melamine and cyromazine in milk by high performance liquid chromatography coupled with online solid-phase extraction using a novel cation exchange restricted access material synthesized by surface initiated atom transfer radical polymerization. AB - A novel strong-cation-exchange restricted access material has been synthesized by atom transfer radical polymerization (ATRP). In the synthesis, poly(3-sulfopropyl methacrylate-co-ethylene dimethacrylate), [p(SPM/EDMA)] was grafted on the silica by surface-initiated ATRP first. The poly(glycerol mono-methacrylate) [pGMMA] was then immobilized on the external surface, which created a chemical diffusion barrier for protein exclusion. The resulting Sil-g-p(SPM/EDMA)-g-pGMMA has both functions of protein exclusion and cation exchange, exhibiting the property of cation-exchange restricted access material. The application of Sil-g-p(SPM/EDMA) g-pGMMA has been studied by the determination of melamine and cyromazine in bovine milk using the online solid-phase extraction/HPLC method. In the process, the Sil-g-p(SPM/EDMA)-g-pGMMA was used for the sample pre-treatment and a HILIC column was employed as the analytical column. The method has shown good accuracy, precision and low limits of detections. The result demonstrated that the Sil-g p(SPM/EDMA)-g-pGMMA can be used for the cation extraction from biological samples by direct HPLC injection. PMID- 24630067 TI - Screening of protein kinase inhibitors in natural extracts by capillary electrophoresis combined with liquid chromatography-tandem mass spectrometry. AB - We report a capillary electrophoresis method in conjunction with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for screening of protein kinase inhibitors (PKIs) in natural extracts. Protein kinase A (PKA), substrate 5 carboxyfluorescein-labeled kemptide (CLK) and inhibitor H-89 were employed for the method development and validation. Enzymatic inhibition assay was performed with electrophoretically mediated microanalysis technique. Once the bioactivity of a natural extract was confirmed, an assay-guided isolation and structure elucidation using LC-MS/MS were accomplished to identify the compounds which are responsible for the observed bioactivity. Totally 33 natural extracts were screened with the method, and baicalin in the extract of Radix Scutellariae was identified to be a new PKI of PKA. This result demonstrated the practical applicability of our method in screening of PKIs from natural products. PMID- 24630068 TI - Finding Gertrude: The resident's voice in Minimum Data Set 3.0. AB - PURPOSE: The new Minimum Data Set 3.0 was designed to improve the assessment process by requiring nursing home (NH) staff to attempt to interview residents with scripted questions to assess subjective states such as pain, mood, and cognitive functioning. Although the case has been made that resident self-report is important, it is unknown whether facilities are doing so in practice. We examined the frequency of attempts to interview residents to elucidate the types of residents able to be interviewed about their clinical conditions and facility characteristics related to the likelihood of attempt. DESIGN AND METHODS: Data come from Minimum Data Set 3.0 annual assessments for 757,044 residents in 15,030 NHs during 2011-2012 and the 2011 Online Survey, Certification, and Reporting database. Hierarchical generalized linear models were conducted to test the association between resident and facility characteristics and the attempt rate of resident interview for 3 clinical domains (cognition, mood, and pain). RESULTS: Over 83% of long-stay residents attempted all 3 self-report clinical items. The rates of attempt for mood, cognition, and pain were 88%, 89%, and 92%, respectively. Results from hierarchical generalized linear models suggest that certain resident characteristics are related to the likelihood of participating in interviews, in particular neither having a diagnosis of dementia nor cognitive impairment, not exhibiting signs of delirium, nor a documented prognosis of 6 months or less to live. Residents in smaller, chain-affiliated nursing homes with fewer Medicare residents and fewer assessments per administrative nurse and registered nurse were more likely to attempt the resident interview items. IMPLICATIONS: This article documents the high rate of NH residents' participation in interviews about their clinical states. Furthermore, we identify types of residents for whom additional investigation into ways to achieve higher rates of participation is required and facility resources that are related to the likelihood of high rates of attempt. PMID- 24630070 TI - Burnout syndrome in oral and maxillofacial surgeons: a critical analysis. AB - The aim of this study was to determine the prevalence of burnout syndrome among Brazilian oral and maxillofacial surgeons and its relationship with socio demographic, clinical, and habit variables. The sample of this study comprised 116 surgeons. The syndrome was quantified using the Maslach Burnout Inventory (General Survey), which defines burnout as the triad of high emotional exhaustion, high depersonalization, and low personal accomplishment. The criteria of Grunfeld et al. were used to evaluate the presence of the syndrome (17.2%). No significant differences between the surgeons diagnosed with and without the syndrome were observed according to age (P=0.804), sex (P=0.197), marital status (P=0.238), number of children (P=0.336), years of professional experience (P=0.102), patients attended per day (P=0.735), hours worked per week (P=0.350), use of alcohol (P=0.148), sports practice (P=0.243), hobbies (P=0.161), or vacation period per year (P=0.215). Significant differences occurred in the variables sex in the emotional exhaustion subscale (P=0.002) and use or not of alcohol in the personal accomplishment subscale (P=0.035). Burnout syndrome among Brazilian surgeons is average, showing a low personal accomplishment. PMID- 24630069 TI - Two-year follow-up of changes in bite force and occlusal contact area after intraoral vertical ramus osteotomy with and without Le Fort I osteotomy. AB - This study was performed to examine the longitudinal changes in bite force and occlusal contact area after mandibular setback surgery via intraoral vertical ramus osteotomy (IVRO). Patients with mandibular prognathism who underwent IVRO (surgical group: 39 men and 39 women) were compared with subjects with class I skeletal and dental relationships (control group; 32 men and 35 women). The surgical group was divided into two subgroups: 1-jaw surgery (n = 30) and 2-jaw surgery (n = 48). Bite force and contact area were measured in maximum intercuspation with the Dental Prescale System before treatment, within 1 month before surgery, and at 1, 3, 6, 9, 12, and 24 months postsurgery. A linear mixed model was used to investigate the time-dependent changes and associated factors. Bite force and contact area decreased during presurgical orthodontic treatment, were minimal at 1 month postsurgery, and increased gradually thereafter. The 1 jaw and 2-jaw subgroups showed no significant differences in bite force. The time dependent changes in bite force were significantly different according to the contact area (P < 0.05). The results of this study suggest that bite force and occlusal contact area gradually increase throughout the postsurgical evaluation period. Increasing the occlusal contact area may be essential for improving bite force after surgery. PMID- 24630071 TI - Mandibular effects of maxillary distraction osteogenesis in cleft lip and palate. AB - Maxillary distraction osteogenesis (DO) is a reliable treatment for severe maxillary deficiency in cleft lip and palate (CLP). The objective was to analyze its long-term effects on the mandible. A retrospective study of 24 CLP treated with maxillary DO using the Polley and Figueroa technique was done; patients were followed for more than 4 years. Preoperative (T0), 6-12 months postoperative (T1), and >= 4 years postoperative (T2) cephalometric radiographs were evaluated. A classical cephalometric analysis was used to assess treatment stability, and a Procrustes superimposition method was used to assess local changes in the shape of the mandible. The mean age of patients at T0 was 15.4 +/- 4.1 years. SNA increased at T1 and T2 (P < 0.001), with no significant relapse between T1 and T2, indicating stability at 1 year after treatment (T0 = 72.4 +/- 5.3 degrees ; T1 = 81.3 +/- 6.2 degrees ; T2 = 79.9 +/- 6.1 degrees ). SNB, facial angle, gonial angle, and symphyseal angle remained stable. Long-term analysis of the mandible demonstrated a minimal counter-clockwise rotation of the body (mandibular plane = -0.2 +/- 3.2 degrees ) and ramus (-0.6 +/- 4.3 degrees ). Maxillary DO in CLP had no significant effect on the shape or rotation of the mandible. The maxillary advancement remained stable after 1 year. PMID- 24630072 TI - Interview with Stacey L. Harmer. PMID- 24630073 TI - Root architecture and root and tuber crop productivity. AB - It is becoming increasingly evident that optimization of root architecture for resource capture is vital for enabling the next green revolution. Although cereals provide half of the calories consumed by humans, root and tuber crops are the second major source of carbohydrates globally. Yet, knowledge of root architecture in root and tuber species is limited. In this opinion article, we highlight what is known about the root system in root and tuber crops, and mark new research directions towards a better understanding of the relation between root architecture and yield. We believe that unraveling the role of root architecture in root and tuber crop productivity will improve global food security, especially in regions with marginal soil fertility and low-input agricultural systems. PMID- 24630074 TI - Interview with Seung Yon Rhee. PMID- 24630075 TI - Interview with Daniel Kliebenstein. PMID- 24630076 TI - Peer pressure and alcohol use in young men: a mediation analysis of drinking motives. AB - BACKGROUND: Peer pressure (PP) has been shown to play a major role in the development and continuation of alcohol use and misuse. To date, almost all the studies investigating the association of PP with alcohol use only considered the PP for misconduct but largely ignored other aspects of PP, such as pressure for peer involvement and peer conformity. Moreover, it is not clear whether the association of PP with alcohol use is direct or mediated by other factors. The aim of the present study was to investigate the association of different aspects of peer pressure (PP) with drinking volume (DV) and risky single-occasion drinking (RSOD), and to explore whether these associations were mediated by drinking motives (DM). METHODS: A representative sample of 5521 young Swiss men, aged around 20 years old, completed a questionnaire assessing their usual weekly DV, the frequency of RSOD, DM (i.e. enhancement, social, coping, and conformity motives), and 3 aspects of PP (i.e. misconduct, peer involvement, and peer conformity). Associations between PP and alcohol outcomes (DV and RSOD) as well as the mediation of DM were tested using structural equation models. RESULTS: Peer pressure to misconduct was associated with more alcohol use, whereas peer involvement and peer conformity were associated with less alcohol use. Associations of drinking outcomes with PP to misconduct and peer involvement were partially mediated by enhancement and coping motives, while the association with peer conformity was partially mediated by enhancement and conformity motives. CONCLUSIONS: Results suggest that PP to misconduct constitutes a risk factor, while peer conformity and peer involvement reflect protective factors with regard to alcohol use. Moreover, results from the mediation analyses suggest that part of the association of PP with alcohol use came indirectly through DM: PP was associated with DM, which in turn were associated with alcohol use. PMID- 24630077 TI - Making change happen: a case study of the successful establishment of a peer administered naloxone program in one Australian jurisdiction. AB - Analysis of how policy processes happen in real-world, contemporary settings is important for generating new and timely learning which can inform other drug policy issues. This paper describes and analyses the process leading to the successful establishment of Australia's first peer-administered naloxone program. Within a case study design, qualitative data were collected using semi-structured interviews with key individuals associated with the initiative (n=9), and a collaborative approach to data analysis was undertaken. Central to policy development in this case was the formation of a committee structure to provide expert guidance and support. The collective, collaborative and relational features of this group are consistent with governing by network. The analysis demonstrates that the Committee served more than a merely consultative role. We posit that the Committee constituted the policy process of stakeholder engagement, communication strategy, program development, and implementation planning, which led to the enactment of the naloxone program. We describe and analyse the roles of actors involved, the goodwill and volunteerism which characterised the group's processes, the way the Committee was used as a strategic legitimising mechanism, the strategic framings used to garner support, emergent tensions and the evolving nature of the Committee. This case demonstrates how policy change can occur in the absence of strong political imperatives or ideological contestation, and the ways in which a collective process was used to achieve successful outcomes. PMID- 24630078 TI - 'Hyped up': assemblages of alcohol, excitement and violence for outer-suburban young adults in the inner-city at night. AB - BACKGROUND: Young adults from across greater Melbourne are drawn to the city centre night time economy (NTE). There is some evidence that young adults who live in outer-suburbs are involved in higher rates of weekend night time assaults than their inner-urban peers, both as perpetrators and as victims. Using the notion of 'assemblages', this article explores outer-suburban people's participation in the affectively charged spaces of inner-city entertainment precincts to show that trouble in the NTE cannot be attributed to alcohol and other drugs alone. METHODS: We provide a narrative analysis of interviews conducted in 2012 with 60 young adult drinkers aged 18-24, half of whom lived in an inner-city area and half in outer-suburbs. RESULTS: More so for young adults from outer-suburbs than those who live closer to the city, going to the city is an event marked out as different from everyday life. Their sense of being 'hyped up' in the inner-city made different sets of practices possible, particularly in relation to drinking and being open to new engagements with friends and sexual partners. Participants also spoke, however, of discomfort, danger and fear. Violence was most likely to occur at points where people felt a dissonance between their heightened affective states and the spaces where they found themselves. CONCLUSION: In this analysis, outer-suburban young adults' positioning within the assemblages of the city centre NTE makes conflict and violence more likely for them. Efforts to improve NTE safety should maintain a focus on managing alcohol availability. Nonetheless additional strategies to decentralise the NTE, ensure better late night public transport to outer-suburbs or to support people to manage sudden affective shifts in NTE might also play a greater part in the overall effort. PMID- 24630079 TI - Do disgusting and fearful anti-smoking advertisements increase or decrease support for tobacco control policies? PMID- 24630080 TI - Treatment of pelvic pain associated with endometriosis: a committee opinion. AB - Pain associated with endometriosis may involve many mechanisms and requires careful evaluation to confirm the diagnosis and exclude other potential causes. Both medical and surgical treatments for pain related to endometriosis are effective, and choice of treatment must be individualized. This document replaces the document by the same name last published in 2008 (Fertil Steril 2008;90:S260 9). PMID- 24630081 TI - Long-term treatment of uterine fibroids with ulipristal acetate ?. AB - OBJECTIVE: To investigate the efficacy and safety of ulipristal acetate (UPA) for long-term treatment of symptomatic uterine fibroids. DESIGN: Repeated intermittent open-label UPA courses, each followed by randomized double-blind norethisterone acetate (NETA) or placebo. SETTING: European clinical gynecology centers. PATIENT(S): Two hundred and nine women with symptomatic fibroids including heavy menstrual bleeding. INTERVENTION(S): Patients received up to four 3-month courses of UPA 10 mg daily, immediately followed by 10-day double-blind treatment with NETA (10 mg daily) or placebo. MAIN OUTCOME MEASURE(S): Amenorrhea, fibroid volume, endometrial histology. RESULT(S): After the first UPA course, amenorrhea occurred in 79% of women, with median onset (from treatment start) of 4 days (interquartile range, 2-6 days). Median fibroid volume change was -45% (interquartile range, -66%; -25%). Amenorrhea rates were 89%, 88%, and 90% for the 131, 119, and 107 women who received treatment courses 2, 3, and 4, respectively. Median times to amenorrhea were 2, 3, and 3 days for treatment courses 2, 3, and 4, respectively. Median fibroid volume changes from baseline were -63%, -67%, and -72% after treatment courses 2, 3, and 4, respectively. All endometrial biopsies showed benign histology without hyperplasia; NETA did not affect fibroid volume or endometrial histology. CONCLUSION(S): Repeated 3-month UPA courses effectively control bleeding and shrink fibroids in patients with symptomatic fibroids. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (www.clinicaltrials.gov) registration numbers NCT01156857 (PEARL III) and NCT01252069 (PEARL III extension). PMID- 24630083 TI - Revis(it)ing Barrett's esophagus. PMID- 24630082 TI - Adherence to recommended intervals for surveillance colonoscopy in average-risk patients with 1 to 2 small (<1 cm) polyps on screening colonoscopy. AB - BACKGROUND: Among average-risk patients, repeat colonoscopy in 5 years is recommended after 1 to 2 small (<1 cm) adenomas are found on screening colonoscopy or in 10 years if hyperplastic polyps are found. However, sparse quantitative data are available about adherence to these recommendations or factors that may improve adherence. OBJECTIVE: To quantify adherence to recommended intervals and to identify factors associated with lack of adherence. DESIGN: Retrospective endoscopic database analysis. SETTING: Tertiary-care institution and Veterans Affairs Health System. PATIENTS: Average-risk individuals undergoing screening colonoscopy found to have 1 to 2 small polyps on screening colonoscopy. MAIN OUTCOME MEASUREMENTS: Frequency of recommending repeat colonoscopy in 5 years if 1 to 2 small adenomas are found and in 10 years if hyperplastic polyps are found. RESULTS: Of 922 outpatient screening colonoscopies with 1 to 2 small polyps found, 90.2% received appropriate recommendations for timing of repeat colonoscopy. Eighty-four percent of patients with 1 to 2 small adenomas and 94% of patients with 1 to 2 hyperplastic polyps received recommendations that were consistent with guidelines. Based on logistic regression analysis, patients aged >70 years (odds ratio [OR] 2.4, 95% confidence interval [CI], 1.0-5.7), fair bowel preparation (OR 12.7; 95% CI, 7.3-22.4), poor bowel preparation (OR 10.0; 95% CI, 4.3-23.6), and the presence of 2 small adenomas versus 1 small adenoma (OR 3.6; 95% CI, 2.2-6.0) were factors associated with "overuse" or recommendations inconsistent with guidelines. LIMITATIONS: Retrospective study design. CONCLUSION: More than 90% of endoscopists' recommendations for timing of surveillance colonoscopy in average-risk patients with 1 to 2 small polyps are consistent with guideline recommendations. Quality of preparation is strongly associated with deviation from guideline recommendations. PMID- 24630084 TI - Narrowing the focus on fibrostenotic eosinophilic esophagitis. PMID- 24630085 TI - Creating a lean endoscopist: does operations management have a role in endoscopy? PMID- 24630086 TI - EUS-guided drainage of debris-containing pancreatic pseudocysts by using combined endoprosthesis and a nasocystic drain. PMID- 24630087 TI - A new through-the-scope balloon-assisted deep enteroscopy platform. PMID- 24630088 TI - Salvaging a sticky situation: a stuck PolyLoop. PMID- 24630089 TI - Hard to swallow: colonic adenocarcinoma in esophagus. PMID- 24630090 TI - Ascites and portal vein thrombosis. PMID- 24630091 TI - Substrate independent silver nanoparticle based antibacterial coatings. AB - Infections arising from bacterial adhesion and colonization on medical device surfaces are a significant healthcare problem. Silver based antibacterial coatings have attracted a great deal of attention as a potential solution. This paper reports on the development of a silver nanoparticles based antibacterial surface that can be applied to any type of material surface. The silver nanoparticles were surface engineered with a monolayer of 2-mercaptosuccinic acid, which facilitates the immobilization of the nanoparticles to the solid surface, and also reduces the rate of oxidation of the nanoparticles, extending the lifetime of the coatings. The coatings had excellent antibacterial efficacy against three clinically significant pathogenic bacteria i.e. Staphylococcus epidermidis, Staphylococcus aureus and Pseudomonas aeruginosa. Studies with primary human fibroblast cells showed that the coatings had no cytotoxicity in vitro. Innate immune studies in cultures of primary macrophages demonstrated that the coatings do not significantly alter the level of expression of pro inflammatory cytokines or the adhesion and viability of these cells. Collectively, these coatings have an optimal combination of properties that make them attractive for deposition on medical device surfaces such as wound dressings, catheters and implants. PMID- 24630092 TI - Force-driven evolution of mesoscale structure in engineered 3D microtissues and the modulation of tissue stiffening. AB - The complex structures of tissues determine their mechanical strength. In engineered tissues formed through self-assembly in a mold, artificially imposed boundary constraints have been found to induce anisotropic clustering of the cells and the extracellular matrix in local regions. To understand how such tissue remodeling at the intermediate length-scale (mesoscale) affects tissue stiffening, we used a novel microtissue mechanical testing system to manipulate the remodeling of the tissue structures and to measure the subsequent changes in tissue stiffness. Microtissues were formed through cell driven self-assembly of collagen matrix in arrays of micro-patterned wells, each containing two flexible micropillars that measured the microtissues' contractile forces and elastic moduli via magnetic actuation. We manipulated tissue remodeling by inducing myofibroblast differentiation with TGF-beta1, by varying the micropillar spring constants or by blocking cell contractility with blebbistatin and collagen cross linking with BAPN. We showed that increased anisotropic compaction of the collagen matrix, caused by increased micropillar spring constant or elevated cell contraction force, contributed to tissue stiffening. Conversely, collagen matrix and tissue stiffness were not affected by inhibition of cell-generated contraction forces. Together, these measurements showed that mesoscale tissue remodeling is an important middle step linking tissue compaction forces and tissue stiffening. PMID- 24630093 TI - The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury. AB - Knockout studies suggest that PTEN limits the regenerative capacities of CNS axons as a dominant antagonist of PI3 kinase, but the transgenic approach is not feasible for treating patients. Although application of bisperoxovanadium may block PTEN function, it is a general inhibitor of phosphotyrosine phosphatases and may target enzymes other than PTEN, causing side effects and preventing firm conclusions about PTEN inhibition on regulating neuronal growth. A pharmacological method to selectively suppress PTEN post-injury could be a valuable strategy for promoting CNS axon regeneration. We identified PTEN antagonist peptides (PAPs) by targeting PTEN critical functional domains and evaluated their efficacy for promoting axon growth. Four PAPs (PAP 1-4) bound to PTEN protein expressed in COS7 cells and blocked PTEN signaling in vivo. Subcutaneous administration of PAPs initiated two days after dorsal over hemisection injury significantly stimulated growth of descending serotonergic fibers in the caudal spinal cord of adult mice. Systemic PAPs induce significant sprouting of corticospinal fibers in the rostral spinal cord and limited growth of corticospinal axons in the caudal spinal cord. More importantly, PAP treatment enhanced recovery of locomotor function in adult rodents with spinal cord injury. This study may facilitate development of effective therapeutic agents for CNS injuries. PMID- 24630094 TI - Lanthanide-based nanocrystals as dual-modal probes for SPECT and X-ray CT imaging. AB - Applications of lanthanide-based nanoparticles for bioimaging have attracted increasing attention. Herein, small size PEG-EuOF:(153)Sm nanocrystals (~5 nm) (PEG = poly(ethylene glycol)bis(carboxymethyl)ether) combined with the radioactive and X-ray absorption properties were synthesized. The distribution of the PEG-EuOF nanocrystals in living animals was studied by ex vivo radioassay, inductively coupled plasma-atomic emission spectrum (ICP-AES) analysis and in vivo SPECT imaging, which indicated that the small size PEG-EuOF:(153)Sm had long blood retention time (blood half-life (t1/2) reach to 4.65 h) and were eliminated significantly through biliary/gastrointestinal pathway in vivo. Meanwhile, benefiting from the high attenuation ability of Eu, the small size PEG-EuOF was successfully applied for lymph node CT imaging, extending the bio-applications of these small nanocrystals. The results of cytotoxicity and in vivo toxicity also showed that the PEG-EuOF nanocrystals have relatively low toxicity, which suggest their safety for in vivo imaging. The studies provide preliminary validation for the use of PEG-EuOF nanocrystals for in vivo bioimaging applications. PMID- 24630095 TI - Oral topical decontamination for preventing ventilator-associated pneumonia: a systematic review and meta-analysis of randomized controlled trials--authors' response. PMID- 24630096 TI - Insertion site care of central venous catheters: are guidelines clear enough? PMID- 24630097 TI - Response to Watkins and Hutchinson. PMID- 24630098 TI - Actin filament dynamics using microfluidics. AB - We describe how combining microfluidics with TIRF and epifluorescence microscopy can greatly facilitate the quantitative analysis of actin assembly dynamics and its regulation, as well as the exploration of issues that were often out of reach with standard single-filament microscopy, such as the kinetics of processes linked to actin self-assembly or the kinetics of interaction with regulators. We also show how the viscous drag force exerted by fluid flowing on the filaments can be calibrated in order to assess the mechanosensitivity of end-binding protein machineries such as formins or adhesion proteins. We also discuss how microfluidics, in conjunction with other techniques, could be used to address the mechanism of coordination between heterogeneous populations of filaments, or the behavior of individual filaments during regulated treadmilling. These techniques also can be applied to study the assembly and regulation of other cytoskeletal polymers such as microtubules, septins, intermediate filaments, as well as the transport of cargoes by molecular motors under a flow-produced load. PMID- 24630099 TI - Bacterial actin-like proteins: purification and characterization of self-assembly properties. AB - The sequence, structure, and assembly dynamics of eukaryotic actins are conserved across phyla. In contrast, actin-like proteins (ALPs) from eubacteria share little sequence homology, form polymers with different architectures, and assemble with different kinetics. The structural and functional diversity of the bacterial ALPs appears to arise from their (i) high degree of functional specialization and (ii) small number of regulatory factors. To understand the molecular mechanism by which a given ALP carries out its biological function, we must, therefore, understand its unique architecture and assembly dynamics. In this chapter, we provide a basic toolbox for studying the self-assembly of uncharacterized ALPs, including methods for characterizing the architecture and stability of polymers, specifying the mechanism of their nucleation, and measuring their rate of growth. Determining these basic properties provides a stable base for more complex reconstitutions of biological function. PMID- 24630100 TI - Quantitative analysis of microtubule self-assembly kinetics and tip structure. AB - Microtubules are dynamic polymers of the cytoskeleton, which play important roles in cell division, polarization, and intracellular transport. Self-assembly of microtubule polymer from alphabeta-tubulin heterodimers is highly variable, with stochastic switching between alternate states of net growth and net shortening, a phenomenon known as dynamic instability. Microtubule tip structures are also variable and directly influence the kinetics of assembly and vice versa. TipTracker, a semiautomated, image processing-based tool, permits high spatial and temporal resolution measurements from fluorescence microscopy images (~10-40 nm, or 1-5 dimer lengths, at 1-10 Hz) with simultaneous tip structure estimation. We provide a walkthrough of the TipTracker code to demonstrate methods used to (1) fit the coordinates of the microtubule backbone; (2) track microtubule tip position; and (3) estimate tip structure from the spatial decay of the tip fluorescence distribution, discuss possible sources of error, and include an example protocol for nanometer-scale tip tracking in living cells. Additionally, we evaluate TipTracker's accuracy on simulated digital images and fixed microtubules to estimate accuracy under realistic imaging conditions. In summary, this chapter demonstrates the use of TipTracker in making robust, high-resolution measurements of microtubule tip dynamics and structures, facilitating quantitative investigations into nanoscale/molecular control of microtubule assembly. Although our primary focus is on microtubules, these methods are, in principle, suitable for other polymer structures, such as F-actin. PMID- 24630102 TI - Rotational movement of formins evaluated by using single-molecule fluorescence polarization. AB - Formin homology proteins (formins) are responsible for the formation of actin structures such as actin stress fibers, actin cables, and cytokinetic contractile rings. Formins are the major actin filament (F-actin) nucleators in the cell. Because formins remain bound to the barbed end after nucleating an actin filament, it was expected that formins might rotate along the double-helical structure of F-actin during processive actin elongation (helical rotation). Here, we describe a method to detect the rotational movement of F-actin elongating from immobilized formins using single-molecule fluorescence polarization (FLP). Tetramethylrhodamine (TMR) attached to Cys-374 of actin emits polarized fluorescence at ~45 degrees with respect to the filament axis. When the TMR labeled F-actin laying at 45 degrees in the visual field rotates, the vertical- and horizontal-polarized fluorescence (FLV and FLH, respectively) of TMR alternately become bright. This technique allowed us to demonstrate the helical rotation of mDia1, a mammalian formin. Adenosine triphosphate (ATP) hydrolysis in actin subunits is not required for helical rotation; however, ATP appears to contribute to accelerating actin elongation by mDia1. When helical rotation is limited by trapping both mDia1 and the pointed-end side, the processive filament elongation is blocked. Thus, mDia1 faithfully rotates along the long-pitch helix of F-actin. In this chapter, we introduce the theoretical concept of single molecule FLP, the optical setup, the preparation of adenosine diphosphate-bound actin, and the procedure to observe the rotational movement of F-actin elongating from immobilized formins. PMID- 24630101 TI - Biochemical reconstitution of the WAVE regulatory complex. AB - The WAVE regulatory complex (WRC) is a 400-kDa heteropentameric protein assembly that plays a central role in controlling actin cytoskeletal dynamics in many cellular processes. The WRC acts by integrating diverse cellular cues and stimulating the actin nucleating activity of the Arp2/3 complex at membranes. Biochemical and biophysical studies of the underlying mechanisms of these processes require large amounts of purified WRC. Recent success in recombinant expression, reconstitution, purification, and crystallization of the WRC has greatly advanced our understanding of the inhibition, activation, and membrane recruitment mechanisms of this complex. But many important questions remain to be answered. Here, we summarize and update the methods developed in our laboratory, which allow reliable and flexible production of tens of milligrams of recombinant WRC of crystallographic quality, sufficient for many biochemical and structural studies. PMID- 24630104 TI - Assaying microtubule nucleation by the gamma-tubulin ring complex. AB - Microtubule organization by microtubule-organizing centers such as the centrosome requires gamma-tubulin, which exists in the gamma-tubulin ring complex (gammaTuRC) that nucleates microtubules. The gammaTuRC is a ring-shaped, macromolecular complex whose core components are gamma-tubulin and the gamma tubulin complex proteins. Despite the recent identification of additional gammaTuRC components, the molecular composition and regulatory properties of the complex remain poorly understood. The ability to purify the gammaTuRC at a large scale for characterization may hold a key to understanding the mechanism by which the gammaTuRC nucleates microtubules. In this chapter, we describe methods to isolate the gammaTuRC from human cell cultures and to perform assays on the purified gammaTuRC. PMID- 24630103 TI - Single-molecule studies of actin assembly and disassembly factors. AB - The actin cytoskeleton is very dynamic and highly regulated by multiple associated proteins in vivo. Understanding how this system of proteins functions in the processes of actin network assembly and disassembly requires methods to dissect the mechanisms of activity of individual factors and of multiple factors acting in concert. The advent of single-filament and single-molecule fluorescence imaging methods has provided a powerful new approach to discovering actin regulatory activities and obtaining direct, quantitative insights into the pathways of molecular interactions that regulate actin network architecture and dynamics. Here we describe techniques for acquisition and analysis of single molecule data, applied to the novel challenges of studying the filament assembly and disassembly activities of actin-associated proteins in vitro. We discuss the advantages of single-molecule analysis in directly visualizing the order of molecular events, measuring the kinetic rates of filament binding and dissociation, and studying the coordination among multiple factors. The methods described here complement traditional biochemical approaches in elucidating actin regulatory mechanisms in reconstituted filamentous networks. PMID- 24630105 TI - Reconstituting dynamic microtubule polymerization regulation by TOG domain proteins. AB - Microtubules (MTs) polymerize from soluble alphabeta-tubulin and undergo rapid dynamic transitions to depolymerization at their ends. Microtubule-associated regulator proteins modulate polymerization dynamics in vivo by altering microtubule plus end conformations or influencing alphabeta-tubulin incorporation rates. Biochemical reconstitution of dynamic MT polymerization can be visualized with total internal reflection fluorescence (TIRF) microscopy using purified MT regulators. This approach has provided extensive details on the regulation of microtubule dynamics. Here, I describe a general approach to reconstitute MT dynamic polymerization with TOG domain microtubule regulators from the XMAP215/Dis1 and CLASP families using TIRF microscopy. TIRF imaging strategies require nucleation of microtubule polymerization from surface-attached, stabilized MTs. The approaches described here can be used to study the mechanism of a wide variety of microtubule regulatory proteins. PMID- 24630106 TI - Generation of differentially modified microtubules using in vitro enzymatic approaches. AB - Tubulin, the building block of microtubules, is subject to chemically diverse and evolutionarily conserved post-translational modifications that mark microtubules for specific functions in the cell. Here we describe in vitro methods for generating homogenous acetylated, glutamylated, or tyrosinated tubulin and microtubules using recombinantly expressed and purified modification enzymes. The generation of differentially modified microtubules now enables a mechanistic dissection of the effects of tubulin post-translational modifications on the dynamics and mechanical properties of microtubules as well as the behavior of motors and microtubule-associated proteins. PMID- 24630107 TI - Engineering defined motor ensembles with DNA origami. AB - Many cytoskeletal motors function in groups to coordinate the spatial and temporal positioning of cellular cargo. While methods to study the biophysical properties of single motors are well established, methods to understand how multiple motors work synergistically or antagonistically are less well developed. Here, we describe a three-dimensional synthetic cargo structure made using DNA origami, which can be used to template defined numbers and types of cytoskeletal motors with programmable geometries and spacing. We describe methods for building the DNA origami structure, covalently attaching motors to DNA, forming the motor DNA origami structure complex, and single-molecule assays to examine the motile properties of motor ensembles. PMID- 24630108 TI - Construction and analyses of elastically coupled multiple-motor systems. AB - Precision analyses of the collective motor behaviors have become important to dissecting mechanisms underlying the trafficking of subcellular commodities in eukaryotic cells. Here, we describe a synthetic approach to create structurally defined multiple protein complexes containing two elastically coupled motor molecules. Motors are connected using a simple DNA-scaffolding molecule and DNA conjugated, artificial protein polymers that function as tunable elastic linkers. The procedure to self-assemble these components produces complexes in high synthetic yield and allows individual multiple-motor systems to be interrogated at the single-complex level. Methods to evaluate cooperative motor responses in a static optical trap are also discussed. While enabling the average transport properties of single/noninteracting and coupled motors to be compared, these procedures can provide insight into the extent to which motors cooperate productively via load sharing as well as the roles loading-rate-dependent phenomena play in collective motor functions. PMID- 24630109 TI - Reconstitution of cortical Dynein function. AB - Cytoplasmic dynein is a major microtubule (MT)-associated motor in nearly all eukaryotic cells. A subpopulation of dyneins associates with the cell cortex and the interaction of this cortical dynein with MTs helps to drive processes such as nuclear migration, mitotic spindle orientation, and cytoskeletal reorientation during wound healing. In this chapter, we describe three types of assays in which interactions between cortical dynein and MTs are reconstituted in vitro at increasing levels of complexity. In the first 1D assay, MTs, nucleated from a centrosome attached to a surface, grow against dynein-coated gold barriers. In this assay configuration, the interactions between MTs and dynein attached to a barrier can be studied in great detail. In the second and third assays, a freely moving dynamic aster is placed in either a 2D microfabricated chamber or a 3D water-in-oil emulsion droplet, with dynein-coated boundaries. These assays can be used to study how cortical dynein positions centrosomes. Finally, we discuss future possibilities for increasing the complexity of these reconstituted systems. PMID- 24630110 TI - Reconstitution of microtubule-dependent organelle transport. AB - Microtubule (MT)-based motor proteins transport many cellular factors to their functionally relevant locations within cells, and defects in transport are linked to human disease. Understanding the mechanism and regulation of this transport process in living cells is difficult because of the complex in vivo environment and limited means to manipulate the system. On the other hand, in vitro motility assays using purified motors attached to beads does not recapitulate the full complexity of cargo transport in vivo. Assaying motility of organelles in cell extracts is therefore attractive, as natural cargoes are being examined, but in an environment that is more amenable to manipulation. Here, we describe the purification and in vitro MT-based motility of phagosomes from Dictyostelium and lipid droplets from rat liver. These assays have the potential to address diverse questions related to endosome/phagosome maturation, fatty acid regulation, and could also serve as a starting point for reconstituting the motility of other types of organelles. PMID- 24630111 TI - Reconstituting the motility of isolated intracellular cargoes. AB - Kinesin, dynein, and myosin transport intracellular cargoes including organelles, membrane-bound vesicles, and mRNA along the cytoskeleton. These motor proteins work collectively in teams to transport cargoes over long distances and navigate around obstacles in the cell. In addition, several types of motors often interact on the same cargo to allow bidirectional transport and switching between the actin and microtubule networks. To examine transport of native cargoes in a simplified in vitro system, techniques have been developed to isolate endogenous cargoes and reconstitute their motility. Isolated cargoes can be tracked and manipulated with high precision using total internal reflection fluorescence microscopy and optical trapping. Through use of native cargoes, we can examine vesicular transport in a minimal system while retaining endogenous motor stoichiometry and the biochemical and mechanical characteristics of both motor and cargo. PMID- 24630113 TI - Directed actin assembly and motility. AB - The actin cytoskeleton is a key component of the cellular architecture. However, understanding actin organization and dynamics in vivo is a complex challenge. Reconstitution of actin structures in vitro, in simplified media, allows one to pinpoint the cellular biochemical components and their molecular interactions underlying the architecture and dynamics of the actin network. Previously, little was known about the extent to which geometrical constraints influence the dynamic ultrastructure of these networks. Therefore, in order to study the balance between biochemical and geometrical control of complex actin organization, we used the innovative methodologies of UV and laser patterning to design a wide repertoire of nucleation geometries from which we assembled branched actin networks. Using these methods, we were able to reconstitute complex actin network organizations, closely related to cellular architecture, to precisely direct and control their 3D connections. This methodology mimics the actin networks encountered in cells and can serve in the fabrication of innovative bioinspired systems. PMID- 24630112 TI - Reconstitution of contractile actomyosin arrays. AB - Networks and bundles comprised of F-actin and myosin II generate contractile forces used to drive morphogenic processes in both muscle and nonmuscle cells. To elucidate the minimal requirements for contractility and the mechanisms underlying their contractility, model systems reconstituted from a known set of purified proteins in vitro are needed. Here, we describe two experimental protocols our lab has developed to reconstitute 1D bundles and quasi-2D networks of actomyosin that are amenable to quantitative biophysical measurement. These assays have enabled our discovery of the mechanisms of contractility in disordered actomyosin assemblies and of a mechanical feedback between contraction and F-actin severing. PMID- 24630114 TI - In vitro reconstitution of dynamic microtubules interacting with actin filament networks. AB - Interactions between microtubules and actin filaments (F-actin) are essential for eukaryotic cell migration, polarization, growth, and division. Although the importance of these interactions has been long recognized, the inherent complexity of the cell interior hampers a detailed mechanistic study of how these two cytoskeletal systems influence each other. In this chapter, we show how in vitro reconstitution can be employed to study how actin filaments and dynamic microtubules affect each other's organization. While we focus here on the effect of steric interactions, these assays provide an ideal starting point to develop more complex studies through the addition of known F-actin-microtubule cross linkers, or myosin II motors. PMID- 24630115 TI - Measuring kinetochore-microtubule interaction in vitro. AB - Many proteins and protein complexes perform sophisticated, regulated functions in vivo. Many of these functions can be recapitulated using in vitro reconstitution, which serves as a means to establish unambiguous cause-effect relationships, for example, between a protein and its phosphorylating kinase. Here, we describe a protocol to purify kinetochores, the protein complexes that attach chromosomes to microtubules during mitosis, and quantitatively assay their microtubule-binding characteristics. Our assays, based on DIC imaging and laser trapping microscopy, are used to measure the attachment of microtubules to kinetochores and the load bearing capabilities of those attachments. These assays provide a platform for studying kinase disruption of kinetochore-microtubule attachments, which is believed to be critical for correcting erroneous kinetochore-spindle attachments and thereby avoiding chromosome missegregation. The principles of our approach should be extensible to studies of a wide range of force-bearing interactions in biology. PMID- 24630117 TI - WAVE regulatory complex activation. AB - The WAVE regulatory complex (WRC) is critical to control of actin polymerization at the eukaryotic cell membrane. By reconstituting WAVE-dependent actin assembly on silica microspheres coated with phospholipid bilayers in mammalian brain extracts, we discovered that membrane recruitment and activation of WRC require the cooperative action of two mammalian GTPases, Arf and Rac. Here, we describe detailed methods to generate phospholipid-coated microspheres and porcine brain extract and outline conditions necessary to reconstitute WRC-dependent motility. In addition, we describe how to generate acylated recombinant GTPases, anchor them to lipid-coated microspheres, and reconstitute GTPase activation of WRC. PMID- 24630116 TI - Micropattern-guided assembly of overlapping pairs of dynamic microtubules. AB - Interactions between antiparallel microtubules are essential for the organization of spindles in dividing cells. The ability to form immobilized antiparallel microtubule pairs in vitro, combined with the ability to image them via TIRF microscopy, permits detailed biochemical characterization of microtubule cross linking proteins and their effects on microtubule dynamics. Here, we describe methods for chemical micropatterning of microtubule seeds on glass surfaces in configurations that specifically promote the formation of antiparallel microtubule overlaps in vitro. We demonstrate that this assay is especially well suited for reconstitution of minimal midzone overlaps stabilized by the antiparallel microtubule cross-linking protein PRC1 and its binding partners. The micropatterning method is suitable for use with a broad range of proteins, and the assay is generally applicable to any microtubule cross-linking protein. PMID- 24630118 TI - Dissecting principles governing actin assembly using yeast extracts. AB - In this chapter, we describe recent protocols that we have developed to trigger actin assembly and actin-based motility in yeast cell extracts. Our method allows for the fast preparation of yeast extracts that are competent in dynamic assembly of distinct actin filament structures of biologically appropriate protein composition. Compared to previous extract-based systems using other eukaryotic cell types, yeast provides a unique advantage for combining reconstituted assays with the preparation of extracts from genetically modified yeast strains. We present a global strategy for dissecting the functions of individual proteins, where the activities of the proteins are analyzed in systems of variable complexity, ranging from simple mixtures of pure proteins to the full complexity of a cell's cytoplasm. PMID- 24630119 TI - Xenopus egg cytoplasm with intact actin. AB - We report optimized methods for preparing Xenopus egg extracts without cytochalasin D, that we term "actin-intact egg extract." These are undiluted egg cytoplasm that contains abundant organelles, and glycogen which supplies energy, and represents the least perturbed cell-free cytoplasm preparation we know of. We used this system to probe cell cycle regulation of actin and myosin-II dynamics (Field et al., 2011), and to reconstitute the large, interphase asters that organize early Xenopus embryos (Mitchison et al., 2012; Wuhr, Tan, Parker, Detrich, & Mitchison, 2010). Actin-intact Xenopus egg extracts are useful for analysis of actin dynamics, and interaction of actin with other cytoplasmic systems, in a cell-free system that closely mimics egg physiology, and more generally for probing the biochemistry and biophysics of the egg, zygote, and early embryo. Detailed protocols are provided along with assays used to check cell cycle state and tips for handling and storing undiluted egg extracts. PMID- 24630120 TI - Glycogen-supplemented mitotic cytosol for analyzing Xenopus egg microtubule organization. AB - Undiluted cytoplasmic extract prepared from unfertilized Xenopus laevis eggs by low-speed centrifugation (CSF extracts) is useful for reconstitution of egg microtubule dynamics and meiosis-II spindle organization, but it suffers limitations for biochemical analysis due to abundant particulates. Here, we describe preparation and the use of fully clarified, undiluted mitotic cytosol derived from CSF extract. Addition of glycogen improves the ability of this cytosol to reconstitute microtubule organization, in part through improved energy metabolism. Using fully clarified, glycogen-supplemented mitotic cytosol, we reconstituted (i) stimulation of microtubule polymerization by Ran.GTP (Groen, Coughlin, & Mitchison, 2011; Ohba, Nakamura, Nishitani, & Nishimoto, 1999) and (ii) self-organization of highly regular bipolar arrays of taxol-stabilized microtubules that we termed "pineapples" (Mitchison, Nguyen, Coughlin, & Groen, 2013). Both systems will be useful for biochemical dissection of spindle assembly mechanisms. We also describe reliable small-scale methods for preparing fluorescent antibody probes that can be used for live imaging in egg extract systems as well as standard immunofluorescence. PMID- 24630121 TI - Spindle assembly on immobilized chromatin micropatterns. AB - We describe a method to assemble meiotic spindles on immobilized micropatterns of chromatin built on a first layer of biotinylated BSA deposited by microcontact printing. Such chromatin patterns routinely produce bipolar spindles with a yield of 60%, and offer the possibility to follow spindle assembly dynamics, from the onset of nucleation to the establishment of a quasi steady state. Hundreds of spindles can be recorded in parallel for different experimental conditions. We also describe the semi-automated image analysis pipeline, which is used to analyze the assembly kinetics of spindle arrays, or the final morphological diversity of the spindles. PMID- 24630122 TI - Preface: the role of reconstitution in cytoskeleton research. PMID- 24630123 TI - The critical corner of cam femoroacetabular impingement: clinical support of an emerging concept. AB - PURPOSE: The purpose of this study was to evaluate the concept of cam femoroacetabular impingement (FAI) occurring medial to the classic anterolateral (AL) quadrant. METHODS: Forty-four patients met the inclusion criteria of cam FAI and underwent arthroscopic AL femoroplasty. Goniometric measurements of intraoperative hip internal rotation (HIR) in 90 degrees of hip flexion and 0 degrees of adduction were obtained. Thirty patients (14 male and 16 female), comprising the substance of this study, exhibited HIR of less than 40 degrees after AL femoroplasty and underwent further anteromedial (AM) femoroplasty with subsequent repeat measurement of HIR. Nonparametric statistical analysis was performed. RESULTS: Preoperative HIR averaged 20.8 degrees (range, 10 degrees to 29 degrees ); intraoperative HIR averaged 29.5 degrees (range, 18 degrees to 39 degrees ) after AL femoroplasty and 42.7 degrees (range, 32 degrees to 61 degrees ) after additional AM femoroplasty. The gain in HIR after AL femoroplasty was 8.7 degrees (range, 2 degrees to 23 degrees ) (P < .0001). The further gain in HIR after AM femoroplasty was 13.2 degrees (range, 2 degrees to 22 degrees ) (P < .0001). The overall gain in HIR after AL and AM femoroplasty was 21.9 degrees (range, 13 degrees to 38 degrees ) (P < .0001). A consistent landmark termed the resident's ridge of the hip accompanied all cases of AM cam impingement. CONCLUSIONS: Femoroplasty of the AM "critical corner" may improve cam decompression and supports the concept of cam impingement extending beyond the classic AL quadrant of the proximal femur. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24630124 TI - Preoperative diagnosis of pathologic conditions of the ligamentum teres: is MRI a valuable imaging modality? AB - PURPOSE: The purpose of this study was to determine the accuracy of 3-Tesla magnetic resonance imaging (MRI) in detecting ligamentum teres (LT) lesions in patients before they undergo hip arthroscopy for the treatment of femoroacetabular impingement. METHODS: From 2010 to 2011, data were prospectively collected on all patients presenting for treatment of hip pain. All patients underwent MRI followed by arthroscopic surgery. A radiologist prospectively documented MRI findings, and the surgeon recorded the findings at arthroscopy. Radiologic and surgical data included classification of the LT as not torn, hypertrophic, partially torn, or completely torn. All MR images were read by a single radiologist, and all surgery was performed by a single surgeon. Arthroscopy was considered the diagnostic gold standard. RESULTS: One hundred forty-two patients with a mean patient age of 35 years (range, 19 to 73 years) met the inclusion criteria. Only one complete LT tear was found in the study. The accuracy of MRI for the diagnosis of LT partial tears was 64%. The sensitivity and specificity of MRI for diagnosing partial tears of the LT were 9% and 91%, [corrected] respectively. The positive predictive value and negative predictive value were 31% and 67%, [corrected] respectively. The sensitivity and specificity of MRI for diagnosing hypertrophic LT were 32% and 78%, respectively. CONCLUSIONS: In this patient population, MRI demonstrated sensitivity and specificity of 34% and 50%, [corrected] respectively, in identifying any pathologic process of the LT. MRI is capable of ruling out [corrected] partial tears of the LT with high sensitivity (91%) and negative [corrected] predictive value (67%). LEVEL OF EVIDENCE: Level II, development of diagnostic criteria on basis of consecutive patients with universally applied gold standard. PMID- 24630125 TI - Follistatin is essential for normal postnatal development and function of mouse oviduct and uterus. AB - Female mice lacking the follistatin gene but expressing a human follistatin-315 transgene (tghFST315) have reproductive abnormalities (reduced follicles, no corpora lutea and ovarian-uterine inflammation). We hypothesised that the absence of follistatin-288 causes the abnormal reproductive tract via both developmental abnormalities and abnormal ovarian activity. We characterised the morphology of oviducts and uteri in wild type (WT), tghFST315 and follistatin-knockout mice expressing human follistatin-288 (tghFST288). The oviducts and uteri were examined in postnatal Day-0 and adult mice (WT and tghFST315 only) using histology and immunohistochemistry. Adult WT and tghFST315 mice were ovariectomised and treated with vehicle, oestradiol-17beta (100ng injection, dissection 24h later) or progesterone (1mg*three daily injections, dissection 24h later). No differences were observed in the oviducts or uteri at birth, but abnormalities developed by adulthood. Oviducts of tghFST315 mice failed to coil, the myometrium was disorganised, endometrial gland number was reduced and oviducts and uteri contained abundant leukocytes. After ovariectomy, tghFST315 mice had altered uterine cell proliferation, and inflammation was maintained and exacerbated by oestrogen. These studies show that follistatin is crucial to postnatal oviductal-uterine development and function. Further studies differentiating the role of ovarian versus oviductal-uterine follistatin in reproductive tract function at different developmental stages are warranted. PMID- 24630126 TI - Recurrence of adult granulosa cell tumor of the ovary: experience at a tertiary care center. AB - Adult granulosa cell tumor (AGCT) is the most common ovarian sex cord stromal tumor with a favorable prognosis. However, a subset of patients develop recurrence. We retrieved and reviewed 156 cases of AGCT reported between 1992 and 2012. The ages ranged from 20 to 84 years (mean, 48 years). The size of the tumor ranged from 0.8 to 25 cm (mean, 10 cm). Histologically, all tumors were composed of round or polygonal cells with indented or grooved nuclei, eosinophilic cytoplasm, and well defined cell borders. A diffuse pattern was seen in the majority followed by microfollicular, trabecular and macrofollicular. The mitotic figures ranged from 2 to a maximum of 21/10 HPFs. Focal necrosis were seen in 17 cases. Associated simple hyperplasia of endometrium was seen in 9 cases, complex hyperplasia in 2, and endometrioid adenocarcinoma of the endometrium in 3 cases. Recurrence was seen in 8 cases with a follow-up of 2 to 19 years (mean, 6 years). The recurrent tumors were mostly >5 cm and sites included the same adnexal site and contralateral ovary, omentum, mesentery of small bowel, abdominal wall, uterine and fallopian tube serosa, lymph nodes, pelvis, and appendix. Histologically, recurrent tumors exhibited a diffuse histologic pattern and a mitotic count of 6.8 as compared to 3.3 in primary tumors. In conclusion, a tumor size of >5 cm and a diffuse histologic pattern were associated with increased recurrence risk. The recurrent tumors hadz increased mitotic figures compared with primary tumors. Appendix, a very rare site of recurrence was seen in one of our cases. PMID- 24630127 TI - EMAS position statement: Menopause for medical students. PMID- 24630128 TI - Pelvic floor dysfunction: does hormone deficiency matter? PMID- 24630129 TI - Non-contraceptive benefits of hormonal contraceptive use during perimenopause? PMID- 24630131 TI - Deleterious effect of smoking on ischemic stroke outcomes: implications for the role of chronic inflammation on atherosclerotic plaque pathogenesis. PMID- 24630132 TI - Atherosclerosis unplugged: potential mechanisms leading to the clinical manifestation of stroke caused by cigarette smoking. PMID- 24630133 TI - Diagnostic workup of primary sclerosing cholangitis: the benefit of adding gadoxetic acid-enhanced T1-weighted magnetic resonance cholangiography to conventional T2-weighted magnetic resonance cholangiography. AB - AIM: To evaluate the value of gadoxetic acid-enhanced T1-weighted (T1W) magnetic resonance cholangiography (MRC) versus conventional T2-weighted (T2W) MRC compared to endoscopic retrograde cholangiopancreatography (ERCP) in patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: Based on T1W MRC, PSC patients were classified into a regular (RG) and a delayed (DG) excreting group, with an absence of gadoxetic acid in the common bile duct at 20 min. Beading, pruning, and gradation of central bile duct stenosis, evaluated by T1W and T2W MRC, were compared to ERCP. Liver parenchymal enhancement was measured in both study groups and compared to a reference group (n = 20) without a history of liver disease. Two readers performed all measurements. RESULTS: Based on beading and pruning of the peripheral bile ducts, sensitivities, specificities, and accuracies for reader 1 were 0.17/0.43, 0/0.17, and 0.15/0.31 for T1W MRC, and 0.83/0.86, 1/0.83, and 0.85/0.85 for T2W MRC (p = 0.004). For reader 2 sensitivities, specificities, and accuracies were 0.25/0.57, 0/0.33, and 0.23/0.46 for T1W MRC, and 0.92/1, 1/0.83, and 0.92/0.92 for T2W MRC (p = 0.012). Compared to ERCP, central bile duct stenoses were significantly overestimated (p < 0.001) by T2W MRC. A significantly lower parenchymal enhancement was found in the DG (n = 7) compared to the RG (n = 13), and compared to the reference group (p < 0.001). CONCLUSION: The combined performance of T2W and T1W MRC may provide a comprehensive imaging workup of PSC, including morphological and functional information resulting in optimal management. PMID- 24630134 TI - Chest CT findings of toxocariasis: correlation with laboratory results. AB - AIM: To assess the relationship between chest computed tomography (CT) findings of patients with toxocariasis and levels of serological markers. MATERIALS AND METHODS: A total of 38 cases of patients diagnosed with toxocariasis by enzyme linked immunosorbent assay (ELISA), CT, and serological markers were retrospectively reviewed. The presence of nodule with or without ground-glass opacity (GGO) halo, consolidation, focal GGO, pleural effusion, and lymphadenopathy at chest CT were evaluated. Statistical analysis was performed with the Fisher's exact test. RESULTS: The most common chest CT findings were nodule (n = 12, 31.6%) and focal GGO (n = 12, 31.6%). In patients with normal eosinophil levels, focal GGO (n = 9, 37.5%) was the most common finding. In contrast, nodule with a GGO halo (n = 7, 50%) was the most common finding in the eosinophilia group. Nodule with a GGO halo was more common in the eosinophilia group, with a statistically significant difference (p = 0.017). Nodule was more common in the eosinophilia group, and focal GGO was more common in the normal eosinophil group. CONCLUSION: The most common chest CT findings in toxocariasis were nodule with or without GGO halo, and focal GGO. In the eosinophilia group, nodule with a GGO halo was significantly more frequent. Other CT findings did not show a statistically significant relationship with serological markers. PMID- 24630136 TI - Sulcogyral pattern and sulcal count of the orbitofrontal cortex in individuals at ultra high risk for psychosis. AB - Three types of orbitofrontal cortex (OFC) sulcogyral patterns have been identified in the general population. The distribution of these three types has been found to be altered in individuals at genetic risk of psychosis, and in patients with first episode psychosis (FEP) and chronic schizophrenia. This study aims at establishing whether altered OFC sulcogyral patterns were present in a large cohort of individuals at ultra high risk (UHR) for psychosis. OFC pattern type was classified and the number of posterior and intermediate sulci present on the surface of the OFC was counted. OFC sulcogyral type and the number of sulci were compared between controls (n=58) and UHR participants who transitioned (n=49) versus those who did not transition (n=77) to psychosis. Finally, the relationship between sulcogyral type and number of sulci with intellectual quotient (IQ), symptom severity and social functioning of UHR individuals was explored. In line with other studies conducted in chronic schizophrenia and FEP, UHR individuals who later transitioned to psychosis showed a reduced incidence of the Type I OFC on the right hemisphere compared to controls (chi(2)=19.847, p<0.001). These highly consistent results point towards the protective effect of possessing a Type I OFC in the right hemisphere. Furthermore, OFC sulcus counts revealed that controls presented with a higher number of posterior (right hemisphere; chi(2)=11.658, p=0.003) and intermediate sulci (left: chi(2)=6.643, p=0.036; right: chi(2)=11.726, p=0.020) when compared to UHR individuals. However, no associations between OFC types or sulcus count and IQ, symptoms and functioning were observed. PMID- 24630138 TI - Collaborative/therapeutic assessment for early psychosis. PMID- 24630137 TI - Re: Caution urged in interpreting a negative study of cannabis use and schizophrenia: a response to Dr. Christine Miller. PMID- 24630139 TI - The CSMD1 genome-wide associated schizophrenia risk variant rs10503253 affects general cognitive ability and executive function in healthy males. AB - BACKGROUND: The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, has reached genome wide support as a risk factor for schizophrenia. There is initial but inconclusive evidence for a role of this variant in aspects of cognition. METHODS: We investigated the neurocognitive effects of the CSMD1 rs10503253 (C/A) polymorphism in a large, demographically homogeneous sample of young, healthy Greek Caucasian males (n=1149) phenotyped for a wide range of neuropsychological measures, most of which have been shown to be reliable endophenotypes for schizophrenia. RESULTS: The risk 'A' allele was associated with poorer performance on measures of general cognitive ability, strategy formation, spatial and visual working memory, set shifting, target detection and planning for problem solving but not for emotional decision making. Most of these effects were dependent on risk "A" allele dose, with AA and CC homozygotes being the worse and the best respectively, while CA individuals were intermediate. Potential genotype effects in Stroop and verbal memory performance were also suggested by our dataset. DISCUSSION: These results underline the relevance of the risk "A" allele to neurocognitive functioning and suggest that its detrimental effects on cognition, may be part of the mechanism by which the CSMD1 mediates risk for schizophrenia. PMID- 24630140 TI - Abbreviated quality of life scales for schizophrenia: comparison and utility of two brief community functioning measures. AB - BACKGROUND: The Heinrichs-Carpenter Quality of Life Scale (QLS) is the most extensively used real-world community functioning scale in schizophrenia research. However, the extensive time required to administer it and the inclusion of items that overlap conceptually with negative symptoms limit its use across studies. The present study examined the validity and utility of two abbreviated QLS measures against the full QLS excluding negative symptom items. METHOD: The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. The validity of two abbreviated QLS measures (7-item and 4 item) were examined with the full QLS, excluding the intrapsychic foundations subscale, using correlation analysis. The utility of the abbreviated measures was explored by examining associations between the functioning scales and clinical variables and longitudinal change. RESULTS: Both abbreviated QLS measures were highly predictive of the full QLS (both r=0.91, p<0.001), with no difference in predictive value between the abridged measures. Functional status was significantly associated with symptoms and cognition. Importantly, the strength of these associations was similar between the abbreviated and full QLS. Finally, multiple regression models examining the explanatory power of amotivation/apathy in predicting functioning scores after other symptoms and neurocognition had been accounted for were essentially identical irrespective of the QLS instrument used as the dependent measure. Longitudinal change was also similar across the three scales. CONCLUSIONS: The 7-item abbreviated QLS is recommended as a brief measure of community functioning for individuals with schizophrenia, especially when assessment of functional outcome is not the focus. PMID- 24630141 TI - Birth brachial plexus palsy caused by cervical rib. PMID- 24630142 TI - Effects of active pharmaceutical ingredients mixtures in mussel Mytilus galloprovincialis. AB - Active pharmaceutical ingredients (APIs) are emergent environmental contaminants widely detected in surface waters as result of incomplete waste water treatment plant (WWTP) removal processes and improper disposal. The assessment of potential effects of APIs on non-target organisms is still scarce since besides presenting multiple chemical structures, properties and modes of action, these compounds occur as complex mixtures. This study comprises a 15-day exposure of mussels Mytilus galloprovincialis to mixtures (at environmentally relevant nominal concentrations) of non-steroidal inflammatory drugs ibuprofen (IBU) and diclofenac (DCF) (250 ng L(-1) each) and selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) (75 ng L(-1)) (MIX 1) along with the addition of classical pro-oxidant copper (Cu) (5 MUg L(-1)) (MIX 2). The goals included the assessment of oxidative stress, neurotoxic and endocrine effects on this sentinel species applying both a multibiomarker and gene expression (here and later gene expression is taken as synonym to gene transcription, although it is acknowledged that it is also affected by, e.g. translation, and mRNA and protein stability) analysis approaches. The results revealed a swifter antioxidant response in digestive glands than in gills induced by MIX 1, nevertheless the presence of Cu in MIX 2 promoted a higher lipid peroxidation (LPO) induction. Neither mixture altered acetylcholinesterase (AChE) activity, while both triggered the formation of vitellogenin-like proteins in females confirming the xenoestrogenic effect of mixtures. All these results varied with respect to those obtained in previous single exposure essays. Moreover, RT-PCR analysis revealed a catalase (CAT) and CYP4Y1 gene expression down- and upregulation, respectively, with no significant changes in mRNA levels of genes encoding superoxide dismutase (SOD) and glutathione-S-transferase (GST). Finally, this study highlights variable tissue and time-specific biomarker responses and gene expression alterations, which along with several interactions between each mixture component on each biomarker confirm the susceptibility of mussels to API mixtures. PMID- 24630143 TI - Manual motor-plan similarity affects lexical recall on a speech-generating device: implications for AAC users. AB - Language production via high-tech alternative/augmentative communication (AAC) devices involves use of motor sequences that are determined by the visuo-spatial characteristics of a particular device. The current study uses traditional short term memory tasks with device-based output to demonstrate that typical talkers show a trend toward device-specific modality interference in short-term device based recall. The theoretical implications of these early findings with regard to models of working memory and the clinical implications are discussed. LEARNING OUTCOMES: (1) Describe two modalities of non-phonological short-term storage, (2) List a potential effect of SGD-based output on modality of short-term word storage, (3) Describe a theoretical implication of device-based representations with regard to models of working memory, and (4) Describe a clinical application of the concept of motor memory in AAC. PMID- 24630145 TI - Oral-diadochokinesis rates across languages: English and Hebrew norms. AB - Oro-facial and speech motor control disorders represent a variety of speech and language pathologies. Early identification of such problems is important and carries clinical implications. A common and simple tool for gauging the presence and severity of speech motor control impairments is oral-diadochokinesis (oral DDK). Surprisingly, norms for adult performance are missing from the literature. The goals of this study were: (1) to establish a norm for oral-DDK rate for (young to middle-age) adult English speakers, by collecting data from the literature (five studies, N=141); (2) to investigate the possible effect of language (and culture) on oral-DDK performance, by analyzing studies conducted in other languages (five studies, N=140), alongside the English norm; and (3) to find a new norm for adult Hebrew speakers, by testing 115 speakers. We first offer an English norm with a mean of 6.2syllables/s (SD=.8), and a lower boundary of 5.4syllables/s that can be used to indicate possible abnormality. Next, we found significant differences between four tested languages (English, Portuguese, Farsi and Greek) in oral-DDK rates. Results suggest the need to set language and culture sensitive norms for the application of the oral-DDK task world-wide. Finally, we found the oral-DDK performance for adult Hebrew speakers to be 6.4syllables/s (SD=.8), not significantly different than the English norms. This implies possible phonological similarities between English and Hebrew. We further note that no gender effects were found in our study. We recommend using oral-DDK as an important tool in the speech language pathologist's arsenal. Yet, application of this task should be done carefully, comparing individual performance to a set norm within the specific language. LEARNING OUTCOMES: Readers will be able to: (1) identify the Speech-Language Pathologist assessment process using the oral-DDK task, by comparing an individual performance to the present English norm, (2) describe the impact of language on oral-DDK performance, and (3) accurately detect Hebrew speakers' patients using this tool. PMID- 24630144 TI - Emotional reactivity and regulation associated with fluent and stuttered utterances of preschool-age children who stutter. AB - PURPOSE: The purpose of this study was to assess the relation between emotional reactivity and regulation associated with fluent and stuttered utterances of preschool-age children who stutter (CWS) and those who do not (CWNS). PARTICIPANTS: Participants were eight 3 to 6-year old CWS and eight CWNS of comparable age and gender. METHODS: Participants were exposed to three emotion inducing overheard conversations--neutral, angry and happy--and produced a narrative following each overheard conversation. From audio-video recordings of these narratives, coded behavioral analysis of participants' negative and positive affect and emotion regulation associated with stuttered and fluent utterances was conducted. RESULTS: Results indicated that CWS were significantly more likely to exhibit emotion regulation attempts prior to and during their fluent utterances following the happy as compared to the negative condition, whereas CWNS displayed the opposite pattern. Within-group assessment indicated that CWS were significantly more likely to display negative emotion prior to and during their stuttered than fluent utterances, particularly following the positive overheard conversation. CONCLUSIONS: After exposure to emotional inducing overheard conversations, changes in preschool-age CWS's emotion and emotion regulatory attempts were associated with the fluency of their utterances. LEARNING OUTCOMES: After reading this article, the reader will be able to: (1) describe various measures of emotional reactivity and regulation, including parent-based reports and behavioral coding, and how they may contribute to childhood stuttering; (2) explain emotional differences between the stuttered and fluent utterances of CWS and CWNS; and (3) discuss how emotions may contribute to CWS' instances of stuttering. PMID- 24630146 TI - Observational study of intra-abdominal pressure monitoring in acute pancreatitis. AB - BACKGROUND: Intra-abdominal hypertension (IAH) is predictive of adverse outcome in critically ill patients; however, its role in acute pancreatitis is unclear, and prospective studies are lacking. We aimed to determine the overall incidence and predictive value of IAH on mortality in acute pancreatitis. METHODS: Transvesical IAP was measured on admission and every 4 hours within high dependency unit/intensive care unit. Serum biochemistry and physiologic parameters permitted calculation of Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, Imrie, and Ranson scores. The primary end point was 30-day mortality. RESULTS: A total of 218 patients with acute pancreatitis were recruited; 30-day mortality was greater in patients with IAH (IAP >=12 mmHg; 37%) than no IAH (2%; P < .001). A total of 14% of patients had IAH on admission; another 3% developed IAH in hospital. Mortality was greater in the latter group (37% vs 50%; P < .01). In the majority of cases IAH developed in line with other organ failure; however, there were several patients in whom the development of IAH appeared to be the sentinel event before rapid clinical decline. An IAP threshold of 9 mmHg had best predictive value for mortality (sensitivity 86%, specificity 87%; area under the ROC curve 0.91). This finding was comparable with other validated markers of severe pancreatitis (Imrie >=3: sensitivity 51%, specificity 70%; Acute Physiology and Chronic Health Evaluation II: sensitivity 67%, specificity 96%; C-reactive protein >150: sensitivity 89%, specificity 83%). CONCLUSION: IAP is a good predictor of mortality and organ failure in acute pancreatitis and compares favorably with other validated prognostic scores. Whether IAH is a phenomenon causative of organ failure or an epiphenomenon, occurring in conjunction with other organ dysfunction, remains unclear. PMID- 24630147 TI - A nomogram for predicting malignancy in thyroid nodules diagnosed as atypia of undetermined significance/follicular lesions of undetermined significance on fine needle aspiration. AB - BACKGROUND: We hypothesized that a nomogram constructed of clinical and imaging variables could be applied to predicting the risk of malignancy in thyroid nodules diagnosed as atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) on ultrasonographic fine-needle aspiration (US-FNA). METHODS: This retrospectively designed study included 393 thyroid nodules in 392 patients (mean age, 49 +/- 12 years), which were diagnosed as AUS/FLUS with US-FNA during the study period. Medical records, US images, and cytopathology results were reviewed and analyzed. The 393 thyroid nodules were divided into training and validation sets. Logistic regression analysis was performed to predict the probability of malignancy, and nomograms were constructed using the training set and subsequently applied to the validation set. RESULTS: Three sets of nomograms were constructed separately using clinical factors and (1) individual US features; (2) final assessment of US; and (3) the number of suspicious US features. All 3 sets of nomograms built were proven accurate and discriminative, these nomograms had an area under the receiver operating characteristic curve (AUC) of 0.817 (95% confidence interval [CI], 0.757-0.877) when using clinical factors and individual US features, an AUC of 0.769 (95% CI, 0.705-0.833) wen using final assessment, and an AUC of 0.779 (95% CI, 0.718-0.840) when using the number of suspicious US features. The AUC of each validation set was 0.754 (95% CI, 0.659-0.850), 0.757 (95% CI, 0.661-0.853), and 0.721 (95% CI, 0.621-0.820), respectively. CONCLUSION: Nomograms constructed in our study using US can be utilized in predicting the probability of malignancy in thyroid nodules diagnosed as AUS/FLUS on US-FNA, and may help in selecting patients who are at high risk for malignancy. PMID- 24630148 TI - Comment on: "video-assisted ablation of pilonidal sinus: a new minimally invasive treatment-a pilot study". PMID- 24630149 TI - Evidence compendium and advice on social distancing and other related measures for response to an influenza pandemic. AB - The role of social distancing measures in mitigating pandemic influenza is not precisely understood. To this end, we have conducted a systematised review, particularly in light of the 2009 pandemic influenza, to better inform the role of social distancing measures against pandemic influenza. Articles were identified from relevant databases and the data were synthesised to provide evidence on the role of school or work place-based interventions, case-based distancing (self-isolation, quarantine), and restriction of mobility and mass gatherings. School closure, whether proactive or reactive, appears to be moderately effective and acceptable in reducing the transmission of influenza and in delaying the peak of an epidemic but is associated with very high secondary costs. Voluntary home isolation and quarantine are also effective and acceptable measures but there is an increased risk of intra-household transmission from index cases to contacts. Work place-related interventions like work closure and home working are also modestly effective and are acceptable, but likely to be economically disruptive. Internal mobility restriction is effective only if prohibitively high (50% of travel) restrictions are applied and mass gatherings occurring within 10 days before the epidemic peak are likely to increase the risk of transmission of influenza. PMID- 24630150 TI - MRI and venographic aspects of pelvic venous insufficiency. AB - Pelvic venous insufficiency is a frequent pathology in multiparous women. Diagnosis can be made by chance or suspected in the case of symptoms suggesting pelvic congestion syndrome or atypical lower limb varicosity fed by pelvic leaks. After ultrasound confirmation, dynamic venography is the reference pretherapeutic imaging technique, searching for pelvic varicosity and possible leaks to the lower limbs. MRI is less invasive and allows a three-dimensional study of the varicosity and, with dynamic angiography, it can assess ovarian reflux. It also helps to plan or even sometimes avoid diagnostic venography. PMID- 24630151 TI - Acute intestinal ischaemia revealing a metastatic ileal endocrine tumour. PMID- 24630152 TI - Ledderhose's disease: radiologic/pathologic correlation of superficial plantar fibromatosis. PMID- 24630153 TI - Adamantinoma of the posterior tibial cortex in a child. PMID- 24630154 TI - Chemoembolization and the arcuate ligament: how to manage it? PMID- 24630155 TI - Effect of misalignment of air-coupled probes on Ao Lamb mode propagating in a metal plate. AB - Proper alignment of air-coupled ultrasonic transducers for generation and reception of Lamb waves is vital in order to acquire a high amplitude wave group. Any misalignment with either the transmitter or the receiver or both adversely influences the amplitude of a Lamb mode. This paper reports a systematic attempt to quantify the reduction in the amplitude of the fundamental anti-symmetric Lamb mode (Ao) in a metal plate caused by misalignments in air-coupled probes. Three different types of misalignments - linear, orientation and synchronised orientation were deliberately introduced in the transducers, and experiments were performed on a 6mm thick aluminium plate. Amplitudes of Ao mode measured at various configurations were normalised with that of Ao mode, captured in a reference configuration. Suitable curves fitted over the experimental data points revealed that Gaussian curves represent appropriately the variations in normalised amplitudes of Ao mode. Moreover, analytical expressions were derived to predict the difference in arrival times of Lamb mode(s) due to orientation and synchronised orientation misalignments. PMID- 24630156 TI - A case of mental nerve paresthesia due to dynamic compression of alveolar inferior nerve along an elongated styloid process. AB - Spontaneous paresthesia of the mental nerve is considered an ominous clinical sign. Mental nerve paresthesia has also been referred to as numb chin syndrome. Several potentially different factors have been investigated for their role in interfering with the inferior alveolar nerve (IAN) and causing mental nerve neuropathy. In the present case, the patient had an elongated calcified styloid process that we hypothesized had caused IAN irritation during mandibular movement. This eventually resulted in progressive loss of sensation in the mental nerve region. To our knowledge, this dynamic irritation, with complete recovery after resection of the styloid process, has not been previously reported. PMID- 24630157 TI - Antimicrobial effects of drug-containing electrospun matrices on osteomyelitis associated pathogens. AB - PURPOSE: To synthesize polydioxanone (PDS)-based drug delivery systems (hereafter referred to as "matrices") containing vancomycin (VANC) and/or rifampicin (RIF) and investigate their effect on the inhibition of biofilm growth containing osteomyelitis (OM)-associated pathogens. MATERIALS AND METHODS: PDS matrices were prepared by electrostatic spinning, and the drugs were incorporated as follows: group (G)1, 5wt%VANC; G2, 10wt%VANC; G3, 5wt%RIF; G4, 10wt%RIF; G5, 5wt%VANC+RIF; and G6, 10wt%VANC+RIF. A control group of pure PDS was also electrospun (G7). Biofilms formed by Staphylococcus aureus and S. epidermidis were grown on the electrospun matrices for 24 hours. The counts of viable cells were assessed after biofilm formation. The fiber morphology and biofilms were imaged using a scanning electron microscope. RESULTS: G5 and G6 and pure PDS (G7) had the lowest and highest mean number of viable cell counts, respectively (P < .05). Small and isolated clusters of bacteria with no mature biofilm present were found on G6. CONCLUSIONS: The results of the present study have provided evidence for the potential use of PDS-based matrices as an effective drug delivery system that could inhibit biofilm formation from OM-associated pathogens. PMID- 24630158 TI - The genetic contribution to recurrent autoimmune nephritis. AB - Glomerulonephritis is a significant cause of chronic kidney disease requiring renal replacement therapy. For patients receiving a transplant, it is known that specific primary pathologies such as membranous nephropathy, IgA nephropathy and FSGS have a high risk of recurrence in the transplant but the reasons for this are unknown and the ability to predict recurrence is poor. The recent discovery that primary MN is an autoimmune disease characterised by an autoantibody to phospholipase A2 receptor 1 and the identification of two genes, PLA2R1 and DQA1 which account for the genetic susceptibility to the disease, open up the potential to understand the mechanism of recurrent MN and therefore to design and manage therapy to prevent recurrence. Transplantation offers a unique ethical experimental context in which to explore the genetic contribution to recurrent autoimmune membranous nephropathy. By analysing the genetic changes in the kidney transplant in the context of anti-PLA2R status post transplant, it may be possible to link genetic markers, anti-PLAR regulation with recurrence and non recurrence of disease. If successful, similar strategies may help unravel mechanisms of recurrent IgA nephropathy and FSGS. PMID- 24630159 TI - Reprint of "Effects of the SSRI citalopram on behaviours connected to stress and reproduction in Endler guppy, Poecilia wingei". AB - Psychoactive drugs, such as selective serotonin reuptake inhibitors (SSRI) have been identified in high levels in effluents from Swedish sewage treatment plants (STP) at concentrations high enough to give pharmacological effects in fish. In humans SSRIs are used in the treatment of depression and they have anxiolytic effects. In the present study we exposed Endler guppy (Poecilia wingei) of both sexes to citalopram that showed the highest concentrations of SSRIs in STP effluents and studied reproductive and non-reproductive behaviour. Male courting behaviours were not affected compared to control fish after 14-28 days exposure to 1 MUgL(-1). In two experiments exposing both sexes to 0.2, 2.3 or 15 MUgL(-1) for 21 days, fish exposed to the two highest doses showed anxiolytic effects when placed in a novel environment (novel tank diving test, NT). Males were only affected by exposure to 15 MUgL(-1). They had significantly longer latency to explore the upper half of the aquarium, more visits and longer time spent in the upper half, and showed less bottom freezing behaviour, all markers of anxiolytic behaviour. In females exposure to 2.3 or 15 MUgL(-1) significantly increased freezing behaviour, while no effects on other behaviour variables were observed. No effects on shoaling behaviour could be discerned. These results show that citalopram have anxiolytic effects on guppy fish and thus affect ecologically relevant behaviours of importance to survival of fish. PMID- 24630160 TI - Three-dimensional laser scanner evaluation of facial soft tissue changes after LeFort I advancement and rhinoplasty surgery: patients with cleft lip and palate vs patients with nonclefted maxillary retrognathic dysplasia (control group). AB - OBJECTIVE: The aim of this study was to analyze the differences in facial soft tissue changes, despite the same extent of upper jaw forward movement, between patients with unilateral cleft lip and palate (uCLP) and those without, after LeFort I osteotomy and secondary rhinoplasty. STUDY DESIGN: Twelve patients with maxillary retrognathic dysplasia and nose deformity were divided in 2 groups, A (uCLP) and B (control), and compared on the basis of the same maxillary advancement. Cephalometry and 3D mean facial model of groups A and B were obtained before and after surgery. Linear and angular measurements were calculated. RESULTS: Upper vermilion and alar base remained unchanged in group A but increased in group B. In both groups, symmetry of the nasal base was improved, and an increase of the sagittal projection of the lips was observed. CONCLUSIONS: 3D analysis showed that surgical procedures for uCLP can provide a satisfactory aesthetic outcome, but some differences are evident in comparison with the control group. PMID- 24630161 TI - A bidirectional relationship of oral-systemic responses: observations of systemic host responses in patients after full-mouth extractions. AB - OBJECTIVE: This investigation tested the hypothesis that systemic inflammatory responses would be attenuated by minimizing the oral microbial burden in patients with moderate to severe periodontitis. STUDY DESIGN: Patients (n = 73) scheduled for full-mouth extractions were categorized as case type I/II (gingivitis/mild periodontitis) or case type III/IV (moderate/severe periodontitis). Serum levels of acute phase proteins (APPs) and immunoglobulin G (IgG) antibody were assessed at baseline and through 1 year after extraction. RESULTS: At baseline, the levels of multiple APPs (e.g., fibrinogen, C-reactive protein) and antibodies to periodontal pathogens were significantly higher with case type III/IV vs I/II. These differences were sustained 12 months after extractions for most APPs. CONCLUSIONS: The results demonstrated that removal of disease by full-mouth extraction of teeth altered the overall burden of challenge to the host. Continued elevation in various APPs in the III/IV group suggested a potential underlying constitutive difference in systemic response characteristics of this population. PMID- 24630162 TI - Neuroepithelial structures associated with the subepithelial nerve plexus of taste buds: a fortuitous finding resembling the juxtaoral organ of Chievitz. AB - Numerous embryologic epithelial remnants are described in the oral region, when intimately associated with peripheral nerves, may pose a diagnostic pitfall for pathologists. The literature contains cases in which the juxtaoral organ of Chievitz (JOC) was identified in specimens removed because of a malignancy and the correct recognition of this structure potentially avoids unnecessary treatment. To our knowledge, this is the description of neuroepithelial structures similar to the JOC were found in the posterior tongue in close association with the subepithelial nerve plexus of taste buds. Four cases are reported. The nerve fibers of the subepithelial nerve plexus showed strong positivity for S-100, CD56, and synaptophysin, and were intimately associated with epithelial islands. CD56 showed positivity around the periphery of the epithelial islands. Proper recognition of these anatomic structures is crucial to prevent misdiagnosis of squamous cell carcinoma with perineural invasion. PMID- 24630163 TI - A 15-year follow-up of temporomandibular joint symptoms and magnetic resonance imaging findings in whiplash patients: a prospective, controlled study. AB - OBJECTIVE: This study aimed to determine the incidence, prevalence, and progression of temporomandibular joint (TMJ) magnetic resonance (MR) imaging findings and symptoms in patients over a 15-year period after whiplash trauma, compared with control participants. STUDY DESIGN: Sixty consecutive patients were enrolled directly after whiplash trauma. The study protocol included TMJ MR imaging at inception and 15 years later, as well as a questionnaire and interview at inception, at 1-year follow-up, and at 15-year follow-up. Fifty-seven patients (95%) participated in all three examinations (85% for MR imaging). Fifty matched control participants were examined. RESULTS: The prevalence of TMJ symptoms was significantly higher in patients compared with control participants at inception (44% vs 20%, P = .0055) and remained significantly higher throughout the study period. The prevalence of disk displacement did not differ significantly between groups either at inception (63% vs 53%) or at 15-year follow-up (63% vs 55%). CONCLUSIONS: This prospective 15-year follow-up suggests that the development of TMJ symptoms, both immediate and delayed, is common in whiplash patients. PMID- 24630164 TI - Valproic acid in normal therapeutic concentration has no neuroprotective or differentiation influencing effects on long term expanded murine neural stem cells. AB - The antiepileptic drug valproic acid (VPA) has shown neuroprotective effects in different cell types including mesencephalic neural primary cultures. Furthermore, an influence on neural differentiation and neurite outgrowth has been described. Nevertheless, results in this regard are contradictory and data on long term expanded neural stem cells are missing. This is why we investigated possible neuroprotective effects of VPA on fetal mesencephalic neural stem cells (fmNSCs) in vitro, using the neurotoxic agent 1-methyl-4-phenyl-pyridin (MPP+). We also examined potential VPA effects on cell expansion and differentiation and the underlying signaling pathways. In our study, we could exclude any relevant toxic effects of 100 MUg/ml and 200 MUg/ml VPA on fmNSCs during expansion and differentiation for up to 96 h. MPP+ treatment in concentrations of 30 and 60 MUM MPP+ significantly decreased the survival rate of fmNSCs during expansion and differentiation. In all used concentrations, VPA did neither reverse these MPP+ effects when applied simultaneously with MPP+ nor after pre-treatment with VPA for 24 h. In contrast, MPP+ effects were emphasized by VPA pretreatment for 24h when applied during cell expansion. Concerning the self-renewing capacity of fmNSCs, measured by BrdU and Ki67 staining, we did not find any significant influence of VPA. Additionally there was no significant influence of therapeutic VPA dosages on astroglial (GFAP), oligodendroglial (GalC) and neuronal (MAP2) differentiation, measured by immunostaining after 10 days of differentiation. Summing up, we did not find any neuroprotective effects of VPA on fmNSCs in vitro, neither during expansion nor during cell differentiation. Also the self renewing and differentiation potential of the used fmNSCs was not altered. These findings have implications for the large community of patients having to take VPA on a chronic base, especially in the light of knowledge that a regular cell replacement out of hippocampal adult stem cells is mandatory for the maintenance of normal cognition through adulthood. PMID- 24630165 TI - When and how does autism begin? AB - Jones and Klin recently found that the well-known decreased fixations to eyes in children with autism spectrum disorder (ASD) are not present throughout infancy; instead a decline in eye fixations between 2 and 6 months predicts diagnosis. This decline is the earliest behavioral pattern linked to autism to date. PMID- 24630167 TI - [Lymphohistiocytic activation syndrome]. PMID- 24630166 TI - Entrainment of neural oscillations as a modifiable substrate of attention. AB - Brain operation is profoundly rhythmic. Oscillations of neural excitability shape sensory, motor, and cognitive processes. Intrinsic oscillations also entrain to external rhythms, allowing the brain to optimize the processing of predictable events such as speech. Moreover, selective attention to a particular rhythm in a complex environment entails entrainment of neural oscillations to its temporal structure. Entrainment appears to form one of the core mechanisms of selective attention, which is likely to be relevant to certain psychiatric disorders. Deficient entrainment has been found in schizophrenia and dyslexia and mounting evidence also suggests that it may be abnormal in attention-deficit/hyperactivity disorder (ADHD). Accordingly, we suggest that studying entrainment in selective attention paradigms is likely to reveal mechanisms underlying deficits across multiple disorders. PMID- 24630168 TI - False hyperlactatemia in life-threatening ethylene glycol poisoning. AB - Ethylene glycol poisoning is rare, but prompt diagnosis is crucial, in order to initiate specific treatments. Herein, we report the case of a patient who was admitted to ICU for coma and extreme metabolic acidosis with unexpected hyperlactatemia on initial ICU blood gas analyzer. Ethylene glycol poisoning was diagnosed, and hyperlactatemia was ruled out on a blood sample sent to the biochemistry department. Interference of blood gas analyzers lactate electrodes with metabolites of ethylene glycol were the source of this apparent hyperlactatemia. Symptoms gradually improved and false hyperlactatemia resolved after renal replacement therapy and fomepizole administration. Time course of ethylene glycol concentration showed similar evolution. After initial confirmation of ethylene glycol presence, this biological interference could thus be used as a surrogate of costly and highly specialised dosages. PMID- 24630169 TI - [Veno-venous extracorporeal oxygenation and veno-arterial extracorporeal oxygenation. Questions, answers]. AB - A round table, organized by the French Society of Perfusion (Sofraperf) at the French national congress on extracorporeal circulations (Perfusion 2013), was attended by perfusionists, anaesthesiologists, intensivists and surgeons around the theme of respiratory veno-venous support and veno-arterial circulatory support with extracorporeal oxygenation in intensive care units. The debate was conducted in a participatory manner by bi-directional questions-answers session between moderators and assistance. The authors report management of this type of therapy that is not perfectly homogeneous, supported on literature data. Cannulae, cannulation, circuit, oxygenator, anticoagulation, control, surveillance, weaning are subject to paragraphs with defined entry whose contents are mutually enriching. PMID- 24630170 TI - [An upper gastro-intestinal bleeding reveals an aortoesophageal fistula due to the rupture of a thoracic aortic aneurysm]. PMID- 24630171 TI - Haemorrhagic lesions in oral mucosa as the presentation of idiopathic thrombocytopenic purpura. PMID- 24630172 TI - [Immediate prediction of recovery, based on emotional impact of vertigo]. AB - INTRODUCTION AND OBJECTIVE: This work presents deeper studies of comorbidity between anxiety and vestibular pathology. The aim of this work was to comprehend the reasons why patients do not feel "fully recovered" even though the treating professionals discharge them. We studied the features of personality that can favour the continuity of the condition. METHODS: The questionnaire for measuring the emotional impact of vertigo makes it possible to determine if the patient has a psychological style with a tendency to develop pathological anxiety levels. Anxiety is a subjective characteristic determinant in difficulties with medical treatment. The questionnaire was applied to 198 patients in Argentina and Mexico in parallel. Each pathology was treated by standard medical procedures. The study focused on determining the correlation between "feeling fully recovered or not at the end of treatment" and the questionnaire scores obtained before the approach. RESULTS: In more than 80% of cases, high scores (>15 points) on the questionnaire were correlated with the difficulty presented by the patients for full recovery from the pathology after medical treatment. CONCLUSIONS: The objective assessments (duration and intensity of symptoms, time of onset of the disease, etc.) do not exactly predict possible difficulties during treatment of vertigo. Consequently, we consider the patient's subjective assessment of how the vestibular pathology affects him or her to be determinant. That key information allows us to predict the course of the illness and the probability of a full recovery. PMID- 24630174 TI - Calcium-dependent regulation of glucose homeostasis in the liver. AB - A major role of the liver is to integrate multiple signals to maintain normal blood glucose levels. The balance between glucose storage and mobilization is primarily regulated by the counteracting effects of insulin and glucagon. However, numerous signals converge in the liver to ensure energy demand matches the physiological status of the organism. Many circulating hormones regulate glycogenolysis, gluconeogenesis and mitochondrial metabolism by calcium-dependent signaling mechanisms that manifest as cytosolic Ca(2+) oscillations. Stimulus strength is encoded in the Ca(2+) oscillation frequency, and also by the range of intercellular Ca(2+) wave propagation in the intact liver. In this article, we describe how Ca(2+) oscillations and waves can regulate glucose output and oxidative metabolism in the intact liver; how multiple stimuli are decoded though Ca(2+) signaling at the organ level, and the implications of Ca(2+) signal dysregulation in diseases such as metabolic syndrome and non-alcoholic fatty liver disease. PMID- 24630173 TI - Atherosclerosis affects calcium signalling in endothelial cells from apolipoprotein E knockout mice before plaque formation. AB - Little is known about how hypercholesterolaemia affects Ca(2+) signalling in the vasculature of ApoE(-/-) mice, a model of atherosclerosis. Our objectives were therefore to determine (i) if hypercholesterolaemia alters Ca(2+) signalling in aortic endothelial cells before overt atherosclerotic lesions occur, (ii) how Ca(2+) signals are affected in older plaque-containing mice, and (iii) whether Ca(2+) signalling changes were translated into contractility differences. Using confocal microscopy we found agonist-specific Ca(2+) changes in endothelial cells. ATP responses were unchanged in ApoE(-/-) cells and methyl-beta cyclodextrin, which lowers cholesterol, was without effect. In contrast, Ca(2+) signals to carbachol were significantly increased in ApoE(-/-) cells, an effect methyl-beta-cyclodextrin reversed. Ca(2+) signals were more oscillatory and store operated Ca(2+) entry decreased as mice aged and plaques formed. Despite clearly increased Ca(2+) signals, aortic rings pre-contracted with phenylephrine had impaired relaxation to carbachol. This functional deficit increased with age, was not related to ROS generation, and could be partially rescued by methyl-beta cyclodextrin. In conclusion, carbachol-induced calcium signalling and handling are significantly altered in endothelial cells of ApoE(-/-) mice before plaque development. We speculate that reduction in store-operated Ca(2+) entry may result in less efficient activation of eNOS and thus explain the reduced relaxatory response to CCh, despite the enhanced Ca(2+) response. PMID- 24630175 TI - Exploring the relationship between cognitive illness representations and poor emotional health and their combined association with diabetes self-care. A systematic review with meta-analysis. AB - OBJECTIVE: Depression and anxiety are common in diabetes and are associated with lower diabetes self-care adherence. How this occurs is unclear. Our systematic review explored the relationship between cognitive illness representations and poor emotional health and their combined association with diabetes self-care. METHODS: Medline, Psycinfo, EMBASE, and CINAHL were searched from inception to June 2013. Data on associations between cognitive illness representations, poor emotional health, and diabetes self-care were extracted. Random effects meta analysis was used to test the relationship between cognitive illness representations and poor emotional health. Their combined effect on diabetes self care was narratively evaluated. RESULTS: Nine cross-sectional studies were included. Increased timeline cyclical, consequences, and seriousness beliefs were associated with poorer emotional health symptoms. Lower perceived personal control was associated with increased depression and anxiety, but not mixed anxiety and depressive symptoms. Remaining cognitive illness representation domains had mixed statistically significant and non-significant relationships across emotional states or were measured only once. Effect sizes ranged from small to large (r=+/-0.20 to 0.51). Two studies explored the combined effects of cognitions and emotions on diabetes self-care. Both showed that cognitive illness representations have an independent effect on diabetes self-care, but only one study found that depression has an independent effect also. CONCLUSIONS: Associations between cognitive illness representations and poor emotional health were in the expected direction - negative diabetes perceptions were associated with poorer emotional health. Few studies examined the relative effects of cognitions and emotions on diabetes self-care. Longitudinal studies are needed to clarify directional pathways. PMID- 24630176 TI - Risk of suicidal ideation in diabetes varies by diabetes regimen, diabetes duration, and HbA1c level. AB - OBJECTIVE: To investigate patient subgroups based on the clinical characteristics of diabetes to evaluate risk factors for suicidal ideation using a large population-based sample in South Korea. METHODS: Data from the Fifth Korea National Health and Nutrition Examination Survey, a cross-sectional, nationally representative survey, were analyzed. The participants were 9159 subjects aged >=40years. We defined patients with diabetes based on self-reported physician diagnosed diabetes. We evaluated clinical risk factors for suicidal ideation according to diabetes regimen, diabetes duration, and glycated hemoglobin (HbA1c) level compared with no diabetes. Given the complex sample design and unequal weights, we analyzed weighted percentages and used survey logistic regression. RESULTS: Diabetes per se was not associated with suicidal ideation. However, suicidal ideation was significantly more prevalent among patients who had injected insulin, had a duration of diabetes >=5years and had HbA1c levels >=6.5 compared with those without diabetes. Depressive symptoms were the most prominent predictor of suicidal ideation. CONCLUSIONS: Insulin therapy, diabetes of long duration, and unsatisfactory glycemic control were identified as risk factors for suicidal ideation; thus, patients with these characteristics warrant special attention. Our findings suggest the need to integrate efforts to manage emotional distress into diabetes care. PMID- 24630177 TI - Do sleep, stress, and illness explain daily variations in fatigue? A prospective study. AB - OBJECTIVE: Fatigue is related to a number of serious diseases, as well as to general well-being. It is also a major cause of sickness absence and use of health facilities. Still, the determinants of variations in fatigue are little investigated. The purpose of present study was to investigate the relationships between the daily variations of fatigue with sleep during the previous night, stress or disease symptoms during the same day - across 42 consecutive days of normal life. METHODS: 50 individuals participated and gave diary reports and used an actigraph across the 42days. The data was analyzed using a multilevel approach with mixed model regression. RESULTS: The analyses showed that the day-to-day variation in fatigue was related to (poor) sleep quality (p<.001) and (reduced) sleep duration (p<.01) the previous night, as well as to higher stress (p<.05), and to the occurrence of a cold or fever (p<.001) during the same day as the fatigue rating. Fatigue was also strongly related to poorer subjective health (p<.001) and sleepiness (p<.001) during the same day. CONCLUSION: The results indicate that prior sleep (and sleepiness) as well as stress and illness are consistently connected to how fatigue is experienced during normal living conditions. PMID- 24630178 TI - Non-REM sleep EEG power distribution in fatigue and sleepiness. AB - OBJECTIVES: The aim of this study is to contribute to the sleep-related differentiation between daytime fatigue and sleepiness. METHODS: 135 subjects presenting with sleep apnea-hypopnea syndrome (SAHS, n=58) or chronic fatigue syndrome (CFS, n=52) with respective sleepiness or fatigue complaints and a control group (n=25) underwent polysomnography and psychometric assessments for fatigue, sleepiness, affective symptoms and perceived sleep quality. Sleep EEG spectral analysis for ultra slow, delta, theta, alpha, sigma and beta power bands was performed on frontal, central and occipital derivations. RESULTS: Patient groups presented with impaired subjective sleep quality and higher affective symptom intensity. CFS patients presented with highest fatigue and SAHS patients with highest sleepiness levels. All groups showed similar total sleep time. Subject groups mainly differed in sleep efficiency, wake after sleep onset, duration of light sleep (N1, N2) and slow wave sleep, as well as in sleep fragmentation and respiratory disturbance. Relative non-REM sleep power spectra distributions suggest a pattern of power exchange in higher frequency bands at the expense of central ultra slow power in CFS patients during all non-REM stages. In SAHS patients, however, we found an opposite pattern at occipital sites during N1 and N2. CONCLUSIONS: Slow wave activity presents as a crossroad of fatigue and sleepiness with, however, different spectral power band distributions during non-REM sleep. The homeostatic function of sleep might be compromised in CFS patients and could explain why, in contrast to sleepiness, fatigue does not resolve with sleep in these patients. The present findings thus contribute to the differentiation of both phenomena. PMID- 24630179 TI - Insomnia increases risk for cardiovascular events in women and in men with low socioeconomic status: a longitudinal, register-based study. AB - OBJECTIVES: Insomnia and short and long sleep durations have all been linked to cardiovascular disease. Male gender and low socioeconomic status are also related to cardiovascular disease, but it is unclear whether these two factors modify the impact of poor sleep on cardiovascular disease incidence. METHODS: Participants (5875 men and 7742 women ages 45 to 64 with no history of cardiovascular disease from the general population of Malmo, Sweden; participation rate 41%) were enrolled from 1992 to 1994 and followed until 2005 or until the first cardiovascular event (defined as myocardial infarction, stroke, or death due to ischemic heart disease), as recorded by official registers. Baseline blood pressure, BMI, and inquiry data concerning psychosocial circumstances and self reported sleep habits were compared with hazard ratios (HRs) of cardiovascular events. RESULTS: Affirming 'moderate' or 'considerable' problems with at least one out of the four insomnia symptoms was associated with cardiovascular event in women (fully-adjusted HR 1.4 [95% CI 1.2-1.6] and population attributable fraction 17.3%). The same was true of men with past or present manual occupation (HR 1.3 [95% CI 1.1-1.6] and population attributable fraction 11.8%). The HRs increased further in women where insomnia symptoms were combined with short or long sleep duration. CONCLUSIONS: Insomnia is a significant public health problem with implications for cardiovascular disease incidence. Taking gender and socioeconomic status into account is a worthwhile approach in research on sleep and cardiovascular disease outcomes. PMID- 24630181 TI - Patient Health Questionnaire 15 as a generic measure of severity in fibromyalgia syndrome: surveys with patients of three different settings. AB - OBJECTIVE: Graduated treatment of patients with functional somatic syndromes (FSS) and fibromyalgia syndrome (FMS) depending on their severity has been recommended by recent guidelines. The Patient Health Questionnaire 15 (PHQ 15) is a validated measure of somatic symptom severity in FSS. We tested the discriminant and transcultural validity of the PHQ 15 as a generic measure of severity in persons with FMS. METHODS: Persons meeting recognized FMS-criteria of the general German population (N=98), of the US National Data Bank of Rheumatic Diseases (N=440), and of a single German pain medicine center (N=167) completed validated self-report questionnaires on somatic and psychological distress (Polysymptomatic Distress Scale, Patient Health Questionnaire 4), health-related quality of life (HRQOL) (Short Form Health Survey 12 or 36) and disability (Pain Disability Index). In addition, self-reports of working status were assessed in the clinical setting. Overall severity of FMS was defined by PHQ 15 scores: mild (0-9), moderate (10-14) and severe (15-30). RESULTS: Persons with mild, moderate and severe FMS did not differ in age and gender. Irrespective of the setting, persons with severe FMS reported more pain sites, fatigue, depressed mood, impaired HRQOL and disability than persons with moderate or mild FMS. Patients with severe FMS in the NDB and in the German clinical center reported more work related disability than patients with mild FMS. CONCLUSION: The PHQ 15 is a valid generic measure of overall severity in FMS. PMID- 24630182 TI - Prevalence and risk factors for suicidal ideation in a multiple sclerosis population. AB - OBJECTIVE: To estimate the prevalence, incidence and determinants of suicidal ideation in the multiple sclerosis (MS) population. METHODS: A sample of 188 subjects were randomly selected from a community-based MS clinic registry and participated in as many as 13 interviews over 6 months. Thoughts of "being better off dead" or of "harming oneself" were assessed using item 9 on the Patient Health Questionnaire, Brief (PHQ-9). RESULTS: At baseline, the 2-week period prevalence of suicidal ideation was 8.3%. Over the course of 6 months, 22.1% of respondents reported having such thoughts at least once. Survival analysis incorporating baseline PHQ-8 scores as a covariate confirmed that being age 65 and over (HR=4.3, 95% CI 1.7-11.3) and having lower quartile self-efficacy ratings (HR=3.5, 95% CI 1.5-8.2) predicted suicidal ideation. Lower levels of task-oriented coping (treated as a continuous variable) also predicted suicidal ideation after adjustment for depressive symptoms (p=0.015), as did self-reported bladder or bowel symptoms (HR=2.6, 95% CI 1.1-6.0) and difficulties with speaking and swallowing (HR=2.9, 95% CI 1.3-6.8). Associations with MS symptoms were not confounded by depressive symptoms. CONCLUSION: This study identified several potentially modifiable factors that may be useful for preventing suicide in people with MS. PMID- 24630180 TI - Ecological validity and clinical utility of Patient-Reported Outcomes Measurement Information System (PROMIS(r)) instruments for detecting premenstrual symptoms of depression, anger, and fatigue. AB - OBJECTIVE: This study examined the ecological validity and clinical utility of NIH Patient Reported-Outcomes Measurement Information System (PROMIS(r)) instruments for anger, depression, and fatigue in women with premenstrual symptoms. METHODS: One-hundred women completed daily diaries and weekly PROMIS assessments over 4weeks. Weekly assessments were administered through Computerized Adaptive Testing (CAT). Weekly CATs and corresponding daily scores were compared to evaluate ecological validity. To test clinical utility, we examined if CATs could detect changes in symptom levels, if these changes mirrored those obtained from daily scores, and if CATs could identify clinically meaningful premenstrual symptom change. RESULTS: PROMIS CAT scores were higher in the pre-menstrual than the baseline (ps<.0001) and post-menstrual (ps<.0001) weeks. The correlations between CATs and aggregated daily scores ranged from .73 to .88 supporting ecological validity. Mean CAT scores showed systematic changes in accordance with the menstrual cycle and the magnitudes of the changes were similar to those obtained from the daily scores. Finally, Receiver Operating Characteristic (ROC) analyses demonstrated the ability of the CATs to discriminate between women with and without clinically meaningful premenstrual symptom change. CONCLUSIONS: PROMIS CAT instruments for anger, depression, and fatigue demonstrated validity and utility in premenstrual symptom assessment. The results provide encouraging initial evidence of the utility of PROMIS instruments for the measurement of affective premenstrual symptoms. PMID- 24630183 TI - Hemoglobin levels in persons with depressive and/or anxiety disorders. AB - OBJECTIVE: Both low and high hemoglobin levels lead to more physical diseases, and both are linked to mortality. Low hemoglobin, often classified as anemia, has also been linked to more depressive symptoms, but whether both hemoglobin extremes are associated with depressive disorder and potentially also with anxiety disorder has not been examined before. This study examines to which extent hemoglobin levels are associated with depression and anxiety disorders in a large cohort. METHODS: The study sample consisted of 2920 persons from the Netherlands Study of Depression and Anxiety. Hemoglobin levels were determined after venipuncture. Depressive and anxiety disorders were determined according to a DSM-IV-based psychiatric interview. Clinical psychiatric characteristics included the severity of depression and anxiety, the duration of symptoms, the age of onset and the antidepressant use. RESULTS: Higher hemoglobin levels were found in those with current depressive and/or anxiety disorders after sociodemographic adjustment and both higher, and lower hemoglobin levels were found in persons with higher depression and anxiety severity. However, after full adjustment for sociodemographics, disease indicators and lifestyle, associations were no longer significant. CONCLUSIONS: This cohort study showed that there is no independent association between depressive and/or anxiety disorders and hemoglobin levels or anemia status. PMID- 24630185 TI - Relationship between effort-reward imbalance and hair cortisol concentration in female kindergarten teachers. AB - OBJECTIVE: The present study aims to investigate the relationship between effort reward imbalance and hair cortisol concentration among teachers to examine whether hair cortisol can be a biomarker of chronic work stress. METHODS: Hair samples were collected from 39 female teachers from three kindergartens. Cortisol was extracted from the hair samples with methanol, and cortisol concentrations were measured with high performance liquid chromatography-tandem mass spectrometry. Work stress was measured using the effort-reward imbalance scale. RESULTS: The ratio of effort to reward showed significantly positive association with hair cortisol concentration. CONCLUSION: The cortisol concentration in the system increases with the effort-reward imbalance. Measurement of hair cortisol can become a useful biomarker of chronic work stress. PMID- 24630184 TI - Relationship between psychiatric disorders and sexually transmitted diseases in a nationally representative sample. AB - OBJECTIVE: Sexually transmitted diseases (STDs) are a significant public health concern. Numerous internalizing and externalizing psychiatric disorders have been found to be related to STD risk. However, to date, no studies have examined several psychiatric disorders simultaneously to account for STD risk. Given that psychiatric disorders often co-occur and can be explained by a limited number of latent dimensions of psychopathology, it is important to examine whether the relationship between STDs and psychiatric disorders is best explained by broad dimensions of psychopathology. METHODS: The current study examined the associations between a range of Axis I and II psychiatric disorders at baseline and rates of STDs at a three-year follow-up in a large, nationally representative sample of adults in the United States (n=34,434). A confirmatory factor analysis (CFA) was conducted to fit three factors, two internalizing and one externalizing. Structural equation modeling (SEM) was used to assess the relationships between and among the factors and STD status and to test for mediation. RESULTS: In bivariate analyses, most Axis I and Axis II disorders were associated with STD diagnosis at Wave 2, whereas the results of the structural model showed that only the externalizing factor was significantly associated with STD diagnosis at Wave 2. Further, the externalizing factor mediated the relationship between one of the internalizing factors and STD diagnosis. CONCLUSION: Findings suggest the unique contribution of externalizing psychopathology to STD risk and the importance of examining latent dimensions of disorders when understanding this relationship between psychiatric disorders and STDs. PMID- 24630186 TI - Interleukin-6 gene polymorphism, chronic stress and atherosclerosis: interleukin 6-174G>C polymorphism, chronic stress and risk of early atherosclerosis in the Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: Interleukin-6 protein has been suggested as a mediator connecting chronic stress and cardiovascular diseases. We investigated whether the functional G174C polymorphism (rs1800795) of interleukin-6 gene is associated with vital exhaustion, a measure of chronic stress, or with preclinical atherosclerosis. METHODS: Associations between the interleukin-6-174G>C polymorphism, preclinical atherosclerosis, and vital exhaustion were examined in 1673 women and men aged 24-39years participating in the Cardiovascular Risk in Young Finns study. Vital exhaustion was measured using Maastricht Questionnaire. Preclinical atherosclerosis was assessed by carotid intima-media thickness using ultrasound techniques. DNA was genotyped for the interleukin-6-174G>C polymorphism (rs1800795). RESULTS: The GG genotype of the interleukin-6-174G>C polymorphism was associated with higher vital exhaustion. Moreover, higher vital exhaustion was associated with greater intima-media thickness in men carrying G alleles, adjusted for cardiovascular risk factors. CONCLUSION: Our findings support a role for the interleukin-6-174G>C polymorphism in increased risk of atherosclerosis in individuals with chronic stress. In addition, individuals carrying the G allele of the interleukin-6-174G>C polymorphism may be more prone to adverse effects of psychosocial stress. PMID- 24630187 TI - Underperformance of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients at neurocognitive tests should be assessed objectively without an a priori judgment about the etiology. PMID- 24630188 TI - Response to 'Underperformance of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients at neurocognitive tests should be assessed objectively'. PMID- 24630189 TI - [Surgery for elderly persons]. PMID- 24630190 TI - [Surgery for the elderly is an urgent multidisciplinary challenge]. PMID- 24630191 TI - [More people live to be very old and with a better functioning]. AB - Death rates for 80+-year-olds are now half of what they were after WWII. The chance of living past 90 years has gone up by roughly 30% per decade for people born in Denmark in 1895, 1905, and 1915 - and the later cohorts are functioning better physically and cognitively. Centenarians are on average functioning physically and cognitively as well as 92-93-year-olds due to selective mortality. A steep increase in the frequency of hospitalization and surgical procedure among 85-100-year-olds is occurring, but there is a lack of knowledge about treatment effects and side effects among the oldest-old. PMID- 24630192 TI - [Growing need for surgery as the number of elderly rises in Denmark]. AB - In Denmark, the elderly population is growing. In the article, data from the Danish Healthcare Registry (2005-2012) was summarized for hospital admissions and outpatient contacts with surgery in patients above 75 years. Also, the number of surgical procedures and surgical-related costs in 2020 were estimated based on demographic data and the rates surgery in 2012. The number of surgical procedures and surgical-related hospital costs will increase by 27.8% from 2012 to 2020, corresponding to the increase in the number of elderly citizens. New strategies and further political prioritization is needed to meet the rising age-related challenges. PMID- 24630193 TI - [Age as risk factor in elective and emergent surgery]. AB - This paper focuses on the current evidence regarding age as an independent predictor of impaired post-operative outcome and on the possibilities of perioperative interventions in elective and emergent surgery. Co-morbidity and functional parameters, i.e. frailty, are better predictors than age and can be combined with intraoperative data to help identifying patients who might benefit from increased level of care and observation. Most elderly patients go through surgery without impaired outcome, however, further studies are needed to identify who might benefit from increased level of care. PMID- 24630194 TI - [Anaesthesia for elderly patients]. AB - Elderly surgical patients comprise a heterogeneous population, especially due to extreme variability in the aging process and the prevalence of chronic disease. Providing anaesthesia can be challenging as the sensitivity to anaesthetic agents is generally increased. Careful preoperative assessment is mandatory but can be difficult, and intraoperative care must be tailored to the extent of organ failure. The aim of this review is to highlight some specific concerns that must be addressed in the perioperative management of elderly patients. PMID- 24630195 TI - [Elderly in the intensive care unit]. AB - The population is ageing and it is estimated that 25% of the population will be over 65 years in 2050, compared to 15% today. Therefore, the number of elderly patients requiring intensive care is expected to grow substantially over the next years. It is very difficult, but important to identify the elderly patients, who can benefit from intensive care. Age alone is a poor predictor while premorbid function, co-morbidity and the degree of critical illness are important predictors. The reason for admission to intensive care units has a major impact on the prognosis. It is shown that the prognosis after elective surgery is good, whereas the prognosis after admitting for acute surgery or medical reasons is bad. PMID- 24630196 TI - [Treatment of post-operative pain in the elderly]. AB - The management of post-operative pain in the elderly represents a challenge due to coexisting diseases, concurrent medications, and age-related pharmacodynamic and pharmacokinetic changes. Analgesic therapy in this group of patients should balance the potential efficacy with the risk of interactions and side effects. In general, doses should be smaller and the dosing intervals longer ("start low and go slow") and the use of regional blocks and non-pharmacological treatment should be encouraged. Continuous assessment of pain, pain relief and side effects is particularly important in elderly patients. PMID- 24630197 TI - [Collaboration between geriatricians and orthopaedic surgeons on elderly patients]. AB - Close collaboration between geriatricians and orthopaedic surgeons on elderly patients with hip fractures reduces mortality, the number of complications, and the length of hospital stay and increases the functional abilities of the patients. In some Danish hospitals the two groups of doctors work closely together, in others there are few or no geriatricians. PMID- 24630198 TI - [Older patients should be offered strength training early post surgery]. AB - The use of fast-track regimes has led to a marked decline in complication rates post surgery. Nevertheless, older people have an increased risk of loss of muscle mass and strength and disability post surgery compared to younger adults. Consequently, attempts to counteract these problems seem highly relevant. The number of studies on the effect of perioperative training is still limited. However, there is increasing evidence that strength training commenced early post surgery is safe and effective in regard to restore muscle function in older patients going through acute or elective surgery. PMID- 24630199 TI - WITHDRAWN: Periprosthetic Bone Mineral Density After Total Hip Arthroplasty With an AMIStem or Quadra Femoral Component Performed by a Minimally Invasive Anterior Approach (AMIS): A Prospective Randomized Clinical Dual-Energy X-ray Absorptiometry Study. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24630200 TI - Frequency of reporting of adverse events in randomized controlled trials of psychotherapy vs. psychopharmacotherapy. AB - BACKGROUND: Psychopharmacology and psychotherapy are the two main therapies in mental health. It is common practice to consider adverse events (AEs) of medications, but it's not clear this occurs with psychotherapy. AIM: This study investigates the frequency with which reports of AEs occur in clinical trials using either psychopharmacology alone, psychotherapy alone, or combined approaches. METHODS: Forty-five articles of randomized trials published in high impact journals were chosen from a Medline search, and separated into three groups of 15 articles: pharmacotherapy alone (M), psychotherapy alone (T) and combined studies that looked at the effect of both a psychotherapeutic (CT) and psychopharmacologic (CM) intervention. Criteria for what defines an AE were established and the papers were rated for mentions of AEs in papers as a whole and by each section. RESULTS: The chi(2)-analysis of AE mentions showed significant differences between the four study conditions in terms of each paper as a whole (chi(2):10.1,p<0.018), and by section. Medication (M+CM) and psychotherapy papers (T+CT) were then combined into two groups to compare the odds that one was more likely to mention AEs than the other. Bivariate logistic regression yielded statistically significant odds ratios ranging from 9.33 to 20.99, with medications being far more likely to mention AEs. CONCLUSION: We believe the difference in reports of AEs mirrors the attitudes researchers and providers. It's critical to consider, and standardize the definition of, AEs in psychotherapy, and imperative to identify and address potential AEs in psychotherapy research. PMID- 24630201 TI - Prevalence and dimensionality of hallucination-like experiences in young adults. AB - BACKGROUND: The study of hallucination-like experiences (HLEs) in non-clinical populations is increasingly used to corroborate etiological models of psychosis. This method capitalizes on the absence of confounding factors that typically affect the study of hallucinations in clinical subjects. AIM: To estimate the prevalence of HLEs in young adults; validate the mutidimensionality and explore the correlates of latent HLEs clusters. METHODS: Cross-sectional survey design. The extended 16-item Launay-Slade Hallucination Scale (LSHS-E) and the 12-item General Health Questionnaire (GHQ-12) were administered to 649 Italian college students (males: 47%). Confirmatory factorial analysis was used to test multidimensionality of the LSHS-E. Hierarchical nested, progressively constrained models were used to assess configural, metric and scalar invariance of the LSHS E. Latent class analysis was used to test the existence of different profiles of responding across the identified hallucination-proneness dimensions. RESULTS: Factor analysis showed that the four-factor model had the best fit. Factors were invariant across demographic variables and levels of psychological distress. Three latent classes were found: a large class with no HLEs (70% of participants), a multisensory HLEs class (18.8%), and a high hallucination proneness class (11%). Among those reporting high levels of HLEs, approximately half reported scores indicative of considerable psychological distress. CONCLUSIONS: Although HLEs have a relatively high prevalence in the general population, the majority of those experiences happen in isolation and are not associated to psychological distress. Approximately half of those individuals experiencing high levels of HLEs report significant psychological distress. This may be indicative of general risk for mental health conditions rather than specific risk for psychosis. PMID- 24630202 TI - Does using tight glycemic control in patients with acute ischemic stroke decrease morbidity or mortality? PMID- 24630203 TI - Effect of provider experience on clinician-performed ultrasonography for hydronephrosis in patients with suspected renal colic. AB - STUDY OBJECTIVE: Hydronephrosis is readily visible on ultrasonography and is a strong predictor of ureteral stones, but ultrasonography is a user-dependent technology and the test characteristics of clinician-performed ultrasonography for hydronephrosis are incompletely characterized, as is the effect of ultrasound fellowship training on predictive accuracy. We seek to determine the test characteristics of ultrasonography for detecting hydronephrosis when performed by clinicians with a wide range of experience under conditions of direct patient care. METHODS: This was a prospective study of patients presenting to an academic medical center emergency department with suspected renal colic. Before computed tomography (CT) results, an emergency clinician performed bedside ultrasonography, recording the presence and degree of hydronephrosis. CT data were abstracted from the dictated radiology report by an investigator blinded to the bedside ultrasonographic results. Test characteristics of bedside ultrasonography for hydronephrosis were calculated with the CT scan as the reference standard, with test characteristics compared by clinician experience stratified into 4 levels: attending physicians with emergency ultrasound fellowship training, attending physicians without emergency ultrasound fellowship training, ultrasound experienced non-attending physician clinicians (at least 2 weeks of ultrasound training), and ultrasound inexperienced non-attending physician clinicians (physician assistants, nurse practitioners, off-service rotators, and first-year emergency medicine residents with fewer than 2 weeks of ultrasound training). RESULTS: There were 670 interpretable bedside ultrasonographic tests performed by 144 unique clinicians, 80.9% of which were performed by clinicians directly involved in the care of the patient. On CT, 47.5% of all subjects had hydronephrosis and 47.0% had a ureteral stone. Among all clinicians, ultrasonography had a sensitivity of 72.6% (95% confidence interval [CI] 65.4% to 78.9%), specificity of 73.3% (95% CI 66.1% to 79.4%), positive likelihood ratio of 2.72 (95% CI 2.25 to 3.27), and negative likelihood ratio of 0.37 (95% CI 0.31 to 0.44) for hydronephrosis, using hydronephrosis on CT as the criterion standard. Among attending physicians with fellowship training, ultrasonography had sensitivity of 92.7% (95% CI 83.8% to 96.9%), positive likelihood ratio of 4.97 (95% CI 2.90 to 8.51), and negative likelihood ratio of 0.08 (95% CI 0.03 to 0.23). CONCLUSION: Overall, ultrasonography performed by emergency clinicians was moderately sensitive and specific for detection of hydronephrosis as seen on CT in patients with suspected renal colic. However, presence or absence of hydronephrosis as determined by emergency physicians with fellowship training in ultrasonography yielded more definitive test results. For clinicians without fellowship training, there was no significant difference between groups in the predictive accuracy of the application according to experience level. PMID- 24630205 TI - Simultaneous bilateral endophthalmitis after immediate sequential bilateral cataract surgery: what's the risk of functional blindness? PMID- 24630204 TI - Intensive lifestyle intervention goals can be achieved as effectively with large groups as with small groups. AB - OBJECTIVE: The purpose of this study was to assess if group size is associated with weight loss outcomes among participants in an adapted diabetes prevention program. METHODS: Adults at high-risk (N=841) for CVD and diabetes were enrolled in the lifestyle intervention in 2011. Multiple logistic regression analyses were used to identify if group size (smaller group<16 participants; larger group >=16 participants) was independently associated with weight loss outcomes among participants. RESULTS: In the bivariate analyses, participants in the smaller groups compared to those in the larger groups were significantly more likely to have a higher baseline body mass index, to attend fewer intervention sessions, and less likely to self-monitor their fat intake for >=14 weeks, and to have lost less weight during the core intervention (5.1 kg [SD 4.7] versus 5.8 kg [4.5]). However, analysis adjusting for age, sex, baseline BMI, achievement of the physical activity goal, number of weeks self-monitoring fat intake, and group size, found only two factors to be independently associated with achievement of the 7% weight loss goal: frequency of self-monitoring of fat intake and achievement of the physical activity goal. CONCLUSIONS: Our findings indicate that intensive lifestyle intervention goals can be achieved as effectively with large or small groups. PMID- 24630206 TI - Caveats about QuantiFERON-TB gold in-tube testing for uveitis. PMID- 24630207 TI - The value of tear osmolarity as a metric in evaluating the response to dry eye therapy in the clinic and in clinical trials. PMID- 24630208 TI - Comments of the editor in chief. PMID- 24630209 TI - Corneal changes in xeroderma pigmentosum: a clinicopathologic report. PMID- 24630210 TI - Reply: To PMID 24211864. PMID- 24630212 TI - Reply: To PMID 24321476. PMID- 24630211 TI - Comparison of refractive stability after non-toric versus toric intraocular lens implantation during cataract surgery. PMID- 24630213 TI - Posterolateral spinal fusion with ostegenesis induced BMSC seeded TCP/HA in a sheep model. AB - Autogenous bone graft is the gold standard for fusion procedure. However, pain at donor site and inconsistent outcome have left a surgeon to venture into some other technique for spinal fusion. The objective of this study was to determine whether osteogenesis induced bone marrow stem cells with the combination of ceramics granules (HA or TCP/HA), and fibrin could serve as an alternative to generate spinal fusion. The sheep's bone marrow mesenchymal stem cells (BMSCs) were aspirated form iliac crest and cultured for several passages until confluence. BMSCs were trypsinized and seeded on hydroxyapatite scaffold (HA) and tricalcium phosphate/hydroxyapatite (TCP/HA) for further osteogenic differentiation in the osteogenic medium one week before implantation. Six adult sheep underwent three-level, bilateral, posterolateral intertransverse process fusions at L1-L6. Three fusion sites in each animal were assigned to three treatments: (a) HA constructs group/L1-L2, (b) TCP/HA constructs group/L2-L3, and (c) autogenous bone graft group/L5-L6. The spinal fusion segments were evaluated using radiography, manual palpation, histological analysis and scanning electron microscopy (SEM) 12 weeks post implantation. The TCP/HA constructs achieved superior lumbar intertransverse fusion compared to HA construct but autogenous bone graft still produced the best fusion among all. PMID- 24630214 TI - Waste to energy--key element for sustainable waste management. AB - Human activities inevitably result in wastes. The higher the material turnover, and the more complex and divers the materials produced, the more challenging it is for waste management to reach the goals of "protection of men and environment" and "resource conservation". Waste incineration, introduced originally for volume reduction and hygienic reasons, went through a long and intense development. Together with prevention and recycling measures, waste to energy (WTE) facilities contribute significantly to reaching the goals of waste management. Sophisticated air pollution control (APC) devices ensure that emissions are environmentally safe. Incinerators are crucial and unique for the complete destruction of hazardous organic materials, to reduce risks due to pathogenic microorganisms and viruses, and for concentrating valuable as well as toxic metals in certain fractions. Bottom ash and APC residues have become new sources of secondary metals, hence incineration has become a materials recycling facility, too. WTE plants are supporting decisions about waste and environmental management: They can routinely and cost effectively supply information about chemical waste composition as well as about the ratio of biogenic to fossil carbon in MSW and off-gas. PMID- 24630215 TI - A new strain for recovering precious metals from waste printed circuit boards. AB - A new strain, Pseudomonas Chlororaphis (PC), was found for dissolving gold, silver, and copper from the metallic particles of crushed waste printed circuit boards (PCBs). The optimized conditions that greatly improved the ability of producing CN- (for dissolving metals) were obtained. Dissolving experiments of pure gold, silver, and copper showed that the metals could be changed into Au+, Ag+, and Cu2+. PC cells and their secreta would adsorb metallic ions. Meanwhile, metallic ions destroyed the growth of PC. Dissolving experiments of metallic particles from crushed waste PCBs were performed by PC. The results indicated that 8.2% of the gold, 12.1% silver, and 52.3% copper were dissolved into solution. This paper contributed significance information to recovering precious metals from waste PCBs by bioleaching. PMID- 24630216 TI - How to do it: thoracoscopic left ventricular assist device implantation using robot assistance. PMID- 24630217 TI - Aortic cannulation with a single purse-string suture. PMID- 24630218 TI - Is hypotension or tissue oxygenation responsible for morbidity and mortality after cardiopulmonary bypass? PMID- 24630219 TI - Reply to the editor. PMID- 24630220 TI - Free right internal thoracic artery graft versus radial artery during total arterial revascularization off-pump coronary artery bypass grafting: truly superior? PMID- 24630221 TI - Systolic anterior motion after mitral valve repair. PMID- 24630222 TI - Various surgical approaches to coronary artery aneurysm. PMID- 24630223 TI - Surgical approach to aortic valve disease with concomitant dilation of the proximal aorta. PMID- 24630224 TI - The importance of pulmonary arterial pressure for the treatment of tricuspid regurgitation. PMID- 24630225 TI - Impairment of tricuspid annular plane systolic excursion and tricuspid annular peak systolic velocity after arterial switch operation. PMID- 24630226 TI - Reply to the editor. PMID- 24630227 TI - Distal in situ pedicled (nonskeletonized) internal thoracic artery graft. PMID- 24630228 TI - Reply to the editor. PMID- 24630229 TI - A lot of drugs and not much oxygen: is the cocktail responsible for delirium? PMID- 24630230 TI - The effects of bicuspid aorta. PMID- 24630231 TI - Reply to the editor. PMID- 24630232 TI - Surgical approach to aortic valve disease with concomitant dilation of the proximal aorta: the authors' response. PMID- 24630233 TI - Reply to the editor. PMID- 24630234 TI - Extracorporeal membrane oxygenation resuscitation in adult patients with refractory septic shock. PMID- 24630235 TI - Twenty years of ECG grading of the severity of ischemia. AB - Shortly following an occlusion of an epicardial coronary artery, changes in the surface electrocardiogram (ECG) can be detected. Initially, T waves in leads with their positive poles facing the ischemic zone become positive, tall and symmetrical. Later, ST segment elevation (STE) becomes apparent. If ischemia continues, changes in the terminal portion of the QRS may also be detected. The changes in the terminal portion of the QRS are believed to be caused by prolongation of the electrical conduction in the ischemic zone and reflect severe ischemia due to lack of protection by preconditioning or collateral circulation. Several groups have shown that patients with the QRS changes of grade 3 ischemia have higher mortality, higher incidence of reinfarction and heart failure than patients presenting with only the T and ST changes of grade 2 ischemia, despite equal success in recanalizing the epicardial coronary artery by either thrombolytic therapy or primary percutaneous coronary intervention. Grade 3 ischemia is associated with more rapid progression of necrosis and larger final infarct size. Further studies are needed to better understand the underlying mechanisms that determine the severity of ischemia and how we should use this method based on the standard 12 lead ECG to implement clinical therapeutic decisions. PMID- 24630237 TI - Optimal scheduling of multiple sensors in continuous time. AB - This paper considers an optimal sensor scheduling problem in continuous time. In order to make the model more close to the practical problems, suppose that the following conditions are satisfied: only one sensor may be active at any one time; an admissible sensor schedule is a piecewise constant function with a finite number of switches; and each sensor either doesn't operate or operates for a minimum non-negligible amount of time. However, the switching times are unknown, and the feasible region isn't connected. Thus, it's difficult to solve the problem by conventional optimization techniques. To overcome this difficulty, by combining a binary relaxation, a time-scaling transformation and an exact penalty function, an algorithm is developed for solving this problem. Numerical results show that the algorithm is effective. PMID- 24630238 TI - Influence of sensory neuropeptides on human cutaneous wound healing process. AB - BACKGROUND: Close interactions exist between primary sensory neurons of the peripheral nervous system (PNS) and skin cells. The PNS may be implicated in the modulation of different skin functions as wound healing. OBJECTIVE: Study the influence of sensory neurons in human cutaneous wound healing. METHODS: We incubated injured human skin explants either with rat primary sensory neurons from dorsal root ganglia (DRG) or different neuropeptides (vasoactive intestinal peptide or VIP, calcitonin gene-related peptide or CGRP, substance P or SP) at various concentrations. Then we evaluated their effects on the proliferative and extracellular matrix (ECM) remodeling phases, dermal fibroblasts adhesion and differentiation into myofibroblasts. RESULTS: Thus, DRG and all studied neuromediators increased fibroblasts and keratinocytes proliferation and act on the expression ratio between collagen type I and type III in favor of collagen I, particularly between the 3rd and 7th day of culture. Furthermore, the enzymatic activities of matrix metalloprotesases (MMP-2 and MMP-9) were increased in the first days of wound healing process. Finally, the adhesion of human dermal fibroblasts and their differentiation into myofibroblasts were promoted after incubation with neuromediators. Interestingly, the most potent concentrations for each tested molecules, were the lowest concentrations, corresponding to physiological concentrations. CONCLUSION: Sensory neurons and their derived neuropeptides are able to promote skin wound healing. PMID- 24630239 TI - Effects of the immunosuppressant rapamycin on the expression of human alpha2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. AB - BACKGROUND: Rapamycin has been shown to exert an anti-fibrotic effect on skin fibrosis in a certain subset of patients with systemic sclerosis (SSc) and in bleomycin-treated animal models. OBJECTIVES: To investigate the mechanism responsible for the anti-fibrotic effect of rapamycin especially by focusing on human alpha2(I) collagen (COL1A2) and matrix metalloproteinase 1 (MMP1) genes in normal and systemic sclerosis (SSc) dermal fibroblasts. METHODS: The expression levels of type I procollagen and MMP1 proteins were analyzed by immunoblotting and the mRNA levels of COL1A2 and MMP1 genes were evaluated by quantitative real time RT-PCR. The activities of COL1A2 and MMP1 promoters were determined by reporter analysis. RESULTS: Rapamycin significantly decreased the levels of type I procollagen protein and COL1A2 mRNA, while significantly increasing the levels of MMP1 protein and mRNA in normal dermal fibroblasts. Similar effects of rapamycin were also observed in SSc dermal fibroblasts. Importantly, the inhibitory and stimulatory effects of rapamycin on the mRNA levels of COL1A2 and MMP1 genes, respectively, were significantly greater in SSc dermal fibroblasts than in normal dermal fibroblasts. In SSc dermal fibroblasts, rapamycin affected the expression of COL1A2 gene at the post-transcriptional level. In contrast, rapamycin altered the expression of MMP1 gene at the transcriptional level through the JNK/c-Jun signaling pathway in those cells. CONCLUSION: Rapamycin has a potential to directly regulate the deposition of type I collagen in extracellular matrix through inhibiting type I collagen synthesis and promoting its degradation by MMP1, suggesting that this drug is useful for the treatment of SSc. PMID- 24630240 TI - Response to "Stage IIIC solitary dermal melanoma". PMID- 24630241 TI - Use of platelet-rich plasma in the healing of chronic ulcers of the lower extremity. AB - INTRODUCTION AND OBJECTIVES: Platelet-rich plasma (PRP) is used as an adjuvant in the treatment of chronic ulcers of the lower extremity and has shown particularly promising results in the case of neuropathic ulcers. There has been less research, however, into its use in venous and hypertensive ulcers. Our aim was to assess the safety and feasibility of using PRP in the treatment of chronic ulcers of the lower extremity and to evaluate its potential benefits in directed healing. MATERIAL AND METHODS: We prospectively selected 11 patients with nonischemic ulcers of the lower extremity that had been present for at least 6 weeks. PRP was injected subcutaneously into the perilesional tissue and applied topically in 4 sessions held at 1-week intervals. We assessed quality of life (SF 12 questionnaire), pain (visual analog scale), and the circumference of the ulcer before and after treatment. RESULTS: There was a predominance of women (8/11, 73%), and venous ulcers (7/11, 64%) were more common than hypertensive ulcers (4/11, 36%). The median age of the patients was 79 years and the median time since onset of the ulcer was 17 months (range, 6-108 months). We observed a significant reduction in pain (P<.05) and a significant improvement in the physical and mental components of the SF-12 (P<.05). The mean reduction in ulcer size was 60%, and complete healing was achieved in 5 cases. No adverse effects were observed. CONCLUSION: The local application of PRP is a valuable and practical procedure that promotes the healing of chronic ulcers of the lower extremity; it can improve patient quality of life and is particularly effective in local pain relief. PMID- 24630243 TI - Ventriculostomy: Frequency, length of stay and in-hospital mortality in the United States of America, 1988-2010. AB - Ventriculostomy is a common neurosurgical procedure. We evaluated a large national sample of data regarding epidemiologic trends in neurosurgical practice relating to ventriculostomy. The USA Nationwide Inpatient Sample (1988 to 2010) provided retrospective data on patients hospitalized who underwent a ventriculostomy procedure. We categorized ventriculostomy procedures as the principal procedure performed for definitive treatment or as any other procedure. We identified 101,577 relevant hospital admissions with an estimated national volume of 507,762 hospital admissions from 1988 to 2010. For all patients, the mean age was 45.0 years and 46.5% were female. The three most common individual principal diagnoses were subarachnoid hemorrhage (19.1%), intracerebral hemorrhage (14.9%), and obstructive hydrocephalus (3.8%). The three most common principal procedures were other excision or destruction of lesion or tissue of brain (16.0%), clipping of aneurysm (13.5%), and temporary tracheostomy (10.8%). Mean length of stay was 20.8 days and in-hospital mortality was 24.5%. In hospital mortality was associated with emergency admission (multivariate odds ratio 1.98; 95% confidence interval 1.92-2.05), age 45 years or greater (mean of data set) (1.91; 1.85-1.98), multiple ventriculostomies (1.55; 1.44-1.67), and ventriculostomy as a principal procedure (1.39; 1.35-1.44). A total of 32.7% of patients were discharged to home. Most (94.3%) hospitalizations had one, 5.0% had two, and 0.7% multiple (three or more) ventriculostomies performed. Neurosurgeons must be aware of the association of in-hospital mortality, especially during the first days of admission, particularly when ventriculostomy is the principal procedure performed for definitive treatment during the hospitalization. PMID- 24630242 TI - Violence in childhood, attitudes about partner violence, and partner violence perpetration among men in Vietnam. AB - PURPOSE: We assess the association of men's exposure to violence in childhood witnessing physical violence against one's mother and being hit or beaten by a parent or adult relative-with their attitudes about intimate partner violence (IPV) against women. We explore whether men's perpetration of IPV mediates this relationship and whether men's attitudes about IPV mediate any relationship of exposure to violence in childhood with perpetration of IPV. METHODS: Five hundred twenty-two married men 18-51 years in Vietnam were interviewed. Multivariate regressions for ordinal and binary responses were estimated to assess these relationships. RESULTS: Compared with men experiencing neither form of violence in childhood, men experiencing either or both had higher adjusted odds of reporting more reasons to hit a wife (aOR, 1.43; 95% CI, 1.03-2.00 and aOR, 1.66; 95% CI, 1.05-2.64, respectively). Men's lifetime perpetration of IPV accounted fully for these associations. Compared with men experiencing neither form of violence in childhood, men experiencing either or both had higher adjusted odds of ever perpetrating IPV (aOR, 3.28; 95% CI, 2.15-4.99 and aOR, 4.56; 95% CI, 2.90-7.17, respectively). Attitudes about IPV modestly attenuated these associations. CONCLUSIONS: Addressing violence in childhood is needed to change men's risk of perpetrating IPV and greater subsequent justification of it. PMID- 24630244 TI - Who chooses vasectomy in Rwanda? Survey data from couples who chose vasectomy, 2010-2012. AB - BACKGROUND: Vasectomy is safe and highly effective; however, it remains an underused method of family planning (FP) in Africa. In view of this, three Rwandan physicians were trained in no-scalpel vasectomy with thermal cautery and fascial interposition on the prostatic end as vasectomy trainers in 2010, and this initiative has resulted in over 2900 vasectomy clients from February 2010 to December 2012. STUDY DESIGN: This cross-sectional descriptive study describes vasectomy clients (n=316) and their wives (n=300) from 15 randomly selected hospitals in Rwanda. RESULTS: The vasectomy clients were mainly over age 40, had young children (age <3) and were married and cohabiting. Limited financial resources, satisfaction with existing family size and avoiding side effects from hormonal methods (wives') were key motivators for vasectomy uptake. High rates of previous FP use and high degree of interspousal communication are known correlates of higher FP use. CONCLUSIONS: Future and current Rwandan FP programs and other interested parties will benefit from understanding which couples elect vasectomy, their motivations for doing so and their service utilization experiences. Better integration of vasectomy counseling and postvasectomy procedures will benefit the program. IMPLICATIONS: Until this project, vasectomy projects in sub-Saharan Africa were viewed as unrealistic. This study confirms factors influencing vasectomy uptake identified in earlier research, but does so within a robust sample of vasectomy users and their wives and provides a strong understanding of who likely vasectomy users are in this context. Promotion of vasectomy services should be considered as an essential element of a healthy contraceptive method mix. PMID- 24630245 TI - Characterization of photo-transformation products of the antibiotic drug Ciprofloxacin with liquid chromatography-tandem mass spectrometry in combination with accurate mass determination using an LTQ-Orbitrap. AB - The presence of pharmaceuticals, especially antibiotics, in the aquatic environment is of growing concern. Several studies have been carried out on the occurrence and environmental risk of these compounds. Ciprofloxacin (CIP), a broad-spectrum anti-microbial second-generation fluoroquinolone, is widely used in human and veterinary medicine. In this work, photo-degradation of CIP in aqueous solution using UV and xenon lamps was studied. The transformation products (TPs), created from CIP, were initially analyzed by an ion trap in the MS, MS/MS and MS(3) modes. These data were used to clarify the structures of the degradation products. Furthermore, the proposed products were confirmed by accurate mass measurement and empirical formula calculation for the molecular ions of TPs using LTQ-Orbitrap XL mass spectrometer. The degree of mineralization, the abundance of detected TPs and degradation pathways were determined. Eleven TPs were detected in the present study. TP1, which was never detected before, was structurally characterized in this work. All TPs still retained the core quinolone structure, which is responsible for the biological activity. As mineralization of CIP and its transformation products did not happen, the formation of stable TPs can be expected in waste water treatment and in surface water with further follow-up problems. PMID- 24630246 TI - Hexabromocyclododecane in polystyrene based consumer products: an evidence of unregulated use. AB - Polystyrene (PS) is made flame retardant by combining with hexabromocyclododecane (HBCD). HBCD can release from consumer products during their production, use or disposal. As a result, it has become a ubiquitous contaminant in the environment with a high potential for bioaccumulation. Therefore, to evaluate the extent of exposure to HBCD from PS, we determined the concentration of HBCD in a variety of products (n=34) made from three types of commonly used PS: expanded PS (EPS), extruded PS foam (XPS), and extruded PS. The concentration of HBCD was highest in EPS, with a mean value and range of 475643+/-16710ngg(-1) and 106-960000ngg(-1), respectively. PS related to building construction and laboratory uses had a significantly higher concentration of HBCD (3300-905000ngg(-1)), except XPS styroboard (191+/-100ngg(-1)). Lower concentrations were measured in most food related products (24.3-199ngg(-1)). However, a relatively high concentration of HBCD was detected in an ice box (960000+/-29000ngg(-1)), aquaculture buoy (53500+/-2100ngg(-1)), and disposable tray (8430+/-730ngg(-1)) used in fish market, raising concern for public health. Our data demonstrate a wide variation in the concentration of HBCD, suggesting a lack of proper controls for the addition of HBCD to PS products. Other brominated flame retardants (BFRs) were also detected in a majority of the XPS products (TBBPA=3.83-545ngg(-1), BTBPE=44 216ngg(-1) and DBDPE=215-4200ngg(-1)). Thus, HBCD is being added to PS along with other BFRs that cannot be ignored. PMID- 24630247 TI - Organophosphorus flame retardants (PFRs) in human breast milk from several Asian countries. AB - In this study, the concentrations of 10 organophosphorus flame retardants (PFRs) were determined in 89 human breast milk samples collected from Japan, the Philippines and Vietnam. Among the targeted PFRs, tris(2-chloroexyl) phosphate (TCEP) and triphenyl phosphate (TPHP) were the predominant compounds and were detected in more than 60% of samples in all three countries. The concentrations of PFRs in human breast milk were significantly higher (p<0.05) in the Philippines (median 70 ng g(-1) lipid wt.) than those in Japan (median 22 ng g( 1) lipid wt.) and Vietnam (median 10 ng g(-1) lipid wt.). The present results suggest that the usage of products containing PFRs in the Philippines is higher than those of Japan and Vietnam. Comparing with a previous literature survey in Sweden, the levels of PFRs in human breast milk from the Philippines were 1.5-2 times higher, whereas levels in Japan and Vietnam were 4-20 times lower, suggesting that these differences might be due to their variation in the usage of flame-retarded products utilized in each country. When daily intake of PFRs to infants via human breast milk was estimated, some individuals accumulated tris(2 butoxyethyl) phosphate (TBOEP) and TCEP were close to reference dose (RfD). This is the first report to identify PFRs in human breast milk samples from Asian countries. PMID- 24630249 TI - The effect of different polychlorinated biphenyls on two aquatic models, the green alga Pseudokirchneriella subcapitata and the haemocytes from the European abalone Haliotis tuberculata. AB - The present study was conducted to determine the toxicity of different polychlorinated biphenyls (PCBs) on the green algae, Pseudokirchneriella subcapitata and the haemocytes from the European abalone, Haliotis tuberculata. Using the algal growth inhibition test, the green algae median Effective Concentration (EC50) values ranged from 0.34MUM for PCB28 to more than 100MUM for PCBs 101 and 153. Considering the MTT viability test, the abalone EC50 values ranged from 1.67MUM for PCB153 to 89MUM for PCB28. Our results in contrast to previous observation in vertebrates did not show significant differences between the dioxin like- and non dioxin like-PCBs toxicities regardless of the model used. However, our results demonstrated that the toxicities of PCBs were species dependent. For example, PCB28 was the most toxic compound for P. subcapitata whereas PCBs 1, 180 and 153 were less toxic for that species. On the contrary, PCB153 was reported as the most toxic for H. tuberculata haemocytes and PCB28 the least toxic. To investigate the mode of action of these compounds, we used an in silico method. Our results suggested that PCBs have a non-specific mode of action (e.g., narcosis) on green algae, and another mode of action, probably more specific than narcosis, was reported for PCBs on the abalone haemocytes. PMID- 24630248 TI - Occurrence of antibiotics and antibiotic resistance genes in a sewage treatment plant and its effluent-receiving river. AB - The extensive use of antibiotics has caused the contamination of both antibiotics and antibiotic resistance genes (ARGs) in the environment. In this study, the abundance and distribution of antibiotics and ARGs from a sewage treatment plant (STP) and its effluent-receiving river in Beijing China were characterized. Three classes of antibiotics including tetracycline, sulfonamide and quinolone were quantified by LC-MS/MS. In the secondary effluent they were detected at 195, 2001 and 3866 ng L(-1), respectively, which were higher than in the receiving river water. A total of 13 ARGs (6 tet genes: tetA, tetB, tetE, tetW, tetM and tetZ, 3 sulfonamide genes: sul1, sul2 and sul3, and 4 quinolone genes: gryA, parC, qnrC and qnrD) were determined by quantitative PCR. For all ARGs, sulfonamide resistance genes were present at relatively high concentrations in all samples, with the highest ARG concentration above 10(-1). ARGs remained relatively stable along each sewage treatment process. The abundances of detected ARGs from the STP were also higher than its receiving river. Bivariate correlation analysis showed that relative tet gene copies (tetB/16S-rRNA and tetW/16S-rRNA) were strongly correlated with the concentrations of tetracycline residues (r(2)>0.8, p<0.05), while no significant correlations occurred between sulfonamides and sul genes. A negative correlation between the relative abundance of quinolone resistance gene (qnrC/16S-rRNA) and the concentrations of enrofloxacin (ENR) was also determined. The difference of ARGs levels in the raw influent and secondary effluent suggested that the STP treatment process may induce to increase the abundance of resistance genes. The results showed that the sewage was an important repository of the resistance genes, which need to be effectively treated before discharge into the natural water body. PMID- 24630250 TI - A comparative study of the terrestrial ecotoxicity of selected protic and aprotic ionic liquids. AB - Ionic liquids (ILs) are a fairly new and very promising group of compounds with a vast variety of possible structures and uses. They are considered to be potentially "green", but their impact on the environment tends to be neglected or not studied enough, especially when it comes to terrestrial ecotoxicity, where there are very few studies performed to date. This work presents a comparative study of the terrestrial ecotoxicity of selected representatives of two ILs groups: a new family of protic ILs (derived from aliphatic amines and organic acids) and some frequently used aprotic ILs (substituted imidazolium and piridinium chlorides). Toxicity of the ILs towards three terrestrial plant species (Allium cepa, Lolium perenne and Raphanus sativus) and soil microorganisms involved in carbon and nitrogen transformation was analyzed. Protic ILs have shown no toxic effect in most of the tests performed. The EC50 values for aprotic ILs are various orders of magnitude lower than the ones for protic ILs in all of the tests. The most toxic ILs are the most complex ones in both of the analyzed groups. Protic ILs seem to have a potential for biodegradation in soil, while aprotic ILs exhibit inhibitory effects towards the carbon transforming microbiota. These findings indicate that protic ILs can be considered as less toxic and safer for the terrestrial environment than the aprotic ILs. PMID- 24630251 TI - Quantitative structure-toxicity relationship of the aquatic toxicity for various narcotic pollutants using the norm indexes. AB - The aquatic toxicity value of hazardous contaminants plays an important role in the risk assessments of aquatic ecosystems. The following study presents a stable and accurate structure-toxicity relationship model based on the norm indexes for the prediction of toxicity value (log(LC50)) for 190 diverse narcotic pollutants (96 h LC50 data for Poecilia reticulata). Research indicates that this new model is very efficient and provides satisfactory results. The suggested prediction model is evidenced by R(2) (square correlation coefficient) and ARD (average relative difference) values of 0.9376 and 10.45%, respectively, for the training set, and 0.9264 and 13.90% for the testing set. Comparison results with reference models demonstrate that this new method, based on the norm indexes proposed in this work, results in significant improvements, both in accuracy and stability for predicting aquatic toxicity values of narcotic pollutants. PMID- 24630252 TI - A fullerene colloidal suspension stimulates the growth and denitrification ability of wastewater treatment sludge-derived bacteria. AB - Fullerene (C60) is a nanoparticle that has been widely studied and applied in numerous commodities. However, there are concerns regarding its potential negative impact on the environment. A fullerene colloidal suspension (nC60) is known for its property of selectively inhibiting the growth of microorganisms. In this study, using denaturing gradient gel electrophoresis fingerprinting technology, we found that fullerene altered the structure of a sludge-derived microbial community. Specifically, the bacteria from Bacillus, Acidovorax and Cloacibacterium genera were enriched in abundance when supplemented with nC60 at pH 6.5 under aerobic conditions. The effects of the fullerene colloidal suspension on a strain of Bacillus isolated from the same microbial community were evaluated to further characterize the growth-stimulating effect of nC60. The biomass of cultures of this strain incubated with nC60 concentrations ranging from 3 mg L(-1) to 7 mg L(-1) was approximately twice that of the control during the stationary phase. The fullerene also induced higher superoxide dismutase activity in Bacillus cereus. Furthermore, the nitrate removal rate of B. cereus increased to nearly 55% in the presence of 5 mg L(-1) nC60, compared to 35% for the control. Meanwhile, the cumulative loading amount of nitrite was reduced from 33 MUg mL(-1) to 25 MUg mL(-1) by the addition of 5 mg L(-1) nC60. Our results demonstrate that the fullerene colloidal suspension is conditionally capable of promoting the growth and denitrification metabolism of certain bacteria, such as B. cereus. Fullerene might have both inhibitory and stimulatory effects on microorganisms in various environments. PMID- 24630253 TI - Effects of age, gender and region on serum concentrations of perfluorinated compounds in general population of Henan, China. AB - 133 Serum samples collected from Henan donors aged from 0 to 88years were analyzed for 12 perfluorinated compounds (PFCs). Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) accounted for 69.19% of the total PFCs in serum samples, with a median concentration of 1.43 and 1.47ngmL(-)(1), respectively. Other PFCs were detected at much lower concentrations, with median concentrations ranging from 0.03 to 0.37ngmL(-)(1). PFOA and PFOS were positively correlated (r=0.219) in serum samples, indicating that they may have common exposure pathways. For all donors (0-88years), significant increases in PFOA (r=0.239, p<0.01), perfluorononanoic acid (PFNA) (r=0.185, p<0.05) and PFOS (r=0.175, p<0.05) concentrations over age were found. Median concentrations of PFOA, PFNA, perfluorodecanoic acid (PFDA), and PFOS were higher in males than in females. Higher PFOA concentrations were found in urban populations than in rural populations. Since PFCs exposure in general population is prevalent, further studies are needed to explore its possible impacts on epidemiological factors. PMID- 24630254 TI - Monitoring temporal trends of air pollution in an urban area using mosses and lichens as biomonitors. AB - Monitoring air quality by using living organisms as biomonitors has received increasing attention in recent years. However, rather few studies were based on the concomitant use of passive biomonitoring (based on the different sensitivity of living organisms to air pollution) and active biomonitoring (based on their capacity to accumulate pollutants in the tissues). We carried out a repeated survey of an urban area in Northern Italy, with the objective of comparing temporal trends of different kinds of air pollutants with bioindication (passive biomonitoring) and bioaccumulation (active biomonitoring) techniques. During a five-year interval, temporal patterns of moss metal concentrations underwent significant changes probably due to intercurring variations in the importance of different pollution sources. Nitrogen (N) concentration in moss tissues also decreased and was paralleled by increasing diversity of epiphytic lichens. Increasing delta(15)N in moss tissues suggested a higher contribution of oxidized N species compared with reduced N species. PMID- 24630255 TI - PCDD/F formation from chlorophenols by lignin and manganese peroxidases. AB - Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) formation was studied, in vitro, with two different chlorophenol mixtures (group "di+tri" 2,4-dichlorophenol; 2,3,4-, 2,3,5-, and 3,4,5-trichlorophenols and group "tri+tetra+penta" with 2,4,5-trichlorophenol, 2,3,4,6-tetrachlorophenol and pentachlorophenol) and two different lignolytic enzymes, lignin and manganese peroxidase (LiP and MnP respectively), which can be found during the composting process of sewage sludge. The concentrations of PCDD/F in final samples are compared to the PCDD/F content of the control samples containing the chlorophenols. High increases were observed for experiments with MnP and phosphate buffer. Experiments that contained tri-, tetra- and pentachlorophenol with MnP resulted in more than 8.10(8)ng of OCDD kg(-1) chlorophenol which was much higher than the initial amount (1.10(7)ng OCDD kg(-1) chlorophenol). In relation to LiP experiments, only those at 37 degrees C showed a moderate increase (from 1.3.10(7) to 2.6.10(7)ng of OCDD kg(-1) chlorophenol). The results agree with the literature in which high amounts of HpCDD and OCDD were found after a composting process and could explain the biogenic formation suggested by others, but the incidence on the total toxicity is less than that expected. PMID- 24630256 TI - Impact of a short-term diazinon exposure on the osmoregulation potentiality of Caspian roach (Rutilus rutilus) fingerlings. AB - The stocks of Caspian roach (Rutilus rutilus), an economically important species in the Caspian Sea, are depleting. Each year millions of artificially produced fingerlings of this species are restocked in the mouth of rivers of the Southern Caspian Sea (e.g. Qare Soo River), where they are exposed to pesticides originating from regional rice and orchard fields. This early exposure to pesticides could affect the hypo-osmoregulatory ability of juvenile fish. Thus, in this study, Caspian roach fingerlings were exposed to environmentally-relevant concentrations of the organophosphate insecticide diazinon for 96 h in fresh water and then transferred to diazinon-free brackish water (BW) for another 96 h. We report that cortisol and glucose levels were significantly increased in all diazinon treatments at all sampling time points in comparison to the control group. Moreover, the thyroid hormone levels of TSH, T4, and T3 significantly decreased in diazinon-exposed fish even after the transfer to BW. The electrolytes were differentially affected during the exposure to diazinon and after the transfer to BW. The number of chloride cells in the gill tissue was significantly increased during diazinon exposure at the higher concentrations and decreased to control levels after transfer to BW. Finally, gill and kidney tissues showed many histopathological changes in diazinon-exposed fish even after 240 h in BW. These results suggest that the release of Caspian roach fingerlings into the diazinon-contaminated Caspian Sea regions may alter their physiology and jeopardize their survival, which could lead to a failure in rebuilding the Caspian roach stocks in the Caspian Sea. PMID- 24630257 TI - Bisphosphonates inhibit bone remodeling in the jaw bones of rats and delay healing following tooth extractions. AB - OBJECTIVE: This study aimed to evaluate the impact of concurrent administration of clinically relevant doses of zoledronic acid (ZA) and dexamethasone (DX) on bone healing after tooth extraction (EXO). MATERIALS AND METHODS: Forty-four Sprague-Dawley rats (6-8 month old) were randomized into five groups: ZA + DX = weekly injection of ZA with DX for 7 weeks; WD = ZA with DX for 3 weeks then DX alone for 4 weeks; C = control saline for 7 weeks; ZA = ZA alone for 7 weeks and DX = DX alone for 7 weeks. ZA was administered at 0.13 mg/kg/week and DX at 3.8 mg/kg/week and body weights recorded at the time of injection. All rats underwent extraction (EXO) of the mandibular and maxillary first molars at 3 weeks and were euthanized at 7 weeks. The extracted and non-extracted sides of both jaws were harvested for micro-CT analyses. RESULTS: All rats, particularly those injected with ZA, exhibited weight gain till EXO followed by decline then recovery. ZA + DX group demonstrated highest fractional bone to tissue volume (BV/TV) in the non extracted side. ZA + DX rats exhibited also highest volume and surface of sequestra. Only sequestra volume was statistically higher in the WD group compared to C group. CONCLUSION: Combined treatment with ZA and DX over a prolonged period inhibits bone remodeling and increased sequestra formation to a greater extent than either drug alone. Trauma caused by these sequestra cutting through the mucosa could play a key role in the development of BRONJ by potentially facilitating infection. ZA withdrawal may promote bone-remodeling reactivation following EXO. PMID- 24630258 TI - Etiological factors of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a common disease among southern Chinese. The major etiological factors proposed for NPC pathogenesis include genetic susceptibility, environment factors and EBV infection. In the high risk population, genetic susceptibility to NPC has been mapped to the HLA loci and adjacent genes in MHC region on chromosome 6p21. Consumption of preserved food including salted fish has been implicated in its etiology in earlier studies. Its contribution to pathogenesis of NPC remains to be determined. A decreasing trend of NPC incidence was observed in Hong Kong, Taiwan and Singapore in recent years which may be accounted by a change of dietary habits. A comprehensive epidemiological study will help to elucidate the relative importance of various risk factors in the pathogenesis of NPC. Despite the close association of EBV infection with NPC, the etiological role of EBV in NPC pathogenesis remains enigmatic. EBV infection in primary nasopharyngeal epithelial cells is uncommon and difficult to achieve. EBV does not transform primary nasopharyngeal epithelial cells into proliferative clones, which contrasts greatly with the well documented ability of EBV to transform and immortalize primary B cells. Genetic alterations identified in premalignant nasopharyngeal epithelium may play crucial roles to support stable EBV infection. Subsequently, latent and lytic EBV gene products may drive clonal expansion and transformation of premalignant nasopharyngeal epithelial cells into cancer cells. Stromal inflammation in nasopharyngeal mucosa is believed to play an important role in modulating the growth and possibly drive the malignant transformation of EBV-infected nasopharyngeal epithelial cells. Furthermore, there are increasing evidences supporting a role of EBV infection to evade host immune surveillance. EBV infected cells may have selective growth advantages in vivo by acquiring a stress resistance phenotype. Understanding the etiological factors and pathogenesis of NPC will contribute effectively to the prevention and treatment of this disease. PMID- 24630259 TI - Cervical node of unknown primary: patterns of care and factors influencing the choice of clinical target volumes. PMID- 24630260 TI - Human papillomavirus status of head and neck cancer as determined in cytologic specimens using the hybrid-capture 2 assay. AB - OBJECTIVE: A standardized assay to determine the HPV status of head and neck squamous cell carcinoma (HNSCC) specimens has not yet been established, particularly for cytologic samples. The goal of this study was to determine whether the hybrid capture-2 (HC-2) assay, already widely used for the detection of high risk HPV in cervical brushings, is applicable to cytologic specimens obtained from patients with suspected HNSCCs. MATERIALS AND METHODS: Fine needle aspirates (FNA) of cervical lymph nodes were pre-operatively obtained from patients with suspected HNSCCs and evaluated for the presence of HPV using the HC 2 assay. HPV analysis was performed on the corresponding resected tissue specimens using p16 immunohistochemistry (IHC) and HR-HPV in situ hybridization (ISH). A cost analysis was performed using the Center for Medicare & Medicaid Services. RESULTS: HPV status of the cervical lymph node metastases was correctly classified using the HC-2 assay in 84% (21/25) of cases. Accuracy was improved to 100% when cytologic evaluation confirmed the presence of cancer cells in the test samples. The estimated cost savings to CMS using the HC-2 assay ranged from $113.74 to $364.63 per patient. CONCLUSIONS: HC-2 is a reliable method for determining the HPV status of HNSCCs. Its application to HNSCCs may reduce costs by helping to localize the primary site during the diagnostic work-up as well as decrease the interval time of determining the HPV status which would be relevant for providing prognostic information to the patient as well as determining eligibility for clinical trials targeting this unique patient population. PMID- 24630261 TI - Using parent and youth reports from the Behavior Assessment System for Children, Second Edition to identify individuals at clinical high-risk for psychosis. AB - Brief self-report screening can help facilitate early identification of individuals at risk for or in early stages of psychosis. Existing screening tools focus on self-reported attenuated positive symptoms to detect potential risk; however, parent reports may also be helpful for assessing symptoms, especially in younger patients. Recent evidence has shown that the "atypicality" scale within the self-report form of the Behavior Assessment System for Children, Second Edition (BASC-2) may be useful for identifying high-risk youth within a more clinically comprehensive and potentially minimally stigmatizing format. The BASC 2 parent report form also includes the atypicality scale, but no research has investigated the relation of this scale to psychosis risk. The aim of the current study is to evaluate the association of parent along with youth reports of BASC-2 atypicality with attenuated positive symptoms as assessed by the Structured Interview for Psychosis-Risk Syndromes (SIPS), in a sample of help-seeking adolescents (n=63). Results indicate that both parent and youth reports of atypicality predict clinician-rated symptoms. Moreover, the combination of parent and youth report significantly improved prediction of SIPS scores over either single-informant scale. These findings suggest that parent report scales, as ascertained through part of a larger, commonly used measure, may help identify youth at risk for psychosis, particularly if used in conjunction with youth self report. PMID- 24630262 TI - A six month randomized controlled trial of long acting injectable risperidone 50 and 100mg in treatment resistant schizophrenia. AB - It has been suggested that atypical antipsychotic drugs (A-APDs) other than clozapine may be effective to improve positive symptoms in some patients with treatment resistant schizophrenia (TRS), if both the dose is higher, and the duration of the trial longer, than those which have been ineffective in non-TRS (NTRS) patients. This hypothesis was tested with long acting injectable risperidone (Risperdal Consta(r), RLAI). One hundred sixty TRS patients selected for persistent moderate-severe delusions or hallucinations, or both, were randomized to RLAI, 50 or 100mg biweekly, in a six month, outpatient, double blind, multicenter trial. We hypothesized that RLAI, 100mg, would be more effective than RLAI, 50mg. However, both doses produced clinically significant and equivalent improvement in PANSS Total, Positive, and Negative subscale scores, as well as key cognitive, global and functional measures, with increasing response during the course of the study, confirming the value of longer clinical trial duration for patients with TRS, but not superiority of the higher dose. The overall response rate was comparable to that previously reported for clozapine and high dose olanzapine, another A-APD, in TRS. Both doses of RLAI were equally well tolerated, producing minimal extrapyramidal side effects and few drop outs. Plasma levels of the active moiety, risperidone+9-hydroxyrisperidone, during treatment with RLAI 100mg, were comparable to those for 6-8 mg/day oral risperidone, which have not been effective in TRS. Further study of RLAI, >= 50 100mg biweekly, should compare it with clozapine and oral risperidone in TRS, with duration of treatment >= six months. PMID- 24630263 TI - [Health status of adults with congenital adrenal hyperplasia due to 21 hydroxylase deficiency]. AB - Congenital adrenal hyperplasia (CAH) is the commonest genetic endocrine disorder. Mutations in the 21-hydroxylase gene account for 95 % of cases. CAH is classified according to symptoms and signs and to age of presentation. The clinical phenotype is typically classified as classic, the severe form, or nonclassic (NCF), the mild or late-onset form. Classic CAH is a life-long chronic disorder. In childhood, treatment focuses on genital surgery and optimization of growth and pubertal development. Priorities change with increasing age, typically focusing on fertility in early adult life and prevention of metabolic syndrome and osteoporosis in middle and older age. Recent studies highlight the importance of long-term follow-up of these patients and of transitional care between childhoods to adult life. In nonclassic CAH women, subfertility is mild compared with the classic form and seems to be mainly due to hormonal imbalance. Menstrual cycle or ovulation disorders observed in these women who consulted for infertility are in most cases corrected by hydrocortisone treatment, which led to simultaneous lowering of plasma androgen levels and rapid occurrence of pregnancy. Hydrocortisone also reduces the incidence of miscarriages. Several studies have reported that near 60 % of nonclassic CAH patients are carriers of a severe mutation. These patients may therefore give birth to a child with the classical form of CAH if their partner is also carrying a severe mutation. Due to the high frequency of CYP21A2 mutations in the general population, it is essential to genotype the partner of NC-CAH patients with one severe mutation to offer genetic counselling. PMID- 24630264 TI - [Cutaneous human papillomavirus infection by EVER2 gene mutation]. PMID- 24630265 TI - [Ketamine in acute and severe major depressive disorder]. AB - CONTEXT: Depression is a frequent, severe and expensive illness. Approximately 20% of depressive episodes are resistant to classic antidepressants. Glutamatergic antagonists, in particular ketamine, established a new, rapid and robust therapeutic approach in resistant depression. RESULTS: The main results in the literature show a rapid and robust antidepressant effect of ketamine, with infra-anesthesic posology (0.5mg/kg) administered in intravenous way. Positive effects are observed on depressive symptoms, suicidal thoughts, and there is a potential synergic action when used in the induction of anesthesia for electroconvulsive therapy. However, effects only last shortly. Side effects are mostly reversible and of mild intensity, no severe consequences were reported. LIMITS: Limits are the lack of power of the included studies, due to small sample sizes, and the scarcity of studies. Misuse of ketamine is an important issue to be taken into account, and few data about ketamine addiction potential and its long-term effects are published at the moment. PMID- 24630266 TI - Pathogenesis of immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody mediated platelet destruction. The platelet, as an accessible target, has made ITP an attractive disorder in the study of autoimmunity. However, the pathogenesis of ITP has proven complex with diverse pre-existing challenges to the immune system in the form of infection, genetic predisposition, underlying autoimmune repertoire, inhibition of platelet production, perturbations of cell mediated affector and effector pathways, sequestered harbors within lymphoid organs, and responsiveness to intervention. This chapter surveys key new insights into the pathogenesis of ITP and attempts to integrate them into a model that may serve as a template for future investigation. PMID- 24630267 TI - [Intense physical exercise, muscle involvement and statin use]. PMID- 24630268 TI - [Iatrogenic dependence to meperidine in the elderly]. PMID- 24630269 TI - Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency. AB - Biotinidase deficiency is an autosomal recessively inherited metabolic disorder that can be easily and effectively treated with pharmacological doses of the vitamin, biotin. Untreated children with profound biotinidase deficiency may exhibit neurological, cutaneous and cellular immunological abnormalities, specifically candida infections. To better understand the immunological dysfunction in some symptomatic individuals with biotinidase deficiency, we studied various aspects of immunological function in a genetically engineered knock-out mouse with biotinidase deficiency. The mouse has no detectable biotinidase activity and develops neurological and cutaneous symptoms similar to those seen in symptomatic children with the disorder. Mice with profound biotinidase deficiency on a biotin-restricted diet had smaller thymuses and spleens than identical mice fed a biotin-replete diet or wildtype mice on either diet; however, the organ to body weight ratios were not significantly different. Thymus histology was normal. Splenocyte subpopulation study showed a significant increase in CD4 positive cells. In addition, in vitro lymphocyte proliferation assays consistently showed diminished proliferation in response to various immunological stimuli. Not all symptomatic individuals with profound biotinidase deficiency develop immunological dysfunction; however, our results do show significant alterations in cellular immunological function that may contribute and/or provide a mechanism(s) for the cellular immunity abnormalities in individuals with biotinidase deficiency. PMID- 24630271 TI - Taliglucerase alfa: an enzyme replacement therapy using plant cell expression technology. AB - Gaucher disease (GD) is a rare, genetic lysosomal storage disorder caused by functional defects of acid beta-glucosidase that results in multiple organ dysfunction. Glycosylation of recombinant acid human beta-glucosidase and exposure of terminal mannose residues are critical to the success of enzyme replacement therapy (ERT) for the treatment of visceral and hematologic manifestations in GD. Three commercially available ERT products for treatment of GD type 1 (GD1) include imiglucerase, velaglucerase alfa, and taliglucerase alfa. Imiglucerase and velaglucerase alfa are produced in different mammalian cell systems and require production glycosylation modifications to expose terminal alpha-mannose residues, which are needed for mannose receptor-mediated uptake by target macrophages. Such modifications add to production costs. Taliglucerase alfa is a plant cell-expressed acid beta-glucosidase approved in the United States and other countries for ERT in adults with GD1. A plant-based expression system, using carrot root cell cultures, was developed for production of taliglucerase alfa and does not require additional processing for postproduction glycosidic modifications. Clinical trials have demonstrated that taliglucerase alfa is efficacious, with a well-established safety profile in adult, ERT-naive patients with symptomatic GD1, and for such patients previously treated with imiglucerase. These included significant improvements in organomegaly and hematologic parameters as early as 6months, and maintenance of achieved therapeutic values in previously treated patients. Ongoing clinical trials will further characterize the long-term efficacy and safety of taliglucerase alfa in more diverse patient populations, and may help to guide clinical decisions for achieving optimal outcomes for patients with GD1. PMID- 24630270 TI - Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes. AB - OBJECTIVE: To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). STUDY DESIGN: UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12 month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. RESULTS: Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] MUmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] MUmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. CONCLUSIONS: Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment. PMID- 24630273 TI - Peptidergic intraepidermal nerve fibers in the skin contribute to the neuropathic pain in paclitaxel-induced peripheral neuropathy. AB - Paclitaxel in chemotherapy-induced peripheral neuropathy (CIPN) is predominantly with a dose-limiting effect on neuropathic pain in clinical strategy. In the present study, the relationship between the neuropathic pain and nerve degeneration in paclitaxel CIPN was investigated. Adult male Sprague-Dawley (SD) rats were divided into three paclitaxel groups (0.5, 1.0, 2.0mg/kg) and a vehicle group with four intraperitoneal (i.p.) injections on alternating days. Our results demonstrated that the paclitaxel groups significantly exhibited the reductions of thermal hyperalgesia and mechanical allodynia. The neurotoxicity of paclitaxel conveyed the degeneration of intraepidermal nerve fibers (IENFs) in hindpaw glabrous skin. Nevertheless, the influence of paclitaxel to the peptidergic IENFs are even unknown. The skin innervation of protein gene product 9.5 (PGP 9.5)-immunoreactive (IR) IENFs in paclitaxel groups revealed the decreasing levels of density (73.54+/-0.72%, 63.17+/-1.77%, 61.79+/-2.68%, respectively; vs. vehicle group, p<0.05) throughout the entire experimental period. Additionally, the diminishing levels of density for peptidergic substance P (SP)-IR IENFs in paclitaxel groups were significantly shown (48.84+/-1.74%, 30.02+/-1.69%, 30.14+/-0.37%, respectively; vs. vehicle group, p<0.05). On the contrary, the density for peptidergic calcitonin gene-related peptide (CGRP)-IR IENFs in paclitaxel groups were revealed the similar decreasing levels (82.75+/ 0.91%, 84.34+/-3.20%, 81.99+/-0.25%, respectively; vs. vehicle group, p<0.05). Linear regression analyses exhibited that densities of IENFs for PGP 9.5, SP, CGRP were correlated with withdrawal latencies (r(2)=0.77, p<0.0001; r(2)=0.75, p<0.0001; r(2)=0.28, p=0.0001, respectively) and mechanical thresholds (r(2)=0.43, p<0.0001; r(2)=0.73, p<0.0001; r(2)=0.40, p<0.0001, respectively). Therefore, the present results suggested that the development of neuropathic pain following paclitaxel injection induced the progressive degeneration of IENFs in skin and gave the evidence that the peptidergic IENFs may play an important role in therapeutic strategy of paclitaxe CIPN. PMID- 24630272 TI - Cocaine-and-Amphetamine Regulated Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: lack of sex differences. AB - Cocaine-and-Amphetamine Regulated Transcript peptide (CART peptide) is known for having an inhibitory effect on dopamine (DA)- and cocaine-mediated actions and is postulated to be a homeostatic, regulatory factor in the nucleus accumbens (NAc). Some sex differences in cocaine-mediated locomotor activity (LMA) and in the expression and function of CART peptide have been reported. However, it is not known if the inhibitory effect of CART peptide on cocaine-mediated LMA is sexually dimorphic. In this study, the effects of CART 55-102 on LMA due to intra NAc DA and i.p. cocaine were determined in male and female Sprague-Dawley rats. The results show that CART 55-102 blunted or reduced both the DA- and cocaine induced LMA in both males and females. In conclusion, CART peptide is effective in blunting DA- and cocaine-mediated LMA in both males and females. PMID- 24630274 TI - Elimination of socioeconomic and racial disparities related to lung cancer: closing the gap at a high volume community cancer center. AB - BACKGROUND: Healthcare disparities have afflicted the healthcare industry for decades and there have been many campaigns in recent years to identify and eliminate disparities. The purpose of this study was to identify disparities in the lung cancer population of a single community cancer center and to report the results in accordance with industry goals. METHODS: This was a retrospective cohort study of data on non-small cell lung cancer patients recorded in the Christiana Care Tumor Registry (CCTR) in Delaware. Gender, age, race, socioeconomic status and insurance status were used as potential variables in identifying disparities. RESULTS: We found no significant disparities between sexes, race or patients who were classified as having socioeconomic status 1-3. There was a lower survival rate associated with having the poorest socioeconomic status and in patients who used Medicare. Uninsured patients had the best survival outcomes and patients with Medicare had the poorest survival outcomes. CONCLUSION: Although we have closed the gap on sex and racial disparities, there remains a difference in survival outcomes across socioeconomic classes and insurance types. PMID- 24630275 TI - CAPOX associated with toxicities of higher grade but improved disease-free survival when compared with FOLFOX in the adjuvant treatment of stage III colon cancer. AB - INTRODUCTION/BACKGROUND: Adjuvant treatment of colon cancer relies on fluoropyrimidine-containing regimens as the intravenous formulation, 5-FU, or its oral prodrug, CA, combined with oxaliplatin (FOLFOX and CAPOX). There is currently no clinical trial comparing the 2 regimens; however, both are considered standard of care treatment options. MATERIALS AND METHODS: We performed a retrospective chart review comparing average relative dose intensity (ARDI), percentage of intended total dose (PITD), overall survival (OS), DFS, and toxicity profiles of these regimens. The patients (n = 176) received either modified FOLFOX6 (n = 93) or CAPOX (n = 83). RESULTS: Oxaliplatin ARDI (80.72% vs. 87.11%; P = .0033) and PITD (70.09% vs. 88.11%; P = .0013) was significantly lower in those treated with CAPOX compared with FOLFOX. CA ARDI (87.10% vs. 93.60%; P < .0001) and PITD (77.19% vs. 88.11%; P = .0006) was significantly lower than 5-FU dosing. Patients treated with CAPOX had more >= Grade 2 toxicities and trended toward more dose-limiting toxicities. Survival analysis demonstrated a trend toward improved OS with CAPOX (hazard ratio [HR], 0.4741; 95% confidence interval [CI], 0.1660-1.354; P = .1663) and improved DFS with CAPOX (HR, 0.4949; 95% CI, 0.2512-0.9749; P = .0420). Multivariate analysis demonstrated similar results with CAPOX being associated with a trend toward improved OS (HR, 0.396; 95% CI, 0.110-1.429; P = .1571) and DFS (HR, 0.458; 95% CI, 0.210-1.001; P = .0504). CONCLUSION: Patients receiving CAPOX had significantly lower ARDI and PITD compared with FOLFOX, but showed trends toward improved outcomes when treated with CAPOX in the adjuvant setting when compared with FOLFOX. PMID- 24630276 TI - Family presence during cardiopulmonary resuscitation could make more natural organ donation. PMID- 24630277 TI - Mechanism-based therapy of genetic neurological disease. PMID- 24630278 TI - Trust but verify: the introduction of plagiarism detection software. PMID- 24630279 TI - No PEDs in pediatrics. PMID- 24630280 TI - Increased association between febrile convulsion and allergic rhinitis in children: a nationwide population-based retrospective cohort study. AB - BACKGROUND AND OBJECTIVES: Febrile convulsions and allergic rhinitis are both common childhood disorders and both are considered as generally benign disorders. Yet, especially in the case of allergic rhinitis, adverse effects on school performance and limited socialization are found. The relationship between febrile convulsions and allergic rhinitis has not been previously reported; thus, this article seeks to explore the association between these two disorders by collecting data from the Taiwanese nationwide cohort database. METHODS: A total of 1304 children with febrile convulsions were identified as the case cohort, and controls were matched based on age, sex, urbanization levels, and parents' occupation on a 1 to 4 ratio. Cox's proportional hazards regression model was used to estimate the hazard ratio and confidence interval of allergic rhinitis disorder among children with febrile convulsions. RESULTS: During an average 6.7 years follow-up period, the incidence of allergic rhinitis in the febrile convulsions case group was higher (65.16 vs 51.45 per 1000 person-years). After 11 years of follow-up, the allergic rhinitis incidence in the febrile convulsion patients was approximate 4% higher than controls (log-rank test P < 0.0001). Risk of allergic rhinitis in the febrile convulsions group was found to be 1.21 times higher than in the control group (95% confidence interval, 1.08-1.36). This risk of allergic rhinitis development is further increased (0.94 vs 18.9) with frequency of febrile convulsions-related medical visits (one to three visits vs more than three visits, P < 0.0001). CONCLUSION: Febrile convulsions may be associated with allergic rhinitis occurrence in children. Children with more than three febrile convulsion-related medical visits had a significantly higher cumulative incidence of allergic rhinitis. Both disorders have previously been reported to have similar cytokine profiles and specific viral infection association. More studies are required to explore a possible link between the two disorders. PMID- 24630281 TI - The GABAA receptor gamma2 subunit (R43Q) mutation in febrile seizures. AB - BACKGROUND: Febrile seizure is the most common form of childhood seizure. Although its exact cause is unclear, many researchers emphasize the importance of its genetic predisposition. Recent genetic studies revealed the importance of the mutations of the gamma-aminobutyric acid A receptor as the etiology of the febrile seizures. R43Q mutation affecting the gamma2-subunit N-terminal domain has been related to childhood absence epilepsy and febrile seizure. METHODS: We investigated R43Q mutations of the GABRG2 gene, located on the long arm of chromosome 5 encoding the gamma2-subunit of the gamma-aminobutyric acid A receptor. We studied 44 patients with febrile seizure and 49 children without any febrile seizure who were admitted to our clinic. RESULTS: We found that 36% of our patient group, the children who experienced febrile convulsions, had heterozygous R43Q mutation. Statistical studies revealed that heterozygous R43Q mutation of gamma-aminobutyric acid A receptor gamma2 subunit was higher in the study group than in the control group (P < 0.01). CONCLUSIONS: Heterozygous gamma aminobutyric acid A receptor gamma2 subunit (R43Q) mutation may have an effect in the development of febrile seizures. PMID- 24630282 TI - Long-term neurocognitive outcome and quality of life in pediatric acute disseminated encephalomyelitis. AB - BACKGROUND: Acute disseminated encephalomyelitis is an inflammatory-demyelinating disorder of the central nervous system usually with a monophasic course and a favorable neurological outcome. Long-term neurocognitive sequelae and quality of life have not yet been fully investigated. AIM: To examine neurocognitive outcome and quality of life in pediatric monophasic acute disseminated encephalomyelitis. METHODS: Of the 36 patients diagnosed with acute disseminated encephalomyelitis at our institution, six were lost to follow-up and eight relapsed (two with multiphasic forms and six with multiple sclerosis). The outcome of the 22 remaining patients was evaluated using four subscales of the Wechsler Intelligence Scales for estimation of IQ, a battery of neuropsychological tests, and semistructured and PedsQL questionnaires for quality of life. The effect of age at onset, neuroradiological recovery, and time elapsed from the acute event on outcome was also investigated. RESULTS: Estimated IQ, neuropsychological mean group scores, and quality of life at follow-up were within the normal range, but 23% of the patients had pathological scores in various neuropsychological functions, among which attention was the most clearly affected. The neuroradiological recovery was not correlated with the result of the neuropsychological tests. Age at onset correlated with linguistic skills, whereas the time elapsed from the acute event had a significant effect on attention tasks: scores were worse in the group of patients with a follow-up shorter than 7 years. CONCLUSION: Our results suggest that pediatric monophasic acute disseminated encephalomyelitis has a favorable neurocognitive outcome. Patients with longer follow-up had a better outcome, suggesting a neurocognitive course that is different from that of multiple sclerosis and a potential for long-term recovery of affected functions. PMID- 24630283 TI - Molecular diagnosis of fragile X syndrome using methylation sensitive techniques in a cohort of patients with intellectual disability. AB - BACKGROUND: Fragile X syndrome, the most common form of inherited intellectual disability, is caused by expansion of CGG trinucleotide repeat at the 5' untranslated region of the FMR1 gene at Xq27. In affected individuals, the CGG repeat expansion leads to hypermethylation and the gene is transcriptionally inactive. Our aim was to identify fragile X syndrome among children with intellectual disability in Saudi Arabia. PATIENTS AND METHODS: The study included 63 patients (53 males, 10 females) presented with intellectual disability, 29 normal subjects, and 23 other family members. DNA samples from six patients previously diagnosed with fragile X syndrome by Southern blot technique were used as positive controls. The method was based on bisulfite treatment of DNA followed by two different techniques. The first technique applied polymerase chain reaction amplification using one set of primers specific for amplifying methylated CpG dinucleotide region; another set designed to amplify the unmethylated CGG repeats. The second technique used the methylation-specific melting curve analysis for detection of methylation status of the FMR1 promoter region. RESULTS: Molecular testing using methylation sensitive polymerase chain reaction had shown amplified products in all normal subjects using unmethylated but not methylated primers indicating normal alleles, whereas amplified products were obtained using methylated polymerase chain reaction primers in fragile X syndrome-positive samples and in 9 of 53 males, indicating affected individuals. Molecular testing using melting curve analysis has shown a single low melting peak in all normal males and in (44/53) patients indicating unmethylated FMR1 gene, whereas high melting peak indicating methylated gene was observed in the fragile X syndrome-positive samples and in 9 of 53 patients. We found 100% concordance between results of both techniques and the results of Southern blot analysis. Three samples have shown both methylated and unmethylated alleles, indicating possible mosaicism. No female patients or carriers could be detected by both techniques. CONCLUSION: The technique can be applied for the rapid screening for fragile X syndrome among patients with intellectual disability. The impact of mosaicism on clinical severity needs further investigation. PMID- 24630284 TI - Therapeutic plasma exchange for malignant refractory status epilepticus: a case report. AB - BACKGROUND: Refractory status epilepticus is a prolongation of status epilepticus despite anticonvulsant therapy with two or three medications in proper doses; it is defined as malignant status epilepticus if it takes weeks or months. Intravenous immunoglobulin, high-dose steroids, magnesium infusion, pyridoxine, hypothermia, ketogenic diet, electroconvulsive therapy, and surgical therapy are the other treatment options for status epilepticus. PATIENT: Our 5-year-old male patient was hospitalized at our pediatric intensive care unit because of status epilepticus secondary to meningoencephalitis. No response could be obtained with many medical and nonmedical therapies in our patient, who developed malignant status epilepticus with unknown etiology. Therapeutic plasma exchange was applied as convulsions continued. RESULT: Ours is the first child for whom therapeutic plasma exchange was successfully applied because of malignant refractory status epilepticus secondary to meningoencephalitis. CONCLUSION: Therapeutic plasma exchange may be a treatment option for children with refractory status epilepticus following presumed meningoencephalitis. PMID- 24630285 TI - Kleine-Levin syndrome: a case report and review of literature. AB - BACKGROUND: Kleine-Levin syndrome presents with recurrent hypersomnia along with a number of other neuropsychiatric features, of which hyperorality has not been described frequently. METHOD: We report a male adolescent who presented with recurrent hypersomnia, hypersexuality, and hyperorality. Magnetic resonance imaging of the brain and overnight polysomnography followed by a multiple sleep latency tests were ordered. Excessive daytime sleepiness was assessed with the Epworth Sleepiness Scale. RESULTS: Magnetic resonance imaging of the brain did not reveal any abnormality. Overnight video-synchronized polysomnography and multiple sleep latency tests ruled out narcolepsy. Epworth Sleepiness Scale score at baseline was 22. He was prescribed lithium carbonate 300 mg twice a day. The symptoms improved within a week after starting lithium carbonate therapy. CONCLUSION: Kleine-Levin syndrome may present with hyperorality, and our patient responded well to lithium carbonate therapy. PMID- 24630286 TI - A novel two-nucleotide deletion in the ATP7A gene associated with delayed infantile onset of Menkes disease. AB - BACKGROUND: Determining the relationship between clinical phenotype and genotype in genetic diseases is important in clinical practice. In general, frameshift mutations are expected to produce premature termination codons, leading to production of mutant transcripts destined for degradation by nonsense-mediated decay. In X-linked recessive diseases, male patients with frameshift mutations typically have a severe or even lethal phenotype. PATIENT: We report a case of a 17-month-old boy with Menkes disease (NIM #309400), an X-linked recessive copper metabolism disorder caused by mutations in the ATP7A copper transporter gene. He exhibited an unexpectedly late onset and experienced milder symptoms. STUDY AND RESULT: His genomic DNA showed a de novo two-nucleotide deletion in exon 4 of ATP7A, predicting a translational frameshift and premature stop codon, and a classic severe phenotype. Characterization of his ATP7A mRNA showed no abnormal splicing. CONCLUSION: We speculate that translation reinitiation could occur downstream to the premature termination codon and produce a partially functional ATP7A protein. Study of the child's fibroblasts found no evidence of translation reinitiation; however, the possibility remains that this phenomenon occurred in neural tissues and influenced the clinical phenotype. PMID- 24630287 TI - Kohlschutter-Tonz syndrome: clinical and genetic insights gained from 16 cases deriving from a close-knit village in Northern Israel. AB - BACKGROUND: Kohlschutter-Tonz syndrome (KTS; MIM 22675) is a rare autosomal recessive disorder characterized by intellectual impairment, spasticity, epilepsy, and amelogenesis imperfecta. We have recently identified the causative gene and mutation underlying KTS, namely, p.R157X, corresponding to ROGDI c.571C>T, which creates a premature stop codon in ROGDI homolog (Drosophila), a gene of unknown function, in KTS patients of Druze origin. PATIENTS: To better delineate the phenotype of KTS, 16 cases (eight female, eight male), from seven families (five kindreds) originating from a Druze village in Northern Israel, all homozygous for the same deleterious mutation, were investigated. Medical records were reviewed, and a detailed medical history was obtained by interview of parents. RESULTS: Age at onset between six and 12 months of age and the intensity of convulsions were variably manifested by affected sibs and mirror the progression of mental and motor deterioration. Amelogenesis imperfecta and deficient speech occur in all cases. By late adolescence and early twenties, individuals with KTS are bedridden, fed by a gastrostomy tube, spastic, and practically have no cognitive and language perception. CONCLUSIONS: KTS, a genetic disease heralded by convulsions, "yellow teeth," and severe mental impairment, allows for a clinical variability as regarding age of onset and severity of seizures that per se predict the speed of mental deterioration. In all cases, however, the morbid course of the disease is ultimately equally devastating by the twenties. PMID- 24630288 TI - Does the co-occurrence of FGFR3 gene mutation in hypochondroplasia, medial temporal lobe dysgenesis, and focal epilepsy suggest a syndrome? AB - BACKGROUND: Hypochondroplasia is a rare skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, and limited extension of the elbow caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that plays a role in controlling nervous system development. Hypochondroplasia with FGFR3 mutation associated with bilateral medial temporal lobe anomalies and focal epilepsy was previously reported in several patients. PATIENT: We report clinical, electroclinical, and neuroradiological findings of one patient affected by hypochondroplasia. RESULTS: Clinical diagnosis was confirmed by molecular analysis of the FGFR3 gene, which showed a N540 K mutation. The patient had normal psychomotor development and showed early-onset focal seizures with left temporal localization on interictal and ictal electroencephalograph. The seizures were well controlled, and the patient has been seizure-free since infancy. Magnetic resonance imaging showed abnormal anteriorly posteriorly infolding in the hippocampus and abnormally oriented parahippocampus sulci, and additional cortical rim dysplasia with gray-white matter junction blurring in the hippocampus. CONCLUSIONS: The present case of hypochondroplasia and FGFR3 mutation in Asn540Lys associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy underscores the possibility of a rare syndrome. PMID- 24630289 TI - Anti-Ma2-associated paraneoplastic encephalitis in a male adolescent with mediastinal seminoma. PMID- 24630290 TI - Imaging findings associated with methylmalonic aciduria. PMID- 24630291 TI - Female sexual function and the clitoral complex using pelvic MRI assessment. AB - OBJECTIVE: To report basic measurements of clitoral anatomy, and explore potential relationships between the clitoral complex and female sexual function using MRI assessment. STUDY DESIGN: In this retrospective descriptive study, 20 sexually active women (>=18 years) who had a recent pelvic MRI for various gynecologic concerns were invited to participate. Outcome measures included demographic data, medical and sexual history, quality of life questionnaires: Female Sexual Function Index (FSFI), Body Exposure during Sexual Activities Questionnaire (BESAQ), and Short Form Quality of Life Questionnaire (SF-12). These data were then compared to detailed clitoral MRI measurements and analyzed using the Pearson correlation and Chi square test. RESULTS: FSFI domains of desire, arousal, lubrication, and orgasm were inversely correlated with clitoral size (p=0.01-0.04), as were SF-12 physical composite scores (p=0.003), suggesting improved sexual function and physical health in women with smaller clitoral structures (specifically the clitoral body and crus). CONCLUSION: Sexual function was improved in women with a smaller-sized clitoris, specifically the clitoral body and crus. PMID- 24630292 TI - Bladder endometriosis: characterization by magnetic resonance imaging and the value of documenting ureteral involvement. AB - OBJECTIVES: To characterize bladder endometriosis by MRI and assess aspects of ureteral involvement. STUDY DESIGN: From 2007 to 2013, bladder endometriosis was diagnosed, surgically treated and histopathologically verified in 18 patients (mean age 31.7+/-4.6 years) retrospectively enrolled under a published MRI protocol at our hospital's Endometriosis Center. Preoperatively, to diagnose disease spread, cystoscopy was performed and MRI in the following sequences: T2 TSE and T1-SE with and without fat saturation in the sagittal and transversal planes after rectovaginal opacification. Nine patients additionally underwent a diffusion-weighted sequence, including calculation of the apparent diffusion coefficient (ADC). By consensus, two experienced radiologists, without prior knowledge of the surgical or cystoscopic findings, retrospectively characterized bladder endometriosis on the MRI scans, also determining anatomic position, size, sequence-dependent features and incidence of hemorrhages, and calculating ADC. The scans were also investigated to determine if MRI could detect ureteral involvement intercurrent with bladder endometriosis. RESULTS: Endometriosis localizations were bladder roof, n=1 (5.6%) and back wall, n=17 (94.4%). Mean lesion size was 3.65+/-1.5ml. Lesions exhibited a lower signal intensity in T2- than in T1-weighted images. High-signal-intensity spots showed an occurrence of 72.2% in fat-suppressed T1-weighted and 61.1% in T2-weighted sequences. Mean ADC was 1251.6+/-220.9mm(2)/s. By MRI, it was not possible to differentiate wall layers and hence infiltration depth. The bladder endometriosis of two women showed direct involvement with the right ureter. Furthermore, one woman had endometriosis of the left distal ureter in addition to bladder endometriosis. All cases of ureteral involvement were detected by MRI. CONCLUSIONS: Characteristic MRI features of bladder endometriosis were found to be low signal intensity in T2 weighted and high-signal-intensity spots in T1- and T2-weighted sequences. Standard-sequence MRI was capable of detecting ureteral involvement, but not bladder wall infiltration depth. PMID- 24630293 TI - Impact on ovarian reserve after laparoscopic ovarian cystectomy with reduced port number: a randomized controlled trial. AB - OBJECTIVES: Single-port access (SPA) laparoscopic ovarian cystectomy has been reported as a comparable procedure to conventional laparoscopy in terms of operative outcomes. However, whether ovarian function after SPA laparoscopic surgery is similar to conventional laparoscopy is questioned due to the limitations in moving instruments. The aim of this study was to evaluate whether the reduced port number affects the ovarian reserve after laparoscopic ovarian cystectomy. STUDY DESIGN: This was a randomized controlled trial of 87 women with benign ovarian cyst, who attended a university hospital and were scheduled for laparoscopic ovarian cystectomy. Women were randomized to SPA, two-port access (TPA), or four-port access (FPA) laparoscopic groups. The primary outcome was the serum anti-Mullerian hormone (AMH) levels: preoperative, 1 week, 1 month and 3 months after the operation. Secondary outcomes were operative outcomes. RESULTS: The mean serum AMH levels of preoperative, 1 week, 1 month and 3 months after laparoscopy were 4.4+/-2.9, 2.7+/-2.2, 2.3+/-1.9, and 2.5+/-1.5ng/mL (in the SPA group), 3.6+/-2.5, 2.3+/-2.2, 2.6+/-3.2, and 2.7+/-2.6ng/mL (in the TPA group), and 3.9+/-3.2, 2.4+/-2.1, 2.5+/-2.0, and 2.8+/-2.2ng/mL (in the FPA group), respectively. There was no statistically significant difference in the serial change of AMH levels among the SPA, TPA and FPA groups. CONCLUSIONS: The laparoscopic ovarian cystectomy with reduced port number does not affect the serial change of ovarian reserve. The SPA or TPA laparoscopy may be the alternative method to conventional laparoscopy in terms of ovarian reserve. PMID- 24630294 TI - Risk of gestational diabetes mellitus in patients undergoing assisted reproductive techniques. AB - OBJECTIVE: To compare the incidence of gestational diabetes mellitus (GDM) between pregnancies conceived spontaneously and pregnancies conceived following assisted reproductive technology (ART). STUDY DESIGN: This cross-sectional study evaluated the medical records of 215 women who conceived spontaneously and 145 women who conceived following ART from September 2011 to October 2012. Exclusion criteria were: polycystic ovary syndrome, maternal age >=40 years, family history of diabetes in first-degree relatives, pre-pregnancy diabetes, glucose intolerance treated with hypoglycaemic agent (e.g. metformin), history of GDM, history of stillbirth, recurrent miscarriage, history of baby with birth weight >=4kg (macrosomia), parity >3, Cushing syndrome, congenital adrenal hyperplasia and hypothyroidism. For better comparison of the incidence of GDM, the ART group was further subdivided into: (i) an in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) group (n=95); and (ii) an intrauterine insemination (IUI) group (n=50). The diagnosis of GDM was based on the criteria of the American Diabetes Association. RESULTS: The incidence of GDM was significantly higher in the IVF/ICSI and IUI groups (43% and 26%, respectively) compared with the spontaneous pregnancy group (10%). Age, pre-pregnancy body mass index (BMI) and weight gain in pregnancy were similar among women with GDM in all three groups. In addition, the incidence of pregnancy-induced hypertension was significantly higher in the IVF/ICSI group (21%) compared with the spontaneous pregnancy group (7%). Logistic regression analysis demonstrated four strong risk factors for GDM: age, BMI, mode of ART and progesterone use during pregnancy. CONCLUSION: This study indicated that the risk of GDM is two-fold higher in women with singleton pregnancies conceived following ART compared with women who conceived spontaneously. In addition, progesterone use during pregnancy was found to be an important risk factor for GDM. This subject requires further study. PMID- 24630295 TI - Vitamin D intake and endometriosis: the good and the bad. PMID- 24630296 TI - Can neonatal sepsis be predicted in late preterm premature rupture of membranes? Development of a prediction model. AB - OBJECTIVE: Women with late preterm premature rupture of membranes (PROM) have an increased risk that their child will develop neonatal sepsis. We evaluated whether neonatal sepsis can be predicted from antepartum parameters in these women. STUDY DESIGN: We used multivariable logistic regression to develop a prediction model. Data were obtained from two recent randomized controlled trials on induction of labor versus expectant management in late preterm PROM (PPROMEXIL trials, (ISRCTN29313500 and ISRCTN05689407). Data from randomized as well as non randomized women, who consented to the use of their medical data, were used. We evaluated 13 potential antepartum predictors for neonatal sepsis. Missing data were imputed. Discriminative ability of the model was expressed as the area under the receiver operating characteristic (ROC) curve and a calibration with both a calibration plot and the Hosmer and Lemeshow goodness-of-fit test. Overall performance of the prediction model was quantified as the scaled Brier score. RESULTS: We studied 970 women. Thirty-three (3.4%) neonates suffered neonatal sepsis. Maternal age (OR 1.09 per year), maternal CRP level (OR 1.01 per mmol/l), maternal temperature (OR 1.80 per degrees C) and positive GBS culture (OR 2.20) were associated with an increased risk of neonatal sepsis. The model had an area under the ROC-curve of 0.71. The model had both a good calibration and accuracy. CONCLUSIONS: Antepartum parameters aid in the more precise prediction of the risk of neonatal sepsis in women with late preterm PPROM. PMID- 24630297 TI - Mental models of pregnancy may explain low adherence to folic acid supplementation guidelines: a cross-sectional international survey. AB - OBJECTIVE: Mental models of pregnancy refer to women's perceptions of whether their pregnancies are susceptible to poor health outcomes. Mental models influence health behaviour during pregnancy. In the present study we examined whether mental models of pregnancy are linked to compliance with folic acid supplementation guidelines. STUDY DESIGN: Cross-sectional survey implemented in four countries (France, Germany, Belgium, and Poland) of women planning a pregnancy (pregnancy planners, n=325) or within the first 18 weeks of pregnancy (currently pregnant, n=326). Logistic regression was used to examine the association between mental models of pregnancy (i.e. whether women felt susceptible to the health consequences of not taking folic acid supplements), maternal background, and use of folic acid supplements. RESULTS: Most women (82.8%) had heard of folic acid but only 45.5% were taking folic acid supplements. Use of folic acid supplements did not differ between pregnancy planners and currently pregnant women. Women who believed that they had good general and obstetric health (e.g. no history of illness or miscarriage) and those living in adverse health environments (e.g. smoking, living in poverty) had mental models of being insusceptible to the health consequences of not taking folic acid supplements (p<0.001) and were the lowest users of folic acid supplements (p<0.01). Mediation analyses showed that perceived susceptibility was the common pathway through which the seemingly disparate predictors of folic acid supplementation (i.e. maternal background characteristics) operate. CONCLUSIONS: Maternal background characteristics may shape women's mental models of pregnancy and its susceptibility to health complications. Mental models could therefore be the common factor explaining poor adherence to folic acid supplementation guidelines. Findings suggest that in the 'invulnerable mum' mental model, perceived susceptibility to health threats is reduced because the good health of the mother is believed to protect the pregnancy from threat, whereas in the 'invulnerable pregnancy' mental model, perceived susceptibility is reduced because pregnancy is viewed as naturally robust or immune to risk. The challenge for the practitioner wanting to increase adherence to periconceptional health advice is to elicit and correct patients' erroneous beliefs about pregnancy. PMID- 24630298 TI - A red fluorescent nude mouse model of human endometriosis: advantages of a non invasive imaging method. AB - OBJECTIVES: To establish red fluorescent human endometriosis lesions in a nude mouse model and dynamically and non-invasively to compare intraperitoneal and subcutaneous injection models. STUDY DESIGN: Primary cultures of endometrial stromal cells (ESCs) and epithelial cells (EECs) isolated from 24 patients with a normal uterine cavity were transfected with 2.5*10(8) (Group 1) and 1.25*10(8) (Group 2) plaque-forming units (PFU) of adenovirus encoding red fluorescent protein (Ad-RFP). Transfection efficiencies, fluorescence intensity and apoptosis rate of the two types of cells were compared in vitro. A mixture of 2.5*10(8) PFU Ad-RFP-infected approximately 400 EECs cell mass and 2*10(6) ESCs for 36h was injected individually into 24 female nude mice subcutaneously (Group A) or intraperitoneally (Group B). From Day 5 after injection, an in vivo imaging system (IVIS) was used to non-invasively observe and compare the lesions of the two groups every week until Day 33. Specifically, the fluorescent intensity, positive rates, persistence time and lesion weight in the implanted human endometriosis lesions were compared. A parametric Student's t-test and two-way analysis of variance were used for statistical analysis. RESULTS: Compared with 1.25*10(8) PFU RFP, a titre of 2.5*10(8) PFU RFP ESCs and EECs incubated for 36h exhibited higher transfection efficiencies and higher fluorescence intensities in vitro. In vivo imaging of the fluorescent human endometriosis lesions originating from an RFP titre of 2.5*10(8) PFU showed that the intensity and lesion weight in Group A were significantly higher than in Group B. However, the two groups had the same RFP-positive rates and fluorescence persistence. The structure of each lesion was evaluated by immunohistochemistry to confirm its human endometrial origin. CONCLUSIONS: The red fluorescent human endometriosis model established by subcutaneously injecting 2.5*10(8) PFU RFP-transfected stromal cells and epithelial cells into nude mice had a higher fluorescent positive rate from Day 5, higher intensity and weight but the same persistence as the intraperitoneal injection model. PMID- 24630299 TI - Effects of urinary incontinence subtypes on women's quality of life (including sexual life) and psychosocial state. AB - OBJECTIVE: Our aim was to investigate the effects of urinary incontinence subtypes on women's quality of life (including sexual life) and psychosocial state. STUDY DESIGN: The patients, who applied to our clinic from March 2011 to August 2011, were identified and stratified into three groups: those with stress incontinence proved urodynamically (USI), those with urge incontinence (UI), and those with mixed incontinence urge incontinence (UI) proved by urodynamic and clinic evaluation. Scores on the Beck anxiety inventory (BAI), pelvic organ prolapse/urinary incontinence sexual questionnaire (PISQ-12), urogenital distress inventory (UDI-6), and incontinence impact questionnaire (IIQ-7) were compared between the urinary incontinence subtypes. RESULTS: According to urodynamic and clinical examination of 111 women with urinary incontinence, 59 (53%) had USI, 35 (32%) had UI, and 17 (15%) had MI. BAI-scores significantly differed between the USI and UI groups (p=0.030) and between the USI and MI groups (p=0.011) not between the UI and MI groups (p=0.597). UDI-6 scores did not significantly differ between the three groups (p=0.845). IIQ-7 scores significantly differed between the USI and MI groups (p=0.003) and between the UI and MI groups (p=0.006) but not between the USI and UI groups. Patients with USI had significantly lower PISQ 12 scores than those with UI (p=0.015). CONCLUSIONS: These differences in the effects of incontinence subtypes should be kept in mind in the evaluation of patients with urinary incontinence. Psychiatric assessment may improve the management of incontinence in women, especially UI and MI. PMID- 24630300 TI - Three-dimensional computerized tomographic angiography for diagnosis and management of intractable postpartum hemorrhage. AB - OBJECTIVE: To report our experience on the value of dynamic three-dimensional computerized tomographic (CT) angiography for immediate diagnosis and management of intractable postpartum hemorrhage (PPH). STUDY DESIGN: Retrospective study of all cases of PPH examined by three-dimensional CT angiography between January 2007 and August 2013 in a single center. In each case, emergency dynamic CT was taken at the early arterial, late arterial and venous phases to identify the extravasated contrast agent that represents active hemorrhage. Images for three dimensional CT angiography were reconstituted from multiplanar CT images. Based on these findings, management procedures were individually determined and those outcomes were compared with angiographic, surgical and clinical findings. RESULTS: Twenty-nine cases with primary PPH and 19 cases with secondary PPH were examined. In primary PPH, extravasation in the early arterial phase was noted in 12 cases. Those included vulvovaginal hematoma (n=4), invasive placenta (n=2), retained placenta (n=2), uterine atony (n=1), retroperitoneal hematoma (n=1), retrovesical hematoma (n=1) and rectus sheath hematoma after cesarean section (n=1). Of these, ten cases were treated by transcatheter arterial embolization (TAE) of the offending vessels with or without additional therapies. In secondary PPH, extravasation was identified in 14 cases. Those included invasive placenta (n=8), uterine artery pseudoaneurysm (n=3), uterine arteriovenous fistula (n=2), and subinvolution of placenta bed (n=1), which were treated by TAE of the offending vessels with or without additional therapies. Successful hemostasis with fertility preservation was achieved in all cases. Complications were not identified except for a case of placenta increta that developed secondary amenorrhea after TAE of both uterine arteries. In subsequent gestation after TAE of both uterine arteries, normal vaginal delivery (n=4), uncomplicated cesarean delivery (n=3), cesarean delivery followed by recurrent arteriovenous fistula (n=1) and spontaneous miscarriage followed by recurrent invasive placenta (n=1) were identified. CONCLUSIONS: This case series emphasizes that three-dimensional CT angiography has significant diagnostic value when the appropriate procedure for management of PPH was immediately determined to avoid potential maternal morbidity and mortality. PMID- 24630301 TI - Hyperreactio luteinalis: timely diagnosis minimizes the risk of oophorectomy and alerts clinicians to the associated risk of placental insufficiency. AB - Hyperreactio luteinalis (HL) is a rare benign condition complicating pregnancy with multicystic bilateral ovarian enlargement, increased serum betahCG levels and spontaneous regression after delivery. HL has been associated with complications of pregnancy and the aim of our research was to review the literature, and add a new unpublished case from our group. We searched the internet-based medical databases for case reports and case series of hyperreactio luteinalis and we evaluated diagnostic path, treatment and outcome of pregnancies. We found 96 cases of HL from 1955 to 2013. HL was asymptomatic in 28% of cases but in 72% of patients there were symptoms like lower abdominal pain, nausea and vomiting, ascites and signs of virilization. Suspicion of malignancy was raised in 38% of cases. Surgical treatment of various types was performed in 48% of cases, with oophorectomy in 40% of this group. Several complications were associated with HL, in particular preeclampsia (PE) occurred in 24% of cases and fetal growth restriction (FGR) in 12%. Mean gestation at delivery was 35 weeks (range 25-42). Although preoperative diagnosis occurred in most cases, suspicion of malignancy was extensive, as was oophorectomy, demonstrating suboptimal understanding of the underlying physiopathology. We propose a diagnostic algorithm for this condition. Training of obstetricians in making the correct diagnosis may prevent unnecessary oophorectomies and may lead to early diagnosis and correct management of associated complications. PMID- 24630302 TI - Full-thickness endometriosis of the bladder: report of 31 cases. AB - OBJECTIVE: To draw attention to the rare condition of endometriosis in the bladder. This is correlated with symptoms not normally connected to endometriosis and therefore often remains underdiagnosed for years. DESIGN AND SETTING: Retrospective study in a university teaching hospital, one of two referral centres in Denmark for surgical treatment of stage III and IV endometriosis. POPULATION: Thirty-one women with deep infiltrating bladder endometriosis. METHODS: All women presenting in the Department of Obstetrics and Gynaecology with deep infiltrating bladder endometriosis between March 2002 and March 2011. We included only patients with symptomatic full-thickness bladder detrusor endometriosis and mucosal involvement. All patients had had bladder symptoms for two to seven years. MAIN OUTCOME MEASURES: Symptoms after surgery and recurrence rate. RESULTS: The main preoperative symptom was urinary frequency. All patients had significant relief of symptoms after operation, and none had recurrence of the bladder endometriosis judged by ultrasound or reported symptoms. Twenty-six (87%) patients had endometriosis in another location as well. Eight had nodules in the recto-vaginal septum. Complete surgical excision of all associated endometriotic lesions was carried out during the same surgical procedure. During the mean follow-up period of 59 months no long-term complications were diagnosed. CONCLUSION: Bladder endometriosis should be considered in patients who present with irritative urological symptoms with aggravation during menstruation or in patients with a history of endometriosis. When patients have symptoms we recommend surgical treatment in cases where medical treatment fails. PMID- 24630303 TI - Of stewardship, motherhood and apple pie. AB - Antibiotic stewardship is universally agreed to be desirable, but optimal models for stewardship remain uncertain. UK stewardship targets the particular antibiotic families-cephalosporins and fluoroquinolones-blamed for the selection of Clostridium-difficile-associated disease. To balance this there have been dramatic increases in the use of penicillin-beta-lactamase inhibitor combinations. By channelling selection pressure in this way, we hazard destroying the utility of these antibiotic classes in turn, as happened with gonorrhoea where penicillins, fluoroquinolones and cefixime were sequentially lost as therapies. Strikingly, in context, almost all carbapenemase-producers are highly resistant to penicillin-beta-lactamase inhibitor combinations, which may select for them. There is an urgent need to explore an alternative stewardship model, seeking to limit total antibiotic use but to maintain heterogeneity in what is used, avoiding concentrated selection pressure. There is also a great need to improve and accelerate diagnostics for infection and resistance, reducing or removing the need for protracted empirical treatment with broad-spectrum agents. PMID- 24630305 TI - Baseline prevalence of antimicrobial resistance and subsequent infection following prostate biopsy using empirical or altered prophylaxis: A bias-adjusted meta-analysis. AB - Transrectal ultrasound-guided prostate biopsy (TRUSPB) is a commonly performed urological procedure. Recent studies suggest that pre-biopsy screening for fluoroquinolone-resistant (FQ-R) pathogens may be useful in reducing post-biopsy infections. We sought to determine the baseline prevalence of fluoroquinolone (FQ) resistance in rectal flora and to investigate the relationship between pre biopsy carriage of FQ-R pathogens and the risk of post-TRUSPB infection. Electronic databases were searched for related literature. Studies were assessed for methodological quality and comparable outcomes prior to meta-analysis (using quality- and random-effects models). Nine studies, representing 2541 patients, were included. The prevalence of FQ resistance was higher (20.4%, 95% CI 18.2 22.6%) in rectal cultures obtained following FQ-based prophylaxis compared with those obtained before (12.8%, 95% CI 10.7-15.0%). Overall infection rates in patients using empirical prophylaxis were higher (3.3%, 95% CI 2.6-4.2%) than in those using altered (targeted/protocol) regimens (0.3%, 95% CI 0-0.9%). Higher infection rates were seen in men with FQ-R rectal cultures (7.1%, 95% CI 4.0 10.5%) than in those with FQ-sensitive (FQ-S) rectal cultures (1.1%, 95% CI 0.5 1.8%). For every 14 men with FQ-R rectal cultures, one additional infection was observed compared with men with FQ-S rectal cultures. Prior FQ use and prior genitourinary infection were significant risk factors for FQ-R colonisation. FQ resistance in rectal flora is a significant predictor of post-TRUSPB infection and may require re-assessment of empirical antimicrobial prophylaxis methods. Altered prophylaxis based on rectal culturing prior to TRUSPB may reduce morbidity and potentially provide economic benefits to health services. PMID- 24630306 TI - Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009-2012. AB - Here we evaluated the frequency of occurrence and antimicrobial susceptibility patterns of Gram-negative bacteria isolated from patients hospitalised with pneumonia in medical centres in the USA (n=28) and Europe and the Mediterranean region (EMR) (n=25) in 2009-2012. Susceptibility testing was performed by reference broth microdilution methods. Overall, 12851 isolates were collected (6873/5978 in USA/EMR). The same top 11 organisms were observed in both geographic regions, but in different rank orders, and Gram-negative organisms represented 61.5/76.1% of strains in USA/EMR. Pseudomonas aeruginosa was the most frequently isolated Gram-negative organism in both regions (20.9/20.9% of cases in USA/EMR) and showed reduced susceptibility to most antimicrobials tested, including ceftazidime (79.6/68.7% susceptibility in USA/EMR), meropenem (76.3/65.8%) and piperacillin/tazobactam (72.9/63.9%). Klebsiella spp. was isolated from 9.7/11.6% of cases and showed extended-spectrum beta-lactamase (ESBL) phenotype rates of 19.5/35.1% in USA/EMR. Meropenem and amikacin were active against 62.3/78.7% and 60.8/85.2% of ESBL phenotype Klebsiella spp. from USA/EMR, respectively. Enterobacter spp. ranked fourth in the USA (5.9%) and sixth in EMR (5.5%), whereas Escherichia coli ranked fifth in the USA (5.5%) and third in EMR (11.8%). Acinetobacter spp. and Stenotrophomonas maltophilia combined were isolated from 8.0/10.7% of cases in USA/EMR. A significant increase in P. aeruginosa susceptibility to meropenem and a significant decrease in gentamicin susceptibility among Klebsiella spp. were noted in EMR. These results confirm that very few agents remain broadly active against the most frequently isolated Gram-negative organisms from patients with pneumonia in US and EMR medical centres. PMID- 24630307 TI - Prevalence and characteristics of fluoroquinolone-resistant Aerococcus urinae isolates detected in Switzerland. PMID- 24630304 TI - Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI Study. AB - The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2 22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (rho = 0.79, P = 0.0021) and trough (rho = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients. PMID- 24630308 TI - [Euthanasia and/or medically assisted suicide: Reflection on the new responsibility of the hospital pharmacist]. AB - CONTEXT: Concern about euthanasia and medically assisted suicide is currently growing around the world and particularly in France. Though not authorized at present in France, the role of hospital pharmacist in this issue needs to be discussed. OBJECTIVES: This article aims to gather medical and legal literature of European Union member states on these issues and particularly in France. To propose a practical thinking on the possible role of hospital pharmacist. RESULTS: Among European Union, euthanasia and/or assisted suicide have already been introduced in some member states' laws. In France, Leonetti law currently sets the legal framework for the management of end of life. To address the society's demand on these issues, French President F. Hollande made two ethics committees responsible for working on it. Both were mainly against euthanasia and assisted suicide. Though a bit forgotten in this debate, hospital pharmacist needs to be associated in the thinking, as the main "drug-keeper". Indeed, guidelines are necessary to outline and ensure a safe drug use, complying with professional ethics, if lethal doses are voluntarily prescribed. CONCLUSION: Pharmaceutical work is in constant evolution and is addressing new issues still unanswered, including assisted suicide and euthanasia. French pharmaceutical authorities should seize upon them, in order to guarantee pharmaceutical ethics. These practices, if authorized by law, should remain exceptional, and law strictly enforced. The pharmacist could be one of these "lawkeepers". PMID- 24630309 TI - [Integration of a hospital pharmacist in the ICU]. AB - The French regulatory system strongly encourages strict regulation of health products' production and distribution, especially concerning risk management and economic aspects. An ICU is an unusual environment for a local pharmacy practice (a nurse for every 2.5 patients, continuous adaptation of therapeutics...). However, a literature review reports interesting data concerning risk management and economics. This article aims to relate the experience of a pharmacist integration in a French teaching hospital ICU (half-time position). PMID- 24630310 TI - Differentiating amorphous mixtures of cefuroxime axetil and copovidone by X-ray diffraction and differential scanning calorimetry. AB - The amorphous, molecular solid dispersion of cefuroxime axetil and copovidone with the mass ratio 71/29 is compared to its pure components in the amorphous state and to an amorphous mechanical mixture with the same mass ratio. Calorimetric studies demonstrate that all these materials are vitreous. By using X-ray diffraction profiles, a clear difference can be observed between the local order of the solid dispersion and that of the mechanical mixture. More generally, it is shown how the presence or absence of additivity in the diffraction data can be used to distinguish between different amorphous mixtures. PMID- 24630311 TI - In vitro microbiological evaluation of novel bis pyrazolones. AB - Two series of bis pyrazolones (one with 3-methyl substituent and the other one with 3-amino substituent on the pyrazolone ring) were synthesized by the cyclization reaction between various hydrazides with esters/cyano esters in ethanolic medium. Structures of newly synthesized compounds were confirmed by elemental analysis, IR, (1)H NMR and mass spectral data. These compounds were screened for antibacterial and antifungal activities. The compounds of series 3 with amino substituent demonstrated better activity than the compounds of series 2 with methyl substituent on the pyrazolone ring. Compounds "e, f, c and d" showed higher antimicrobial activity than the compounds "b and a". The antimicrobial potentials of the synthesized compounds were compared with that of standards. PMID- 24630312 TI - Antifungal and antibacterial activity of marine microorganisms. AB - In order to explore marine microorganisms with pharmaceutical potential, marine bacteria, collected from different coastal areas of the Moroccan Atlantic Ocean, were previously isolated from seawater, sediment, marine invertebrates and seaweeds. The antimicrobial activities of these microorganisms were investigated against the pathogens involved in human pathologies. Whole cultures of 34 marine microorganisms were screened for antimicrobial activities using the method of agar diffusion against three Gram-positive bacteria, two Gram-negative bacteria, and against yeast. The results showed that among the 34 isolates studied, 28 (82%) strains have antimicrobial activity against at least one pathogen studied, 11 (32%) strains have antifungal activity and 24 (76%) strains are active against Gram-positive bacteria, while 21 (62%) strains are active against Gram-negative bacteria. Among isolates having antimicrobial activity, 14 were identified and were assigned to the genera Acinetobacter, Aeromonas, Alcaligenes, Bacillus, Chromobacterium, Enterococcus, Pantoea and Pseudomonas. Due to a competitive role for space and nutrient, the marine microorganisms can produce antibiotic substance; therefore, these marine microorganisms were expected to be potential resources of natural antibiotic products. PMID- 24630313 TI - [Oral administration of medications to infants: Implementation of a preliminary risk analysis in a hospital service of pediatrics]. AB - PURPOSE: The objective of this study was to reduce the risk of errors when administering oral medications to infants aged 28 days to 2 years. MATERIAL AND METHODS: The method of the preliminary risk analysis (PRA) was implemented by a multidisciplinary group in a hospital service of pediatrics. The study focused on the phase of preparation of drugs by nurses before administration. RESULTS: This analysis revealed 41 scenari, 16 were criticality unacceptable. In particular, their analysis highlighted the impact of the drug dosage form, the lack of scientific information and the human factor on this preparation. Eleven action sheets have been written. DISCUSSION: The risk management requires significant human investment, material resources and organizational solutions: formations, information, i.e. computerized prescribing, dispensing and administering system, centralized drug preparations, automated drugs cabinets or unit drug daily dispensing system. CONCLUSION: Control these risks means to get specific actions at pediatric wards, enhance dispensing system by the hospital pharmacist and the support of the pharmaceutical industry to get commercially available pediatric drugs. PMID- 24630314 TI - [Perception of vaccination and role of the pharmacist: A survey among final year pharmacy students in France]. AB - INTRODUCTION: In France, the " HPST " law of 21 July 2009 assigns new responsibilities to pharmacists. Given the fact that the majority of vaccination coverage targets set by the Public Health Act of August 9, 2004 is not met, the question arises in how far pharmacies in town can contribute to better promotion and accessibility of vaccination. The objective of this investigation was to describe the perception of vaccination by final year pharmacy students and how they see their future professional contribution to improving vaccination coverage. METHODS: A cross-sectional study was conducted in February 2013 using a questionnaire sent by email to all final year students enrolled in a French school of pharmacy. RESULTS: Among the 293 responding student (9.8% of the target population), 96% declared to be in favor of vaccination somewhat or strongly. The results for students in favor (not in favor) were as follows: the most frequently sources of influence for opinion on vaccination were university training 84% (83%), the personal doctor 38% (50%), health authorities 31% (33%). Ninety percent (83%) and over were fully vaccinated against diphtheria, tetanus, polio, measles and hepatitis B, and 43% (27%) were satisfied with their medical school training on vaccination. Eighty-six percent of students were in favor of transmitting customers pharmaceutical sales data (" Dossier Pharmaceutique ") to individual electronic vaccination records. With regard to vaccination in pharmacies, 69% (42%) of students were in favor given medical prescription, 54% (33%) upon prescription by the pharmacist, 43% (50%) if administered by a nurse and 69% (42%) within the context of certification system for vaccination in pharmacies. DISCUSSION: Within the limits of bias possibly introduced by the low response rate, the results of this survey suggest that future pharmacists can be considered strategic partners improving vaccination coverage. The influence which university training can on vaccination perception have should be optimised. PMID- 24630315 TI - [Preparation of citrulline microspheres by spray drying technique for colonic targeting]. AB - INTRODUCTION: Citrulline is an amino acid that becomes essential in situations of intestinal insufficiency such as short bowel syndrome. It is therefore interesting to provide the patients with dosage forms for routing citrulline to the colon. The aim of this work is to formulate microspheres of citrulline for colonic targeting by the technique of spray drying. MATERIAL AND METHODS: Eudragit((r)) FS 30D was selected as polymer to encapsulate citrulline using the spray drying technique. Citrulline and Eudragit((r)) FS 30D were dissolved in water and ethanol, respectively. The aqueous and the ethanolic solutions were then mixed in 1:2 (v/v) ratio. Microspheres were obtained by nebulizing the citrulline-Eudragit((r)) FS 30D solution using a Mini spray dryer equipped with a 0.7mm nozzle. The microspheres have been formulated using citrulline and Eudragit((r)) FS 30D. The size distribution of microspheres was determined by light diffraction. The morphology of the microspheres was studied by electron microscopy. Manufacturing yields, encapsulation rate and dissolution profiles were also studied. RESULTS AND DISCUSSION: The microspheres obtained had a spherical shape with a smooth surface and a homogeneous size except for the microspheres containing the highest concentration of polymer (90 %). The formulation showed that the size and morphology of the microspheres are influenced by the polymer concentration. Manufacturing yields were about 51 % but encapsulation rate were always very high (above 90 %). The in vitro dissolution study showed that the use of the Eudragit((r)) FS 30D under these conditions is not appropriate to change the dissolution profile of the citrulline. CONCLUSION: This technique has led to the formulation of microspheres with good physical properties in terms of morphology and size. The compression of the microspheres should help to control citrulline release for colonic targeting. PMID- 24630316 TI - Guideline on management of solitary pulmonary nodule. AB - The aim of the proposed recommendations is be a tool to facilitate decision making in patients with a solitary pulmonary nodule (SPN). For an optimal decision, accessibility to the different diagnostics techniques and patient preferences need to be incorporated. The first assessment, which includes a chest computed tomography scan, separates a group of patients with extrapulmonary neoplasm or a high surgical risk who require individualized management. Another two groups of patients are patients with SPN up to 8mm and those who have a subsolid SPN, for which specific recommendations are established. SPN larger than 8mm are classified according to their probability of malignancy into low (less than 5%), where observation is recommended, high (higher than 65%), which are managed with a presumptive diagnosis of localized stage carcinoma, and intermediate, where positron emission tomography-computed tomography has high yield for reclassifying them into high or low probability. In cases of intermediate or high probability of malignancy, transbronchial needle aspiration or biopsy of the nodule may be an option. Radiologic observation with low radiation computed tomography without contrast is recommended in SPN with low probability of malignancy, and resection with videothoracoscopy in undiagnosed cases with intermediate or high probability of malignancy. PMID- 24630317 TI - Recurrent tracheoesophageal fistula in children with repaired esophageal atresia and the usefulness of flexible bronchoscopy. PMID- 24630318 TI - [Naso-ethmoido-maxillary protrusion (NEMP): a specific dysmorphosis]. AB - Naso-ethmoido-maxillary protrusion (NEMP) is a rare dental and facial dysmorphosis, with excessive growth of basicranium, ethmoid, maxillary, and nasal bones. The clinical presentation includes nasal and upper lip protrusion, telecanthus, a class 2 malocclusion with maxillary protrusion and exoclusion. The craniofacial field is increased in Delaire's analysis. Contrary to isolated maxillary protrusion secondary to membranous ossification dysfunction, NEMP is a constitutional anomaly resulting from an excessive primary growth of the chondrocranium. The therapeutic management of NEMP should take into account these specificities. PMID- 24630319 TI - Research focused mainly on bias will paralyse forensic science. PMID- 24630320 TI - Direct detection of blood in fingermarks by MALDI MS profiling and imaging. AB - The determination of the presence of blood in fingermarks constitutes important intelligence in a criminal investigation as it helps to reconstruct the events that have taken place at a scene of crime. Various methodologies have been reported and are currently employed for the detection of the presence of blood including optical, spectroscopic and chemical development approaches. However, most methods only give an indication that blood may be present and, therefore, these methods are described as presumptive tests. Here we show the use of Matrix Assisted Laser Desorption Ionisation Mass Spectrometry Profiling and Imaging (MALDI MSP and MALDI MSI) for the determination of the presence of blood in fingermarks by specifically detecting the molecules of haem and haemoglobin through their mass-to-charge ratios. Furthermore, preliminary experiments are shown which demonstrate that this technology is compatible with other methods currently employed for enhancing fingermarks in blood (or contaminated by blood). The application of the developed protocols to a crime scene blood trace, demonstrates the feasibility of using this technology in routine casework. These findings open up a new line of research for the development of robust MALDI MSP and MALDI MSI protocols for the detection and chemical imaging of bloodied marks. PMID- 24630321 TI - Application of laser induced breakdown spectroscopy to examination of writing inks for forensic purposes. AB - The research was focused on the analysis of writing inks using the laser induced breakdown spectroscopy (LIBS) technique. 34 samples of blue, 30 of black, and 21 of red writing inks were analyzed under optimized conditions to determine the variation of chemical composition of inks between different colours, brands and types. Nine elements (Ba, Cr, Cu, Fe, Li, Mo, Mn, Ni and W) were taken into account during comparative analysis of inks. Because of the strong effect of the paper spectrum, elements often found in inks (Ca, Al, Mg, Na, Ti, and Si) were eliminated from LIBS analysis of inks. It was determined that the LIBS method is capable of revealing qualitative elemental differences between ink samples. The discrimination power of this method was found to be 83, 82 and 61% for blue, black and red inks, respectively. Inks produced by the same producer were able to be differentiated in some cases. The results showed the potential of LIBS for forensic purposes as an effective and robust technique, requiring a small amount of sample and giving analytical information in a very short time. PMID- 24630322 TI - Evaluation of LumicyanoTM cyanoacrylate fuming process for the development of latent fingermarks on plastic carrier bags by means of a pseudo operational comparative trial. AB - There are a number of studies discussing recent developments of a one-step fluorescent cyanoacrylate process. This study is a pseudo operational trial to compare an example of a one-step fluorescent cyanoacrylate product, LumicyanoTM, with the two recommended techniques for plastic carrier bags; cyanoacrylate fuming followed by basic yellow 40 (BY40) dyeing and powder suspensions. 100 plastic carrier bags were collected from the place of work and the items were treated as found without any additional fingermark deposition. The bags were split into three and after treatment with the three techniques a comparable number of fingermarks were detected by each technique (average of 300 fingermarks). The items treated with LumicyanoTM were sequentially processed with BY40 and an additional 43 new fingermarks were detected. LumicyanoTM appears to be a suitable technique for the development of fingermarks on plastic carrier bags and it can help save lab space and time as it does not require dyeing or drying procedures. Furthermore, contrary to other one-step cyanoacrylate products, existing cyanoacrylate cabinets do not require any modification for the treatment of articles with LumicyanoTM. To date, there is little peer reviewed articles in the literature on trials related to LumicyanoTM and this study aims to contribute to fill this gap. PMID- 24630323 TI - A comparison of the use of vacuum metal deposition versus cyanoacrylate fuming for visualisation of fingermarks and grab impressions on fabrics. AB - Both vacuum metal deposition (VMD) and cyanoacrylate fuming (CAF) are techniques used to visualise latent fingermarks on smooth non-porous surfaces such as plastic and glass. VMD was initially investigated in the 1970s as to its effectiveness for visualising prints on fabrics, but was abandoned when radioactive sulphur dioxide was found to be more effective. However, interest in VMD was resurrected in the 1990s when CAF was also used routinely. We now report on studies to determine whether VMD or CAF is the more effective technique for the detection of marks on fabrics. Four different fabrics, nylon, polyester, polycotton and cotton, were utilised during this study, along with 15 donors who ranged in their age and ability to leave fingermarks, from good to medium to poor, thus reflecting the general population. Once samples were collected they were kept for a determined time (1, 2, 3, 4, 5, 6, 7, 14, 21 or 28 days) and then treated using either the gold and zinc metal VMD process or standard cyanoacrylate fuming. The smoother fabrics, such as nylon, consistently produced greater ridge detail whereas duller fabrics, like cotton tended only to show empty prints and impressions of where the fabric had been touched, rather than any ridge details. The majority of fabrics did however allow the development of touch marks that could be targeted for DNA taping which potentially could lead to a DNA profile. Of the two techniques VMD was around 5 times more effective than CAF, producing a greater amount of ridge detail, palmar flexion creases and target areas on more samples and fabrics. PMID- 24630324 TI - Experimental forensic studies of the preservation of pollen in vehicle fires. AB - The implications of the recent recommendations of the Law Commission regarding the use of admissibility tests have the potential to be far reaching for forensic disciplines that rely on the expertise of highly qualified expert witnesses. These disciplines will need a concomitant body of peer-reviewed experiments that provides a basis for the interpretations of such evidence presented in court. This paper therefore, presents such results from two experiments which were undertaken to address specific issues that were raised in cases presented in the British courtroom. These studies demonstrate that there is a variability in the persistence of Lily, Daffodil and Tulip pollen when exposed to high temperatures between 0.5min and 1440min (24h). It was possible to identify all three pollen types after 30min of exposure to 400 degrees C, and after shorter time frames the threshold for successful identification was 700 degrees C after 0.5min for all pollen types tested and 500 degrees C for Daffodil and Lily after 5min of heat exposure. Over longer time periods (18h (1080min)) the different pollen types were found to persist in a viable form for identification at 300 degrees C (Lily), 200 degrees C (Daffodil) and 50 degrees C (Tulip). These findings, albeit from a small sample of pollen types, provide empirical contextual information that would contribute to such evidence having sufficient scientific weight to meet admissibility criteria and be viable evidence for a court. These studies demonstrate the value in seeking pollen evidence from even such extreme crime scenes as encountered in vehicular fires. PMID- 24630325 TI - A collaborative approach for incorporating forensic case data into crime investigation using criminal intelligence analysis and visualisation. AB - There is an increasing awareness that the articulation of forensic science and criminal investigation is critical to the resolution of crimes. However, models and methods to support an effective collaboration between the partners are still poorly expressed or even lacking. Three propositions are borrowed from crime intelligence methods in order to bridge this gap: (a) the general intelligence process, (b) the analyses of investigative problems along principal perspectives: entities and their relationships, time and space, quantitative aspects and (c) visualisation methods as a mode of expression of a problem in these dimensions. Indeed, in a collaborative framework, different kinds of visualisations integrating forensic case data can play a central role for supporting decisions. Among them, link-charts are scrutinised for their abilities to structure and ease the analysis of a case by describing how relevant entities are connected. However, designing an informative chart that does not bias the reasoning process is not straightforward. Using visualisation as a catalyser for a collaborative approach integrating forensic data thus calls for better specifications. PMID- 24630326 TI - Perception problems of the verbal scale. AB - Many forensic scientists use a verbal scale to describe the significance or weight to be attached to their opinion. Although there is a considerable amount of work in the field of psychology regarding people's perception of quantitative descriptors such as those used in the verbal scale, there has been no published work relating to the use of such descriptors in a forensic context. Our aim was to assess the extent to which the verbal expressions used by the expert in court are perceived and the extent to which they are differentiated by potential jurors. Four hundred volunteers were asked to indicate the level of strength they perceived from the use of the verbal scale characters within excerpts from purported expert witness statements. Although preliminary, these results show that there are serious misunderstandings of the verbal scale. It does not achieve the purpose for which it was created. The terms used are unlikely to be understood properly by lay people and it would appear that they are actually misunderstood. PMID- 24630327 TI - The effect of frame rate on the ability of experienced gait analysts to identify characteristics of gait from closed circuit television footage. AB - Forensic gait analysis is increasingly being used as part of criminal investigations. A major issue is the quality of the closed circuit television (CCTV) footage used, particularly the frame rate which can vary from 25 frames per second to one frame every 4s. To date, no study has investigated the effect of frame rate on forensic gait analysis. A single subject was fitted with an ankle foot orthosis and recorded walking at 25 frames per second. 3D motion data were also collected, providing an absolute assessment of the gait characteristics. The CCTV footage was then edited to produce a set of eight additional pieces of footage, at various frame rates. Practitioners with knowledge of forensic gait analysis were recruited and instructed to record their observations regarding the characteristics of the subject's gait from the footage. They were sequentially sent web links to the nine pieces of footage, lowest frame rate first, and a simple observation recording form, over a period of 8 months. A sample-based Pearson product-moment correlation analysis of the results demonstrated a significant positive relationship between frame rate and scores (r=0.868, p=0.002). The results of this study show that frame rate affects the ability of experienced practitioners to identify characteristics of gait captured on CCTV footage. Every effort should therefore be made to ensure that CCTV footage likely to be used in criminal proceedings is captured at as high a frame rate as possible. PMID- 24630328 TI - Raman identification of drug of abuse particles collected with colored and transparent tapes. AB - Raman microscopy is a useful tool for the analysis of drug particles collected with adhesive tapes. In this work, first, the spectra of thirty drugs of abuse, degradation products, metabolites, and common cutting agent standards were recorded and the Raman bands observed were summarized providing the forensic analyst useful information for the identification of drug evidence. Then, the collection of different drug particles by a fingerprint lifting tape commonly used to remove and store fingerprints and fibers, and a white and green packaging tape, followed by the subsequent identification of the drugs by confocal Raman spectroscopy was performed. The particles were analyzed on top of the tapes, trapped between glass slides and the tapes, trapped in the tape folded over itself in the case of the transparent tape, and after folding and unfolding the tape in the case of the colored tape. The results obtained by the different approaches show that both tapes did not compromise the drugs spectra. However, the use of transparent tape is preferred because this tape allows the previous visual detection of the particles. Finally, several drug and sugar particles were spread over a clean table and inside a pocket, and the particles were collected with transparent tape and then properly identified. Although good results were obtained in both cases, the amount of fibers and other substances present in the collection area made the previous detection of the particles difficult and increases the analysis time. PMID- 24630329 TI - On the added value of forensic science and grand innovation challenges for the forensic community. AB - In this paper the insights and results are presented of a long term and ongoing improvement effort within the Netherlands Forensic Institute (NFI) to establish a valuable innovation programme. From the overall perspective of the role and use of forensic science in the criminal justice system, the concepts of Forensic Information Value Added (FIVA) and Forensic Information Value Efficiency (FIVE) are introduced. From these concepts the key factors determining the added value of forensic investigations are discussed; Evidential Value, Relevance, Quality, Speed and Cost. By unravelling the added value of forensic science and combining this with the future needs and scientific and technological developments, six forensic grand challenges are introduced: i) Molecular Photo-fitting; ii) chemical imaging, profiling and age estimation of finger marks; iii) Advancing Forensic Medicine; iv) Objective Forensic Evaluation; v) the Digital Forensic Service Centre and vi) Real time In-Situ Chemical Identification. Finally, models for forensic innovation are presented that could lead to major international breakthroughs on all these six themes within a five year time span. This could cause a step change in the added value of forensic science and would make forensic investigative methods even more valuable than they already are today. PMID- 24630330 TI - Re: perception problems of the verbal scale. PMID- 24630331 TI - Re: perception problems of the verbal scale. Reply. PMID- 24630332 TI - Professional standards and accreditation of forensic anthropology in the United Kingdom. PMID- 24630333 TI - Comparing femoral version after intramedullary nailing performed by trauma trained and non-trauma trained surgeons: is there a difference? AB - INTRODUCTION: As with some procedures, trauma fellowship training and greater surgeon experience may result in better outcomes following intramedullary nailing (IMN) of diaphyseal femur fractures. However, surgeons with such training and experience may not always be available to all patients. The purpose of this study is to determine whether trauma training affects the post-operative difference in femoral version (DFV) following IMN. MATERIALS AND METHODS: Between 2000 and 2009, 417 consecutive patients with diaphyseal femur fractures (AO/OTA 32A-C) were treated via IMN. Inclusion criteria for this study included complete baseline and demographic documentation as well as pre-operative films for fracture classification and post-operative CT scanogram (per institutional protocol) for version and length measurement of both the nailed and uninjured femurs. Exclusion criteria included bilateral injuries, multiple ipsilateral lower extremity fractures, previous injury, and previous deformity. Of the initial 417 subjects, 355 patients met our inclusion criteria. Other data included in our analysis were age, sex, injury mechanism, open vs. closed fracture, daytime vs. nighttime surgery, mechanism of injury, and AO and Winquist classifications. Post-operative femoral version of both lower extremities was measured on CT scanogram by an orthopaedic trauma fellowship trained surgeon. Standard univariate and multivariate analyses were performed to determine statistically significant risk factors for malrotation between the two cohorts. RESULTS: Overall, 80.3% (288/355) of all fractures were fixed by trauma-trained surgeons. The mean post-operative DFV was 8.7 degrees in these patients, compared to 10.7 degrees in those treated by surgeons of other subspecialties. This difference was not statistically significant when accounting for other factors in a multivariate model (p>0.05). The same statistical trend was true when analyzing outcomes of only the more severe Winquist type III and IV fractures. Additionally, surgeon experience was not significantly predictive of post-operative version for either trauma or non-trauma surgeons (p>0.05 for both). CONCLUSIONS: Post-operative version or percentage of DFV >15 degrees did not significantly differ following IMN of diaphyseal femur fractures between surgeons with and without trauma fellowship training. However, prospective data that removes the inherent bias that the more complex cases are left for the traumatologists are required before a definitive comparison is made. PMID- 24630334 TI - Body composition, physical performance and muscle quality of active elderly women. AB - Fat gain is one of the major factors aggravating physical disability in the elderly population, which presents an increase in fat mass and a decrease in lean mass compared to the young population. For this reason it is important to assess body composition and the effects of these alterations in obese elderly women. The purpose of this study was to assess body composition, physical performance and muscle quality in active elderly women. Cross-sectional study included 75 elderly women (29 eutrophic and 46 obese) 65-80 years old. Body composition was evaluated by dual energy X-ray absorptiometry (DXA) and the physical performance was determined by 6-minute walk test (6MWT), handgrip strength (HS) and knee extension strength (KES). Muscle quality was calculated as the ratio between muscle strength and lean mass. Fat free mass, lean mass, fat mass and percent body fat were significantly higher in the obese group (p<0.05). Furthermore, the obese group showed a poorer performance than the eutrophic group in the 6MWT (432.31+/-66.13 m and 472.07+/-74.03 m, respectively, p=0.01). HS and KES did not differ between groups, however, regarding muscle quality, the obese group exhibited a impaired in comparison to the eutrophic group in the upper (11.45+/ 2.57 kg and 13.31+/-2.03 kg, respectively, p<0.01) and lower limb (2.91+/-1.16 kg and 3.44+/-0.97 kg, respectively, p=0.05). The increase in muscle mass detected in the obese elderly was not sufficient to maintain adequate muscle quality and physical function, showing a negative influence of the excess of body fat. PMID- 24630335 TI - Incidence of first heart failure hospitalisation and mortality in Aboriginal and non-Aboriginal patients in Western Australia, 2000-2009. AB - OBJECTIVES: To compare the incidence of first heart failure (HF) hospitalisation, antecedent risk factors and 1-year mortality between Aboriginal and non Aboriginal populations in Western Australia (2000-2009). METHODS: A population based cohort aged 20-84 years comprising Aboriginal (n=1013; mean 54+/-14 years) and non-Aboriginal patients (n=16,366; mean 71+/-11 years) with first HF hospitalisation was evaluated. Age and sex-specific incidence rates and HF antecedents were compared between subpopulations. Regression models were used to examine 30-day and 1-year (in 30-day survivors) mortality. RESULTS: Aboriginal patients were younger, more likely to reside in rural/remote areas (76% vs 23%) and to be women (50.6% vs 41.7%, all p<0.001). Aboriginal (versus non-Aboriginal) HF incidence rates were 11-fold higher in men and 23-fold in women aged 20-39 years, declining to about 2-fold in patients aged 70-84 years. Ischaemic and rheumatic heart diseases were more common antecedents of HF in younger (<55 years) Aboriginal versus non-Aboriginal patients (p<0.001). Hypertension, diabetes, chronic kidney disease, renal failure, chronic obstructive pulmonary disease, and a high Charlson comorbidity index (>=3) were also more prevalent in younger and older Aboriginal patients (p<0.001). Although 30-day mortality was similar in both subpopulations, Aboriginal patients aged<55 years had a 1.9 risk adjusted hazard ratio (HR) for 1-year mortality (p=0.015). CONCLUSIONS: Aboriginal people had substantially higher age and sex-specific HF incidence rate and prevalence of HF antecedents than their non-Aboriginal counterparts. HR for 1 year mortality was also significantly worse at younger ages, highlighting the urgent need for enhanced primary and secondary prevention of HF in this population. PMID- 24630336 TI - Spectral analysis of the heart sounds in children with and without pulmonary artery hypertension. AB - BACKGROUND: Pulmonary artery hypertension (PAH) is difficult to recognize clinically. Digital stethoscopes offer an opportunity to re-evaluate the diagnosis of PAH. We hypothesized that spectral analysis of heart sound frequencies using recordings from a digital stethoscope would differ between children with and without PAH. METHODS: We recorded heart sounds using a digital stethoscope from 27 subjects (12 males) with a median age of 7 years (3 months to 19 years) undergoing simultaneous cardiac catheterization. 13 subjects had a mean pulmonary artery pressure (mPAp)<25 mm Hg (8-24 mm Hg). 14 subjects had a mPAp>=25 mm Hg (25-97 mm Hg). We applied the fast Fourier transform, power spectral analysis, separability testing, and linear discriminant analysis with leave-one-out cross-validation to the heart sounds recorded from the cardiac apex and 2nd left intercostal space (LICS) to examine the frequency domain. The significance of the results was determined using a t-test and rank-sum test. RESULTS: The relative power of the frequencies 21-22 Hz of the heart sounds recorded at the 2nd LICS was decreased significantly in subjects mPAp>=25 mm Hg versus<25 mm Hg. CONCLUSIONS: Heart sound signals of patients with PAH contain significantly less relative power in the band 21-22 Hz compared to subjects with normal PAp. Information contained in the frequency domain may be useful in diagnosing PAH and aid the development of auscultation based techniques for diagnosing PAH. In the future, utilizing the diagnostic information contained in heart sounds recordings may require analysis of both the time and frequency domains. PMID- 24630337 TI - In-hospital and 1-year outcomes of acute heart failure patients according to presentation (de novo vs. worsening) and ejection fraction. Results from IN-HF Outcome Registry. AB - BACKGROUND: To investigate the outcomes of hospitalized patients with both de novo and worsening heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF) (LVEF >= 50%), compared to those with reduced LVEF (HFrEF). METHODS AND RESULTS: We studied 1669 patients (22.6% HFpEF) hospitalized for acute HF in the prospective multi-center nationwide Italian Network on Heart Failure (IN-HF) Outcome Registry. In all patients LVEF was assessed during hospitalization. De-novo HF presentations constituted 49.6% of HFpEF and 43.1% of HFrEF hospitalizations. All-cause mortality during hospitalization was lower in HFpEF than HFrEF (2.9% vs 6.5%, p=0.01), but this mortality difference was not significant at 1 year (19.6% vs 24.4%, p=0.06), even after adjusting for clinical covariates. Similarly, there were no differences in 1-year mortality between HFpEF and HFrEF when compared by cause of death (cardiovascular vs non cardiovascular) or mode of presentation (worsening HF vs de novo). Rehospitalization rates (all-cause, non-cardiovascular, cardiovascular, HF related) at 90 days and 1 year were also similar. Mode of presentation influenced rehospitalizations in HFpEF, where those presenting with worsening HFpEF had higher all-cause (36.8% vs 21.6%, p=0.001), cardiovascular (28.1% vs 14.9%, p=0.002), and HF-related (21.1% vs 7.7%, p=0.0003) rehospitalization rates at 1 year compared to those with de novo presentations. CONCLUSIONS: Outcomes at 1 year following hospitalization for HFpEF are as poor as that of HFrEF. A prior history of HF decompensation or hospitalization identifies patients with HFpEF at particularly high risk of recurrent events. These findings may have implications for clinical practice, quality and process improvements and trial design. PMID- 24630338 TI - Association of renal tubular damage with cardio-renal anemia syndrome in patients with heart failure. AB - BACKGROUND: Cardio-renal anemia syndrome (CRAS) has begun to gather attention as a vicious circle since chronic heart failure (CHF), chronic kidney disease (CKD), and anemia are all able to be caused and exacerbated by each other. However, it remains unclear whether renal tubular damage (RTD), another type of kidney dysfunction, is associated with this vicious circle. The aim of the present study was to assess the association of RTD with CRAS in patients with CHF. METHODS AND RESULTS: We included 300 consecutive patients with CHF. RTD was defined as a urinary beta2-microglobulin to creatinine ratio >= 300 MUg/g. Patients with RTD had lower serum iron and higher levels of high sensitivity C-reactive protein than those without it. Multivariate logistic analysis showed that RTD was closely associated with anemia in patients with CHF, after adjustment for confounding factors. During a median period of 1,098 days, there were 86 cardiac events, including 14 cardiac deaths and 72 re-hospitalizations for worsening heart failure. Net reclassification improvement was significantly improved by addition of RTD to the model including age, New York Heart Association functional class, brain natriuretic peptide, anemia, and CKD. All patients were divided into 3 groups: CRAS+RTD group, CRAS group, and control group. Kaplan-Meier analysis demonstrated that CRAS+RTD had the greatest risk in patients with CHF. CONCLUSIONS: RTD was associated with normocytic anemia, accompanying iron deficiency and inflammation. RTD added prognostic information to conventional CRAS, suggesting the importance of RTD in cardio-renal anemia interaction. PMID- 24630339 TI - Fluid vesicles in flow. AB - We review the dynamical behavior of giant fluid vesicles in various types of external hydrodynamic flow. The interplay between stresses arising from membrane elasticity, hydrodynamic flows, and the ever present thermal fluctuations leads to a rich phenomenology. In linear flows with both rotational and elongational components, the properties of the tank-treading and tumbling motions are now well described by theoretical and numerical models. At the transition between these two regimes, strong shape deformations and amplification of thermal fluctuations generate a new regime called trembling. In this regime, the vesicle orientation oscillates quasi-periodically around the flow direction while asymmetric deformations occur. For strong enough flows, small-wavelength deformations like wrinkles are observed, similar to what happens in a suddenly reversed elongational flow. In steady elongational flow, vesicles with large excess areas deform into dumbbells at large flow rates and pearling occurs for even stronger flows. In capillary flows with parabolic flow profile, single vesicles migrate towards the center of the channel, where they adopt symmetric shapes, for two reasons. First, walls exert a hydrodynamic lift force which pushes them away. Second, shear stresses are minimal at the tip of the flow. However, symmetry is broken for vesicles with large excess areas, which flow off-center and deform asymmetrically. In suspensions, hydrodynamic interactions between vesicles add up to these two effects, making it challenging to deduce rheological properties from the dynamics of individual vesicles. Further investigations of vesicles and similar objects and their suspensions in steady or time-dependent flow will shed light on phenomena such as blood flow. PMID- 24630340 TI - Line active molecules promote inhomogeneous structures in membranes: theory, simulations and experiments. AB - We review recent theoretical efforts that predict how line-active molecules can promote lateral heterogeneities (or domains) in model membranes. This fundamental understanding may be relevant to membrane composition in living cells, where it is thought that small domains, called lipid rafts, are necessary for the cells to be functional. The theoretical work reviewed here ranges in scale from coarse grained continuum models to nearly atomistic models. The effect of line active molecules on domain sizes and shapes in the phase separated regime or on fluctuation length scales and lifetimes in the single phase, mixed regime, of the membrane is discussed. Recent experimental studies on model membranes that include line active molecules are also presented together with some comparisons with the theoretical predictions. PMID- 24630341 TI - Bending lipid membranes: experiments after W. Helfrich's model. AB - Current description of biomembrane mechanics originates for a large part from W. Helfrich's model. Based on his continuum theory, many experiments have been performed in the past four decades on simplified membranes in order to characterize the mechanical properties of lipid membranes and the contribution of polymers or proteins. The long-term goal was to develop a better understanding of the mechanical properties of cell membranes. In this paper, we will review representative experimental approaches that were developed during this period and the main results that were obtained. PMID- 24630342 TI - Coupling of bending and stretching deformations in vesicle membranes. AB - Biomimetic membranes are fluid and can undergo two different elastic deformations, bending and stretching. The bending of a membrane is primarily governed by two elastic parameters: its spontaneous (or preferred) curvature m and its bending rigidity kappa. These two parameters define an intrinsic tension scale, the spontaneous tension 2 kappam2. Membrane stretching and compression, on the other hand, are determined by the mechanical tension acting within the membrane. For vesicle membranes, the two elastic deformations are coupled via the enclosed vesicle volume even in the absence of mechanical forces as shown here by minimizing the combined bending and stretching energy with respect to membrane area for fixed vesicle volume. As a consequence, the mechanical tension within a vesicle membrane depends on the spontaneous curvature and on the bending rigidity. This interdependence, which is difficult to grasp intuitively, is then illustrated for a variety of simple vesicle shapes. Depending on the vesicle morphology, the magnitude of the mechanical tension can be comparable to or can be much smaller than the spontaneous tension. PMID- 24630343 TI - Orthoconic liquid crystals--a case study. AB - Since the early investigations on liquid crystals it was realized how the confining surfaces often determine the textures and even properties of the material. This influence is particularly complex and important for chiral materials. When we come to chiral smectics the surfaces may have dramatic effects. These are illustrated on the ferroelectric liquid crystals; they then again increase in importance for the antiferroelectric liquid crystals where the most recent example is given by the orthoconic liquid crystals. PMID- 24630344 TI - Interfacial slip on rough, patterned and soft surfaces: a review of experiments and simulations. AB - Advancements in the fabrication of microfluidic and nanofluidic devices and the study of liquids in confined geometries rely on understanding the boundary conditions for the flow of liquids at solid surfaces. Over the past ten years, a large number of research groups have turned to investigating flow boundary conditions, and the occurrence of interfacial slip has become increasingly well accepted and understood. While the dependence of slip on surface wettability is fairly well understood, the effect of other surface modifications that affect surface roughness, structure and compliance, on interfacial slip is still under intense investigation. In this paper we review investigations published in the past ten years on boundary conditions for flow on complex surfaces, by which we mean rough and structured surfaces, surfaces decorated with chemical patterns, grafted with polymer layers, with adsorbed nanobubbles, and superhydrophobic surfaces. The review is divided in two interconnected parts, the first dedicated to physical experiments and the second to computational experiments on interfacial slip of simple (Newtonian) liquids on these complex surfaces. Our work is intended as an entry-level review for researchers moving into the field of interfacial slip, and as an indication of outstanding problems that need to be addressed for the field to reach full maturity. PMID- 24630345 TI - Supramolecular gels from lipopeptide gelators: template improvement and strategies for the in-situ preparation of inorganic nanomaterials and for the dispersion of carbon nanomaterials. AB - Lipopeptide amphiphiles are an important class of biobased and biomimetic surfactants that are easily prepared from the cheapest organic reagents, such as natural fatty and amino acids, and in many cases, the resulting compounds are able to harden not only common organic solvents but also waxes, water and ionic liquids. Well-tailored, these gelators can be selective for one variety of liquid, which leads to the formation of a robust gel that is able to incorporate various different elements. In this review, we attempted to provide our opinion regarding the molecular design of the lipopeptide gelator candidates. In addition, we summarized each type of element that is necessary for creating potent supramolecular gel templates that are useful for inorganic nano- and micro material preparation. This review is not only limited to recent papers found in the literature; a portion of our unpublished results are also provided as a supplement to illustrate our point of view regarding this subject. PMID- 24630346 TI - Co-morbid anxiety disorders predict early relapse after inpatient alcohol treatment. AB - INTRODUCTION: Alcohol dependence and anxiety disorders often co-occur. Yet, the effect of co-morbid anxiety disorders on the alcohol relapse-risk after treatment is under debate. This study investigated the effect of co-morbid anxiety disorders on relapse rates in alcohol dependence. We hypothesized that co-morbid anxiety disorders would be particularly predictive for early relapse, but not late relapse. SUBJECTS AND METHODS: In a prospective design, male alcohol dependent patients (n=189) were recruited from an inpatient detoxification clinic. Psychiatric diagnoses and personality traits were assessed using the Mini International Neuropsychiatric Interview for psychiatric disorders and the Temperament and Character Inventory. The addiction severity index was used to assess addiction severity and follow-up. RESULTS: One year after detoxification, 81 patients (53%) relapsed and nine patients (7%) were deceased, due to alcohol related causes. Co-morbid anxiety disorder, marital status, addiction severity, in particular legal problems, and harm avoidance predicted relapse. Anxiety disorders specifically predicted early relapse. CONCLUSION: Alcohol dependence is a severe mental disorder, with high relapse rates and high mortality. Alcohol dependent patients with co-morbid anxiety disorders are particularly prone to relapse during the first three months of treatment. These patients may therefore require additional medical and psychological attention. PMID- 24630347 TI - Randomized controlled trial of early enteral fat supplement and fish oil to promote intestinal adaptation in premature infants with an enterostomy. AB - OBJECTIVE: To test the hypothesis that early enteral supplementing fat and fish oil decreases the duration of parenteral nutrition (PN) and increases enteral nutrition (EN) before bowel reanastomosis in premature infants with an enterostomy. STUDY DESIGN: Premature infants (<2 months old) who had an enterostomy and tolerated enteral feeding at 20 mL/kg/day were randomized to usual care (control=18) or early supplementing enteral fat supplement and fish oil (treatment=18). Intravenous lipid was decreased as enteral fat intake was increased. Daily weight, clinical and nutrition data, and weekly length and head circumference were recorded. The primary outcomes were the duration of PN and volume of EN intake, and the secondary outcomes were weight gain (g/day), ostomy output (mL/kg/d), and serum conjugated bilirubin level (mg/dL) from initiating feeding to reanastomosis. Data were analyzed by Student t test or Wilcoxon rank sum test. RESULTS: There were no differences in the duration of PN, ostomy output, and weight gain between the 2 groups before reanastomosis. However, supplemented infants received less intravenous lipid, had greater EN intake, and lower conjugated bilirubin before reanastomosis, and they also received greater total calorie, had fewer sepsis evaluations and less exposure to antibiotics and central venous catheters before reanastomosis, and had greater weight and length gain after reanastomosis (all P<.05). CONCLUSION: Early enteral feeding of a fat supplement and fish oil was associated with decreased exposure to intravenous lipid, increased EN intake, and reduced conjugated bilirubin before reanastomosis and improved weight and length gain after reanastomosis in premature infants with an enterostomy. PMID- 24630349 TI - Timing of caffeine therapy in very low birth weight infants. PMID- 24630348 TI - Botulinum toxin A for nonambulatory children with cerebral palsy: a double blind randomized controlled trial. AB - OBJECTIVES: To examine the efficacy and safety of intramuscular botulinum toxin A (BoNT-A) to reduce spasticity and improve comfort and ease of care in nonambulant children with cerebral palsy (CP). STUDY DESIGN: Nonambulant children with CP (n = 41; Gross Motor Function Classification System level IV = 3, level V = 38; mean age 7.1 years, range 2.3-16 years, 66% male) were randomly allocated to receive either intramuscular BoNT-A injections (n = 23) or sham procedure (n = 18) combined with therapy. The analysis used generalized estimating equations with primary outcome the Canadian Occupational Performance Measure (COPM) at 4 weeks postintervention and retention of effects at 16 weeks. Adverse events (AE) were collected at 2, 4, and 16 weeks by a physician masked to group allocation. RESULTS: There were significant between group differences favoring the BoNT-A treated group on COPM performance at 4 weeks (estimated mean difference 2.2, 95% CI 0.8, 3.5; P = .002) and for COPM satisfaction (estimated mean difference 2.2, 95% CI 0.5, 3.9; P = .01). These effects were retained at 16 weeks for COPM satisfaction (estimated mean difference 1.8, 95% CI 0.1, 3.5; P = .04). There were more mild AE at 4 weeks for the BoNT-A group (P = .002), however, there were no significant between-group differences in the reporting of moderate and serious AE. CONCLUSIONS: In a double-blind randomized sham-controlled trial, intramuscular BoNT-A and therapy were effective for improving ease of care and comfort for nonambulant children with CP. There was no increase in moderate and severe AE in the children who had BoNT-A injections compared with the sham group. PMID- 24630351 TI - Sickle cell anemia: an underappreciated and unaddressed contributor to global childhood mortality. PMID- 24630350 TI - Effects of prenatal methamphetamine exposure on behavioral and cognitive findings at 7.5 years of age. AB - OBJECTIVE: To examine child behavioral and cognitive outcomes after prenatal exposure to methamphetamine. STUDY DESIGN: We enrolled 412 mother-infant pairs (204 methamphetamine-exposed and 208 unexposed matched comparisons) in the Infant Development, Environment, and Lifestyle study. The 151 children exposed to methamphetamine and 147 comparisons who attended the 7.5-year visit were included. Exposure was determined by maternal self-report and/or positive meconium toxicology. Maternal interviews assessed behavioral and cognitive outcomes using the Conners' Parent Rating Scale-Revised: Short Form. RESULTS: After adjusting for covariates, children exposed to methamphetamine had significantly higher cognitive problems subscale scores than comparisons and were 2.8 times more likely to have cognitive problems scores that were above average on the Conners' Parent Rating Scale-Revised: Short Form. No association between prenatal methamphetamine exposure and behavioral problems, measured by the oppositional, hyperactivity, and attention-deficit/hyperactivity disorder index subscales, were found. CONCLUSIONS: Prenatal methamphetamine exposure was associated with increased cognitive problems, which may affect academic achievement and lead to increased negative behavioral outcomes. PMID- 24630352 TI - Neuroblastoma presenting as raccoon eyes. PMID- 24630353 TI - Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroid-dependent and colchicine-resistant recurrent pericarditis. AB - OBJECTIVE: To evaluate the long-term response and safety of interleukin-1 receptor antagonist (anakinra) in recurrent pericarditis. STUDY DESIGN: Fifteen patients (12 children, 3 adults) were enrolled in a multicenter retrospective study. All the patients were corticosteroid-dependent and 14 had received colchicine. Anakinra was given at 1-2 mg/kg/d. The primary outcome of the study was a reduction of at least 70% of disease flares after anakinra treatment compared with the pretreatment period. Secondary outcomes were: (1) number of complete or partial responders to anakinra and time for complete response; (2) number of patients who discontinued other ongoing treatments (non-steroidal anti inflammatory drugs, corticosteroid, colchicine) and time needed for discontinuation; (3) number of relapses during continuous anakinra treatment; and (4) number of relapses during anakinra tapering or discontinuation. RESULTS: All patients treated had a complete response within a few days and were able to rapidly withdraw concomitant treatments, including corticosteroids. During daily treatment, no patient had a relapse of the disease; 14 patients started tapering and 6 of them experienced a relapse, with a prompt response after anakinra reintroduction. Overall, after a median follow-up of 39 months (range 6-57), a 95% reduction of flares was observed compared with pretreatment period. CONCLUSION: The long-term use of anakinra in monotherapy is associated with persistent control of recurrent pericarditis. PMID- 24630354 TI - Increase in the incidence of differentiated thyroid carcinoma in children, adolescents, and young adults: a population-based study. AB - OBJECTIVE: To investigate trends in incidence of differentiated thyroid carcinomas among children and adolescents and young adults. STUDY DESIGN: In this ecological time-trends study, we selected cases of differentiated thyroid carcinomas (1984-2010) in patients <30 years from Surveillance, Epidemiology, and End Results 9 cancer registries by using International Classification of Diseases for Oncology, 3rd edition, codes for papillary and follicular cancers. Patients with multiple other primary diseases before differentiated thyroid carcinomas were excluded. SEER*Stat software, version 8.0.4 (National Cancer Institute, Bethesda, Maryland) was used to calculate age-standardized rates (estimated per 1,000,000/persons) and annual percentage changes (APCs) were calculated by the Joinpoint model (Joinpoint software, version 4.0.4; National Cancer Institute). RESULTS: Rates ranged from 2.77 (1990) to 9.63 (2009) and from 18.35 (1987) to 50.99 (2009), for male and female subjects, respectively. A significant increasing trend in incidence was observed for both male (APC 3.44; 95% CI 2.60 4.28) and female (APC 3.81; 95% CI 3.38-4.24) patients. When a stratified analysis on the basis of tumor size was performed, significant increasing trends were noted for the following categories: <0.5 cm (females: APC 5.09, 95% CI 3.54 6.65), 0.5-0.9 cm (females: APC 8.45, 95% CI 7.09-9.82), 1.0-1.9 cm (males: APC 5.09, 95% CI 3.20-7.01; females: APC 3.42, 95% CI 2.78-4.07), and >=2 cm (males: APC 2.62, 95% CI 1.64-3.60; females: APC 2.96, 95% CI 2.34-3.59). CONCLUSIONS: Incidence rates for differentiated thyroid carcinomas are increasing among children and adolescents and young adults in the US. The increasing trends for larger tumors rules out diagnostic scrutiny as the only explanation for the observed results. Environmental, dietary, and genetic influences should be investigated. PMID- 24630355 TI - Preterm birth and dyscalculia. AB - OBJECTIVE: To evaluate whether the risk for dyscalculia in preterm children increases the lower the gestational age (GA) and whether small-for-gestational age birth is associated with dyscalculia. STUDY DESIGN: A total of 922 children ranging from 23 to 41 weeks' GA were studied as part of a prospective geographically defined longitudinal investigation of neonatal at-risk children in South Germany. At 8 years of age, children's cognitive and mathematic abilities were measured with the Kaufman Assessment Battery for Children and with a standardized mathematics test. Dyscalculia diagnoses were evaluated with discrepancy-based residuals of a linear regression predicting children's math scores by IQ and with fixed cut-off scores. We investigated each GA group's ORs for general cognitive impairment, general mathematic impairment, and dyscalculia by using binary logistic regressions. RESULTS: The risk for general cognitive and mathematic impairment increased with lower GA. In contrast, preterm children were not at increased risk of dyscalculia after statistically adjusting for child sex, family socioeconomic status, and small-for-gestational age birth. CONCLUSION: The risk of general cognitive and mathematic impairments increases with lower GA but preterm children are not at increased risk of dyscalculia. PMID- 24630356 TI - Proactive parents are assets to the health and well-being of teens. AB - OBJECTIVES: To analyze parents who self-identified themselves as being proactive parents (PPs) compared with non-PPs who were queried about their teen's health to understand common adolescent health concerns, parenting practices/behaviors around health, and whether their adolescent had received a preventive care visit in the last year STUDY DESIGN: Secondary analyses of parents (n = 504) from a nationally representative online panel were surveyed to assess health beliefs/attitudes, perceived adolescent health concerns, frequency of health discussions, topics that pediatricians should discuss, and their teen's last annual visit. Demographics, parental beliefs, frequency of health conversations, and topics that physicians should discuss were compared. Logistic regression determined the likelihood of PPs compared with non-PPs reporting a teen annual health visit within the last year. RESULTS: Greater education and having a single child household were slightly more common among PPs. PPs expressed greater concern about their teens getting good grades, getting sick, and their teen's future (P < .001). PPs indicated a greater severity of worry (P < .02) across all health topics and rated issues of sexual health, vaccines, and stress/mental health as very important for pediatricians to discuss (P < .01). Controlling for demographics, PPs were 3.4 (95% CI 2.06-5.56) times more likely to report an annual visit of their teen in the last year. CONCLUSION: PPs are an asset to the health promotion and the well-being of their teens. PPs were more likely to have their teen receive an annual visit, report more frequent discussions about health, and place a high value on physician discussions about health. PMID- 24630358 TI - Stem cell-based therapy for newborn lung and brain injury: feasible, safe, and the next therapeutic breakthrough? PMID- 24630357 TI - Yield of skeletal survey by age in children referred to abuse specialists. AB - OBJECTIVE: To determine rates of skeletal survey completion and injury identification as a function of age among children who underwent subspecialty evaluation for concerns of physical abuse. STUDY DESIGN: This was a retrospective secondary analysis of an observational study of 2609 children <60 months of age who underwent evaluation for possible physical abuse. We measured rates of skeletal survey completion and fracture identification for children separated by age into 6-month cohorts. RESULTS: Among 2609 subjects, 2036 (78%) had skeletal survey and 458 (18%) had at least one new fracture identified. For all age groups up to 36 months, skeletal survey was obtained in >50% of subjects, but rates decreased to less than 35% for subjects >36 months. New fracture identification rates for skeletal survey were similar between children 24-36 months of age (10.3%, 95% CI 7.2-14.2) and children 12-24 months of age (12.0%, 95% CI 9.2 15.3) CONCLUSIONS: Skeletal surveys identify new fractures in an important fraction of children referred for subspecialty consultation with concerns of physical abuse. These data support guidelines that consider skeletal survey mandatory for all such children <24 months of age and support a low threshold to obtain skeletal survey in children as old as 36 months. PMID- 24630359 TI - Evidence for a (15)N positive excursion in terrestrial foodwebs at the Middle to Upper Palaeolithic transition in south-western France: Implications for early modern human palaeodiet and palaeoenvironment. AB - The Middle to Upper Palaeolithic transition around 35,000 years ago coincides with the replacement of Neanderthals by anatomically modern humans in Europe. Several hypotheses have been suggested to explain this replacement, one of them being the ability of anatomically modern humans to broaden their dietary spectrum beyond the large ungulate prey that Neanderthals consumed exclusively. This scenario is notably based on higher nitrogen-15 amounts in early Upper Palaeolithic anatomically modern human bone collagen compared with late Neanderthals. In this paper, we document a clear increase of nitrogen-15 in bone collagen of terrestrial herbivores during the early Aurignacian associated with anatomically modern humans compared with the stratigraphically older Chatelperronian and late Mousterian fauna associated with Neanderthals. Carnivores such as wolves also exhibit a significant increase in nitrogen-15, which is similar to that documented for early anatomically modern humans compared with Neanderthals in Europe. A shift in nitrogen-15 at the base of the terrestrial foodweb is responsible for such a pattern, with a preserved foodweb structure before and after the Middle to Upper Palaeolithic transition in south western France. Such an isotopic shift in the terrestrial ecosystem may be due to an increase in aridity during the time of deposition of the early Aurignacian layers. If it occurred across Europe, such a shift in nitrogen-15 in terrestrial foodwebs would be enough to explain the observed isotopic trend between late Neanderthals and early anatomically modern humans, without any significant change in the diet composition at the Middle to Upper Palaeolithic transition. PMID- 24630360 TI - Occupant accelerations and injury potential during an ambulance-to-curb impact. AB - This paper presents real world acceleration data for an ambulance driving up and over a curb. A full scale reenactment was performed for a litigated case in which a patient on a gurney in an ambulance claimed a variety of bodily injuries after the ambulance struck a curb. A height and weight matched surrogate rode on the gurney during the tests. Results demonstrated that peak vehicle and occupant accelerations never exceeded 1.1g's. To address the claimed injuries, the accelerations likely sustained by the patient were compared to those experienced during daily life. Since ambulances are wide vehicles that travel fast on potentially narrow arterial, collector or local roadways, curb or median impacts may occur during the normal course of driving. Thus, these results may be useful for forensic experts in dealing with similar cases involving claimed injuries following curb impacts. PMID- 24630361 TI - Vestibular stimulation does not diminish the desire for amputation. PMID- 24630362 TI - Biophysical probing of Spartina maritima photo-system II changes during prolonged tidal submersion periods. AB - Submergence is one of the major constrains affecting wetland plants, with inevitable impacts on their physiology and productivity. Global warming as a driving force of sea level rise, tend to increase the submersion periods duration. Photosynthesis biophysical probing arise as an important tool to understand the energetics underlying plant feedback to these constrains. As in previous studies with Spartina maritima, there was no inhibition of photosynthetic activity in submerged individuals. Comparing both donor and acceptor sides of the PSII, the first was more severely affected during submersion, driven by the inactivation of the OEC with consequent impairment of the ETC. Although this apparent damage in the PSII donor side, the electron transport per active reaction centre was not substantially affected, indicating that this reduction in the electron flow is accompanied by a proportional increase in the number of active reaction centres. These conditions lead to the accumulation of excessive reducing power, source of damaging ROS, counteracted by efficient energy dissipation processes and anti-oxidant enzymatic defences. This way, S. maritima appears as a well-adapted species with an evident photochemical plasticity towards submersion, allowing it to maintain its photosynthetic activity even during prolonged submersion periods. PMID- 24630363 TI - Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1 related amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis, but the mechanism through which androgens modify the ALS phenotype is unknown. Here, we show that androgen ablation by surgical castration extends survival and disease duration of a transgenic mouse model of ALS expressing mutant human SOD1 (hSOD1-G93A). Furthermore, long-term treatment of orchiectomized hSOD1-G93A mice with nandrolone decanoate (ND), an anabolic androgenic steroid, worsened disease manifestations. ND treatment induced muscle fiber hypertrophy but caused motor neuron death. ND negatively affected survival, thereby dissociating skeletal muscle pathology from life span in this ALS mouse model. Interestingly, orchiectomy decreased androgen receptor levels in the spinal cord and muscle, whereas ND treatment had the opposite effect. Notably, stimulation with ND promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, our results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis. PMID- 24630364 TI - High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. AB - Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3-4, 7-8, 11-12, and 15-16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7-8, 11-12, and 15-16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3-4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3-4 months but in non-Tg control mice microglial activation was not observed until the age of 15-16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice. PMID- 24630365 TI - Chronic kidney disease in patients with the Philadelphia-negative chronic myeloproliferative neoplasms. AB - BACKGROUND: The progression of kidney function and frequency of chronic kidney disease (CKD) in patients with the Philadelphia-negative myeloproliferative neoplasms (MPN) is unknown, although CKD is linked to increased mortality. METHODS: This longitudinal retrospective study evaluates the estimated glomerular filtration rate (eGFR) in 143 MPN patients over a period of 9 years. RESULTS: 29% of patients had CKD stage 3 or 4 at time of diagnosis. 20% of patients had a rapid annual loss of eGFR (>3mL/min/1.73m(2)) and eGFR was negatively correlated to monocyte and neutrophil counts. CONCLUSION: Kidney impairment might contribute to the increased mortality observed in MPN patients. PMID- 24630366 TI - Use of a high sensitive nanofluidic array for the detection of rare copies of BCR ABL1 transcript in patients with Philadelphia-positive acute lymphoblastic leukemia in complete response. AB - Monitoring of minimal residual disease (MRD) by quantification of BCR-ABL1 transcript levels has become a main part of the management of patients with BCR ABL1-positive acute lymphoblastic leukemia (ALL) in treatment with tyrosine kinase inhibitors (TKIs). The failure to achieve molecular negativity shortly after starting TKI has been demonstrated to be predictive of relapse, suggesting that an accurate measurement of low BCR-ABL1 levels may have a role in preventing hematological relapse. Despite the big efforts made by many European laboratories within the European Study Group, at the time of writing a standardized procedure to quantify and express results is still missing for BCR-ABL1-positive ALL. In this study, in order to detect with high sensitivity low levels of BCR-ABL1 transcripts, we used a new technology and a new molecular approach based on microfluidic digital polymerase chain reaction (dPCR) using Taqman chemistry and we compared obtained results with those generated by the conventional method based on reverse transcriptase PCR reaction (RQ-PCR) for BCR-ABL1 and total ABL1, with TaqMan chemistry and with Applied Biosystems instrument. We demonstrated the dPCR is high-sensitive (able to detect a single copy of BCR-ABL1) and reliable (results are comparable to those obtained by BCR-ABL1 quantification with conventional technology), allowing an accurate monitoring of BCR-ABL1-positive ALL patients in complete remission. PMID- 24630367 TI - Anaerobic treatment of low-strength wastewater: a comparison between single and staged anaerobic fluidized bed membrane bioreactors. AB - Performance of a single anaerobic fluidized membrane bioreactor (AFMBR) was compared with that of a staged anaerobic fluidized membrane bioreactor system (SAF-MBR) that consisted of an anaerobic fluidized bed bioreactor (AFBR) followed by an AFMBR. Both systems were fed with an equal COD mixture (200mg/L) of acetate and propionate at 25 degrees C. COD removals of 93-96% were obtained by both systems, independent of the hydraulic retention times (HRT) of 2-4h. Over more than 200d of continuous operation, trans-membrane pressure (TMP) in both systems was less than 0.2bar without significant membrane fouling as a result of the scouring of membrane surfaces by the moving granular activated carbon particles. Results of bulk liquid suspended solids, extracellular polymeric substances (EPS), and soluble microbial products (SMP) analyses also revealed no significant differences between the two systems, indicating the single AFMBR is an effective alternative to the SAF-MBR system. PMID- 24630369 TI - A new insight to the physical interpretation of activated carbon and iron doped carbon material: sorption affinity towards organic dye. AB - To enhance the potential of activated carbon (AC), iron incorporation into the AC surface was examined in the present investigations. Iron doped activated carbon (FeAC) material was synthesized and characterized by using surface area analysis, energy dispersive X-ray (EDX), temperature programmed reduction (TPR) and temperature programmed desorption (TPD). The surface area of FeAC (543 m(2)/g) was found to be lower than AC (1043 m(2)/g) as a result of the pores widening due to diffusion of iron particles into the porous AC. Iron uploading on AC surface was confirmed through EDX analysis, showing up to 13.75 wt.% iron on FeAC surface. TPR and TPD profiles revealed the presence of more active sites on FeAC surface. FeAC have shown up to 98% methylene blue (MB) removal from the aqueous media. Thermodynamic parameters indicated the spontaneous and exothermic nature of the sorption processes. PMID- 24630368 TI - Continuous volatile fatty acid production from waste activated sludge hydrolyzed at pH 12. AB - This study adopted rapid alkaline treatment at pH 12 to hydrolyze 66% of total chemical oxygen demands. Then the hydrolyzed liquor was fermented in a continuous flow stirred reactor to produce volatile fatty acids (VFAs) at 8-h hydraulic retention time and at 35 degrees C. The maximum VFA productivity reached 365 mg VFAs g(-1) volatile suspended solids in a 45-d operation, with most produced VFAs being acetate and propionate, principally produced by protein degradation. The Bacteroidia, epsilon-proteobacteria and the Clostridia were identified to be the classes correlating with the fermentation processes. The fermented liquor was applied to denitrifying phosphorus removal process as alternative carbon source after excess phosphorus and nitrogen being recycled via struvite precipitation. Fermented liquors from alkaline hydrolysis-acid fermentation on waste activated sludge are a potential renewable resource for applications that need organic carbons. PMID- 24630370 TI - Effect of fungal and phosphoric acid pretreatment on ethanol production from oil palm empty fruit bunches (OPEFB). AB - Oil palm empty fruit bunches (OPEFB), a lignocellulosic residue of palm oil industries was examined for ethanol production. Milled OPEFB exposed to simultaneous saccharification and fermentation (SSF) with enzymes and Saccharomyces cerevisiae resulted just in 14.5% ethanol yield compared to the theoretical yield. Therefore, chemical pretreatment with phosphoric acid, a biological pretreatment with white-rot fungus Pleurotus floridanus, and their combination were carried out on OPEFB prior to the SSF. Pretreatment with phosphoric acid, combination of both methods and just fungal pretreatment improved the digestibility of OPEFB by 24.0, 16.5 and 4.5 times, respectively. During the SSF, phosphoric acid pretreatment, combination of fungal and phosphoric acid pretreatment and just fungal pretreatment resulted in the highest 89.4%, 62.8% and 27.9% of the theoretical ethanol yield, respectively. However, the recovery of the OPEFB after the fungal pretreatment was 98.7%, which was higher than after phosphoric acid pretreatment (36.5%) and combined pretreatment (45.2%). PMID- 24630371 TI - A comprehensive review on biosorption of heavy metals by algal biomass: materials, performances, chemistry, and modeling simulation tools. AB - Heavy metals contamination has become a global issue of concern due to their higher toxicities, nature of non-biodegradability, high capabilities in bioaccumulation in human body and food chain, and carcinogenicities to humans. A series of researches demonstrate that biosorption is a promising technology for removal of heavy metals from aqueous solutions. Algae serve as good biosorbents due to their abundance in seawater and fresh water, cost-effectiveness, reusability and high metal sorption capacities. This article provides a comprehensive review of recent findings on performances, applications and chemistry of algae (e.g., brown, green and red algae, modified algae and the derivatives) for sequestration of heavy metals. Biosorption kinetics and equilibrium models are reviewed. The mechanisms for biosorption are presented. Biosorption is a complicated process involving ion-exchange, complexation and coordination. Finally the theoretical simulation tools for biosorption equilibrium and kinetics are presented so that the readers can use them for further studies. PMID- 24630372 TI - (11)C-Methionine uptake in secondary brain epilepsy. AB - Carbon-11 methionine ((11)C-Methionine) is a radio-labeled amino acid currently utilized in Positron Emission Tomography (PET) for imaging primary and metastatic brain tumors. Its clinical use relies mostly on oncologic applications, but the tracer has the potential to investigate other non-malignant conditions. So far, very limited evidence concerns the use of (11)C-Methionine in patients suffering from seizure; however, the tracer can find a proper utilization in this setting especially as a diagnostic complement to (18)F-Fluorodeoxyglucose ((18)F-FDG). Herein we report the case of a 57-year-old patient presenting with epileptic crises secondary to a brain metastasis from bladder carcinoma, who was investigated in our institution with (11)C-Methionine PET. The scan documented the disease recurrence in the left parietal lobe associated with a diffused tracer uptake in the surrounding cerebral circumvolutions, derived from the comitial status. After surgical removal of the metastatic lesion, the patient experienced a complete recovery of symptoms and no further onset of secondary seizure. PMID- 24630373 TI - 18F-FDG PET-CT usefulness in extra-pancreatic involvement in IgG4 related diseases. AB - IgG4-related diseases are a group of recently identified entities that include disorders that were previously known by other names, such as Mikulicz disease, Kuttner's tumor, Riedel thyroiditis, among others, as well as some new ones described in the last years. These pathologies are a challenge for the medical community in terms of diagnosis and characterization due to their wide spectrum of clinical presentation. Functional imaging can provide a new approach to the comprehension of physiopathology, staging and targeting site of biopsy of IgG4 related diseases. In this clinical note, we describe five patients who underwent 18F-FDG PET-CT and correlate their findings with previous reports. PMID- 24630374 TI - Calls for restricting the marketing of unhealthy food to children: Canadian cardiovascular health care and scientific community get ignored by policy makers. What can they do? PMID- 24630375 TI - Taking another "look" at sodium. PMID- 24630376 TI - Physiological evidence of a deficit to enhance the empathic response in schizophrenia. AB - Empathy is crucial for maintaining effective social interactions. Research has identified both an early-emotional sharing and a late-cognitive component of empathy. Although considered a functionally vital social cognition process, empathy has scarcely been studied in schizophrenia (SZ). We used event-related potentials (ERPs) to study the temporal dynamics of empathic response in 19 patients with SZ and 18 matched healthy controls (HC) using an empathy for physical pain paradigm. Participants responded to pictures of hands in neutral and painful situations in an active empathic condition and one manipulated by task demands. Additionally, subjective ratings of the stimuli and empathic self reports were collected. People with SZ had (1) decreased early-emotional ERP responses to pictures of others in pain; (2) decreased modulation by attention of late-cognitive ERP responses; (3) lower ratings of perspective taking and higher ratings of personal distress which were both related to decreased modulation of late-cognitive empathic responses; (4) a significant relationship between high affective overlap between somebody else's pain and their own pain and decreased modulation of late-cognitive empathic responses; (5) a distinct relationship between regulatory deficits in late-cognitive empathy and functioning. Patients had present but reduced early and late empathy-related ERPs. Patients also reported increased personal distress when faced with distress in others. The late ERP responses are thought to be associated with self-regulation and response modulation. The magnitude of these late responses was inversely associated with reported levels of personal distress in both patients and controls. Additionally, regulatory deficits in cognitive empathy were highly related with deficits in functioning. Decreased ability to regulate one's own emotional engagement and response to emotions of others may be an important source of distress and dysfunction in social situations for patients with schizophrenia. PMID- 24630377 TI - Composite Scale of Morningness: psychometric properties, validity with Munich ChronoType Questionnaire and age/sex differences in Poland. AB - The present study aimed at testing psychometric properties of the Composite Scale of Morningness (CSM) and validating it with mid sleep on free days (MSF) derived from the Munich ChronoType Questionnaire (MCTQ) in Poland, along with analyzing age and sex differences in the CSM and MSF. A sample of 952 Polish residents (62.6% females) aged between 13 and 46 was tested. Additionally, a sample of 33 university students were given MCTQ and filled in a sleep diary for 8 days. MSF derived from MCTQ was related to the one from sleep diary (r=.44). The study revealed good reliability of the CSM (alpha=.84) and its validity: greater morningness preference was associated with earlier MSF from MCTQ (r=-.52). CSM scores were distributed over its full range, with a mean of 34, and did not differ between sexes, although females were earlier than males by 23minutes in MSF. Regarding age, eveningness estimated with both CSM and MSF was greatest in subjects aged 16-18years, and a shift toward eveningness during puberty and a shift back toward morningness in older age was observed. The Polish version of the CSM consisted of two components of morningness. Cutoff scores were: for evening types (lower 10%) 24 or less, for morning types (upper 10%) 43 or more. The Polish CSM presents good psychometric properties, which are similar to those reported in other language versions, and also presents sex/age patterns similar to those found previously. PMID- 24630378 TI - Palliative care nurses' recognition and assessment of patients with delirium symptoms: a qualitative study using critical incident technique. AB - BACKGROUND: Delirium is prevalent in palliative care inpatient settings and management is often challenging. Despite nurses' integral patient care role, little is known about palliative care nurses' capacity to recognise, assess and respond to patients' delirium symptoms. OBJECTIVE: To explore the experiences, views and practices of inpatient palliative care nurses in delirium recognition and assessment. SETTINGS AND PARTICIPANTS: 30 nurses from nine Australian specialist palliative care inpatient services. DESIGN AND METHODS: Critical incident technique (CIT) guided a series of semi-structured interviews. Prior to interviews participants were given a vignette of a palliative care inpatient with an unrecognised hypoactive delirium, to prompt their recollection and recounting of a similar clinical incident. Clearly recalled and described incidents were analysed using thematic content analysis. FINDINGS: 20 of 30 participants recalled and described 28 relevant delirium incidents. Two themes and six sub themes provide a general description of participants' experiences, views and practice in delirium recognition and assessment. Participants experience distress related to caring for patients with delirium and express compassion and empathy for delirious patients. Enhancing their delirium knowledge, strengthening collaborative multidisciplinary team relationships and better communication are important supports. Some participants, usually those in advance practice roles, describe more comprehensive assessment capabilities that incorporate clinical expertise with whole person awareness, yet systematic and structured delirium screening and assessment processes and application of the delirium diagnosis criteria are largely missing. Use of ambiguous terminology to describe delirium symptoms contributes to ineffective practice. CONCLUSIONS: The findings of this study expands our understanding of how palliative care nurses' capacity to recognise and assess patients' delirium symptoms in the inpatient setting could be strengthened. PMID- 24630379 TI - Colored ultrafast acoustics: from fundamentals to applications. AB - The aim of this paper is to review the various laser-wavelength effects reported in the field of ultrafast acoustics (UA). First observed by chance in 1999, a wavelength change can indeed have a strong effect on the signal detected in UA. After the physical origin of the effect was clarified and from a systematic exploration we established that all the opto-acoustic mechanisms acting in UA are influenced by the laser-wavelength. From that we suggested original applications of UA to fundamental and applied physics. So emerged a new field, now referred as Colored Picosecond Acoustics or APiC. PMID- 24630380 TI - Association between VO2 peak estimated by a 1-km treadmill walk and mortality. A 10-year follow-up study in patients with cardiovascular disease. AB - PURPOSE: The aim of this study is to assess the association between peak oxygen uptake (VO2 peak), determined using a perceptually regulated 1-km walking test (1k-TWT), and all-cause mortality in cardiac patients. METHODS: 1255 male patients, aged 25-85 years, completed a moderate 1k-TWT to estimate VO2 peak. Subjects were followed for all-cause mortality for up to 10 years. Cox proportional hazard models were employed to determine variables associated with mortality. Based on the estimated VO2 peak, the sample was subdivided into quartiles and mortality risks were calculated. To assess the discriminatory accuracy of the estimated VO2 peak for estimating survival, receiver-operating characteristics curves were constructed. RESULTS: During a median 8.2 year follow up, a total of 141 deaths from any cause occurred, yielding an average annual mortality of 1.4%. The strongest predictor of all-cause mortality was the estimated VO2 peak (c-statistic 0.71, 95% confidence intervals: 0.69-0.74, P<0.0001). Survival decreased in a graded fashion from the highest estimated VO2 peak quartile to the lowest quartile. Compared to the lowest quartile, the hazard ratios (95% confidence intervals) for the second, third, and fourth quartiles were 0.77 (0.35-1.33), 0.43 (0.20-0.91), and 0.16 (0.05-0.54) respectively (P for trend <0.0001). An 89% reduction in mortality risk was observed among a subset of subjects in the fittest quartile who improved their estimated VO2 peak over the follow-up period relative to subjects in the least fit quartile who did not improve. CONCLUSION: VO2 peak estimated by a novel 1k-TWT predicts survival in subjects with stable cardiovascular disease. PMID- 24630381 TI - Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts. AB - BACKGROUND: Receptor for advanced glycation end products (RAGE) signaling pathway plays a vital role in diabetic cardiovascular complications. Calcitriol has been shown to exert various beneficial cardiovascular effects. The purpose of this study is to determine whether calcitriol can modulate RAGE expression, and study the potential mechanisms in diabetic hearts. METHODS: Streptozotocin (65 mg/kg, intraperitoneal injection once) induced diabetic rats were treated with or without subcutaneous injections of calcitriol at a dose of 150 ng/kg/day for 4 weeks. Western blot was used to evaluate protein expressions of myocardial RAGE, TNF-alpha, p65 subunit of NF-kappaB (p65), alpha subunit of inhibitor of kappaB (IkappaBalpha), subunits of NADPH oxidase (NOX4 and p22(phox)), angiotensin II type 1 receptor (AT1R), TGF-beta1, TGF-beta receptor I, total and phosphorylated SMAD2/3 and ERK, matrix metalloproteinases 2 (MMP2), tissue inhibitors of metalloproteinases 2 (TIMP2) and procollagen I. RESULTS: As compared to control, diabetic rats had increased expressions of cardiac RAGE, TNF-alpha, p22(phox), AT1R, and TGF-beta1, which were significantly attenuated in the diabetic rats treated with calcitriol. Calcitriol-treated diabetic hearts also had lesser expressions of p-SMAD2/3 and p-ERK signaling than those of diabetic hearts. Moreover, diabetic hearts had increased expressions of MMP2 and procollagen I and decreased TIMP2. However, calcitriol reverted the diabetic effects in procollagen I but not in MMP2 or TIMP2. CONCLUSIONS: Calcitriol decreased diabetic effects on RAGE and fibrosis, which may be caused by its modulation on AT1R and the anti inflammatory and antioxidative potentials. Therefore, calcitriol may attenuate diabetic cardiomyopathy. PMID- 24630382 TI - Risk factors and incidence of stroke and MACE in Chinese atrial fibrillation patients presenting to emergency departments: a national wide database analysis. AB - BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism in patients with atrial fibrillation (AF) are largely derived from western cohorts. The purpose of the present study is to assess the potential risk factors for stroke and major adverse cardiac events (MACE) in a large population of Chinese AF patients presenting to emergency department. METHODS: The Chinese AF registry is a multicenter, prospective, observational study with 1 year follow up. Patients who presented to an emergency department with atrial fibrillation or atrial flutter were recruited from November 2008 to October 2011. The MACE included all cause mortality, stroke, non-central nervous system systemic embolism and major bleed. RESULTS: A total of 2016 AF patients (1104 women) were included in the final analysis. Multivariate Cox regression analysis showed that the risk factors for stroke were female gender (1.419 (1.003 2.008), p=0.048), age >= 75 (2.576 (1.111-4.268), p<0.001), previous stroke/TIA (2.039 (1.415-2.939), p<0.001), LVSD (1.700 (1.015-2.848), p=0.044) and previous major bleeding (2.481 (1.141-5.397), p=0.022). For MACE, age >= 75 (3.042 (2.274 4.071), p<0.001), heart failure (1.371 (1.088-1.728), p=0.008), previous stroke/TIA (1.560 (1.244-1.957), p<0.001), LVSD (1.424 (1.089-1.862), p=0.010) and COPD (1.393 (1.080-1.798), p=0.011) were independent risk factors. History of hypertension and diabetes was not associated with the events, neither stroke nor MACE. For non-anticoagulation patients, the c-statistic for predicting stroke was 0.685 (0.637-0.732) and for MACE was 0.717 (0.687-0.746), respectively. CONCLUSIONS: We demonstrated that, except for the traditional risk factors, clinicians should pay more attention to patients with prior major bleeding or COPD in Chinese AF patients presenting to emergency department. PMID- 24630383 TI - N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio 1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH. METHODS: Male Wistar rats were injected with a single dose (60mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2AR), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca(2+)-ATPase activity and vascular activity of LASSBio-1386 were evaluated. RESULTS AND CONCLUSIONS: The RV systolic pressure was elevated in the PAH model and reduced from 49.6 +/- 5.0 mm Hg (MCT group) to 27.2 +/- 2.1 mm Hg (MCT+LASSBio-1386 group; P<0.05). MCT administration also impaired the EC, increased the RV and pulmonary arteriole size, and promoted endothelial dysfunction of the pulmonary artery rings. In the PAH group, the eNOS, A2AR, SERCA2a, and PLB levels were changed compared with the control; in addition, the Ca(2+)-ATPase activity was reduced. These alterations were related with MCT injected rats, and LASSBio-1386 had favorable effects that prevented the development of PAH. LASSBio-1386 is effective at preventing endothelial and RV dysfunction in PAH, a finding that may have important implications for ongoing clinical evaluation of A2AR agonists for the treatment of PAH. PMID- 24630385 TI - A proposal for an updated neuropsychopharmacological nomenclature. AB - Current psychopharmacological nomenclature remains wedded in an earlier period of scientific understanding, failing to reflect contemporary developments and knowledge, does not aid clinicians in selecting the best medication for a given patient, and tends to confuse patients by prescribing a drug that does not reflect their identified diagnosis (e.g. prescribe "antipsychotics" to depression). Four major colleges of Neuropsychopharmacology (ECNP, ACNP, Asian CNP, and CINP) proposed a new template comprising a multi-axial pharmacologically driven nomenclature tested by four surveys. The template has five axes: 1-class (primary pharmacological target and relevant mechanism); 2-family (reflecting the relevant neurotransmitter and mechanism); 3-neurobiological activities; 4 efficacy and major side effects; and 5-approved indications. The results of the surveys suggest that the clinicians found the available indication-based nomenclature system dissatisfactory, non-intuitive, confusing, and doubt-inducing for them and the patients. The proposed five-axis template seeks to upend current usage by placing pharmacology rather than indication as the primary axes, with the proposed nomenclature relating primarily to Axis 1-the class, and usage of the other axes would largely depend upon the extent to which the clinician seeks to deepen the scientific and clinical base of his involvement. A significant proportion of the participants in the four surveys were in favour of the proposed system, a similar number wanted to consider the idea further, and only a small proportion (8.6%) were against it. The proposed five-axis pharmacology based nomenclature template is a system which might refresh and reflect the current scientific concepts of neuropsychopharmacology. PMID- 24630384 TI - Epicardial and endocardial electrophysiological guided thoracoscopic surgery for atrial fibrillation: a multidisciplinary approach of atrial fibrillation ablation in challenging patients. AB - INTRODUCTION: Patients with atrial fibrillation (AF) with enlarged atria or previous pulmonary vein isolation (PVI) are challenging patients for catheter ablation. Thoracoscopic surgery is an effective treatment for these patients but comes at the cost of an increase in adverse events. Recently, electrophysiological (EP) guided approaches to thoracoscopic surgery have been described which consist of EP guidance by measurement of conduction block across ablation lines. In this study we describe the efficacy and safety of EP-guided thoracoscopic surgery for AF in patients with enlarged atria and/or prior failed catheter ablation. METHODS & RESULTS: A total of 72 patients were included. Two different approaches to EP-guided thoracoscopic surgery were implemented: epicardial or endocardial EP-guidance at the time of surgery. Residual intraoperative conduction requiring additional ablation was detected with epicardial or endocardial mapping techniques in 50% and 11%, respectively. Additional epicardial or endocardial ablation was performed until bidirectional block was confirmed. Follow-up consisted of an ECG and a 24h Holter at 3, 6 and 12 months after the procedure. A total of 57 patients (79%) had freedom of AF and were off anti-arrhythmic drugs at one year follow-up (30 paroxysmal (83%), 27 persistent AF (75%)). Adverse events occurred in 13 patients (6 major). None of our patients died and all events were reversible. CONCLUSION: EP-guidance of thoracoscopic surgery can be safely performed both epicardially and endocardially and is associated with a high rate of long-term maintenance of sinus rhythm in patients with enlarged atria and/or a previously failed ablation. PMID- 24630386 TI - Risk of mortality in individuals with low QRS voltage and free of cardiovascular disease. AB - The prognostic significance of low QRS voltage (LQRSV) in the electrocardiogram (ECG) of individuals free of cardiovascular disease (CVD) is unclear. We evaluated the association between LQRSV and all-cause mortality in 6,440 participants (53% women, mean age 60 years) from the Third National Health and Nutrition Examination Survey, a representative sample of the US population. Participants with history of CVD or major ECG abnormalities were excluded. LQRSV was automatically defined from standard 12-lead ECG as QRS complex amplitudes of <0.5 mV in all frontal leads and/or <1.0 mV in all precordial leads. Mortality data through 2006 were obtained from National Death Index records. LQRSV was detected in 1.4% (n = 89) of the participants. During a median follow-up of 13.8 years, 2,000 deaths occurred. The mortality rate in individuals with LQRSV was almost twice that in those without LQRSV (51.1 vs 23.5 events per 1,000 person years, p <0.01). In a demographic-adjusted model, LQRSV was associated with 63% increased risk of mortality (hazard ratio 1.63, 95% confidence interval [1.21, 2.18]). The magnitude of this risk did not appreciably change after additional adjustment for body mass index, smoking status, systolic blood pressure, blood pressure medication use, dyslipidemia, diabetes, cancer, pulmonary disease, and ECG abnormalities (hazard ratio 1.61, 95% confidence interval [1.20, 2.16]) and was consistent across age, race, and sex subcategories. In conclusion, LQRSV is associated with an increased risk of mortality in individuals free of apparent CVD. More research is warranted to determine the mechanisms by which LQRSV is associated with increased risk of mortality in apparently healthy individuals. PMID- 24630387 TI - Effect of echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy on mortality and risk of defibrillator therapy for ventricular arrhythmias in heart failure patients (from the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region [STARTER] trial). AB - Echocardiography-guided left ventricular (LV) lead placement at the site of latest mechanical activation improves heart failure outcomes in patients receiving a cardiac resynchronization therapy defibrillator (CRT-D). In this study, we test the hypothesis that a strategy of echocardiography-guided LV lead placement improves patient survival rate free from appropriate CRT-D therapy for ventricular arrhythmias. Patients enrolled in the prospective, randomized Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial and treated with a CRT-D device (108 with the echo-guided strategy and 75 with the routine strategy) were followed to the end point of death or first appropriate CRT-D therapy. Over a follow-up period of 3.7 +/- 2.1 years, 62 patients (33%) died and 40 (22%) received appropriate CRT-D therapy. Compared with the routine group, patients in the echo-guided group had improved CRT-D therapy-free survival rate (hazard ratio = 0.64, 95% confidence interval = 0.42 to 0.98, p = 0.038). Patients randomized to the echo-guided LV lead placement were more likely to resynchronize their LV compared with the routine group (72% vs 48%, respectively, p = 0.006). Patients whose LV did resynchronize after CRT-D had improved therapy free survival rate compared with those whose LV did not resynchronize (hazard ratio = 0.49, 95% confidence interval = 0.28 to 0.86, p = 0.012). In conclusion, a strategy of echo-guided LV lead placement improved the patient survival rate free from defibrillator therapy in CRT-D recipients. PMID- 24630388 TI - Comparison of pulmonary vein isolation using cryoballoon versus conventional radiofrequency for paroxysmal atrial fibrillation. AB - The aim of this study was to compare the results of pulmonary vein isolation using conventional irrigated radiofrequency (RF) approach versus the cryoballoon (CB) ablation. From January 2008 to December 2011, a total of 426 patients with drug-resistant symptomatic paroxysmal atrial fibrillation underwent pulmonary vein isolation as the index procedure by conventional manual RF or CB ablation at our center. A final population of 396 patients was considered for analysis and divided into 2 groups: conventional RF ablation (n = 260) and CB ablation (n = 136). At a mean follow-up of 23 +/- 13 months (median 27, range 4 to 68), the success rate for RF ablation group was 57.3% (149 patients) and was 63.2% (86 patients) for cryoablation group (p = 0.25). Procedural times were significantly shorter in the cryoablation group (192 +/- 49 vs 112 +/- 58 minutes, p <0.000001) but not fluoroscopy times (36 +/- 14 vs 31 +/- 17 minutes, p = 0.45). No clinical predictors were found to predict atrial fibrillation recurrences. Complication rates were similar in both groups except for phrenic nerve palsy that was uniquely observed in the CB group (8.1%, p <0.00001). All phrenic nerve palsies resolved during follow-up. In conclusion, on a medium-term follow-up, conventional point-by-point RF ablation and CB ablation showed similar success rates. Procedural times were significantly shorter in the CB approach. The most frequent complication during CB procedures was phrenic nerve palsy, which occurred in 8.1% of patients and resolved in all during the follow-up period. PMID- 24630389 TI - Validation of a new risk score to predict contrast-induced nephropathy after percutaneous coronary intervention. AB - Contrast-induced nephropathy (CIN) is a frequent, potentially lethal complication of percutaneous coronary interventions (PCIs). We prospectively validated the diagnostic performance of a simple CIN risk score in a large multicenter international cohort of patients who underwent PCI. About 2,882 consecutive patients treated with elective or urgent PCI were enrolled. A simple CIN risk score was calculated for all patients by allocating points according to a prespecified scale (pre-existing renal disease = 2; metformin use = 2; previous PCI = 1; peripheral arterial disease = 2; and injected volume of contrast medium >=300 ml = 1). CIN was defined as an increase, compared with baseline, of serum creatinine by >=25%, or by >=0.5 mg/dl, 48 hours after PCI. CIN occurred in 15.7% of the study population. The predictive accuracy of the CIN risk score was good (c-statistic 0.741, 95% confidence interval 0.713 to 0.769). Receiver-operating characteristic analysis identified a score of >=3 as having the best diagnostic accuracy. Examination of the performance of the proposed risk score using different definitions of CIN yielded a robust predictive ability. The score exhibited good discrimination (area under the curve >=0.700) across all predefined subgroups of the study population. Compared with 2 previously published risk scores for CIN, our score demonstrated higher discriminative ability and resulted in a net reclassification improvement and an integrated discrimination improvement (p <0.001). In conclusion, the new risk score can easily be applied in the setting of urgent or elective PCI, allows for robust risk assessment and offers the potential to improve the peri-interventional management of patients at risk for CIN. PMID- 24630391 TI - Discrimination and diabetes. PMID- 24630390 TI - Global estimates of diabetes prevalence for 2013 and projections for 2035. AB - INTRODUCTION: Diabetes is a serious and increasing global health burden and estimates of prevalence are essential for appropriate allocation of resources and monitoring of trends. METHODS: We conducted a literature search of studies reporting the age-specific prevalence for diabetes and used the Analytic Hierarchy Process to systematically select studies to generate estimates for 219 countries and territories. Estimates for countries without available source data were modelled from pooled estimates of countries that were similar in regard to geography, ethnicity, and economic development. Logistic regression was applied to generate smoothed age-specific prevalence estimates for adults 20-79 years which were then applied to population estimates for 2013 and 2035. RESULTS: A total of 744 data sources were considered and 174 included, representing 130 countries. In 2013, 382 million people had diabetes; this number is expected to rise to 592 million by 2035. Most people with diabetes live in low- and middle income countries and these will experience the greatest increase in cases of diabetes over the next 22 years. CONCLUSION: The new estimates of diabetes in adults confirm the large burden of diabetes, especially in developing countries. Estimates will be updated annually including the most recent, high-quality data available. PMID- 24630392 TI - Endoscopic resection of intranasal meningo-encephalocele accompanying meningioma. AB - This paper aims to present the case of a 43-year-old woman diagnosed with a rare condition of meningoencephalocele that arose from a meningioma, and treated with endoscope-assisted transnasal tumor extirpation and repair of the skull base defect with tensor fascia lata flap. Endoscope-assisted operation is a viable and minimally invasive alternative to traditional craniotomy. With improved endoscopic equipment and operative technique, we can perform more reliable surgery and provide better quality of life for these patients. PMID- 24630393 TI - Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer. AB - BACKGROUND: Biliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis. PATIENTS AND METHODS: Baseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model. RESULTS: Eight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ? 2. A NLR ? 3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ? 3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ? 3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06-1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR 1.26, 95% CI; 1.02-1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR 1.70, 95% CI; 1.10-2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04-2.44, P = 0.048). CONCLUSION: Baseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials. PMID- 24630394 TI - The role of tumour FoxP3 as prognostic marker in different subtypes of head and neck cancer. AB - Expression of the forkhead transcription factor (FoxP3)--an established marker of regulatory T cells--has been found in other cell types as well, including tumour cells. Recent studies indicated that high tumour FoxP3 expression might be associated with a poor outcome of patients with several types of solid cancers. Here, we investigated the role of FoxP3 expressed by the tumour cells in the prognosis of larynx and oro-hypopharynx squamous cell carcinoma (LSCC and OHSCC)- two major subtypes of head and neck cancer. To this end, we analysed by immunohistochemistry the expression of tumour FoxP3 in tissues from 83 LSCC and 89 OHSCC patients in relation to overall survival. In multivariate analysis we found that high tumour FoxP3 expression significantly associated with poor survival in OHSCC but not in LSCC patients. In further studies, we combined the prognostic value of FoxP3 with selected markers of inflammation (cyclooxygenase 2; COX2) or with markers of enhanced tumour migration/invasion (AHNAK and CORTACTIN). Interestingly, we found that the combination of FoxP3 and AHNAK (in LSCC) or FoxP3 and CORTACTIN (in OHSCC) had significantly stronger prognostic values than either marker analysed individually. Combination of FoxP3 and COX2 enhanced the prognostic accuracy only in OHSCC. Thus, our study identifies novel individual and combination markers that might have enhanced and distinct prognostic relevance in different subtypes of head and neck cancer. PMID- 24630395 TI - Expression and possible role of IGF-IR in the mouse gastric myenteric plexus and smooth muscles. AB - Insulin-like growth factor-I (IGF-I) and its receptor (IGF-IR) have tremendous trophic effects on the central, peripheral and enteric neurons. The loss of IGF IR contributes to the development of diabetic gastroparesis. However, the nature and the function of the IGF-IR(+) cells in the gastric myenteric plexus remain unclear. In this study, anti-ChAT, anti-S100beta or anti-c-KIT antibodies were used to co-label IGF-IR(+) cells and neurons, glial cells or interstitial cells of Cajal (ICCs), respectively. We also generated type 1 diabetic mice (DM) to explore the influence of impaired IGF-I/IGF-IR in the myenteric neurons. Results showed that IGF-IR was expressed in the epithelium, smooth muscles and myenteric plexi of the mouse stomach. Most of the IGF-IR(+) cells in the myenteric plexi were ChAT(+) cholinergic neurons, but not enteric glial cells and there were more IGF-IR(+) neurons and fibers in the gastric antrum than in the corpus. The IGF IR(+)/ChAT(+) neurons and ICCs were closely juxtaposed, but distinctly distributed in the myenteric plexus, indicating a possible role for the IGF IR(+)/ChAT(+) neurons in the mediation of gastric motility through ICCs. Moreover, the decrease of IGF-IR and cholinergic neurons in the myenteric plexi and smooth muscles of DM mice suggested that IGF-I/IGF-IR signaling might play a role in neuron survival and neurite outgrowth, as well as stem cell factor (SCF) production, which is required for the development of ICCs. Our results provide insights into the effects of IGF-I/IGF-IR signaling on the development of gastrointestinal motility disorders. PMID- 24630396 TI - Altered expression and localization of desmoglein 3 in esophageal squamous cell carcinoma. AB - Desmoglein 3 (DSG3), a transmembrane cadherin of the desmosomal cell-cell adhesion structure, plays vital roles in the maintenance of normal epithelial tissue architecture. Reports implicating a role for DSG3 expression in cancer are few and contradictory. In this study, immunohistochemical staining was employed to investigate DSG3 expression and subcellular localization in esophageal squamous cell carcinoma (ESCC), and to correlate changes with clinical characteristics. Results indicate that in normal squamous cell epithelia, strong DSG3 immunoreactivity was observed in the Stratum spinosum, and localization occurred only at the cell membrane. In ESCC, DSG3 immunoreactivity displayed an abnormal cytoplasmic localization that was correlated with cell differentiation (P=0.018). Most strikingly, in 74.1% of the tumors, DSG3 expression was up regulated and correlated with regional lymph node metastasis (P=0.036). Moreover, in patients without lymph node metastasis, cytoplasmic localization of DSG3 correlated with poor prognosis (P=0.044). These results suggest that DSG3 is involved in the development of ESCC and imply that DSG3 overexpression is likely to be an essential contributor to the aggressive features of esophageal cancer. PMID- 24630397 TI - Use of polyetheretherketone in the fabrication of a maxillary obturator prosthesis: a clinical report. AB - To treat a patient who needed a replacement for a maxillary obturator prosthesis, a new obturator prosthesis was fabricated from polyetheretherketone (PEEK), a material often used in medicine but seldom in dentistry. This material provided the patient with a better-adjusted, more functional, and lighter prosthesis. PMID- 24630398 TI - Effects of post core materials on stress distribution in the restoration of mandibular second premolars: a finite element analysis. AB - STATEMENT OF PROBLEM: Previous studies have not resolved the question as to which post and core combination optimizes the stress distribution within the post restoration and tooth. PURPOSE: The purpose of this study was to determine which post and core combination provides the most favorable stress distribution upon loading. MATERIAL AND METHODS: Three-dimensional models of teeth were created with the Ansys program to simulate different materials used for post and cores (Ti, NiCr, AuPd, zirconia, zirconia post/composite resin core, glass fiber post/composite resin core, and carbon fiber post/composite resin core) and metal ceramic crowns (nickel chromium alloy [Group NiCr] and gold palladium alloy [Group AuPd]). A force of 400 N was applied to the occlusal surface, and von Mises equivalent stress values were calculated. RESULTS: Carbon fiber post/composite resin core/metal ceramic crowns with NiCr alloy core had the highest stress values in the weakened root, tooth/post interface, and post. NiCr post/NiCr core/metal ceramic crowns with NiCr alloy core had the lowest stress values in the weakened root and post. The zirconia post and core had the lowest stress value in the tooth/post interface. CONCLUSIONS: A post material with a high elastic modulus led to lower stress in the weakened root (approximately 6%) and tooth/post interface (approximately 12%) and to higher stress in the post (approximately 5 times). A composite resin core led to higher stress in the weakened root (approximately 11% to 17%) and lower deformation in the tooth/post interface (approximately 17.5%) and post materials (approximately 24%). Group AuPd resulted in lower stress in the root and high stress in the post (approximately 4.5% to 7%) and affected the amount of deformation in posts with a composite resin core. PMID- 24630399 TI - A comparison of the marginal fit of crowns fabricated with digital and conventional methods. AB - STATEMENT OF PROBLEM: Little evidence is available with regard to the marginal fit of crowns fabricated with digital impressions and computer-aided design/computer-aided manufacturing technology in comparison with crowns fabricated from conventional techniques. PURPOSE: The purpose of this study was to determine and compare the marginal fit of crowns fabricated with digital and conventional methods. MATERIAL AND METHODS: The maxillary right second premolar was prepared for a ceramic crown in a typodont. The typodont was then digitized with a laboratory scanner, and the digital file was used to mill a replica of the maxillary arch from a monolithic block of yttria-stabilized zirconia to serve as the master model. Digital impressions of the prepared maxillary right second premolar were recorded with a scanning unit. Scan files were exported as .STL files and sent by e-mail to a dental laboratory. The files were input into a digital design workflow for digital articulation, digital waxing, and design of the definitive crown. Fifteen crowns were produced by milling computer-aided designed lithium disilicate glass ceramic blocks with a 5-axis milling. Fifteen lithium disilicate glass ceramic crowns were produced with a conventional impression and a laboratory fabrication method. The original zirconia die was removed from the zirconia master model to evaluate the crown margins. Circumferential marginal gap measurements were made at 8 measurement locations: mescal, distal, buccal, palatal and associated line angles (mesiobuccal, mesiolingual, distobuccal, and distolingual). Measurements were made to determine the vertical component of the marginal gap according to the definition of marginal fit. RESULTS: A total of 240 images (2 groups, 15 crowns per group, 8 sites per crown) were recorded and measured. The overall mean +/-SD vertical gap measurement for the digitally made crowns was 48 +/-25 MUm, which was significantly smaller than that for the conventionally made crowns (74 +/-47 MUm). CONCLUSION: The fully digital fabrication method provided better margin fit than the conventional method. PMID- 24630400 TI - Prosthetic rehabilitation of maxillary dentoalveolar defects with fixed dental prostheses: two clinical reports. AB - Traumatic injuries or congenital malformations may cause soft and hard tissue defects resulting in the loss of alveolar bone and attached mucosa. Restoring the defective area presents a challenge for clinicians. The prosthetic rehabilitation of 2 patients with maxillary dentoalveolar defects with 2 different prosthetic designs is presented. The esthetic and functional requirements of the patients were fulfilled. PMID- 24630401 TI - A cohort study on Actinobacillus pleuropneumoniae colonisation in suckling piglets. AB - Actinobacillus pleuropneumoniae causes respiratory disease in pigs and despite the use of preventive measures such as vaccination and antimicrobials clinical outbreaks still occur. At weaning often many piglets are not colonised. If differences in prevalence between litters are large and if factors were known that could explain these differences, this may provide an opportunity to raise groups of A. pleuropneumoniae free piglets. To this end, a cohort study was performed on two endemically infected farrow-to-finish farms. Seventy-six of 133 sows were selected using stratified random selection by parity. Farmers complied with a strict hygiene and animal management protocol to prevent transmission between litters. Tonsil brush and serum samples taken three weeks before parturition were tested for antigen with an apxIVA qPCR and antibodies with Apx and Omp ELISAs, respectively. Three days before weaning tonsil brush samples from all piglets (n=871) were collected and tested for antigen. Whereas all sows tested positive both in serology tests as well as qPCR, 0.41 of the litters tested fully negative and 0.73 of all piglets tested negative. The proportion of positively tested piglets in positive litters ranged from 0.08-1.0 (median=0.36). A grouped logistic regression model with a beta binomial distribution of the probability for piglets to become infected was fitted to the data and associations with explanatory variables were explored. To test the possibility that alternatively the clustering was caused by onwards transmission among the piglets, a transmission model was fitted to the data incorporating sow-piglet and piglet-piglet transmission, but this model did not fit better. The results of this study showed that the number of colonised suckling piglets was highly clustered and mainly attributable to the variability of infectiousness of the dam, but no dam related risk factor for colonisation status of litter or piglets within litters could be identified. PMID- 24630402 TI - A conceptual framework for economic optimization of single hazard surveillance in livestock production chains. AB - Economic analysis of hazard surveillance in livestock production chains is essential for surveillance organizations (such as food safety authorities) when making scientifically based decisions on optimization of resource allocation. To enable this, quantitative decision support tools are required at two levels of analysis: (1) single-hazard surveillance system and (2) surveillance portfolio. This paper addresses the first level by presenting a conceptual approach for the economic analysis of single-hazard surveillance systems. The concept includes objective and subjective aspects of single-hazard surveillance system analysis: (1) a simulation part to derive an efficient set of surveillance setups based on the technical surveillance performance parameters (TSPPs) and the corresponding surveillance costs, i.e., objective analysis, and (2) a multi-criteria decision making model to evaluate the impacts of the hazard surveillance, i.e., subjective analysis. The conceptual approach was checked for (1) conceptual validity and (2) data validity. Issues regarding the practical use of the approach, particularly the data requirement, were discussed. We concluded that the conceptual approach is scientifically credible for economic analysis of single-hazard surveillance systems and that the practicability of the approach depends on data availability. PMID- 24630403 TI - Modelling the continental-scale spread of Schmallenberg virus in Europe: approaches and challenges. AB - Following its emergence in northern Europe in 2011 Schmallenberg virus (SBV), a vector-borne disease transmitted by the bites of Culicoides midges, has spread across much of the continent. Here we develop simple models to describe the spread of SBV at a continental scale and, more specifically, within and between NUTS2 regions in Europe. The model for the transmission of SBV between regions suggests that vector dispersal is the principle mechanism for transmission, even at the continental scale. The within-region model indicates that there is substantial heterogeneity amongst regions in the force of infection for cattle and sheep farms. Moreover, there is considerable under-ascertainment of SBV affected holdings, though the level of under-ascertainment varies between regions. We contrast the relatively simple approach adopted in this study with the more complex continental-scale micro-simulation models which have been developed for pandemic influenza and discuss the strengths, weaknesses and data requirements of both approaches. PMID- 24630404 TI - Comparison of two methods for collecting antibiotic use data on small dairy farms. AB - Antibiotics are commonly used in animal agriculture; they can improve animal health and productivity, but their use may also represent a public health threat. Very little is known about antibiotic use on small farms in lower/middle income countries. To understand antibiotic use on these farms and promote the judicious use of these drugs, pharmacoepidemiologic data are necessary. However, acquiring such data can be difficult, as farmers are often illiterate (and therefore cannot participate in written surveys or keep treatment records), antibiotics can be obtained over-the-counter (in which case no prescriptions are generated) and monitoring and surveillance systems for drug use are often non-existent. The goal of this study was to compare two methods of acquiring pharmacoepidemiologic data pertaining to antibiotics that are well-adapted to farms in lower-middle income countries: self-report and the collection of discarded drug packaging. A convenience sample of 20 farmers in Cajamarca, Peru, participated in the study. Farmers placed discarded antibiotic packaging in bins for six months. At the end of the six-month period, farmers were interviewed and asked to recall the antibiotic usage that occurred on their farm over the past month and past six months; these self-reported data were quantitatively and qualitatively compared to the bin contents collected in the last month and previous six months. We found that the agreement between the bins and self-report was relatively poor for both the quantity and types of antibiotics used. The bins appeared to perform better than self-report when bottles and mLs of antibiotics were measured, while self report appeared to perform better for intra-mammary infusions. The bins also appeared to perform better when data pertaining to an extended time period (six months) were collected. The results of this study will provide guidance to investigators seeking to collect pharmacoepidemiologic data in similar environments. PMID- 24630405 TI - Atypical hemolytic-uremic syndrome immediately after heart transplantation. PMID- 24630406 TI - A multi-institutional study of malignancies after heart transplantation and a comparison with the general United States population. AB - BACKGROUND: The purpose of these studies was to determine the incidence and survival of patients with specific malignancies with respect to age and transplant year and to compare the data with the normal non-transplant population. METHODS: Data from 6,211 primary cardiac transplants between July 31, 1993, and December 30, 2008, were collected by 35 institutions participating in the Cardiac Transplant Research Database. Data were compared with information collected by the Surveillance Epidemiology and End Results (SEER) Cancer Statistics Review 1975-2006. RESULTS: Multivariable analysis showed older age (relative risk [RR], 2.1; p < 0.0001) and earlier transplant year (RR, 1.8; p < 0.0001) were highly significant risk factors. Aggregate malignancy incidence in the modern era (2001 to 2008) did not differ significantly from the normal population, which appeared to be attributable to a lower rate of malignancies other than lung cancer, lymphoma, and melanoma (actual/expected ratio, 0.71). From 2001 to 2008, rates were significantly higher for lung cancer (actual/expected ratio, 1.86; p = 0.006) and lymphoma (actual/expected ratio, 4.3, p < 0.0001) than in the normal population. The highest risk for lymphoma was in younger adults who received transplants at ages 18 to 35 years (actual/expected ratio, 27). The highest risk for lung cancer was in patients who underwent transplantation at ages 55 to 65 years (actual/expected ratio, 28). Once diagnosed with malignancy, subsequent survival at 5 years was 21% for lung cancer and 32% for lymphoma. CONCLUSIONS: The risk of malignancy has markedly declined during a 15-year period such that the aggregate rate of malignancy approached that of the general population in the United States. However, the distribution of malignancies was not the same, with a greater prominence of lung cancer and lymphoproliferative disease. PMID- 24630407 TI - Creation of a functional Potts shunt by stenting the persistent arterial duct in newborns and infants with suprasystemic pulmonary hypertension of various etiologies. AB - BACKGROUND: The surgical creation of a Potts shunt has been reported in children with suprasystemic idiopathic pulmonary artery (PA) hypertension (IPAH) refractory to any medical therapy. This surgical approach allows acute decompression of the right ventricle (RV) and thereby avoids ventricular failure. We present 4 newborns and infants with different causes of pulmonary hypertension (PH) in whom interventional stenting of the patent ductus arteriosus (PDA) was used to create a "functional" Potts shunt. METHODS: Suprasystemic PH was diagnosed by cardiac catheterization in 2 newborns with complex left heart obstructive lesions, a patient with persistent PH of the newborn (PPHN), and an infant with IPAH and was accompanied by RV dilation and imminent RV failure. RESULTS: Stenting of the PDA was performed uneventfully during cardiac catheterization in all patients and led to stabilization of clinical symptoms. The 2 patients with complex cardiac lesions subsequently underwent successful biventricular repair. In the PPHN patient, the stented PDA was closed interventionally when PA pressures dropped and a significant left-to-right shunt occurred. PA pressures in the patient with IPAH remained high while the stented PDA still served as RV decompression in avoidance of lung transplantation. CONCLUSIONS: Newborns and infants with suprasystemic PH of varying etiologies may benefit from the creation of a functional Potts shunt by stenting the PDA. This strategy should be considered in patients with suprasystemic IPAH or PPHN as a temporary or permanent therapy when a PDA can be identified at cardiac catheterization. It may also be beneficial in patients with PH due to left heart obstructions by serving as a bridge to further corrective surgery. PMID- 24630408 TI - Impaired cholesterol efflux capacity and vasculoprotective function of high density lipoprotein in heart transplant recipients. AB - BACKGROUND: High-density lipoprotein (HDL) metabolism is significantly altered in heart transplant recipients. We hypothesized that HDL function may be impaired in these patients. METHODS: Fifty-two patients undergoing coronary angiography between 5 and 15 years after heart transplantation were recruited in this cross sectional study. Cholesterol efflux capacity of apolipoprotein B-depleted plasma was analyzed using a validated assay. The vasculoprotective function of HDL was studied by means of an endothelial progenitor cell migration assay. RESULTS: HDL cholesterol levels were similar in heart transplant patients compared with healthy controls. However, normalized cholesterol efflux and vasculoprotective function were reduced by 24.1% (p < 0.001) and 27.0% (p < 0.01), respectively, in heart transplant recipients compared with healthy controls. HDL function was similar in patients with and without cardiac allograft vasculopathy (CAV) and was not related to C-reactive protein (CRP) levels. An interaction effect (p = 0.0584) was observed between etiology of heart failure before transplantation and steroid use as factors of HDL cholesterol levels. Lower HDL cholesterol levels occurred in patients with prior ischemic cardiomyopathy who were not taking steroids. However, HDL function was independent of the etiology of heart failure before transplantation and steroid use. The percentage of patients with a CRP level >=6 mg/liter was 3.92-fold (p < 0.01) higher in patients with CAV than in patients without CAV. CONCLUSIONS: HDL function is impaired in heart transplant recipients, but it is unrelated to CAV status. The proportion of patients with a CRP level >=6 mg/liter is prominently higher in CAV-positive patients. PMID- 24630409 TI - Disaster easily averted? Data confidentiality and the hospital desktop computer. AB - OBJECTIVE: We specifically identified the hospital desktop computer as a potential source of breaches in confidentiality. We aimed to evaluate if there was accessible, unprotected, confidential information stored on the desktop screen on computers in a district general hospital and if so, how a teaching intervention could improve this situation. DESIGN: An unannounced spot check of 59 ward computers was performed. Data were collected regarding how many had confidential information stored on the desktop screen without any password protection. An online learning module was mandated for healthcare staff and a second cycle of inspection performed. SETTING: A district general hospital. PARTICIPANTS: Two doctors conducted the audit. Computers in clinical areas were assessed. All clinical staff with computer access underwent the online learning module. INTERVENTION: An online learning module regarding data protection and confidentiality. RESULTS: In the first cycle, 55% of ward computers had easily accessible patient or staff confidential information stored on their desktop screen. This included handovers, referral letters, staff sick leave lists, audits and nursing reports. The majority (85%) of computers accessed were logged in under a generic username and password. The intervention produced an improvement in the second cycle findings with only 26% of computers being found to have unprotected confidential information stored on them. CONCLUSIONS: The failure to comply with appropriate confidential data protection regulations is a persistent problem. Education produces some improvement but we also propose a systemic approach to solving this problem. PMID- 24630410 TI - ICP OES and CV AAS in determination of mercury in an unusual fatal case of long term exposure to elemental mercury in a teenager. AB - In this work, a case of deliberate self-poisoning is presented. A 14-year-old girl suddenly died during one of the several hospitalizations. Abdominal computer tomography showed a large number of metallic particles in the large intestine. Analysis of blood and internal organs for mercury and other toxic metals carried out by inductively coupled plasma optical emission spectrometry (ICP OES) revealed high concentrations of mercury in kidneys and liver (64,200 and 2470ng/g, respectively), less in stomach (90ng/g), and none in blood. Using cold vapor-atomic absorption spectrometry (CV AAS), high levels of mercury were confirmed in all examined materials, including blood (87ng/g), and additionally in hair. The results of analysis obtained by two techniques revealed that the exposure to mercury was considerable (some time later, it was stated that the mercury originated from thermometers that had been broken over the course of about 1 year, because of Munchausen syndrome). CV AAS is a more sensitive technique, particularly for blood samples (negative results using ICP OES), and tissue samples - with LOQ: 0.63ng/g of Hg (CV AAS) vis-a-vis 70ng/g of Hg (ICP OES). However, ICP OES may be used as a screening technique for autopsy material in acute poisoning by a heavy metal, even one as volatile as mercury. PMID- 24630411 TI - Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series. AB - Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure-activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles. PMID- 24630412 TI - Schiff's base derivatives bearing nitroimidazole and quinoline nuclei: new class of anticancer agents and potential EGFR tyrosine kinase inhibitors. AB - New Schiff's base derivatives 5a-j have been synthesized by reaction between 2 phenoxyquinoline-3-carbaldehydes 3a-j and 2-(2-methyl-5-nitro-1H-imidazol-1 yl)acetohydrazide 4 in presence of nickel(II) nitrate as a catalyst in ethanol under reflux in good yield (78-92%). All compounds were tested for anticancer and inhibition of EGFR. Of the compounds studied, majority of the compounds showed effective antiproliferation and inhibition of EGFR and HER-2 activities. Compound 5h showed most effective inhibition (IC50=0.12+/-0.05 MUM) by binding in to the active pocket of EGFR receptor with minimum binding energy (DeltaGb=-58.3691 kcal/mol). The binding was stabilized by two hydrogen bonds, two pi-cation and one pi-sigma interactions. Compound 5d showed most effective inhibition (IC50=0.37+/-0.04 MUM). PMID- 24630413 TI - Structural requirement and stereospecificity of tetrahydroquinolines as potent ecdysone agonists. AB - Tetrahydroquinoline (THQ)-type compounds are a class of potential larvicides against mosquitoes. The structure-activity relationships (SAR) of these compounds were previously investigated (Smith et al., Bioorg. Med. Chem. Lett. 2003, 13, 1943-1946), and one of cis-forms (with respect to the configurations of 2-methyl and 4-anilino substitutions on the THQ basic structure) was stereoselectively synthesized. However, the absolute configurations of C2 and C4 were not determined. In this study, four THQ-type compounds with cis configurations were synthesized, and two were submitted for X-ray crystal structure analysis. This analysis demonstrated that two enantiomers are packed into the crystal form. We synthesized the cis-form of the fluorinated THQ compound, according to the published method, and the enantiomers were separated via chiral HPLC. The absolute configurations of the enantiomers were determined by X-ray crystallography. Each of the enantiomers was tested for activity against mosquito larvae in vivo and competitive binding to the ecdysone receptor in vitro. Compared to the (2S,4R) enantiomer, the (2R,4S) enantiomer showed 55 times higher activity in the mosquito larvicidal assay, and 36 times higher activity in the competitive receptor binding assay. PMID- 24630414 TI - Pretreatment neutrophil-to-lymphocyte ratio is associated with advanced pathologic tumor stage and increased cancer-specific mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy. AB - BACKGROUND: Pretreatment neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been associated with adverse survival in a variety of malignancies. However, the relationship between NLR and oncologic outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) has not been well studied. OBJECTIVE: To evaluate the association of preoperative NLR with clinicopathologic outcomes following RC. DESIGN, SETTING, AND PARTICIPANTS: We identified 899 patients who underwent RC without neoadjuvant therapy at our institution between 1994 and 2005 and who had a pretreatment NLR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Preoperative NLR (within 90 d prior to RC) was recorded. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazard and logistic regression models were used to analyze the association of NLR with clinicopathologic outcomes. RESULTS AND LIMITATIONS: Median postoperative follow-up was 10.9 yr (interquartile range: 8.3-13.9 yr). Higher preoperative NLR was associated with significantly increased risks of pathologic, extravesical tumor extension (odds ratio [OR]: 1.07; p=0.03) and lymph node involvement (OR: 1.09; p=0.02). Univariately, 10-yr cancer specific survival was significantly worse among patients with a preoperative NLR (>=2.7 [51%] vs. <2.7 [64%]; p<0.001). Moreover, on multivariate analysis, increased preoperative NLR was independently associated with greater risks of disease recurrence (hazard ratio [HR]: 1.04; p=0.02), death from bladder cancer (HR: 1.04; p=0.01), and all-cause mortality (HR: 1.03; p=0.01). CONCLUSIONS: Elevated preoperative NLR among patients undergoing RC is associated with significantly increased risk for locally advanced disease as well as subsequent disease recurrence, and cancer-specific and all-cause mortality. These data suggest that serum NLR may be a useful prognostic marker for preoperative patient risk stratification, including consideration for neoadjuvant therapy and clinical trial enrollment. PMID- 24630415 TI - OnabotulinumtoxinA: how deep will it go? PMID- 24630417 TI - Validated comprehensive outcome measures will aid regulation. PMID- 24630416 TI - Ongoing Gleason grade migration in localized prostate cancer and implications for use of active surveillance. PMID- 24630418 TI - Percutaneous suprapubic tube after robotic assisted radical prostatectomy: true or placebo benefit? PMID- 24630419 TI - Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial. AB - BACKGROUND: Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE: To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized double blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION: Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS: Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS: Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY: This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00708201. PMID- 24630420 TI - Understanding the promise: considering the experiences of women living with HIV to maximize effectiveness of HIV prevention technologies. AB - BACKGROUND: The United States' response to HIV was designed primarily to meet the needs of single men without dependent children and its prevention strategies focused primarily on individual behavior change with little attention to the social, cultural, and economic factors fueling HIV risk, especially among indigent and marginalized women. In 2012, the President's Advisory Council called for an updating of the National HIV/AIDS Strategy's Implementation Plan to "achieve specific, targeted and measurable goals for reducing HIV incidence and ... improving health care access and health outcomes for women living with HIV." OUTCOME MEASURES: Women living with HIV and those at greatest risk of HIV generally live side by side in the same communities and under the same conditions, separated in status only by a positive HIV test and its consequences. Thus, women openly living with HIV constitute an identifiable and accessible source of first-hand information regarding the barriers that keep women out of HIV prevention and care. Their insights, rooted in lived experience, can vitally inform the development of realistic HIV prevention goals and strategies for the successful integration of HIV prevention into the services already accessed by high-risk women. Their expertise, however, is largely untapped. CONCLUSIONS: In this article, women living with HIV summarize the substantial deficits that exist with regard to woman-focused HIV prevention efforts nationally and the policy and practice changes needed to reduce the domestic impact of the HIV epidemic on women and girls. They also outline opportunities for movement in this direction as implementation of the National HIV/AIDS Strategy proceeds. PMID- 24630421 TI - Anticipating the traumatic brain injury-related health care needs of women veterans after the Department of Defense change in combat assignment policy. AB - BACKGROUND: Female service members' presence in combat zones during Operation Enduring Freedom and Operation Iraqi Freedom is unprecedented both in terms of the number of women deployed and the nature of their involvement. In light of changing Department of Defense policy governing the deployment of women in combat zones, this article intends to set the groundwork for estimating future combat related injuries and subsequent Veterans Health Administration (VHA) utilization while focusing on traumatic brain injury (TBI). METHODS: The article summarizes and presents the results of a study that examines veterans who present to VHA for TBI evaluation. For a national sample of veterans, a dataset including information on post-screening utilization, diagnoses, and location of care was constructed. The dataset included self-reported health symptoms and other information obtained from a standardized national VHA post-screening clinical evaluation, the comprehensive TBI evaluation (CTBIE). FINDINGS: Both women and men utilize high levels of VHA health care after a CTBIE. However, there are gender differences in the volume and types of services used, with women utilizing different services than their male counterparts and incurring higher costs, including higher overall and outpatient costs. CONCLUSION: As women veterans seek more of their health care from the VHA, there will be a need for more coordinated care to identify and manage deployment-related TBI and common comorbidities such as posttraumatic stress disorder, depression, and chronic pain. Deployment connected injuries are likely to rise because of the rescinding of the ban on women in combat. This in turn has critical implications for VHA strategic planning and budgeting. PMID- 24630422 TI - Full-time employed and a family caregiver: a profile of women's workload, effort, and health. AB - BACKGROUND: Women provide care for elderly family members while managing their other responsibilities, including full-time employment. METHODS: This descriptive study used an inductively derived workload-effort-health theoretical model to examine workload, effort, and health among 46 full-time employed family caregivers [CG] of community-dwelling older adults from a larger, nonprobability, cross-sectional sample of 110 CGs. FINDINGS: The women's caregiving workload (time, difficulty, care recipient's [CR] function), effort (perceived exertion of energy experienced in doing a workload), self-assessed health [SAH], depressive symptoms, and sources of help were richly described, and several associations were found, including higher physical and mental effort, were significantly correlated with higher workload time and difficulty and lower CR function, but not SAH. Higher mental effort and workload, and poorer SAH were significantly correlated with high depressive symptoms. Worse effort, workload, and health experiences were reported by daughters and by women who lived with their CR; those who did not have family or formal caregiving help had higher mental effort and were more depressed, suggesting an area for further study. CONCLUSIONS: Suggestions are offered for richer measurement of employment status, caregiving workload, and effort. Findings provide a unique profile of full-time employed women CGs' workload, effort (that is, how they do the work), and health, toward a stronger understanding of how women manage multiple workloads. Workplace policies are needed to address workload, effort and health in this informal caregiving workforce. PMID- 24630423 TI - Out-of-pocket costs and insurance coverage for abortion in the United States. AB - BACKGROUND: Since 1976, federal Medicaid has excluded abortion care except in a small number of circumstances; 17 states provide this coverage using state Medicaid dollars. Since 2010, federal and state restrictions on insurance coverage for abortion have increased. This paper describes payment for abortion care before new restrictions among a sample of women receiving first and second trimester abortions. METHODS: Data are from the Turnaway Study, a study of women seeking abortion care at 30 facilities across the United States. FINDINGS: Two thirds received financial assistance, with those with pregnancies at later gestations more likely to receive assistance. Seven percent received funding from private insurance, 34% state Medicaid, and 29% other organizations. Median out-of pocket costs when private insurance or Medicaid paid were $18 and $0. Median out of-pocket cost for women for whom insurance or Medicaid did not pay was $575. For more than half, out-of-pocket costs were equivalent to more than one-third of monthly personal income; this was closer to two thirds among those receiving later abortions. One quarter who had private insurance had their abortion covered through insurance. Among women possibly eligible for Medicaid based on income and residence, more than one third received Medicaid coverage for the abortion. More than half reported cost as a reason for delay in obtaining an abortion. In a multivariate analysis, living in a state where Medicaid for abortion was available, having Medicaid or private insurance, being at a lower gestational age, and higher income were associated with lower odds of reporting cost as a reason for delay. CONCLUSIONS: Out-of-pocket costs for abortion care are substantial for many women, especially at later gestations. There are significant gaps in public and private insurance coverage for abortion. PMID- 24630424 TI - Upper urinary tract tumors associated to Lynch syndrome: a case report. PMID- 24630425 TI - Extraction of a bladder stone in a child as described by the renaissance physician Cristobal Mendez. AB - INTRODUCTION: in his Libro del exercicio y de sus provechos (Book of exercise and profits), the Spanish Renaissance physician Christopher Mendez (1500-1553) describes extracting a bulk stone from the bladder of a child younger than 5 years in the land of colonial Mexico. This is the first description of a surgical procedure in America. MATERIAL AND METHODS: Biographical data were collected on Christopher Mendez. The electronic facsimile of the Book of exercise and profits was read. The historical aspects of perineal lithotomy and etiology of bladder stones were analyzed. RESULTS: In chapter seven of the third treatise (page 120), Mendez speaks about the removal of a bladder stone in a boy named "Villasenor". It uses the word "open" to describe the procedure, corresponding to a lithotomy more than a necropsy. It attributes the etiology of excess movements after ingestion and suggests a possible hereditary etiology. DISCUSSION: Perineal lithotomy was a common practice in ancient times for children due to the high incidence of bladder stones. The technique was very invasive and was improved over the centuries. CONCLUSIONS: The surgery described by Mendez for the child called Villasenor most likely corresponds to a perineal lithotomy. A congenital cause could play a role in its etiology. PMID- 24630426 TI - Use of health care resources and associated costs in non-institutionalized vulnerable elders with overactive bladder treated with antimuscarinic agents in the usual medical practice. AB - OBJECTIVE: To evaluate the use of resources and health costs in vulnerable elderly institutionalized patients with overactive bladder (OAB) treated with fesoterodine, tolterodine or solifenacin in routine medical practice. MATERIAL AND METHODS: A multicenter retrospective study, from the records of patients treated during 2008-2010 in three geographical locations and starting treatment with antimuscarinic (fesoterodine, solifenacin and tolterodine) for OAB. The attribute of vulnerability was based on collecting at least 3 of the Vulnerable Elders Survey criteria-13, age>75 years, poor/average age for health and difficulty in at least one daily physical activity. MAIN MEASURES: morbidity, persistence and resource use and costs. Monitoring of patients was conducted over 52 weeks. A general linear model with covariates and bootstraping (1000) at random was used to construct the 95% CI of the cost differences between drugs. RESULTS: Records of 552 patients (50.8% women, mean age: 80.2 years) were analyzed. Treated with fesoterodine (N=58), solifenacin (N=252) or tolterodine (N=212). The use of absorbent was 20.7%, 29.4% and 33.0% (P=.186), respectively. Persistence to treatment was slightly greater with fesoterodine. The patient healthcare costs/year were lower with fesoterodine, ?1,775 (1550-2014) vs. solifenacin ?2,062 (1911-2223) and tolterodine ?2,149 (1,978-2,307), P=.042, as a result of lower utilization visits and concomitant medication. CONCLUSIONS: Despite the potential limitations of the study, the vulnerable elderly non institutionalized patients with OAB treated with fesoterodine, compared to solifenacin or tolterodine were associated with lower resource utilization and healthcare costs. PMID- 24630427 TI - Analysis of inpatient dermatologic consultations. PMID- 24630428 TI - The utility of skin ultrasound for the diagnosis of complications of tissue filler materials. PMID- 24630429 TI - Patient perspectives on triggers, adherence to medical recommendations, and disease control in atopic dermatitis: the DATOP study. AB - INTRODUCTION AND OBJECTIVES: To analyze the triggers of atopic dermatitis (AD), adherence to medical recommendations, disease control, and health-related quality of life (HRQOL) from the patient's perspective. PATIENTS AND METHODS: This was a multicenter, cross-sectional, epidemiological study with the participation of adults (age >16 years; n=125) and children (age, 2-15 years, n=116). Patients had a history of at least 12 months of moderate to severe AD with a moderate to severe flare (Investigator Global Assessment score>2) at the time of recruitment. The Mann-Whitney U test was used to evaluate relationships between disease severity, determined according to the Scoring in Atopic Dermatitis index, and triggers reported by patients, adherence to recommendations and pharmacological therapy, HRQOL, and patient-perceived control. RESULTS: The most common triggers were cosmetic products, clothing, mites, detergents/soaps, and changes in temperature. In 47.2% of adults and 39.7% of children, pharmacological therapy was not initiated at flare onset. Adherence was highest to pharmacological therapy, skin moisturizing, and medical care recommendations. Disease control was considered insufficient by 41.6% of adults and 27. 6% of pediatric patients and, in adults, this was associated with the severity of AD (P=.014). CONCLUSIONS: The therapeutic control of AD is susceptible to improvement, especially in adults. Although patients state that they follow medical recommendations, a significant percentage of patients do not apply recommended treatments correctly. Better education about the disease and its management would appear to be necessary to improve disease control and HRQOL. PMID- 24630430 TI - Congenital fascial dystrophy or stiff skin syndrome: a case report. PMID- 24630431 TI - A dish of disquietude. PMID- 24630432 TI - A comparison between print vs. internet methods for a clinical trial recruitment- a pan European OCD study. AB - Recruitment for clinical studies presents a serious challenge in terms of meeting both time and budget constraints. The internet offers a potentially powerful means for quick and effective recruitment-either as an add-on or as alternative to traditional methods. We developed a Google search based solution which enhances patient recruitment. Recruitment via internet was associated with greater exposure to relevant applicants and better response to treatment as compared to traditional printed ads. PMID- 24630433 TI - Juvenile cannabinoid treatment induces frontostriatal gliogenesis in Lewis rats. AB - Cannabis abuse in adolescence is associated with a broad array of phenotypical consequences, including a higher risk for schizophrenia and other mental disturbances related to dopamine (DA) imbalances. The great variability of these sequelae likely depends on the key influence of diverse genetic vulnerability factors. Inbred rodent strains afford a highly informative tool to study the contribution of genetic determinants to the long-term effects of juvenile cannabinoid exposure. In this study, we analyzed the phenotypical impact of the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 2mg/kg/day from postnatal day 35 48) in adolescent Lewis rats, an inbred strain exhibiting resistance to psychotomimetic effects of environmental manipulations. At the end of this treatment, WIN-injected animals displayed increased survival of new cells (mainly oligodendroglia precursors) in the striatum and prefrontal cortex (PFC), two key terminal fields of DAergic pathways. To test whether these changes may be associated with enduring behavioral alterations, we examined the consequences of adolescent WIN treatment in adulthood (postnatal days 60-70), with respect to DA levels and metabolism as well as multiple behavioral paradigms. Rats injected with WIN exhibited increased turnover, but not levels, of striatal DA. In addition, cannabinoid-treated animals displayed increases in acoustic startle latency and novel-object exploration; however, WIN treatment failed to induce overt deficits of sensorimotor gating and social interaction. These results indicate that, in Lewis rats, juvenile cannabinoid exposure leads to alterations in frontostriatal gliogenesis, as well as select behavioral alterations time locked to high DAergic metabolism, but not overt schizophrenia-related deficits. PMID- 24630434 TI - Letter to the editor regarding "Application of principal component analysis in clinical gait research" by Federolf and colleagues. PMID- 24630435 TI - Evaluation of the efficacy of deep brain stimulation in the surgical treatment of cervical dystonia. AB - OBJECTIVE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a promising therapeutic option for patients with medically refractory dystonia. We present the results after 1 year of DBS of the GPi in 4 patients with cervical dystonia. MATERIALS AND METHODS: Four patients with medically refractory cervical dystonia who underwent stereotactic pallidal DBS surgery between June 2010 and November 2011 were included in this retrospective study. Preoperative and postoperative evaluations at 3, 6 and 12 months after surgery were performed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). RESULTS: The 4 patients experienced a sustained improvement, with a mean TWSTRS reduction of 74.25%, at 12 months follow-up. Disability improved by 80.5% (mean) at 1 year follow-up. No stimulation-related side effects were reported. CONCLUSION: Pallidal DBS is a valid and effective second-line treatment for patients with cervical focal dystonia. Our results support its use in patients with an insufficient response to medical treatment. PMID- 24630436 TI - [Detection of venous air embolism and patent foramen ovale in neurosurgery patients in sitting position]. AB - INTRODUCTION: Early detection of venous air embolism (VAE) during neurosurgical procedures in sitting position decreases the severity of its complications. OBJECTIVES: our aim was to analyse the detection of VAE and its impact on patients operated in a sitting position, verify air aspiration through a central venous catheter and assess the feasibility of the routine use of transcranial Doppler (TCD) for intraoperative diagnosis of patent foramen ovale (PFO). MATERIAL AND METHODS: We performed a prospective study of consecutive neurosurgical procedures performed in the sitting position for 5 years. Precordial Doppler and end-tidal carbon dioxide were the diagnostic methods for VAE. PFO was explored by TCD after anaesthetic induction. RESULTS: 136 patients were operated in the sitting position, 93 craniotomies and 43 cervical spine procedures. Twenty-two patients (16.2%) were diagnosed with VAE (21.5% of craniotomies and 4.7% of spinal surgeries; p=.013). In 59% of cases, air was aspirated through the central venous catheter. There was haemodynamic involvement in 3 patients, impaired oxygenation in 4 and clinically relevant pneumocephalus in 5 of them. Two patients (1.4%) were diagnosed with PFO, but did not present episodes of VAE or paradoxical air embolism. CONCLUSIONS: The series analysed confirmed a higher incidence of VAE in craniotomies than in cervical spine surgery in a sitting position. We were able to aspirate air through the central venous catheter in more than half the cases. No patients suffered critical intraoperative complications following our approach. The low incidence of PFO detected with TCD will imply a modification of our protocol performed on anaesthetised patients. PMID- 24630437 TI - Assessment of home infusion program for treating nonlaryngeal hereditary angioedema attacks. PMID- 24630438 TI - Lung volumes in the pathogenesis of obstructive sleep apnea. PMID- 24630439 TI - Assessment for self-blame and trauma symptoms during the medical evaluation of suspected sexual abuse. AB - The purpose of this study was to describe behavioural and emotional symptoms and to examine the effect of abuse-related factors, family responses to disclosure, and child self-blame on these symptoms in children presenting for medical evaluations after disclosure of sexual abuse. A retrospective review was conducted of 501 children ages 8-17. Trauma symptoms were determined by two sets of qualitative measures. Abstracted data included gender, ethnicity, and age; severity of abuse and abuser relationship to child; child responses regarding difficulty with sleep, school, appetite/weight, sadness, or self-harm, parent belief in abuse disclosure, and abuse-specific self-blame; responses to the Trauma Symptom Checklist in Children-Alternate; and the parent's degree of belief in the child's sexual abuse disclosure. Overall, 83% of the children had at least one trauma symptom; 60% had difficulty sleeping and one-third had thoughts of self-harm. Child age and abuse severity were associated with 3 of 12 trauma symptoms, and abuse-specific self-blame was associated with 10 trauma symptoms, after controlling for other variables. The children of parents who did not completely believe the initial disclosure of abuse were twice as likely to endorse self-blame as children of parents who completely believed the initial disclosure. Screening for behavioural and emotional problems during the medical assessment of suspected sexual abuse should include assessment of self-blame and family responses to the child's disclosures. In addition, parents should be informed of the importance of believing their child during the initial disclosure of abuse and of the impact this has on the child's emotional response to the abuse. PMID- 24630440 TI - Youth exposure to violence prevention programs in a national sample. AB - This paper assesses how many children and youth have had exposure to programs aimed at preventing various kinds of violence perpetration and victimization. Based on a national sample of children 5-17, 65% had ever been exposed to a violence prevention program, 55% in the past year. Most respondents (71%) rated the programs as very or somewhat helpful. Younger children (5-9) who had been exposed to higher quality prevention programs had lower levels of peer victimization and perpetration. But the association did not apply to older youth or youth exposed to lower quality programs. Disclosure to authorities was also more common for children with higher quality program exposure who had experienced peer victimizations or conventional crime victimizations. The findings are consistent with possible benefits from violence prevention education programs. However, they also suggest that too few programs currently include efficacious components. PMID- 24630441 TI - Conditional cash transfers as a strategy for reduction of abuse, neglect, exploitation, and exclusion. PMID- 24630442 TI - Emotional support and adult depression in survivors of childhood sexual abuse. AB - The goals of this study were to evaluate the effects of emotional support from friends and parents at two time points (adolescence and adulthood) on adult depression in a nationally representative sample of survivors of childhood sexual abuse (CSA), and examine whether the associations were moderated by the identity of the perpetrator (parent/caregiver vs. not). Data were taken from Waves I and IV of the National Longitudinal Study of Adolescent Health (Add Health). The study sample included 1,238 Add Health participants with a history of CSA and an equivalently sized comparison group of individuals with no history of CSA. Parental support was measured using four items from each wave that assessed the warmth of participants' relationships with their parents and their satisfaction with those relationships. Friend support in adolescence was measured using participants' perceptions of how much their friends cared about them and in adulthood using participants' self-reported number of close friends. Depression was measured using a 10-item subscale of the CES-D. Logistic regressions showed that support from friends and parents in adulthood were significantly associated with lower odds of adult depression in CSA survivors who reported non parent/caregiver abuse. Among survivors of parent/caregiver abuse, emotional support was not significantly associated with adult depression regardless of when or by whom it was provided. In conclusion, emotional support in adulthood from friends and parents is associated with reduced odds of adult depression in CSA survivors, but only in cases where the abuse was perpetrated by someone other than a parent or caregiver. PMID- 24630443 TI - 3D high-resolution contrast enhanced MRI of carotid atheroma--a technical update. AB - OBJECTIVE: Development of a fast 3D high-resolution magnetic resonance imaging (MRI) protocol for improved carotid artery plaque imaging. METHODS: Two patients with carotid atherosclerosis disease underwent 3D high-resolution MRI which included time-of-flight and T1-weighted variable flip angle, fast-spin-echo (FSE) imaging, pre- and post-intravenous gadolinium-based contrast agent administration. RESULTS: Good quality images with intrinsic blood suppression were obtained pre- and post-contrast administration using a 3D FSE sequence. The plaque burden, lipid core volume, hemorrhage volume and fibrous cap thickness were well determined. CONCLUSIONS: 3D high-resolution MR imaging of carotid plaque using TOF and 3D FSE can achieve high isotropic resolution, large coverage, and excellent image quality within a short acquisition time. PMID- 24630444 TI - External lumbar cerebrospinal fluid drainage in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis of controlled trials. AB - INTRODUCTION: External lumbar drainage is a promising measure for the prevention of delayed aneurysmal subarachnoid hemorrhage-related ischemic complications. METHODS: Controlled studies evaluating the effects of external lumbar drainage in patients with aneurysmal subarachnoid hemorrhage were included. Primary outcomes were: new cerebral infarctions and severe disability. Secondary outcomes were: clinical deterioration due to delayed cerebral ischemia, mortality, and the need of definitive ventricular shunting. Results were presented as pooled relative risks, with their 95% confidence intervals (95% CI). RESULTS: A total of 6 controlled studies were included. Pooled relative risks were: new cerebral infarctions, 0.48 (95% CI: 0.32-0.72); severe disability, 0.5 (95% CI: 0.29 0.85); delayed cerebral ischemia-related clinical deterioration, 0.46 (95% CI: 0.34-0.63); mortality, 0.71 (95% CI: 0.24-2.06), and need of definitive ventricular shunting, 0.80 (95% CI: 0.51-1.24). Assessment of heterogeneity only revealed statistically significant indexes for the analysis of severe disability (I(2)=70% and P=.01). CONCLUSION: External lumbar drainage was associated with a statistically significant decrease in the risk of delayed cerebral ischemia related complications (cerebral infarctions and clinical deterioration), as well as the risk of severe disability; however, it was not translated in a lower mortality. Nevertheless, it is not prudent to provide definitive recommendations at this time because of the qualitative and quantitative heterogeneity among included studies. More randomized controlled trials with more homogeneous outcomes and definitions are needed to clarify its impact in patients with aneurysmal subarachnoid hemorrhage. PMID- 24630445 TI - Effect of fire on phosphorus forms in Sphagnum moss and peat soils of ombrotrophic bogs. AB - The effect of burning Sphagnum moss and peat on phosphorus forms was studied with controlled combustion in the laboratory. Two fire treatments, a light fire (250 degrees C) and a severe fire (600 degrees C), were performed in a muffle furnace with 1-h residence time to simulate the effects of different forest fire conditions. The results showed that fire burning Sphagnum moss and peat soils resulted in losses of organic phosphorus (Po), while inorganic phosphorus (Pi) concentrations increased. Burning significantly changed detailed phosphorus composition and availability, with severe fires destroying over 90% of organic phosphorus and increasing the availability of inorganic P by more than twofold. Our study suggest that, while decomposition processes in ombrotrophic bogs occur very slowly, rapid changes in the form and availability of phosphorus in vegetation and litter may occur as the result of forest fires on peat soils. PMID- 24630446 TI - A new approach of Integrated Health Responses (IHR(s)) modeling for ecological risk/health assessments of an urban stream. AB - The objective of this study was to evaluate the ecological health of an urban stream using Integrated Health Responses (IHRs). Water chemistry analysis, habitat health, and ecotoxicity tests were conducted in the stream along with analyses of molecular/biochemical, physiological biomarkers, and population-level responses in indicator species. Chemical stresses, measured as nutrient levels, ionic content and organic matter concentrations were significantly greater (p<0.01) at the downstream than the reference site (RF). The habitat health was largely impacted in the downstream reaches and had a negative relation with the land-use pattern of % urban area. Comet assay, 7-ethoxyresorufin-O-deethylase (EROD), acetylcholinesterase (AChE), and vitellogenin (VTG) were evaluated for low-level biomarker responses on DNA/physiological conditions of target species. The multi-metric fish model (Mm-F) was used to test the community-level response in relation to chemical and physical habitat stresses. The impaired responses of separate biomarker and bioindicator at the downstream sites occurred at all organizations from molecular/biochemical level to community level. Using all biomarkers/bioindicators, the star-plot model of IHRs was developed and then the integrative health/risk assessments were conducted in the urban stream. The reduced values of IHRs occurred in the downstream sites and the impacts were attributed to effluents from wastewater treatment plants (WTPs) and industrial complex. Ecological health impairments, thus, were evident in the urban reach, and reflected the long-term community responses as well as short-term responses of molecular biomarkers. The degradation of the urban stream was mainly due to a combined effect of chemical pollution and physical habitat modifications. PMID- 24630447 TI - Characterization of materials released into water from paint containing nano SiO2. AB - In order to assess the possible risks of applications containing engineered nanomaterials, it is essential to generate more data about their release and exposure, so far largely overlooked areas of research. The aim of this work was to study the characterization of the materials released from paint containing nano-SiO2 during weathering and exposure to water. Panels coated with nano-SiO2 containing paint and a nano-free reference paint were exposed to accelerated weathering cycles in a climate chamber. The total release of 89 six-hour cycles of UV-illumination and precipitation was 2.3% of the total SiO2 contained in the paint. Additional tests with powdered and aged paint showed that the majority of the released Si was present in dissolved form and that only a small percentage was present in particulate and nano-particulate form. TEM imaging of the leachates indicated that the majority of the particulate Si was contained in composites together with Ca, representing the paint matrix, and only few single dispersed SiO2-NPs were detected. The results suggest that toxicological and ecotoxicological studies need to consider that the released particles may have been transformed or are embedded in a matrix. PMID- 24630448 TI - Persistent organochlorine pesticides residues in cow and goat milks collected from different regions of Ethiopia. AB - The present study investigated the bioaccumulation of organochlorines in two milk producing animals (goats and cows) grazed on the same feed to explore the extent of organochlorines availability in milk and any species effect on the bioaccumulation pattern. Six organochlorine pesticides: aldrin, alpha-endosulfan, beta-endosulfan, p,p'-DDE, o,p'-DDT and p,p'-DDT were determined in samples collected from four regions in Ethiopia. Aldrin (11.6MUgkg(-1)) was detected only in one cow milk sample and alpha-endosulfan was detected in one goat milk sample at a level of 142.1MUgkg(-1), and in one cow milk sample (47.8MUgkg(-1)) from the same region. p,p'-DDE was detected in 40% of the milk samples analyzed while o,p' DDT and p,p'-DDT were found in high amounts in almost all samples. The average total DDT (excluding DDD) in the samples was 328.5MUgkg(-1). Regions known for their malaria epidemics were the most contaminated with DDT residue. The accumulation pattern in both species was not clear under natural sampling. PMID- 24630449 TI - Sorption of polar herbicides and herbicide metabolites by biochar-amended soil. AB - Biochar-amended soil has been proven to possess superior sorption capacities for several environmental pollutants compared with pure soil. However, the role of biochar in the immobilization of polar pesticides and their metabolites has hardly been tested. The aim of this study was therefore to investigate the effect of a soil amendment with biochar on the sorption of selected polar herbicides and herbicide metabolites (log Kow 0.3-<2). To simulate worst-case sorption, a sandy soil (1.7% organic matter) was amended with 1.5% biochar (fresh or composted) to determine sorption/desorption isotherms of the test compounds. One herbicide (imazamox) and three herbicide metabolites (methyl-desphenyl-chloridazon, metazachlor oxalic acid, metazachlor sulfonic acid) were tested, i.e. three anionic and one neutral polar compound. The results showed that the presence of biochar increased the sorption capacity of the soil only in the case of the uncharged compound methyl-desphenyl-chloridazon, for which the average distribution coefficients in biochar-amended soils were higher than in pure soil by a factor of 2.1-2.5. However, this effect rather seemed to reflect the increased soil organic carbon content after the addition of biochar than a preferred sorption of methyl-desphenyl-chloridazon to biochar. In the case of the three anionic compounds imazamox, metazachlor oxalic acid and metazachlor sulfonic acid, biochar amendment did not increase the sorption capacity of the soil for these compounds, presumably as a result of its negative net charge. Similarly, desorption experiments did not show any significant effect of the biochar amendment on desorption. This suggests that the potential of using biochar to mitigate the leaching of the tested polar pesticides or metabolites is limited. PMID- 24630450 TI - A new mechanism of macrophyte mitigation: how submerged plants reduce malathion's acute toxicity to aquatic animals. AB - A growing body of evidence suggests that aquatic plants can mitigate the toxicity of insecticides to sensitive aquatic animals. The current paradigm is that this ability is driven primarily by insecticide sorption to plant tissues, especially for hydrophobic compounds. However, recent work shows that submerged plants can strongly mitigate the toxicity of the relatively hydrophilic insecticide malathion, despite the fact that this compound exhibits a slow sorption rate to plants. To examine this disparity, we tested the hypothesis that the mitigating effect of submerged plants on malathion's toxicity is driven primarily by the increased water pH from plant photosynthesis causing the hydrolysis of malathion, rather than by sorption. To do this, we compared zooplankton (Daphnia magna) survival across five environmentally relevant malathion concentrations (0, 1, 4, 6, or 36 MUg L(-1)) in test containers where we chemically manipulated water pH in the absence of plants or added the submerged plant (Elodea canadensis) but manipulated plant photosynthetic activity via shading or no shading. We discovered that malathion was equally lethal to Daphnia at all concentrations tested when photosynthetically inactive (i.e. shaded) plants were present (pH at time of dosing=7.8) or when pH was chemically decreased (pH=7.7). In contrast, when photosynthetically active (i.e. unshaded) plants were present (pH=9.8) or when pH was chemically increased (pH=9.5), the effects of 4 and 6 MUg L(-1) of malathion on Daphnia were mitigated strongly and to an equal degree. These results demonstrate that the mitigating effect of submerged plants on malathion's toxicity can be explained entirely by a mechanism of photosynthesizing plants causing an increase in water pH, resulting in rapid malathion hydrolysis. Our findings suggest that current ecotoxicological models and phytoremediation strategies may be overlooking a critical mechanism for mitigating pesticides. PMID- 24630451 TI - The bark of holm oak (Quercus ilex, L.) for airborne Cr(VI) monitoring. AB - In this work, the bark of holm oak was used as a bioindicator to study the atmospheric distribution of Cr(VI). The chosen method (alkaline extraction and atomic absorption determination) was found in the literature, adapted for use with the matrix involved, and validated. The method had some limits, but provided an excellent estimation of Cr(VI) concentrations with good sensitivity and a reasonable time of analysis and cost. Thirty-four samples of holm oak collected in three areas characterised by different possible sources of pollution (the area near a former chromate production plant, an urban area, and a rural "reference" area) were analysed, obtaining concentrations ranging from 1.54 to 502 MUg g(-1) near the industrial plant, ranging from 0.22 to 1.35 MUg g(-1) in the urban area, and mostly below the detection limit (0.04 MUg g(-1)) in the rural area. The bark of holm oak proved to be a good bioindicator to detect Cr(VI) in the environment. The extraction procedure followed by atomic absorption analysis is simple, provides good sensitivity, and it is suitable for environmental studies. PMID- 24630452 TI - Adsorption and mobility of metals in build-up on road surfaces. AB - The study investigated the adsorption and bioavailability characteristics of traffic generated metals common to urban land uses, in road deposited solids particles. To validate the outcomes derived from the analysis of field samples, adsorption and desorption experiments were undertaken. The analysis of field samples revealed that metals are selectively adsorbed to different charge sites on solids. Zinc, copper, lead and nickel are adsorbed preferentially to oxides of manganese, iron and aluminium. Lead is adsorbed to organic matter through chemisorption. Cadmium and chromium form weak bonding through cation exchange with most of the particle sizes. Adsorption and desorption experiments revealed that at high metal concentrations, chromium, copper and lead form relatively strong bonds with solids particles while zinc is adsorbed through cation exchange with high likelihood of being released back into solution. Outcomes from this study provide specific guidance for the removal of metals from stormwater based on solids removal. PMID- 24630453 TI - Influence of zero-valent iron nanoparticles on nitrate removal by Paracoccus sp. AB - Nitrate contamination in drinking water is a major threat to public health. This study investigated the efficiency of denitrification of aqueous solutions in the co-presence of synthesized nanoscale zero-valent iron (nZVI; diameter: 20-80 nm) and a previously isolated Paracoccus sp. strain YF1. Various influencing factors were studied, such as oxygen, pH, temperature, and anaerobic corrosion products (Fe(2+), Fe(3+) and Fe3O4). With slight toxicity to the strain, nZVI promoted denitrification efficiency by providing additional electron sources under aerobic conditions. For example, 50 mg L(-1) nZVI increased the nitrate removal efficiency from 66.9% to 85.2%. However, a high concentration of nZVI could lead to increased production of Fe(2+), a toxic ion which could compromise the removal efficiency. Kinetic studies suggest that denitrification by both free cells, and nZVI-amended cells fitted well to the zero-order model. Temperature and pH are the major factors affecting nitrate removal and cell growth, with or without the presence of nZVI. In this study, nitrate removal and cell growth increased in the pH range of 6.5-8.0, and temperature range of 25-35 degrees C. These conditions favor the growth of the strain, which dominated denitrification in all scenarios involved. As for anaerobic corrosion products, compared with Fe(2+) and Fe(3+), Fe3O4 promoted denitrification by serving as an electron donor. Finally, scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD) confirmed attachments of nZVI on the surface of the cell, and the formation of iron oxides. This study indicated that, as an electron donor source with minimal cellular toxicity, nZVI could be used to promote denitrification efficiency under biotic conditions. PMID- 24630454 TI - Contaminant-specific targeting of olfactory sensory neuron classes: connecting neuron class impairment with behavioural deficits. AB - The olfactory system of fish comprises several classes of olfactory sensory neurons (OSNs). The odourants L-alanine and taurocholic acid (TCA) specifically activate microvillous or ciliated OSNs, respectively, in fish. We recorded electro-olfactograms (EOG) in fathead minnows (Pimephales promelas; a laboratory reared model species) and wild yellow perch (Perca flavescens) whose olfactory chambers were perfused with either L-alanine or TCA to determine if OSN classes were differentially vulnerable to contaminants, in this case copper or nickel. Results were consistent in both species and demonstrated that nickel targeted and impaired microvillous OSN function, while copper targeted and impaired ciliated OSN function. This result suggests that contaminant-specific effects observed in model laboratory species extrapolate to wild fish populations. Moreover, fathead minnows exposed to copper failed to perceive a conspecific alarm cue in a choice maze, whereas those exposed to nickel could respond to the same conspecific cue. These results demonstrate that fathead minnows perceive conspecific, damage released alarm cue by ciliated, but not microvillous, OSNs. Fish living in copper contaminated environments may be more vulnerable to predation than those in clean lakes owing to targeted effects on ciliated OSNs. PMID- 24630455 TI - Decolorization and degradation of xenobiotic azo dye Reactive Yellow-84A and textile effluent by Galactomyces geotrichum. AB - Galactomyces geotrichum MTCC 1360 exhibited 86% decolorization of azo dye Reactive Yellow-84A (50mgL(-1)) within 30h at 30 degrees C and pH 7.0 under static condition. Examination of azoreductase, laccase and tyrosinase enzyme activities confirmed their prominent role in Reactive Yellow-84A degradation. Considerable reduction of COD (73%) and TOC (62%) during degradation of the dye was indicative of conversion of complex dye into simple products, which were further analyzed by HPLC, FTIR, GC-MS and HPTLC. The degradation products were identified as 4(5-hydroxy, 4-amino cyclopentane) sulfobenzene and 4(5-hydroxy cyclopentane) sulfobenzene by GC-MS. In addition, when G. geotrichum was applied to decolorize textile effluent, it showed 85% of true color removal (ADMI removal) within 72h, along with a significant reduction in TOC and COD. Phytotoxicity studies revealed the less toxic nature of degraded Reactive Yellow 84A as compared to original dye. PMID- 24630456 TI - Sources of hydroxyl radical in headwater streams from nitrogen-saturated forest. AB - Hydroxyl radical (HO) photoformation rate (RHO) was determined in headwater stream samples from nitrogen (N)-saturated forests, (1) to quantify the sources of HO in headwater streams and (2) to evaluate the nitrate NO3(-)-induced enhancement of HO formation in stream water caused by N saturation in forested watersheds. Stream water fulvic acid extracted from the forested watersheds was used to quantify the contribution of dissolved organic matter (DOM) to RHO. The results showed that almost all (97%; 81-109%) RHO sources in our headwater stream samples were quantitatively elucidated; the photolysis of NO3(-) (55%; 34-75%), nitrite [N(III)] (2%; 0.5-5.2%), and DOM-derived HO formation, from which photo Fenton reactions (18%; 12-26%) and the direct photolysis of fluorescent dissolved organic matter (FDOM) (22%; 10-40%), was successfully separated. FDOM, which accounted for 53% (24-96%) of DOM in total organic carbon bases, was responsible for HO formation in our headwater streams. High NO3(-) leaching caused by N saturation in forested watersheds increased RHO in the headwaters, indicating that N-saturated forest could significantly change photoinduced and biogeochemical processes via enhanced HO formation in downstream water. PMID- 24630457 TI - Characterization of n-alkanes and their carbon isotopic composition in sediments from a small catchment of the Dianchi watershed. AB - The biomarker composition and stable carbon isotope values of organic matter (OM) in sediment cores from Shuanglong catchment of the Dianchi watershed show an unimodal n-alkane distribution ranging from C15-C33 with a strong predominance of odd-numbered n-alkanes, maximizing at n-C27, n-C29 and n-C31. Organic carbon to nitrogen (OC/N) ratio indicates a strong terrestrial influence on the OM. The values of delta(13)C27, delta(13)C29 and delta(13)C31 of n-alkanes range from 36.10/00 to -26.10/00, -34.10/00 to -30.10/00 and -33.80/00 to -28.70/00, respectively, suggesting a mainly C3 land plants origin. The carbon preference index (CPI25-31), odd-even preference (OEP27-31), average chain length (ACL25 33), pristine/phytane (pr/ph), Paq, (C27+C29)/2C31, nC16-23/nC24-33 and 3C17/(C21+C23+C25) values are also consistent with the predominance of C3 land plant-derived OM. Different sources of OM are reflected by the peak of n-C15, ascribed to a contribution by aquatic algae and photosynthetic bacteria. Eutrophication seems to be enhanced by both autochthonous (weak) and allochthonous (strong) contributions of OM. A major factor affecting the OM accumulation in the catchment and OM transportation to the Dianchi Lake may be increased by human activities from 1871 to 2011. PMID- 24630458 TI - The sensitivity of Daphnia magna and Daphnia curvirostris to 10 veterinary antibacterials and to some of their binary mixtures. AB - Aim of this study was to evaluate the suitability of Daphnia curvirostris for the acute toxicity test usually performed on Daphnia magna, and to compare the sensitivity of the two species toward 10 antibacterials [enrofloxacin (EFX), ciprofloxacin(CPX), sulfaguanidine (SGD), sulfadiazine (SDZ), sulfamethazine (SMZ), sulfaquinoxaline (SQO), sulfaclozine (SCZ), sulfamerazine (SMA), sulfadimethoxine (SDM) and trimethoprim (TMP)] and some of their binary mixtures. Furthermore, a tentative prolonged-toxicity test (lasting 13d) was settled up in order to evidence toxic responses with drug concentrations that were uneffective in the classic 48h immobilization test. Results showed that D. curvirostris was more sensitive than D. magna to the majority of compounds (6 out of 10). Lowest 48h EC50s were obtained with EFX (4.3mgL(-1) in D. curvirostris) and SGD (6.2mgL( 1) in D. magna). The toxicity of paired compounds was always concentration additive or less than concentration-additive. In the prolonged-toxicity test mortality and/or reproduction inhibition were constantly observed. It was concluded that: (1) D. curvirostris could be a suitable model for the evaluation of acute toxicity of antibacterials since its sensitivity was generally greater than that of D. magna; (2) the toxicity of EFX and SGD should be given special attention as the two compounds, in the prolonged test, showed to be active at concentrations of 0.9mgL(-1) and 2.5mgL(-1), respectively; (3) the concentration addition is usually a reasonable worst case estimation of the environmental impact of antibacterial mixtures. PMID- 24630459 TI - Effects of pH and phosphate on CeO2 nanoparticle dissolution. AB - As the result of rapidly grown nanotechnology industries, release of engineered nanoparticles (ENPs) to environment has increased, posing in a serious risk to environmental and human health. To better understand the chemical fate of ENPs in aquatic environments, solubility of CeO2 NPs was investigated using batch dissolution experiments as a function of pH (1.65-12.5), [phosphate] and particle size (33 and 78 nm). It was found that CeO2 dissolution was only significant at pH<5 and inversely proportional to surface area. After 120 h, the release of Ce was ~3 times greater in large NPs than that in small NPs that is likely contributed by the difference in exchangeable Ce(III) impurity (small: 0.3 mM kg( 1), large: 1.56 mM kg(-1)). When 100 MUM of phosphate was added, the dissolution rate of CeO2 NPs was decreased in small NPs by 15% at pH 1.65 and 75% at pH 4.5 and in large NPs by 56% at pH 1.65 and 63% at pH 4.5. The inner-sphere surface complexation of P that is revealed by the zeta potential measurements is effectively suppressing the CeO2 NP dissolution. Predicting the fate and transport of CeO2 NPs in aquatic environment, pH and P ligands might play important roles in controlling the solubility of CeO2 NPs. PMID- 24630460 TI - Nickel phytoremediation potential of the Mediterranean Alyssoides utriculata (L.) Medik. AB - This study investigated the accumulation and distribution of nickel in the leaves and roots of the Mediterranean shrub Alyssoides utriculata to assess its potential use in phytoremediation of Ni contaminated soils. Total (AAS and ICP MS) Ni, Ca and Mg contents were analyzed in the plants and related to their bioavailability (in EDTA) in serpentine and non-serpentine soils. To find the relationships between the soil available Ni and the Ni content of this species, we also evaluated possible interactions with Ca and Mg. The bioaccumulation factor (BF) and the translocation factor (TF) were determined to assess the tolerance strategies developed by A. utriculata and to evaluate its potential for phytoextraction or phytostabilization. The leaf Ni is higher than 1000 MUg g(-1) which categorizes the species as a Ni-hyperaccumulator and a great candidate for Ni-phytoextraction purposes. In addition to the accumulation of Ni, the leaf Mg is also correlated with soil bioavailable concentrations. The Ca uptake and translocation were significantly lower in serpentine plants (higher Ni), as such, the leaf Ca is probably greatly influenced either by the soil's Ni or the soil Ca/Mg ratio. The BFs and TFs are strongly higher than 1 and generally did not significantly differed between plants from serpentine (higher Ni) and non serpentine soils (lower Ni). The present study highlights for the first time that A. utriculata could be suitable for cleaning Ni-contaminated areas and provides a contribution to the very small volume of data available on the potential use of native Mediterranean plant species from contaminated sites in phytoremediation technologies. PMID- 24630461 TI - Sorption and degradation of 17beta-estradiol-17-sulfate in sterilized soil-water systems. AB - To identify abiotic processes that govern the fate of a sulfate conjugated estrogen, 17beta-estradiol-17-sulfate (E2-17S), soil batch experiments were conducted to investigate the dissipation, sorption, and degradation of radiolabeled E2-17S under sterilized conditions. The aqueous dissipation half lives (DT50) for E2-17S ranged from 2.5 to 9.3h for the topsoil of high organic carbon (OC) content (1.29%), but E2-17S remained at ~80% of applied dose in the low OC (0.26%) subsoil by 14 d. The non-linear sorption isotherms indicated limited sorption of E2-17S, and the concentration-dependent log KOC values were 2.20 and 2.45 for the topsoil and subsoil, respectively. Additionally, two types of hydroxyl E2-17S (OH-E2-17S and diOH-E2-17S) were found as major metabolites in the aqueous phase, which represented 9-25% and 6-7% of applied dose for the topsoil and subsoil at 14 d, respectively. Free estrogens, 17beta-estradiol (E2) and estrone (E1), were detected from the sorbed phase of the soil-water systems. PMID- 24630462 TI - Selective removal of phosphate from wastewater using hydrated metal oxides dispersed within anionic exchange media. AB - Hydrated ferric oxide (HFeO), hydrated zirconium oxide (HZrO) and hydrated copper oxide (HCuO) were immobilized within a microporous anion exchange resin (IRA 400), forming hybrid media for enhanced phosphate removal from aqueous systems. Empirical data from batch kinetic trials fitted the pseudo second order mechanism for chemical adsorption and each media was rate limited by intraparticle diffusion overall. These models were also used to predict the adsorption rate constants and the equilibrium adsorption capacities, which ranged from 26.51 to 30.44 mgP g(-1), and from 24.15 to 27.90 mgP g(-1) of media for the calculated and experimental capacities, respectively. The phosphate adsorption behavior by the hybrid materials fit both the Langmuir and Freundlich adsorption isotherms (R(2)>0.94), and the maximum adsorption capacities were 111.1 mgP g(-1) for HFeO, 91.74 mgP g(-1) for HZrO and 74.07 mgP g(-1) for HCuO. The effect of competing ions such as sulfate reduced these capacities to 18.52 mgP g(-1) for HFeO and 18.97 mgP g(-1) for HZrO. Despite this decrease, HFeO was capable of reducing the phosphate in a real wastewater matrix by 83%, and the HZrO media was able to reduce it by 86%, suggesting that such hybrid media have the potential for application at full scale. PMID- 24630463 TI - Inter- and intra-rater reliability of the GAITRite system among individuals with sub-acute stroke. AB - Technology-based assessment tools with semi-automated processing, such as pressure-sensitive mats used for gait assessment, may be considered to be objective; therefore it may be assumed that rater reliability is not a concern. However, user input is often required and rater reliability must be determined. The purpose of this study was to assess the inter- and intra-rater reliability of spatial and temporal characteristics of gait in stroke patients using the GAITRite system. Forty-six individuals with stroke attending in-patient rehabilitation walked across the pressure-sensitive mat 2-4 times at preferred walking speeds, with or without a gait aid. Five raters independently processed gait data. Three raters re-processed the data after a delay of at least one month. The intraclass correlation coefficients (ICC) and 95% confidence intervals of the ICC were determined for velocity, step time, step length, and step width. Inter-rater reliability for velocity, step time, and step length were high (ICC>0.90). Intra-rater reliability was generally greater than inter-rater reliability (from 0.81 to >0.99 for inter-rater versus 0.77 to >0.99 for intra rater reliability). Overall, this study suggests that GAITRite is a reliable assessment tool; however, there still remains subjectivity in processing the data, resulting in no patients with perfect agreement between raters. Additional logic checking within the processing software or standardization of training could help to reduce potential errors in processing. PMID- 24630464 TI - Evaluation of postural equilibrium and fall risk during pregnancy. AB - OBJECTIVE: The hormonal, anatomical and physiological states change during pregnancy. Due to these alterations, pregnant women are at increased risk of falling throughout this period. The aim of this study is to evaluate postural equilibrium and risk of falls during pregnancy by comparing dynamic postural stability between pregnant and non-pregnant control women. METHODS: Eighty pregnant women (the first, second and third trimester of pregnancy; 25, 30 and 25, respectively) and thirty nonpregnant control women were evaluated and compared in terms of dynamic postural stability using the Biodex Balance System. Overall (OA), anterior-posterior (AP), medial-lateral (ML) stability index and fall risk test (FRT) scores were obtained from the mean scores of the three trials at platform stability of level 8. RESULTS: No significant differences for OA, APSI and MLSI were found among the pregnant women in the first and second trimester and nonpregnant control subjects. Overall, anteroposterior and mediolateral index scores were significantly higher in pregnant women in the third trimester than nonpregnant controls (p<0.05). Fall risk test scores of third trimester patients were found to be significantly higher than the first and second trimester and nonpregnant control women (p<0.001). CONCLUSIONS: Pregnancy has a negative effect on postural stability. Postural equilibrium decreases during pregnancy, particularly in the third trimester. Using postural stability tests may detect pregnant women with a high fall risk. PMID- 24630465 TI - Ultrasound evaluation of foot muscles and plantar fascia in pes planus. AB - BACKGROUND: Multiple intrinsic and extrinsic soft tissue structures that apply forces and support the medial longitudinal arch have been implicated in pes planus. These structures have common functions but their interaction in pes planus is not fully understood. The aim of this study was to compare the cross sectional area (CSA) and thickness of the intrinsic and extrinsic foot muscles and plantar fascia thickness between normal and pes planus feet. METHODS: Forty nine adults with a normal foot posture and 49 individuals with pes planus feet were recruited from a university population. Images of the flexor digitorum longus (FDL), flexor hallucis longus (FHL), peroneus longus and brevis (PER), flexor hallucis brevis (FHB), flexor digitorum brevis (FDB) and abductor hallucis (AbH) muscles and the plantar fascia were obtained using a Venue 40 ultrasound system with a 5-13 MHz transducer. RESULTS: The CSA and thickness of AbH, FHB and PER muscles were significantly smaller (AbH -12.8% and -6.8%, FHB -8.9% and 7.6%, PER -14.7% and -10%), whilst FDL (28.3% and 15.2%) and FHL (24% and 9.8%) were significantly larger in the pes planus group. The middle (-10.6%) and anterior (-21.7%) portions of the plantar fascia were thinner in pes planus group. CONCLUSION: Greater CSA and thickness of the extrinsic muscles might reflect compensatory activity to support the MLA if the intrinsic foot muscle function has been compromised by altered foot structure. A thinner plantar fascia suggests reduced load bearing, and regional variations in structure and function in feet with pes planus. PMID- 24630466 TI - Latent profile analysis of eating episodes in anorexia nervosa. AB - BACKGROUND: Despite being characterized primarily by disturbances in eating behavior, relatively little is known about specific eating behaviors in anorexia nervosa (AN) and how they relate to different emotional, behavioral, and environmental features. METHODS: Women with AN (n = 118) completed a 2-week ecological momentary assessment (EMA) protocol during which they reported on daily eating- and mood-related patterns. Latent profile analysis was used to identify classes of eating episodes based on the presence or absence of the following indicators: loss of control; overeating; eating by oneself; food avoidance; and dietary restraint. RESULTS: The best-fitting model supported a 5 class solution: avoidant eating; solitary eating; binge eating; restrictive eating; and loss of control eating. The loss of control and binge eating classes were characterized by high levels of concurrent negative affect and a greater likelihood of engaging in compensatory behaviors. The restrictive eating class was associated with the greatest number of concurrently-reported stressful events, while the avoidant and solitary eating episode classes were characterized by relatively few accompanying stressful events. Body checking was least likely to occur in conjunction with restrictive eating behaviors. CONCLUSIONS: Results support the presence of discrete types of eating episodes in AN that are associated with varying degrees of negative affect, stress, and behavioral features of eating disorders. Loss of control and dietary restriction may serve distinct functional purposes in AN, as highlighted by their differing associations with negative affect and stress. Clinical interventions for AN may benefit from targeting functional aspects of eating behavior among those with the disorder. PMID- 24630467 TI - Do prefrontal midline electrodes provide unique neurophysiologic information in Major Depressive Disorder? AB - Brain oscillatory activity from the midline prefrontal region has been shown to reflect brain dysfunction in subjects with Major Depressive Disorder (MDD). It is not known, however, whether electrodes from this area provide unique information about brain function in MDD. We examined a set of midline sites and two other prefrontal locations for detecting cerebral activity differences between subjects with MDD and healthy controls. Resting awake quantitative EEG (qEEG) data were recorded from 168 subjects: 47 never-depressed adults and 121 with a current major depressive episode. Individual midline electrodes (Fpz, Fz, Cz, Pz, and Oz) and prefrontal electrodes outside the hairline (Fp1, Fp2) were examined with absolute and relative power and cordance in the theta band. We found that MDD subjects exhibited higher values of cordance (p = 0.0066) at Fpz than controls; no significant differences were found at other locations, and power measures showed trend-level differences. Depressed adults showed higher midline cordance than did never-depressed subjects at the most-anterior midline channel. Salient abnormalities in MDD may be detectable by focusing on the prefrontal midline region, and EEG metrics from focused electrode arrays may offer clinical practicality for clinical monitoring. PMID- 24630468 TI - CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors. AB - Stressful life events during childhood and adolescence are important risk factors for the development of psychopathologies later in life. The corticotropin releasing hormone (CRH) and the CRH receptor 1 (CRHR1) have been implicated in the link between early life adversity and adult anxiety and depression, with rodent studies identifying the very early postnatal period as highly susceptible to this programming. Here, we investigated whether stress exposure during the peripubertal period - comprising juvenility and puberty - is effective in inducing long-lasting changes in the expression of CRHR1 and CRHR2 in the hippocampus and amygdala, and whether treating animals with a CRHR1 antagonist following stress exposure could reverse behavioral alterations induced by peripuberty stress. We show that peripuberty stress leads to enhanced expression of the Crhr1, but not Crhr2, gene in the hippocampal CA1 and the central nucleus of the amygdala, in association with social deficits in the social exploration test and increased stress-coping behaviors in the forced swim test. Treatment with the CRHR1 antagonist NBI30775 (10 mg/kg) daily for 1 week (from P43 to P49), immediately following peripuberty stress exposure, prevented the occurrence of those psychopathological behaviors at adulthood. These findings highlight peripuberty as a period of plasticity for the enduring modulation of the CRHR1 system and support a growing body of data implicating the CRHR1 system in the programming effects of early life stress on eventual psychopathology. They also support recent evidence indicating that temporarily tackling CRHR1 during development might represent a therapeutic opportunity to correct behavioral trajectories linking early stress to adult psychopathology. PMID- 24630469 TI - Point of care testing and cardiac surgery 2014. PMID- 24630470 TI - Rapid and correct prediction of thrombocytopenia and hypofibrinogenemia with rotational thromboelastometry in cardiac surgery. AB - OBJECTIVES: In the present study, the authors have investigated whether rotational thromboelastometry (ROTEM) could predict thrombocytopenia and hypofibrinogenemia in cardiac surgery using the clot amplitude after 5 minutes (A5). Another parameter, PLTEM, in which the contribution of fibrinogen is eliminated by subtracting a fibrin-specific ROTEM test (FIBTEM) from an extrinsically-activated ROTEM test (EXTEM), was investigated. Furthermore, the turnaround time of ROTEM was compared to conventional laboratory tests. DESIGN: Prospective cohort study. SETTING: Single academic medical center. PARTICIPANTS: Ninety-seven patients undergoing cardiac surgery between July 2011 until August 2012. INTERVENTIONS: The correlations between EXTEM/FIBTEM A5, A10, and maximal clot formation (MCF), EXTEM/PLTEM (A5/A10, and MCF) and platelet count, and FIBTEM (A5/A10, and MCF) and fibrinogen were evaluated using the Pearson's correlation coefficient and receiver-operating characteristic curves. Turnaround times of ROTEM tests and conventional laboratory tests were assessed in the central laboratory. MEASUREMENTS AND MAIN RESULTS: EXTEM A5 and FIBTEM A5 showed an excellent correlation with A10 (R:0.99/1.00) and MCF (R:0.97/0.99). The correlation between EXTEM A5 and platelet count (R:0.74) was comparable with the correlation of A10 (R:0.73) and MCF (R:0.70) with platelet count. FIBTEM A5 predicted fibrinogen levels (R:0.87) as well as A10 (R:0.86) and MCF (R:0.87). PLTEM A5 (R:0.85) correlated better with platelet count than EXTEM A5 (R:0.74; p = 0.04) and showed significantly better area under the curve values than EXTEM for predicting thrombocytopenia (A5 p = 0.012, A10 p = 0.019). Turnaround time for ROTEM tests, 12 minutes, was comparable with emergency requests for platelet count, 13 minutes, and shorter than emergency requests for fibrinogen levels, 37 minutes. CONCLUSIONS: Implementation of PLTEM and FIBTEM A5 in ROTEM-guided transfusion protocols may improve transfusion management. PMID- 24630472 TI - Methylene blue: between scylla (meta-analysis) and charybdis (propensity). PMID- 24630471 TI - Thromboelastograph with Platelet Mapping(TM) predicts postoperative chest tube drainage in patients undergoing coronary artery bypass grafting. AB - OBJECTIVE: The goal of this study was to evaluate the ability of Thromboelastograph with Platelet Mapping (TEG-PM(TM)) to predict postoperative bleeding tendency in patients with a history of recent anti-platelet therapy undergoing coronary artery bypass grafting (CABG). DESIGN: A retrospective analysis. Association between predictor variables (MAADP [maximum amplitude produced by adenosine diphosphate], MAAA [maximum amplitude produced by arachidonic acid], percent of platelets inhibited by clopidogrel, percent of platelets inhibited by aspirin) and the outcomes as elevated chest tube drainage (CTD) and blood transfusion were investigated by logistic regression model. CTD was considered elevated if it was >= 600 mL within 12 hours after surgery. SETTING: A university hospital. PARTICIPANTS: Patients on antiplatelet therapy scheduled to undergo CABG that had TEG-PM(TM) done as a point-of-care test. INTERVENTIONS: None. RESULTS: A total of 78 patients had preoperative TEG-PM(TM) test and on-pump CABG surgeries performed on the same day. Among them, 20 patients (25.6%) had elevated CTD. Decreased MAADP (odds ratio [OR] 0.94), increased percent inhibition of platelets by clopidogrel (OR 1.03), and lower body mass index (BMI) (OR 0.78) were significantly associated with elevated CTD. The same parameters were also associated with platelets transfusion: MAADP (OR 0.94), percent of inhibition of platelets by clopidogrel (OR 1.03) and BMI (OR 0.77). CONCLUSIONS: TEG-PM(TM) parameters and BMI are predictive of elevated CTD and platelets transfusion. A 1 mm decrease in MAADP increases the likelihood of elevated CTD and the likelihood of platelets transfusion by 6% whereas 1 unit decrease in BMI is associated with an increased likelihood of elevated CTD and platelets transfusion by 22% and 23% respectively. PMID- 24630473 TI - Methylene blue: the Trojan horse. PMID- 24630474 TI - Immunotherapy applications of carbon nanotubes: from design to safe applications. AB - Carbon nanotubes (CNTs) have the potential to overcome significant challenges related to vaccine development and immunotherapy. Central to these applications is an improved understanding of CNT interactions with the immune system. Unique properties such as high aspect ratio, flexible surface chemistry, and control over structure and morphology may allow for enhanced target specificity and transport of antigens across cell membranes. Although recent work has demonstrated the potential of CNTs to amplify the immune response as adjuvants, other results have also linked their proinflammatory properties to harmful health effects. Here, we review the recent advances of CNT-based immunological research, focusing on current understandings of therapeutic efficacy and mechanisms of immunotoxicology. PMID- 24630475 TI - Metalloprotein mimics - old tools in a new light. AB - Metalloproteins utilize metal cofactors to catalyze essential reactions in all organisms. They carry out thermodynamically challenging substrate conversions such as the oxidation of water or hydrocarbons, the reduction of nitrogen to ammonium, and generation of molecular hydrogen. Besides their fundamental role in nature, metalloenzymes have promising biotechnological applications that aim to generate high-value chemicals, drugs, nutrients, biofuels, or electricity. Recent reports that a chemically synthesized compound is able to reconstitute [2Fe] hydrogenases, harboring an especially elaborate and highly efficient metal cofactor, promise to pave the way for gaining much deeper insight into the function of even complex metal enzymes. What is more, synthetic biology approaches such as the chemical synthesis of artificial hydrogenases seem to be in reach. PMID- 24630476 TI - Microbial advanced biofuels production: overcoming emulsification challenges for large-scale operation. AB - Isoprenoids and alkanes produced and secreted by microorganisms are emerging as an alternative biofuel for diesel and jet fuel replacements. In a similar way as for other bioprocesses comprising an organic liquid phase, the presence of microorganisms, medium composition, and process conditions may result in emulsion formation during fermentation, hindering product recovery. At the same time, a low-cost production process overcoming this challenge is required to make these advanced biofuels a feasible alternative. We review the main mechanisms and causes of emulsion formation during fermentation, because a better understanding on the microscale can give insights into how to improve large-scale processes and the process technology options that can address these challenges. PMID- 24630477 TI - Purifying biopharmaceuticals: knowledge-based chromatographic process development. AB - The purification of biopharmaceuticals is commonly considered the bottleneck of the manufacturing process. Increasing product diversity, along with growing regulatory and economic constraints raise the need to adopt new rational, systematic, and generally applicable process development strategies. Liquid chromatography is the key step in most purification processes and a well understood unit operation, yet this understanding is still rarely effectively utilized during process development. Knowledge of the composition of the mixture, the molecular properties of the solutes and how they interact with the resins are required to rationalise the design choices. Here, we provide an overview of the advances in the determination and measurement of these properties and interactions, and outline their use throughout the different stages of downstream process development. PMID- 24630479 TI - [Evaluation of a pilot health promotion and stress management program for Pharmacy and Biochemistry students and professionals]. AB - OBJECTIVES: The beneficial results of a theory-practice pilot stress management program for Pharmacy and Biochemistry professionals and students. Its importance as a complement of traditional academic education, as well as its potential for Pharmaceutical Care is also discussed. MATERIALS AND METHODS: A total of 27 students and 26 professionals took part in a program of 10 sessions, aimed at improving stress management. Ten of the students and 10 professionals were randomly assigned to control groups. Salivary cortisol levels and anxiety level tests before and after the program were used to assess efficacy. RESULTS: Both the cortisol and the anxiety levels significantly decreased among students and professionals after the program, whereas it significantly increased in the student control group. Anxiety levels significantly decreased in both students and professionals. CONCLUSIONS: This type of pilot program proved effective for students. In the case of health professionals, the sample size needs to be increased in order to achieve an acceptable level of statistical power. Considering the shift of the pharmaceutical profession towards Pharmaceutical Care, the training of competences and attitudes like those described in this work could be of value. PMID- 24630478 TI - Chemically programmed antibodies. AB - Due to their unlimited chemical diversity, small molecules can rival monoclonal antibodies (mAbs) with respect to specificity and affinity for target molecules. However, key pharmacological properties of mAbs remain unmatched by small molecules. Chemical programming strategies have been developed for site-specific and covalent conjugation of small molecules to mAbs with unique reactivity centers. In addition to blending favorable features of small molecules and mAbs, chemically programmed antibodies (cpAbs) are economically attractive because they utilize the same mAb for an almost unlimited number of target molecule specificities, reducing manufacturing costs and shortening drug discovery and development time. Preclinical studies and clinical trials have begun to demonstrate the broad utility of cpAbs for the treatment and prevention of human diseases. PMID- 24630480 TI - [Incidence of adverse events in a private hospital in Chile]. AB - OBJECTIVES: To determine the incidence and type of adverse events (AE) in hospitalized patients in Vespucio Clinic, to describe their immediate causes, define avoidable AE and determine the services with highest AE rate. MATERIAL AND METHOD: Retrospective cohort study, in patients discharged between 16 and 31 January 2012. For the identification of AE, medical history was reviewed, and the AE screening guide adapted from the Harvard study was applied. The Spanish version of Modular Review Form MRF2 used in the ENEAS 2005 Study was applied to the patients with positive screening. RESULTS: From the 500 patients studied, 31 had some AE related to health care (6.2%), with an incidence of 3.46 for every 100 patient bed days (minor events 2.72, moderate 0.65, and severe 0.09). The associated processes were: Care 32.4%, medication 13.5%, infections associated with health care 10.8%, and diagnostics 8.1%. More than two-thirds (67.6%) were considered avoidable. Of the adverse events, 40.5% required additional procedures, and 35.1% additional treatment. Hospital stay was extended by an average of 5.5 days in 5.4%, and 8.11% led to re-admission. Most of them (91.9% did not cause any incapacity. The departments with the highest AE rates per 100 bed patients days were: Critical Care Unit (21.4), obstetrics and gynecology (7), and medical/surgical wards (6) CONCLUSIONS: This is the first study conducted in a private hospital in our country that allowed us to identify the incidence, overall rate, and the rate by departments of adverse events, their severity, preventability and causal factors. PMID- 24630481 TI - Rapid influenza diagnostic test use and antiviral prescriptions in outpatient settings pre- and post-2009 H1N1 pandemic. AB - BACKGROUND: Rapid influenza diagnostic tests (RIDTs) can be used at the point-of care and are often the only influenza tests readily available in outpatient facilities. OBJECTIVES: To determine the use of RIDTs and antiviral prescription practices in outpatient facilities. STUDY DESIGN: Surveys were mailed to U.S. physician's offices, emergency departments, and community health centers in 2008 (pre-2009 H1N1 pandemic) and 2010 (post-2009 H1N1 pandemic). The 2010 survey included questions to evaluate changes in testing and treatment practices among various risk groups subsequent to the 2009 H1N1 pandemic. RESULTS: In both surveys, respondents using RIDTs relied on RIDT results to guide prescribing antiviral medications. Greater than two-thirds of these respondents reported prescribing antiviral medications both pre- and post-pandemic for patients within 48h of onset of flu-like symptoms with a positive RIDT (69% pre-pandemic; 67% post-pandemic). After the pandemic (2010 survey), outpatient providers also reported prescribing antivirals to those with flu-like symptoms for 31% of children <2 years, 23% of children 2-5 years, 37% of pregnant patients, and 74% of other patients at high risk; while these figures were higher than pre pandemic, they represent a failure to use CDC guidelines to prescribe antivirals for patients with suspected influenza who are at higher risk for complications. CONCLUSIONS: Clinicians in outpatient facilities often relied on RIDT findings to aid in making antiviral treatment decisions; however their treatment practices were not always consistent with CDC guidelines. The use of RIDTs and antiviral medicines were influenced by the 2009 H1N1 pandemic. PMID- 24630482 TI - Macroarray assay for differential diagnosis of meningoencephalitis in southern Africa. AB - BACKGROUND: Many cases of acute febrile illness with nervous manifestations go undiagnosed, partly because the potential pathogens are not investigated routinely. OBJECTIVE: To develop a multiplex PCR-based macroarray for detection of 29 pathogens associated with febrile disease, aseptic meningitis and meningoencephalitis in southern Africa, including common viruses, bacteria, parasites and selected arboviruses. STUDY DESIGN: Pathogens were identified by hybridization of PCR amplicons to probes on a macroarray chip, followed by colorimetric detection. RESULTS: Positive control specimens for all 29 targets were detected with high sensitivity. Twenty-seven clinical samples previously found positive for various etiologies of febrile disease and meningoencephalitis, including less common infections such as Crimean Congo haemorrhagic fever, Rift Valley fever, West Nile and rabies were all identified. Testing of a blinded panel of 16 specimens in triplicate demonstrated high repeatability. Screening of 138 specimens from patients with febrile and/or neurological signs that could not be solved in routine investigations yielded 5 additional diagnoses. CONCLUSION: A highly sensitive, specific and easily interpreted test was developed to detect 29 pathogens associated with febrile and nervous disease. PMID- 24630483 TI - Individual detection of 14 high risk human papilloma virus genotypes by the PapType test for the prediction of high grade cervical lesions. AB - BACKGROUND: HR HPV genotypes when assayed collectively, achieve high sensitivity but low specificity for the prediction of CIN2+. Knowledge of the specific genotypes in an infection may facilitate the use of HR HPV detection in routine clinical practice. OBJECTIVES: To compare the rate of HR HPV detection and the accuracy of CIN2+ prediction between PapType test (Genera Biosystems) and other commercially available HR HPV assays, and to examine the value of full HPV genotyping. STUDY DESIGN: PreservCyt samples from 1099 women referred for abnormal cervical cytology were used. CIN2+ was chosen as the primary end-point but CIN3+ was also evaluated. A hierarchy of HR HPV genotypes was created using PPV and this was used to create 3 groups of genotypes with potentially different management. RESULTS: The PapType assay has a specificity of 22.4% and a sensitivity of 94.6% for CIN2+ prediction. Classification into Groups A (HPV33 and HPV16, very highly predictive), B (HPV31, 18, 52, 35, 58, 51 highly predictive) and C (HPV68, 45, 39, 66, 56, 59, intermediate predictive) could double the specificity (44.5%) but only slightly reduce the sensitivity for CIN2+ (91.5%) and CIN3+ (94.0%). CONCLUSIONS: The PapType assay is a simple, reproducible and effective test for HR HPV detection and genotyping. HPV 33 was found to have a very high PPV and should therefore be managed as for HPV16. PMID- 24630484 TI - Role of vitamin D derivatives in intestinal tissue of patients with inflammatory bowel diseases. AB - BACKGROUND AND AIM: The adhesion molecule expression and matrix metalloproteinases (MMPs) are proposed to be major factors for intestinal injury mediated by T cells in (IBD) and are up-regulated in intestinal mucosa of IBD patients. To investigate the effect of vitamin D derivatives on adhesion molecules and MMPs in colonic biopsies of IBD patients. METHODS: Biopsies from inflamed and non-inflamed tract of terminal ileum and colon and PBMC from the same IBD patients were cultured with or without vitamin D derivatives. MMP activity and adhesion molecule levels were determined. RESULTS: 1,25(OH)2D3 and ZK 191784 significantly decrease ICAM-1 protein levels in the biopsies obtained only from the inflamed region of intestine of UC patients, while MAdCAM-1 levels decrease in the presence of 1,25(OH)2D3 in the non-inflamed region, and, in the presence of ZK, in the inflamed one. In CD patients 1,25(OH)2D3 and ZK decrease ICAM-1 and MAdCAM-1 in the biopsies obtained from the non-inflamed and inflamed regions, with the exception of ICAM-1 in the inflamed region in the presence of 1,25(OH)2D3. The expression of MMP-9, MMP-2, and MMP-3 decreases in the presence of vitamin D derivatives in UC and CD with the exception of 1,25(OH)2D3 that does not affect the levels of MMP-9 and MMP-2 in CD. Vitamin D derivatives always affect MMP-9, MMP-2 and ICAM-1 in PBMC of UC and CD patients. CONCLUSIONS: Based on the increased expression of ICAM-1, MAdCAM-1 and MMP-2,-9,-3 in IBD, our study suggests that vitamin D derivatives may be effective in the management of these diseases. PMID- 24630485 TI - Early post-operative endoscopic recurrence in Crohn's disease patients: data from an Italian Group for the study of inflammatory bowel disease (IG-IBD) study on a large prospective multicenter cohort. AB - INTRODUCTION: The incidence of endoscopic recurrence (ER) in Crohn's disease following curative resection is up to 75% at 1 year. Endoscopy is the most sensitive method to detect the earliest mucosal changes and the severe ER at 1 year seems to predict a clinical relapse. METHODS: The aim of this prospective study was to evaluate the incidence of early ER 6 months after curative resection. Secondary outcome was to evaluate the role of 5-aminosalicylic acid (5 ASA) in the prevention of ER at 6 months. A total of 170 patients were included in the study. They were carried-out from the evaluation of the appearance of ER during a trial performed to assess the role of azathioprine vs. 5-ASA as early treatment of severe ER. All the patients started 5-ASA treatment 2 weeks after surgery. RESULTS: Six months after surgery ER was observed in 105 patients (62%). The endoscopic score was reported as severe in 78.1% of them (82 out of 105). At univariable analysis only ileo-colonic disease influenced the final outcome associating to a lower risk of severe ER (p=0.04; OR 0.52, 95% CI 0.277-0.974). CONCLUSION: In this prospective Italian multicenter IG-IBD study a great proportion of ER occur within 6 months from ileo-colonic resection, with a significant rate of severe ER. Furthermore this study confirms the marginal role of 5-ASA in the prevention of ER. This suggests that post-surgical endoscopic evaluation should be performed at 6 months instead of 1 year to allow an adequate early treatment. PMID- 24630486 TI - Mortality and causes of death in patients with inflammatory bowel disease: a nationwide register study in Finland. AB - BACKGROUND AND AIM: Increased mortality has been reported in Crohn's disease (CD) but mostly not in ulcerative colitis (UC). We evaluated the overall and cause specific mortality in a nationwide cohort of patients with inflammatory bowel disease (IBD) in Finland. METHODS: A total of 21,964 patients with IBD (16,649 with UC and 5315 with CD) from the Special Reimbursement register were diagnosed 1987-1993 and 2000-2007 and followed up to the end of 2010 by collating these figures with the national computerized Cause-of-Death Register of Statistics Finland. In each cause-of-death category, the number of deaths reported was compared to that expected in general population, and expressed as a standardized mortality ratio (SMR). RESULTS: Overall mortality was increased among patients with CD (SMR 1.33, 95% confidence interval 1.21-1.46) and UC (1.10, 1.05-1.15). SMR was significantly increased for gastrointestinal causes in CD (6.53, 4.91 8.52) and UC (2.81, 2.32-3.34). Patients with UC were found also to have increased SMR from pulmonary (1.24, 1.02-1.46) and cardiovascular disease (1.14, 1.06-1.22) and cancers of the colon (1.90, 1.38-2.55), rectum (1.79, 1.14-2.69) and biliary tract (5.65, 3.54-8.54), whereas SMR from alcohol-related deaths was decreased (0.54, 0.39-0.71). Patients with CD had a significantly increased SMR for pulmonary diseases (2.01, 1.39-2.80), infections (4.27, 2.13-7.63) and cancers of the biliary tract (4.51, 1.23-11.5) and lymphoid and hematopoietic tissue (2.95, 1.85-4.45). CONCLUSIONS: In this Finnish nationwide study increased overall mortality in both CD and UC was observed. The excess mortality of 14% in IBD is mainly due to deaths related to inflammation in the gut. PMID- 24630487 TI - Pain severity and pain catastrophizing predict functional disability in youth with inflammatory bowel disease. AB - BACKGROUND: Abdominal pain is commonly reported by youth with IBD. In a significant subset of youth, pain severity and pain catastrophizing (i.e., unhelpful thoughts related to the pain) may contribute to more negative outcomes and greater impairment in functioning. This study aimed to examine relationships of pain severity and pain catastrophizing with functional disability among a sample of youth with inflammatory bowel disease (IBD). METHODS: Seventy-five youth aged 11 to 18 years completed ratings of abdominal pain severity, pain catastrophizing, and functional disability using validated measures. Disease activity was rated by treating physicians. RESULTS: Over half of participants reported abdominal pain in the past two weeks, and pain was present among those with and without clinical disease activity. Nearly one-third of youth reported mild to moderate functional disability. After controlling for gender, pain severity accounted for 15% of the variance in patient functional disability. Moreover, pain catastrophizing contributed significant variance to the prediction of functional disability (approximately 7%) beyond the role of pain severity. CONCLUSIONS: Greater attention to the role of pain catastrophizing in contributing to functional disability in youth with IBD may be important given that pain-related cognitions are modifiable via intervention. PMID- 24630488 TI - Increased expression of CXCL16, a bacterial scavenger receptor, in the colon of children with ulcerative colitis. AB - BACKGROUND AND AIMS: CXCL16 is a scavenger receptor which has been connected to phagocytosis of bacterial antigens in experimental colitis. It has also been shown to have a pivotal role in the development of experimental colitis in mice. The increased expression of CXCL16 has been demonstrated in inflamed lesions of patients with Crohn disease. Our aim was to study the expression of CXCL16 in the colon of patients with ulcerative colitis. METHODS: Relative quantitative reverse transcription-polymerase chain reaction was applied to explore the gene expressions of CXCL16, its receptor CXCR6, and interleukin 8, an inflammatory marker, in the colonic biopsies of children with active ulcerative colitis (n=19), children with ulcerative colitis in remission (n=9) and children with no inflammatory condition in colon (n=14). RESULTS: An increased expression of CXCL16 in the colonic biopsies of children with ulcerative colitis was found both in active disease (p=0.006) and in remission (p=0.033), when compared to children without inflammatory condition. The gene expressions of interleukin 8 and CXCL16 correlated with each other (rs=0.67, p=0.01). The expression of CXCR6 mRNA was comparable between the study groups (p=0.50). CONCLUSIONS: The gene expression of CXCL16 was increased in patients with ulcerative colitis both in active disease and in remission suggesting an important role of the molecule in the pathogenesis of the condition. PMID- 24630489 TI - Risk assessment of human infection with avian influenza A (H7N9) virus in Taiwan. PMID- 24630490 TI - Pancreatitis and myopericarditis complication in leptospirosis infection. PMID- 24630491 TI - Blood substitutes: why haven't we been more successful? AB - Persistent safety concerns have stalled the development of viable hemoglobin (Hb) based oxygen carriers (HBOCs). HBOCs have several advantages over human blood, including availability, long-term storage, and lack of infectious risk. The basis of HBOC toxicity is poorly understood, however, several mechanisms have been suggested, including Hb extravasation across the blood vessel wall, scavenging of endothelial nitric oxide (NO), oversupply of oxygen, and heme-mediated oxidative side reactions. Although there are some in vitro and limited animal studies supporting these mechanisms, heme-mediated reactivity appears to provide an alternative path that can explain some of the observed pathophysiological changes. Moreover, recent mechanistic and animal studies support a role for globin and heme scavengers in controlling oxidative toxicity associated with Hb infusion. PMID- 24630492 TI - Localization of epileptogenic zones in Lennox-Gastaut syndrome (LGS) using graph theoretical analysis of ictal intracranial EEG: a preliminary investigation. AB - INTRODUCTION: Precise localization of epileptogenic zones is essential for the successful surgical treatment of refractory epilepsy including Lennox-Gastaut syndrome (LGS). The surgical resection areas are generally determined by epileptologists based on diverse neuroimaging modalities; however, exact epileptogenic zones cannot be accurately localized in many patients with LGS using the conventional methods. Therefore, new reliable algorithms are still required for enhancing the success rate of the resective epilepsy surgery. In the present study, we introduce an approach to localize epileptogenic zones in LGS based on the graph theoretical analysis of ical intracranial EEG (iEEG). METHODS: Four patients with LGS who became seizure-free after the resective epilepsy surgery were selected. Before the surgery, their epileptogenic zones were delineated using EEG, iEEG, and several conventional imaging modalities. Phase locking value (PLV) analysis was applied to construct functional connectivity networks during ictal events, and then several graph theoretical indices including betweenness centrality (BC) were evaluated for each iEEG sensor to find the primary hubs of the ictal epileptic network. The graph theoretical index values were then overlaid on 3D individual cortical surface. RESULTS: The iEEG channels with high BC values coincided well with the surgical resection areas. Among various graph theoretical measures such as local efficiency, participation coefficient, and eigenvector centrality, only BC showed fair correspondence with the surgical resection areas. CONCLUSIONS: The primary hubs in the ictal epileptic networks coincided well with areas of surgical resection in LGS patients with successful surgical outcomes. This observation warrants further studies to determine if the graph theoretical network analysis of ictal iEEG recordings can serve as a new auxiliary tool to localize epileptogenic zones in LGS. PMID- 24630493 TI - Pacemaker in complicated and refractory breath-holding spells: when to think about it? AB - BACKGROUND: Breath-holding spells (BHS) are benign non-epileptic paroxysmal events of infancy, rarely occurring with high frequency and complicated by prolonged syncope, convulsions and even status epilepticus. In these cases response to medical treatment is often unsatisfactory. Pacemaker implantation is a possible therapeutic option, but its indications, efficacy and complications have not been clarified yet. OBJECTIVE: To report a new case of BHS treated with pacemaker and to review its indications and efficacy in patients with severe BHS. METHODS: We extensively searched the literature in PubMed on cardiac pacing in patients with BHS and we described a new case. RESULTS: A previously healthy boy presented at the age of 4 months with frequent BHS inconstantly associated to prolonged syncope and post-anoxic non-epileptic and epileptic seizures. Parental reassurance, iron supplementation and piracetam were ineffective. After cardiac pacing at the age of 16 months, BHS and their complications disappeared. We identified 47 patients with BHS treated with pacemaker in the literature. Based on the available data, in all patients asystole or marked bradycardia were documented during BHS or stimulating maneuvers; syncope complicated BHS in 100% of cases and post-anoxic convulsions in 78.3%. Medical treatment before pacing, when administered, was ineffective or poorly tolerated. After pacing, BHS complications disappeared in 86.4% of cases, and decreased in 13.6%. Technical problems with the device were reported in 25.7% of patients and mild medical complications in 11.4%. CONCLUSIONS: Pacemaker could be reasonably considered in subjects with frequent and severe BHS, poor response to medications, and demonstration of cardioinhibition during spells. PMID- 24630494 TI - Spontaneous regression of sequestrated lumbar disc herniations: Literature review. AB - Lumbar disc herniations (LDH) may regress with conservative management; however, this phenomenon is poorly understood for the sequestrated subtype of LDH. We present one of the first comprehensive literature reviews specifically addressing the spontaneous regression of sequestrated intervertebral discs. We reviewed all publications with lumbar disc herniations, sequestrated subtype. Our results were then narrowed to patients who experienced spontaneous regression of the sequestration. Based on our literature review of 53 cases, patients with sequestrated lumbar disc herniations experienced symptomatic resolution in a mean of 1.33+/-1.34 months and radiographic resolution in 9.27+/-13.32 months. Symptomatic patients with sequestrated discs present similarly to those with other types of lumbar disc herniations. Sequestrations may have the highest likelihood to radiographically regress in the shortest time frame in comparison to the remaining subtypes of LDH. The most likely mechanism for regression is an inflammatory response elicited against the free fragment. Patients with disc sequestrations may be managed conservatively, in the absence of intractable pain, inability to walk, weakness or symptoms suggestive of cauda equina syndrome. PMID- 24630495 TI - Psychiatric comorbidities in Asian adolescent asthma patients and the contributions of neuroticism and perceived stress. AB - PURPOSE: Psychiatric comorbidity is reported to be common among adolescents with asthma, but little is known about its underlying psychological factors. OBJECTIVE: This study explored the profile of anxiety and depressive comorbidities among adolescents with well-controlled and poorly controlled asthma and the contribution of neuroticism and perceived stress. METHODS: The Revised Child Anxiety and Depression Scale, Neuroticism subscale of Big Five Inventory, Perceived Stress Scale, and Asthma Control Test were administered to 198 adolescents (aged 12-19 years) with well-controlled (n = 137) and poorly controlled asthma (n = 61) as well as 171 healthy neighborhood controls. RESULTS: Adolescents with poorly controlled asthma, compared with well-controlled asthma patients and healthy controls, had higher scores of depression (p = .006), panic attacks (p = .002), total anxiety (p = .038), and total internalizing symptoms (p = .017), after adjusting for gender, age, ethnicity, smoking status, and family housing type. Adolescents with asthma had higher neuroticism (p = .025), perceived stress (p = .022), and body mass index (p = .006) and lower self-rated health (p < .001) than healthy controls. No significant differences in psychiatric comorbidity scores were observed after accounting for differences in underlying psychological and physical factors. Among asthma patients, increased asthma control was associated with decreased scores of psychiatric comorbidity (p < .01), but the association was not significant after allowing for decreased neuroticism and perceived stress. CONCLUSIONS: The diagnosis of asthma and poor asthma control in adolescents is associated with excess psychiatric comorbidity, which is likely due to increased neuroticism and perceived stress. PMID- 24630496 TI - Biosorption of antimony(V) onto Fe(III)-treated aerobic granules. AB - Iron precipitate was produced with 0.1M FeCl3 and bound with the amino or hydroxyl groups of the granules surface, accompanied with removal of Ca, Mg, K and Na from the biomass matrix. The Fe(III)-treated granules exhibited much higher adsorption capacity of antimony(V) than the untreated granules, peaked at pH 3.4 at a maximum capacity of 22.6 mg g(-1) of dry mass. The intraparticle diffusion and film diffusion resistances controlled the Sb(V) adsorption onto the Fe(III)-treated granules. Fe(III) treatment is a cost-effective and easy-to implement process to modify the surface of aerobic granules to enhance their adsorption capacity to Sb(V). PMID- 24630497 TI - Dry dilute acid pretreatment by co-currently feeding of corn stover feedstock and dilute acid solution without impregnation. AB - Impregnation of lignocellulose materials with dilute acid solution is a routine operation in conventional dilute acid pretreatment. The dry dilute acid pretreatment (DDAP) at high solids content up to 70% is naturally considered to require longer impregnation time. In this study, a co-currently feeding operation of corn stover and dilute sulfuric acid solution without any impregnation was tested for DDAP. The DDAP pretreated corn stover without impregnation is found to be essentially no difference in pretreatment efficiency compared to those with impregnation in the helically agitated reactor. The yield from cellulose to ethanol in SSF again shows no obvious difference between the DDAP pretreated corn stover with and without impregnation. This study suggests that impregnation in DDAP was not necessary under the helical agitation mixing. The results provided a useful way of cost reduction and process simplification in pretreatment. PMID- 24630498 TI - Chromatographic behavior of new antiepileptic active compounds on different reversed-phase materials. AB - A chromatographic and thermodynamic study of the derivatives of 4,5-disubstituted 2,4-dihydro-3H-1,2,4-triazole-3-thiones (and their Mannich bases) was undertaken. Three reversed-phase materials: a Zorbax Extend-C18, Cogent UDC Cholesterol and Regis IAM. PC. DD. 2 were studied. Plots of logk vs. the volume fraction of organic solvent in the mobile phase (phi) and the van't Hoff relationships were constructed. The van't Hoff plots revealed at least one phase transition on Cogent UDC Cholesterol and Regis IAM. PC. DD. 2. Obtained results indicated that adsorption was enthalpy-entropy driven. Cholesterol phase and Regis IAM. PC. DD. 2 in contrast to conventional octadecyl silica phase at aqueous-organic mobile phase demonstrated some liquid crystals behavior at defined conditions. PMID- 24630499 TI - Isopropyl derivative of cyclofructan 6 as chiral selector in liquid chromatography and capillary electrophoresis. AB - Cyclofructans and preferentially their derivatives can serve as chiral selectors for the separation of different enantiomers/atropisomers. Moreover, the strong ionophoric nature of the 18-crown-6 ether core of cyclofructan 6 for barium cations may be exploited to enhance or modify enantioselectivity. In this work isopropyl-cyclofructan-6 was used as a chiral selector for the separation of binaphthyl atropisomers in HPLC and CE. The data from both separation systems were compared with each other. While in HPLC the chiral selector was bonded to silica gel to afford a chiral stationary phase, in capillary electrophoresis it was freely mobile in the background electrolytes (BGE). This significant difference is reflected in the separation potential of the two separation systems. All five analytes could be baseline separated in HPLC (reversed phase mode) while only one derivative was baseline resolved in CE. This result was attributed to the more rigid nature of the immobilized chiral selector. Addition of Ba(2+) to the mobile phase or BGE improved chiral separations in both systems. The results may help to elucidate the interaction mechanism in these systems with cyclofructan derivatives and to gain some general knowledge of their separation potential. PMID- 24630500 TI - On-line hydrogenation of biodiesel-Toward a reference method for the determination of glycerides and total glycerol. AB - A reliable method with ensured traceability of the measurement results for free and bound glycerol (as monoacylglycerides, diacylglycerides and triacylglyerides) in biodiesel was developed, giving results beyond the state of the art of the current standard methodologies. The proposed method is based on an on-line hydrogenation using gas chromatography coupled to flame ionization detection and hydrogen as carrier gas. After sample introduction the hydrogenation takes place on a fused silica pre-column coated with a palladium catalyst. This approach allows an immediate and reliable hydrogenation of vegetable oils and biodiesels from different feedstocks. All glycerides are converted into their saturated analogues, resulting in simplified chromatograms with structurally clearly defined analytes, and increased sensitivity for trace amounts of compounds. The method has been successfully in-house validated and combined uncertainty values have been assigned to the final results, which were less than 8% for free glycerol, the sum of monoacylglycerides, the sum of diacylglycerides and the sum of triacylglycerides. PMID- 24630501 TI - Qualitative analysis and enantiospecific determination of angular-type pyranocoumarins in Peucedani Radix using achiral and chiral liquid chromatography coupled with tandem mass spectrometry. AB - Angular-type pyranocoumarins (APs), the derivatives of khellactone, are widely documented as the main active constituents in Peucedani Radix (Chinese name: Qian hu). Owing to the natural occurrence of chiral centers, enantiomers of APs are extensively distributed in the original plant, and enantioselective performances have been definitely demonstrated for these enantiomers. In current study, the chemical characterization of the major and minor APs in Peucedani Radix was performed using ultra high performance liquid chromatography coupled with diode array detector and hybrid ion trap-orbitrap mass spectrometry. On the other hand, a heart-cut two-dimensional achiral-chiral liquid chromatography combining triple quadropole-linear ion trap mass spectrometry system (2D LC-MS/MS) was developed for simultaneous enantiospecific quantification of eighteen coumarins, including seven pairs of enantiomers. Eleven APs (1-11) were recruited to propose UV absorption characteristics and electrospray ionization fragmentation patterns of APs. A total of 42 components were categorized into APs based on their UV spectral properties and identified according to the proposed mass fragmentation pathways, while two linear-type furanocoumarins (12-13) were unambiguously assigned by further purification. A Capcell core RP-C18 column was employed in the primary LC dimension to achieve efficient racemic separation for the main chemical constituents (1-9 and 12-13) in Peucedani Radix, while a Chiralpak AD-RH column was utilized in the secondary dimension to contribute enantioselective separation for seven enantiomerically enriched components (1, 3 and 5-9). Collectively, the results provided the chemical evidences for revealing the material basis of the therapeutic effects of Peucedani Radix, and the developed 2D LC-MS/MS system in the present study is expected to be an ideal tool for the quality control of Peucedani Radix as well as a reliable technique for complex matrices containing both achiral and chiral components. PMID- 24630502 TI - Computational design of an enantioselective molecular imprinted polymer for the solid phase extraction of S-warfarin from plasma. AB - An enantioselective molecular imprinted polymer for S-warfarin was designed computationally by using the density functional theory (DFT) at B3LYP/631G+ (d, p) level and Gaussian 2003 package. The effect of polymerization solvent was also evaluated by the polarizable continuum model (PCM) and it was based on the measurement of interaction energies (DeltaE) between S-warfarin and monomers in different polymerization solvents. The computational method showed that the methacrylic acid (MAA) and acetonitrile (AN) had the highest stabilization energy for the pre-polymerization adducts. Additionally, the mole ratio of 1:3 give the highest DeltaE, therefore, the polymer was synthesized by the thermal bulk polymerization method with the mole ratio of S-warfarin-(MAA)3. The enantioselective extraction of MIP for R and S-warfarin was evaluated by chiral separation chromatography and polarimetry methods. The results revealed that the proposed S-warfarin molecular imprinted polymer has a moderate recognition for extraction of R-warfarin in a racemic mixture and had no recognition for other foreign drugs. In a racemic mixture of R and S-warfarin, the polymer is able to remove about 20% of R-warfarin. The linearity between responses (peak areas) and concentrations of S-warfarin in plasma sample was found in the range of 15.4 3080ngmL(-1) (R(2)=0.999).The linear range for a racemic mixture of R, S-warfarin in plasma which has been obtained by RP-C18-HPLC-UV method, was 12.0-2500ngmL(-1) (R(2)=0.998). The polymer was used for analysis of a real sample and as expected the accurate results were obtained. PMID- 24630503 TI - High failure rate of the laparoscopic-adjustable gastric band as a primary bariatric procedure. AB - BACKGROUND: Determinants of success of a bariatric procedure are many but paramount is the ability to durably produce significant and reliable weight loss. We sought to determine the primary success of the laparoscopic adjustable gastric band (LAGB) by defining failure as clinical weight loss failure with an intact band (excess weight loss [EWL]<20%) or band removal (terminal removal or conversion to a secondary bariatric procedure). METHODS: A retrospective chart review was performed on patients who underwent an LAGB as a primary bariatric procedure between January 2003 and December 2007. Data collected included body mass index (BMI), weight, postoperative follow-up length, EWL, and adjustment number, as well as complications of the LAGB. RESULTS: Sixteen of 120 patients had the band removed. Nine were terminally removed for unmanageable symptoms, and 7 were converted to an alternative bariatric procedure. The average follow-up for the 104 patients with an intact band was 4.8 years. The average EWL for successful intact bands was 44.9+/-19.4%; however, an additional 35.6% of patients had an EWL<20%. Patients with an EWL<20% had a significantly higher preoperative BMI and fewer band adjustments. In total, 44% of patients had band failure because of clinical weight loss failure (31%) or eventual band removal (13%). CONCLUSION: This study finds that the LAGB failed as a primary bariatric procedure for 44% of patients because of either inadequate weight loss or adequate weight loss with unmanageable symptoms. This suggests that the LAGB should be abandoned as a primary bariatric procedure for the majority of morbidly obese patients because of its high failure rate. PMID- 24630504 TI - Gynecologic Oncology: an update on our progress. PMID- 24630505 TI - Entecavir 1mg versus combined lamivudine/adefovir dipivoxil in chronic HBV Egyptian patients resistant to LAM monotherapy, non-randomised controlled study. AB - BACKGROUND AND STUDY AIMS: The development of antiviral-resistant mutations with long-term treatment remains a major concern in the treatment of chronic hepatitis B virus (HBV) infection. The study aimed to compare the therapeutic efficacy of entecavir 1mg versus combined lamivudine/adefovir dipivoxil (Lam/Adv) in chronic HBV patients resistant to lamivudine monotherapy. PATIENTS AND METHODS: This study included two groups of lamivudine-resistant patients who received lamivudine 100mg for 1-3 years. Group 1 was composed of 25 cases (52% HBeAg+ve) who received combined Lam/Adv, and group 2 was composed of 13 patients (30.8% HBeAg+ve) who received entecavir 1mg. Pre-enrolment assessment included biochemical, serological and quantitative HBV-DNA testing as well as HBeAg and hepatitis B envelope antibody (HBeAb) assessment. Evaluation was done at 3, 6, 12, 24 and 36 months of treatment by the same parameters. Hepatitis B surface antigen and antibody (HbsAg and HBsAb) were assessed after each year of treatment. RESULTS: At the end of 36 months of treatment, 16 cases (69%) in group 1 completed the study period, versus 13 (100%) in group 2. Two cases in group 1 underwent HBeAg seroconversion, accompanied by HBV-DNA undetectability, at 6 and 12months, respectively; no cases were seroconverted in group 2. Both treatments achieved improvement in alanine aminotransferase (ALT), bilirubin and alpha foetoprotein equally at the end of the study. HBV-DNA undetectability was better achieved in group 2 when compared to group 1. HBeAg seroconversion was only achieved in two cases in group 1, whereas no cases lost HBeAg in group 2. None of our cases achieved HbsAg seroconversion or loss at the end of the study period. CONCLUSION: The entecavir 1-mg monotherapy group achieved better HBV-DNA undetectability starting at 3 months of treatment when compared to the Lam/Adv group; however, both lines of treatment showed almost similar results over the rest of the study period. HBeAg seroconversion was only achieved in two cases in the combined Lam/Adv group, whereas no cases lost HBeAg in the other group. PMID- 24630506 TI - Apoptotic and anti-apoptotic seromarkers for assessment of disease severity of non-alcoholic steatohepatitis. AB - BACKGROUND AND STUDY AIMS: This study aimed to find out non-invasive markers for the assessment of severity of non-alcoholic steatohepatitis (NASH) in an attempt to decrease the need for liver biopsy. It also aimed to evaluate the key role of apoptosis in the pathogenesis of the disease and the suggested role of anti apoptotic factors in therapeutic modalities and disease prognosis. PATIENTS AND METHODS: The serum levels of soluble Fas (s. Fas), s. Fas ligand, cytokeratin 18 (CK-18) fragment and Bcl-2 were measured in 80 patients and 15 non-hepatic subjects as control. The patients were divided based on histological examination of liver biopsy into three groups. Group I included 40 patients with NASH, group II had 40 patients with non-alcoholic fatty liver disease (NAFLD) non-NASH and group III had 15 non-hepatic subjects as control. Apoptosis of hepatocytes was assessed by morphological examination using a light microscope and expressed as number per square millimetre. RESULTS: There was a significant increase in the serum levels of s. Fas, s. Fas ligand and CK-18 fragments in the NASH group. The anti-apoptotic protein Bcl-2 showed significantly low levels in NASH patients. Apoptosis of hepatocytes was significantly higher in the NASH group. The degree of apoptosis was inversely correlated with the level of Bcl-2. A significant correlation between both s. Fas and CK-18 fragment with liver histology with regard to lobular inflammation and ballooning was found. CONCLUSIONS: Increased serum levels of s. Fas and CK-18 fragment in the NASH group and its correlation with the severity of disease suggested the key role of apoptosis in NASH pathogenesis which can be used for the assessment of the severity of NASH. A high level of anti-apoptotic Bcl-2 in NAFLD suggests its protective role in disease progress. PMID- 24630507 TI - Non alcoholic fatty liver disease (NAFLD) in a Sudanese population: What is the prevalence and risk factors? AB - BACKGROUND AND STUDY AIMS: Non alcoholic fatty liver disease (NAFLD) is a common clinical condition associated with obesity and considered as possible precursor of more serious disease like Non alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. There is very little research work carried concerning NAFLD in African countries in relation to prevalence and risk factors. Therefore, the aim of this study is to determine the prevalence of NAFLD and risk factors among asymptomatic co-patients accompanying patients admitted to gastroenterology wards at the National Centre for GI & Liver Diseases, Ibn Sina Hospital (Khartoum, Sudan). PATIENTS AND METHODS: Subjects with liver disease, excess alcohol intake (the intake of more than 21 units of alcohol per week for men and 14 units for women per week) and pregnancy were excluded from this study. The age, sex, body mass index (BMI), history and duration of diabetes and hypertension were recorded. Ultrasound was offered followed by clinical examination and blood sample was taken for assessment of liver function from each subject (total number of participants was 100). RESULTS: NAFLD was diagnosed in 20 patients, giving prevalence of 20%. There was no statistical significance between the two sexes. The mean age of subjects with NAFLD was 53 years old and without NAFLD was 40 years (p<0.05). Importantly, the prevalence of NAFLD increased with age and BMI. Due to small number of diabetic individuals and hypertension, these two conditions were not statistically significant when related to NAFLD. CONCLUSION: The estimated prevalence of NAFLD in our study is 20% and this figure is comparable to the prevalence of NAFLD in Asian countries. Males and females were nearly equally affected and the prevalence of NAFLD increased with age and BMI, making obesity a main risk factor. PMID- 24630508 TI - Erectile dysfunction in patients with chronic hepatitis C virus infection. AB - BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) infection is a major public health problem worldwide and in Egypt. Several studies have suggested that chronic HCV infection may be associated with erectile dysfunction (ED) in men. The aim of our study was to detect the prevalence of ED among male patients with chronic HCV infection. PATIENTS AND METHODS: The study included 150 male patients with chronic HCV infection (124 patients with chronic hepatitis and 26 patients with HCV-associated liver cirrhosis). The Child-Pugh score was used to assess the severity of cirrhosis. An Arabic validated version of the five-item International Index of Erectile Function (IIEF-5) was used to detect the presence and severity of ED. RESULTS: The patients' age ranged from 20 to 80 years with mean age+/ standard deviation (SD; 50+/-17.19) years. The prevalence of ED among patients with chronic HCV infection was found to be 29.3%. The prevalence was significantly higher in cirrhotic as compared to chronic hepatitis patients (p<0.001) and the average ED score was significantly lower in patients with liver cirrhosis than in those with chronic hepatitis. There was a highly significant relation between the severity of ED and the severity of liver disease. There was a significant negative correlation between serum bilirubin and ED score and a significant positive correlation between serum albumin and ED score in patients with liver cirrhosis. CONCLUSION: About 30% of patients with chronic HCV infection were found to have ED; so, given the high prevalence of HCV infection in Egypt, chronic HCV infection may be considered in the differential diagnosis of ED. There was a highly significant relation between the severity of ED and the severity of liver disease and the majority of patients with liver cirrhosis proved to be suffering from ED, which may be related to the associated hypoalbuminaemia. PMID- 24630509 TI - Congenital glucose-galactose malabsorption: a descriptive study of clinical characteristics and outcome from Western Saudi Arabia. AB - BACKGROUND AND STUDY AIMS: Congenital glucose galactose malabsorption (CGGM) is a rare autosomal recessive disorder caused by a defect in the sodium-coupled transport of glucose and galactose across the intestinal brush border presenting with neonatal diarrhoea. The aim of this study was to report the clinical and laboratory characteristics of patients with CGGM from the Western Saudi Arabia. PATIENTS AND METHODS: This is a retrospective review of CGGM patients in three major hospitals in the city of Jeddah, Saudi Arabia, namely King Abdulaziz University Hospital, King Faisal Specialist Hospital and Research Centre, and Maternity Children Hospital in the period between November 2001 and October 2011. RESULTS: Twenty-four patients with CGGM have been described. The median age at diagnosis was 4.5 months. Twelve (50%) were males. Sixteen (66.7%) were Saudi and 8 (33.3%) were non Saudi (5 Arabs and 3 Asians). Parents of 21 patients were consanguineous. Nine (37.5%) had affected siblings with CGGM. All presented with diarrhoea resulted in dehydration. Hypernatremia was seen in 7 (29.2%) patients, renal tubular acidosis in 4 patients. Renal stones and nephrocalcinosis were detected in 3 (12.5%) patients at 8 months, 12 months and 7 years, respectively. The median follow up was 41.6 months. All but three demonstrated normal weight gain. Five patients reported one or more symptoms of bloating (n=3), diarrhoea (n=3) and abdominal pain (n=1) during follow up. All had normal development and none had neurological complications secondary to dehydration. CONCLUSION: Early recognition and management of this condition are crucial to prevent consequences of dehydration and death. PMID- 24630510 TI - Wait-and-see policy versus cholecystectomy after endoscopic sphincterotomy for bile-duct stones in high-risk patients with co-existing gallbladder stones: a prospective randomised trial. AB - BACKGROUND AND STUDY AIMS: Endoscopic sphincterotomy (ES) is one of the most important advances in the treatment of common bile duct (CBD) stones. However, the use of ES to remove CBD stones in high-risk patients without cholecystectomy is still debatable. The aim of this study was to compare the efficacy of a wait and-see policy versus cholecystectomy after ES for CBD stones in high-risk patients with co-existing cholelithiasis. PATIENTS AND METHODS: A total of 162 patients after undergoing ES with the clearance of CBD stones were randomised after informed consent to cholecystectomy or conservative management of their gallbladder stones. RESULTS: The results indicated that cholecystectomy after ES for CBD stones significantly reduced the biliary complications in high-risk patients. CONCLUSION: Every patient who has both CBD stones and gallstones with significant co-morbid illnesses, after clearance of CBD stones by ES, should undergo early cholecystectomy. PMID- 24630511 TI - Endoanal ultrasound assessment of sphincter defects and thinning--correlation with anal manometry. AB - BACKGROUND AND STUDY AIMS: This study aims to determine if anal sphincter defects/thinning observed at endoanal ultrasound correlates with anal pressures recorded at anal manometry. PATIENTS AND METHODS: A total of 30 consecutive patients with history suggestive of anal sphincter pathology underwent anal endosonography with documentation of internal and external sphincter defects/thinning. The same patients underwent anal manometry with documentation of maximum resting and maximum squeeze pressures. Patients with a sphincter defect (SD) were compared to patients without a sphincter defect (NSD) and both groups were compared with respect to findings in manometry. The Mann-Whitney U test was used for statistical analysis. This study was approved by the Institutional Ethics Committee. RESULTS: A statistically significant correlation was found between decreased maximal resting pressure and decreased internal anal sphincter (IAS) thickness or an IAS defect. The correlation between MSP and external sphincter pathology was significantly less consistent in our study. CONCLUSION: Our study showed a statistically significant correlation between maximum resting pressure and observation of internal sphincter defects at endoanal ultrasound. The patients with documented internal sphincter defects have significantly reduced maximum resting pressures. There was however, no correlation between external sphincter defects and decrease in maximum squeeze pressure as has been observed in other studies. Until a manometry cut-off can be set to discriminate between the absence and presence of defects, both manometry and ultrasound should be offered to patients with history suggesting anal sphincter pathology. PMID- 24630513 TI - Melena revealing a nasopharyngeal leech: a paediatric case. AB - Leech infestation occurs after swimming or ingestion of freshwater, especially in rural areas. Symptoms are different depending on the binding site of the leech. At the nasopharynx, it is mainly responsible for epistaxis. We report a case of an unknown pharyngeal location of a leech in a three year-old girl responsible for melena and leading to a severe anaemia. PMID- 24630512 TI - Safety of non-anaesthesiologist-administered propofol sedation in ERCP. AB - BACKGROUND AND STUDY AIMS: Propofol is increasingly being used for sedation purposes during endoscopic retrograde cholangiopancreatography (ERCP). This study aimed to evaluate the safety of non-anaesthesiologist administration of propofol (NAAP) during therapeutic ERCP. PATIENTS AND METHODS: Patients, who underwent ERCP at Centre for Liver and Digestive Diseases, Holy Family Hospital, Rawalpindi, were included in the study. Propofol sedation was administered by a physician who was a non-anaesthesiologist certified in basic and advanced cardiac life support. The total study duration was 6 months. The primary outcome variable was the frequency of any sedation-related complication. RESULTS: A total of 156 patients (41% males and 59% females) were enrolled in the study. The mean propofol dose used during the procedure was 201+/-132 mg. The mean propofol dose, when adjusted to weight and duration of procedure, was 0.05+/-0.04 mg kg(-1)min( 1). According to the American Society of Anesthesiologists (ASA) classification, 136 (87%) patients were placed in ASA class I and II and 20 (13%) patients were of ASA class III. Only two patients developed sedation-related complication: one minor requiring bag-mask ventilation and other major requiring mechanical ventilation via endotracheal intubation. Both were managed by the trained non anaesthesiologist and gastroenterologist at the place of procedure. No patients required cardiopulmonary resuscitation and admission to the intensive care unit. There were no sedation-related deaths. CONCLUSION: NAAP sedation can be considered safe for low-risk patients (ASA class I and II) undergoing ERCP. The presence of a trained anaesthetist is advisable in high-risk patients (ASA class III and higher) with significant co-morbidities. PMID- 24630514 TI - Pancreatic panniculitis: a rare complication of pancreatitis secondary to ERCP. AB - Panniculitis is an uncommon and rare complication of systemic fat necrosis in patients with pancreatic diseases. The skin manifestations are independent of the severity of the pancreatic pathology and can occur at any time. The lesions can precede, be concomitant with or rarely follow the pancreatic illness. We report a case of acute pancreatitis post Endoscopic Retrograde Cholangio Pancreatography (ERCP) for common bile duct stone, with subcutaneous panniculitis. We noted a complete resolution within two weeks after the treatment of the pancreatic pathology. PMID- 24630515 TI - Rosai-Dorfman disease with exclusive intra-abdominal lymphadenopathy masquerading as Wilkie's syndrome. AB - Rosai-Dorfman disease is a rare histiocytic proliferative disorder with a distinctive microscopic appearance. Patients usually present with nonspecific symptoms and massive cervical lymphadenopathy. Exclusive involvement of intra abdominal lymph nodes is unusual and presentation mimicking Wilkie's syndrome due to compression of the third part of the duodenum by enlarged retroduodenal lymph nodes is rare. This entity should be included in the differential diagnosis with infectious, granulomatous and malignant causes of intra-abdominal lymphadenopathy. We highlight an uncommon presentation and discuss the challenges in the diagnosis and management of Rosai-Dorfman disease. PMID- 24630516 TI - Henoch-Schonlein purpura: hitting the 'target' on CT. AB - This image highlights the common findings on CT in Henoch-Schonelin Purpura, namely 'target sign' and comb sign. We discuss the common CT findings in this disease. PMID- 24630517 TI - A note from the editor's desk. PMID- 24630518 TI - Overexpression of B7-H3 in CD133+ colorectal cancer cells is associated with cancer progression and survival in human patients. AB - Cancer stem-like cells are enriched in CD133-positive (CD133(+)) colorectal cancer (CRC) cells. To date, the biological significance of CD133 expression in cancer stem-like cells is still unknown. B7-H3, a costimulatory molecule, plays a pivotal role in tumor immune escape by inhibiting the functions of T cells. To identify a new marker to predict the tumor grade of CRC, we analyzed the expression of B7-H3 and CD133 in colorectal tumor samples, and their clinical significance was determined. By using a series of techniques including pathologic tissue microarray technology, immunohistochemistry, and immunofluorescent staining, we found B7-H3 was expressed in 56.73% of the CRC cases (59/104) sampled; CD133 was detected in 26.92% of the CRC cases (28/104) sampled. Further analysis indicated that 22 of these CD133(+) samples expressed B7-H3. We also found coexpression of CD133 and B7-H3 in tumor tissue samples (r = 0.321, P < 0.01). Moreover, in contrast to individual CD133 or B7-H3 expression, the coexpression of B7-H3 and CD133 was evidently associated with the depth of tumor invasion, lymphatic metastasis, distant metastasis, and Dukes' stage, suggesting it is a valuable biomarker for the progression of CRC. Indeed, the patients with coexpression of B7-H3 and CD133 had a poorer survival than the other patients (P < 0.05). In summary, our results reveal that B7-H3 was aberrantly expressed in CD133(+) CRC cells, and the expression level was closely associated with tumor progression. PMID- 24630519 TI - The effects of enalapril and losartan on mechanical ventilation-induced sympathoadrenal activation and oxidative stress in rats. AB - BACKGROUND: Mechanical ventilation (MV) is a method of maintaining appropriate gas exchange in patients who are unable to sustain adequate alveolar ventilation. While lifesaving in the short-term, prolonged MV leads to altered cardiovascular responses and enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated the involvement of the sympathoadrenergic and renin angiotensin system in MV-induced altered cardiovascular responses. METHODS: Sprague-Dawley rats were divided into six groups: (1) spontaneous breathing (SB); (2) SB + enalapril (100 MUg/kg intravenous infusion); (3) SB + losartan (100 MUg/kg infusion); (4) 12 h of MV; (5) MV + enalapril; and (6) MV + losartan. After the animals were sacrificed, blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxylase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked immunosorbent assay and total antioxidant capacity were assayed in plasma. RESULTS: Our findings indicated that MV increases the sympathetic activation markers in adrenal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain tissues, while preserving the tissue glutathione content and plasma antioxidant capacity. CONCLUSIONS: These data demonstrate that the inhibition of the renin-angiotensin system by enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy. PMID- 24630520 TI - Systematic review and meta-analysis of rectal washout on risk of local recurrence for cancer. AB - BACKGROUND: It has been shown that intraluminal washout (WO) can prevent local recurrence (LR) of rectal cancer. This meta-analysis was to evaluate the association of rectal WO and the risk of LR after anterior resection in patients with rectal cancer. METHODS: The relevant studies were identified by a search of the MEDLINE, Embase, Wiley Online Library, and Cochrane Oral Health Group Specialized Register with no restrictions on October 18, 2013, and these studies were included in a systematic review and meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in fixed effects model. RESULTS: A total of nine studies were included in our study, yielding a total of 5519 patients, and pooled ORs for overall LR in corresponding subgroups were calculated. Rectal WO was associated with a lower risk for LR (240/4176, 5.75% versus 9.75%, 131/1343, OR = 0.53, 95% CI = 0.42-0.68, and P < 0.00001) in patients with anterior resection, having total mesorectal excisions (234/3942, 5.93% versus 9.34%, 97/1039, OR = 0.59, 95% CI = 0.46-0.75, and P < 0.00001), and after radical resection (RR; 122/2665, 4.99% versus 8.90%, 74/831, OR = 0.56, 95% CI = 0.41-0.78, and P = 0.0005), with an overall LR rate of 6.72% (371/5519). But, the stability of RRs is not high in the total mesorectal excisions or RR subgroup by sensitivity analysis. CONCLUSIONS: The use of rectal WO decreases risks of LR in patients after anterior resection of cancer. PMID- 24630522 TI - Analysis of potential antiviral resistance mutation profiles within the HBV reverse transcriptase in untreated chronic hepatitis B patients using an ultra deep pyrosequencing method. AB - The potential antiviral resistance mutations within hepatitis B virus (HBV) reverse transcriptase (RT) region for nucleos(t)ide analogues (NA) are not well known. Especially, the effect of pre-existing antiviral drug resistance mutations in untreated patients in comparison to the resistance developed after treatment is not still clear. Sixteen naive chronic hepatitis B patients were studied. None of the patients had received NA treatment prior to the serum samples being collected. Forty-two potential NA resistance (NAr) mutation sites were screened by ultra-deep pyrosequencing (UDPS). After therapy, mutations conferring treatment resistance were detected by LiPA. Serum samples taken before treatment showed no classic primary or compensatory/secondary drug resistance mutations. However, NAr mutations found in 6 isolates (37.5%) involved 7 positions including rtL91I, rtT128I, rtQ215P, rtF221Y, rtN238D, rtC256S, and rtI266G. Substitutions at 3 NAr mutation sites (rtT128I, rtN238D, and rtC256S) were detected in 3 unresponsive patients developing drug resistance after NA treatment. One patient with rtI266G mutation also developed drug resistance after lamivudine (LAM) therapy. However, the relationship between rtI266G mutation and NA drug resistance was not previously reported. These results suggest that association of potential mutations besides the primary and secondary/compensatory resistance mutations should be investigated. Investigation of NAr mutations before treatment may be important for the success of the treatment. PMID- 24630521 TI - Short-term physical inactivity impairs vascular function. AB - BACKGROUND: Sedentarism, also termed physical inactivity, is an independent risk factor for cardiovascular diseases. Mechanisms thought to be involved include insulin resistance, dyslipidemia, hypertension, and increased inflammation. It is unknown whether changes in vascular and endothelial function also contribute to this excess risk. We hypothesized that short-term exposure to inactivity would lead to endothelial dysfunction, arterial stiffening, and increased vascular inflammation. METHODS: Five healthy subjects (four men and one woman) underwent 5 d of bed rest (BR) to simulate inactivity. Measurements of vascular function (flow-mediated vasodilation to evaluate endothelial function; applanation tonometry to assess arterial resistance), inflammation, and metabolism were made before BR, daily during BR, and 2 d after BR recovery period. Subjects maintained an isocaloric diet throughout. RESULTS: BR led to significant decreases in brachial artery and femoral artery flow-mediated vasodilation (brachial: 11 +/- 3% pre-BR versus 9 +/- 2% end-BR, P = 0.04; femoral: 4 +/- 1% versus 2 +/- 1%, P = 0.04). The central augmentation index increased with BR (-4 +/- 9% versus 5 +/- 11%, P = 0.03). Diastolic blood pressure increased (58 +/- 7 mm Hg versus 62 +/- 7 mm Hg, P = 0.02), whereas neither systolic blood pressure nor heart rate changed. 15-Hydroxyeicosatetraenoic acid, an arachidonic acid metabolite, increased but the other inflammatory and metabolic biomarkers were unchanged. CONCLUSIONS: Our findings show that acute exposure to sedentarism results in decreased endothelial function, arterial stiffening, increased diastolic blood pressure, and an increase in 15-hydroxyeicosatetraenoic acid. We speculate that inactivity promotes a vascular "deconditioning" state characterized by impaired endothelial function, leading to arterial stiffness and increased arterial tone. Although physiologically significant, the underlying mechanisms and clinical relevance of these findings need to be further explored. PMID- 24630523 TI - [The nuclear receptor NOR-1 regulates the activation of vascular cells and vascular remodelling in response to hemodynamic stress]. AB - INTRODUCTION: Previous studies have shown that the loss of NOR-1 function modulates the activation of vascular smooth muscle cells (VSMC). In this study we use a mouse that over-expresses human NOR-1 in VSMC to analyze the effect of a gain of NOR-1 function on the activation of VSMC and in the hyperplasia of the intima induced by hemodynamic stress. METHODS: To generate the transgenic animal the human NOR-1 cDNA was placed under the control of the SM22alpha promoter. The expression of NOR-1 was analyzed by real time PCR, Western blot, immunohistochemistry and immunocitochemistry, and NOR-1 functionality was evaluated by luciferase activity assays. The incorporation of tritiated thymidine was determined as a cell proliferation index. The left carotid artery was ligated, and cross-sections were subjected to morphometric and immunostaining analysis. RESULTS: The transgenic mouse exhibited significant levels of human NOR 1 in aorta and carotid arteries. In aortic VSMC from transgenic mice an increase in the transcriptional activity of ciclin D2 was detected, as well as higher proliferative rates and increased levels of the marker Myh10. In these animals, carotid artery ligation induced a greater neointimal formation and a higher stenotic grade than in wild-type animals, in accordance with the labelling detected for Myh10 and phosphorylated Histone H3. CONCLUSIONS: These results reinforce the role of NOR-1 in VSMC proliferation and in vascular remodelling, and allow us to propose this model as a useful tool to study the involvement of NOR-1 in vascular function and in vascular diseases such as atherosclerosis and restenosis. PMID- 24630524 TI - Ceramide-enriched LDL induces cytokine release through TLR4 and CD14 in monocytes. Similarities with electronegative LDL. AB - INTRODUCTION: In vitro ceramide-enriched LDL (CER-LDL) reproduces most of the properties of electronegative LDL (LDL(-)), a heterogeneous subfraction of LDL found in plasma. LDL(-) comprises several modifications of LDL and has an increased content in ceramide (CER). It promotes cytokine release in monocytes through CD14 and TLR4. CER-LDL also induces cytokine release in these cells but the mechanism is unknown. AIM: To evaluate TLR4 and CD14 as the putative receptors involved in cytokine release induced by CER-LDL. METHODS: CER-LDL was obtained by incubating native LDL with CER-enriched liposomes. CER content in CER LDL was assessed by thin layer chromatography of lipid extracts. CER-LDL and LDL( ) were incubated for 20 h with human monocytes in the presence or absence of a TLR4 signaling inhibitor. Both LDLs were also incubated with two human monocytic cell lines, normal and THP1 overexpressing CD14 (THP1-CD14) cells. The release of IL-6, IL-10 and MCP-1 was evaluated by ELISA in culture medium. RESULTS: The release of IL-6, IL-10 and MCP-1 induced by CER-LDL in monocytes was inhibited by VIPER (90% inhibition), a specific TLR4 inhibitor. The cytokine release induced by CER-LDL was negligible in THP1, cells presenting a very low CD14 expression. In contrast, the induction of cytokine release in THP1-CD14 was high and dependent on the CER content in LDL. CONCLUSION: CER-LDL induces IL-6, IL-10 and MCP-1 release through the activation of CD14 and TLR4 in monocytes, reproducing the behavior of LDL(-). The increased content of CER in LDL(-) is then related to the inflammatory action of LDL(-). PMID- 24630525 TI - A natural history of human tree climbing. AB - Walking and running have dominated the literature on human locomotor evolution at the expense of other behaviors with positive and negative fitness consequences. For example, although modern hunter-gatherers frequently climb trees to obtain important food resources in the canopy, these behaviors are seldom considered within the existing framework of primate positional behavior. As a result, inferences about the arboreal performance capabilities of fossil hominins based on a resemblance to humans may be more complicated than previously assumed. Here we use ethnographic reports of human tree climbing to critically evaluate hypotheses about the performance capabilities of humans in trees compared with other primates. We do so by reviewing the ecological basis of tree climbing behavior among hunter-gatherers and the diversity of human climbing techniques and styles. Results suggest that the biological and adaptive significance of human climbing has been underestimated, and that some humans are surprisingly competent in trees, particularly during vertical climbing and activities in the central core of trees. We conclude that while hominins evolved enhanced terrestrial locomotor performance through time, such shifts may have imposed only minor costs on vertical climbing abilities. The diversity of the locomotor repertoire of modern humans must therefore be taken into account when making form function inferences during the behavioral reconstruction of fossil hominins. PMID- 24630526 TI - Middle Pleistocene bifaces from Fengshudao (Bose Basin, Guangxi, China). AB - The Bose (also Baise) Basin in Guangxi, southern China is well known for the presence of Paleolithic bifacially worked implements. The Bose Basin handaxes came to the attention of the international scientific community primarily for two reasons: 1) the age at 803 ka (thousands of years), places it at the Early to Middle Pleistocene transition; and 2) the presence of bifaces tests the validity of the Movius Line and whether it was time to simply discard the model. However, questions were almost immediately raised because the age was based on the supposed association of Australasian tektites that may or may not have been redeposited, and at the time of the initial publications all of the Bose Basin handaxes were surface collected. Thus, whether the Bose bifaces can necessarily be associated with the tektites and whether the tektites themselves were redeposited are important considerations. Here, we report the findings from recent excavations from the Fengshudao site located in the Bose Basin. The primary findings are: 1) the in situ excavation of tektites, which do not appear to have been redeposited, in association with bifaces from one stratigraphic level from one site indicates that the age of these stone tools should be around 803 ka; 2) the Fengshudao hominins were utilizing locally-available quartz, quartzite, and sandstone river cobbles; and 3) in a number of aspects, the Fengshudao handaxe morphology differs from the typical western Acheulean, and are quite large and thick compared with even the bifaces from other regions of eastern Asia (e.g., Luonan Basin, China; Imjin/Hantan River Basins, Korea). Although Fengshudao may be a case of western Acheulean hominins dispersing into the Bose Basin from nearby South Asia, it is quite possible that the Fengshudao bifaces can be considered an example of convergent evolution. PMID- 24630528 TI - Loop de loop: viral RNA evades IFIT1 targeting. AB - In a landmark finding published in Science, Hyde et al. have demonstrated that a hairpin RNA structure adjacent to the 5' cap of alphavirus genomic RNA confers the ability of these viruses to evade restriction by the interferon-induced host protein IFIT1. PMID- 24630527 TI - Ordering microbial diversity into ecologically and genetically cohesive units. AB - We propose that microbial diversity must be viewed in light of gene flow and selection, which define units of genetic similarity, and of phenotype and ecological function, respectively. We discuss to what extent ecological and genetic units overlap to form cohesive populations in the wild, based on recent evolutionary modeling and on evidence from some of the first microbial populations studied with genomics. These show that if recombination is frequent and selection moderate, ecologically adaptive mutations or genes can spread within populations independently of their original genomic background (gene specific sweeps). Alternatively, if the effect of recombination is smaller than selection, genome-wide selective sweeps should occur. In both cases, however, distinct units of overlapping ecological and genotypic similarity will form if microgeographic separation, likely involving ecological tradeoffs, induces barriers to gene flow. These predictions are supported by (meta)genomic data, which suggest that a 'reverse ecology' approach, in which genomic and gene flow information is used to make predictions about the nature of ecological units, is a powerful approach to ordering microbial diversity. PMID- 24630529 TI - Caffeine supplementation during IVM improves frequencies of nuclear maturation and preimplantation development of dromedary camel oocytes following IVF. AB - Caffeine supplementation during oocyte IVM has been reported to improve preimplantation embryo development and the quality of in vitro-produced blastocysts in a range of species; but no studies have been done in camels. The present study investigated the effect of caffeine supplementation during dromedary camel oocyte IVM on nuclear maturation rates, IVF events, and subsequent preimplantation development. Cumulus-oocyte complexes obtained at slaughter were matured in vitro in caffeine supplemented medium either for 30 hours (caffeine 30 hours) or in the medium without caffeine supplement for 24 hours and then transferred to freshly prepared IVM medium supplemented with 10 mM caffeine for another 6 hours (caffeine 6 hours). Cumulus-oocyte complexes matured for 30 hours in the medium without caffeine supplement were used as a control. Matured oocytes were fertilized in vitro by epididymal spermatozoa of mature male camels collected from a local slaughterhouse. Eighteen hours after insemination, presumptive zygotes were cultured in modified KSOMaa medium for 7 days. Maturation and fertilization rates were significantly higher in the caffeine 6 hour group compared with the control group (P < 0.05), whereas IVM of oocytes in caffeine-supplemented medium for 30 hours did not affect these parameters (P > 0.05). Interestingly, IVM of oocytes in caffeine supplemented medium for 6 hours significantly (P < 0.05) increased the frequencies of blastocyst development by more than two-fold when compared with control (27.78% vs. 11.76%). In conclusion, culturing dromedary camel oocytes in maturation medium without caffeine for 24 hours and then in the medium supplemented with 10 mM caffeine for 6 hours during 30-hour IVM can significantly improve frequencies of nuclear maturation, fertilization rate, and subsequent preimplantation development. PMID- 24630530 TI - [Acute aortic dissection, the fundamentals of the history and physical examination]. PMID- 24630531 TI - [Breast cancer screening program in France: for optimization of the information]. AB - BACKGROUND: Based on international and national recommendations, organized breast cancer screening in France raises questions of medical ethics built around the key concepts of individual autonomy and public health policy. Because of the evolving knowledge, professionals and institutions involved in the program must review the ethical values associated with this medical practice. METHODS: The ethical aspects of organized breast cancer screening were studied. In response to newly acquired knowledge highlighted by a review of texts governing this practice in France, proposals for changes resulting from reflections of a working group coordinated by the National Cancer Institute are presented. RESULTS: Ethical issues raised by screening must find expression in the general principles of the program's organization: acceptability of screening, efficiency, adverse effects, equity of access, free care..., but also at different stages of the procedure: information delivery, first and second invitations, refusal of further diagnostic investigation... CONCLUSION: A better match between breast cancer screening and recently developed knowledge requires optimal information delivery to women targeted by the program as well as a stronger role for the referring healthcare professional. PMID- 24630532 TI - [Awareness disorders in Alzheimer's disease and in mild cognitive impairment]. AB - INTRODUCTION: Awareness disorders in Alzheimer's disease still remains unclear despite much research regarding this phenomenon. Papers report various and contrasted results with varying frequency from one study to another. Hence, the interest in awareness in Alzheimer's disease remains limited. Nevertheless, this symptom is closely associated with caregivers' burden and increases the patient's dependency, since the patient is unable to avoid dangers, requiring some care services or institutionalization The purpose of this current review is to recall the main neuro-anatomical and theoretical basis of awareness disorders, and to highlight the recent findings in Alzheimer's disease and in its pre-clinical stages. METHOD: With this in mind, we have conducted a non-exhaustive search using the pubmed online database to collect the most important reviews and the most recent findings regarding awareness disorders in Mild Cognitive Impairment (MCI) and/or in Alzheimer's disease. LITERATURE FINDINGS: In Alzheimer's disease, the links between awareness disorders and other variables, such as severity of dementia or depression, change from one study to the other and do not permit one to understand whether unawareness is an intrinsic or extrinsic reaction to the pathological process itself. Recent results suggest executive, cognitive and behavioral correlates more than psychopathological correlates, although the latter cannot be excluded. In Mild Cognitive Impairment, studies show varied results. Some studies report that patients suffering from Mild Cognitive Impairment can be compared to healthy control subjects and both groups have better awareness than patients with Alzheimer's disease. However, other studies show contrary results and awareness disorders might be a predictor of conversion from Mild Cognitive Impairment to dementia, as with apathy, in which the ability to cope with difficulties represents one of the main features. DISCUSSION: These controversial results are due to the heterogeneity of Alzheimer patients and in particular of MCI patients, but also to various conceptions of awareness disorders in Alzheimer's disease; none of them, however, taking into account all its diversity and complexity. Thus, neurological approaches underline neuropsychological dysfunctions linked to right frontal and/or hemispheric damage but are based on brain injury or strokes, which are events that differ greatly from a neurodegenerative disease involving progressive cognitive, emotional and social disturbances. Psychiatric approaches have taken into account the various aspects of insight, which before were often forbidden and reduced to a categorical point of view, and so could contribute to a better understanding of awareness disorders in Alzheimer's disease. However, these aspects have been conceptualized for psychiatric patients, suffering from positive symptoms, where compliance in treatment is the central key. Insight in neurological diseases is more focused on negative symptoms and generally concerns a basic perception of impairments in mainly cognitive domains. Moreover, modeling has often opposed neurological and psychological mechanisms, so awareness disorders are out of scope of a primary and secondary symptomatology. Although some authors have proposed to take into account these two mechanisms (unawareness and denial), clinical practice has shown that it was impossible to distinguish them both. Finally, some social cognitive approaches are able to demonstrate that there is no correlation between severity of dementia and awareness disorders. Nevertheless, the Self-concept, underlying this point of view, does not permit distinguishing neuropsychological from psycho-social factors. Moreover, only one evaluation tool based on Self-modeling in Alzheimer's disease exists, and to conceptualize Self in a specific pathology does not permit the comparison of this pathology to others or to healthy control subjects. So, the authors present the multidimensional model proposed by Clare et al., and some perspectives to stimulate future research, and perform potential meta-analyses. PMID- 24630533 TI - Irradiation of existing atherosclerotic lesions increased inflammation by favoring pro-inflammatory macrophages. AB - BACKGROUND AND PURPOSE: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE(-/-) mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. MATERIAL AND METHODS: ApoE(-/-) mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. RESULTS: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. CONCLUSIONS: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro inflammatory macrophages in the plaque. PMID- 24630534 TI - Evolution of treatment for nasopharyngeal cancer--success and setback in the intensity-modulated radiotherapy era. AB - BACKGROUND AND PURPOSE: To assess the therapeutic gains and setbacks as we evolved from the 2-dimensional radiotherapy (2DRT) to conformal 3-dimensional (3DRT) and to intensity-modulated (IMRT) era. MATERIALS AND METHODS: 1593 consecutive patients from 1994 to 2010 were retrospectively analyzed. Evolving changes in the different era included advances in staging investigation, radiotherapy technique, dose escalation, and use of chemotherapy. RESULTS: The 3DRT era achieved significant improvement in local failure-free rate (L-FFR), disease-specific survival (DSS) and overall survival (OS). Neurological damage and bone/soft tissue necrosis were significantly reduced. However, the improvement in distant failure-free rate (D-FFR) was insignificant, and more hearing impairment occurred due to chemotherapy. Significantly higher D-FFR was achieved in the IMRT era, but L-FFR did not show further improvement. 5-Year DSS increased from 78% in the 2DRT, to 81% in the 3DRT, and 85% in the IMRT era, while the corresponding neurological toxicity rate decreased from 7.4% to 3.5% and 1.8%. CONCLUSIONS: Significant improvement in survival and reduction of serious toxicity was achieved as we evolved from 2DRT to 3DRT and IMRT era; the therapeutic ratio for all T-categories improved with more conformal techniques. Improvements in tumor control were attributed not only to advances in RT technique, but also to better imaging and increasing use of potent chemotherapy. However, it should also be noted that hearing impairment significantly increased due to chemotherapy, L-FFR reached a plateau in the 3DRT era, and it is worrisome that the result for T4 remained unsatisfactory. Besides exploring for more potent chemotherapy and innovative methods, the guideline on dose constraint should be re-visited to optimize the therapeutic ratio. PMID- 24630535 TI - Integrating pretreatment diffusion weighted MRI into a multivariable prognostic model for head and neck squamous cell carcinoma. AB - INTRODUCTION: In head and neck squamous cell carcinoma (HNSCC) the ability to anticipate an individual patient's outcome is very valuable. With this study we wanted to assess the prognostic value of pretreatment apparent diffusion coefficient (ADC) in a large patient population and integrate it into a multivariable prognostic model. METHODS: From 2004 to 2010 175 patients with pathology proven HNSCC were included in this study. All patients underwent a pretreatment MRI with diffusion weighted imaging (DWI) using six b-values. For each tumor, three ADC values were calculated using different b-value combinations: ADC(low) (b 0-50-100 s/mm(2)), ADChigh (b 500-750-1000 s/mm(2)) and ADC(avg) (all b-values). The clinical and radiological variables included: tumor and nodal volume, tumor location and age. Disease recurrence was analyzed using competing risk regression. A prognostic model for disease recurrence was developed, and internal validation was performed using bootstrapping and by dividing patients in three equal sized groups based on prognosis. RESULTS: One hundred and sixty-one patients were eligible for analysis. Median follow-up was 50 months (range 4-86). A total of 67 patients experienced disease recurrence during follow-up (42%). ADC(high) was a prognostic factor for disease recurrence (adjusted hazard ratio: 1.14 per 10(-4) mm(2)/s, 95% CI 1.04-1.25). Harrell's c index of the multivariable prognostic model was 0.62 (95% CI 0.56-0.70) after internal validation. The validated 3-year disease recurrence rates for the groups with worst, intermediate, and best prognosis were 56%, 33% and 31% respectively. CONCLUSION: Pretreatment ADC value derived from high b-values is an independent prognostic factor in HNSCC and increases the performance of a multivariable prognostic model in addition to known clinical and radiological variables. Integration of other biomarkers and external validation is necessary to ensure its clinical applicability. PMID- 24630536 TI - Development and validation of a scoring system for late anorectal side-effects in patients treated with radiotherapy for prostate cancer. AB - PURPOSE: To develop and validate a scoring system for evaluation of long term anorectal dysfunction following radiotherapy for prostate cancer. MATERIALS AND METHODS: Patients treated for prostate cancer with radiotherapy filled in questionnaires on anorectal function and quality of life. Items for the condensed anorectal dysfunction score (RT-ARD) were identified and weighted by binomial regression analysis. The score was tested in a separate patient material by receiver operating characteristic (ROC) analysis and correlations to quality of life domains. RESULTS: A total of 309 patients participated in the study. The items selected were "incontinence for solid stool", "ability to defer defecation", "unproductive call to stool", "clustering of stool", and "mucus in stool." Patients were grouped into three categories according to the RT-ARD score; 0-8 (no RT-ARD), 9-23 (minor RT-ARD), 24-45 (major RT-ARD). ROC analyses revealed high sensitivity (91%) and specificity (85%) for major RT-ARD. The prediction model demonstrated a perfect fit in 60%, moderate fit in 36% and no fit in 4%. There was good correlation between the RT-ARD score and quality of life. CONCLUSIONS: The RT-ARD score is a validated and simple instrument for evaluation of anorectal dysfunction following radiotherapy for prostate cancer, and the RT-ARD score correlates to the patient's quality of life. PMID- 24630537 TI - Impact of post operative intensity modulated radiotherapy on acute gastro intestinal toxicity for patients with endometrial cancer: results of the phase II RTCMIENDOMETRE French multicentre trial. AB - PURPOSE/OBJECTIVE: Whole "conventional" pelvic irradiation (up to 45-50Gy) following hysterectomy is associated with a high rate of adverse gastro intestinal (GI) adverse events, of which around 60% correspond to acute grade 2 toxicity. The phase II RTCMIENDOMETRE trial was designed to test the hypothesis that IMRT could reduce the incidence of grade 2 or more acute GI toxicity to less than 30% in patients irradiated post-operatively for an endometrial cancer. MATERIALS/METHODS: Patients with post-operative stage Ib G3, Ic or II endometrial carcinomas with no history of chronic inflammatory bowel disease were eligible. Guidelines for volume delineation and dose prescription were detailed in the protocol. The investigators were advised to use a web-based atlas developed for the RTOG 0418 study. The dose of the vaginal and nodal PTV was 45Gy in 25 fractions. To assess the ability of the participating centres to comply with the protocol guidelines, they were requested to complete a dummy run procedure before inclusion of their 1st patient. GI and genito-urinary (GU) toxicity were graded according to the CTCAE V 3.0 classification and were prospectively recorded every week during irradiation, as well as at time of brachytherapy insertions and during the follow-up visit at week 15 (W15). Special attention was given to note any changes to the grade of adverse events between W5 and W15. RESULTS: From May 2008 to April 2010, 49 patients from 6 centres were recruited for the trial. One patient could not be treated, one patient died of vascular stroke at W3 without toxicity, and 1 patient refused to be followed-up after treatment. Thus, 46 cases were available for analysis at W15. The distribution by stage was as follows: Ib 16.3%, Ic 64.2%, II 20.4%. Thirty six patients (75%) received an additional vaginal vault boost of 6-10Gy delivered by HDR brachytherapy in 1 or 2 fractions. Among the 47 patients who completed IMRT, 27% (95% CI 14.5-39.7%) developed at least 1 GI grade 2 adverse event (diarrhoea in 92% of cases), which mainly occurred at W4 and W5. No event corresponding to grade 3 or above was recorded. At W15, the number of patients complaining about GI events was low: 5 patients complained about persistent grade 1 diarrhoea, and 4 patients complained about haemorrhoids. Nineteen percent (95% CI 8.9-32.6%) of patients experienced grade 2 cystitis or urinary frequency which had disappeared by W15. CONCLUSION: In accordance with our hypothesis, post-operative IMRT resulted in a low rate (less than 30%) of acute GI grade 2 toxicity, in patients with endometrial carcinomas. At W15, no patient demonstrated a grade 2 adverse event, and the prevalence of remaining grade 1 events was less than 20%. PMID- 24630539 TI - Dose-response relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance. AB - PURPOSE: To examine potential dose-response relationships with various non-small cell lung cancer (NSCLC) SBRT fractionation regimens delivered with online CT based image guidance. METHODS: 505 tumors in 483 patients with clinical stage T1 T2N0 NSCLC were treated with SBRT using on-line cone-beam-CT-based image guidance at 5 institutions (1998-2010). Median maximum tumor dimension was 2.6 cm (range 0.9-8.5 cm). Dose fractionation prescription was according to each institution's protocol with the most common schedules of 18-20 GyX3, 12 GyX4, 12 GyX5, 12.5 GyX3, 7.5 GyX8 (median = 54 Gy, 3 fractions). Median prescription (Rx) BED10 = 132 Gy (50.4-180). Median values (Gy) of 3D planned doses for BED10 were GTV(min) = 164.1, GTV(mean) = 188.4, GTV(max) = 205.9, PTV(min) = 113.9, PTV D99 = 123.9, PTV(mean) = 164.7, PTV D1 = 197.3, PTV(max) = 210.7. Mean follow-up = 1.6 years. RESULTS: 26 cases (5%) had local recurrence (LR) for a 2-year rate of 6% and 3 year rate of 9%. All BED10 GTV&PTV endpoints were associated with LR as continuous variables on univariate analysis (p<0.05). Rx and PTV(mean) dose appeared to have the highest correlation with LR with area under ROC curve of 0.69 and 0.65 respectively and optimal cut points of 105 and 125 Gy, respectively. 2-year LR was 4% for PTV(mean)>125 vs 17% for <125 Gy (p<0.01) with sensitivity = 84% and specificity = 57% for predicting LR. 2-year LR for Rx BED10>105 was 4% vs 15% for <105 Gy (p<0.01). Longer treatment duration (? 11 elapsed days) demonstrated a 2-year LR of 14% vs 4% for ? 10 days (p<0.01). GTV size was associated with LR on univariate analysis as a continuous variable (p = 0.02) with 2-year LR = 3% for <2.7 cm vs 9% for ? 2.7 cm (p = 0.03). BED10 (p = 0.01) and elapsed days during RT (p = 0.05) were independent predictors on multivariate analysis as continuous variables. CONCLUSIONS: There is a substantial dose-response relationship for local control of NSCLC following image guided SBRT with optimal PTV(mean) BED10>125 Gy. Shorter treatment duration was also associated with better local control in this dataset. PMID- 24630538 TI - Hyperfractionated Accelerated Radiotherapy (HART) with maintenance chemotherapy for metastatic (M1-3) Medulloblastoma--a safety/feasibility study. AB - BACKGROUND AND PURPOSE: To evaluate feasibility and toxicity of Hyperfractionated Accelerated Radiotherapy (HART) 1.24Gy b.i.d. followed by chemotherapy for M1-3 Medulloblastoma (MB). The aim of HART was to use hyperfractionation to improve therapeutic ratio combined with acceleration to minimise tumour cell repopulation during radiotherapy (RT). MATERIALS AND METHODS: Between February 2002 and May 2008, 34 eligible patients (22 male, 12 female) aged 3-15years (median 7) with metastatic MB (M1-9; M2-3, M3-22) received HART with a craniospinal radiotherapy (CSRT) dose of 39.68Gy followed by 22.32Gy boost to the whole posterior fossa and 9.92Gy metastatic boosts. The 8th and subsequent patients received vincristine (VCR) 1.5mg/m(2) weekly*8 doses over 8weeks starting during the 1st week of RT. Maintenance chemotherapy comprised 8 six-weekly cycles of VCR 1.5mg/m(2) weekly*3, CCNU 75mg/m(2) and cisplatin 70mg/m(2). RESULTS: Median duration of HART was 34days (range 31-38). Grade 3-4 toxicities included mucositis (8), nausea (10), anaemia (5), thrombocytopaenia (2), leucopaenia (24). With 4.5-year median follow-up, 3-year EFS and OS were 59% and 71%, respectively. Of 10 relapses, 1 was outside the central nervous system (CNS), 1 posterior fossa alone and 8 leptomeningeal with 3 also associated with posterior fossa. CONCLUSION: HART with or without VCR was well tolerated and may have a place in the multi modality management of high-risk MB. PMID- 24630540 TI - [Extrarespiratory manifestations of Mycoplasma pneumoniae: a case report]. AB - Extrapulmonary manifestations of Mycoplasma pneumoniae are sometimes severe and may even be life-threatening. A 10-year-old patient was hospitalized due to a flu like illness lasting 48 h with impaired general condition, after an extended stay in Africa. There was an inflammatory syndrome associated with hyponatremia, but malaria was negative. A triple antibiotic therapy with ceftriaxone, amikacin, and josamycin was started. The progression was marked by the appearance of hypoxemia pneumoniae associated with extrarespiratory manifestations. He initially presented with acute polyradiculoneuropathy, followed by thrombotic events associated with polyserositis, polyarthritis, a maculopapular rash, and then a hemophagocytic syndrome. Bacteriological samples isolated M. pneumoniae in nasopharyngeal secretions with a positive serology. The appropriate antibiotic therapy associated with corticosteroids and immunoglobulins led to clinical improvement and the patient progressed toward complete recovery. The pathogenesis of M. pneumoniae infection remains largely unknown. However, two main categories have been proposed. The lung injury is caused by the invasion of the respiratory epithelium, whereas the extrarespiratory manifestations are probably due to immunological disorders. The knowledge of extrarespiratory manifestations and their pathomechanisms allows further adjustments to therapeutic management. PMID- 24630541 TI - [Cerebral vasculopathy in pediatric sickle-cell anemia]. AB - In children with sickle-cell anemia, cerebral vasculopathy is a frequent and severe complication. It is attributed not only to erythrocyte sickling but also to multiple physiological modifications associated with sickle-cell anemia: platelet and leukocyte activation, endothelial injury and remodeling, coagulation activation, hemolysis and subsequent chronic inflammation, impaired vasomotricity, etc. Intracranial large-vessel remodeling leads to clinical cerebral infarction, whereas microvascular injury and impaired vasoreactivity lead to so-called silent infarcts, which are actually associated with impaired cognitive development. Primary prevention strategies have been developed to screen children for cerebral vasculopathy and to further reduce stroke risk. Annual transcranial Doppler beginning at 2 years of age is recommended, allowing risk stratification. Patients at high risk are enrolled in a monthly transfusion exchange program, which reduces the risk of a first stroke by 90 %. Chronic transfusion therapy has also demonstrated efficacy in preventing a second stroke, as a secondary prevention strategy. Lifelong treatment is recommended, as recurrent stroke has been observed when transfusion is discontinued. The burden of chronic transfusion is heavy for patients. Furthermore, several studies have shown that, despite preventing clinically symptomatic stroke, chronic transfusion therapy may not be effective concerning silent infarct progression. Other therapeutic options are currently being explored to obtain better protection with reduced side effects. PMID- 24630542 TI - [Nicolau syndrome after intramuscular injection]. AB - Nicolau syndrome is a rare, potentially severe complication that may occur after any drug injection, particularly after intramuscular injection. It is characterized by the acute onset of cutaneous and soft-tissue aseptic necrosis. Here, we report the case of a 14-year-old boy diagnosed with Nicolau syndrome on the right lower limb, after a benzathine-penicillin intramuscular injection for suspected rheumatic fever. The short-term progression was marked by uncomplicated rhabdomyolysis and the constitution of homolateral testicular torsion. The cutaneous-muscular disorders evolved favorably under symptomatic treatment. We discuss this insufficiently known complication of intramuscular injection, which may motivate reduced use of this route of drug administration in children and strict adherence to the procedure. Furthermore, it is important to note that Nicolau syndrome may evolve to homolateral testicular torsion, as, to the best of our knowledge, is reported for the first time in this case. PMID- 24630543 TI - Corticomotor excitability of arm muscles modulates according to static position and orientation of the upper limb. AB - OBJECTIVE: We investigated how multi-joint changes in static upper limb posture impact the corticomotor excitability of the posterior deltoid (PD) and biceps brachii (BIC), and evaluated whether postural variations in excitability related directly to changes in target muscle length. METHODS: The amplitude of individual motor evoked potentials (MEPs) was evaluated in each of thirteen different static postures. Four functional postures were investigated that varied in shoulder and elbow angle, while the forearm was positioned in each of three orientations. Posture-related changes in muscle lengths were assessed using a biomechanical arm model. Additionally, M-waves were evoked in the BIC in each of three forearm orientations to assess the impact of posture on recorded signal characteristics. RESULTS: BIC-MEP amplitudes were altered by shoulder and elbow posture, and demonstrated robust changes according to forearm orientation. Observed changes in BIC-MEP amplitudes exceeded those of the M-waves. PD-MEP amplitudes changed predominantly with shoulder posture, but were not completely independent of influence from forearm orientation. CONCLUSIONS: Results provide evidence that overall corticomotor excitability can be modulated according to multi-joint upper limb posture. SIGNIFICANCE: The ability to alter motor pathway excitability using static limb posture suggests the importance of posture selection during rehabilitation aimed at retraining individual muscle recruitment and/or overall coordination patterns. PMID- 24630544 TI - Influence of radial head prosthetic design on radiocapitellar joint contact mechanics. AB - HYPOTHESIS: Our aim was to test whether anatomically designed metallic radial head implants could better reproduce native radiocapitellar contact pressure and areas than nonanatomic implants. METHODS: The distal humerus and proximal radius from 6 cadaveric upper extremities were serially tested in supination with 100 N of compression force at 4 angles of flexion (0 degrees , 30 degrees , 60 degrees , and 90 degrees ). By use of a thin flexible pressure transducer, contact pressures and areas were measured for the native radial head, an anatomic implant, a nonanatomic circular monopolar implant, and a bipolar nonanatomic implant. The data (mean contact pressure and mean contact area) were modeled using a 2-factor repeated-measures analysis of variance with P <= .05 considered to be significant. RESULTS: The mean contact areas for the prosthetic radial heads were significantly less than those seen with the intact radial heads at every angle tested (P < .01). The mean contact pressures increased significantly with all prosthetic radial head types as compared with the native head. The mean contact pressures increased by 29% with the anatomic prosthesis, 230% with the monopolar prosthesis, and 220% with the bipolar prosthesis. Peak pressures of more than 5 MPa were more commonly observed with both the monopolar and bipolar prostheses than with the anatomic or native radial heads. CONCLUSIONS: The geometry of radial head implants strongly influences their contact characteristics. In a direct radius-to-capitellum axial loading experiment, an anatomically designed radial head prosthesis had lower and more evenly distributed contact pressures than the nonanatomic implants that were tested. PMID- 24630545 TI - A blinded, randomized, controlled trial assessing conservative management strategies for frozen shoulder. AB - BACKGROUND: There is little evidence for the optimal form of nonoperative treatment in the management of frozen shoulder. This study assesses the efficacy of current physiotherapy strategies. METHODS: All primary care referrals of frozen shoulder to our physiotherapy department were included during a 12-month period. Of these referrals, 17% met the inclusion criteria for primary idiopathic frozen shoulder. The 75 patients were randomly assigned to 1 of 3 groups: group exercise class, individual physiotherapy, and home exercises alone. A single independent physiotherapist, who was blinded to the treatment groups, made all assessments. Range of motion, Constant score, Oxford Shoulder Score, Short Form 36, and Hospital Anxiety and Disability Scale (HADS) outcome measures were performed at baseline, 6 weeks, 6 months, and 1 year. RESULTS: The exercise class group improved from a mean Constant score of 39.8 at baseline to 71.4 at 6 weeks and 88.1 at 1 year. There was a significant improvement in shoulder symptoms on Oxford and Constant scores (P < .001). This improvement was greater than with individual physiotherapy or home exercises alone (P < .001). The improvement in range of motion was significantly greater in both physiotherapy groups over home exercises (P < .001). HADS scores significantly improved during the course of treatment (P < .001). The improvement in HADS anxiety score was significantly greater in both physiotherapy intervention groups than in home exercises alone. CONCLUSIONS: A hospital-based exercise class can produce a rapid recovery from a frozen shoulder with a minimum number of visits to the hospital and is more effective than individual physiotherapy or a home exercise program. PMID- 24630546 TI - The influence of psychiatric comorbidity on perioperative outcomes after shoulder arthroplasty. AB - BACKGROUND: Psychiatric comorbidity has been associated with increased health risks and poor long-term treatment outcomes in numerous medical disciplines, but its effect in short-term perioperative settings is incompletely understood. The purpose of this study was to evaluate the influence of a preoperative diagnosis of depressive disorder, anxiety disorder, schizophrenia, or dementia on in hospital (1) adverse events, (2) blood transfusion, and (3) nonroutine discharge in patients undergoing shoulder arthroplasty. METHODS: Using the National Hospital Discharge Survey (NHDS) database, we identified 348,824 discharges having undergone partial or total shoulder arthroplasty from 1990 to 2007. Multivariable regression analysis was performed for each of the outcome variables. RESULTS: The prevalence of diagnosed depressive disorder was 4.4%, anxiety disorder, 1.6%; schizophrenia, 0.6%; and dementia, 1.5%. Preoperative psychiatric disorders, with the exception of schizophrenia, were associated with higher rates of adverse events. Depression and schizophrenia were associated with higher perioperative rates of blood transfusion. Any preoperative psychiatric illness was associated with higher rates of nonroutine discharge. CONCLUSIONS: Patients with preoperative psychiatric illness undergoing shoulder arthroplasty are at increased risk for perioperative morbidity and posthospitalization care. Preoperative screening of psychiatric illness might help with planning of shoulder arthroplasty. PMID- 24630547 TI - Assessment of medial elbow laxity by gravity stress radiography: comparison of valgus stress radiography with gravity and a Telos stress device. AB - BACKGROUND: Valgus instability was reported to be higher with the elbow in 60 degrees of flexion, rather than in 30 degrees of flexion, although there are no studies using valgus stress radiography by gravity (gravity radiography) with the elbow in 60 degrees of flexion. METHODS: Fifty-seven patients with medial elbow pain participated. For both elbows, valgus stress radiography by use of a Telos device (Telos radiography) and gravity radiography, with the elbow in 60 degrees of flexion, were performed for the assessment of medial elbow laxity. In both radiographs, the medial elbow joint space (MJS) on the affected side was compared with that on the opposite side, and the increase in the MJS on the affected side was assessed. RESULTS: For the Telos radiographs, the mean MJS was 4.7 mm on the affected side and 4.0 mm on the opposite side, with the mean increase in the MJS on the affected side being 0.7 mm. For the gravity radiographs, the mean MJS was 5.0 mm on the affected side and 4.2 mm on the opposite side, with the mean increase in the MJS on the affected side being 0.8 mm. There were significant correlations between the Telos and gravity radiographs in the MJS on the affected side, the MJS on the opposite side, and the increase in the MJS on the affected side (respectively, P < .0001). There was also a high level of intraobserver and interobserver reliability for the assessment of the gravity radiographs. CONCLUSIONS: Gravity radiography is useful for assessment of medial elbow laxity, similar to Telos radiography. PMID- 24630548 TI - The relationship between positive or negative phrasing and patients' coping with lateral epicondylitis. AB - BACKGROUND: Research suggests that phrases with negative content can affect patients' response to medical procedures and how they cope with medical illnesses. We hypothesized that patients with lateral epicondylitis who describe their condition in positive phrases cope better than those who do not. METHODS: We prospectively followed up 91 patients with lateral epicondylitis for 12 months. The patients indicated their baseline coping status based on the Pain Catastrophizing Scale (PCS) and were discharged with a wait-and-see policy. During follow-up interviews, the patients described the nature of their condition in their own words and were then categorized into either positive or negative phrasing groups. We compared these two groups regarding current coping status and whether they had sought additional treatment. We also analyzed for the factors associated with these outcomes. RESULTS: There were no significant differences in baseline PCS scores between the two groups. At follow-up, patients in the positive phrasing group (n = 62) had significantly lower PCS scores and were less likely to seek additional treatment than those in the negative phrasing group (n = 29). Multivariable analyses showed that positive phrasing and low pain levels were independently associated with improvement in PCS scores and that negative phrasing and depression were independently associated with patients' seeking additional treatment. CONCLUSION: Patients' positive phrasing about their condition are associated with improvement in their coping status and with less use of medical resources in the case of lateral epicondylitis. This study suggests that patients with more positive attitudes toward their illness cope and comply better when a wait-and-see treatment is recommended by their physicians. PMID- 24630549 TI - Low transcondylar fractures of the distal humerus: results of open reduction and internal fixation. AB - BACKGROUND: This study presents the outcomes of low transcondylar fractures of the distal humerus treated by open reduction and internal fixation. METHODS: Between 1996 and 2010, 263 distal humeral fractures were managed at our institution. Patients with a true low transcondylar fracture treated by open reduction and internal fixation were included. Fourteen patients form the basis of this study. Fracture fixation was achieved through a triceps-sparing approach, a triceps tongue, or an olecranon osteotomy. Internal fixation was performed with parallel plates, orthogonal plates, a single lateral plate, or a single medial plate. The clinical outcome was measured with pain levels, range of motion, and the Mayo Elbow Performance Score. Radiographs at latest follow-up were assessed for union, delayed union, nonunion, and hardware failure. RESULTS: At most recent follow-up, 11 patients had no pain, 2 had mild pain, and 1 had moderate pain. The mean Mayo Elbow Performance Score was 85. The mean arch of motion was 95 degrees . Complications included nonunion, delayed union, wound complications, deep infection, and heterotopic ossification. DISCUSSION: Stable internal fixation of low transcondylar fractures is perceived as difficult to achieve because of the very small size of the distal fragment. However, the results of our study indicate that internal fixation of low transcondylar fractures of the distal humerus is associated with a high union rate and satisfactory clinical results. Elbow arthroplasty does not need to be considered for most patients with a low transcondylar distal humeral fracture. PMID- 24630550 TI - Intra-articular osteotomy for malunited articular fractures of the distal end of the humerus. AB - BACKGROUND: The precarious anatomy of the articular surface of the distal humerus, as well as its meager subchondral bony support and limited soft-tissue attachments, presents enormous challenges for the operative correction of post traumatic intra-articular deformities. This study presents 8 patients who underwent articular osteotomy with a mean follow-up period of 10.6 years, with an emphasis on functional, patient-rated, and radiographic outcomes. METHODS: Eight patients (mean age, 39 years; range, 17-60 years) were followed up for a mean period of 10.6 years. The original fracture was a type C variant in 4 patients, a type B unicondylar fracture in 2, and a type B articular shearing fracture in 2. The initial injury was treated operatively in 5 patients and nonoperatively in 3. The osteotomy and reconstruction were performed on average 8 months after injury (range, 6-11 months). The mean preoperative elbow arc of motion was 37 degrees . Two patients had ulnar nerve dysfunction. RESULTS: All the osteotomies healed after the index procedure without evidence of avascular necrosis. Two patients required a second procedure for stiffness. At follow-up, the mean arc of elbow motion improved to 104 degrees (P = .001), with a mean flexion contracture of 26 degrees . The mean Disabilities of the Arm, Shoulder and Hand score at follow-up was 13 (range, 1-37); the mean patient satisfaction rating on a Likert scale (from 0 to 10) was 9.1; and the mean Mayo Elbow Performance Index score was 83 points (range, 70-100 points). Grade II osteoarthritic changes were seen in 3 patients, grade I in 3, and grade 0 in 2. CONCLUSIONS: In selected patients with a defined intra-articular malunion, the results of our experience support corrective osteotomy. PMID- 24630551 TI - Reconstruction of an elbow joint after blast injury by arthroplasty with a custom made modified total elbow prosthesis: a case report. PMID- 24630552 TI - Stress fractures of bilateral clavicles in an adolescent gymnast. PMID- 24630553 TI - Reverse shoulder arthroplasty glenoid fixation. PMID- 24630554 TI - Response "Reverse shoulder arthroplasty glenoid fixation". PMID- 24630555 TI - Regarding "Ligamentous repair of acute lateral collateral ligament rupture of the elbow". PMID- 24630556 TI - Survival kinetics of Listeria monocytogenes on raw sheep milk cured cheese under different storage temperatures. AB - Raw sheep milk cured cheese produced in the Castilla y Leon region (Spain) constitutes a traditional semi-hard aromatic cheese typically aged for three to six months. This product is catalogued as ready-to-eat since it is not submitted to any further treatment before consumption. Thus, foodborne pathogens such as Listeria monocytogenes can represent a health concern for susceptible consumers. This study was aimed at evaluating the survival of L. monocytogenes on raw sheep milk cured cheese under different storage temperatures. Log-linear+shoulder and Weibull type models were fitted to data observed in order to estimate kinetic parameters. The Arrhenius relationship was further used to predict the impact of temperature on L. monocytogenes behavior during storage at 4, 12 and 22 degrees C. Additionally, growth of lactic acid bacteria (LAB) as a representative group of the indigenous microbiota was evaluated. Results obtained indicated that the time to eradication (time when absence of L. monocytogenes in the analyzed samples was observed) was 114, 104, and 77 days for cheese samples stored at 4, 12 and 22 degrees C, respectively. The LAB population showed an increase at 12 and 22 degrees C during storage. However, an increase of 1 log CFU/g was observed during the first 2 weeks irrespectively of the storage temperature. The log linear+shoulder model indicated a good fit to observed data. Likewise, the Arrhenius relationship explained sufficiently the dependency of temperature on L. monocytogenes behavior. This study demonstrated that cheese storage at ambient temperatures could lead to the preservation of its quality properties as well as its safety against L. monocytogenes. PMID- 24630557 TI - Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agents. AB - Twenty six new pyrazoline substituted benzenesulfonylureas (2a-z) were synthesized and tested for in vitro anticancer activity. Fourteen derivatives (2i, 2k-2p, 2r, 2s-2x) were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Among them four compounds (2i, 2n, 2v and 2x) exhibited significant growth inhibition and further screened at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 MUM). The compounds 2i, 2n, 2v and 2x showed effective growth inhibition (GI50 MID) values of 2.62, 3.93, 3.33, 3.74 MUM respectively beside cytostatic activity TGI (MG-MID) values of 8.42, 65.80, 24.00 and 36.06 MUM respectively. The compound 2i displayed remarkable antiproliferative activity in 8 different cell lines with GI50 less than 2 MUM. Compounds 2n, 2v and 2x also displayed good antiproliferative activity against 11, 18 and 14 different cell lines respectively with GI50 less than 3 MUM. PMID- 24630559 TI - Efficient synthesis of novel glutamate homologues and investigation of their affinity and selectivity profile at ionotropic glutamate receptors. AB - A convenient synthesis of four new enantiomerically pure acidic amino acids is reported and their affinity at ionotropic glutamate receptors was determined. The new compounds are higher homologues of glutamic acid in which the molecular complexity has been increased by introducing an aromatic/heteroaromatic ring, that is a phenyl or a thiophene ring, that could give additional electronic interactions with the receptors. The results of the present investigation indicate that the insertion of an aromatic/heteroaromatic ring into the amino acid skeleton of glutamate higher homologues is well tolerated and this modification could be exploited to generate a new class of NMDA antagonists. PMID- 24630558 TI - Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase. AB - The goal of this research was to identify structurally novel, non quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme. PMID- 24630560 TI - Inhibitory effect of Rhus verniciflua Stokes extract on human aromatase activity; butin is its major bioactive component. AB - Rhus verniciflua Stokes has been used as a traditional herbal medicine in Asia. In this study, the effect of R. verniciflua extract on human aromatase (cytochrome P450 19, CYP19) activity was investigated to elucidate the mechanism for the effect of R. verniciflua extract on androgen hormone levels. Androstenedione was used as a substrate and incubated with R. verniciflua extract in cDNA-expressed CYP19 supersomes in the presence of NADPH, and estrone formation was measured using liquid chromatography-tandem mass spectrometry. R. verniciflua extract was assessed at concentrations of 10-1000 MUg/mL. The resulting data showed that R. verniciflua extract inhibited CYP19-mediated estrone formation in a concentration-dependent manner with an IC50 value of 136 MUg/mL. Subsequently, polyphenolic compounds from R. verniciflua extract were tested to identify the ingredients responsible for the aromatase inhibitory effects by R. verniciflua extract. As a result, butin showed aromatase inhibitory effect in a concentration-dependent manner with an IC50 value of 9.6 MUM, whereas the inhibition by other compounds was negligible. These results suggest that R. verniciflua extract could modulate androgen hormone levels via the inhibition of CYP19 activity and butin is a major ingredient responsible for this activity. PMID- 24630561 TI - Evaluation of structural effects on 5-HT(2A) receptor antagonism by aporphines: identification of a new aporphine with 5-HT(2A) antagonist activity. AB - A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and alpha1A adrenergic receptors. With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism. Compound 12b was the most potent 5-HT2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to alpha1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to alpha1A antagonism. PMID- 24630562 TI - Synthesis and evaluation of carbon-linked analogs of dual orexin receptor antagonist filorexant. AB - Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles. PMID- 24630563 TI - Synthesis and tripanocidal activity of ferrocenyl and benzyl diamines against Trypanosoma brucei and Trypanosoma cruzi. AB - Trypanosoma brucei and Trypanosoma cruzi are the etiologic agents of sleeping sickness and Chagas disease, respectively, two of the 17 preventable tropical infectious diseases (NTD) which have been neglected by governments and organizations working in the health sector, as well as pharmaceutical industries. High toxicity and resistance are problems of the conventional drugs employed against trypanosomiasis, hence the need for the development of new drugs with trypanocidal activity. In this work we have evaluated the trypanocidal activity of a series of N1,N2-dibenzylethane-1,2-diamine hydrochlorides (benzyl diamines) and N1-benzyl,N2-methyferrocenylethane-1,2-diamine hydrochlorides (ferrocenyl diamines) against T. brucei and T. cruzi parasite strains. We show that incorporation of the ferrocenyl group into the benzyl diamines increases the trypanocidal activity. The molecules exhibit potential trypanocidal activity in vitro against all parasite strains. Cytotoxicity assay was also carried out to evaluate the toxicity in HepG2 cells. PMID- 24630565 TI - Prevalence of Helicobacter pylori infection in Lanyu island. PMID- 24630564 TI - Synthesis and evaluation of new diaryl ether and quinoline hybrids as potential antiplasmodial and antimicrobial agents. AB - Synthesis and bioevaluation of new diaryl ether hybridized quinoline derivatives as antiplasmodial, antibacterial and antifungal agents is reported. It was encouraging to discover that several compounds displayed 2-3 folds better efficacy than chloroquine in chloroquine-resistant K1 strain of Plasmodium falciparum. Further, a few members of the library displayed good antibacterial efficacy against gram positive strains of bacteria but none of the compounds displayed any significant antifungal activity. PMID- 24630566 TI - Evidence-based health policy supported by science and technology research planning. PMID- 24630567 TI - Does the evidence say a 4-point change in ADAS-cog score is clinically significant? PMID- 24630568 TI - Open access, fauxpen access: problems in transparency and proposed solutions. PMID- 24630569 TI - A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1. AB - Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal. PMID- 24630570 TI - Neonatal seizures: aetiology by means of a standardized work-up. AB - Neonatal seizures are an alarming symptom and are frequent in neonates. It is important to find the cause of neonatal seizures to start a specific treatment and to give a meaningful prognosis. The aim of this study is to investigate the incidence of different aetiologies of neonatal seizures in our hospital by a specific work-up. METHODS: All full-term born neonates from January 2002 till September 2009 with neonatal seizures, admitted to our neonatal intensive care unit were included (n = 221). Aetiology was investigated by means of a standardized aetiologic work-up. RESULTS: The frequencies of aetiologies of neonatal seizures were: hypoxic-ischemic encephalopathy (HIE) (n = 119; 53.9%), metabolic or electrolyte disorders (n = 24; 10.9%), intracranial hemorrhage (n = 20; 9.0%), ischemic infarction (n = 16; 7.2%), intracranial infections (n = 14; 6.3%), congenital malformations of the central nervous system (n = 7; 3.2%), inborn errors of metabolism (n = 5; 2.3%), epileptic syndromes (n = 1; 0.5%), HIE + hypoglycemia (n = 4; 1.8%), HIE + intracranial hemorrhage (n = 3; 1.4%), HIE + ischemic infarction (n = 1; 0.5%), ischemic infarction + intracranial hemorrhage (n = 1; 0.5%), idiopathic (n = 4, 1.8%), intoxications (n = 1; 0.5%) and unknown (n = 1; 0.5%). CONCLUSION: Our work-up is a practical tool to find the aetiology of neonatal seizures. PMID- 24630571 TI - Sling exposure after treatment of urinary incontinence with sub-urethral transobturator slings. AB - OBJECTIVE: Sub-urethral slings are the "gold standard" when treating female urinary incontinence, but placing the prosthetic material has its own specific complication, exposure. STUDY DESIGN: A retrospective study was performed on all patients who had a sub-urethral sling (TVT-O or TVT Secur) in Lille University Hospital Centre from 2006 to 2008. Follow-up was undertaken to look for re intervention and to try to determine the risk factors. RESULTS: A total of 386 patients were studied with a median follow-up of 4 years. The rate of exposure was 4.32%. TVT Secur gave rise to more exposures (13.79%) than TVT-O (3.51%) (p=0.0203). Association with Prolift for cure of prolapse significantly reduced the rate of exposure of sub-urethral slings (p=0.0161). CONCLUSIONS: It seems important not to use mini-slings of the TVT Secur type as they induce a higher rate of prosthetic exposure. Cure of urinary incontinence may be done with cure of prolapse at the same surgical operation without higher risk of exposure. PMID- 24630572 TI - Does flushing the endometrial cavity with follicular fluid after oocyte retrieval affect pregnancy rates in subfertile women undergoing intracytoplasmic sperm injection? A randomized controlled trial. AB - OBJECTIVE: Follicular fluid of mature oocytes is rich in growth factors and cytokines that may exert paracrine and autocrine effects on implantation. The aim of this study was to investigate if flushing the endometrial cavity with follicular fluid after oocyte retrieval improved pregnancy rates in subfertile women undergoing intracytoplasmic sperm injection (ICSI). STUDY DESIGN: One hundred subfertile women undergoing ICSI between April 2012 and September 2012 at the centre for reproductive medicine, Cairo University, Egypt were enrolled in this open label, parallel randomized controlled study. Patients were randomized into two groups at the start of treatment using a computer-generated programme and sealed opaque envelopes: the follicular fluid group (n=50) and the control group (n=50). Inclusion criteria were: age 20-38 years; basal follicle stimulating hormone <10mIU/ml; body mass index <35kg/m(2); and ostradiol >1000pg/ml and <4000pg/ml on the day of human chorionic gonadotrophin administration. Exclusion criteria were: evidence of endometriosis; uterine myoma; hydrosalpinges; endocrinological disorders; history of implantation failure in previous in-vitro fertilization/ICSI cycles; and severe male factor infertility. RESULTS: Clinical pregnancy and implantation rates were higher in the follicular fluid group compared with the control group [354% (17/48) vs 319% (15/47); p=0718] and (18.6% vs 11.3%; p=0.153), respectively. However, the difference was not statistically significant. CONCLUSION: Flushing the endometrial cavity with follicular fluid after oocyte retrieval neither improved nor adversely affected clinical pregnancy and implantation rates in subfertile women undergoing ICSI. PMID- 24630573 TI - The dynamics of serum anti-Mullerian-hormone levels during controlled ovarian hyperstimulation with GnRH-antagonist short protocol in polycystic ovary syndrome and low responders. AB - OBJECTIVE: To determine whether the decrease in AMH levels during ovarian hyperstimulation for IVF occurs in patients with polycystic ovary syndrome (PCOS) and patients with low ovarian reserve (LOR), as in normal cycling women. STUDY DESIGN: A cohort of 22 infertile patients treated in a single tertiary center with a GnRH-antagonist short protocol for IVF were prospectively included and divided into three groups: PCOS with hyperandrogenism (n=7), LOR (n=8) and control (n=7). Serum AMH levels were measured before and during FSH treatment, on the day of HCG administration, at the mid-luteal phase, and 14 days after embryo transfer. The three groups were compared using an ANOVA model in the case of continuous data and with Fisher's exact test when the data were discrete. RESULTS: In the PCOS group, AMH levels increased at the beginning of the stimulation, but later decreased, until the mid-luteal stage. In the other two groups, AMH levels decreased throughout ovarian stimulation until the mid-luteal stage. In all groups, AMH levels returned to baseline levels two weeks after HCG administration, regardless of treatment outcome (pregnancy or not). CONCLUSIONS: AMH levels decline during controlled ovarian hyperstimulation with a GnRH antagonist short protocol in women with low and normal ovarian reserves. In contrast, in women with PCOS, an increase in AMH levels precedes this decline. These findings may support the hypothesis that androgens may play a role in AMH regulation in women. PMID- 24630574 TI - Authors' response: nuchal cord and cesarean delivery in China. PMID- 24630575 TI - Mapping new territory: emerging challenges in cervical cancer prevention. PMID- 24630576 TI - Assessment of Ethidium bromide and Ethidium monoazide bromide removal from aqueous matrices by adsorption on cupric oxide nanoparticles. AB - The present study was undertaken to develop an effective adsorbent and to study the adsorption of Ethidium bromide and Ethidium monoazide bromide from aqueous solution using the CuO nanoparticles. The characteristics of CuO nanoparticles were determined and found to have a surface area 89.59m(2)/g. Operational parameters such as pH, contact time and adsorbent concentration, initial concentration and temperature were also studied. The amount of removal increases with the increase in pH from one to seven and reaches the maximum when the pH is nine. Adsorption data fitted well with the Langmuir, Freundlich and Florry Huggins models. The results show that the best fit was achieved with the Langmuir isotherm equation with maximum adsorption capacities of 0.868 and 0.662mg/g for Ethidium bromide and Ethidium monoazide bromide, respectively. The adsorption process was found to follow pseudo-second-order kinetics. The calculated thermodynamic parameters, namely DeltaG, DeltaH and DeltaS showed that adsorption of Ethidium bromide and Ethidium monoazide bromide was spontaneous and endothermic under examined conditions. PMID- 24630577 TI - [Analysis of the results of the SEIMC External Quality Control Program. Year 2012]. AB - The External Quality Control Program of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) include controls for bacteriology, serology, mycology, parasitology, mycobacteria, virology and molecular microbiology. This article presents the most relevant conclusions and lessons from the 2012 controls. As a whole, the results obtained in 2012 confirm the excellent skill and good technical standards found in previous editions. However, erroneous results can be obtained in any laboratory and in clinically relevant determinations. Once again, the results of this program highlighted the need to implement both internal and external controls in order to assure the maximal quality of the microbiological tests. PMID- 24630578 TI - [Analysis of the results of the HIV-1, HCV and HBV viral load of SEIMC External Quality Control Program. Year 2012]. AB - Human immunodeficiency virus type 1 (HIV-1) and hepatitis B (HBV) and C virus (HCV) viral load determinations are among the most relevant markers for the follow up of patients infected with these viruses. External quality control tools are crucial to ensure the accuracy of results obtained by microbiology laboratories. This article summarized the results obtained from the 2012 SEIMC External Quality Control Programme for HIV-1, HCV, and HBV viral loads. In the HIV-1 program, a total of five standards were sent. One standard consisted in seronegative human plasma, while the remaining four contained plasma from three different viremic patients, in the range of 2-5 log10 copies/mL; two of these standards were identical aiming to determine repeatability. A significant proportion of the laboratories (22.3% on average) obtained values out of the accepted range (mean+/-0.25 log10 copies/mL), depending on the standard and on the method used for quantification. Repeatability was excellent, with up to 98.9% of laboratories reporting results within the limits (Delta < 0.5 log10 copias/mL). The HBV and HCV program consisted of two standards with different viral load contents. Most of the participants, 84% in the case of HCV and 88% in the HBV, obtained all the results within the accepted range (mean+/-1.96 SD log10 UI/mL). Data from this analysis reinforce the utility of proficiency programmes to ensure the quality of the results obtained by a particular laboratory, as well as the importance of the post-analytical phase on the overall quality. Due to the remarkable interlaboratory variability, it is advisable to use the same method and the same laboratory for patient follow up. PMID- 24630579 TI - [Infection by human cytomegalovirus]. AB - Prevalence of human cytomegalovirus infection is very high worldwide. Following primary infection, the virus remains latent, being able to cause recurrences either by reinfection with a new strain or by reactivation of the replication of the latent virus. The most severe disease is seen in congenital infection and in immunosuppressed patients, in whom the virus act as an opportunistic pathogen. Serological techniques are the methods of choice in primary infection and to determine the immune status against CMV in organ donor and receptor. Although well-standardized studies are lacking, the recent commercial availability of methods that measure cellular immune response are promising to predict the risk of CMV disease in immunosuppressed individuals. Molecular assays, that have gradually been substituting viral culture and/or antigen detection, are the most widely used methods for the diagnosis and control of CMV infection. PMID- 24630580 TI - [Antimicrobial susceptibility testing of anaerobic bacteria]. AB - The anaerobic bacteria resistance to antibiotics is increasing, and even has appeared against the most active of those, like metronidazol and carbapenems. This fact forces to make and periodical sensibility tests -at least in the most aggressive and virulent species, in cases that they are isolated from life locations and in the absence of therapeutic response- to check the local sensibility and to establish suitable empiric therapies, all based on multicentric studies carried out in order to this or well to check the activity of new antibiotics. For the laboratory routine, the easiest sensibility method is the E-test/MIC evaluator. Another alternative is microdilution, that's only normalized for Bacteroides. There are preliminary facts that allow the use of disc diffusion method in some species of Bacteroides and Clostridium. For the temporal and multicentric studies, the procedure is dilution in agar plate, the reference method. PMID- 24630581 TI - [Importance of quality control for the detection of beta-lactam antibiotic resistance in Enterobacteriaceae]. AB - beta-lactam antimicrobial agents are frequently used to treat infections caused by Enterobacteriaceae. The main mechanism of resistance to these antibiotics is the production of certain enzymes, collectively named beta-lactamases. Due to their substrate profile and their epidemiological implications, the most clinically important beta-lactamases are extended-spectrum beta-lactamases, class C beta-lactamases and carbapenemases. Phenotypic detection of these enzymes may be complicated and is based on the use of specific inhibitors of each beta lactamase and on the loss of activity on some beta-lactam indicators. Various international committees postulate that it is no longer necessary to interpret the susceptibility results or determine the mechanism of resistance. Several critics disagree, however, and consider that susceptibility results should be interpreted until more data are available on the clinical efficacy of treatment with beta-lactams. Given these methodological difficulties and constant changes in the interpretation criteria, we consider that training and external quality controls are essential to keep updated in this field. For learning purposes, these external quality controls should always be accompanied by a review of the results and methodology used, and the analysis of errors. In this paper we review and contextualize all the aspects related to the detection and interpretation of these beta-lactamases. PMID- 24630582 TI - [Lyme disease]. AB - Lyme disease (LD) is a worldwide-distributed multisystemic process caused by Borrelia burgdorferi sensu lato (s.l.) and transmitted by hard ticks. In fact, it is the most common tick-borne infectious disease in the northern hemisphere. In Spain it is transmitted by Ixodes ricinus ticks and Borrelia garinii is the genoespecies of B. burgdorferi s.l. mostly involved in our area. LD is known as "the last great imitator" due to the broad clinical spectrum that may cause. Except in the case of erythema migrans (pathognomonic feature of the disease), the remaining clinical manifestations should be confirmed using microbiological tests. This review is intended to provide readers a current vision of the etiology, epidemiology, clinical manifestations, laboratory diagnosis and treatment of Lyme disease in our environment. Controversial aspects arising from the use of non-validated microbiological tests that are being used without scientific rigor are highlighted. PMID- 24630584 TI - [Microbiological diagnosis of viral respiratory infections in the adult patient]. AB - Conventional techniques for the diagnosis of respiratory viruses are still being used, although molecular methods are now considered as a gold standard in this field. Molecular techniques have a great number of advantages such as an excellent sensitivity, specificity, adaptability to emerging viruses, capability for multiplex and for automation. With all the available repertoire of techniques for microbiological diagnosis, the knowledge relative to respiratory viruses is growing up not only for new aetiological agents but also for its epidemiology. The advances in molecular and non-molecular fast diagnostic methods for one or more respiratory viruses allow quick decisions in the management of the patient. However, there are also disadvantages. The great sensitivity of molecular techniques has meant a significant increase in the rate of multiple detections of respiratory viruses, whose clinical involvement is difficult to interpret. Finally, it remains to show whether the use of new techniques, of high cost, in the microbiological routine diagnosis of acute respiratory viral infections in the hospitalized patient, is cost effective. PMID- 24630583 TI - [Reemergence of measles. Epidemic situation in the Valencian Community during the years 2011 and 2012]. AB - Measles incidence declined until becomes a sporadic reporting and infrequent notification in the last decade. The reemergence of the disease reached 744 cases in 2012, a rate of 14.50*10(5) inhabitants. A classic design in Public Health Surveillance was performed: retrospective analysis of cumulative incidence and characteristics of the affected subjects. Those dates were in record linkage with Valencia Microbiology Network (RedMIVA). Finally, 976 cases of measles were confirmed in 2011-2012 epidemic period. Time-line distribution shows three waves with amplitude length on 12-15 weeks. Proportion of unvaccinated or unknown subjects came up to 85% of cases. 25 outbreaks were reported, 499 cases associated. In 7 of the 10 community outbreaks early cases were from Roma population unvaccinated. In the city of Valencia was applied post-exposure prophylaxis in 32 schools and was observed low coverage: between 63% and 77% in 8 schools and less than 50% in 4. Serum negative rate was 12.4% and we highlight the rate under 16 months: 44.8%. Cohorts of 20-59 years had negative rates between 13.5 to 5.9%. The origin of the epidemic was the importation of cases to a territory with inadequate immune protection against measles. Its impact and development was conditioned by previous immunization coverage, the social and ethnic pattern of different areas or quarters and the extensive application of post-exposure prophylaxis at school and family contacts of cases. PMID- 24630585 TI - [Paradoxical cutaneous reactions associated with tocilizumab therapy]. AB - INTRODUCTION: Tocilizumab (TCZ) is a humanized antihuman interleukin (IL)-6 receptor antibody recommended for the treatment of moderate to severe active rheumatoid arthritis, adult-onset Still disease, Castleman disease and more recently, systemic juvenile idiopathic arthritis. Like anti-TNFalpha, rituximab and less frequently abatacept, TCZ can induce paradoxical cutaneous eruption like psoriasis with predominantly palmoplantar presentation. CASE REPORT: We report a 47-year-old woman with psoriastic arthritis who developed under anti-TNFalpha therapy and later under tocilizumab a paradoxical palmoplantar eruption. CONCLUSION: The specific underlying mechanisms of this side effect are unclear but relapse of these lesions seems to be observed with certain biological agents. PMID- 24630586 TI - [Obstructive sleep apnea syndrome: a cause of cognitive disorders in the elderly?]. AB - Obstructive sleep apnea syndrome is a chronic disease characterized by repeated upper airway obstructions during sleep, resulting in fragmented sleep with arousals, nocturnal intermittent hypoxemia and diurnal dysfunctions. Despite its high prevalence in elderly, sleep apnea syndrome seems to be underestimated and difficult to be recognized because of the lack of clinical symptoms specificity in this population. Among the numerous consequences of the obstructive sleep apnea syndrome, cognitive impairment prevails on the attention, executive functions and memory. Neuroimaging studies in human and experimental models allowed to highlight neural correlates of these cognitive dysfunctions in obstructive sleep apnea syndrome. The obstructive sleep apnea syndrome with cognitive impairment shares some features with Alzheimer's disease, involving genetic predisposition ApoE4, hippocampus and synaptic plasticity abnormalities. In this context, the question arises whether obstructive sleep apnea syndrome is a possible etiological or aggravating factor of cognitive decline in elderly with mild cognitive impairment or Alzheimer's disease. Although there are conflicting results in studies evaluating therapeutic efficiency of continuous positive air pressure, obstructive sleep apnea syndrome seems nevertheless as a correctable factor, at least for its impact on some cognitive consequences. Looking for sleep apnea syndrome in elderly with cognitive decline should be considered in a global, diagnosis and therapeutic management. PMID- 24630587 TI - [Combined variable immunodeficiency with unusal features. A case report]. AB - INTRODUCTION: The association granulomatosis - combined variable immunodeficiency (CVID) - is well known from the clinicians. However, the association with a large granular lymphocyte (LGL) leukemia has not been yet reported. CASE REPORT: We report a 50-year-old woman, followed for CVID associated with a granulomatous disease. During the follow-up, the patient developed a granulomatous lymphocytic interstitiel lung disease (GLILD). Secondarily, she presented a LGL leukemia. CONCLUSION: To our knowledge, this is the first reported case of an association between CVID and LGL leukemia. PMID- 24630588 TI - [Cost of systemic lupus erythematosus for adult patients with active and treated disease in France (LUCIE study)]. AB - PURPOSE: To evaluate in France the annual direct medical cost of adult patients with active systemic lupus erythematosus (SLE) on medication and estimate the cost of a flare. METHODS: A two-year, observational, retrospective, multicenter study, carried out between December 2010 and February 2011. Patients' characteristics, SLE disease activity and severity, rate of flares, healthcare consumption (medications, hospitalisations, etc.) were evaluated. Medical costs were assessed from the national Health Insurance perspective. Cost predictors were estimated using multivariate regression models. RESULTS: Eight centres specialized in SLE management included 93 eligible patients (including 50.5% severe). The mean age was 39.9 (11.9) years and 93.5% were women. At baseline, the mean SLE duration was 9.8 (6.6) years. The mean scores of the SELENA-SLEDAI instrument and the SLICC/ACR index were higher in severe patients (9.8 vs 5.6, and 1.2 vs 0.4 respectively; P<0.001). Over the study period, 51% of patients received the combination containing at least corticosteroids or immunosuppressants. The mean annual direct medical cost of severe patients was ?4660 versus ?3560 for non-severe patients (non-significant difference). The cost of medications (61.8% of the annual cost) was higher in severe patients (?3214 vs ?1856; P<0.05). Immunosuppressants and biologics represented 26.5% and 4.6% of the annual total cost respectively. Patients experienced on average 1.10 (0.59) flares/year, of which 0.50 were severe flare. The occurrence of a new severe flare incremented the annual cost of ?1330 (P<0.05). CONCLUSION: Medications represented the major component of the annual direct medical cost. Severe flares increase significantly the cost of SLE care management. PMID- 24630589 TI - Natural and anthropogenic aerosols in the Eastern Mediterranean and Middle East: possible impacts. AB - The physical and chemical properties of airborne particles have significant implications on the microphysical cloud processes. Maritime clouds have different properties than polluted ones and the final amounts and types of precipitation are different. Mixed phase aerosols that contain soluble matter are efficient cloud condensation nuclei (CCN) and enhance the liquid condensate spectrum in warm and mixed phase clouds. Insoluble particles such as mineral dust and black carbon are also important because of their ability to act as efficient ice nuclei (IN) through heterogeneous ice nucleation mechanisms. The relative contribution of aerosol concentrations, size distributions and chemical compositions on cloud structure and precipitation is discussed in the framework of RAMS/ICLAMS model. Analysis of model results and comparison with measurements reveals the complexity of the above links. Taking into account anthropogenic emissions and all available aerosol-cloud interactions the model precipitation bias was reduced by 50% for a storm simulation over eastern Mediterranean. PMID- 24630590 TI - Impacts of food web structure and feeding behavior on mercury exposure in Greenland Sharks (Somniosus microcephalus). AB - Benthic and pelagic food web components in Cumberland Sound, Canada were explored as sources of total mercury (THg) to Greenland Sharks (Somniosus microcephalus) via both bottom-up food web transfer and top-down shark feeding behavior. Log10THg increased significantly with delta(15)N and trophic position from invertebrates (0.01 +/- 0.01 MUg . g(-1) [113 +/- 1 ng . g(-1)] dw in copepods) to Greenland Sharks (3.54 +/- 1.02 MUg . g(-1)). The slope of the log10THg vs. delta(15)N linear regression was higher for pelagic compared to benthic food web components (excluding Greenland Sharks, which could not be assigned to either food web), which resulted from THg concentrations being higher at the base of the benthic food web (i.e., in benthic than pelagic primary consumers). However, feeding habitat is unlikely to consistently influence shark THg exposure in Cumberland Sound because THg concentrations did not consistently differ between benthic and pelagic shark prey. Further, size, gender and feeding behavior (inferred from stable isotopes and fatty acids) were unable to significantly explain THg variability among individual Greenland Sharks. Possible reasons for this result include: 1) individual sharks feeding as generalists, 2) high overlap in THg among shark prey, and 3) differences in turnover time between ecological tracers and THg. This first assessment of Greenland Shark THg within an Arctic food web revealed high concentrations consistent with biomagnification, but low ability to explain intra-specific THg variability. Our findings of high THg levels and consumption of multiple prey types, however, suggest that Greenland Sharks acquire THg through a variety of trophic pathways and are a significant contributor to the total biotic THg pool in northern seas. PMID- 24630591 TI - Language, motor and cognitive development of extremely preterm children: modeling individual growth trajectories over the first three years of life. AB - Survival rate of extremely low gestational age (ELGA) newborns has increased over 80% in the last 15 years, but its consequences on the short- and longer-term developmental competencies may be severe. The aim of this study was to describe growth trajectories of linguistic, motor and cognitive skills among ELGA children, compared to full-term (FT) peers, from the first to the third year of life, a crucial period for development. Growth curve analysis was used to examine individual and group differences in terms of initial status at 12 months and rate of growth through the second and the third year of life with five points of assessment. Twenty-eight monolingual Italian children, of whom 17 were ELGA (mean GA 25.7 weeks) and 11 were FT children, were assessed through the BSID-III at 12, 18, 24, 30 and 36 months for language skills and at 12, 24 and 30 months for motor and cognitive skills. ELGA children presented significantly lower scores than FT peers in language, motor and cognitive skills and they did not overcome their disadvantage by 3 years, even if their corrected age was taken into account. Concerning growth curves, in motor development a significant increasing divergence was found showing a Matthew effect with the preterm sample falling further behind the FT sample. In linguistic and cognitive development, instead, a stable gap between the two samples was found. In addition, great inter-individual differences in rate of change were observed for language development in both samples. Our findings highlight the theoretical and clinical relevance of analyzing, through growth curve analyses, the developmental trajectories of ELGA children in language skills taking into account their inter-individual variability also across motor and cognitive domains. LEARNING OUTCOMES: After reading this article, the reader will interpret: (a) characteristics and growth trajectories of ELGA children from the first to the third year of life with respect to FT children in language, motor and cognitive development; (b) the method of growth curve analyses to describe group as well as inter-individual trajectories; (c) the rate of inter-individual variability in language as well as motor and cognitive skills, which gives useful indications for early interventions. PMID- 24630592 TI - Syntactic bootstrapping in children with Down syndrome: the impact of bilingualism. AB - PURPOSE: The purpose of the study was to add to our knowledge of bilingual learning in children with Down syndrome (DS) using a syntactic bootstrapping task. METHOD: Four groups of children and youth matched on non-verbal mental age participated. There were 14 bilingual participants with DS (DS-B, mean age 12;5), 12 monolingual participants with DS (DS-M, mean age 10;10), 9 bilingual typically developing children (TD-B; mean age 4;1) and 11 monolingual typically developing children (TD-M; mean age 4;1). The participants completed a computerized syntactic bootstrapping task involving unfamiliar nouns and verbs. The syntactic cues employed were a for the nouns and ing for the verbs. RESULTS: Performance was better on nouns than verbs. There was also a main effect for group. Follow-up t-tests revealed that there were no significant differences between the TD-M and TD-B or between the DS-M and DS-B groups. However, the DS-M group performed more poorly than the TD-M group with a large effect size. Analyses at the individual level revealed a similar pattern of results. CONCLUSION: There was evidence that Down syndrome impacted performance; there was no evidence that bilingualism negatively affected the syntactic bootstrapping skills of individuals with DS. These results from a dynamic language task are consistent with those of previous studies that used static or product measures. Thus, the results are consistent with the position that parents should be supported in their decision to provide bilingual input to their children with DS. LEARNING OUTCOMES: Readers of this article will identify (1) research evidence regarding bilingual development in children with Down syndrome and (2) syntactic bootstrapping skills in monolingual and bilingual children who are typically developing or who have Down syndrome. PMID- 24630593 TI - SMN1 duplications contribute to sporadic amyotrophic lateral sclerosis susceptibility: evidence from a meta-analysis. AB - OBJECTIVE: To investigate the association between SMN1 and SMN2 copy number variations (CNVs) and sporadic amyotrophic lateral sclerosis (SALS) by a meta analysis. METHODS: Through searching PubMed and EMBASE database (or manual searching) up to November 2013 using the following keywords: "survival motor neuron gene", "SMN", and "amyotrophic lateral sclerosis", "ALS" or "motor neuron disease". Nine studies were identified as eligible for this meta-analysis. The association between SMN genes and the SALS risk was investigated based on SMN1 and SMN2 CNVs. The heterogeneity across the studies was tested, as was publication bias. RESULTS: The analysis showed significant association for SMN1 duplications in SALS risk: the risk estimates were OR=1.76, 95%CI=1.33-2.32, p<0.0001 (still significant when the p value was Bonferroni adjusted to 0.01). However, there was no significant association between SMN1 deletions and SALS risk after Bonferroni correction (OR=1.78, 95%CI=1.02-3.11, p=0.04). In addition, SMN2 copy number statuses were not associated with SALS in our pooled study. No evidence of publication bias was observed. CONCLUSION: Our meta-analysis suggested that SMN1 duplications are a genetic risk factor in SALS, while there was no modulator effect of the SMN2 gene. In addition, it was possible that SMN1 deletions in predisposition to SALS vary across different countries. More studies were required to warrant the findings of this study. PMID- 24630594 TI - Does Tropheryma whipplei contribute to travelers' diarrhea?: A PCR analysis of paired stool samples in French travelers to Senegal. AB - BACKGROUND: Tropheryma whipplei was recently associated with acute infections as gastroenteritis in children. We hypothesize that T. whipplei may be a contributing microbe in traveler's diarrhea. METHOD: The presence of T. whipplei was investigated by using a specific PCR on stool samples of travelers to Senegal before and after traveling, independently of the occurrence of diarrhea. RESULTS: A total of 59 travelers returned both stool samples before and after travel and 16 (27%) experienced diarrhea during travel. Fifty-three patients (89.8%) were negative for T. whipplei before and after travel. Two patients (3.4%) were negative before and positive after travel. Two patients (3.4%) were positive before travel and negative after travel. Finally, two patients (3.4%) were positive before and after travel. There were no carriage differences of T. whipplei, visiting Senegal or staying in France. We found no significant association of T. whipplei carriage and travel-associated diarrhea but this may have been impacted by the use of doxycycline. CONCLUSIONS: This is the first report of T. whipplei carriage acquired during travel to tropical area. Further study addressing this issue in larger cohorts of travelers to Senegal, including individuals visiting friends and relatives in their country of origin and the protective role of doxycycline malaria chemoprophylaxis may help to understand the potential contribution of T. whipplei to travelers' diarrhea. PMID- 24630595 TI - Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. AB - Pneumocystis jirovecii is the only fungus of its kind to be pathogenic in humans. It is primarily responsible for pneumonia (PJP). The key to understanding immune defences has focused on T-cells, mainly because of the HIV infection epidemic. Patients presenting with PJP all have a CD4 count below 200/mm(3). The introduction of systematic primary prophylaxis and the use of new anti-retroviral drugs have significantly reduced the incidence of this disease in the HIV infected population, mainly in developed countries. The increasingly frequent use of corticosteroids, chemotherapy, and other immunosuppressive drugs has led to an outbreak of PJP in patients not infected by HIV. These patients presenting with PJP have more rapid and severe symptoms, sometimes atypical, leading to delay the initiation of a specific anti-infective therapy, sometimes a cause of death. However, the contribution of new diagnostic tools and a better understanding of patients at risk should improve their survival. PMID- 24630596 TI - [Diagnosing a case of disseminated histoplasmosis with a blood smear]. PMID- 24630597 TI - Impact of 2011 French guidelines on antibiotic prescription for acute otitis media in infants. AB - OBJECTIVE: In 2011, new guidelines on antibiotic prescription for acute otitis media (AOM) were published in France to decrease the use of third generation cephalosporins that promote the carriage of extended-spectrum beta-lactamase producing Escherichia coli. Our objective was to assess the impact of the 2011 French recommendations on the type of antibiotics prescribed for AOM. METHODS: Fourteen thousand six hundred and sixty-one children, 6 to 24 months of age, presenting with AOM were included in 2 studies, between November 1, 2009 and October 31, 2012. The first one was conducted with the support of 62 private practice pediatricians; the second one was conducted in 7 pediatric emergency departments. Three periods of 1 year each were defined. RESULTS: Antibiotics were prescribed in 12,471 (85.1%) of cases of AOM during the study period. Amoxicillin prescriptions was multiplied by 25, between the first year (2.6%) and the last year (66.1%). Conversely, prescriptions of cefpodoxime proxetil and amoxicillin clavulanic acid decreased from 33.6% and 62.0% in the first year to 5.2% and 27.7% in the last year, respectively. This trend was observed in both private practices and in the pediatric emergency departments. CONCLUSION: Amoxicillin became the most frequently prescribed antibiotic for AOM in 2012, complying with the 2011 French guidelines, while the proportion of prescribed broad-spectrum antibiotics decreased. Our study highlights the importance of guidelines to decrease the prescription of broad-spectrum antibiotics, a crucial factor in the prevention of antibiotic resistance. PMID- 24630598 TI - Preoperative predictors of pain following total knee arthroplasty. AB - Total knee arthroplasty has provided dramatic improvements in function and pain for the majority of patients with knee arthritis, yet a significant proportion of patients remain dissatisfied with their results. We performed a prospective analysis of 215 patients undergoing TKA who underwent a comprehensive array of evaluations to discover whether any preoperative assessment could predict high pain scores and functional limitations postoperatively. Patients with severe pain with a simple knee range-of-motion test prior to TKA had a 10 times higher likelihood of moderate to severe pain at 6 months. A simple test of pain intensity with active flexion and extension preoperatively was a significant predictor of postoperative pain at 6 months after surgery. Strategies to address this particular patient group may improve satisfaction rates of TKA. PMID- 24630599 TI - Cost benefit analysis of topical tranexamic acid in primary total hip and knee arthroplasty. AB - The purpose of this study was to provide a cost-benefit analysis of topical tranexamic acid (TXA) in primary total hip and knee arthroplasty patients. A retrospective cohort of 591 consecutive patients, 311 experimental and 280 control, revealed a transfusion rate reduction from 17.5% to 5.5%, increased postoperative hemoglobin, and decreased delta hemoglobin without an increase in adverse events (all P < 0.001). This led to saving $83.73 per patient based on transfusion costs alone after accounting for the cost of TXA. Hospital disposition to home compared to subacute nursing facility was also significantly increased by 9.3% (P < 0.02). We conclude that topical TXA reduces transfusion rate, increases home disposition, and reduces cost in primary hip and knee arthroplasty. PMID- 24630602 TI - Multiple trauma, resuscitation, and 15 minutes of esophageal intubation: survival without neurologic deficit. PMID- 24630601 TI - VEGFA activates erythropoietin receptor and enhances VEGFR2-mediated pathological angiogenesis. AB - Clinical and animal studies implicate erythropoietin (EPO) and EPO receptor (EPOR) signaling in angiogenesis. In the eye, EPO is involved in both physiological and pathological angiogenesis in the retina. We hypothesized that EPOR signaling is important in pathological angiogenesis and tested this hypothesis using a rat model of oxygen-induced retinopathy that is representative of human retinopathy of prematurity. We first determined that EPOR expression and activation were increased and that activated EPOR was localized to retinal vascular endothelial cells (ECs) in retinas at postnatal day 18 (p18), when pathological angiogenesis in the form of intravitreal neovascularization occurred. In human retinal microvascular ECs, EPOR was up-regulated and activated by VEGF. Lentiviral-delivered shRNAs that knocked down Muller cell-expressed VEGF in the retinopathy of prematurity model also reduced phosphorylated EPOR (p-EPOR) and VEGFR2 (p-VEGFR2) in retinal ECs. In human retinal microvascular ECs, VEGFR2 activated EPOR caused an interaction between p-EPOR and p-VEGFR2; knockdown of EPOR by siRNA transfection reduced VEGF-induced EC proliferation in association with reduced p-VEGFR2 and p-STAT3; however, inhibition of VEGFR2 activation by siRNA transfection or semaxanib (SU5416) abolished VEGFA-induced proliferation of ECs and phosphorylation of VEGFR2, EPOR, and STAT3. Our results show that VEGFA induced p-VEGFR2 activates EPOR and causes an interaction between p-EPOR and p VEGFR2 to enhance VEGFA-induced EC proliferation by exacerbating STAT3 activation, leading to pathological angiogenesis. PMID- 24630603 TI - A healthy young woman with headache and focal seizures. PMID- 24630600 TI - FOXO transcription factors: key regulators of cellular quality control. AB - FOXO transcription factors are conserved regulators of longevity downstream of insulin signaling. These transcription factors integrate signals emanating from nutrient deprivation and stress stimuli to coordinate programs of genes involved in cellular metabolism and resistance to oxidative stress. Here, we discuss emerging evidence for a pivotal role of FOXO factors in promoting the expression of genes involved in autophagy and the ubiquitin-proteasome system--two cell clearance processes that are essential for maintaining organelle and protein homeostasis (proteostasis). The ability of FOXO to maintain cellular quality control appears to be critical in processes and pathologies where damaged proteins and organelles accumulate, including aging and neurodegenerative diseases. PMID- 24630604 TI - E-point septal separation: a bedside tool for emergency physician assessment of left ventricular ejection fraction. AB - OBJECTIVES: Rapid assessment of left ventricular ejection fraction (LVEF) may be critical among emergency department (ED) patients. This study examined the predictive relationship between ED physician performed bedside mitral-valve E point septal separation (EPSS) measurements to the quantitative, calculated LVEF. We further evaluated the relationship between ED physician visual estimates of global cardiac function (GCF) and calculated LVEF values. METHODS: A prospective observational study was conducted on a sequential convenience sample of patients receiving comprehensive transthoracic echocardiography (TTE). Three ED ultrasound fellows performed bedside ultrasound examinations to obtain both EPSS measurements and subjective visual GCF estimates. A linear regression analysis was conducted to examine the relation of EPSS to the calculated LVEF from the comprehensive TTE. Agreement (modified Cohen kappa) between ED ultrasound fellow GCF estimates and the calculated LVEF was also assessed. RESULTS: Linear regression analyses revealed a significant correlation (r=0.73, P<.001) between bedside EPSS and the calculated LVEF. The sensitivity and specificity of an EPSS measurement of greater than 7 mm for severe systolic dysfunction (LVEF<=30%) were 100.0% (95% confidence interval, 62.9-100.0) and 51.6% (95% confidence interval, 38.6-64.5), respectively. Subjective estimates of GCF were moderately correlated with calculated LVEF (Cohen kappa=0.58). CONCLUSIONS: Measurements of EPSS by ED physicians were significantly associated with the calculated measurements of LVEF from comprehensive TTE. Subjective visual estimates of GCF, however, demonstrated only moderate agreement with the calculated LVEF. An EPSS measurement greater than 7 mm was uniformly sensitive at identifying patients with severely reduced LVEF. PMID- 24630605 TI - Hot asphalt burns: a review of injuries and management options. AB - Hot asphalt burns to human tissue can increase the likelihood of infection and potential conversion of partial thickness to full-thickness injuries. Successful intervention for hot asphalt burns requires immediate and effective cooling of the asphalt on the tissue followed by subsequent gradual removal of the cooled asphalt. A review of the literature reveals that multiple substances have been used to remove asphalt, including topical antibiotics, petroleum jelly, a commercial product known as De-Solv-It (ORANGE-SOL, Chandler, AZ), sunflower oil, baby oil, liquid paraffin, butter, mayonnaise, and moist-exposed burn ointment (MEBO). Although many of these products may be effective in the removal of asphalt, they may not be readily available in an emergency department setting. Topical antibiotics are readily available, are more commonly described in the medical literature, and would be expected to be effective in the removal of asphalt. We developed guidelines for on scene (first-aid) management and the initial care of such patients upon presentation to a health care facility. These guidelines emphasize the principles of early cooling, gradual removal of adherent asphalt using topical antibiotics, and avoidance of the use of topical agents, which are likely to result in tissue toxicity. PMID- 24630606 TI - Magnetic resonance imaging and computed tomography utilization trends in an academic ED. AB - OBJECTIVE: The objective of this study is to examine the annual utilization trends of emergency department (ED)-ordered magnetic resonance imaging (MRI) and computed tomography (CT) at an urban academic hospital from 2007 to 2011. We hypothesized that MRI and CT use would increase annually over the study period. METHODS: This was a retrospective observational study of ED encounters between January 1, 2007, and December 31, 2011. All patients seen by a provider were identified, and demographics were abstracted. Type of CT and/or MRI examination, clinical indication, and final disposition were collected. Records of patients with an ED-ordered MRI were also examined for presence of a CT within +/-3 days of their encounter date. Unadjusted linear regression was used to assess for differences among years for both CT and MRI. Secondary outcomes were descriptively summarized. RESULTS: A total of 7089 MRI (20 per 1000) and 85,673 CT (243 per 1000) examinations were ordered over a 60-month period. Computed tomography use decreased significantly (P=.021). Magnetic resonance imaging use significantly increased (2.2 per 1000 ED visits each year, P=.005). Magnetic resonance imaging of the head was ordered most frequently (10.7 per 1000). The overwhelming majority of MRI images were completed for acute neurologic/behavioral problem. Of patients with an MRI completed, 89.4% had a CT completed within 3 calendar days with most of the CT examinations (81%) completed during the encounter. CONCLUSION: There was a steady increase in MRI testing in our academic ED, with most MRIs ordered for acute neurologic or behavioral changes. There was a corresponding decreasing trend for CT scans. PMID- 24630607 TI - Contrast-enhanced ultrasound to determine correct central venous catheter position. PMID- 24630608 TI - Urosepsis-induced takotsubo. PMID- 24630609 TI - Establishment of the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) Biomarker Support Network. PMID- 24630610 TI - Utilization of pastoral care services for a screening, brief intervention, and referral-to-treatment program at an urban level I trauma center. PMID- 24630611 TI - Postural control in children with and without neurofibromatosis type 1. AB - Previous research has evaluated the motor proficiency of children with neurofibromatosis type 1 (NF1) and found delays on the balance subtest. However the balance subtest was found to have low sensitivity for identifying balance impairments. This study examines the differences in postural control between children with NF1 and peers with typical development using a force plate. A single limb stance test on a force plate was completed for all participants. The force plate variables, center of pressure maximum distance in the anterior/posterior direction (COPmax A/P) and center of pressure velocity (COPvel A/P) were compared between groups. The NF1 group's performance was significantly poorer than the control group in both COPmax A/P (p=.01) and COPvel A/P (p=.01). When separated into specific age ranges, only the children in the NF1 group between 5 and 12years of age demonstrated statistically significant differences in the COP variables. The COP variables for the 13- to 18-year-old group were not significantly different. These results indicate that young children with NF1 have poor postural control. However, postural control appears to improve with maturation. PMID- 24630612 TI - Assessment of upper body accelerations in young adults with intellectual disabilities while walking, running, and dual-task running. AB - There is an increasing interest about upper body accelerations during locomotion and how they are altered by physical impairments. Recent studies have demonstrated that cognitive impairments affect gait stability in the elderly (i.e., their capacity for smoothing upper body accelerations during walking) but little attention has been paid to young adults with intellectual disabilities. The purpose of this study was to examine upright stability in young adults with intellectual disabilities during walking, running, and dual-task running (playing soccer). To this aim a wearable trunk-mounted device that permits on-field assessment was used to quantify trunk acceleration of 18 male teenagers with intellectual disabilities (IDG) and 7 mental-age-matched healthy children (HCG) who participated in the same soccer program. We did not find any significant difference during walking in terms of speed, whereas speed differences were found during running (p=.001). Upper body accelerations were altered in a pathology specific manner during the dual task: the performance of subjects with autistic disorders was compromised while running and controlling the ball with the feet. Differences in upright locomotor patterns between IDG and HCG emerged during more demanding motor tasks in terms of a loss in the capacity of smoothing accelerations at the trunk level. PMID- 24630613 TI - Production and characterization of medium-chain-length polyhydroxyalkanoates by Pseudomonas mosselii TO7. AB - The polyhydroxyalkanoate (PHA) production and growth of Pseudomonas mosselii TO7, a newly isolated Pseudomonas species from the wastewater of a vegetable oil manufacturing facility, was analyzed. Phenotypic analysis and phylogenetic analysis of the 16S rRNA gene revealed that it is closely related to Pseudomonas mosselii. In the presence of palm kernel and soybean oils, P. mosselii TO7 produced up to 50% cell dry weight (CDW) medium-chain-length (MCL) PHAs comprising high poly(3-hydroxyoctanoate) (P(3HO)) content; P(3HO) content increased to 45% CDW when grown in octanoate using a single-step culture process. The PHA monomer was identified by (13)C nuclear magnetic resonance spectroscopy. The average molecular weight and polydispersity index of PHA were 218.30 +/- 31.73 and 2.21 +/- 0.18, respectively. The PHA produced by P. mosselii TO7 in the presence of palm kernel oil had two melting temperature (Tm) values of 37.2 degrees C and 55.7 degrees C with melting enthalpy (DeltaHm) values of 51.09 J g( 1) and 26.57 J g(-1), respectively. Inhibition analyses using acrylic and 2 bromooctanoic acids revealed beta-oxidation as the primary pathway for MCL-PHA biosynthesis using octanoic acid. Moreover, Pseudomonas putida GPp104 PHA(-), harboring the PHA synthase genes of P. mosselii (phaC1pm and phaC2pm) was used for heterologous expression, which demonstrated that phaC1pm is the main PHA synthesis enzyme, and 3-hydroxyoctanoyl-CoA is its major substrate. This was the first report of a P. mosselii TO7 isolate producing high-yield P(3HO) through utilization of plant oils. PMID- 24630614 TI - Microfluidic perfusion culture chip providing different strengths of shear stress for analysis of vascular endothelial function. AB - We developed a microfluidic perfusion cell culture chip that provides three different shear stress strengths and a large cell culture area for the analysis of vascular endothelial functions. The microfluidic network was composed of shallow flow-control channels of three different depths and deep cell culture channels. The flow-control channels with high fluidic resistances created shear stress strengths ranging from 1.0 to 10.0 dyn/cm(2) in the cell culture channels. The large surface area of the culture channels enabled cultivation of a large number (approximately 6.0 * 10(5)) of cells. We cultured human umbilical vein endothelial cells (HUVECs) and evaluated the changes in cellular morphology and gene expression in response to applied shear stress. The HUVECs were aligned in the direction of flow when exposed to a shear stress of 10.0 dyn/cm(2). Compared with conditions of no shear stress, endothelial nitric oxide synthase mRNA expression increased by 50% and thrombomodulin mRNA expression increased by 8 fold under a shear stress of 9.5 dyn/cm(2). PMID- 24630615 TI - Analysis of specific proteolytic digestion of the peptidoglutaminase-asparaginase of koji molds. AB - AsGahB, a peptidoglutaminase-asparaginase acting as the main glutaminase in Aspergillus sojae, was previously purified from the cytoplasm of overexpressing strains. Here, we found that specific proteolytic digestion of AsGahB by extracellular proteases of koji molds is similar to that of AsGahA which exists in proteolytic form under solid-state culture. PMID- 24630616 TI - Enrichment of amino acid-oxidizing, acetate-reducing bacteria. AB - In anaerobic condition, amino acids are oxidatively deaminated, and decarboxylated, resulting in the production of volatile fatty acids. In this process, excess electrons are produced and their consumption is necessary for the accomplishment of amino acid degradation. In this study, we anaerobically constructed leucine-degrading enrichment cultures from three different environmental samples (compost, excess sludge, and rice field soil) in order to investigate the diversity of electron-consuming reaction coupled to amino acid oxidation. Constructed enrichment cultures oxidized leucine to isovalerate and their activities were strongly dependent on acetate. Analysis of volatile fatty acids (VFAs) profiles and community structure analysis during batch culture of each enrichment indicated that Clostridium cluster I coupled leucine oxidation to acetate reduction in the enrichment from the compost and the rice field soil. In these cases, acetate was reduced to butyrate. On the other hand, Clostridium cluster XIVb coupled leucine oxidation to acetate reduction in the enrichment from the excess sludge. In this case, acetate was reduced to propionate. To our surprise, the enrichment from rice field soil oxidized leucine even in the absence of acetate and produced butyrate. The enrichment would couple leucine oxidation to reductive butyrate synthesis from CO2. The coupling reaction would be achieved based on trophic link between hydrogenotrophic acetogenic bacteria and acetate-reducing bacteria by sequential reduction of CO2 and acetate. Our study suggests anaerobic degradation of amino acids is achieved yet-to-be described reactions. PMID- 24630617 TI - Detailed evaluation of one step nucleic acid (OSNA) molecular assay for intra operative diagnosis of sentinel lymph node metastasis and prediction of non sentinel nodal involvement: experience from a London teaching hospital. AB - One step nucleic acid (OSNA) is a molecular diagnostic assay for intra-operative detection of sentinel node metastases. This study compared OSNA with standard histopathology in 283 nodes from 170 patients to evaluate sensitivity, specificity and concordance of the two methods. Additional analysis was done to investigate how cytokeratin 19 mRNA copy number affects prediction of non sentinel node positivity. OSNA sensitivity was 93.2% and specificity 95.8%. Concordance between OSNA and histology was 95.6%. In the patients who had axillary clearance, the OSNA mRNA copy number on the sentinel node had 100% negative predictive value for histologically proven metastasis. mRNA copy numbers <1400 were not associated with histologically proven metastasis in subsequent nodes at axillary clearance. OSNA is a reliable method for the intra-operative evaluation of axillary lymph node metastasis even when half of the lymph node is used. Identification of mRNA copy number threshold predicting the positivity of non-sentinel axillary nodes seems to be feasible and would be clinically important. PMID- 24630618 TI - Squamous cell carcinoma arising in a diabetic foot ulcer. AB - Diabetic complications such as poor circulation and nerve damage can result in loss of sensation and slower wound healing in the lower extremities. The possibility of malignancy arising in association with chronic osteomyelitis in the diabetic foot should also be considered. PMID- 24630619 TI - Clinical factors associated with absolute and relative measures of glycemic variability determined by continuous glucose monitoring: an analysis of 480 subjects. AB - AIM: Factors associated with absolute and relative measures of glycemic variability have not been determined by continuous glucose monitoring (CGM) and concurrent measurement of fasting C-peptide levels. METHODS: We analyzed CGM data for subjects with type 1 diabetes (T1D; n=81) and type 2 diabetes (T2D; insulin treated, n=168; not insulin-treated, n=231) who underwent CGM between October 2009 and September 2011 at Samsung Medical Center. Correlations between clinical factors and both standard deviation (SD) and coefficient of variance (CV) in CGM were analyzed by multiple regression. RESULTS: Regardless of the type of diabetes and insulin therapy, higher CV, but not SD, was significantly associated with a minimum glucose level of <70 mg/dL (3.9 mmol/l) in CGM (p<0.001). In T1D, fasting C-peptide levels inversely correlated with SD while BMI inversely correlated with CV, and duration of diabetes, and HDL levels positively correlated with CV. Use of pre-mixed insulin increased both SD and CV. In insulin-treated T2D, fasting C peptide levels inversely correlated with both SD and CV while HbA1c correlated with SD, and duration of diabetes positively correlated with CV. In T2D without insulin therapy, age, BMI, HbA1c, HDL, triglyceride levels and use of sulfonylurea positively correlated with SD while HDL levels and use of sulfonylurea positively correlated with CV, and LDL levels inversely correlated with CV. CONCLUSIONS: Relative glycemic variability (CV) was determined by factors different from those that affect absolute glycemic variability (SD). Some of these factors were indicators of higher insulin sensitivity and residual insulin secretion. PMID- 24630620 TI - [Multicentric study of medical care and practices in spinal muscular atrophy type 1 over two 10-year periods]. AB - AIM: Questions about care practices and the role of palliative care in pediatric neurodegenerative diseases have led the Neuromuscular Committee of the French Society of Neurology to conduct a retrospective study in spinal muscular atrophy type 1, a genetic disease most often leading to death before the age of 1 year. MATERIAL AND METHODS: A retrospective multicenter study from pediatricians included in the reference centers of pediatric neuromuscular diseases was carried out on two 10-year periods (1989-1998 and 1999-2009). RESULTS: The 1989-1998 period included 12 centers with 106 patients, the 1999-2009 period 13 centers with 116 children. The mean age of onset of clinical signs was 2.1 months (range, 0-5.5 months), the median age at diagnosis was 4 months (range, 0-9 months) vs 3 months. The median age of death was 7.5 months (range, 0-24 months) vs 6 months. The care modalities included physiotherapy (90 %), motor support (61 % vs 26 % for the previous period), enteral nutrition by nasogastric tube (52 % vs 24 %), and 3.4 % of children had a gastrostomy (vs 1.8 %). At home, pharyngeal aspiration was used in 64 % (vs 41 %), oxygen therapy in 8 %, noninvasive ventilatory support in 7 %. The mean age at death was 8.1 months (range, 0-24 months) vs 7 months, the time from diagnosis to death was 4 months vs 3 months. Death occurred at home in 23 % vs 17 %, in a pediatric unit in 62 % vs 41 %. The use of analgesics and sedative drugs was reported in 60 % of cases: 40 % morphine (vs 18 %) and benzodiazepines in 48 % (vs 29 %). Respiratory support was limited mostly to oxygen by nasal tube (55 % vs 54 %), noninvasive ventilation in 9 % of the cases, and intubation and assisted mechanical ventilation (2 %). DISCUSSION AND CONCLUSION: These results confirm a change in practices and the development of palliative care in children with a French consensus of practices quite different from the standard care in North-America and closer to the thinking of English medical teams. A prospective study within the 2011 national hospital clinical research program (PHRC 2011) is beginning in order to evaluate practices and the role of families and caregivers. PMID- 24630621 TI - [Mediterranean spotted fever in a 3-year-old child]. AB - We report the case of a 3-year-old patient with Mediterranean spotted fever (MSF). The patient was infected through a tick bite in the forests surrounding Paris. Treatment with azithromycin was started with good results. MSF is not exceptional and should be considered in patients with fever, rash, and eruptions even outside the usual infested areas. PMID- 24630623 TI - [Severe human parechovirus-3 sepsis in a 6-week-old infant]. AB - Febrile infants under 3 months of age are often treated with broad-spectrum intravenous antibiotics while awaiting culture results, to prevent mother-to child bacterial infections. Human parechoviruses (HPeV) have recently been described as etiologic agents of meningitis and severe sepsis in neonates and young infants. They are rarely investigated and are therefore probably underestimated. They cause acute clinical symptoms that can incorrectly suggest a bacterial infection. In the present case, a 6-week-old infant infected with HPeV developed severe sepsis, complicated by hepatic cytolysis, meningitis, acute renal failure, and mild hemophagocytic lymphohistiocytosis. HPeV type 3 was found by routine specific RT-PCR in cerebrospinal fluid, stools, and plasma. The outcome was spontaneously favorable after 4 days. Early diagnosis of the HPeV infection by routine specific RT-PCR reduces unnecessary antibiotic use and extended hospitalization in febrile young infants. PMID- 24630624 TI - [Divorce and joint physical custody]. AB - This work first recalls the definition of joint physical custody, as well as the current legal procedure for obtaining it, its practical implementation, the financial implications for parents, and finally some statistics. Some psychological and psychopathological reflections on the impact of divorce on children are then presented before considering the question of joint physically custody with regard to attachment theory and depending on the age of the child (a great caution seems to be required before three years). The article concludes with a brief discussion of parental alienation syndrome. PMID- 24630625 TI - [YEL-AND meningoencephalitis in a 4-year-old boy consecutive to a yellow-fever vaccine]. AB - Yellow fever is a vector-borne disease transmitted by an endemic mosquito in sub Saharan Africa and tropical South America. It causes fever and possibly liver and renal failure with hemorrhagic signs, which may be fatal. The yellow-fever vaccine is an attenuated vaccine that is recommended for all travelers over the age of 9 months in high-risk areas. Adverse effects have been reported: minor symptoms (such as viral syndrome), hypersensitivity reactions, and major symptoms such as viscerotropic disease (YEL-AVD) and neurotropic disease (YEL-AND). The yellow-fever vaccine-associated autoimmune disease with central nervous system involvement (such as acute disseminated encephalomyelitis) associates fever and headaches, neurologic dysfunction, seizures, cerebrospinal fluid (CSF) pleocytosis, and elevated protein, with neuroimaging consistent with multifocal areas of demyelization. The presence of antibodies or virus in CSF, within 1-30 days following vaccination, and the exclusion of other causes is necessary for diagnosis. We describe herein the case of a 4-year-old child who presented with severe encephalitis consecutive to a yellow-fever vaccine, with favorable progression. Diagnosis is based on the chronology of clinical and paraclinical signs and the presence of yellow-fever-specific antibodies in CSF. The treatment consists of symptomatic treatment and immunoglobulin injection. PMID- 24630626 TI - Direct regulation of the NADPH oxidase RBOHD by the PRR-associated kinase BIK1 during plant immunity. AB - The rapid production of reactive oxygen species (ROS) burst is a conserved signaling output in immunity across kingdoms. In plants, perception of pathogen associated molecular patterns (PAMPs) by surface-localized pattern recognition receptors (PRRs) activates the NADPH oxidase RBOHD by hitherto unknown mechanisms. Here, we show that RBOHD exists in complex with the receptor kinases EFR and FLS2, which are the PRRs for bacterial EF-Tu and flagellin, respectively. The plasma-membrane-associated kinase BIK1, which is a direct substrate of the PRR complex, directly interacts with and phosphorylates RBOHD upon PAMP perception. BIK1 phosphorylates different residues than calcium-dependent protein kinases, and both PAMP-induced BIK1 activation and BIK1-mediated phosphorylation of RBOHD are calcium independent. Importantly, phosphorylation of these residues is critical for the PAMP-induced ROS burst and antibacterial immunity. Our study reveals a rapid regulatory mechanism of a plant RBOH, which occurs in parallel with and is essential for its paradigmatic calcium-based regulation. PMID- 24630627 TI - "I should know better": the roles of relationships, spirituality, disclosure, stigma, and shame for older women living with HIV seeking support in the South. AB - The population of older people living with HIV in the United States is growing. Little is known about specific challenges older HIV-infected women face in coping with the disease and its attendant stressors. To understand these issues for older women, we conducted semi-structured in-depth interviews with 15 women (13 African American, 2 Caucasian) 50 years of age and older (range 50-79 years) in HIV care in the southeastern United States, and coded transcripts for salient themes. Many women felt isolated and inhibited from seeking social connection due to reluctance to disclose their HIV status, which they viewed as more shameful at their older ages. Those receiving social support did so mainly through relationships with family and friends, rather than romantic relationships. Spirituality provided great support for all participants, although fear of disclosure led several to restrict connections with a church community. Community level stigma-reduction programs may help older HIV-infected women receive support. PMID- 24630629 TI - [A special issue on rare malignant tumors and their networks]. PMID- 24630630 TI - [Rare tumors: limits of expertise and external consultation]. PMID- 24630628 TI - Barriers and facilitators to engagement in lifestyle interventions among individuals with HIV. PMID- 24630631 TI - [The RENAPE network: towards a new healthcare organization for the treatment of rare tumors of the peritoneum. Description of the network and role of the pathologists]. AB - As part of the national 2009-2013 Cancer Plan, and with the support of the National cancer Institute and the French ministry of health, the National network for the treatment of rare peritoneal malignancies (RENAPE) has been organized. Its main objective is to optimize the framework for the healthcare management and treatment of rare peritoneal malignancies. This specific organization covers the whole national territory including clinical expert and specialized structures and should lead to an appropriate treatment based on expertise and proximity. Within the RENAPE network, the RENA-PATH group gathers the pathologists actively involved in the management of rare peritoneal malignancies. The actions of RENA PATH are focused primarily on the harmonization of pathological diagnostic criteria, reporting of new cases in the RENAPE registry and histology reviewing. PMID- 24630632 TI - Current concepts in pseudomyxoma peritonei. AB - Each year, about two per million individuals will be diagnosed with pseudomyxoma peritonei, a disease characterised by the intra-abdominal growth of neoplastic mucin-secreting cells on peritoneal surfaces. The distribution of the disease within the abdomen is not random but depends on physiological principles. Most cases derive from neoplasms of the appendix. In the past, the ovary was considered a common primary site. However, we now know that the ovary is only rarely the source of pseudomyxoma, and that lesions which would previously have been called "borderline mucinous tumours of the ovary" are typically metastatic from the appendix. The grade of the neoplastic cells in pseudomyxoma is an important prognostic factor, but unfortunately there is no consensus on terminology. An international expert group of pathologists and clinicians is currently working on the harmonisation of terminology in this field. Expertise in the management of pseudomyxoma can be achieved by concentrating the treatment of patients in specialised centres or through the development of networks. PMID- 24630633 TI - [Peritoneal pseudomyxoma: an overview emphasizing pathological assessment and therapeutic strategies]. AB - Pseudomyxoma peritonei is a clinical entity characterized by a gelatinous ascite associated with mucinous tumor deposits spreading on peritoneal surface and potentially invading abdominal organs. It is considered as a tumor process linked, in most of cases, to a mucinous appendiceal neoplasm. Pseudomyxoma peritonei may benefit from a therapeutic strategy combining cytoreductive surgery and intra-peritoneal chemotherapy, which has led to a major prognosis improvement. Different classifications are available and the last one corresponds to the WHO 2010 version, which individualizes pseudomyxoma peritonei in two classes: low grade and high grade mucinous carcinoma. The very low frequency of this entity and its specific therapeutic strategy need specific health care centres, as well as physicians and pathologists collaborating through dedicated networks. The aim of this article is to summarize the pathology, causes, mechanisms and therapeutic approaches of pseudomyxoma peritonei, as well as their interfaces with dedicated networks. PMID- 24630634 TI - [Peritoneal malignant mesothelioma: review and recent data]. AB - Peritoneal malignant mesothelioma is a rare tumor, less common than its pleural counterpart. It develops from the mesothelial cells overlying peritoneum and preferentially occurs in male, with an average age ranging from 47 to 60.5 years. Asbestos whose impact is less strong than in pleural mesothelioma, SV 40 virus, chronic peritonitis could be implicated as factors favoring the development of peritoneal mesothelioma. Clinical symptoms are not specific, and the imagery remains little or not contributive. The 2004 WHO classification recognizes 3 different types, which differ in terms of presentation and prognosis: diffuse epithelioid mesothelioma (the most common), sarcomatoid mesothelioma and biphasic mesothelioma. Many variants are described within these groups. Immunohistochemistry is mandatory to affirm or disprove peritoneal malignant mesothelioma diagnosis, based on a panel of antibodies divided in positive markers and negative markers. Indeed an accurate diagnosis is necessary to define a therapeutic strategy more and more frequently based on the combination of radical surgery and hyperthermic intra peritoneal chemotherapy. Such an approach significantly improves the prognosis of these aggressive diseases. PMID- 24630635 TI - [TENpath network, an expertise pathology network dedicated to sporadic and inherited adult neuroendocrine tumors: first evaluation and first lessons]. AB - TENpath is a network for the expert pathological diagnosis of malignant neuroendocrine tumors of the adult, both familial and sporadic, created by the French National Institute of Cancer in 2010. After 3years of activity, a first evaluation can be made. The perimeter of the network includes all neuroendocrine tumors (except small cell carcinomas of the lung), medullary carcinomas of the thyroid and extra-adrenal paragangliomas. The objectives of the network are not only the pathological review of all newly diagnosed cases of neuroendocrine tumors, but also the epidemiological surveillance, the training of pathologists, the production of recommendations and the initiation of research projects. The organisation of the network includes a database in which all referred cases are declared and a virtual expert system making it possible collegial expertises in line. Twenty-two expert centers are currently participating to TENpath. A total of 1350 cases have been referred in 2011 and 1518 in 2012. Major discrepancies amounted up to 5.9% in 2011 and to 2.9% in 2012. They mainly involved problems of differential diagnosis and wrong evaluations of the differentiation status of the tumor. The lessons to draw from the first years of TENpath are: (a) the long standing underestimation of the actual number of patients with neuroendocrine tumors in France, (b) a better delineation, based on objective data, of the cases raising actual problems of diagnosis, (c) the existence of cases raising problems of classification even to experts and justifying a particular effort of research. These informations will be important to discuss the future evolution of TENpath. PMID- 24630636 TI - [Gastroenteropancreatic neuroendocrine tumors: what must the pathologist know and do in 2014?]. AB - The diagnostic management of a possible case of gastroenteropancreatic neuroendocrine tumor has much changed in the last 10 years. It is now made of four successive steps. The first step is the positive diagnosis, i.e. the definitive identification of the neuroendocrine nature of the tumor: it relies on morphological and immunohistochemical arguments; several national and international recommendations have now clarified the immunohistochemical arguments necessary for, and sufficient to make a diagnosis of gastroenteropancreatic neuroendocrine tumor. The second step is the determination of the grade, essential for the evaluation of the risk of progression: it relies on the determination of the proliferative capacities, according to the proposals of the European NeuroEndocrine Tumor Society (ENETS), later adopted by WHO in 2010. The third step is the histoprognostic classification, which must use a standardized terminology: it is required to use the specific classification proposed in 2010 by WHO in the framework of the revision of the classifications of digestive tumors. The last step is staging, which relies on the use of one of the existing TNM classifications, that, official, proposed by UICC/AJCC or that proposed by ENETS. The minimal informations, which must be present in the pathological report have been stated by the Societe Francaise de Pathologie, at the request of the French National Cancer Institute. PMID- 24630638 TI - [Pathologists and the French network of expertise on rare cancers ENT: The REFCORpath]. AB - Aerodigestive tract tumors are very diverse, either in terms of location, or histologically. Also, this heterogeneity poses particular problems for the histological diagnosis but also for the establishment of the most appropriate treatment. Thus, the network REFCOR (reseau d'expertise francais sur les cancers ORL rares/French expert network on rare ENT cancers) was created to better understand these issues, by proposing an epidemiological and diagnostic approach with research collaborations. This network is dedicated to all primary malignant tumors of the salivary glands, ear, nasal cavity and sinuses and all head and neck malignancies other than conventional squamous cell carcinoma. The REFCORpath network consists of expert pathologists and offers, through a network of scanned images, a second opinion or even a third. PMID- 24630637 TI - [The French mesothelioma network from 1998 to 2013]. AB - Mesothelioma is a rare disease less than 0.3% of cancers in France, very aggressive and resistant to the majority of conventional therapies. Asbestos exposure is nearly the only recognized cause of mesothelioma in men observed in 80% of case. In 1990, the projections based on mortality predicted a raise of incidence in mesothelioma for the next three decades. Nowadays, the diagnosis of this cancer is based on pathology, but the histological presentation frequently heterogeneous, is responsible for numerous pitfalls and major problems of early detection toward effective therapy. Facing such a diagnostic, epidemiological and medico-legal context, a national and international multidisciplinary network has been progressively set up in order to answer to epidemiological survey, translational or academic research questions. Moreover, in response to the action of the French Cancer Program (action 23.1) a network of pathologists was organized for expert pathological second opinion using a standardized procedure of certification for mesothelioma diagnosis. We describe the network organization and show the results during this last 15years period of time from 1998-2013. These results show the major impact on patient's management, and confirm the interest of this second opinion to provide accuracy of epidemiological data, quality of medico-legal acknowledgement and accuracy of clinical diagnostic for the benefit of patients. We also show the impact of these collaborative efforts for creating a high quality clinicobiological, epidemiological and therapeutic data collection for improvement of the knowledge of this dramatic disease. PMID- 24630639 TI - [The observatory of rare malignant gynecologic tumors]. AB - The observatory of gynecological rare tumors (TMRG) has been initially created for ovarian rare neoplasms (TMRO). Because of the similarities between ovarian and other gynecological tumors, this observatory has been then extended to all gynecological rare tumors. The recognition by INCa of three national expert centers (centre Leon-Berard, hopitaux de Paris, institut Gustave-Roussy) in rare gynecological cancers and a network of regional expert centers in 2010, expend the experience of the website "Observatoire francophone des tumeurs rares de l'ovaire". The major goals of this gynecology rare tumors experts network, are to promote systematic second opinion for initial diagnostic by experts in gynecopathology, systematic multidisciplinary advice by surgeons and medical oncologist experts, to disseminate clinical guidelines dedicated to rare gynecological tumors, to promote specific fundamental and translational research within clinical trials dedicated to rare tumors. At the end, we would like to improve benefit in term of survival and/or fertility for all these potential young patients. PMID- 24630640 TI - [National network of paediatric central nervous system tumours reviewing by the Groupe d'Etude de Neuropathologie Oncologique Pediatrique (GENOP)]. AB - Diagnosis of paediatric tumours of the central nervous system is often difficult because WHO classification criteria are mainly defined for adults tumours and do not always apply to their paediatric counterparts. These tumours are rare (400 cases/year among more than 50 pathological subtypes per year in France). Pathological diagnosis may be a challenge for a general pathologist with a too low number of paediatric cases in his recruitment. Hence, a reference group of paediatric neuropathologists was formed (GENOP) on the behalf of the comite "Tumeurs Cerebrales" de la Societe Francaise de lutte contre les Cancers de l'Enfant. This network is supported by the Institut National du Cancer (INCa). GENOP aim is to structure a centralised review of paediatric central nervous system tumours in order to harmonise neuropathological diagnosis at the national level and enhance patients care. Cases assessed during the last 3 years led GENOP to better identify tumours subtypes for which there is a diagnostic challenge. A set of immunohistochemical or molecular specialised techniques was developed, leading to an increased diagnostic accuracy. It allowed a better distinction between diffuse and circumscribed glioma, a better recognition of glioneuronal differentiation and a better subtyping of embryonal tumours such as medulloblastomas. Inter-observer agreement varied according to the tumour subtypes. PMID- 24630641 TI - [Rythmic-pathology: the French national pathology network for thymic epithelial tumours]. AB - Epithelial thymic tumours are rare and sometimes difficult to classify. Since 2010, the French National Cancer Institute supports a French national network, called Rythmic, devoted to the treatment of these tumours through regional and national multidisciplinary conferences using the web. All the tumours are secondarily reviewed by a French pathology national network for classification and staging. This review focuses on the presentation of the Rythmic network, and mainly to the Pathology review process. PMID- 24630642 TI - Factor V Leiden mutation modulates the bleeding phenotype in warfarin sensitive patients. PMID- 24630643 TI - Decichine enhances hemostasis of activated platelets via AMPA receptors. AB - INTRODUCTION: Dencichine, one of the non-protein amino acids present in the roots of Panax notoginseng, has been found to shorten bleeding time of mice and increase the number of platelets. However, the exact underlying mechanisms have not been elucidated yet. This study was aimed to identify the hemostatic effect of dencichine and uncover its mechanisms. MATERIALS AND METHODS: Hemostatic effect was assessed by measuring tail bleeding time and coagulation indices of rats. PT, APTT, TT and FIB concentration were measured using a Sysmex CA-1500 plasma coagulation analyzer. Platelet aggregation rate was determined by using a platelet aggregometer. Concentration of cyotosolic calcium was evaluated by Fluo 3 and levels of cyclic adenosine monophosphate (cAMP) and thromboxane A2 (TXA2) were measured by ELISA method. RESULTS AND CONCLUSION: Dencichine administered orally shortened tail bleeding time, reduced APTT and TT but increased the concentration of FIB in plasma in a dose-dependent manner. When induced with trap, dencichine could elevate the cytoplasmic concentration of calcium, and secretion of TXA2 as well as the ratio of TXA2 to PGI2 from platelets. Meanwhile, it decreased the level of intracellular cAMP. However, CNQX could block the enhanced hemostatic effect of dencichine. These results suggested that dencichine exerted hemostatic function via AMPA receptors on platelets, therefore, facilitated coagulation cascade in a paracrine fashion by control of platelet cytosolic calcium influx, cAMP production and TXA2 release. Current study may contribute to its clinical use in therapy of hemorrhage. PMID- 24630644 TI - The importance of extended thromboprophylaxis in patients undergoing major surgery for cancer. PMID- 24630645 TI - Studies of fibrin formation and fibrinolytic function in patients with the antiphospholipid syndrome. AB - OBJECTIVE: The antiphospholipid syndrome (APS) is defined by persistent antiphospholipid antibodies together with thrombosis and/or pregnancy morbidity. We investigated the tightness of fibrin clot and fibrinolytic function in plasma samples from APS patients compared with two control groups. MATERIAL AND METHODS: APS patients (n=49), healthy controls (HC) (n=19) and warfarin-treated nonAPS thrombosis controls (nonAPS-TC) (n=39) were investigated. Fibrin permeability was assessed as the permeability coefficient (Ks) by a flow measurement technique. Additionally, clot density and fibrinolytic function was analysed by a turbidimetric clotting and lysis assay. Fibrin structure was visualised using scanning electron microscopy. Finally, the number of cell-derived microparticles (MPs) in the samples were correlated to fibrin permeability RESULTS AND CONCLUSIONS: The Ks value was lower in samples from APS-patients compared to HC and nonAPS-TC (p<0.0001 for both) indicating a less permeable fibrin clot in APS patients. Scanning electron microscopy images confirmed compact fibrin with smaller intrinsic pores and thinner fibers in samples from APS patients as compared to HC. Prolonged fibrinolysis (clot lysis) times were present in the subgroup of APS patients with previous arterial thrombosis (n=15) as compared to HC and to nonAPS-TC (all p-values<0.05). In conclusion, tighter fibrin clots were formed in plasma from APS patients compared with healthy controls and warfarin treated patients with thrombosis of "nonAPS origin". This new observation presents a possible mechanism contributing to the thrombotic predisposition of APS patients. Impaired fibrinolysis, selectively present among APS patients with previous arterial thrombosis, may further aggravate the pro-thrombotic state in this APS subgroup. PMID- 24630646 TI - Development of a locally sustainable functional food based on mutandabota, a traditional food in southern Africa. AB - A probiotic dairy product was developed on the basis of a traditional dish called mutandabota to enable resource-poor populations in southern Africa to benefit from a functional food. Mutandabota is widely consumed in rural southern Africa, making it an ideal food matrix to carry probiotics. First, a process to produce probiotic mutandabota was designed. Raw cow milk was boiled and subsequently cooled to ambient temperature (25 degrees C). Next, dry pulp from the fruit of the baobab tree (Adansonia digitata L.) was added to the milk at a concentration of 4% (wt/vol). This mixture was inoculated with the probiotic Lactobacillus rhamnosus yoba and left to ferment for 24h, while the growth of the bacterial culture was monitored. Final ingredients were then added to produce probiotic mutandabota that had 14% (wt/vol) baobab fruit pulp and 7% (wt/vol) sugar in cow milk. The pH of probiotic mutandabota was pH 3.5, which ensures that the product is microbiologically safe. The viable plate count of L. rhamnosus yoba increased from 5.8 +/- 0.3 log cfu/mL at the point of inoculation to 8.8 +/- 0.4 log cfu/mL at the moment of consumption, thereby meeting the criterion to have a viable count of the probiotic bacterium in excess of 6 log cfu/mL of a product. Baobab fruit pulp at 4% promoted growth of L. rhamnosus yoba with a maximal specific growth rate (MUmax) of 0.6 +/- 0.2/h at 30 degrees C. The developed technology, though specific for this particular product, has potential to be applied for the delivery of probiotics through a variety of indigenous foods in different regions of the world. Upon consumption, probiotic mutandabota is expected to improve the population's intestinal health, which is especially relevant for vulnerable target groups such as children and elderly people. PMID- 24630647 TI - Technical note: Evaluation of an ear-attached movement sensor to record cow feeding behavior and activity. AB - The ability to monitor dairy cow feeding behavior and activity could improve dairy herd management. A 3-dimensional accelerometer (SensOor; Agis Automatisering BV, Harmelen, the Netherlands) has been developed that can be attached to ear identification tags. Based on the principle that behavior can be identified by ear movements, a proprietary model classifies sensor data as "ruminating," "eating," "resting," or "active." The objective of the study was to evaluate this sensor on accuracy and precision. First, a pilot evaluation of agreement between 2 independent observers, recording behavior from 3 cows for a period of approximately 9h each, was performed. Second, to evaluate the sensor, the behavior of 15 cows was monitored both visually (VIS) and with the sensor (SENS), with approximately 20 h of registration per cow, evenly distributed over a 24-h period, excluding milking. Cows were chosen from groups of animals in different lactation stages and parities. Each minute of SENS and VIS data was classified into 1 of 9 categories (8 behaviors and 1 transition behavior) and summarized into 4 behavioral groups, namely ruminating, eating, resting, or active, which were analyzed by calculating kappa (kappa) values. For the pilot evaluation, a high level of agreement between observers was obtained, with kappa values of >= 0.96 for all behavioral categories, indicating that visual observation provides a good standard. For the second trial, relationships between SENS and VIS were studied by kappa values on a minute basis and Pearson correlation and concordance correlation coefficient analysis on behavior expressed as percentage of total registration time. Times spent ruminating, eating, resting, and active were 42.6, 15.9, 31.6, and 9.9% (SENS) respectively, and 42.1, 13.0, 30.0, and 14.9% (VIS), respectively. Overall kappa for the comparison of SENS and VIS was substantial (0.78), with kappa values of 0.85, 0.77, 0.86, and 0.47 for "ruminating," "eating," "resting," and "active," respectively. Pearson correlation and concordance correlation coefficients between SENS and VIS for "ruminating," "eating," "resting," and "active" were 0.93, 0.88, 0.98, and 0.73, and 0.93, 0.75, 0.97, and 0.35, respectively. In conclusion, the results provide strong evidence that the present ear sensor technology can be used to monitor ruminating and resting behavior of freestall housed dairy cattle. Our results also suggest that this technology shows promise for monitoring eating behavior, whereas more work is needed to determine its suitability to monitor activity of dairy cattle. PMID- 24630648 TI - The relationship between compost bedded pack performance, management, and bacterial counts. AB - The objective of this study was to assess the relationships among temperature, moisture, carbon-to-nitrogen (C:N) ratio, space per cow, and bacterial counts from bedding material collected from compost bedded pack (CBP) barns. A field survey of 42 routinely aerated CBP barns was conducted in Kentucky between October 2010 and March 2011. Two bedding material samples of 1,064.7 cm(3) each were collected during a single site visit from 9 evenly distributed locations throughout each barn and thoroughly mixed to create a composite sample representative of the entire CBP. Bacterial counts were determined for coliforms, Escherichia coli, streptococci, staphylococci, and Bacillus spp. University of Kentucky Regulatory Services (Lexington) laboratory personnel performed nutrient analyses to determine moisture, carbon, and nitrogen contents. Surface and 10.2 cm pack depth temperatures were collected for each of the 9 evenly distributed locations and the mean calculated to produce a composite temperature. Space per cow was calculated as the total CBP area divided by number of cows housed on the CBP. The GLM procedure of SAS (SAS Institute Inc., Cary, NC) generated models to describe factors affecting bacterial counts. Bacterial counts were 6.3 +/- 0.6, 6.0 +/- 0.6, 7.2 +/- 0.7, 7.9 +/- 0.5, and 7.6 +/- 0.5 log 10 cfu/g of dry matter for coliform, Escherichia coli, streptococci, staphylococci, and Bacillus spp., respectively. Composite temperature, CBP moisture, C:N ratio, and space per cow had no effect on coliform counts. Escherichia coli reached a peak concentration when the C:N ratio was between 30:1 and 35:1. Staphylococci counts increased as ambient temperature increased. Streptococci counts decreased with increased space per cow and composite temperature and increased with increasing ambient temperature and moisture. Streptococci counts peaked at a C:N ratio ranging from 16:1 to 18:1. Bacillus spp. counts were reduced with increasing moisture, C:N ratio, and ambient temperature. Mastitis-causing bacteria thrive in similar conditions to that of composting bacteria and microbes, making elimination of these at higher temperatures (55 to 65 degrees C) difficult in an active composting environment. Producers must use recommended milking procedures and other preventative practices to maintain low somatic cell count in herds with a CBP barn. PMID- 24630649 TI - Prediction of liveweight of cows from type traits and its relationship with production and fitness traits. AB - Liveweight (LWT) data for Australian Holstein cows was predicted from different type traits based on actual LWT and type data of 932 cows collected from 20 different herds over a 3-yr period. In addition to LWT measured using scales, visual estimates of LWT were also available on 90% of the cows with LWT data. The future predictive ability of different models was assessed using 10-fold cross validation. The relationships between LWT and selected type traits, including body condition score (BCS), were also calculated to assess the usefulness of various traits to predict LWT genetically. The relationships of predicted LWT measures with production and fitness traits were also estimated in an attempt to assess the consequence of continuous selection on an economic index that includes predicted LWT with a negative economic value. The heritability of LWT was 0.4. Among type traits, stature, chest width, bone quality, BCS, udder depth, central ligament, and muzzle width were correlated with LWT both genetically and phenotypically and were used to predict LWT of cows. Predicted LWT measures, using several sets of traits and visually estimated LWT were genetically highly correlated with each other (>0.73). Phenotypically, visually estimated LWT of cows was slightly more correlated with actual LWT than that predicted from type traits, but genetically both approaches gave the same accuracy. The predicted estimates of LWT were also positively genetically correlated with energy corrected milk yield and had near zero correlation with survival. The correlations of different measures of LWT with fertility traits were unfavorable or near zero, suggesting that selection for reduced LWT may not cause deterioration in fertility traits. However, it may be useful to consider broadening the breeding objective to include traits that are associated with energy balance, particularly if traits such as BCS and bone quality are included in the set of traits used to predict LWT. Based on the results from this study, the inclusion of predicted LWT with negative economic values into the breeding objective would have no negative effect on fitness traits. PMID- 24630650 TI - Dairy cows seek isolation at calving and when ill. AB - Dairy cows are typically gregarious, but isolate themselves in the hours before calving when kept on pasture. Self-isolation is also a common behavior of ill animals. The objectives of this study were to determine if dairy cows would (1) isolate to calve when housed indoors in an individual maternity pen and (2) continue to isolate when ill after calving. We selected individuals from a pool of 79 multiparous Holstein dairy cows based on inclusion criteria created to address each objective. Cows were moved from a group pen to 1 of 10 adjacent maternity pens. Half of these individual pens were partially covered with plywood, creating a secluded corner as well as a window that provided visual access to the group pen. The other individual pens were uncovered on all sides. For our first objective, we selected 39 cows that were moved into the maternity pens >8h before calving (partially covered: n=19; uncovered: n=20). For our second objective, we selected 18 cows housed in the partially covered pens: 9 cows with high rectal temperature after calving and signs of an infectious disease (mastitis, metritis, pneumonia, or some combination), and 9 healthy cows paired with ill cows based on the amount of time they spent in the maternity pen before calving. Ten-minute scan sampling was used to record the location and lying time from 6h before to 72 h after calving. Individual feed intake was measured after calving. Binomial tests were used to determine if cows in both pen types were more likely to calve in the corner or window side of the pen. Repeated measures ANOVA were used to determine if cows used the corner more as calving approached and if ill cows spent more time lying or more time in the corner compared with healthy cows in the 72 h after calving. Cows in the uncovered pens were equally likely to calve on both sides of the pen (10 vs. 10), but 79% of cows in the partially covered pens calved on the corner side of the pen (15 vs. 4). Cows in the partially covered pens used the corner side of the pen more in the 1h before and after calving compared with those housed in the uncovered pens. Ill cows housed in the partially covered pens ate less, tended to spend more time lying down, and spent more time in the corner of the pen compared with healthy cows. These results indicate that periparturient dairy cows seek seclusion to calve and when ill, which suggests that adding a secluded area to maternity and hospital pens may be beneficial. PMID- 24630651 TI - The effects of feeding 3-nitrooxypropanol on methane emissions and productivity of Holstein cows in mid lactation. AB - The objective of the current study was to determine the effects of adding 3 nitrooxypropanol to the diet of lactating Holstein cows on methane emissions, rumen fermentation, ruminal microbial profile, and milk production. Twelve ruminally cannulated Holstein cows in midlactation were used in a crossover design study with 28-d periods. Cows were fed a diet containing 38% forage on a dry matter basis with either 2,500 mg/d of 3-nitrooxypropanol (fed as 25 g of 10% 3-nitrooxypropanol on silicon dioxide) or 25 g/d of silicon dioxide (control). After a 21-d diet adaptation period, dry matter intake (DMI) and milk yield were recorded daily. Rumen fluid and digesta were collected on d 22 and 28 for volatile fatty acid analysis and microbial profiling. Enteric methane emissions were measured on d 23 to 27 using the sulfur hexafluoride tracer gas technique. Feeding 3-nitrooxypropanol did not affect DMI; however, methane production was reduced from 17.8 to 7.18 g/kg of DMI. No change in milk or milk component yields was observed, but cows fed 3-nitrooxypropanol gained more body weight than control cows (1.06 vs. 0.39 kg/d). Concentrations of total volatile fatty acids in ruminal fluid were not affected by treatment, but a reduction in acetate proportion and a tendency for an increase in propionate proportion was noted. As such, a reduction in the acetate-to-propionate ratio was observed (2.02 vs. 2.36). Protozoa counts were not affected by treatment; however, a reduction in methanogen copy count number was observed when 3-nitrooxypropanol was fed (0.95 vs. 2.69 * 10(8)/g of rumen digesta). The data showed that feeding 3 nitrooxypropanol to lactating dairy cows at 2,500 mg/d can reduce methane emissions without compromising DMI or milk production. PMID- 24630652 TI - Agreement between milk fat, protein, and lactose observations collected from the Dairy Herd Improvement Association (DHIA) and a real-time milk analyzer. AB - The objective of this study was to quantify the agreement between AfiLab real time milk analyzer (Afimilk, Kibbutz Afikim, Israel) measures for fat, protein, and lactose based on near-infrared spectrum light scattering, and those collected on Dairy Herd Improvement Association (DHIA) test days and measured with the Bentley 2000 analyzer (Bentley Instruments Inc., Chaska, MN), which uses mid infrared spectrum light. The AfiLab data were collected twice daily for each milking cow in the herd at 12-h intervals from the double-12 parlor at the University of Florida Dairy Unit (Hague, FL) from January 2010 to December 2011. Bentley data for the 23 DHIA test days in 2010 and 2011 were also obtained. Approximately 450 cows were tested each month. Tested milk was collected during 1 milking each month, alternating monthly between morning and evening milkings. AfiLab data were matched with Bentley fat and protein (n=10,273; 23 test days) and lactose (n=6,741; 16 test days). Overall means +/- standard deviations (SD) of monthly mean Bentley fat, protein, and lactose were 3.74 +/- 0.80%, 3.06 +/- 0.37%, and 4.76 +/- 0.30%, respectively. Overall means +/- SD of monthly mean AfiLab minus Bentley observations were -0.08 +/- 0.12 percentage points (PP) for fat (n=23), 0.02 +/- 0.11 PP for protein (n=23), and -0.02 +/- 0.08 PP for lactose (n=16). Overall means +/- SD of monthly within-test-day SD of AfiLab minus Bentley observations were 0.66 +/- 0.11 PP for fat, 0.27 +/- 0.03 PP for protein, and 0.26 +/- 0.03 PP for lactose. Overall means +/- SD of the corresponding monthly correlations were 0.59 +/- 0.09 for fat, 0.67 +/- 0.04 for protein, and 0.46 +/- 0.08 for lactose. Averaging the AfiLab observations from up to 6 milkings before and after the test-day milking improved the agreement for protein and lactose but not for fat. Averaging the 13 protein observations improved the mean difference to 0.01 +/- 0.10 PP and the SD of the difference to 0.23 +/- 0.03 PP. The correlation increased to 0.78 +/- 0.04. Averaging the 13 lactose observations improved the SD of the difference to 0.23 +/- 0.02 PP, but the mean of the difference decreased to -0.03 +/- 0.09 PP. The correlation for lactose increased to 0.55 +/- 0.05. Generally, AfiLab slightly overestimated low Bentley components and underestimated high Bentley components. We found some evidence for a systematic cow effect on lack of agreement for lactose, but not for fat and protein. The agreement between AfiLab and Bentley observations was better for protein and lactose than that for fat. Combinations of AfiLab observations from various milkings improved the agreement for protein and lactose. AfiLab real-time milk analyzers may be helpful to estimate DHIA observations. PMID- 24630653 TI - Identification of predictive biomarkers of disease state in transition dairy cows. AB - In dairy cows, periparturient disease states, such as metritis, mastitis, and laminitis, are leading to increasingly significant economic losses for the dairy industry. Treatments for these pathologies are often expensive, ineffective, or not cost-efficient, leading to production losses, high veterinary bills, or early culling of the cows. Early diagnosis or detection of these conditions before they manifest themselves could lower their incidence, level of morbidity, and the associated economic losses. In an effort to identify predictive biomarkers for postpartum or periparturient disease states in dairy cows, we undertook a cross sectional and longitudinal metabolomics study to look at plasma metabolite levels of dairy cows during the transition period, before and after becoming ill with postpartum diseases. Specifically we employed a targeted quantitative metabolomics approach that uses direct flow injection mass spectrometry to track the metabolite changes in 120 different plasma metabolites. Blood plasma samples were collected from 12 dairy cows at 4 time points during the transition period ( 4 and -1 wk before and 1 and 4 wk after parturition). Out of the 12 cows studied, 6 developed multiple periparturient disorders in the postcalving period, whereas the other 6 remained healthy during the entire experimental period. Multivariate data analysis (principal component analysis and partial least squares discriminant analysis) revealed a clear separation between healthy controls and diseased cows at all 4 time points. This analysis allowed us to identify several metabolites most responsible for separating the 2 groups, especially before parturition and the start of any postpartum disease. Three metabolites, carnitine, propionyl carnitine, and lysophosphatidylcholine acyl C14:0, were significantly elevated in diseased cows as compared with healthy controls as early as 4 wk before parturition, whereas 2 metabolites, phosphatidylcholine acyl alkyl C42:4 and phosphatidylcholine diacyl C42:6, could be used to discriminate healthy controls from diseased cows 1 wk before parturition. A 3-metabolite plasma biomarker profile was developed that could predict which cows would develop periparturient diseases, up to 4 wk before clinical symptoms appearing, with a sensitivity of 87% and a specificity of 85%. This is the first report showing that periparturient diseases can be predicted in dairy cattle before their development using a multimetabolite biomarker model. Further research is warranted to validate these potential predictive biomarkers. PMID- 24630654 TI - Short communication: Bacterial counts in recycled manure solids bedding replaced daily or deep packed in freestalls. AB - An experiment was conducted to compare bacterial counts of mastitis pathogens in deep-packed manure solids bedding with those in manure solids bedding replaced daily from mattresses. Eighteen Holstein cows were housed in 1 pen with 18 stalls. One row of 9 stalls was equipped with mattresses topped with bedding. The back one-third of these stalls toward the alleyway was covered in 25 mm of recycled manure solids, which was removed daily for the next 6 d and replaced with bedding from the brisket board and lunge space areas of stalls. The second row of 9 stalls was bedded for 3 wk with 100 to 150 mm of deep-pack recycled manure bedding from which only fecal matter was removed daily. After 3 wk, bedding treatments were changed between rows in a switchback design. Mean total gram-negative bacterial counts did not differ between treatments throughout the experiment. Coliform and Klebsiella spp. bacterial counts were lower in daily replaced bedding compared with deep pack across the experiment and on each of d 0, 1, 2, and 6. Streptococcal counts were reduced in daily replacement stalls compared with deep-pack stalls on d 0 and greater in daily replacement stalls compared with deep-pack stalls on d 1, 2, and 6. Daily replacement of recycled manure bedding from the back one-third of the stalls appeared to be an effective approach to reducing exposure to coliforms, specifically Klebsiella, but not streptococci. However, bacterial counts in bedding from both treatments were elevated throughout the trial and resulted in considerable risk for exposure to teats and development of intramammary infections. PMID- 24630655 TI - Treatment with a nonsteroidal antiinflammatory drug after calving did not improve milk production, health, or reproduction parameters in pasture-grazed dairy cows. AB - Previous research results have indicated an increase in pregnancy rate in pasture grazed cows treated with a nonsteroidal antiinflammatory drug (NSAID) 3 to 4 wk postcalving, when a high proportion of nucleated cells from within the uterus were polymorphonucleated; however, no effect on milk production was detected. It was hypothesized that this lack of effect on milk production was because the administration of the NSAID was too late after calving. The aims of the current study were to evaluate the timing of administering a propionic acid-derived NSAID (i.e., carprofen) on milk production, metabolic status, uterine health, and reproductive performance. Six-hundred and thirty-nine cows (134 primiparous and 505 multiparous) calving between July 4 and September 5, 2012, in 2 herds (herd 1: n=228; herd 2: n=411) were enrolled. Using a randomized block design, cows were allocated to 1 of 3 treatment groups as they calved: (1) no treatment (control; n=221), (2) NSAID administered on d 1, 3, and 5 postcalving (early; n=214), and (3) NSAID administered on d 19, 21, and 23 postcalving (late; n=204). Milk production and composition, and body condition were determined weekly. Blood was sampled at 4 time points (1 precalving and 3 postcalving) to determine the effects of treatment on indicators of metabolic health and energy status. Uterine health was determined by measuring the proportion of nucleated cells that were polymorphonucleated following cytobrush sampling of the uterus between d 13 to 24 and d 30 to 49 postcalving. Irrespective of timing of application, NSAID did not affect milk production, body weight, or body condition during early lactation. Treatment with an NSAID 19 to 23 d postcalving increased the proportion of cows submitted for breeding during the first 3 wk of the seasonal breeding program (control: 85%, early: 83%, and late: 92%), but did not affect conception or pregnancy rates. No detectable effect of treatment on uterine health or circulating metabolites and minerals existed, although cows in the early NSAID treatment group had marginally lower serum beta-hydroxybutyrate concentrations (0.1 mmol/L) than the other groups between 2 and 26 d in milk. In conclusion, administration of this particular NSAID at either 1 or 3 wk after calving did not improve milk production, indicators of health, or reproductive performance. PMID- 24630656 TI - Within- and across-breed genomic predictions and genomic relationships for Western Pyrenees dairy sheep breeds Latxa, Manech, and Basco-Bearnaise. AB - Genotypes, phenotypes and pedigrees of 6 breeds of dairy sheep (including subdivisions of Latxa, Manech, and Basco-Bearnaise) from the Spain and France Western Pyrenees were used to estimate genetic relationships across breeds (together with genotypes from the Lacaune dairy sheep) and to verify by forward cross-validation single-breed or multiple-breed genetic evaluations. The number of rams genotyped fluctuated between 100 and 1,300 but generally represented the 10 last cohorts of progeny-tested rams within each breed. Genetic relationships were assessed by principal components analysis of the genomic relationship matrices and also by the conservation of linkage disequilibrium patterns at given physical distances in the genome. Genomic and pedigree-based evaluations used daughter yield performances of all rams, although some of them were not genotyped. A pseudo-single step method was used in this case for genomic predictions. Results showed a clear structure in blond and black breeds for Manech and Latxa, reflecting historical exchanges, and isolation of Basco Bearnaise and Lacaune. Relatedness between any 2 breeds was, however, lower than expected. Single-breed genomic predictions had accuracies comparable with other breeds of dairy sheep or small breeds of dairy cattle. They were more accurate than pedigree predictions for 5 out of 6 breeds, with absolute increases in accuracy ranging from 0.05 to 0.30 points. They were significantly better, as assessed by bootstrapping of candidates, for 2 of the breeds. Predictions using multiple populations only marginally increased the accuracy for a couple of breeds. Pooling populations does not increase the accuracy of genomic evaluations in dairy sheep; however, single-breed genomic predictions are more accurate, even for small breeds, and make the consideration of genomic schemes in dairy sheep interesting. PMID- 24630657 TI - Correlation between standard plate count and somatic cell count milk quality results for Wisconsin dairy producers. AB - The objective of this study was to determine if a correlation exists between standard plate count (SPC) and somatic cell count (SCC) monthly reported results for Wisconsin dairy producers. Such a correlation may indicate that Wisconsin producers effectively controlling sanitation and milk temperature (reflected in low SPC) also have implemented good herd health management practices (reflected in low SCC). The SPC and SCC results for all grade A and B dairy producers who submitted results to the Wisconsin Department of Agriculture, Trade, and Consumer Protection, in each month of 2012 were analyzed. Grade A producer SPC results were less dispersed than grade B producer SPC results. Regression analysis showed a highly significant correlation between SPC and SCC, but the R(2) value was very small (0.02-0.03), suggesting that many other factors, besides SCC, influence SPC. Average SCC (across 12 mo) for grade A and B producers decreased with an increase in the number of monthly SPC results (out of 12) that were <= 25,000 cfu/mL. A chi-squared test of independence showed that the proportion of monthly SCC results >250,000 cells/mL varied significantly depending on whether the corresponding SPC result was <= 25,000 or >25,000 cfu/mL. This significant difference occurred in all months of 2012 for grade A and B producers. The results suggest that a generally consistent level of skill exists across dairy production practices affecting SPC and SCC. PMID- 24630658 TI - Peripartal progesterone and prolactin have little effect on the rapid transport of immunoglobulin G into colostrum of dairy cows. AB - Colostrum formation and lactogenesis in the mammary gland and the timing of parturition are regulated by endocrine signals. Changes in progesterone (P4) and prolactin (PRL) are considered key events that inhibit colostrum formation, trigger parturition, and signal the onset of lactation. The goal of our study was to determine if colostrum yield and composition and immunoglobulin transfer are affected by prepartum milking relative to the decrease in P4, peak of PRL, or occurrence of parturition. Twenty-three multiparous cows were randomly assigned to 1 of 2 groups: (1) control with first milking at 4h postcalving (CON, n=11), and (2) treatment group with first milking approximately 1d before calving and second milking at 4h after parturition (APM, n=12). Colostrum yields were recorded and proportional samples were analyzed for immunoglobulin G (IgG) concentration. Blood plasma samples for the analyses of P4 and PRL were collected 3 times daily at 8-h intervals for 4d prepartum and again taken at 4h after parturition. Total colostrum mass of APM cows was higher than that of CON cows. Immunoglobulin G concentration and protein content did not differ between antepartum milking in APM cows and postpartum milking in CON cows. Colostrum IgG concentration and protein content in APM cows at the postpartum milking were lower compared with the IgG concentration established at the prepartum (APM) and postpartum milkings of CON cows. Immunoglobulin G mass did not differ in first and second colostrum collection in APM cows but was lower compared with that of CON cows. The sum of IgG mass in APM cows (prepartum + postpartum collections) did not differ from that of CON cows. Lactose and fat in milk (concentration and mass) increased from first to second milking in APM cows. Total mass of lactose and fat in APM cows (prepartum + postpartum collections) was greater compared with that of CON cows. The finding that the time of milking relative to parturition, P4 decrease, and PRL peak slightly affected yield and quality of colostrum emphasizes the complex interactions of numerous endocrine and morphological changes occurring during colostrogenesis and lactogenesis in dairy cows. The considerably rapid transfer of immunoglobulins into colostrum of prepartum-milked cows within a few hours leads to the hypothesis that the transfer of IgG can be very fast and-contrary to earlier findings-persist at least until parturition. PMID- 24630659 TI - The energy expenditure of 2 Holstein cow strains in an organic grazing system. AB - Until recently, measurements of energy expenditure (EE; herein defined as heat production) in respiration chambers did not account for the extra energy requirements of grazing dairy cows on pasture. As energy is first limiting in most pasture-based milk production systems, its efficient use is important. Therefore, the aim of the present study was to compare EE, which can be affected by differences in body weight (BW), body composition, grazing behavior, physical activity, and milk production level, in 2 Holstein cow strains. Twelve Swiss Holstein-Friesian (HCH; 616 kg of BW) and 12 New Zealand Holstein-Friesian (HNZ; 570 kg of BW) cows in the third stage of lactation were paired according to their stage of lactation and kept in a rotational, full-time grazing system without concentrate supplementation. After adaption, the daily milk yield, grass intake using the alkane double-indicator technique, nutrient digestibility, physical activity, and grazing behavior recorded by an automatic jaw movement recorder were investigated over 7d. Using the (13)C bicarbonate dilution technique in combination with an automatic blood sampling system, EE based on measured carbon dioxide production was determined in 1 cow pair per day between 0800 to 1400 h. The HCH were heavier and had a lower body condition score compared with HNZ, but the difference in BW was smaller compared with former studies. Milk production, grass intake, and nutrient digestibility did not differ between the 2 cow strains, but HCH grazed for a longer time during the 6-h measurement period and performed more grazing mastication compared with the HNZ. No difference was found between the 2 cow strains with regard to EE (291 +/- 15.6 kJ) per kilogram of metabolic BW, mainly due to a high between-animal variation in EE. As efficiency and energy use are important in sustainable, pasture-based, organic milk production systems, the determining factors for EE, such as methodology, genetics, physical activity, grazing behavior, and pasture quality, should be investigated and quantified in more detail in future studies. PMID- 24630660 TI - Effects of an exogenous protease on the fermentation and nutritive value of corn silage harvested at different dry matter contents and ensiled for various lengths of time. AB - The objective of this experiment was to evaluate the effects of adding an experimental protease to corn plants harvested at different maturities on silage fermentation and in vitro ruminal starch digestibility (IVSD). Corn plants were harvested at maturities resulting in plants with 31 or 40% dry matter (DM). Plants were chopped, kernel processed, and treated with (1) only a 0.1 M phosphate buffer (pH 5.5, 5% vol/wt of fresh forage), (2) buffer with protease to obtain a final concentration of 20mg of protease/kg of wet forage, and (3) buffer with protease to obtain a final concentration of 2,000 mg of protease/kg of wet forage. Treated forages (about 500 g) were ensiled in nylon-polyethylene pouches and stored between 21 and 23 degrees C for 0, 45, 90, and 150 d. Data were analyzed as a 2 * 3 * 4 factorial arrangement of treatments, with the main effects of harvest DM, dose of protease, days of ensiling, and their interactions. The treatment with the highest dose of protease resulted in more robust fermentations across harvest DM with higher concentrations of lactic and acetic acids compared with untreated silage. Concentrations of soluble protein (% of crude protein) increased with time of ensiling, regardless of DM content at harvest. However, averaged over both harvest DM contents, it increased by 37% for silages treated with the high dose of protease compared with an average 11% increase for untreated silages and silage treated with the low dose of protease, between d 0 and 45. Averaged over both harvest DM contents, the concentration of soluble protein peaked in silages treated with the high dose of protease after 45 d of ensiling, whereas it peaked at d 90 in untreated silages and silage treated with the low dose of protease. Similar changes occurred in the concentration of NH3-N due to length of ensiling and treatment with protease. In fresh forages, the concentration of starch for early- and late-harvested forages was similar, but IVSD was lower in the latter. After 45 d of ensiling, IVSD was highest in both early- and late-harvested silages that were treated with the high level of protease. After 150 d of ensiling, IVSD was similar among silages treated with protease, regardless of DM at harvest. Treating corn plants with a high dose of an experimental protease at harvest accelerated proteolysis during ensiling, resulting in corn silages with levels of IVSD after 45 d of ensiling that were only obtained in untreated corn silages after 150 d of ensiling. PMID- 24630661 TI - Short communication: Automatic detection of social competition using an electronic feeding system. AB - The objective of this study was to determine if data derived from a system that electronically monitors feeding behavior could be used to identify competitive interactions of dairy cows at the feed bunk. A short interval between successive feeding events of 2 cows at 1 feed bin was predicted to be associated with a competitive replacement: when one cow displaced a feeding cow and then took her position at the bin. To identify the interval between feeding events that best predicted these replacement events, the feeding activity of 5 Holstein dairy cows was monitored using an electronic feeding system and video recordings. The number of times a cow was replaced at the feed bunk over 3 consecutive 24-h periods was determined using video analysis and these events were paired with the corresponding feeding events recorded by an electronic feeding system (Roughage Intake Control system; Insentec B.V., Marknesse, the Netherlands). A pooled analysis of all 5 cows showed that the optimal interval for predicting replacements at the feed bunk was 26s (sensitivity=86% and specificity=82%); this interval was termed the replacement criterion. This criterion was then applied to feeding data from a sample of 24 independent Holstein dairy cows, each observed for 3d during the week following calving. Video had previously been used to measure the number of times each cow was an actor and reactor of a displacement (when one cow displaced a feeding cow but did not necessarily take her position at the bin). Despite the differences in measures, the number of replacements (as estimated by our algorithm) was positively correlated with the number of displacements [as measured using video; correlation coefficient (r)=0.63 as actor, r=0.69 as reactor]. Estimates of an index of success in competitive interactions (number of times actor/number of times actor = number of times reactor) generated using the 2 methods were highly correlated (r=0.94). These results suggest that competitive behavior at the feed bunk can be automatically quantified using data derived from an electronic feeding system. PMID- 24630662 TI - Technical note: Effects of frozen storage on the mechanical properties of the suspensory tissue in the bovine claw. AB - It is proposed that a softening of the suspensory tissue in the claw is involved in the development of lameness and claw lesions in cattle. A relatively small amount of research has been carried out to verify this theory. Research in this area would be simplified if mechanical testing of the suspensory tissue could be performed on frozen and stored specimens. The current study tested whether freezing of the specimens changes the suspensory tissues' mechanical properties. Limbs from 3 freshly slaughtered Danish Holstein dairy cows and 6 nonpregnant Angus heifers, without clinical signs of lameness, were allocated to 1 of 2 treatments (frozen or nonfrozen) in such a way that each cow was represented in each treatment group with a frozen limb and a corresponding nonfrozen limb (i.e., frozen left front, fresh right front, and so on). The frozen limbs were kept at 18 degrees C for a week before processing and the nonfrozen limbs were processed within 2h of slaughter. Two samples measuring 8 * 8 mm were cut from the abaxial side of each claw in such a way that the sample included the horn of the abaxial wall, pedal bone, and the interposed corium. The samples were kept on ice until being mounted in a large deformation rheometer with an extension testing frame, fixed by the horn and the pedal bone, and loaded to failure. During deformation force and displacement data were recorded, from which corresponding stress and strain were calculated. Young's modulus (a measure of tissue elasticity or stiffness) and a measure of physiological support (PS; force needed to displace the sample 1mm) were calculated from the data. The response variables, Young's modulus and PS, were analyzed separately by a mixed model. The explanatory variables were treatment (frozen or nonfrozen), limb (front or back), claw (medial or lateral), position of the sample (dorsal or palmar-plantar), and group (Angus or Holstein). Interactions between group and treatment and between limb, claw, and sample position were included in the model. Cow identity was included as a random effect. Model reduction was performed by stepwise backward elimination, until all remaining terms were significant at the 5% level or less. Freezing had no effect on the elasticity of the suspensory apparatus or on PS. However, PS was affected by limb (hind legs had higher PS values than front) and the position of the sample (palmar-plantar samples had higher PS values than dorsal). The Angus group had higher PS values than the Holstein group, but the groups differed in age, parity, body weight, lactation, housing, and management, as well as in breed; therefore, further studies are needed to investigate these effects. The results indicate that mechanical testing of bovine claw suspensory tissue can be performed on specimens that have been frozen, thus aiding research in the mechanical aspect of bovine lameness and claw lesions. PMID- 24630663 TI - Genetic merit for fertility traits in Holstein cows: IV. Transition period, uterine health, and resumption of cyclicity. AB - The objective of this study was to monitor the dry matter intake (DMI), metabolic status, uterine health, and resumption of cyclicity in cows with similar genetic merit for milk production traits but with either good (Fert+) or poor genetic merit (Fert-) for fertility traits. Twenty-six cows were enrolled in the study and data are reported for 15 Fert+ and 10 Fert- cows that completed the study. All cows received a total mixed ration diet during early lactation and were turned out to pasture in late spring. Dry matter intake was recorded daily from wk -2 to 5 relative to parturition. Blood metabolites and metabolic hormones were measured from wk -2 to 8 relative to parturition. Milk production, body condition score, and body weight until wk 35 of lactation are reported. To monitor uterine health, vaginal mucus was scored weekly on a scale of 0 (no pus) to 3 (>= 50% pus) from parturition to wk 8 and uterine polymorphonuclear neutrophil count was measured at wk 3 and 6 postpartum. Prepartum DMI was similar between genotypes, but Fert+ cows had significantly greater DMI than Fert- cows (19.7 vs. 16.8 kg of dry matter/d) during the postpartum period. Energy balance at wk 1 was significantly greater in Fert+ cows than in Fert- cows [2.3 vs. -1.12 unite fourragere lait (UFL)/d]. The Fert+ cows had significantly greater daily milk solids production (1.89 vs. 1.74 kg/d) and tended to have greater daily milk yield (24.2 vs. 22.3 kg/d). The Fert+ cows had significantly greater mean circulating insulin-like growth factor-I (102.62 vs. 56.85 ng/mL) and tended to have greater mean circulating insulin (3.25 vs. 2.62 MUIU/mL) compared with Fert- cows from wk -2 to 8 relative to parturition. Mean circulating glucose (3.40 vs. 3.01 mmol/L) concentrations were significantly greater in Fert+ cows compared with Fert- cows from wk -2 to 3 relative to parturition. The Fert+ cows maintained significantly greater mean body condition score throughout lactation compared with Fert- cows (2.98 vs. 2.74 units). Moreover, Fert+ cows had better uterine health compared with Fert- cows, as evidenced by lower weekly vaginal mucus scores from wk 2 to 6 postpartum and, based on uterine cytology, smaller proportions were classified as having endometritis at wk 3 (0.42 vs. 0.78) and 6 (0.25 vs. 0.75). Also, a significantly greater proportion of Fert+ cows had resumed cyclicity by wk 6 postpartum (0.86 vs. 0.20) compared with Fert- cows. Hence, we report for the first time that genetic merit for fertility traits is associated with postpartum uterine health status. Superior uterine health and earlier resumption of cyclicity may be mediated through differences in DMI, energy balance, insulin, insulin-like growth factor-I, and body condition score profiles. Importantly, phenotypic improvement in fertility traits was achieved without antagonizing milk production. PMID- 24630664 TI - Diurnal variations of progesterone, testosterone, and androsta-1,4-diene-3,17 dione in the rumen and in vitro progesterone transformation by mixed rumen microorganisms of lactating dairy cows. AB - Five Holstein lactating dairy cows fed 5 total mixed rations (TMR) with different forage combinations were used in a 5 * 5 Latin square design to investigate diurnal variations of progesterone (P4), testosterone, and androsta-1,4-diene 3,17-dione (ADD) concentrations in the rumen. Meanwhile, different P4 inclusion levels [0 (control), 2, 20, 40, 80, and 100 ng/mL in culture fluids] were incubated in vitro for 6, 12, 24, 36, 48, and 72 h together with rumen mixed microorganisms grown on a maize-rich feed mixture (maize meal:Chinese ryegrass hay = :1) with an aim to determine microbial P4 transformation into testosterone and ADD. Ruminal P4, testosterone, and ADD concentrations of lactating dairy cows were greater in the TMR with forage combination of corn silage plus alfalfa hay or Chinese wild ryegrass hay than the TMR with the corn stover-based forage combination. The diurnal fluctuation pattern showed that P4, testosterone, and ADD concentrations in the rumen were greater at nighttime than daytime and peaked 6h after feeding in the morning or afternoon. The in vitro batch cultures showed that the P4 elimination rate was highest at the P4 addition of 20 ng/mL and declined with the further increased addition of P4. The treatments after dosing P4 exhibited a shorter time than the control group until half of the initial P4 inclusion was eliminated (i.e., half time), and the lowest half time (1.46 h) occurred at the P4 addition of 20 ng/mL. In summary, the ruminal steroids concentration was affected by forage type and quality, and the rumen microorganisms exhibited great ability to transform P4 into testosterone and ADD, depending on incubation time and initial P4 addition level, suggesting that the host might affect the metabolism of its rumen microorganisms via the endogenous steroids. PMID- 24630665 TI - Regulation of lipid droplet-associated proteins following growth hormone administration and feed restriction in lactating Holstein cows. AB - Lipid metabolism plays a crucial role in the adaptation of dairy cows to periods of energy insufficiency. The objective of the current study was to determine if lipolytic proteins are consistently regulated when energy mobilization is stimulated by different factors. We evaluated 2 models of altered energy balance in mid-lactation Holstein cows, including feed restriction (FR) and administration of bovine growth hormone (GH), by quantifying the abundance and (or) phosphorylation of hormone-sensitive lipase (HSL), perilipin (PLIN), and adipose triglyceride lipase (ATGL). For GH administration, adipose tissue and blood samples were collected 4d before and 3 and 7d after administration of GH (n=20 cows). Similarly, adipose and blood samples were obtained 6d before and 1 and 4d after initiation of FR (n=18 cows). Estimated net energy balance decreased and nonesterified fatty acid concentration increased in both experimental models. Decreased ATGL and PLIN protein abundance was observed with GH administration and FR. Additionally, the abundance of phosphorylated HSLSer565 decreased in both models. Decreased abundance of phosphorylated PLIN was observed with GH administration, but not FR. Decreased ATGL protein abundance appears to be a consistent response to energy insufficiency in lactating cows, as this response was also described with negative energy balance at the onset of lactation. In contrast, the abundance of PLIN protein and phosphorylation of HSL using antibodies targeting serine residue 565 of HSL (HSLSer565) were altered in the current research, but not at the onset of lactation. Our findings demonstrate that lipolysis is altered through the regulation of multiple proteins, and that this regulation differs according to physiological state in lactating cows. PMID- 24630666 TI - Effect of prepartum grouping strategy on displacements from the feed bunk and feeding behavior of dairy cows. AB - The objective of the current study was to determine whether providing stable pen management affected displacements from the feed bunk and feeding behavior of prepartum dairy cows. Two hundred and twenty-four nonlactating Jersey primiparous and multiparous cows were enrolled in the study. The 2 treatments were all-in-all out (AIAO; 44 cows were moved into the close-up prepartum pen as 1 group, with no additions during the 5-wk repetition) or traditional (TRD; with weekly entrance of new cows to maintain a pen density of 44 cows). Cows (253 +/- 3 d of gestation) were balanced for parity and projected 305-d mature-equivalent milk yield and assigned randomly to either AIAO or TRD treatments. At enrollment, cows with a body condition score <2 or >4 (1-5 scale; 1 = emaciated and 5 = obese) or with a locomotion score >3 (1-5 scale; 1 = normal gait and 5 = severely lame) were not included. Displacements from the feed bunk were measured weekly for both treatments when TRD cows were moved into the close-up pen (d 0) and additionally on d 1, 2, 3, and 7 for 3h after fresh feed delivery. A displacement rate was created to take into account differences in stocking density throughout the experiment. Displacement rate was calculated as the number of displacements divided by the number of cows in the pen at that time. Feeding behavior was measured using video 10-min scan sampling for 24-h periods at d 0, 1, 2, and 7. Displacements and feeding behavior were recorded for all 5 wk of each repetition. Treatment * week interactions were detected for number of displacements and displacement rate. The TRD treatment had more displacements from the feed bunk than AIAO in wk 1, 3, and 5, with no differences in wk 2 and 4. Similarly, the TRD treatment had a greater displacement rate than the AIAO treatment in wk 1 and 5, with a tendency in wk 3. No differences between the treatments were detected in wk 2 and 4. A treatment * week interaction existed for feeding time. Cows housed in the AIAO treatment had longer average feeding times in wk 2 with a tendency in wk 3, but spent 39 fewer minutes eating than those in the TRD treatment during the wk 1 of the study. Housing prepartum close-up cows with stable pen management reduced displacements from the feed bunk and altered average daily feeding times. PMID- 24630667 TI - Reproductive performance of lactating dairy cows managed for first service using timed artificial insemination with or without detection of estrus using an activity-monitoring system. AB - Lactating dairy cows (n=1,025) on a commercial dairy farm were randomly assigned at 10 +/- 3 d in milk (DIM) to 1 of 3 treatments for submitting cows to first artificial insemination (AI) and were fitted with activity-monitoring tags (Heatime; SCR Engineers Ltd., Netanya, Israel) at 24 +/- 3 DIM. Cows (n=339) in treatment 1 were inseminated based on increased activity from the end of the voluntary waiting period (50 DIM) until submission to an Ovsynch protocol; cows without increased activity from 21 to 65 DIM began an Ovsynch protocol at 65 +/- 3 DIM, whereas cows without increased activity from 21 to 50 DIM but not from 51 to 79 DIM began an Ovsynch protocol at 79 +/- 3 DIM. Cows (n=340) in treatment 2 were inseminated based on activity after the second PGF2alpha injection of a Presynch-Ovsynch protocol at 50 DIM, and cows without increased activity began an Ovsynch protocol at 65 +/- 3 DIM. Cows (n=346) in treatment 3 were monitored for activity after the second PGF2alpha injection of a Presynch-Ovsynch protocol, but all cows received timed AI (TAI) at 75 +/- 3 DIM after completing the Presynch Ovsynch protocol. The activity-monitoring system detected increased activity in 56, 69, and 70% of cows in treatments 1, 2, and 3, respectively. Treatment-2 cows had the fewest average days to first AI (62.5), treatment-3 cows had the most average days to first AI (74.9), and treatment-1 cows had intermediate average days to first AI (67.4). Treatment-1 and -2 cows in which inseminations occurred as a combination between increased activity and TAI had fewer overall pregnancies per AI (P/AI) 35 d after AI (32% for both treatments) compared with treatment-3 cows, all of which received TAI after completing the Presynch-Ovsynch protocol (40%). Based on survival analysis, although the rate at which cows were inseminated differed among treatments, treatment did not affect the proportion of cows pregnant by 300 DIM. Thus, use of an activity-monitoring system to inseminate cows based on activity reduced days to first AI, whereas cows receiving 100% TAI after completing a Presynch-Ovsynch protocol had more P/AI. The trade-off between AI service rate and P/AI in the rate at which cows became pregnant was supported by an economic analysis in which the net present value ($/cow per year) differed by only $4 to $8 among treatments. We conclude that a variety of strategies using a combination of AI based on increased activity using an activity-monitoring system and synchronization of ovulation and TAI can be used to submit cows for first AI. PMID- 24630668 TI - Multiple cases of methicillin-resistant CC130 Staphylococcus aureus harboring mecC in milk and swab samples from a Bavarian dairy herd. AB - The discovery of a new mecA homolog, mecC, necessitates a modification of diagnostic procedures for the identification of methicillin-resistant Staphylococcus aureus (MRSA), as most assays used for the genotypic and phenotypic mecA detection cannot currently recognize mecC. Although the prevalence, distribution, and importance of mecC are not yet completely understood, an exchange of mecC-MRSA between humans and animals seems possible. All previously reported observations of mecC-positive strains have been sporadic. To the best of our knowledge, this is the first report about multiple cases of mecC-positive Staph. aureus in 1 dairy herd. Clonal complex 130 Staph. aureus harboring mecC were found in milk samples from 16 of 56 lactating cows kept in a herd in Bavaria, Germany. Almost all quarter milk samples positive for mecC-MRSA had the lowest possible California Mastitis Test score; composite somatic cell counts obtained from monthly milk recordings showed a mean of 51,600 cells/mL in mecC-MRSA affected cows. Additionally, mecC-positive clonal complex 130 Staph. aureus were detected in swab samples from the mammary skin and a teat lesion of 1 cow from this herd. This report suggests that mecC-carrying strains are able to spread among livestock, and that they have the ability to cause multiple cases in single herds. Therefore, future studies targeting MRSA in dairy cows need to consider mecC. PMID- 24630669 TI - Supplemental fat for dairy calves during mild cold stress. AB - Eighty-one Holstein and Holstein-cross dairy calves fed calf milk replacer (CMR) were used to determine response to increasing amounts of supplemental fat during mild cold stress. Calves (n=27) were randomly assigned to 1 of 3 treatments: (1) low fat [LF; 28% crude protein:15% fat milk replacer (28:15 MR)]; (2) medium fat [MF; 28:15 MR+113 g/d of commercial fat supplement (FS)]; (3) high fat (HF; 28:15 MR+227 g/d of FS). The MF and HF calves received FS from d 2 to 21, and all calves were fed LF from d 22 to 49. The CMR was fed at 1.4% of birth body weight (BBW) from d 1 to 10, at 1.8% of BBW from d 11 to 42, and at 0.9% of BBW from d 43 to 49. Calves were weaned on d 49 and remained in hutches until d 56. The CMR was reconstituted to 13% solids. Calves were fed a commercial starter grain (19.2% crude protein on a dry matter basis) ad libitum and offered warm water after CMR feeding. Calves were fed CMR twice daily at 0630 and 1730 h in hutches bedded with straw. Starter intake, CMR intake, and ambient temperature were measured daily, and body weight (BW), hip height, and body length were measured weekly. Data were analyzed using PROC MIXED in SAS (SAS Institute Inc., Cary, NC) as a randomized design with linear and quadratic contrasts. Calf BBW averaged 42.0 +/- 1.0 kg, total serum protein averaged 5.8 +/- 0.1mg/dL, and birth ambient temperature averaged 5.0 +/- 1.1 degrees C. Feeding FS increased metabolizable energy intake (MEI) over maintenance but decreased efficiency of conversion of BW gain:MEI. Starter intake by LF calves was greatest until the beginning of weaning, after which starter intake was similar among treatments. Because of higher starter intake, total MEI was similar among treatments. Feed efficiency through d 49 was greater for calves fed MF and HF. Average daily gain during fat supplementation was greater for MF and HF than for LF. Lack of increase in BW gain and feed efficiency between MF and HF treatments indicated that HF did not result in advantages over MF. Supplementing fat to preweaned calves fed CMR increased BW gain and decreased starter intake through d 21 which had carryover effects on starter intake on d 49 and reduced hip height and tended to reduced withers height and body length by d 56. The addition of supplemental fat to LF, during mild cold stress, may result in a suboptimal ratio of crude protein to metabolizable energy in the CMR. PMID- 24630670 TI - Lactose and galactose content in cheese results in overestimation of moisture by vacuum oven and microwave methods. AB - Moisture determination in cheese is a critical test for regulatory compliance, functionality, and economic reasons. Common methods for moisture determination in cheese rely upon the thermal volatilization of water from cheese and calculation of moisture content based on the resulting loss of mass. Residual sugars, such as lactose and galactose, are commonly present in cheeses at levels ranging from trace amounts to 5%. These sugars are capable of reacting with other compounds in cheese, especially under the thermal conditions required for moisture determination, to yield volatile reaction products. The hypothesis of this work is that residual sugars in cheese will be converted into volatile compounds over the course of moisture determination at a level sufficient to result in overestimated cheese moisture. A full-factorial statistical design was used to evaluate the effects of cheese type, sugar type, sugar level, method type, and all interactions. Cheddar and low-moisture, part-skim (LMPS) Mozzarella cheeses were prepared with 1, 3, and 5% added lactose or galactose, and subjected to either vacuum oven or microwave-based moisture determination methods. Browning index and colorimetry were measured to characterize the color and extent of browning. Volatile analyses were performed to provide chemical evidence of the reactions proposed. The presence of residual sugars altered moisture calculations as a function of cheese type, sugar type, sugar level, method type, and numerous interactions. At higher concentrations of residual sugar, the percentage moisture determinations were increased by values of up to 1.8. Measures of browning reactions, including browning index, colorimetry, and volatile profiles demonstrate that the proposed browning reactions played a causative role. This work establishes the need to consider cheese type, sugar type, sugar levels, and method type as a means of more accurately determining moisture levels. PMID- 24630671 TI - Effect of a short dry period on milk yield and content, colostrum quality, fertility, and metabolic status of Holstein cows. AB - We evaluated the effect of shortening the dry period (DP) on milk and energy corrected milk (ECM) yields, milk components, colostrum quality, metabolic status, and reproductive parameters. Primiparous (n=372) and multiparous (n=400) Israeli Holstein cows from 5 commercial dairy herds were subjected to a 60-d or 40-d DP. Cows within each herd were paired according to milk production, age, days in milk, and expected calving. Analysis of the data from all cows, irrespective of age, revealed significant differences in milk and ECM yields that favored the 60-d DP, with a prominent effect in 2 of 5 examined herds. In primiparous cows, milk and ECM yields were similar between groups in 4 of 5 farms. In multiparous cows undergoing a 60-d (vs. 40-d) DP, milk and ECM yields were higher in 3 herds. These differences could not be explained by milk and ECM yields in cows diagnosed with metritis, ketosis, and mastitis (defined by a somatic cell count threshold of 250,000 cell/mL), distribution of infected and noninfected cows, or new infections during DP and after calving. Including the milk and ECM yields from an average of 19.55 d from the previous lactation revealed higher milk and ECM yields for 40-d (vs. 60-d) DP cows in all herds. Analyzing 2 consecutive lactations revealed similar milk and ECM yields between groups in 4 out of 5 herds. In 1 herd, yields were higher in the 40-d compared with the 60-d DP group. One week after calving, the nonesterified fatty acid concentrations of 40-d DP cows were significantly lower than those of 60-d DP cows, indicating better postpartum energy balance. Colostrum quality, measured as IgG concentration, did not differ between the 2 DP groups. Cows assigned to 40-d DP had better reproductive performance, as reflected by fewer days to first insemination, a lower proportion with >90 d to first insemination, and fewer days to pregnancy. With respect to primiparous cows, a short DP increased conception rate after first artificial insemination and decreased the proportion of nonpregnant cows after 150 d in milk. In light of these findings, we suggest that a short DP be applied for its economic and physiological benefits. This is highly relevant to dairy herds located in regions such as Israel, Spain, and Florida that suffer from reduced milk production during the hot season. PMID- 24630672 TI - Re: Gonenc M, Dural AC, Celik F, et al: Enhanced postoperative recovery pathways in emergency surgery: a randomized controlled clinical trial. PMID- 24630673 TI - Overview and phylogeny of Mycobacterium tuberculosis complex organisms: implications for diagnostics and legislation of bovine tuberculosis. AB - Members of the Mycobacterium tuberculosis complex (MTBC) cause a serious disease with similar pathology, tuberculosis; in this review, bovine tuberculosis will be considered as disease caused by any member of the MTBC in bovids. Bovine tuberculosis is responsible for significant economic loss due to costly eradication programs and trade limitations and poses a threat to both endangered and protected species as well as to public health. We here give an overview on all members of the MTBC, focusing on their isolation from different animal hosts. We also review the recent advances made in elucidating the evolutionary and phylogenetic relationships of members of the MTBC. Because the nomenclature of the MTBC is controversial, its members have been considered species, subspecies or ecotypes, this review discusses the possible implications for diagnostics and the legal consequences of naming of new species. PMID- 24630674 TI - Open access publishing: a disruptive innovation. PMID- 24630675 TI - Diverse voices. PMID- 24630676 TI - Response to: Development of integrated mental health care: critical workforce competencies. PMID- 24630677 TI - Commentary on: Vessey, J.A., diFazio, R.L., & Strout, T.D. (2013). Youth bullying: a review of the science and a call to action. Nursing Outlook, 61, 337 345. PMID- 24630678 TI - Veteran Affairs Centers of Excellence in Primary Care Education: transforming nurse practitioner education. AB - To integrate health care professional learners into patient-centered primary care delivery models, the Department of Veterans Affairs has funded five Centers of Excellence in Primary Care Education (CoEPCEs). The main goal of the CoEPCEs is to develop and test innovative structural and curricular models that foster transformation of health care training from profession-specific "silos" to interprofessional, team-based educational and care delivery models in patient centered primary care settings. CoEPCE implementation emphasizes four core curricular domains: shared decision making, sustained relationships, interprofessional collaboration, and performance improvement. The structural models allow interprofessional learners to have longitudinal learning experiences and sustained and continuous relationships with patients, faculty mentors, and peer learners. This article presents an overview of the innovative curricular models developed at each site, focusing on nurse practitioner (NP) education. Insights on transforming NP education in the practice setting and its impact on traditional NP educational models are offered. Preliminary outcomes and sustainment examples are also provided. PMID- 24630679 TI - Becoming a nurse faculty leader: taking risks by doing the right thing. AB - Risk taking is a key aspect of academic leadership essential to meeting the challenges and opportunities in higher education. What are the practices of risk taking in nurse faculty leaders? This interpretive phenomenological study examines the experience and meaning of risk taking among nurse leaders. The theme of doing the right thing is brought forth through in-depth hermeneutic analysis of 14 individual interviews and two focus group narratives. The practice of doing the right thing is propelled and captured by leaders through a sense professional responsibility, visioning the future, and being true to self and follow one's core values. This study develops an evidence base for incorporating ways of doing the right thing in leadership development activities at a time when there is tremendous need for highly effective leaders in academic settings. Examining the practices of doing the right thing as a part of leadership development lays a foundation for building the next generation of nursing leaders prepared to navigate the ever-changing and complex academic and health care environments. PMID- 24630680 TI - Credentialing: the need for a national research agenda. AB - A national research agenda is needed to promote inquiry into the impact of credentialing on health care outcomes for nurses, patients, and organizations. Credentialing is used here to refer to individual credentialing, such as certification for nurses, and organizational credentialing, such as American Nurses Credentialing Center Magnet recognition for health care organizations or accreditation of providers of continuing education in nursing. Although it is hypothesized that credentialing leads to a higher quality of care, more uniform practice, and better patient outcomes, the research evidence to validate these views is limited. This article proposes a conceptual model in which both credentials and standards are posited to affect outcomes in health care. Potential research questions as well as issues in research design, measurement, data collection, and analysis are discussed. Credentialing in nursing has implications for the health care professions and national policy. A growing body of independent research that clarifies the relationship of credentialing in nursing to outcomes can make important contributions to the improvement of health care quality. PMID- 24630681 TI - What clinical activities do advanced-practice registered dietitian nutritionists perform? Results of a Delphi study. AB - Activities performed by advanced-practice registered dietitian nutritionists (RDNs) have yet to be clearly elucidated. The study aimed to gain consensus on the practice activities of advanced-practice RDNs who provide direct clinical nutrition care. A three-round Delphi study was conducted. Purposive sampling identified 117 RDN experts working as clinicians and/or managers in direct care settings that met inclusion criteria for advanced-level practice. In Round 1, 85 experts provided open-ended advanced-level practice activities linked to the Nutrition Care Process sections. Using content analysis, the responses were coded into activity statements. In Round 2, experts rated the essentiality of these activities. In Round 3, experts re-rated statements not reaching consensus while viewing their previous rating, the group median, and comments. Median ratings of 1.0 to 3.0 were defined as essential, 4.0 were neither essential nor nonessential, and 5.0 to 7.0 were nonessential. Consensus was reached when the interquartile range of responses to each question was <2.0. Seventy-six (89.4%) experts completed all rounds. From 770 comments, 129 activity statements were generated. All statements reached consensus: 97.7% as essential; 0.8% as nonessential; and 1.5% as neither. Of essential activities, 67.5% were highly essential with limited variability (median=1.0; interquartile range<=2.0). Advanced-practice RDNs' tasks are patient-centered and reflect complex care; involve a comprehensive and discriminating approach; are grounded in advanced knowledge and expertise in clinical nutrition; include use of advanced interviewing, education, and counseling strategies; and require communication with patient, families, and the health care team. The high-level of consensus from experts suggest advanced-level clinical nutrition practice exists and can be defined. PMID- 24630682 TI - Cruciferous vegetable intake is inversely correlated with circulating levels of proinflammatory markers in women. AB - BACKGROUND: Higher intakes of cruciferous vegetables or their constituents have been shown to lower inflammation in animal studies. However, evidence for this anti-inflammatory effect of cruciferous vegetable consumption in humans is scarce. OBJECTIVE/DESIGN: In this cross-sectional analysis, we evaluated associations of vegetable intake with a panel of inflammatory and oxidative stress markers among 1,005 middle-aged Chinese women. Dietary intake of foods was assessed by a food frequency questionnaire. RESULTS: Multivariable-adjusted circulating concentrations of tumor necrosis factor-alpha (TNF-alpha), interlukin 1beta (IL-1beta), and IL-6 were lower among women with higher intakes of cruciferous vegetables. The differences in concentrations of inflammatory biomarkers between extreme quintiles of cruciferous vegetable intake were 12.66% for TNF-alpha (Ptrend=0.01), 18.18% for IL-1beta (Ptrend=0.02), and 24.68% for IL 6 (Ptrend=0.02). A similar, but less apparent, inverse association was found for intakes of all vegetables combined but not for noncruciferous vegetables. Levels of the urinary oxidative stress markers F2-isoprostanes and their major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP, were not associated with intakes of cruciferous vegetables or all vegetables combined. CONCLUSIONS: This study suggests that the previously observed health benefits of cruciferous vegetable consumption may be partly associated with the anti-inflammatory effects of these vegetables. PMID- 24630683 TI - Social media offers unprecedented opportunities for vibrant exchange of professional ideas across continents. PMID- 24630684 TI - ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer. AB - BACKGROUND: Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed. OBJECTIVE: To examine the association between ERG expression at diagnosis and the risk of progression during AS. DESIGN, SETTING, AND PARTICIPANTS: This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10-12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall AS progression was defined as clinical progression: increased clinical tumour category >=cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events. RESULTS AND LIMITATIONS: A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p<0.0001) and of the subgroups PSA progression (p<0.0001) and histopathologic progression (p<0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3-29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7-68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62-3.72; p<0.0001). The main limitation of this study is its observational nature. CONCLUSIONS: In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes. PATIENT SUMMARY: The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression. PMID- 24630686 TI - Postprandial hypotension: a systematic review. AB - BACKGROUND: Postprandial hypotension (PPH) is an important clinical problem, which has received inappropriately little attention. METHODS: A systematic search of the databases PubMed, Embase, Cochrane Library, and Web of Knowledge, from their inception to the present time, was conducted to identify studies relevant to the epidemiology, pathophysiology, and/or management of PPH. RESULTS: A total of 417 full-text papers were retrieved from database searching and, following screening, 248 were retained. Of these, 167 papers were considered eligible for inclusion. CONCLUSIONS: PPH occurs commonly in older people and represents a major cause of morbidity. Although the pathophysiology of PPH remains poorly defined, diverse factors, including impairments in sympathetic and baroreflex function, release of vasodilatory peptides, the rate of small intestinal nutrient delivery, gastric distension, and splanchnic blood pooling, appear important. Current pharmacologic and nonpharmacologic management is suboptimal. Research into the pathophysiology of PPH represents a priority so that management can be targeted more effectively. PMID- 24630685 TI - Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). AB - BACKGROUND: Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo. OBJECTIVE: To investigate ZA for the prevention of BMs in high risk localised PCa. DESIGN, SETTING, AND PARTICIPANTS: Randomised open-label multinational study with patients having at least one of the following: prostate specific antigen >=20 ng/ml, node-positive disease, or Gleason score 8-10. INTERVENTION: Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for <=4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups. RESULTS AND LIMITATIONS: A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4+/-0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients. CONCLUSIONS: ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr. PATIENT SUMMARY: Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr. TRIAL REGISTRATION: The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762. PMID- 24630687 TI - Scleral lenses in the management of ocular surface disease. AB - PURPOSE: To describe the management of ocular surface disease with commercially available scleral lenses. DESIGN: Retrospective case series at a tertiary referral center. PARTICIPANTS: A total of 212 patients (346 eyes) who were evaluated for scleral lens therapy for the management of ocular surface disease between June 1, 2006, and November 30, 2011. METHODS: Retrospective review of medical records and analysis of a survey mailed to all patients who completed the scleral lens fitting process to evaluate the long-term success of scleral lens therapy in the management of ocular surface disease. MAIN OUTCOME MEASURES: Therapeutic outcome of scleral lens therapy, improvement in visual acuity with scleral lenses, indications for scleral lens wear, and efficiency of fitting process. RESULTS: Of the 212 subjects, 115 (188 eyes) successfully completed the scleral lens fitting process, and therapeutic goals (improved comfort, ocular surface protection, or resolution of keratopathy) were achieved in all but 2 of these subjects. Visual acuity improved with scleral lens wear, from 0.32 +/- 0.37 logarithm of the minimal angle of resolution (logMAR) (mean +/- standard deviation; Snellen equivalent, 20/42) with habitual correction to 0.12 +/- 0.19 logMAR (Snellen equivalent, 20/26) with scleral lenses (P<0.001). The most common indications for scleral lens therapy were undifferentiated ocular surface disease, exposure keratopathy, and neurotrophic keratopathy. Subjects had attempted an average of 3.2 (range, 0-8) other forms of intervention before scleral lens wear. Scleral lens fitting was completed in an average of 3 visits (range, 2-6), with an average of 1.4 lenses/eye (range, 1-4). Three patients experienced complications during scleral lens wear that resolved without loss of visual acuity, enabling resumption of scleral lens wear. CONCLUSIONS: Commercially available scleral lenses can be successfully used in the management of moderate to severe ocular surface disease. The scleral lens fitting process can be completed efficiently for most eyes by using diagnostic trial lenses. In addition to protecting the ocular surface, scleral lenses improve visual acuity in patients whose surface disease has compromised vision. PMID- 24630688 TI - The impact of topical corticosteroid use before diagnosis on the outcome of Acanthamoeba keratitis. AB - OBJECTIVE: To examine the impact of topical corticosteroid use before the diagnosis of Acanthamoeba keratitis (AK) on final visual outcomes and to determine the prognostic factors predicting poorer outcomes. DESIGN: Cohort study. PARTICIPANTS: A total of 209 eyes of 196 patients with retrievable medical records, diagnosed with AK at Moorfields Eye Hospital, London, between January 1991 and April 2012. One eye was randomly excluded from analysis in the 13 cases of bilateral AK. METHODS: Patient demographic, initial clinical examination findings, and management details were collected. The outcomes of patients treated with topical corticosteroids before diagnosis of AK were compared with those not treated with topical corticosteroids before diagnosis. A multivariable logistic model, optimized for prior corticosteroid use, was used to derive the odds ratios (ORs) of a suboptimal visual outcome. MAIN OUTCOME MEASURES: Suboptimal visual outcome was defined as final visual acuity (VA) <= 20/80, corneal perforation, or need for keratoplasty. RESULTS: Acanthamoeba keratitis was diagnosed on microbiological culture in 94 eyes (48.0%), on histopathologic examination in 27 eyes (13.8%), on confocal microscopy in 38 eyes (19.4%), and on the basis of a typical clinical course and response to treatment in 37 eyes (18.9%). Final VA and prior corticosteroid use data were available for 174 eyes (88.8%). In multivariable analysis, corticosteroid use before diagnosis was associated with suboptimal visual outcome (OR, 3.90; 95% confidence interval [CI], 1.78-8.55), as were disease stage 3 at presentation (OR, 5.62; 95% CI, 1.59-19.80) and older age (60+ years) at diagnosis (OR, 8.97; 95% CI, 2.13-37.79). CONCLUSIONS: Corticosteroid use before diagnosis of AK is highly predictive of a poorer visual outcome. This is largely due to the initial misdiagnosis of AK as herpetic keratitis. It is important to include AK in the differential diagnosis of keratitis in all contact lens users with keratitis, particularly before making a diagnosis of herpes keratitis and before the use of topical corticosteroids in the therapy of any indolent keratitis. PMID- 24630689 TI - Outcomes and prognostic factors of patients with lung cancer and pneumonia induced respiratory failure in a medical intensive care unit: a single-center study. AB - PURPOSE: To evaluate the outcomes and prognostic factors of 28-day mortality following medical intensive care unit (MICU) admission of patients with lung cancer and pneumonia-induced respiratory failure. MATERIALS AND METHODS: Patients admitted to the MICU of a tertiary referral hospital between 2000 and 2009 were retrospectively studied. RESULTS: In total, 143 patients were included. Their mean age was 65+/-8 years and 94% were male. The 28-day mortality rate was 57%. Multivariate analysis was performed to identify variables associated with 28-day mortality. At 72 hours after admission, a history of radiotherapy (OR=2.80, 95% CI: 1.15-6.78), PaO2/FiO2 (P/F) ratio at admission of <100 mmHg (OR=5.62, 95% CI: 2.10-15.07), P/F ratio after 72 hours of <100 mmHg (OR=4.61, 95% CI: 1.24-17.15), and arterial pH after 72 hours of <7.30 (OR=5.78, 95% CI: 1.15-28.89) were associated with increased mortality. CONCLUSIONS: The prognosis of patients with lung cancer and severe pneumonia after 72 hours of MICU management mainly depends on the severity of the underlying lung injury, which is reflected by a history of radiotherapy and a low P/F ratio, rather than on cancer stage or disease status. PMID- 24630690 TI - Initial interrater reliability for a novel measure of patient mobility in a cardiovascular intensive care unit. AB - PURPOSE: The purpose of this study was to determine the interrater reliability of the Perme Intensive Care Unit Mobility Score. MATERIALS AND METHODS: This was a prospective observational study. Data were collected from 20 patients admitted in a cardiovascular intensive care unit. The interrater reliability was tested using the intraclass correlation coefficient with 95% confidence interval and the Cohen kappa coefficient of 0.9, using a 2-tailed alpha of .05 to provide a 90% power. RESULTS: The 15 items of the Perme ICU Mobility Score were individually analyzed. Interrater reliability (Cohen kappa coefficient) for items 2, 3, 5, 6, 7, 8, 13, and 15 was 1.0000; for item 1, 0.8276; item 4, 0.8000; item 9, 0.6000; item 10, 0.7297; item 11, 0.7260; item 12, 0.7872; and item 14, 0.9048; the intraclass correlation coefficient (95% confidence interval) was 0.9880 (0.97743-0.99859). CONCLUSIONS: The Perme ICU Mobility Score is a reliable tool to assess mobility status of patients admitted to the cardiovascular intensive care unit in a specific moment in time, which can be an important tool for research and clinical practice. PMID- 24630691 TI - Recognition of RNA duplex by a neomycin-Hoechst 33258 conjugate. AB - DNA minor groove binding drugs such as Hoechst 33258 have been shown to bind to a number of RNA structures. Similarly, RNA binding ligands such as neomycin have been shown by us to bind to a number of A-form DNA structures. A neomycin-Hoechst 33258 conjugate was recently shown to bind B-DNA, where Hoechst exhibits high affinity for the minor groove of A/T tract DNA and neomycin docks into the major groove. Further studies now indicate that the Hoechst moiety of the conjugate can be driven to bind RNA duplex as a consequence of neomycin binding in the RNA major groove. This is the first example of Hoechst 33258 binding to RNA duplex not containing bulges or loop motifs. PMID- 24630692 TI - Facile synthesis, cytotoxicity and bioimaging of Fe(3+) selective fluorescent chemosensor. AB - The designing and development of fluorescent chemosensors have recently been intensively explored for sensitive and specific detection of environmentally and biologically relevant metal ions in aqueous solution and living cells. Herein, we report the photophysical results of alanine substituted rhodamine B derivative 3 having specific binding affinity toward Fe(3+) with micro molar concentration level. Through fluorescence titration at 599nm, we were confirmed that ligand 3 exhibited ratiometric fluorescence response with remarkable enhancement in emission intensity by complexation between 3 and Fe(3+) while it appeared no emission in case of the competitive ions (Sc(3+), Yb(3+), In(3+), Ce(3+), Sm(3+), Cr(3+), Sn(2+), Pb(2+), Ni(2+), Co(2+), Cu(2+), Ba(2+), Ca(2+), Mg(2+), Ag(+), Cs(+), Cu(+), K(+)) in aqueous/methanol (60:40, v/v) at neutral pH. However, the fluorescence as well as colorimetric response of ligand-iron complex solution was quenched by addition of KCN which snatches the Fe(3+) from complex and turn off the sensor confirming the recognition process was reversible. Furthermore, bioimaging studies against L-929 cells (mouse fibroblast cells) and BHK-21 (hamster kidney fibroblast), through confocal fluorescence microscopic experiment indicated that ligand showed good permeability and minimum toxicity against the tested cell lines. PMID- 24630693 TI - Some non-conventional biomolecular targets for diamidines. A short survey. AB - Increasing the affinity of diamidines for AT-rich regions of DNA has long been an important goal of medicinal chemists who wanted to improve the antiparasitic and antifungal properties of that class of derivatives. In recent years it was demonstrated that diamidines could interfere with many other biomolecular targets including ion channels as well as enzymes and modulate some RNA-protein, DNA protein, and protein-protein interactions. It is therefore not surprising that diamidines now emerge as novel potential drug candidates for the treatment of various diseases, i.a. neurodegenerative disorders, acidosis-related pathological conditions, hypertension, thrombosis, type 2 diabetes, myotonic dystrophy, and cancers. A summary of the most striking results obtained to date in those domains is presented is this review. PMID- 24630694 TI - Design and synthesis of silicon-containing steroid sulfatase inhibitors possessing pro-estrogen antagonistic character. AB - Steroid sulfatase (STS) is a potential target for treatment of postmenopausal hormone-dependent breast cancer. Several steroidal STS inhibitors have been reported, but steroidal compounds are difficult to optimize and may interact with other targets. On the other hand, we have shown that diphenylmethane (DPM) derivatives act as estrogen receptor (ER) agonists and antagonists. Here, we aimed to design and synthesize non-steroidal DPM-type STS inhibitors that would also serve as pro-estrogen antagonists, releasing a metabolite with ERalpha antagonistic activity upon hydrolysis by STS. We synthesized a series of compounds and evaluated their biological activities by means of STS-inhibitory activity assay and ER reporter gene assay. Among them, silicon-containing compound 16a showed strong STS-inhibitory activity (IC50=0.17MUM). Further, its putative metabolite (12a) exhibited potent ERalpha-antagonistic activity (IC50=29.7nM). PMID- 24630695 TI - Decreasing acidity in a series of aldose reductase inhibitors: 2-Fluoro-4-(1H pyrrol-1-yl)phenol as a scaffold for improved membrane permeation. AB - Targeting long-term diabetic complications, as well as inflammatory pathologies, aldose reductase inhibitors (ARIs) have been gaining attention over the years. In the present work, in order to address the poor membrane permeation of previously reported ARIs, derivatives of N-phenylpyrrole, bearing groups with putative pKa>=7.4, were synthesized and evaluated for aldose reductase inhibitory activity. The 2-fluorophenol group proved the most promising moiety, and further modifications were explored. The most active compound (31), identified as a submicromolar inhibitor (IC50=0.443MUM), was also selective against the homologous enzyme aldehyde reductase. Cross-docking revealed that 31 displays a peculiar interaction network that may be responsible for high affinity. Physicochemical profiling of 31 showed a pKa of 7.64, rendering it less than 50% ionized in the physiological pH range, with potentially favorable membrane permeation. The latter was supported from the successful inhibition of sorbitol formation in rat lenses and the ability to permeate rat jejunum. PMID- 24630696 TI - Characterization of the four isomers of (123)I-CMICE-013: a potential SPECT myocardial perfusion imaging agent. AB - Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) is widely used in the assessment of coronary artery disease (CAD). We have developed (123)I-CMICE-013 based on rotenone, a mitochondrial complex I (MC-1) inhibitor, as a promising new MPI agent. Our synthesis results in a mixture of four species of (123)I-CMICE-013 A, B, C, D. In this study, we separated the four species and evaluated their biodistribution and imaging properties. The cold analogs (127)I-CMICE-013 A, B, C, D were isolated and characterized and their chemical structures proposed. METHODS: (123)I-CMICE-013 was synthesized by radiolabeling rotenone with Na(123)I in trifluoroacetic acid (TFA) with iodogen as the oxidizing agent at 60 degrees C for 45min, and the four species were separated by RP-HPLC. The cold analogs (127)I-CMICE-013 A, B, C and D were isolated with a similar procedure and characterized by NMR and mass spectrometry. Biodistribution and microSPECT imaging studies were carried out on normal rats. RESULTS: We propose the mechanism of the rotenone iodination and the structures of the four species. First, I(+) forms an intermediate three-membered ring with 6' and 7' carbons. Second, the lone electron pair of the water molecule attacks the 6' or 7'-carbon, following by the formation of 6'-OH, and 7'-I bonds as in major products C and D, or 6'-I and 7'-OH bonds as in minor products A and B. The weaker 6'-I bond in the intermediate prompts the nucleophilic attachment of water at the favorable 6'-carbon to generate C and D. MicroSPECT images of (123)I-CMICE-013 A, B, C, D in rats showed clear visualization of myocardium and little interference from lung and liver. The imaging time activity curves and biodistribution data showed complex profiles for the four isomers, which is not expected from the structure activity relationship theory. CONCLUSION: (123/127)I CMICE-013 A and B are constitutional isomers with C and D, while A and C are diastereomers of B and D, respectively. Overall, the biological characteristics of the four species are not correlated perfectly with their molecular structures. PMID- 24630697 TI - Providing recording of clinical consultation to patients - a highly valued but underutilized intervention: a scoping review. AB - OBJECTIVE: The benefits of providing patients with recorded clinical consultations have been mostly investigated in oncology settings, generally demonstrating positive outcomes. There has been limited synthesis of evidence about the practice in wider context. Our aim was to summarize, in a scoping review, the evidence about providing consultation recordings to patients. METHODS: We searched seven literature databases. Full text articles meeting the inclusion criteria were retrieved and reviewed. Arksey and O'Malley's framework for scoping studies guided the review process and thematic analysis was undertaken to synthesize extracted data. RESULTS: Of 5492 abstracts, 33 studies met the inclusion criteria. Between 53.6% and 100% (72% weighted average) of patients listened to recorded consultations. In 60% of reviewed studies patients shared the audio-recordings with others. Six themes identified in the study provided evidence for enhanced information recall and understanding by patients, and positive reactions to receiving recorded consultations. There has been limited investigation into the views of providers and organizations. Medico-legal concerns have been reported. CONCLUSION: Patients place a high value on receiving audio-recordings of clinical consultations and majority benefit from listening to consultation recordings. PRACTICE IMPLICATIONS: Further investigation of the ethical, practical and medico-legal implications of routinely providing recorded consultations is needed. PMID- 24630698 TI - The influence of patient-centered communication during radiotherapy education sessions on post-consultation patient outcomes. AB - OBJECTIVE: To adapt an observational tool for assessing patient-centeredness of radiotherapy consultations and to assess whether scores for this tool and an existing tool assessing patient-perceived patient-centeredness predict patient outcomes. METHODS: The Measure of Patient-Centered Communication (MPCC), an observational coding system that assesses depth of discussion during a consultation, was adapted to the radiotherapy context. Fifty-six radiotherapy patients (from 10 radiation therapists) had their psycho-education sessions recorded and coded using the MPCC. Patients also completed instruments assessing their perception of patient-centeredness, trust in the radiation therapist, satisfaction with the consultation, authentic self-representation (ASR) and state anxiety. RESULTS: The MPCC correlated weakly with patient-perceived patient centeredness. The Feelings subcomponent of the MPCC predicted one aspect of ASR and trust, and interacted with level of therapist experience to predict trust. Patient-perceived patient-centeredness, which exhibited a ceiling effect, predicted satisfaction. CONCLUSION: Patient-centered communication is an important predictor of patient outcomes in radiotherapy and obviates some negative aspects of radiation therapists' experience on patient trust. As in other studies, there is a weak association between self-reported and observational coding of PCC. PRACTICE IMPLICATIONS: Radiation therapists have both technical and supportive roles to play in patient care, and may benefit from training in their supportive role. PMID- 24630699 TI - SEM study of the oral cavity of members of the Kyphosidae and Girellidae (Pisces, Teleostei), with remarks on Crenidens (Sparidae), focusing on teeth and taste bud numbers and distribution. AB - The present study compares dental morphology and taste bud distribution in the oral cavity of four species of the teleost family Kyphosidae, five species of Girellidae and one species of Sparidae. Some of these species are predominantly herbivorous, while others are omnivorous with a high portion of invertebrates in their diets. All the kyphosids feature one row of frontal cusped teeth on their jaws and areas of miniature teeth on the tongue and palate; the girellid species feature 2-5 rows of denticulate teeth, and no teeth inside the oral cavity. The total number of taste buds in the oral cavity is higher in Girella spp. than in the kyphosids, and their number is species-specific, not correlated with fish size. For example, Kyphosus bigibbus of 500mm standard length bears 1780 taste buds, while the kyphosid Neoscorpis lithophilus of 80mm bears 3460. The maximum number of taste buds, 7900, is found in Girella punctata of 60mm standard length, and the minimum number, 1320, in Kyphosus vaigiensis of 175mm. The higher number of taste buds appears to characterize species that possess a more diversified diet. The present study contributes to our understanding of the differences between the two families Kyphosidae and Girellidae. In particular, it relates the eco-morphological adaptations to the type of diet consumed by the various species. PMID- 24630700 TI - The impact of multidrug resistance on outcomes in ventilator-associated pneumonia. AB - Multidrug-resistant (MDR) organisms in ventilator-associated pneumonia were found in 49 of 107 patients and were associated with home antibiotics, pre-ventilator associated pneumonia hospital stay, and health care exposure. Overall, MDR organisms were associated with increased mortality (P = .006). On multivariate analysis, MDR status was modulated by organism class. In nonfermenting gram negative rods, no association between MDR and mortality was found, but, in all other organisms, MDR was associated with increased mortality risk (hazard ratio, 6.15; 95% confidence interval: 1.80-21.05, P = .004). PMID- 24630701 TI - Relationship between death and infections among patients hospitalized in internal medicine departments: a prevalence and validation study. AB - BACKGROUND: We assessed the burden of infection-related death at internal medicine departments in Denmark and the validity of 2 population-based registries for diagnoses of infection. METHODS: We reviewed medical records of all inpatients who died at a large university hospital during 2008 with an infection diagnosis in the Cause of Death Registry (CDR) or Hospital Discharge Registry (HDR). We computed the positive predictive value of infection diagnoses and completeness of each registry with 95% confidence intervals (CIs) and the prevalence of infection-related deaths by capture-recapture analysis. RESULTS: Among 458 deaths, 193 patients (42.1%) had an infection diagnosis of which 40.0% (183 out of 458) were verified. The positive predictive value of an infection diagnosis was 96.0% (95% CI, 92.0%-98.3%) in the CDR and 95.3% (CI, 90.9%-97.9%) in the HDR. Completeness of the CDR was 79.2% (CI, 72.9%-84.6%) and completeness of the HDR was 77.0% (CI, 70.6%-82.7%). By capture-recapture analysis we estimated that 43.2% of all deaths (198 out of 458) were related to infection. CONCLUSIONS: The large proportion of deaths in internal medicine departments that are related to infection emphasizes the need for optimized infection prevention and treatment strategies. CDR and HDR are valid sources for identifying infection and may supplement each other for increased completeness of infection-related death in epidemiologic research. PMID- 24630702 TI - Relationship between local family physician supply and influenza vaccination after controlling for individual and neighborhood effects. AB - BACKGROUND: Family physicians (FPs) play an important role in influenza vaccination. We investigated how local FP supply is associated with influenza vaccination, controlling for both individual-level and county-level characteristics. METHODS: The 2008-2010 individual-level data from the Behavioral Risk Factor Surveillance System were merged with county-level data from the Area Resource File (n = 985,157). Multivariate logistic analyses were performed to predict influenza vaccination using the number of FPs per 1000 population as the key predictor, adjusting for individual-level demographic, socioeconomic, and health information, as well as county-level racial composition and income level. Additional analyses were performed across racial/ethnic and employment status categories. RESULTS: Increasing local FP supply was associated with higher odds (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.49-1.67) and varied across racial/ethnic groups (Hispanic: aOR, 2.05, 95% CI, 1.55-2.72; non Hispanic white: aOR, 1.57, 95% CI, 1.48-1.66; non-Hispanic black: aOR, 1.49, 95% CI, 1.18-1.89), employment status categories, and county types. CONCLUSIONS: FP supply was significantly associated with influenza vaccination. The association was greatest among those who were Hispanic, residing in a rural area, or out of work. Our findings lend support to initiatives aimed at increasing the FP supply, particularly among disadvantaged populations. PMID- 24630703 TI - Load cycling enhances bioactivity at the resin-dentin interface. AB - OBJECTIVES: The purpose of this study was to evaluate if mechanical loading promotes bioactivity at the resin interface after bonding with three different adhesive approaches. METHODS: Dentin surfaces were subjected to three different treatments: demineralisation by (1) 37% phosphoric acid (PA) followed by application of an etch-and-rinse dentin adhesive Single Bond (SB) (PA+SB), (2) by 0.5 M ethylenediaminetetraacetic acid (EDTA) followed by SB (EDTA+SB), (3) application of a self-etch dentin adhesive: Clearfil SE Bond (SEB). Bonded interfaces were stored in simulated body fluid during 24 h or 3w. One half of each tooth was submitted to mechanical loading. Remineralisation of the bonded interfaces was assessed by AFM imaging/nano-indentation, Raman spectroscopy/cluster analysis, dye assisted confocal microscopy evaluation (CLSM) and Masson's trichrome staining. RESULTS: Loading cycling for 3w promoted an increase of mechanical properties at the resin-dentin interface. Cluster analysis demonstrated an augmentation of the mineral-matrix ratio in SB-loaded specimens. CLSM showed an absent micropermeability and nanoleakage after loading EDTA+SB and SEB specimens. Trichrome staining reflected a narrow demineralised dentin matrix after loading, almost not observable in EDTA+SB and SEB. SIGNIFICANCE: In vitro mechanical loading promoted mineralization in the resin-dentin interfaces, at 24 h and 3w of storage. PMID- 24630704 TI - Comparative prognostic value of low-density lipoprotein cholesterol and C reactive protein in patients with stable coronary artery disease treated with percutaneous coronary intervention and chronic statin therapy. AB - BACKGROUND: The comparative prognostic value of low density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI) and statin therapy is poorly investigated. METHODS: The study included 7595 patients with stable CAD treated with PCI. Based on a cut-off of 100mg/dl for LDL-C and 3mg/L for CRP, patients were divided into 4 groups: patients with LDL-C<=100mg/dl and CRP<=3mg/L (n=2795); patients with LDL-C>100mg/dl and CRP<=3mg/L (n=2091); patients with LDL-C<=100mg/dl and CRP>3mg/L (n=1296); and patients with LDL C>100mg/dl and CRP>3mg/L (n=1413). Statins at discharge were prescribed in all patients. The primary outcome was 1-year all-cause mortality. RESULTS: One-year mortality was 2.1% (160 deaths): 1.2% (33 deaths) among patients with LDL-C <=100mg/dl and CRP<=3mg/L, 1.4% (28 deaths) among patients with LDL-C>100mg/dl and CRP<=3mg/L, 4.8% (60 deaths) among patients with LDL-C<=100mg/dl and CRP>3mg/L and 2.9% (39 deaths) among patients with LDL-C>100mg/dl and CRP>3mg/L (P<0.001). After adjustment, CRP (hazard ratio [HR]=1.64, 95% confidence interval [CI] 1.33-2.02, for 1 standard deviation increase in the logarithmic scale) but not LDL-C (HR=1.03 [0.90-1.17], for 30mg/dl increase) showed an independent association with 1-year mortality. CRP (P=0.045) but not LDL-C (P=0.294) increased the discriminatory power of multivariable model for prediction of mortality. CONCLUSION: In patients with stable CAD treated with PCI and statin therapy, CRP but not LDL-C was independently associated with increased risk of 1 year mortality. PMID- 24630705 TI - One size does not fit all: case report of two percutaneous closures of aortic pseudoaneurysm and review of the literature. AB - Aortic pseudoaneurysms (PSAs) are common complications following cardiac surgery, and carry significant morbidity and mortality. Surgical management of aortic PSAs is associated with high mortality, however there are emerging reports of transcatheter techniques for closure of aortic PSAs. We present two cases of ascending aorta PSA which developed following cardiac surgery and were treated percutaneously with novel closure devices. We also describe a comprehensive review of the literature of all published cases of ascending aorta PSA which have been closed percutaneously, and report on the success rate and available devices for percutaneous closure. PMID- 24630706 TI - Molecular and epidemiological data on Anisakis spp. (Nematoda: Anisakidae) in commercial fish caught off northern Sardinia (western Mediterranean Sea). AB - Anisakiasis is a fish-borne zoonosis caused by third stage larvae of the nematode Anisakis sp. present in fish or cephalopods. This is the first contribution to the molecular identification and epidemiology of Anisakis spp. in commercial fish from the Gulf of Asinara (Sardinia, western Mediterranean Sea). Between April 2006 to November 2011, 777 specimens of 10 fish species (Engraulis encrasicolus, Merluccius merluccius, Micromesistius poutassou, Phycis blennoides, Sardina pilchardus, Sardinella aurita, Scomber colias, Sphyraena viridensis, Trachurus mediterraneus, Trachurus trachurus) were examined for Anisakis sp. larvae. A total of 1286 larvae were found in 218 fish. The great majority of larvae were located in the body cavity, and only a small part (60, 4.7%) in the muscle. All the Type I larvae (1272) were identified as Anisakis pegreffii and all the Type II (14) as Anisakis physeteris, confirming that A. pegreffii is the dominant species and the most important agent of human anisakiasis in the western Mediterranean Sea. PMID- 24630707 TI - The maintenance of anthelmintic efficacy in sheep in a Mediterranean climate. AB - To determine how far management practices on small ruminant dairy flocks in southern Italy have influenced the development of anthelmintic resistance (AR), faecal egg count (FEC) reduction tests were run on 54 sheep farms using the FLOTAC technique with a sensitivity of 2 eggs per gram of faeces. Tests were run on groups of sheep (12-20 animals per group) using six anthelmintics administered orally: levamisole on 8 farms, ivermectin (half and full dose) on 8 farms, moxidectin on 3 farms, monepantel on 8 farms, netobimin on 22 farms (pooled samples) and albendazole on 5 farms (pooled samples). Different formulae and statistics were used to calculate FEC reductions and confidence intervals based on the presence of a control group and/or the use of pooled samples. A very high average efficacy was obtained with all anthelmintics tested as follows: levamisole 99.3% (range across farms 98-100%), ivermectin half dose 99.5% (98.0 100%), ivermectin full dose 99.9% (99.3-100%), moxidectin 100% (99.9-100%), monepantel 99.4% (97-100%), netobimin 99.1% (92-100%) and albendazole 100%. The results suggest that the development of AR in small ruminants could be limited in countries with a Mediterranean type of climate provided that refugia of the nematode populations are maintained, anthelmintic use is restricted and movement of animals is not permitted to spread resistance. PMID- 24630708 TI - Molecular detection of co-infections with Anaplasma phagocytophilum and/or Babesia canis canis in Dirofilaria-positive dogs from Slovakia. AB - Recently, several arthropod-borne infections have been introduced into previously non-endemic regions in Europe as the result of various global changes. At the same time, endemic regions are expanding and the risk of co-infections is rising, due to climate change that allows vectors to move and spread infectious diseases into new areas. The aim of the current study was to confirm simultaneous infections with Anaplasma phagocytophilum and/or Babesia canis canis in Dirofilaria-infected dogs from Slovakia, central Europe. Genomic DNA was isolated from 366 blood samples of microfilaraemic dogs without clinical signs of infection. Samples were further screened for the presence of canine tick-borne pathogens using PCR and sequencing. This survey revealed co-infection with four arthropod-borne pathogens, in particular, Dirofilaria repens, Dirofilaria immitis, A. phagocytophilum, and B. canis canis. While D. repens, responsible for canine subcutaneous dirofilariosis, is scattered through the whole territory of the country, D. immitis occurs only in endemic areas of southeastern and southwestern Slovakia in mixed infection with D. repens. Co-infection with A. phagocytophilum was reported in 3.27% of the dogs positive for D. repens; mixed infection with D. repens and B. canis canis was detected in 3.55% of the tested blood samples. Eastern Slovak Lowland represents a natural focus of B. canis canis and is a highly endemic area for canine dirofilariosis. The presence of triple infection with D. repens, A. phagocytophilum, and B. canis canis was detected in one dog originating from the eastern lowland region of Slovakia. This study highlights the importance of co-infected, clinically healthy dogs in the spreading of several different arthropod-borne pathogens and the necessity for detailed epidemiological surveys, especially in newly infested areas. PMID- 24630709 TI - First finding of Echinococcus multilocularis DNA in soil: preliminary survey in Varmia-Masuria Province, northeast Poland. AB - The aim of this study was to estimate the presence of Echinococcus multilocularis DNA in the soil in rural areas of Varmia-Masuria Province, Poland, which is the region with the highest recorded number of human alveolar echinococcosis (AE) cases in this country. In total, 62 soil samples were analyzed. Samples were collected in forests near the lairs of foxes, as well as from arable fields, kitchen gardens and farmyards. The parasite DNA was detected in 11.3% of the samples. This study is the first environmental survey of the presence of E. multilocularis DNA in soil. The results demonstrate that the soil can be a direct source of human infections. These results should motivate the appropriate institutions to introduce informative and educational campaigns about the risk of infection, as well as developing methods for protecting the population, especially those living in at-risk areas. PMID- 24630710 TI - Age related susceptibility of pigs to Cryptosporidium scrofarum infection. AB - Piglets from 4 to 8 weeks of age originated from a Cryptosporidium-free research breed were orally inoculated with 1 * 10(6) infectious oocysts of Cryptosporidium scrofarum. The number of shed oocysts per gram of faeces served to describe the infection intensity and prepatent period. In addition, faecal samples collected daily and tissue samples of the small and large intestine collected at 30 days post-inoculation were examined for the C. scrofarum small subunit ribosomal RNA gene using PCR. The piglets inoculated at 4-weeks of age remained uninfected, whereas 5-week-old and older animals were fully susceptible with a prepatent period ranging from 4 to 8 days. Susceptible pigs shed oocysts intermittently, and shedding intensity, reaching a mean maximum of 6000 oocysts per gram, did not differ significantly among infected animals. This study demonstrates that pigs become susceptible to C. scrofarum infection as late as 5-weeks of age. The mechanisms of age related susceptibility remain unknown. PMID- 24630711 TI - Asymptomatic or infect dog, symptomatic or sick/severely sick dog: the nomenclature did not change the clinical pathological classification in canine leishmaniasis. PMID- 24630712 TI - Multi-test decision tree and its application to microarray data classification. AB - OBJECTIVE: The desirable property of tools used to investigate biological data is easy to understand models and predictive decisions. Decision trees are particularly promising in this regard due to their comprehensible nature that resembles the hierarchical process of human decision making. However, existing algorithms for learning decision trees have tendency to underfit gene expression data. The main aim of this work is to improve the performance and stability of decision trees with only a small increase in their complexity. METHODS: We propose a multi-test decision tree (MTDT); our main contribution is the application of several univariate tests in each non-terminal node of the decision tree. We also search for alternative, lower-ranked features in order to obtain more stable and reliable predictions. RESULTS: Experimental validation was performed on several real-life gene expression datasets. Comparison results with eight classifiers show that MTDT has a statistically significantly higher accuracy than popular decision tree classifiers, and it was highly competitive with ensemble learning algorithms. The proposed solution managed to outperform its baseline algorithm on 14 datasets by an average 6%. A study performed on one of the datasets showed that the discovered genes used in the MTDT classification model are supported by biological evidence in the literature. CONCLUSION: This paper introduces a new type of decision tree which is more suitable for solving biological problems. MTDTs are relatively easy to analyze and much more powerful in modeling high dimensional microarray data than their popular counterparts. PMID- 24630713 TI - Visual circuits get the VIP treatment. AB - Behavioral state, specifically locomotion, has been shown to enhance sensory responses in primary visual cortex. In this issue of Cell, Fu et al. reveal the circuit elements that mediate this plasticity and suggest that these circuits may serve a general modulatory function across primary sensory areas. PMID- 24630714 TI - Sugarcoating ER Stress. AB - The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis. PMID- 24630715 TI - Inflammasome: putting the pieces together. AB - Microbial and danger signals result in inflammasome activation and release of inflammatory cytokines through mechanisms that remain elusive. Cai et al. and Lu et al. show that triggering of inflammasome sensors induces prion-like polymerization of the adaptor ASC into filaments. These structures function as platforms for inflammatory cytokine production and represent a unified mechanism for inflammasome assembly. PMID- 24630716 TI - Silent mutations make some noise. AB - Synonymous mutations do not alter amino acids and are generally considered nonfunctional in cancer. Supek et al. now present a compelling analysis suggesting that such silent mutations can be oncogenic by altering transcript splicing and thereby affecting protein function. PMID- 24630717 TI - The interdependence of membrane shape and cellular signal processing. AB - Cellular membranes are constantly reshaped by vesicular fission and fusion as well as by interactions with the dynamic cytoskeleton. Signaling activity at membranes depends on their geometric parameters, such as surface area and curvature; these affect local concentration and thereby regulate the potency of molecular reactions. A membrane's shape is thus inextricably tied to information processing. Here, we review how a trinity of signaling, cytoskeletal dynamics, and membrane shape interact within a closed-loop causality that gives rise to an energy-consuming, self-organized system that changes shape to sense the extracellular environment. PMID- 24630718 TI - A cortical circuit for gain control by behavioral state. AB - The brain's response to sensory input is strikingly modulated by behavioral state. Notably, the visual response of mouse primary visual cortex (V1) is enhanced by locomotion, a tractable and accessible example of a time-locked change in cortical state. The neural circuits that transmit behavioral state to sensory cortex to produce this modulation are unknown. In vivo calcium imaging of behaving animals revealed that locomotion activates vasoactive intestinal peptide (VIP)-positive neurons in mouse V1 independent of visual stimulation and largely through nicotinic inputs from basal forebrain. Optogenetic activation of VIP neurons increased V1 visual responses in stationary awake mice, artificially mimicking the effect of locomotion, and photolytic damage of VIP neurons abolished the enhancement of V1 responses by locomotion. These findings establish a cortical circuit for the enhancement of visual response by locomotion and provide a potential common circuit for the modulation of sensory processing by behavioral state. PMID- 24630719 TI - Forgetting is regulated via Musashi-mediated translational control of the Arp2/3 complex. AB - A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for time dependent memory loss in C. elegans. Tissue-specific rescue demonstrates that MSI 1 function is necessary in the AVA interneuron. Using RNA-binding protein immunoprecipitation (IP), we found that MSI-1 binds to mRNAs of three subunits of the Arp2/3 actin branching regulator complex in vivo and downregulates ARX-1, ARX 2, and ARX-3 translation upon associative learning. The role of msi-1 in forgetting is also reflected by the persistence of learning-induced GLR-1 synaptic size increase in msi-1 mutants. We demonstrate that memory length is regulated cooperatively through the activation of adducin (add-1) and by the inhibitory effect of msi-1. Thus, a GLR-1/MSI-1/Arp2/3 pathway induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the actin cytoskeleton in neurons. PMID- 24630720 TI - Hexosamine pathway metabolites enhance protein quality control and prolong life. AB - Aging entails a progressive decline in protein homeostasis, which often leads to age-related diseases. The endoplasmic reticulum (ER) is the site of protein synthesis and maturation for secreted and membrane proteins. Correct folding of ER proteins requires covalent attachment of N-linked glycan oligosaccharides. Here, we report that increased synthesis of N-glycan precursors in the hexosamine pathway improves ER protein homeostasis and extends lifespan in C. elegans. Addition of the N-glycan precursor N-acetylglucosamine to the growth medium slows aging in wild-type animals and alleviates pathology of distinct neurotoxic disease models. Our data suggest that reduced aggregation of metastable proteins and lifespan extension depend on enhanced ER-associated protein degradation, proteasomal activity, and autophagy. Evidently, hexosamine pathway activation or N-acetylglucosamine supplementation induces distinct protein quality control mechanisms, which may allow therapeutic intervention against age-related and proteotoxic diseases. PMID- 24630721 TI - Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. AB - The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N acetylglucosamine (UDP-GlcNAc) for glycan synthesis and O-linked GlcNAc (O GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress. PMID- 24630722 TI - Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. AB - Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain (PYD) interactions between sensors and ASC and through caspase activation and recruitment domain (CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo- and hetero-PYD/PYD associations, as confirmed by structure guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. PAPERFLICK: PMID- 24630723 TI - Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. AB - Pathogens and cellular danger signals activate sensors such as RIG-I and NLRP3 to produce robust immune and inflammatory responses through respective adaptor proteins MAVS and ASC, which harbor essential N-terminal CARD and PYRIN domains, respectively. Here, we show that CARD and PYRIN function as bona fide prions in yeast and that their prion forms are inducible by their respective upstream activators. Likewise, a yeast prion domain can functionally replace CARD and PYRIN in mammalian cell signaling. Mutations in MAVS and ASC that disrupt their prion activities in yeast also abrogate their ability to signal in mammalian cells. Furthermore, fibers of recombinant PYRIN can convert ASC into functional polymers capable of activating caspase-1. Remarkably, a conserved fungal NOD-like receptor and prion pair can functionally reconstitute signaling of NLRP3 and ASC PYRINs in mammalian cells. These results indicate that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation. PMID- 24630724 TI - Heme-mediated SPI-C induction promotes monocyte differentiation into iron recycling macrophages. AB - Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80(+)VCAM1(+) bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor BACH1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Furthermore, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insights into iron homeostasis. PMID- 24630725 TI - S-glutathionylation of cryptic cysteines enhances titin elasticity by blocking protein folding. AB - The giant elastic protein titin is a determinant factor in how much blood fills the left ventricle during diastole and thus in the etiology of heart disease. Titin has been identified as a target of S-glutathionylation, an end product of the nitric-oxide-signaling cascade that increases cardiac muscle elasticity. However, it is unknown how S-glutathionylation may regulate the elasticity of titin and cardiac tissue. Here, we show that mechanical unfolding of titin immunoglobulin (Ig) domains exposes buried cysteine residues, which then can be S glutathionylated. S-glutathionylation of cryptic cysteines greatly decreases the mechanical stability of the parent Ig domain as well as its ability to fold. Both effects favor a more extensible state of titin. Furthermore, we demonstrate that S-glutathionylation of cryptic cysteines in titin mediates mechanochemical modulation of the elasticity of human cardiomyocytes. We propose that posttranslational modification of cryptic residues is a general mechanism to regulate tissue elasticity. PMID- 24630726 TI - SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells. AB - Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages. PAPERCLIP: PMID- 24630727 TI - Single-molecule dynamics of enhanceosome assembly in embryonic stem cells. AB - Enhancer-binding pluripotency regulators (Sox2 and Oct4) play a seminal role in embryonic stem (ES) cell-specific gene regulation. Here, we combine in vivo and in vitro single-molecule imaging, transcription factor (TF) mutagenesis, and ChIP exo mapping to determine how TFs dynamically search for and assemble on their cognate DNA target sites. We find that enhanceosome assembly is hierarchically ordered with kinetically favored Sox2 engaging the target DNA first, followed by assisted binding of Oct4. Sox2/Oct4 follow a trial-and-error sampling mechanism involving 84-97 events of 3D diffusion (3.3-3.7 s) interspersed with brief nonspecific collisions (0.75-0.9 s) before acquiring and dwelling at specific target DNA (12.0-14.6 s). Sox2 employs a 3D diffusion-dominated search mode facilitated by 1D sliding along open DNA to efficiently locate targets. Our findings also reveal fundamental aspects of gene and developmental regulation by fine-tuning TF dynamics and influence of the epigenome on target search parameters. PMID- 24630728 TI - Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. AB - Dnmt1 epigenetically propagates symmetrical CG methylation in many eukaryotes. Their genomes are typically depleted of CG dinucleotides because of imperfect repair of deaminated methylcytosines. Here, we extensively survey diverse species lacking Dnmt1 and show that, surprisingly, symmetrical CG methylation is nonetheless frequently present and catalyzed by a different DNA methyltransferase family, Dnmt5. Numerous Dnmt5-containing organisms that diverged more than a billion years ago exhibit clustered methylation, specifically in nucleosome linkers. Clustered methylation occurs at unprecedented densities and directly disfavors nucleosomes, contributing to nucleosome positioning between clusters. Dense methylation is enabled by a regime of genomic sequence evolution that enriches CG dinucleotides and drives the highest CG frequencies known. Species with linker methylation have small, transcriptionally active nuclei that approach the physical limits of chromatin compaction. These features constitute a previously unappreciated genome architecture, in which dense methylation influences nucleosome positions, likely facilitating nuclear processes under extreme spatial constraints. PMID- 24630730 TI - Synonymous mutations frequently act as driver mutations in human cancers. AB - Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. Here, we present evidence that these "silent" mutations frequently contribute to human cancer. Selection on synonymous mutations in oncogenes is cancer-type specific, and although the functional consequences of cancer-associated synonymous mutations may be diverse, they recurrently alter exonic motifs that regulate splicing and are associated with changes in oncogene splicing in tumors. The p53 tumor suppressor (TP53) also has recurrent synonymous mutations, but, in contrast to those in oncogenes, these are adjacent to splice sites and inactivate them. We estimate that between one in two and one in five silent mutations in oncogenes have been selected, equating to ~6% 8% of all selected single-nucleotide changes in these genes. In addition, our analyses suggest that dosage-sensitive oncogenes have selected mutations in their 3' UTRs. PMID- 24630729 TI - Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. AB - Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs. PMID- 24630731 TI - SnapShot: talin and the modular nature of the integrin adhesome. AB - Integrin alphabeta transmembrane heterodimers play central roles in metazoan development and physiology by mediating adhesion and by transmitting forces and biochemical signals across the plasma membrane. In this SnapShot, we present a simplified "modular" view of the integrin adhesome, centered on the talin integrin interaction, and provide examples of how this view can help to unravel the adhesome's remarkable functional diversity and plasticity. PMID- 24630732 TI - Chiasmal haemorrhage secondary to glioma with unusual MRI appearance. AB - OBJECTIVE: To report a unique case of haemorrhagic presentation of a chiasmal and optic tract glioma (OPG) appearing as an extra-axial lesion on MRI scans. CASE REPORT: A 30-year-old female with a preoperative radiological diagnosis of dermoid cyst was operated. No lesion was found in the chiasmal or carotid cisterns within the operative field. The right posterolateral corner of the chiasma and the beginning of the right optic tract appeared swollen. The area was incised and a haemorrhagic fluid poured through the opening. Several samples were taken and the pathological diagnosis was of pilocytic glioma. CONCLUSIONS: We present a unique case of chiasmal bleeding into the optic pathway secondary to an optic glioma which radiologically mimicked an intracisternal cyst. In similar cases, rapid clinical evolution of the symptoms may be vital for the differential diagnosis. Surgery is warranted to prevent permanent damage to the visual pathway. PMID- 24630733 TI - Strong correlation between glycaemic variability and total glucose exposure in type 2 diabetes is limited to subjects with satisfactory glycaemic control. AB - AIMS: This study investigated the relationship between markers of overall glucose exposure, postprandial glucose excursions and glycaemic variability in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 63 patients with T2DM (mean age 56 years) were enrolled. All wore a continuous glucose monitoring system (CGMS) device for 72 h to collect data on markers of overall glucose exposure, postprandial glucose excursions and glycaemic variability parameters. RESULTS: Spearman's correlation analysis revealed significant correlations between all markers of overall glucose exposure and various parameters related to glucose excursions. The percent coefficient of variation (CV) showed the strongest correlation with glycated albumin (r=0.470, P<0.01). In participants with HbA1c levels < 7.5% (n=33), almost all glycaemic markers and glycaemic variability parameters were significantly correlated with each other. Also, all postprandial glucose excursion parameters showed significant correlation with other glycaemic markers, and all markers of overall glucose exposure were significantly related to mean glucose, postprandial glucose excursions and glycaemic variability parameters (except CV). In contrast, in participants with HbA1c levels >= 7.5% (n=30), no parameters of postprandial glucose excursions and glycaemic variability were related to any markers of chronic glycaemia. CONCLUSION: Postprandial glucose excursions may explain glycaemic variability and total glucose exposures in well-controlled T2DM patients. PMID- 24630734 TI - Novel T-cell inhibiting peptides delay the onset of Type 1 diabetes in non-obese diabetic mice. AB - The aim of this study was to investigate the effectiveness of immunomodulatory peptides in preventing the spontaneous onset of Type 1 diabetes in NOD mice. Two such peptides, CP and C1, were injected intraperitoneally in NOD mice three times a week starting at two different time points, nine weeks and 11 weeks of age, and blood sugar levels monitored for the development of diabetes. CP was shown to be effective in delaying the onset of diabetes compared to control (P = 0.006). The timing of peptide administration was crucial since delay in treatment did not prevent the onset of diabetes (nine weeks versus 11 weeks of age). C1 was effective in delaying the onset of Type 1 diabetes with borderline significance when given at week 11 (P = 0.05). These findings confirm the efficacy of these peptides in the prevention and possible treatment for Type 1 diabetes and thereby create new opportunities for genetic manipulation. PMID- 24630735 TI - Evolution of carfilzomib dose and schedule in patients with multiple myeloma: a historical overview. AB - Carfilzomib is a proteasome inhibitor that binds selectively and irreversibly to its target. In July 2012, carfilzomib received accelerated approval in the United States for the treatment of relapsed and refractory multiple myeloma. Based on emerging preclinical data and clinical results, the total dose, infusion time, and administration schedule of carfilzomib have evolved during phase I and phase II clinical studies, with the aim of optimizing the risk-benefit profile of the agent. Based on in vitro and in vivo findings and encouraging phase I tolerability data, a consecutive-day, twice-weekly dosing schedule was implemented early in the development program. Other phase II studies have led to further refinements in the dosing schedule of carfilzomib, resulting in the current approved schedule for carfilzomib to be administered intravenously over 2 10 min on 2 consecutive days each week for 3 weeks of a 28-day cycle. Prolonged infusion over 30 min has also been assessed in clinical studies to enable the use of higher carfilzomib doses with the aim of improving drug tolerability and efficacy. These data collectively informed the dosing and scheduling schemas for carfilzomib in ongoing trials, including phase I and II studies of combination regimens, and the randomized phase III trials ASPIRE, FOCUS, ENDEAVOR, and CLARION. Additional studies are underway to examine alternative dosing schedules (e.g., once-weekly dosing [CHAMPION-1]). PMID- 24630737 TI - Community Wise: paving the way for empowerment in community reentry. AB - Theoretical approaches traditionally applied in mental health and criminal justice interventions fail to address the historical and structural context that partially explains health disparities. Community Wise was developed to address this gap. It is a 12week group intervention informed by Critical Consciousness Theory and designed to prevent substance abuse, related health risk behaviors, psychological distress, and reoffending among individuals with a history of incarceration and substance abuse. This paper reports findings from the first implementation and pilot evaluation of Community Wise in two community-based organizations. This pre-posttest evaluation pilot-tested Community Wise and used findings to improve the intervention. Twenty-six participants completed a phone and clinical screening, baseline, 6- and 12-week follow-ups, and a focus group at the end of the intervention. Measures assessed participants' demographic information, psychological distress, substance use, criminal offending, HIV risk behaviors, community cohesion, community support, civic engagement, critical consciousness, ethnic identification, group cohesion, client satisfaction, and acquired treatment skills. Research methods were found to be feasible and useful in assessing the intervention. Results indicated that while Community Wise is a promising intervention, several changes need to be made in order to enhance the intervention. Community Wise is a new approach where oppressed individuals join in critical dialogue, tap into existing community resources, and devise, implement and evaluate their own community solutions to structural barriers. PMID- 24630738 TI - Involuntary detention and treatment of the mentally ill: China's 2012 Mental Health Law. AB - The long-awaited Mental Health Law of China was passed on 26 October 2012 and took effect on 1 May 2013. Being the first national legislation on mental health, it establishes a basic legal framework to regulate mental health practice and recognizes the fundamental rights of persons with mental disorders. This article focuses on the system of involuntary detention and treatment of the mentally ill under the new law, which is expected to prevent the so-called "Being misidentified as mentally disordered" cases in China. A systematic examination of the new system demonstrates that the Mental Health Law of China implicitly holds two problematic assumptions and does not provide adequate protection of the fundamental rights of the involuntary patients. Administrative enactments and further national legislative efforts are needed to remedy these flaws in the new law. PMID- 24630736 TI - A CULLINary ride across the secretory pathway: more than just secretion. AB - Mulitmeric cullin-RING ubiquitin ligases (CRLs) represent the largest class of ubiquitin ligases in eukaryotes. However, most CRL ubiquitylation pathways remain uncharacterized. CRLs control a myriad of functions by catalyzing mono- or poly ubiquitylation of target proteins. Recently, novel CRLs have been identified along the secretory pathway where they modify substrates involved in diverse cellular processes such as vesicle coat assembly and cell cycle progression. This review discusses our current understanding of CRL ubiquitylation within the secretory pathway, with special emphasis on the emerging role of the Golgi as a ubiquitylation platform. CRLs are also implicated in endosome function, where their specific roles are less well understood. PMID- 24630739 TI - Police officer perceptions of the impact of Crisis Intervention Team (CIT) programs. AB - The Crisis Intervention Team (CIT) program is an approach for law enforcement officers to safely response to individuals who are experiencing a mental health crisis. Research must identify the components of CIT that are instrumental to the overall effectiveness of the program. For instance, recent studies report that CIT may have a transformative effect on officers' attitudes by increasing exposure to and familiarity with mental illness. This study explores this possibility further by examining 57 CIT officers' experiences with mental illness and attitudes about CIT. Specifically, we assessed how personal and professional exposure to mental illness associates with officers' perceptions about CIT generally, as well as with opinions about the officers' confidence in their abilities and the perceived effectiveness of the police department in responding to individuals in mental health crisis. Our findings indicate that CIT is rated very positively by officers. We found that officers' attitudes about the impact of CIT on improving overall safety, accessibility of services, officer skills and techniques, and the preparedness of officers to handle calls involving persons with mental illness are positively associated with officers' confidence in their abilities or with officers' perceptions of overall departmental effectiveness. There is further evidence that personal contact with individuals with mental illness affects the relationship between attitudes that CIT impacts overall safety and perceived departmental effectiveness. The results of this exploratory study underscore the importance of CIT officers' perceptions of key elements of CIT and the role of exposure to mental illness in examining program effectiveness. PMID- 24630740 TI - Mental health specialized probation caseloads: are they effective? AB - With the large and growing number of persons with mental illnesses under probation supervision, a form of specialized probation called specialized mental health caseload (SMHC) has been implemented. This study explores the effectiveness of a prototypic SMHC implemented statewide. A quasi-experimental design was used to compare criminal justice, mental health, and community engagement outcomes among three caseloads: a newly established SMHC supervising no more than 30 clients per officer (N=1367); an established SMHC supervising roughly 50 clients per officer (N=495); and a traditional caseload of clients receiving mental health treatment and supervised by officers with average caseloads of over 130 clients (N=5453). Using a mixed methods approach, we found that the SMHC was implemented with high adherence to fidelity, and comparisons based on different caseload samples generally support the effectiveness of the specialized mental health caseload, particularly on criminal justice outcomes. Future studies using random assignment are needed to examine the connection among mental health symptoms, compliance with treatment and probation supervision, and recidivism. PMID- 24630741 TI - Psychosis-proneness correlates with expression levels of dopaminergic genes. AB - Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. PMID- 24630742 TI - Impact of primary negative symptoms on functional outcomes in schizophrenia. AB - OBJECTIVE: Negative symptoms are known to undermine functional outcomes in people with schizophrenia; however, most studies have not accounted for whether these symptoms were primary or secondary to other psychopathological factors. The present study examined the impact of primary negative symptoms on functional outcomes in patients with schizophrenia. METHOD: The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Negative symptoms were significantly and inversely related to each domain of functioning examined. These relationships remained after statistically controlling for the influence of potential sources of secondary negative symptoms. In addition, the relationships between negative symptoms and specific domains of functioning remained in patients who had mild/absent positive, depressive, anxiety and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in antipsychotic-free patients. CONCLUSIONS: Primary negative symptoms significantly contribute to the functional impairment seen in people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms is required to guide the search for effective therapeutics that promote functional recovery. PMID- 24630743 TI - Latent structure of the symptomatology of hospitalized patients with bipolar mania. AB - Several studies have attempted to understand the dimensions of psychiatric symptoms in manic episodes, but only a few have been able to model the latent structure of mania in bipolar disorder patients using confirmatory factor analysis. The objective of the present study was to search for the best model of the symptomatology of hospitalized manic patients. To achieve this goal, 117 manic inpatients during a manic crisis participated in this research. Exploratory factor analysis was conducted followed by confirmatory factor analysis using an exploratory factor analysis solution and three other theory-based models. The exploratory factor analysis results revealed a six-factor structure: depression, suicide, insomnia, mania, psychosis, and anxiety. This solution also presented the best fit to the data when tested with confirmatory factor analysis. A five factor solution, without suicide as a separate dimension, appeared to be more theoretically suitable. Another important finding was that anxiety was an independent dimension in mania. Some hypotheses are discussed in light of contemporary theories, and future studies should investigate this aspect further. PMID- 24630744 TI - A genetic variant in the microRNA-146a gene is associated with susceptibility to alcohol use disorders. AB - BACKGROUND: Polymorphisms in the microRNA (miRNA) regulatory pathways are novel functional genetic variants whose association with alcoholism susceptibility has not been previously studied. Given the potential relationship between certain miRNAs and alcohol use disorders (AUDs), this study was designed to explore the association between two polymorphisms within hsa-miR-146a and hsa-miR-196a2 genes and susceptibility to these diseases. METHODS: Three hundred and one male patients with AUDs and 156 sex-matched healthy volunteers were enrolled. Polymorphisms were genotyped using TaqMan((r)) PCR assays. Allele and genotype frequencies were compared between groups and logistic regression analysis was also performed to analyze the model of inheritance. RESULTS: There was a significantly higher prevalence of allele C carriers (47.8%) of the miR-146a G>C polymorphism (rs2910164) among patients with AUDs when compared with controls (35.9%), and multivariable logistic regression analysis showed that the C allele was associated with these AUDs (OR=1.615, 95% CI 1.067-2.442; P=0.023). Neither the genotype nor the allele distribution of miR-196a2 polymorphism (rs11614913) was significantly different between groups. CONCLUSIONS: This is the first genetic association study to explore the relationship of miRNA polymorphisms with AUDs and to show an association of the miR-146a C>G rs2910164 allelic variant with this disease. PMID- 24630745 TI - Apathy in nursing home residents with dementia: results from a cluster-randomized controlled trial. AB - PURPOSE: Here we evaluate an interdisciplinary occupational and sport therapy intervention for dementia patients suffering from apathy. SUBJECTS AND METHODS: A prospective, controlled, rater-blinded, clinical trial with two follow-ups was conducted as part of a larger cluster-randomized trial in 18 nursing homes in Berlin. n=117 dementia patients with apathy, defined as a score of 40 or more on the apathy evaluation scale (AES) or presence of apathy on the Neuropsychiatric Inventory (NPI), were randomly assigned to intervention or control group. The intervention included 10 months of brief activities, provided once a week. The primary outcome measure was the total score on the AES scale measured directly after the intervention period and again after 12 months. RESULTS: We found significant group differences with respect to apathy during the 10 month intervention period (F2,82=7.79, P<0.01), which reflected an increase in apathy in the control group, but not in the intervention group. Within one year after the intervention was ceased, the treatment group worsened and no longer differed significantly from the control group (P=0.55). CONCLUSIONS: Our intervention was effective for the therapy of apathy in dementia, when applied, but not one year after cessation of therapy. PMID- 24630746 TI - Utilization patterns of antidepressants between 1991 and 2011 in a population based cohort of middle-aged and elderly. AB - BACKGROUND: In middle-aged and older patients in whom antidepressant use increased in last decades, patterns of use might be of concern The objective of this study was to investigate the patterns of prevalence, incidence and duration of antidepressant use in an ageing population. METHODS: All participants (aged>45 years) from the population-based Rotterdam Study were followed from January 1st 1991 until death, loss to follow-up, or end of the study period (December 31st 2011). Antidepressant drug dispensing, based on pharmacy records, were subdivided into Tricyclic Antidepressants (TCAs), Selective Serotonin Reuptake Inhibitors (SSRIs) and other antidepressants. One-year prevalence, 5-year incidence and duration of antidepressant use were calculated. RESULTS: Yearly prevalence of antidepressant use increased from 3.9% in 1991 to 8.3% of the population in 2011. The increase in SSRI use was 5.8-fold, whereas use of other antidepressants doubled and TCA use remained stable over time. Incidence of all antidepressants decreased from 23.9 to 14.2 per 1000 person-years between 1992 and 2011. The duration of a first treatment episode increased over time. CONCLUSION: Despite the prevalence of antidepressant use increased over time, incidence did not, which is most likely explained by a longer treatment duration and recurrent episodes. PMID- 24630747 TI - A decade of outcomes and predictors of sac enlargement after endovascular abdominal aortic aneurysm repair using zenith endografts in a Japanese population. AB - PURPOSE: To present 10-year outcomes and risk factors for sac enlargement after endovascular aneurysm repair (EVAR) using the Zenith AAA Endovascular Graft (Cook, Inc, Bloomington, Indiana) in a Japanese population. MATERIAL AND METHODS: During the period 1999-2011, 127 patients underwent elective EVAR using Zenith endografts at a single institution. A retrospective investigation looked at initial rates of technical success and complications, 10-year rate of freedom from all-cause and aneurysm-related mortality, freedom from secondary intervention and sac enlargement, and risk factors for second intervention and sac enlargement. RESULTS: The median age of the patients was 78 years, and the median follow-up time was 43 months. The initial technical success rate was 98.4% (125 of 127 patients). Major adverse events occurred in 7 of 127 (5.5%) patients. Rates of freedom from all-cause and aneurysm-related mortality at 1, 3, 5, and 10 years were 95%, 87%, 77%, and 39% (all-cause mortality) and 100%, 100%, 99%, and 93% (aneurysm-related mortality). Rates of freedom from secondary intervention at 1, 3, 5, and 10 years were 97%, 91%, 88%, and 70%. Rates of primary freedom from sac enlargement at 1, 3, 5, and 10 years were 99%, 87%, 75%, and 67%. Multivariate analysis revealed aneurysm sac diameter as an independent risk factor for a secondary intervention. Preoperative sac diameter combined with an angulated short (AS) proximal neck was a risk factor for sac enlargement. CONCLUSIONS: The 10-year results of EVAR using Zenith endografts in a Japanese population were comparable to results from Western countries. Larger aneurysms and AS neck were predictors of sac enlargement after EVAR. PMID- 24630748 TI - Inferior vena cava filter retrieval: effectiveness and complications of routine and advanced techniques. AB - PURPOSE: To investigate the success and safety of routine versus advanced inferior vena cava (IVC) filter retrieval techniques. MATERIALS AND METHODS: A retrospective review was performed of patients who underwent IVC filter placement and/or a retrieval attempt over a 10-year period. Retrieval technique(s), preretrieval computed tomography, preretrieval venography, and clinical/imaging follow-up for 30 days after retrieval were analyzed. Mean filter dwell time was 134 days (range, 0-2,475 d). RESULTS: Filter retrieval was attempted 231 times in 217 patients (39% female, 61% male; mean age, 50.7 y), with success rates of 73.2% (169 of 231) and 94.7% (54 of 57) for routine and advanced filter retrieval techniques, respectively. The overall filter retrieval complication rate was 1.7% (four of 231); complications in four patients (with multiple complications in some cases) included IVC dissection, IVC intussusception, IVC thrombus/stenosis, filter fracture with embedded strut, IVC injury with hemorrhage, and vascular injury from complicated venous access. The rate of complications associated with filter retrievals that required advanced technique was significantly higher than seen with routine technique (5.3% vs 0.4%; P < .05). Longer dwell time, more transverse tilt, and presence of an embedded hook were associated with significantly increased rates of failed retrieval via routine technique (P < .05). CONCLUSIONS: IVC filters can be retrieved with a high overall success rate (98.2%) and a low complication rate (1.7%) by using advanced techniques when the routine approach has failed; however, the use of advanced techniques is associated with a significantly higher complication rate. PMID- 24630749 TI - Vascular artifact mimicking thrombosis on MR imaging using ferumoxytol as a contrast agent in abdominal vascular assessment. AB - PURPOSE: To describe an artifact that mimics thrombosis when assessing abdominal vasculature on magnetic resonance (MR) imaging using ferumoxytol in patients with contraindications to gadolinium-based contrast agents and to evaluate factors that may contribute to this artifact. MATERIALS AND METHODS: Three radiologists in consensus retrospectively evaluated 61 abdominal MR imaging examinations using ferumoxytol as an intravenous contrast agent for the presence of an observed artifact that can mimic thrombosis. Patient demographics and contrast agent bolus concentrations were compared with an unpaired Wilcoxon signed rank test. RESULTS: An artifact mimicking thrombosis was observed in 30 of 61 examinations, all on the arterial phase sequences. In examinations with this artifact, the average concentration of administered ferumoxytol was greater than in examinations where the artifact was not observed (P < .01). Several additional vascular findings were observed, including portal vein thrombosis (n = 2) and aneurysm (n = 1), renal vein thrombosis (n = 2), abdominal aortic aneurysm (n = 1), abdominal and iliac artery dissection (n = 3), and sequelae of portal hypertension (n = 8). CONCLUSIONS: Although MR imaging using ferumoxytol as an intravenous contrast agent can be useful in detecting abdominal vascular abnormalities, an artifact mimicking vascular thrombosis was observed in nearly half of the examinations. PMID- 24630750 TI - Fluoroscopic versus laparoscopic implantation of peritoneal dialysis catheters: a retrospective cohort study. AB - PURPOSE: A previous clinical trial showed that radiologic insertion of first peritoneal dialysis (PD) catheters by modified Seldinger technique is noninferior to laparoscopic surgery in patients at low risk in a clinical trial setting. The present cohort study was performed to confirm clinical effectiveness of radiologic insertion in everyday practice, including insertion in patients with expanded eligibility criteria and by fellows in training. MATERIALS AND METHODS: Between 2004 and 2009, 286 PD catheters were inserted in 249 patients, 133 with fluoroscopic guidance in the radiology department and 153 by laparoscopic surgery. Survival analyses were performed with the primary outcome of complication-free catheter survival and secondary outcomes of overall catheter survival and patient survival. Outcomes were assessed at last follow-up, as long as 365 days after PD catheter insertion. RESULTS: In the radiologic group, unadjusted 365-day complication-free catheter, overall catheter, and patient survival rates were 22.6%, 81.2%, and 82.7%, respectively, compared with 22.9% (P = .52), 76.5% (P = .4), and 92.8% (P = .01), respectively, in the laparoscopic group. Frequencies of individual complications were similar between groups. Adjusting for patient age, comorbidity, and previous PD catheter, the hazard ratio (HR) for catheter complications by radiologic versus laparoscopic insertion is 0.90 (95% confidence interval [CI], 0.62-1.31); the HR for overall catheter survival is 1.25 (95% CI, 0.59-2.65); and that for death is 2.47 (95% CI, 0.84 7.3). CONCLUSIONS: Radiologic PD catheter insertion is a clinically effective alternative to laparoscopic surgery, although there was poorer long-term survival with radiologic catheter placement, possibly because of preferential selection of radiologic insertion for more frail patients. PMID- 24630751 TI - Early treatment response evaluation after yttrium-90 radioembolization of liver malignancy with CT perfusion. AB - PURPOSE: To evaluate computed tomography (CT) perfusion for assessment of early treatment response after transarterial radioembolization of patients with liver malignancy. MATERIALS AND METHODS: Dynamic contrast-enhanced CT liver perfusion was performed before and 4 weeks after transarterial radioembolization in 40 patients (25 men and 15 women; mean age, 64 y +/- 11; range, 35-80 y) with liver metastases (n = 27) or hepatocellular carcinoma (HCC) (n = 13). Arterial perfusion (AP) of tumors derived from CT perfusion and tumor diameters were measured on CT perfusion before and after transarterial radioembolization. Success of transarterial radioembolization was evaluated on morphologic follow-up imaging (median follow-up time, 4 mo) based on Response Evaluation Criteria in Solid Tumors (Version 1.1). CT perfusion parameters before and after transarterial radioembolization for different response groups were compared. Kaplan-Meier curves were plotted to illustrate overall 1-year survival rates. RESULTS: Liver metastases showed significant differences in AP before and after transarterial radioembolization in responders (P < .05) but not in nonresponders (P = .164). In HCC, AP values before and after transarterial radioembolization were not significantly different in responders and nonresponders (P = .180 and P = .052). Tumor diameters were not significantly different on CT perfusion before and after transarterial radioembolization in responders and nonresponders with liver metastases and HCC (P = .654, P = .968, P = .148, P = .164). In patients with significant decrease of AP in liver metastases after transarterial radioembolization, 1-year overall survival was significantly higher than in patients showing no reduction of AP. CONCLUSIONS: CT perfusion showed early reduction of AP in liver metastases responding to transarterial radioembolization; tumor diameter remained unchanged early after treatment. No significant early treatment response to transarterial radioembolization was found in patients with HCC. In patients with liver metastases, a decrease of AP after transarterial radioembolization was associated with a higher 1-year overall survival rate. PMID- 24630752 TI - New antiplatelet agents in the treatment of acute coronary syndromes. AB - Effective antagonism of the P2Y12 platelet receptor is central to the treatment of acute coronary syndrome (ACS) patients, especially in the setting of percutaneous coronary intervention and stenting. According to consensus guidelines, early revascularization and intensive antiplatelet therapy are key to reducing the complications that arise from myocardial ischaemia and the recurrence of cardiovascular events. Until recently, clopidogrel was the key P2Y12 antagonist advocated, but due to several limitations as an antiplatelet agent, newer drugs with more predictable, rapid and potent effects have been developed. Prasugrel and ticagrelor are now the recommended first-line agents in patients presenting with non-ST-segment elevation ACS and ST-segment elevation ACS, due to large-scale randomized trials that demonstrated net clinical benefit of these agents over clopidogrel, as stated in the European guidelines. Although no study has directly compared the two agents, analysis of the data to date suggests that certain patient types, such as diabetics, those with ST-segment elevation myocardial infarction or renal failure and the elderly may have a better outcome with one agent over the other. Further studies are needed to confirm these differences and answer pending questions regarding the use of these drugs to optimize efficacy while minimizing adverse events, such as bleeding. The aim of this review is to provide an overview of the current P2Y12 receptor antagonists in the treatment of ACS, with a focus on issues of appropriate agent selection, timing of treatment, bleeding risk and the future role of personalized treatment using platelet function and genetic testing. PMID- 24630753 TI - Heart failure with systolic dysfunction complicating acute myocardial infarction differential outcomes but similar eplerenone efficacy by ST-segment or non-ST segment elevation: A post hoc substudy of the EPHESUS trial. AB - BACKGROUND: Differential outcomes in patients with acute systolic heart failure (HF) complicating acute myocardial infarction (AMI) and the efficacy of mineralocorticoid receptor antagonists according to non-ST-segment and ST-segment elevation myocardial infarction (NSTEMI, STEMI) status has not been specifically investigated. METHODS: In the EPHESUS study, 6632 patients with acute HF and left ventricular ejection fraction<40% were randomized 3-14 days post-AMI (median 7.3 +/- 3.0 days) to receive eplerenone (n=3319) or placebo (n=3313). Among them, 6392 patients with available data on baseline ST-segment status (4634 STEMI; 1758 NSTEMI) were compared using a Cox model analysis stratified according to quintiles of propensity score (PS), taking into account major baseline risk factors, including revascularization. RESULTS: STEMI and NSTEMI patients differed significantly across a large variety of baseline characteristics. During 30 months of follow-up, all-cause death occurred in 19% and 13% (P<0.0001), cardiovascular death in 16% and 12% (P<0.0001), cardiovascular death and hospitalization in 33% and 26% (P<0.0001) and death from progression of HF in 5% and 3% (P<0.0001) of unadjusted NSTEMI and STEMI patients, respectively. After Cox model PS adjustment without revascularization, NSTEMI status still proved to be a risk factor for all-cause death, cardiovascular death and death from progression of HF. After Cox model PS adjustment including revascularization, none of the outcomes differed between STEMI and NSTEMI patients. Eplerenone morbidity and mortality benefits were consistent in the STEMI and NSTEMI subgroups. CONCLUSION: In patients with acute systolic HF complicating AMI, eplerenone improves outcomes equally in STEMI and NSTEMI patients. Worse outcomes associated with NSTEMI could be explained by more co-morbidities, less aggressive therapies and, mainly, less frequent revascularization. PMID- 24630754 TI - Associations between objectively measured physical activity and quality of life in cancer patients with brain metastases. AB - CONTEXT: Physical activity has demonstrated benefits for quality of life (QoL) and cancer-related fatigue earlier in the cancer trajectory; however, less is known regarding its role in patients with end-stage cancer. OBJECTIVES: The primary aim of this study was to examine the association between objectively measured physical activity and QoL in cancer patients with brain metastases. METHODS: Patients diagnosed with brain metastases, aged 18 years or older, cognitively intact, and with Palliative Performance Scale scores greater than 30%, were recruited from a multidisciplinary brain metastases clinic. A cross sectional survey interview assessed self-reported QoL (McGill Quality of Life Questionnaire), self-reported physical function (Late-Life Function and Disability Instrument), and symptoms (Edmonton Symptom Assessment System). Participants wore activPALTM (PAL Technologies, Ltd., Glasgow, UK) accelerometers recording triaxial movement for seven days during palliative whole brain radiotherapy. RESULTS: A total of 31 patients were recruited. Median survival was 171 days from time of study consent, with 90% (28 of 31) of deaths by two year follow-up. Participants who stood for 1.6 hours or more per day had better QoL (mean=1.0; 95% confidence interval [CI]=0.1 to 1.9; P=0.034). Participants who stood for 1.6 hours or more per day had better QoL (mean=1.0; 95% CI=0.1 to 1.9; P=0.034). Participants who sat or were supine for 20.7 hours or more per day had better advanced lower extremity functioning (mean=-6.1; 95% CI=-11.9 to -0.3; P=0.040) and total functioning (mean=-10.6; 95% CI=-21.1 to -0.04; P=0.049), but worse depression (mean=2.1; 95% CI=0.3 to 3.9; P=0.028), anxiety (mean=2.8; 95% CI=0.7 to 5.0; P=0.012), and feeling of well-being (mean=1.9; 95% CI=0.2 to 3.6; P=0.028). CONCLUSION: Sedentary behavior appears to be associated with better physical functioning but worse psychosocial functioning in cancer patients with brain metastases. PMID- 24630755 TI - Caprine arthritis encephalitis virus detection in blood by loop-mediated isothermal amplification (LAMP) assay targeting the proviral gag region. AB - Caprine arthritis encephalitis virus (CAEV), of the genus Lentivirus of the Retroviridae family, causes persistent disease, which is characterized by polyarthritis and mastitis in adult goats and progressive paresis (leukoencephalomyelitis) in kids. A loop-mediated isothermal amplification (LAMP) assay was developed for the detection of CAEV in blood samples. Species-specific primers amplifying the gag gene region in the provirus were used for the detection of CAEV. The LAMP assay result was obtained 30 min after incubation on a constant temperature at 63 degrees C in a heat block. Resulting amplicons were visualized by addition of SYBR green dye after the reaction and checked by agarose gel electrophoresis. The sensitivity of LAMP assay was evaluated by comparing the result with the nested polymerase chain reaction. Based on the experiments, the result of the assay indicated a rapid and sensitive test for the detection of CAEV. PMID- 24630756 TI - Antibody responses and viral load in patients with Crimean-Congo hemorrhagic fever: a comprehensive analysis during the early stages of the infection. AB - This study was performed to assess viral load, viral nucleocapsid (N), and glycoprotein precursor (GPC) antibodies in consecutive samples obtained from Crimean-Congo hemorrhagic fever patients to reveal viral replication kinetics and antiviral immune responses during the early stages of the infection. Among 116 samples from 20 individuals, 43.9% and 76.7% were positive for viral RNA and IgM/IgG antibodies, respectively, whereas both markers could be detected in 22.4%. Mean duration of viremia was 3 days (range: 1-6 days). N-IgM antibodies were identified as the initial serological marker during the infection, becoming detectable in a median of 2-3 days after disease onset, followed by GPC-IgM (4-6 days) and IgG antibodies (5-6 days). Clearance of viremia followed or coincided N IgM response. Partial S gene sequences amplified in viremic patients were identical or closely related to previously characterized strains and grouped within European lineage I group II viruses via neighbor-joining analysis without significant amino acid substitutions. PMID- 24630757 TI - Lack of association between CALHM1 p.P86L variation and Alzheimer's disease in the Han Chinese population. AB - In recent years, several studies have reported calcium homeostasis modulator 1 (CALHM1) was a potential gene related to Alzheimer's disease (AD) susceptibility. However, whether CALHM1 p.P86L variation (rs2986017), a risk factor for AD is still controversial. Two independent studies have been performed in the Chinese population and the conclusions have not reached an agreement. In the present study, we performed a replication case-control study in 1301 Chinese subjects including 452 sporadic AD patients and 849 unrelated age and gender-matched controls, to determine whether this variation is a risk factor for AD in the Han Chinese population. We failed to replicate the positive association between the CALHM1 p.P86L variation and AD. In addition, we also examined p.P86L variation in a meta-analysis of 5 independent studies performed in Chinese and other Asian populations and negative association was found in total 2328 AD patients and 2865 controls. Our study suggests that CALHM1 p.P86L variation may not be an AD susceptibility factor in the Han Chinese population. PMID- 24630758 TI - Dose estimation of animal experiments at the THOR BNCT beam by NCTPlan and Xplan. AB - Dose estimation of animal experiments affects many subsequent derived quantities, such as RBE and CBE values. It is important to ensure the trustiness of calculated dose of the irradiated animals. However, the dose estimation was normally calculated using simplified geometries and tissue compositions, which led to rough results. This paper introduces the use of treatment planning systems NCTplan and Xplan for the dose estimation. A mouse was taken as an example and it was brought to hospital for micro-PET/CT scan. It was found that the critical organ doses of an irradiated mouse calculated by simplified model were unreliable in comparison to Xplan voxel model. The difference could reach the extent of several tenths percent. It is recommended that a treatment planning system should be introduced to future animal experiments to upgrade the data quality. PMID- 24630760 TI - [AGGIR scale: a contribution to specifying the needs of disabled elders]. AB - Several instruments are used for the assessment of the disability, and the scale AGGIR (Autonomie Gerontologie Groupes Iso-Ressources) is the one most commonly used in France. This scale covers so-called instrumental dimensions, that correspond to relatively complex activities with the dominating cognitive component (cooking, medication use, finances, etc.) as well as dimensions with the dominating physical component (so-called fundamental dimensions that are related to such activities as walking, dressing, toileting, etc.). However, at present, only the fundamental activities are taken into account while assessing the dependency of the elderly within the scale AGGIR. The aim of our study was to identify the relative importance of these two dimensions (fundamental and instrumental) in the definition and identification of difficulties that older people encounter in their everyday life. A principal components analysis was carried out using 525 AGGIR scales of non-institutionalized elders living at their homes. The results indicate that the inclusion of instrumental activities may improve the assessment of dependency of the elderly and thus facilitate the implementation of appropriate responses to the needs of disabled people. PMID- 24630759 TI - Relations among prospective memory, cognitive abilities, and brain structure in adolescents who vary in prenatal drug exposure. AB - This investigation examined how prospective memory (PM) relates to cognitive abilities (i.e., executive function, attention, working memory, and retrospective memory) and brain structure in adolescents who vary in prenatal drug exposure (PDE). The sample consisted of 105 (55 female and 50 male) urban, primarily African American adolescents (mean age=15.5 years) from low socioeconomic status (SES) families. Approximately 56% (n=59) were prenatally exposed to drugs (heroin and/or cocaine) and 44% (n=46) were not prenatally exposed, but the adolescents were similar in age, gender, race, and SES. Executive functioning, attentional control, working memory, retrospective memory, and overall cognitive ability were assessed by validated performance measures. Executive functioning was also measured by caregiver report. A subset of 52 adolescents completed MRI (magnetic resonance imaging) scans, which provided measures of subcortical gray matter volumes and thickness of prefrontal, parietal, and temporal cortices. Results revealed no differences in PM performance by PDE status, even after adjusting for age and IQ. Executive function, retrospective memory, cortical thickness in frontal and parietal regions, and volume of subcortical regions (i.e., putamen and hippocampus) were related to PM performance in the sample overall, even after adjusting for age, IQ, and total gray matter volume. Findings suggest that variations in PM ability during adolescence are robustly related to individual differences in cognitive abilities, in particular executive function and retrospective memory, and brain structure, but do not vary by PDE status. PMID- 24630761 TI - Low intensity resistance training improves systolic function and cardiovascular autonomic control in diabetic rats. AB - AIMS: We evaluated the effects of low intensity resistance training (RT) on left ventricular (LV) function, baroreflex sensitivity (BRS), and cardiovascular autonomic control of streptozotocin-induced diabetic rats. METHODS: Male Wistar rats were divided into (n=8 each group): sedentary control (SC), trained control (TC), sedentary diabetic (SD), and trained diabetic (TD). Trained groups underwent low intensity RT (40%-50% 1 repetition maximum) for 10 weeks. Echocardiographic evaluation, arterial pressure (AP), heart rate (HR), BRS, and autonomic measurements were performed. RESULTS: Diabetes induced an increase in glycemia and a reduction in body weight in diabetics when compared with control animals. Diabetic rats displayed cardiac dysfunction, reduced systolic AP and HR, impaired BRS and autonomic derangement when compared to control rats. RT improved ejection fraction (SD: 68%+/-1.3% vs. TD: 75%+/-3.0%) and velocity of circumferential fiber shortening (SD: 0.32+/-0.02 vs. TD: 0.40+/-0.01 circ/seg.10(-4)). Trained diabetic rats presented increased AP (+10.2%), HR (+10.4%), and BRS after RT protocol. CONCLUSIONS: Low intensity RT induced an increase in systolic function in diabetic rats. This may be due to positive LV remodeling and BRS improvement, which may have played an important role in the attenuation of hemodynamic impairment and cardiac autonomic neuropathy in streptozotocin-diabetic rats. PMID- 24630762 TI - Vitreous biomarkers in diabetic retinopathy: a systematic review and meta analysis. AB - The aim of this study was to perform a systematic meta-analysis of biomarkers investigated with diabetic retinopathy (DR) in the vitreous, and to explore the molecular pathway interactions of these markers found to be consistently associated with DR. Relevant databases [PubMed and ISI web of science] were searched for all published articles investigating molecular biomarkers of the vitreous associated with DR. Based on set exclusion/inclusion criteria available data from studies with human vitreous samples were extracted and used for our meta-analysis. The interactions of significant biomarkers in DR were investigated via STRING and KEGG pathway analysis. Our meta-analysis of DR identifies eleven biomarkers as potential therapeutic candidates alternate to current anti-VEGF therapy. Four of these are deemed viable therapeutic targets for PDR; ET receptors (ET A and ET B), anti-PDGF-BB, blocking TGF-beta using cell therapy and PEDF. The identification of supplementary or synergistic therapeutic candidates to anti VEGF in the treatment of DR may aid in the development of future treatment trials. PMID- 24630763 TI - Prevalence and associations of diabetic retinopathy in a large cohort of prediabetic subjects: the Gutenberg Health Study. AB - AIMS: To evaluate the prevalence of diabetic retinopathy/maculopathy (DR/DMac) and its associations with cardiovascular risk factors (CRF) in participants with prediabetes (PwPD) in a large European cohort within the population-based Gutenberg Health Study (GHS). METHODS: The study was based on a sub-cohort of the GHS (n=5,000, age: 35-74 y). Prediabetes was diagnosed according to HbA1c levels (5.7-6.4%). DR/DMac was graded from fundus photographs. Blood samples and comprehensive questionnaires served for evaluation of laboratory results and CRF. RESULTS: The prevalence of prediabetes was 22.4%, and of DR/DMac 8.1%/0.2%, respectively. The majority of participants had mild DR (7.2%). A percentage of 0.5 of PwPD presented with moderate and 0.3% with severe non-proliferative disease. None of the subjects had proliferative DR. No independent association was found between any of the analyzed CRF [hypertension, smoking, (family) history of myocardial infarction, congestive heart failure, coronary heart disease, stroke, obesity, dyslipidemia, chronic obstructive pulmonary disease, peripheral artery disease and chronic kidney disease] and DR. CONCLUSIONS: Although prevalences of prediabetes and DR in this Caucasian cohort are considerable, retinopathy findings are mainly mild, and no association was found for DR/DMac and CRF. PMID- 24630764 TI - Surgical repair of cor triatriatum sinister: the Mayo Clinic 50-year experience. AB - BACKGROUND: Cor triatriatum is a rare congenital cardiac defect in which the atrium is divided into 2 chambers by a membrane causing obstruction to the blood flow in either the left atrium (cor triatriatum sinister) or the right atrium (cor triatriatum dexter) eventually leading to cardiac failure. We sought to review our surgical experience with cor triatriatum sinister. METHODS: Twenty five patients underwent surgical correction of cor triatriatum between May 1960 and September 2012. There were 11 males and 14 females with a mean age of 27.4 years (age range, 1 day to 73 years). RESULTS: All patients underwent excision of cor triatriatum membrane using cardiopulmonary bypass. Twenty patients (80%) required concomitant cardiac surgical procedures. There was no early mortality. None of the patients had any residual atrial obstruction. Two infants who had concomitant repair of complex congenital anomalies died at 2 and 5 months postoperatively after discharge from hospital. Kaplan-Meier survival at 10 years was 83%. All patients were in New York Heart Association class I or II at a mean follow-up of 12.8 years (maximum 44 years). CONCLUSIONS: Surgical repair of cor triatriatum provides satisfactory early and long-term survival with low risk for additional intervention. Cor triatriatum with complex congenital anomalies may be associated with adverse outcome. PMID- 24630765 TI - Eight patients with multiple bilateral thoracic anomalies: a new syndrome or bilateral Poland's syndrome? AB - BACKGROUND: Poland's syndrome is a rare congenital anomaly characterized by an absence or hypoplasia of the greater and smaller pectoral muscles, breast or nipple anomalies, hypoplasia of subcutaneous tissue, chest wall deformities, pectoral and axillary alopecia, and hand anomalies. Poland's syndrome is usually unilateral. We present 8 patients with multiple bilateral thoracic anomalies. METHODS: Eight patients were admitted to our clinic with an abnormal thoracic appearance and restriction of shoulder mobilization. Bilateral multiple muscles, including the greater pectoral muscle and some other thoracic muscles, could not be palpated during physical examination. All patients were evaluated, with a preliminary diagnosis of bilateral Poland's syndrome. RESULTS: All patients exhibited partial or complete absence of bilateral greater pectoral muscles, absence or hypoplasia of bilateral smaller pectoral muscles, bilateral shoulder protrusion to the front, limited abduction of both shoulders, absence or hypoplasia of other bilateral thoracic muscles (serratus anterior, latissimus dorsi, and trapezius muscles), and scapula alata. CONCLUSIONS: All patients with Poland's syndrome have unilateral hypoplasia or absence of the greater pectoral muscle as the main feature. Poland's syndrome is routinely described as a unilateral syndrome. Cases of Poland's syndrome are typically sporadic. Our patients had different additional bilateral anomalies. In particular, the main problems our patients had were the position of the shoulders and limited abduction of both upper extremities. In contrast to patients with Poland's syndrome, half of our cases were familial. We consider our patients important examples in that they either present a new syndrome or show that Poland's syndrome can be bilateral. PMID- 24630766 TI - Operative management of acquired thoracic dystrophy in adults after open pectus excavatum repair. AB - BACKGROUND: In young children, acquired thoracic dystrophy (ATD) is associated with extensive resection of cartilage, often during open pectus excavatum (PE) repair. Progressive dyspnea or exercise intolerance may develop in these patients secondary to cardiac compression or restrictive pulmonary function. Surgical treatment of ATD by attempting to increase the overall thoracic volume has been controversial. We describe our experience with adults presenting for surgical correction of ATD. METHODS: A retrospective medical record review was performed for all patients with ATD presenting for surgical evaluation from December 2010 through February 2013. RESULTS: Ten adult male patients were evaluated for treatment of ATD after an open Ravitch procedure for PE. Nine patients, whose mean age was 34 years (range, 21-42 years), elected to proceed with surgical treatment. The mean age of the initial repair was 3.7 years. Extensive reconstruction, chest wall expansion, and placement of stainless steel support bars and titanium plating were performed in all patients. Eight patients had minor complications, and major complications occurred in 3 patients. Respiratory failure with prolonged ventilator support occurred in 3 patients. There were no reoperations or deaths. At mean follow-up of 16 months (range, 6-31 months), all patients subjectively reported improvement in their ability to exercise and in their symptoms, including dyspnea with exertion. CONCLUSIONS: ATD may be associated with early childhood Ravitch repair. Adults may present with disabling symptoms related to cardiac compression and restrictive pulmonary function. Reconstruction with sternal elevation and expansion of the anterior chest subjectively improves symptoms. PMID- 24630768 TI - Urgent cardiac surgery during pregnancy: a continuous challenge. AB - BACKGROUND: Cardiac surgery during pregnancy is reserved for cases of failure of medical treatment due to its detrimental maternal and fetal effects. METHODS: Between March 2003 and December 2012, 23 pregnant women with severe valve malfunction required open heart surgery. The mean age was 30.3+/-4.9 years. Gestational age ranged from 14 to 39 weeks. Twenty patients (87%) presented with signs of right ventricular failure. The main presenting lesion was severe aortic stenosis in 3 patients (13%), mitral stenosis in 3 patients (13%), and stuck mechanical mitral valve prosthesis in 17 patients (73.9%). RESULTS: Fourteen patients were operated upon on emergency basis, and 9 patients on urgent basis. Two patients have continued their pregnancy to full term after cardiac surgery. Delivery was done immediately before surgery in 11 patients (47.8%). There were 10 intrauterine fetal deaths, all at gestational age below 28 weeks, 4 were confirmed before induction of anesthesia and 6 after surgery. There were 13 surviving babies, 7 premature babies (30.4%), and 6 full term babies (26.1%). Neonatal complications included respiratory distress syndrome in (38.5%) and prolonged hospital stay (46.2%). Maternal hospital morbidities included oliguria (65.2%), bleeding (30.4%), prolonged intensive care stay (56.5%), and prolonged hospital stay (26.2%). The in-hospital mortality was 8.7%. CONCLUSIONS: Urgent and emergency valve replacement in pregnant women can be achieved with good maternal morbidity and mortality; however, high incidence of fetal losses might be expected when surgery is performed at an early gestational age. PMID- 24630767 TI - Measurement of mitral leaflet and annular geometry and stress after repair of posterior leaflet prolapse: virtual repair using a patient-specific finite element simulation. AB - BACKGROUND: Recurrent mitral regurgitation after mitral valve (MV) repair for degenerative disease occurs at a rate of 2.6% per year and reoperation rate progressively reaches 20% at 19.5 years. We believe that MV repair durability is related to initial postoperative leaflet and annular geometry with subsequent leaflet remodeling due to stress. We tested the hypothesis that MV leaflet and annular stress is increased after MV repair. METHODS: Magnetic resonance imaging was performed before and intraoperative three-dimensional (3D) transesophageal echocardiography was performed before and after repair of posterior leaflet prolapse in a single patient. The repair consisted of triangular resection and annuloplasty band placement. Images of the heart were manually co-registered. The left ventricle and MV were contoured, surfaced, and a 3D finite element (FE) model was created. Elements of the posterior leaflet region were removed to model leaflet resection and virtual sutures were used to repair the leaflet defect and attach the annuloplasty ring. RESULTS: The principal findings of the current study are the following: (1) FE simulation of MV repair is able to accurately predict changes in MV geometry including changes in annular dimensions and leaflet coaptation; (2) average posterior leaflet stress is increased; and (3) average anterior leaflet and annular stress are reduced after triangular resection and mitral annuloplasty. CONCLUSIONS: We successfully conducted virtual mitral valve prolapse repair using FE modeling methods. Future studies will examine the effects of leaflet resection type as well as annuloplasty ring size and shape. PMID- 24630769 TI - Test-retest reliability of handgrip strength measurement using a hydraulic hand dynamometer in patients with cervical radiculopathy. AB - OBJECTIVE: The purpose of this study was to evaluate the test-retest reliability of handgrip strength measurement using a hydraulic hand dynamometer in patients with cervical radiculopathy (CR). METHODS: A convenience sample of 19 participants (14 men and 5 women; mean +/- SD age, 50.5 +/- 12 years) with CR was measured using a Jamar hydraulic hand dynamometer by the same rater on 2 different testing sessions with an interval of 7 days between sessions. Data collection procedures followed standardized grip strength testing guidelines established by the American Society of Hand Therapists. During the repeated measures, patients were advised to rest their upper limb in the standardized arm position and encouraged to exert 3 maximum gripping efforts. The mean value of the 3 efforts (measured in kilogram force [Kgf]) was used for data analysis. The intraclass correlation coefficient, SEM, and the Bland-Altman plot were used to estimate test-retest reliability and measurement precision. RESULTS: Grip strength measurement in CR demonstrated an intraclass correlation coefficient of 0.976, suggesting excellent test-retest reliability. The small SEM in both testing sessions (SEM1, 2.41 Kgf; SEM2, 2.51 Kgf) as well as the narrow width of the 95% limits of agreements (95% limits of agreement, -4.9 to 4.4 Kgf) in the Bland-Altman plot reflected precise measurements of grip strength in both occasions. CONCLUSIONS: Excellent test-retest reliability for grip strength measurement was measured in patients with CR, demonstrating that a hydraulic hand dynamometer could be used as an outcome measure for these patients. PMID- 24630770 TI - Reliability of the Goutallier classification in quantifying muscle fatty degeneration in the lumbar multifidus using magnetic resonance imaging. AB - OBJECTIVE: The purpose of this study was to investigate the reliability of the Goutallier classification system (GCS) for grading muscle fatty degeneration in the lumbar multifidus (LM) using magnetic resonance imaging (MRI) examinations. METHODS: Lumbar spine MRI scans were obtained retrospectively from the radiology department imaging system. Two examiners (a chiropractic diagnostic imaging resident and a board certified chiropractic radiologist with 30 years of experience) independently graded each LM at the L4/5 and L5/S1 intervertebral level. ImageJ pixel analysis software (version 1.47; National Institutes of Health, Bethesda, MD) was used independently by 2 observers to quantify the percent fat of the LM and allow correlation between LM percent fat and GCS grade. Twenty-five subject MRIs were randomly selected. Magnetic resonance imaging scans were included if they were obtained using a 1.5 T imaging system and were excluded if there was evidence of spinal infection, tumor, fracture, or postoperative changes. For all tests, P < .05 was defined as significant. RESULTS: Intraobserver reliability grading LM fat ranged from a weighted kappa (kappaw) of 0.71 to 0.93. Mean interobserver reliability grading LM fat was kappa(w), 0.76 to kappa(w), 0.85. There was a significant (P < .001) correlation between LM percent fat and GCS grade. Furthermore, interobserver reliability in determining percent fat was between intraclass correlation coefficient, 0.73 to intraclass correlation coefficient, 0.90. CONCLUSIONS: In this study, the GCS was reliable in grading LM fatty degeneration and correlated positively with a quantified percent fat value. In addition, ImageJ software (National Institutes of Health) was reliable between raters when quantifying LM percent fat. PMID- 24630771 TI - Primary surgical treatment of pelvic aggressive angiomyxoma is not always advisable in ER positive patients. PMID- 24630772 TI - Urologic surgery in gynecologic oncology: a large single-institution experience. AB - OBJECTIVE: The increasing tendency to a tailored treatment in gynecologic oncology has required the extension of the intervention to other non gynecological structures, as the urinary district. Moreover the role of the urological surgery in gynecologic oncology is still not completely explored. The objective of the study is to evaluate the occurrence of urological procedures in gynecologic oncology surgery. METHODS: Patients admitted to the Division of Gynecologic Oncology, Catholic University of Sacred Hearth, Rome, Italy, between January 2009 and December 2012, were retrospectively analyzed. Clinical charts identified the occurrence of urological procedures in major gynecological surgery. RESULTS: A total of 728 patients were analyzed for the study. A total of 204 urologic procedures were carried out in 83 patients. In all patients, preoperative hydronephrosis appears to be the only statistically significant predisposing factor to urological procedures. At multivariate analysis, stratifying data for different neoplasm, recurrence was the only adjunctive significant variable for ovarian cancer, as well as neo-adjuvant treatment and recurrence for cervical cancer. CONCLUSIONS: This study has identified preoperative factors influencing the needing of urological procedures in different gynecologic neoplasms, allowing a proper planning of surgical treatment, tailored on each patient. PMID- 24630773 TI - Reply letter to "Primary surgical treatment of pelvic aggressive angiomyxoma is not always advisable in ER positive patients". PMID- 24630774 TI - Is primary tumor resection associated with a longer survival in colon cancer and unresectable synchronous metastases? A 4-year multicentre experience. AB - AIM: To explore the survival impact of primary tumor resection (PTR) in patients with metastatic colon cancer (mCC) and unresectable metastases. METHODS: We retrospectively studied a multicenter cohort of consecutive mCC patients with unresectable metastases receiving first-line chemotherapy. A weighted Cox proportional regression model was used to balance for clinical variables associated with the probability of undergoing PTR, using inverse probability of treatment weighting (IPTW) based on a propensity score. RESULTS: Ninety-six patients were included. PTR was performed in 69 (72%). The rates of secondary resection of metastases (p = 0.02) and bevacizumab administration (p = 0.02) were higher in the PTR group. Raw median overall survival (OS) was 23.1 months (95%CI[14.6-27.8]) in the PTR group and 22.1 months (95%CI[12.3-23.7]) in the non PTR group (p = 0.11). After adjustment on IPTW, OS was 23.1 months (95%CI[17.0 28.7]) in the PTR group and 17.2 months (95%CI[13.5-22.2]) in the non-PTR group (HR 0.68; 95%CI[0.50-0.93]; p = 0.016). This result remained significant on multivariate analysis (HR 0.71; 95%CI[0.50-1.00]; p = 0.05). CONCLUSION: In mCC patients with unresectable metastases receiving chemotherapy, up-front PTR was independently associated with prolonged OS. Patients eligible for secondary metastases resection and/or bevacizumab may benefit the most from PTR. Randomized controlled trials are mandatory. PMID- 24630775 TI - Epigenetics in health and disease: heralding the EWAS era. PMID- 24630776 TI - Chronic kidney disease and the ageing population. PMID- 24630777 TI - DNA methylation and body-mass index: a genome-wide analysis. AB - BACKGROUND: Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome wide analysis of methylation at CpG sites in relation to BMI. METHODS: 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0.05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. FINDINGS: 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value <=0.05) between methylation at five probes across three different genes and BMI. The associations with three of these probes--cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A--were confirmed in both the primary and second replication cohorts. For every 0.1 increase in methylation beta value at cg22891070, BMI was 3.6% (95% CI 2.4-4.9) higher in the discovery cohort, 2.7% (1.2-4.2) higher in the primary replication cohort, and 0.8% (0.2-1.4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1.72 * 10( 5)) but not in skin (p=0.882). We observed a significant inverse correlation (p=0.005) between methylation at cg22891070 and expression of one HIF3A gene expression probe in adipose tissue. Two single nucleotide polymorphisms- rs8102595 and rs3826795--had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. INTERPRETATION: Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people. FUNDING: The European Commission, National Institute for Health Research, British Heart Foundation, and Wellcome Trust. PMID- 24630779 TI - Middle lobe syndrome in children today. AB - Middle lobe syndrome in children is a distinct clinical and radiographic entity that has been well described in the pediatric literature. However, issues regarding its etiology, clinical presentation, and management continue to puzzle the clinical practitioner. Pathophysiologically, there are two forms of middle lobe syndrome, namely obstructive and nonobstructive. Middle lobe syndrome may present as symptomatic or asymptomatic, as persistent or recurrent atelectasis, or as pneumonitis or bronchiectasis of the middle lobe and/or lingula. A lower threshold of performing a chest radiograph is warranted in children with persistent or recurrent nonspecific respiratory symptoms, particularly if there is clinical deterioration, in order to detect middle lobe syndrome and to initiate a further diagnostic and therapeutic workup. PMID- 24630778 TI - Use of targeted therapies for advanced renal cell carcinoma in the Asia-Pacific region: opinion statement from China, Japan, Taiwan, Korea, and Australia. AB - Rates of renal cell carcinoma (RCC) morbidity and mortality vary widely by geography, with increasing incidence in most countries. Interestingly, RCC incidence is significantly lower in Asian countries relative to other regions, which is attributed to environmental and genetic influences. Additionally, it has been demonstrated that different ethnic groups differ in their RCC characteristics which might lead to varied responses to therapy. In this review, physicians drawn from countries across the Asia-Pacific region--China, Japan, Taiwan, Republic of Korea, and Australia--take all available data into consideration to develop the first opinion statement on treatment of advanced RCC in the region. We have sought to determine what factors influence treatment patterns and availability of therapeutic agents in our respective countries, discussed whether these factors are fully justified or should be modified, and considered what additional efforts should be undertaken to optimize treatment outcomes in RCC. Additionally, we have addressed the limitations on treatment of RCC in the region, capturing the restrictive situations of targeted therapy use in the Asia-Pacific region, mainly because of drug availability and treatment reimbursement. Often this illustrates the gap between Western and regional or even among local guidelines, the opinions of leading physicians regarding the treatment, and the realistic access to agents for most patients. Proposals made in this document are based on clinical experience and data from clinical trials of RCC therapies in which Asian patients have been included. PMID- 24630780 TI - Willingness and ability to pay for physician services in six Central and Eastern European countries. AB - Patient charges for physician services are implemented in high-income countries and often are considered in the Central and Eastern Europe (CEE). However, there is no evidence on the potential consumption effects of service charges in these countries. This study provides evidence on the potential impact of patient charges on the consumption of specialized physician services in six CEE countries: Bulgaria, Hungary, Lithuania, Poland, Romania, and Ukraine. We apply a semi-parametric survival analysis to stated willingness and ability to pay (WATP) in order to identify potential demand pools and their price, income and age semi elasticity. Data are collected through a survey held in 2010 among representative samples of about 1000 respondents in each country. Our results suggest that median WATP in the studied countries is comparable to the cost of the services. The obtained demand pools appear to be theoretically valid and externally consistent. They provide information on the shares of population that would be WATP certain fee levels, and their heterogeneity across socio-demographic groups gives an idea about the population groups that will need to be exempted. PMID- 24630781 TI - Does feedback influence patient - professional communication? Empirical evidence from Italy. AB - Healthcare providers often look for feedback from patient surveys. Does health professional awareness of patient survey results improve communication between patients and providers? To test this hypothesis, we analyzed the data of two surveys on organizational-climate and patient experience in Italy. The two surveys were conducted in 26 hospitals in the Tuscany region and involved 8942 employees and 5341 patients, respectively. Statistical analysis showed that the patient experience index significantly improved by 0.35 points (scale: 0-100) when the professionals' knowledge of the patient survey results increased by 1%. These findings suggest that the control systems should focus more on the dissemination phase of patient survey results among health professionals in order to improve the quality of services. PMID- 24630782 TI - Physical growth and nutritional status of Car Nicobarese and Moplah children of Andaman-Nicobar Islands in India. AB - The objective of this cross-sectional study was to assess growth and nutritional status of Car Nicobarese children and compare it with Moplah children, who live in a similar environment. A total of 436 Car Nicobarese children and 438 Moplah children, aged 6-10 years, were selected for the study. The anthropometric measurements included stature, body weight, sitting height, bi-acromial breadth, bi-iliac breadth, mid-upper arm circumference, skinfold thickness of biceps, triceps and subscapular region. 50th percentile (median) growth curves were calculated among the studied children and compared with Centers for Disease Control and Prevention (CDC) 2000 reference. Z scores of weight for age (WAZ), height for age (HAZ) and BMI for age (BMIZ) were computed using growth references of the CDC 2000. It was observed that the Car Nicobarese children were shorter but heavier than Moplah children of both sexes all through the age range, which was also reflected in median value of anthropometric variables. Car Nicobarese children were nutritionally better compared to Moplah children based on the nutritional indices. The major differences between Car Nicobarese and Moplah children were found in their arm muscularity rather than arm adiposity. Overall, Car Nicobarese children were nutritionally in normal and better condition than Moplah children. However, present dietary change (intake of high calories and fat diet) of Car Nicobarese population may be reflected in the form of childhood obesity in the recent future, which has already been observed in their adult population. PMID- 24630783 TI - Thrombus burden and myocardial damage during primary percutaneous coronary intervention. AB - Large thrombus burden (LTB) lesions in the context of primary percutaneous coronary intervention (p-PCI) have been related to unsuccessful angiographic reperfusion and unfavorable clinical outcomes. However, the hazard of LTB treatment on myocardial damage has not been evaluated. We investigated the impact of LTB on myocardial damage using contrast-enhanced cardiac magnetic resonance (CE-CMR) in the setting of p-PCI. In 327 patients, who underwent p-PCI without thrombus aspiration within 12 hours from symptom onset, we prospectively assessed the impact of LTB on infarct size and microvascular damage using CE-CMR. LTB was defined by the presence of Thrombolysis In Myocardial Infarction thrombus score >=3 in patent infarct-related artery (IRA); or by "cut-off" occlusion pattern and/or large reference vessel diameter (>=3.5 mm) in occluded IRA. One hundred ninety-seven patients (60.2%) showed LTB and 130 (39.8%) did not. Distal embolization occurred in 18.8% patients with versus 6.9% without LTB (p = 0.003). At CE-CMR, patients with LTB had larger infarct size index (27.5 +/- 11.1 vs 22.1 +/- 17.5, p = 0.009) and more often transmural necrosis (70.5% vs 55.4%, p = 0.008) compared with patients without LTB. Excluding patients with distal embolization, patients with LTB still had larger necrosis. At multivariate analysis, occluded (IRA) at baseline, anterior infarction, and presence of LTB predicted transmural necrosis. In conclusion, LTB in the setting of p-PCI is related to larger myocardial damage as detected by CE-CMR, regardless of angiographic detectable distal embolization. PMID- 24630784 TI - Impact of chronic obstructive pulmonary disease on Valve Academic Research Consortium-defined outcomes after transcatheter aortic valve implantation (from the FRANCE 2 Registry). AB - The purposes of the present study were to determine the impact of chronic obstructive pulmonary disease (COPD) on Valve Academic Research Consortium defined outcomes in patients undergoing transcatheter aortic valve implantation (TAVI). A total of 3,933 consecutive patients underwent TAVI from January 2010 to December 2011 in 34 centers and were included in the French national TAVI registry "FRANCE 2"; 895 (22.7%) had concomitant COPD, 3,038 (77.3%) did not. There were no significant differences in procedural characteristics or 30-day Valve Academic Research Consortium-defined outcomes between those with and without COPD. Multivariate regression analysis showed COPD to be an independent predictor of 1-year mortality and combined efficacy end point after adjustment for concomitant co-morbidities (hazard ratio 1.19, 95% confidence interval 1.005 to 1.41, p = 0.03 and hazard ratio 1.52, 95% confidence interval 1.29 to 1.79, p <0.001, respectively). The higher mortality rate at 1 year in patients with COPD was related to cardiovascular deaths (COPD 10.0% vs non-COPD 6.2%, p = 0.008). Subgroup analysis found that the effect of COPD on 1-year mortality rate was constant across different subgroups, especially the type of approach and the type of anesthesia subgroups. In conclusion, concomitant COPD in patients referred for TAVI characterizes a high-risk population. The excess in mortality is largely determined by a higher rate of cardiovascular deaths and exists regardless of the type of procedure performed and its results. PMID- 24630785 TI - Impact of sugar-sweetened beverages on blood pressure. AB - The impact of sugar-sweetened beverages (SSBs) on blood pressure (BP) has been debated, with some evidence suggesting that their increased intake is related to higher risk of developing hypertension. We conducted a systematic review exploring the relation between consumption of SSB and BP. A comprehensive search in 5 electronic databases along with a bibliography search was performed. The keywords "sugar sweetened beverages," "sugary drinks," "added sugars," "blood pressure," and "hypertension" were indexed in all combinations. Studies were included that reported the effects of intake of SSBs on BP. We excluded studies with <100 subjects and those involving subjects aged <12 years. Of 605 potentially relevant studies, a total of 12 studies (409,707 participants) met our inclusion criteria; 6 were cross sectional studies, whereas the rest were prospective cohort studies. All 12 studies showed positive relation between increased SSB intake and hypertension; however, statistical significance was reported in 10 of these studies. Of the 12 studies, 5 reported an increase in mean BP whereas 7 reported an increase in the incidence of high BP. In conclusion, our systematic review shows that the consumption of SSBs is associated with higher BP, leading to increased incidence of hypertension. Restriction on SSB consumption should be incorporated in the recommendations of lifestyle modifications for the treatment of hypertension. Interventions to reduce intake of SSBs should be an integral part of public health strategy to reduce the incidence of hypertension. PMID- 24630786 TI - Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. AB - Patients with hypertrophic cardiomyopathy (HC) are reported to have a mortality rate of about 1.0% per year, and those patients without sudden death risk factors and with no or mild symptoms are generally considered to have a benign clinical presentation. However, the risk of sudden death and the outcome in this latter subgroup have not been investigated systematically and remain unresolved. We assessed the risk of sudden death and outcome in 653 consecutive patients with HC without risk factors and with no or mild symptoms. Over a median follow-up of 5.3 years, 35 patients (5.4%) died of HC-related causes. Mean age at death was 46 +/- 20 years in patients who died suddenly and 66 +/- 15 and 72 +/- 9 years, respectively, in patients who died of heart failure or stroke. Event rate was 0.6% per year for sudden death, 0.2% per year for heart failure death, and 0.1% per year for stroke-related death. Sudden death risk was independently and inversely related to age, and risk of heart failure or stroke death was directly related to age (p = 0.020). At 10 years after the initial evaluation, sudden death risk was 5.9%, with sudden death rate being the lowest (0.3% per year) in patients with normal left atrial dimension (<=40 mm). In conclusion, in patients with HC without conventional risk factors and with no or mild symptoms, the risk of sudden death was not negligible, with an event rate of 0.6% per year. Heart failure and stroke-related death were less common and largely confined to older patients. These results underscore the need for a more accurate assessment of the sudden death risk in patients with HC. PMID- 24630787 TI - Impact of Vice President Cheney on public interest in left ventricular assist devices and heart transplantation. AB - Although celebrity illnesses attract a significant amount of media attention in the United States, there are few studies that have looked at how celebrity health conditions impact the awareness of the illness in the general population. Recently, Vice President Cheney underwent left ventricular assist device (LVAD) implantation and subsequently a cardiac transplant. The aim of this study was to determine whether there was evidence of increased interest in these 2 procedures as assessed by social media. We determined the relative frequency of Google searches for LVAD and heart transplantation from 2004 to 2013 using Google trends. We also counted the number of YouTube videos and Twitter messages posted monthly concerning LVADs over a 7-year time frame. There was a significant spike in the Google search interest for LVAD and heart transplantation in the month when Vice President Cheney underwent the respective procedure. Similarly, there was a large increase in YouTube videos and Twitter messages concerning LVADs shortly after he was implanted. In total, these data support the concept that a public figure's illness can significantly influence the public's interest in that condition and its associated therapies. PMID- 24630788 TI - Impact of obesity and nonobesity on grading the severity of aortic valve stenosis. AB - We tested the hypothesis that the disproportionate increase of body surface area in obesity may lead to the overestimation of aortic stenosis (AS) severity when the aortic valve area (AVA) is indexed (AVAI) for body surface area in 1,524 patients enrolled in the Simvastatin and Ezetimibe in AS study. Obesity was defined as a body mass index of >=30 kg/m(2). Peak aortic jet velocity, mean aortic gradient, AVA, and energy loss (EL) did not differ, although AVAI and EL indexed (ELI) for body surface area were significantly smaller in the obese group (n = 321) compared with the nonobese (n = 1,203) group (both p <0.05). Severe AS by AVAI (<0.6 cm(2)/m(2)) but nonsevere by AVA (>1.0 cm(2); AVAI/AVA discordance) was found in 15% of the patients, whereas severe AS by ELI (<0.6 cm(2)/m(2)) but nonsevere by EL (>1.0 cm(2); ELI/EL discordance) was found in 9% of the patients. Obesity was associated with a 2.4-fold higher prevalence of AVAI/AVA discordance and a 1.6-fold higher prevalence of ELI/EL discordance. Discordant grading was also associated with male gender, larger body size, higher mean aortic gradient, and stroke volume (all p <0.05). During a median follow-up of 4.3 years, 419 patients were referred for aortic valve replacement and 177 patients died or were hospitalized because of heart failure. In the Cox regression analyses, AVAI/AVA discordance was associated with a 28% higher rate of aortic valve replacement (p <0.05) but did not predict the rate of combined death and hospitalization for heart failure. In conclusion, using AVAI and ELI for the grading of stenosis in patients with obesity may lead to overestimation of true AS severity. PMID- 24630789 TI - Outcomes in patients with ST-segment elevation acute myocardial infarction treated with clopidogrel versus prasugrel (from the INFUSE-AMI trial). AB - Prasugrel is more potent than clopidogrel, but it is not known whether this translates into clinical benefit in patients undergoing primary percutaneous coronary intervention (PCI) with bivalirudin for ST elevation myocardial infarction. In the Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction trial, 452 patients with anterior STEMI undergoing primary PCI with bivalirudin were randomized to intralesional abciximab or placebo and to thrombus aspiration or no aspiration. Clopidogrel or prasugrel were administered at physician discretion. The primary end point was infarct size at 30 days by cardiac magnetic resonance imaging. Clinical events at 30 days and 1 year were independently adjudicated. Propensity score was used to adjust for nonrandom allocation of the drugs. Prasugrel and clopidogrel were administered to 155 patients (34.3%) and 297 patients (65.7%), respectively. Patients receiving prasugrel were younger with higher left ventricular ejection fraction and greater use of drug-eluting stents. Prasugrel treated patients had higher rates of procedural success (94% vs 89%, p = 0.03), Thrombolysis In Myocardial Infarction (TIMI) 3 flow (95% vs 90%, p = 0.06), and lower corrected TIMI frame counts (21 +/- 6 vs 23 +/- 11, p = 0.008). At 30 days, infarct size was marginally lower in the prasugrel group (median [interquartile range] = 16.4% [6.5 to 20.0] vs 17.6% [8.1 to 25.7], p = 0.06). At 1 year, prasugrel group had significantly fewer deaths (1.3% vs 8.3%, p = 0.004) and fewer episodes of severe heart failure (2.0% vs 7.7%, p = 0.02). These findings persisted after propensity score adjustment. There were no significant differences in major bleeding. Stent thrombosis was 0% versus 2.5%, respectively, p = 0.054. We conclude that prasugrel was associated with improved efficacy and similar safety compared with clopidogrel in patients undergoing primary PCI with bivalirudin. PMID- 24630790 TI - Impact of major bleeding on long-term mortality in anemic versus nonanemic patients undergoing percutaneous coronary intervention using bivalirudin. AB - Bleeding complications after percutaneous coronary intervention (PCI) have been associated with higher short and long-term mortality. Bivalirudin has been shown to reduce bleeding complications in patients who underwent PCI; however, the impact of anemia on bleeding complications and long-term mortality has not been studied. A total of 11,991 patients who underwent PCI over a period of 8 years with bivalirudin as the primary antithrombotic agent were included. Anemia was defined according to the World Health Organization definition. Bleeding complications were prospectively collected. Survival analysis was performed using multivariable Cox proportional hazards models. Of the 11,991 patients, 4,815 patients (40%) had baseline anemia. Major bleeding occurred in 3.3% of patients with anemia compared with 0.7% of patients without anemia (p <0.001) driven largely by transfusion events. In the overall study population, major bleeding was a significant predictor of mortality (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.04 to 1.8, p = 0.027) at a mean follow-up of 2.6 years (interquartile range 1.4 to 3.5). In patients with anemia, major bleeding remained an independent predictor of mortality (HR 1.5, 95% CI 1.1 to 2.0, p = 0.008); however, in patients without anemia, it did not (HR 1.25, 95% CI 0.52 to 3.03, p = 0.62). In patients who underwent PCI with bivalirudin therapy, major bleeding is associated with early and long-term mortality, which is more pronounced in patients with baseline anemia. PMID- 24630791 TI - Periprocedural glycemic control in patients with diabetes mellitus undergoing coronary angiography with possible percutaneous coronary intervention. AB - Periprocedural hyperglycemia is an independent predictor of mortality in patients who underwent percutaneous coronary intervention (PCI). However, periprocedural management of blood glucose is not standardized. The effects of routinely continuing long-acting glucose-lowering medications before coronary angiography with possible PCI on periprocedural glycemic control have not been investigated. Patients with diabetes mellitus (DM; n = 172) were randomized to continue (Continue group; n = 86) or hold (Hold group; n = 86) their clinically prescribed long-acting glucose-lowering medications before the procedure. The primary end point was glucose level on procedural access. In a subset of patients (no DM group: n = 25; Continue group: n = 25; and Hold group: n = 25), selected measures of platelet activity that change acutely were assessed. Patients with DM randomized to the Continue group had lower blood glucose levels on procedural access compared with those randomized to the Hold group (117 [97 to 151] vs 134 [117 to 172] mg/dl, p = 0.002). There were two hypoglycemic events in the Continue group and none in the Hold group, and no adverse events in either group. Selected markers of platelet activity differed across the no DM, Continue, and Hold groups (leukocyte platelet aggregates: 8.1% [7.2 to 10.4], 8.7% [6.9 to 11.4], 10.9% [8.6 to 14.7], p = 0.007; monocyte platelet aggregates: 14.0% [10.3 to 16.3], 20.8% [16.2 to 27.0], 22.5% [15.2 to 35.4], p <0.001; soluble p selectin: 51.9 ng/ml [39.7 to 74.0], 59.1 ng/ml [46.8 to 73.2], 72.2 ng/ml [58.4 to 77.4], p = 0.014). In conclusion, routinely continuing clinically prescribed long-acting glucose-lowering medications before coronary angiography with possible PCI help achieve periprocedural euglycemia, appear safe, and should be considered as a strategy for achieving periprocedural glycemic control. PMID- 24630792 TI - Usefulness of coronary and carotid imaging rather than traditional atherosclerotic risk factors to identify firefighters at increased risk for cardiovascular disease. AB - Cardiovascular disease (CVD) accounts for 45% of deaths in on-duty firefighters, in contrast to 15% of all deaths occurring on conventional jobs. Therefore, with the goal of developing a tailored prevention program, we assessed CVD risk in a cohort of 50 firefighters using imaging and traditional risk factors. Participants were aged >=40 years without a history of CVD or diabetes. CVD risk was assessed by way of history, physical examination, blood tests, risk scores, coronary artery calcium (CAC), and carotid intima-media thickness (cIMT). Median age was 46 years; 90% of subjects were men, 92% were white, and 30% were former smokers. Only 4% of subjects were hypertensive but 48% were prehypertensive. Only 14% of subjects had a normal body mass index; 38% were overweight, 48% were obese, and 46% had a high waist circumference. Based on fasting glucose >=100 mg/dl or hemoglobin A1c >=5.6%, 50% of subjects had prediabetes and 2% had diabetes. Median total cholesterol was 196 mg/dl; median high-sensitivity C reactive protein was 1.0 mg/L. CAC was detected in 22% of subjects and carotid plaque was detected in 36%. Using standard reference databases, 54% of subjects had cIMT greater than the seventy-fifth percentile; 66% had carotid plaque and/or cIMT greater than the seventy-fifth percentile. Atherogenic lipoprotein markers and risk scores did not differ between firefighters who had subclinical atherosclerosis and those who did not. Traditional CVD risk assessment does not adequately identify at-risk firefighters. In contrast, CAC and cIMT were useful for identifying increased risk and implementing primary prevention. In conclusion, early detection and integration of imaging with traditional risk assessment will be important in preventing premature death and disability among firefighters. PMID- 24630793 TI - Multifaceted regulation of somatic cell reprogramming by mRNA translational control. AB - Translational control plays a pivotal role in the regulation of the pluripotency network in embryonic stem cells, but its effect on reprogramming somatic cells to pluripotency has not been explored. Here, we show that eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs), which are translational repressors, have a multifaceted effect on the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs). Loss of 4E-BP expression attenuates the induction of iPSCs at least in part through increased translation of p21, a known inhibitor of somatic cell reprogramming. However, MEFs lacking both p53 and 4E-BPs show greatly enhanced reprogramming resulting from a combination of reduced p21 transcription and enhanced translation of endogenous mRNAs such as Sox2 and Myc and can be reprogrammed through the expression of only exogenous Oct4. Thus, 4E-BPs exert both positive and negative effects on reprogramming, highlighting the key role that translational control plays in regulating this process. PMID- 24630795 TI - Prevalence and persistence of Escherichia coli in the airways of cystic fibrosis patients - an unrecognized CF pathogen? AB - Cystic fibrosis (CF) patients suffer from chronic recurrent bacterial airway infections, which eventually lead to reduced life expectancy. Escherichia coli has not been considered as a CF pathogen. A total of 176 patients were observed over 5.6 years on average from 2002 to 2009 in two CF centers in Muenster, Germany. Sputum and throat swab cultures were screened for E. coli. E. coli isolates were analyzed for clinical microbiologic characteristics as well as strain identity, clonal distribution and phenotypic variability. In 45 patients (25.6%) E. coli was cultured at least once, mostly at medium to high bacterial load and primarily from patients less than 5 and older than 8 years. In 19 patients (10.8%) the same E. coli strain was isolated at least 3 times within a period of more than 6 months, with a mean persistence of 29 months. Multi-locus sequence typing revealed a distinctively strong association of CF E. coli with the B2 major clonal group. During persistence, long-term colonizing strains exhibited phenotypic variability known for typical CF pathogens such as surface capsule overproduction and changes in colony size or hemolytic activity. E. coli was occasionally or persistently isolated in a quarter of CF patients, mostly in very young or older patients. The relatively high bacterial load of E. coli colonization, the distinct association with the highly virulent extra-intestinal B2 clonal group and phenotypic variability in the long-term colonizing strains suggests a previously unrecognized clinical significance of E. coli as a CF pathogen. PMID- 24630794 TI - Two miRNA clusters reveal alternative paths in late-stage reprogramming. AB - Ectopic expression of specific factors such as Oct4, Sox2, and Klf4 (OSK) is sufficient to reprogram somatic cells into induced pluripotent stem cells (iPSCs). In this study, we examine the paths taken by cells during the reprogramming process by following the transcriptional activation of two pluripotent miRNA clusters (mir-290 and mir-302) in individual cells in vivo and in vitro with knockin reporters. During embryonic development and embryonic stem cell differentiation, all cells sequentially expressed mir-290 and mir-302. In contrast, during OSK-induced reprogramming, cells activated the miRNA loci in a stochastic, nonordered manner. However, the addition of Sall4 to the OSK cocktail led to a consistent reverse sequence of locus activation (mir-302 then mir-290) and increased reprogramming efficiency. These results demonstrate that cells can follow multiple paths during the late stages of reprogramming, and that the trajectory of any individual cell is strongly influenced by the combination of factors introduced. PMID- 24630796 TI - Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. AB - PURPOSE: To use anterior segment optical coherence tomography (AS-OCT) to compare corneal stroma demarcation line depth after corneal collagen crosslinking (CXL) with 2 treatment protocols. SETTING: Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece. DESIGN: Prospective comparative interventional case series. METHODS: Corneal collagen crosslinking was performed in all eyes using the same ultraviolet-A (UVA) irradiation device (CCL-365). Eyes were treated for 30 minutes with 3 mW/cm(2) according to the standard Dresden protocol (Group 1) or for 10 minutes with 9 mW/cm(2) of UVA irradiation intensity (Group 2). One month postoperatively, 2 independent observers measured the corneal stroma demarcation line using AS-OCT. RESULTS: Sixteen patients (21 eyes) were enrolled. Group 1 comprised 7 patients (9 eyes) and Group 2, 9 patients (12 eyes). The mean corneal stroma demarcation line depth was 350.78 MUm +/- 49.34 (SD) (range 256.5 to 410 MUm) in Group 1 and 288.46 +/- 42.37 MUm (range 238.5 to 353.5 MUm) in Group 2; the corneal stroma demarcation line was statistically significantly deeper in Group 1 than in Group 2 (P=.0058, t test for unpaired data). CONCLUSION: The corneal stroma demarcation line was significantly deeper after a 30-minute CXL treatment than after a 10 minute CXL procedure with high-intensity UVA irradiation. PMID- 24630797 TI - Regression of severe corneal neovascularization after a triple procedure: phacoemulsification, intraocular lens implantation, and Descemet-stripping automated endothelial keratoplasty. AB - We report a case of complete regression of severe corneal neovascularization after a triple procedure-phacoemulsification, intraocular lens implantation, and Descemet- stripping automated endothelial keratoplasty. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 24630798 TI - [Charcot arthropathy]. PMID- 24630799 TI - Sporadic porphyria cutanea tarda: treatment with chloroquine decreases hyperglycemia and reduces development of metabolic syndrome. PMID- 24630800 TI - Monitoring of PAEMs and beta-agonists in urine for a small group of experimental subjects and PAEs and beta-agonists in drinking water consumed by the same subjects. AB - This 5-month study contains two parts: (1) to monitor the concentrations of 11 phthalate esters metabolites (PAEMs) and two beta-agonists in human urine samples collected from a small group of consented participants including 16 females and five males; and (2) to analyze the residues of phthalate esters (PAEs) and beta agonists in various categories of drinking water consumed by the same group of subjects. Each category of human urine and drinking water had 183 samples of its own. The analytical results showed that nine PAEMs were detected in human urine and eight PAEs were detected in drinking water samples. It was found that average concentrations of PAEMs increased as the age increased, but no significant difference between sexes. Further, using the principal component analysis, the loadings of age effect were found to be two times greater than that of gender effect in terms of four DEHP metabolites. Regarding beta-agonists of concern (i.e., ractopamine and salbutamol), they were neither detected in human urine nor drinking water samples in this study. PMID- 24630801 TI - Patients using dental pain to obtain narcotics from emergency physicians--a dental perspective. PMID- 24630802 TI - Resurgence of intravenous Opana as a cause of secondary thrombotic thrombocytopenic purpura. PMID- 24630803 TI - Comparison of coronary calcification of the culprit lesion between diabetic and non-diabetic patients with acute coronary syndrome. PMID- 24630804 TI - ED use by older adults attempting suicide. AB - OBJECTIVE: The objective of this study was to describe patterns of older adult patient visits to emergency departments (EDs) for self-harm and suicide-related injuries. METHODS: A retrospective, secondary data analysis of the Nationwide Emergency Department Sample was conducted. Nationally representative estimates of patient visits by older adults attempting suicide were calculated using available sampling weights. Population estimates were calculated using estimates from the US Census Bureau. RESULTS: Findings suggest that 22,444 ED patient visits were made by adults aged 65 years and older for suicide-related injuries, representing an estimated population rate of 63 ED patient visits per 100000 adults aged 65 years and older, with nearly half of all visits involving substance use. Total ED and hospital charges exceeded $353.9 million. CONCLUSIONS: Effort is needed to better integrate and deliver suicide screening and support services in the ED, while also connecting at-risk older adults with mental health services before and after the ED encounter. PMID- 24630805 TI - Diagnosis of metacarpal fracture with equivocal x-ray by point-of-care ultrasound: a case report. AB - Metacarpal fractures represent a very common injury among patients presenting to the emergency department. Diagnosis is of utmost importance given the high morbidity associated with lack of full hand function. We report a case of a 37 year-old man who sustained extremity trauma after a mechanical fall. He presented with an examination that revealed diffuse tenderness over the wrist and hand. X ray of the hand was equivocal for a metacarpal fracture; however, point-of-care ultrasound revealed disruption of the bony cortex confirming the diagnosis. The patient was splinted and referred for follow-up with a hand specialist. Point-of care ultrasound may be useful for the diagnosis of hand fractures, which may reduce health care costs and radiation exposure in the future. PMID- 24630806 TI - Patients with epilepsy are at an increased risk of subsequent stroke: a population-based cohort study. AB - PURPOSE: Epilepsy is well known as a disorder in poststroke patients. However, studies that have investigated the association between epilepsy and the risk of subsequent stroke are limited. This population-based study investigated the incidence and risk of stroke in patients with epilepsy by using the Taiwan National Health Insurance claims data. METHODS: We identified 3812 patients newly diagnosed with epilepsy in 2000-2008 and 15,248 nonepilepsy comparisons frequency matched according to sex, age, and index year. We searched for subsequent stroke diagnoses in both cohorts until the end of 2009. The incidence rates and hazard ratios of stroke were estimated based on sex, age, the average defined daily doses (DDDs) of antiepilepsy drugs, and comorbidity. RESULTS: The stroke incidence of the epilepsy cohort was 3-fold higher than that of the comparison cohort. The age-specific results indicated that in the epilepsy cohort and the comparison cohort, the risk was the highest for the youngest group (20-39 years). CONCLUSION: The patients with epilepsy exhibited a higher incidence of cerebral stroke than the general population did. In addition, younger patients with epilepsy and patients who took a high doses of antiepileptic drugs exhibited a high risk of stroke. PMID- 24630807 TI - Can heart rate variability in children with epilepsy be used to predict seizures? AB - PURPOSE: The aim of this study was to examine interictal, pre-ictal and ictal autonomic system disturbance by comparing heart rate variability in children with uncontrolled epilepsy with that seen in healthy controls and children with controlled epilepsy. METHODS: Our study group included 20 children with refractory epilepsy, our control groups were composed of 20 children with well controlled epilepsy and 20 healthy children. All subjects were evaluated by Holter ECG monitoring and 12-lead ECG to assess heart rate variability and QTc dispersion. The study group was also evaluated by Holter ECG during seizures. RESULTS: The study group exhibited significantly more pathological QTc dispersion than did the control groups. Heart rate variability was significantly suppressed: reduced parasympathetic activity with lower low frequency (LF) and high frequency (HF) band values were observed in the study group. Findings were similar in the well-controlled epilepsy group and the healthy group but differed from the uncontrolled epilepsy group. The examination of heart rate variability parameters during and before seizures revealed higher nLF and LF/HF ratio and lower nHF values demonstrating increased sympathetic activity. CONCLUSION: We suggest that children with refractory epilepsy have abnormalities of autonomic nervous system functioning which could be linked to the increased risk of sudden unexpected death seen in the patient group. It is possible that a chronically reduced vagal tone predisposes patients to a more dramatic stress response during their seizures. It is possible that heart rate variability parameter arising prior to seizures could be used to predict future seizures. PMID- 24630808 TI - A community study in Cornwall UK of sudden unexpected death in epilepsy (SUDEP) in a 9-year population sample. AB - PURPOSE: Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is underestimated by healthcare professionals. One argument that physicians use to justify the failure to discuss SUDEP with patients and their families is that there is a lack of evidence for any protective interventions. However, there is growing evidence of potentially modifiable risk factors for SUDEP; although large-scale trials of interventions are still lacking. We determined the main risk factors associated with SUDEP in a comprehensive community sample of epilepsy deaths in Cornwall UK from 2004 to 2012. METHODS: We systemically inspected 93 cases of all epilepsy and epilepsy associated deaths which occurred in Cornwall between 2004 and 2012 made available to us by the HM Cornwall coroner. These are the deaths where epilepsy was a primary or a secondary cause. RESULTS: 48 cases met the criteria for SUDEP and we elicited associated relevant risk factors. Many findings from our study are comparable to what has been reported previously. New points such as most of the population had increase in either or both seizure frequency/intensity within six months of death and majority did not have an epilepsy specialist review in the last one year to demise were noted. CONCLUSION: This study is the first epidemiological study in England occurring in a whole population identifying systemically all deaths and the first large scale review in UK of SUDEP deaths since 2005. Being a community based study a key issue which was highlighted was that in the SUDEPs examined many might have been potentially preventable. PMID- 24630809 TI - Measurement of levetiracetam drug levels to assist with seizure control and monitoring of drug interactions with other anti-epileptic medications (AEMs). AB - PURPOSE: Levetiracetam (LEV) therapeutic range (20-40mg/L) and potential drug interactions were assessed in people with epilepsy (PWE). METHOD: Fifty-two PWE had LEV and concomitant medications [carbamazepine (CBZ); valproate (VPA); lamotrigine (LTG)] blood levels measured and compared to seizure activity. Lacosamide (LCM) levels were unavailable. Adopted therapeutic ranges were: 20 40mg/L - LEV; 25-50MUmol/L - total CBZ; 6-13MUmol/L - free CBZ; 300-750MUmol/L - total VPA; 30-75MUmol/L - free VPA; and 40-60MUmol/L - LTG. Seizure-freedom was assessed and patients followed for almost two years. RESULTS: 23 of 52 PWE (44%) used LEV monotherapy and 16/23 (70%) had 'therapeutic' LEV with 13/16 (81%) seizure-free. 29 of 52 (56%) used polytherapy and 16/29 (55%) had 'therapeutic' LEV with 7/16 (44%) seizure-free. 11 of 29 (38%) used CBZ: 4/11 (36%) had therapeutic mean LEV levels and 7/11 (64%) were seizure-free. Fourteen (48%) used VPA: 9/14 (64%) had therapeutic mean LEV levels and 8/14 (57%) were seizure-free. 13 of 29 (45%) used LTG: 8/13 (62%) had therapeutic mean LEV levels and 5/13 (38%) were seizure-free. LEV did not alter CBZ, but CBZ affected LEV. LEV elevated VPA free levels but not VPA total levels. Dosage/concentration was lowered with polytherapy. CONCLUSION: LEV range (20-40mg/L) assisted epilepsy management and anti-epileptic medication interactions were suggested with polytherapy thus possibly explaining the impaired efficacy of LEV with polytherapy. PMID- 24630810 TI - Incidence of pneumothorax in advanced and/or metastatic soft tissue sarcoma patients during pazopanib treatment. PMID- 24630811 TI - DNA double-strand break repair in a cellular context. AB - Substantial insight into the mechanisms responding to DNA double-strand breaks has been gained from molecular, biochemical and structural approaches. Attention is now focusing on understanding the interplay between the pathways, how they interface through the cell cycle and the communication with other DNA transactions, such as replication and transcription. Understanding these aspects will facilitate an assessment of how cancer cells have modified these processes to achieve unlimited proliferative capacity and adaptability, and pave the way to identify targets suitable for therapy. Here, we briefly overview the processes responding to double-strand breaks and discuss our current understanding of their interplay in a cellular context. PMID- 24630815 TI - The effects of resveratrol on hyperoxia-induced lung injury in neonatal rats. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that causes significant morbidity and mortality in premature infants. Inflammation and oxidative injury play an important role in the pathogenesis of BPD. Resveratrol is an antioxidant and anti-inflammatory agent. In this study, the histopathological and biochemical effects of resveratrol on a hyperoxia-induced lung injury model in newborn rats were investigated. METHODS: The experiment was performed on newborn rat pups from the 3(rd) to 13(th) postnatal day and they were randomly divided into four groups: Group 1 (air-exposed + saline, n = 10), Group 2 (air-exposed + resveratrol, n = 11), Group 3 (hyperoxia-exposed + saline, n = 6) and Group 4 (hyperoxia-exposed + resveratrol, n = 7). Resveratrol was administered (30 mg/kg/day) intraperitoneally. The histopathological effects of resveratrol on lung tissue were assessed by alveolar surface area, fibrosis, and smooth muscle actin (SMA) score, and the biochemical effects on lung tissue were assessed by glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and nuclear factor kappa B (NF-kappaB) levels. RESULTS: The alveolar surface area, fibrosis, SMA score, and NO levels were found to be significantly higher in Group 3 compared with Group 1 (p < 0.05). In addition, it was found that resveratrol treatment significantly reduced the SMA score and the NO and TNF-alpha levels, and increased the GSH and SOD levels in the hyperoxia group (p < 0.05). CONCLUSION: This experimental study showed that oxidative stress and NO contributed to the pathogenesis of hyperoxia induced lung injury, and that resveratrol had a preventive effect on hyperoxic lung injury through its anti-inflammatory and antioxidant properties. PMID- 24630813 TI - Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. AB - Thermogenesis, the production of heat energy, is the specific, neurally regulated, metabolic function of brown adipose tissue (BAT) and contributes to the maintenance of body temperature during cold exposure and to the elevated core temperature during several behavioral states, including wakefulness, the acute phase response (fever), and stress. BAT energy expenditure requires metabolic fuel availability and contributes to energy balance. This review summarizes the functional organization and neurochemical influences within the CNS networks governing the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolically driven alterations in BAT thermogenesis and energy expenditure that contribute to overall energy homeostasis. PMID- 24630814 TI - Circuits controlling energy balance and mood: inherently intertwined or just complicated intersections? AB - Recent reports of adverse psychiatric events from seemingly different types of weight loss therapies highlight a previously underestimated overlap between CNS circuits that control energy balance and those that regulate mood. In this Perspective, we discuss a few potential brain sites where the homeostatic and the hedonic pathways may intersect and suggest that a better understanding of both pathways is necessary for the development of more effective and safer antiobesity therapies. PMID- 24630812 TI - Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications. AB - Significant comorbidities between obesity-related metabolic disease and stress related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward-driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the interrelationships between metabolism, stress, and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease. PMID- 24630817 TI - Reliability of scar assessments performed with an integrated skin testing device the DermaLab Combo((r)). AB - BACKGROUND: The DermaLab Combo((r)) is a device with potential to make objective measurements of key scar components - pigmentation, vascularity, pliability and thickness. This study assessed the inter-rater and test-retest reliability of these measurements. METHOD: Three raters performed scar assessments on thirty patients with burn scars using the DermaLab Combo((r)). Measurements of pigmentation, vascularity, pliability and thickness were made and intra-class correlation coefficients (ICC) were derived for inter-rater and test-retest reliability. RESULTS: Inter-rater reliability was found to be "excellent" in the 'best' and 'worst' areas of the index scar and normal skin for pigmentation (ICC: 0.94-0.98) and thickness (ICC: 0.86-0.96). Test-retest reliability was also "excellent" for pigmentation (ICC: 0.87-0.89) and thickness (ICC: 0.92-0.97) in all areas. Vascularity showed "good" to "excellent" inter-rater reliability (ICC: 0.66-0.84) in all areas however test-retest reliability was "low" (ICC: 0.29 0.42). Test-retest reliability was "excellent" for pliability (ICC: 0.76-0.91). Technical limitations were encountered making measurements in some scars for thickness, and in particular, pliability. CONCLUSION: The DermaLab Combo((r)) measured pigmentation, thickness and pliability with "excellent" reliability. If future studies provide protocols to improve test-retest reliability of vascularity measurements and obtain pliability measurements more successfully, the DermaLab Combo((r)) will be valuable device for scar assessment. PMID- 24630816 TI - Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT. AB - INTRODUCTION: Human antimicrobial peptides are of interest for the development of positron emission tomography (PET) tracers as they exhibit desirable characteristics that make them good candidates for targeting vectors. Due to their natural role in the innate immune system they selectively bind to pathogenic bacteria and yeast, whilst remaining minimally immunogenic and cytotoxic to humans. Research into ubiquicidin (UBI)-based tracers has focused on (99m)Tc as a radionuclide, however, the use of bi-functional chelators such as 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), in combination with 68Ga as a radionuclide, allows for a simple radiolabeling procedure which is preferable in a clinical setting using PET/CT. METHODS: The peptides fragments UBI29-41, UBI30-41 were synthesized by standard microwave Fmoc/tert-butyl (tBu)-solid phase synthetic protocols. Characterizations were performed using analytical HPLC and LC/MS. Both NOTA-conjugated peptides were exposed to (nat)Ga3+; their complexed form was quantified by direct LC/MS injection. This complexation was utilized to testify bacterial and mammalian cell binding potential of fluorophore-linked NOTA UBI29-41/30-41. 68Ga labeled NOTA-UBI fragments were also tested for competitive interaction to Staphylococcus aureus to proof the binding target. 68Ga was eluted from SnO2- and TiO2-based 68Ge/68Ga generators using fractionated elution and anion exchanged-based post-procession. NOTA-peptide radiolabeling was carried out including optimization of buffer molarity, NOTA-peptide concentration(s), incubation temperature and -duration as well as considering various SPE purification cartridges. RESULTS: Pure UBI29-41, UBI30-41 and NOTA-UBI30-41 were successfully characterized. Both, NOTA-UBI fragments exhibited complexation rates to (nat)Ga3+)>= 99%. The percentage binding was significantly higher to Staphylococcus aureus bacilli over Mt4 human leucocytes (P>0.05) for NOTA-UBI29 41[Lys(Abz)]0.03) after pre-incubation with excess unlabeled NOTA-UBI. Reproducible 68Ga radiolabeling ranged for 51-85% and 46-78% for NOTA-UBI29-41 and NOTA-UBI30-41, respectively. CONCLUSION: Aside from successful peptide syntheses the first ever 68Ga-radiolabeling method is reported for NOTA-UBI fragments. The NOTA-conjugation didn't compromise the selective and specific interaction with bacterial cells in vitro. Both tracers are warranting prospective imaging of infection with PET/CT. PMID- 24630818 TI - Evidence based management for paediatric burn: new approaches and improved scar outcomes. AB - Little evidence has been produced on the best practice for managing paediatric burns. We set out to develop a formal approach based on the finding that hypertrophic scarring is related to healing-time, with durations under 21 days associated with improved scar outcome. Incorporating new advances in burn care, we compared outcomes under the new approach to a cohort treated previously. Our study was a retrospective cross-sectional case note study, with demographic, treatment and outcome information collected. The management and outcome of each case was assessed and compared against another paediatric burns cohort from 2006. 181 burns presenting across a six month period were analysed (2010 cohort) and compared to 337 children from a previous cohort from 2006. Comparison of patients between cohorts showed an overall shift towards shorter healing-times in the 2010 cohort. A lower overall rate of hypertrophic scarring was seen in the 2010 cohort, and for corresponding healing-times after injury, hypertrophic scarring rates were halved in comparison to the 2006 cohort. We demonstrate that the use of a structured approach for paediatric burns has improved outcomes with regards to healing-time and hypertrophic scarring rate. This approach allows maximisation of healing potential and implements aggressive prophylactic measures. PMID- 24630819 TI - Prophylactic antibiotic therapy after inhalation injury. AB - OBJECTIVE: Inhalation injury is suspected in patients with facial and neck burn injuries and in patients who suffered burns in an enclosed space. Inhalation injury is associated with a disappointingly high morbidity and mortality in spite of advances in diagnostics and therapy.Prophylactic antibiotic therapy in patients with diagnosed inhalation injury is still a controversial subject.The epidemiologic characteristics of the burn patients with diagnosed inhalation injury in our clinic receiving prophylactic antibiotic therapy and mortality of these patients will be referred in this study. METHODS: Patients >16 years of age admitted to the burn unit between January 2008 and December 2012 and fulfilling the burn center referral criteria according the German Burn Association were enrolled in the study. RESULTS: 58 patients (male:female 47:11) were diagnosed with an inhalation injury by their admission. The average length of hospital stay was 27.5 days, whereas of the patients with no inhalation injury was 16 days (p=0.04). 56.9% of the patients underwent tracheostomy. An escalation of the antibiotic therapy was done in 39.7% of the patients with inhalation injury and in 20.3% of the patients without one. The mortality of inhalation injury patients was 12.1%. CONCLUSIONS: The development of pneumonia is not influenced in a statistical significant way by the use of prophylactic antibiotics. We do recommend the administration of prophylactic antibiotic therapy to patients with diagnosed inhalation trauma, as the mortality of these patients was lower in comparison to other studies. PMID- 24630820 TI - The effect of burn rehabilitation massage therapy on hypertrophic scar after burn: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of burn rehabilitation massage therapy on hypertrophic scar after burn. METHOD: One hundred and forty-six burn patients with hypertrophic scar(s) were randomly divided into an experimental group and a control group. All patients received standard rehabilitation therapy for hypertrophic scars and 76 patients (massage group) additionally received burn scar rehabilitation massage therapy. Both before and after the treatment, we determined the scores of visual analog scale (VAS) and itching scale and assessed the scar characteristics of thickness, melanin, erythema, transepidermal water loss (TEWL), sebum, and elasticity by using ultrasonography, Mexameter((r)), Tewameter((r)), Sebumeter((r)), and Cutometer((r)), respectively. RESULTS: The scores of both VAS and itching scale decreased significantly in both groups, indicating a significant intragroup difference. With regard to the scar characteristics, the massage group showed a significant decrease after treatment in scar thickness, melanin, erythema, TEWL and a significant intergroup difference. In terms of scar elasticity, a significant intergroup difference was noted in immediate distension and gross skin elasticity, while the massage group significant improvement in skin distensibility, immediate distension, immediate retraction, and delayed distension. CONCLUSION: Our results suggest that burn rehabilitation massage therapy is effective in improving pain, pruritus, and scar characteristics in hypertrophic scars after burn. PMID- 24630821 TI - Response to letter to the editor: 'construction of skin substitutes using minced split-thickness autografts and biodegradable synthetic scaffolds'. PMID- 24630822 TI - A clinical trial designed to evaluate the safety and effectiveness of a thermosensitive hydrogel-type cultured epidermal allograft for deep second-degree burns. AB - This study is a phase 1 and 2 clinical trial for investigating the safety profile, effective treatment dose and effectiveness of the newly developed thermosensitive hydrogel-type cultured epidermal allograft. For phase 1, the keratinocytes were divided into 3 groups as follows, with 5 patients in each group: (1) low-dose group (6.7*10(6)/1.5mL), (2) medium-dose group (2*10(7)/1.5mL), and (3) high-dose group (6.0*10(7)/1.5mL). The second phase of the trial proceeded with 10 cases after choosing the most effective dose based on the analysis of the first phase. When comparing re-epithelialization time, medium and high-dose group showed significantly shorter re-epithelialization time than low-dose group (p=0.003 and p=0.002). A total of 15 cases, 5 cases selected from phase 1 and 10 cases test in phase 2 with the medium dose, were compared with the re-epithelialization period. The re-epithelialization period was 9.6+/-4.0 days in the test site and 12.4+/-4.8 days in the control site. In the test site, re epithelialization was 2.8+/-1.8 days faster than in the control site (p<0.0001). There was no significant adverse reaction in our clinical trial. In conclusion, this new type of CEAllo accelerates wound healing time and shows the safety. PMID- 24630823 TI - Alteration of biomechanical properties of skin in acute cold contact injury. AB - BACKGROUND: The prevalence of acute cold injury has increased recently. Despite new research findings, these injuries and their resulting tissue damage are still not entirely understood. Especially, little is known about alteration of skin biomechanical properties. METHODS: A total of 36 acute cold contact wounds with different depths were generated on the abdomen of six Gottingen minipigs. Alteration of biomechanical properties of skin was evaluated objectively after 15 and 360 min using a Cutometer device. Biopsies for histological evaluation were taken, and the depth of injury was correlated with biomechanical properties. RESULTS: Calculated elasticity (Ue), firmness of skin (R0) and overall elasticity (R8) demonstrated a continuous decrease, whereas other parameters demonstrated an initial increase with increasing depth of injury 15 min after wound generation. All parameters showed an increase compared to healthy skin, 360 min after wound generation. Furthermore, an alteration of values over time was detected. CONCLUSION: Alteration of biomechanical properties of skin is a function of damaged tissue structures. The presented results demonstrate a decrease of main elastic parameters with increasing depth of injury and indicate progressive tissue damage over time. Skin elasticity measurements are a valuable tool in acute cold contact injury depth assessment and may act as an influencing factor in management decisions. PMID- 24630824 TI - Electronic cigarette use outcome expectancies among college students. AB - BACKGROUND: E-cigarette use outcome expectancies and their relationships with demographic and e-cigarette use variables are not well understood. Based on past cigarette as well as e-cigarette use research, we generated self-report items to assess e-cigarette outcome expectancies among college students. The objective was to determine different dimensions of e-cigarette use expectancies and their associations with e-cigarette use and use susceptibility. METHODS: Self-report data were collected from 307 multiethnic 4- and 2-year college students [M age=23.5 (SD=5.5); 65% Female; 35% current cigarette smokers] in Hawaii. Data analyses were conducted by using factor and regression analyses. RESULTS: Exploratory factor analysis among e-cigarette ever-users indicated 7 factors: 3 positive expectancy factors (social enhancement, affect regulation, positive sensory experience) and 4 negative expectancy factors (negative health consequences, addiction concern, negative appearance, negative sensory experience). Confirmatory factor analysis among e-cigarette never-users indicated that the 7-factor model fitted reasonably well to the data. Being a current cigarette smoker was positively associated with positive expectancies and inversely with negative expectancies. Higher positive expectancies were significantly associated with greater likelihood of past-30-day e-cigarette use. Except addiction concern, higher negative expectancies were significantly associated with lower likelihood of past-30-day e-cigarette use. Among e cigarette never-users, positive expectancy variables were significantly associated with higher intentions to use e-cigarettes in the future, adjusting for current smoker status and demographic variables. CONCLUSIONS: E-cigarette use expectancies determined in this study appear to predict e-cigarette use and use susceptibility among young adults and thus have important implications for future research. PMID- 24630825 TI - Is Internet addiction a psychopathological condition distinct from pathological gambling? AB - AIMS: The behavioural-addiction perspective suggests that Internet addiction (IA) and pathological gambling (PG) could share similar characteristics with substance dependence. Despite the similarities between IA and PG, it is not clear whether these disorders share different or similar psychopathological conditions. The aim of the present study was to test whether IA patients presented different psychological symptoms, temperamental traits, coping strategies and relational patterns compared with PG patients. The hypothesis was that IA patients will show greater interpersonal disengagement than PG patients. METHODS: Two clinical groups (31 IA patients and 11 PG patients) and a control group (38 healthy subjects) matched with the clinical groups for gender and age were enrolled. The clinical groups were gathered in a psychiatric service for IA and PG in a hospital. Anxiety, depression, coping strategies, attachment, temperament, and global assessment of functioning were measured. MANOVAs, ANOVAs and post-hoc comparisons were carried out in order to test the hypothesis. RESULTS: Despite IA and PG showing similar differences with the control group on the levels of depression, anxiety and global functioning, the two clinical groups showed different temperamental, coping and social patterns. Specifically IA patients compared with the PG patients showed a greater mental and behavioural disengagement associated with an important interpersonal impairment. The two clinical groups shared an impulsive coping strategy and socio-emotional impairments. CONCLUSIONS: Despite IA and PG patients presenting similar clinical symptoms, IA condition was characterised by a more relevant mental, behavioural, and social disengagement compared to PG condition. PMID- 24630826 TI - Newcomers to Al-Anon family groups: Who stays and who drops out? AB - Al-Anon Family Groups (Al-Anon), a 12-step mutual-help program for people concerned about another's drinking, is the most widely used form of help for concerned others (COs) in the US. This study assessed the prevalence of dropout, and predictors of dropout, in the six months following newcomers' initial attendance at Al-Anon meetings. Al-Anon's World Service Office mailed a random sample of groups, which subsequently yielded a sample of 251 newcomers who completed surveys at baseline and 6 months later. At the 6-month follow-up, 57% of newcomers at baseline had dropped out (had not attended any Al-Anon meetings during the past month). At baseline, individuals who later dropped out of Al-Anon were less likely to have been referred to Al-Anon by their drinker's health care provider, and reported less severe problems than individuals who continued to attend, but dropouts were more often concerned about their drinker's psychological health; newcomers with these concerns may have found them incompatible with Al-Anon's philosophy. Dropouts reported high rates of problems, suggesting that COs who drop out of Al-Anon would benefit from ongoing help and support. PMID- 24630827 TI - Endovascular treatment of acute ischemic stroke: Honolulu shock and thereafter. AB - Recently, use of mechanical clot retrievers for acute stroke has gradually spread. However, 3 recent randomized controlled trials failed to show superiority of endovascular treatment compared to intravenous recombinant tissue plasminogen activator (IV rt-PA) alone or standard care. On the other hand, a Japanese nationwide survey demonstrated the efficacy of endovascular treatment in the IV rt-PA failed and ineligible patients, especially with the proximal artery occlusion such as the internal carotid artery. Earlier initiation and higher reperfusion of endovascular treatment seemed to be the main reason for the better result in this survey compared with the reported randomized studies. Because next generation devices such as stent retrievers have been shown to provide better effects in terms of clinical outcomes compared with the Merci retriever, the efficacy of endovascular treatment is expected to be confirmed again by randomized controlled trials in the near future. PMID- 24630829 TI - Nontraumatic convexal subarachnoid hemorrhage concomitant with acute ischemic stroke. AB - BACKGROUND: Nontraumatic convexal subarachnoid hemorrhage (cSAH) rarely occurs subsequent to acute ischemic stroke. The incidence, clinical background characteristics, and outcomes in acute ischemic stroke patients with cSAH were investigated. METHODS: Our stroke center database was reviewed to identify patients with acute ischemic stroke/transient ischemic attack (TIA) who demonstrated acute cSAH within 14 days of admission between 2005 and 2011. Background characteristics, clinical course, and outcomes at discharge and 3 months after onset were investigated in these patients. RESULTS: Of 4953 acute stroke/TIA patients, cSAH was observed in 8 (.14%) patients (7 men, mean age 71 years): 7 were detected incidentally, and the other was found immediately after a convulsion. Two patients died during their hospital stay, 1 died after discharge, and 3 were dependent at 3 months. Major artery occlusion or severe stenosis was observed in 5 patients. Two patients subsequently developed subcortical hemorrhage. On gradient echo imaging, lobar cerebral microbleeds were observed in 2 patients, and chronic superficial siderosis was observed in 2 patients. CONCLUSIONS: In this retrospective review of cases with ischemic stroke and cSAH, over half of patients had occlusion of major arteries. Cerebral amyloid angiopathy was suggested by magnetic resonance imaging findings and subsequent events in 3 patients. The overall outcome was unfavorable although the causal relationship with cSAH was unclear. PMID- 24630828 TI - Thrombophilic risk factors in different types of retinal vein occlusion in Tunisian patients. AB - BACKGROUND: Retinal vein occlusion (RVO) is the second most common cause of vision loss because of retinal vascular disease. There are 2 types of RVO: branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). The pathogenesis of RVO is multifactorial. The role of factor V Leiden (FVL) and prothrombin mutations was examined in patients with CRVO and BRVO. METHODS: FVL and prothrombin were investigated by extracting DNA of 88 patients with RVO. Sixteen of the patients were diagnosed with CRVO, 4 with hemispheric retinal vein occlusion, and 68 with BRVO. The genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Significant differences were found in the frequencies of the genotypes for both the FVL (G1691A) (P<10(-3), odds ratio [OR]=17.4, confidence interval [CI]=6.20-59) and prothrombin (G20210A) (P=.007, OR=5.11, CI=1.30-29) polymorphisms between RVO patients and healthy controls. Additionally, the frequency of the GA genotype for the G1691A polymorphism was significantly higher among the patients in a subset of BRVO compared with controls (P<10(-3), OR=21.4, CI=7.34-74.2). However, no statistically significant differences were found in the frequencies of the prothrombin G20210A polymorphism between the BRVO group and healthy controls (P=.09, OR=3.13, CI=64-19.9). The frequency of both G1691A and G20210A genotypes among the patients of a CRVO subgroup was significantly higher compared with controls (P<10(-3), OR=11.4, CI=2.94-44.2; P=.007, OR=10.8, CI=2.15-54.1, respectively), suggesting an association between these polymorphisms and CRVO. CONCLUSIONS: Large study would be required to understand completely the contribution of these markers in the risk of all types of RVO. PMID- 24630830 TI - Anemia on admission increases the risk of mortality at 6 months and 1 year in hemorrhagic stroke patients in China. AB - BACKGROUND: The relationship between anemia and intracerebral hemorrhage is not clear. We investigated the associations between anemia at the onset and mortality or dependency in patients with intracerebral hemorrhage (ICH) registered at the China National Stroke Registry (CNSR). METHODS: The CNSR recruited consecutive patients with diagnoses of ICH in 2007-2008. Their vascular risk factors, clinical presentations, and outcomes were recorded. The mortality and dependency at 1, 3, and 6 months and at 1 year were compared between ICH patients with and without anemia. A favorable outcome was defined as a modified Rankin Scale (mRS) score of 2 or less and a poor outcome as an mRS score of 3 or more. Multivariable logistic regression was performed to analyze the association between anemia and the 2 outcomes after adjusting for age, gender, body mass index, history of smoking and heavy drinking, National Institutes of Health Stroke Scale score on admission, random glucose value on admission, and hematoma volume. RESULTS: Anemia was identified in 484 (19%) ICH patients. Compared with ICH patients without anemia, patients with anemia had no difference in mortality rate at discharge and at 1 month. The rate of mortality at 3 months, 6 months, 1 year, and dependency at 1 year were significantly higher for those patients with anemia than those without (P<.05, P<.001, P<.001, and P<.05, respectively). After adjusting for potential confounders, anemia was an independent risk factor for death at 6 months and 1 year (adjusted odds ratio [OR]=1.338, 95% confidence interval 1.01-1.78, and adjusted OR=1.326, 95% confidence interval 1.00-1.75) in ICH patients. CONCLUSIONS: Anemia independently predicted mortality at 6 months and 1 year after the initial episode of intercerebral hemorrhage. PMID- 24630831 TI - Modeling genomic regulatory networks with big data. AB - High-throughput sequencing, large-scale data generation projects, and web-based cloud computing are changing how computational biology is performed, who performs it, and what biological insights it can deliver. I review here the latest developments in available data, methods, and software, focusing on the modeling and analysis of the gene regulatory interactions in cells. Three key findings are: (i) although sophisticated computational resources are increasingly available to bench biologists, tailored ongoing education is necessary to avoid the erroneous use of these resources. (ii) Current models of the regulation of gene expression are far too simplistic and need updating. (iii) Integrative computational analysis of large-scale datasets is becoming a fundamental component of molecular biology. I discuss current and near-term opportunities and challenges related to these three points. PMID- 24630832 TI - Celecoxib and ion channels: a story of unexpected discoveries. AB - Celecoxib (Celebrex), a highly popular selective inhibitor of cyclooxygenase-2, can modulate ion channels and alter functioning of neurons and myocytes at clinically relevant concentrations independently of cyclooxygenase inhibition. In experimental systems varying from Drosophila to primary mammalian and human cell lines, celecoxib inhibits many voltage-activated Na(+), Ca(2+), and K(+) channels, including NaV1.5, L- and T-type Ca(2+) channels, KV1.5, KV2.1, KV4.3, KV7.1, KV11.1 (hERG), while stimulating other K(+) channels-KV7.2-5 and, possibly, KV11.1 (hERG) channels under certain conditions. In this review, we summarize the information currently available on the effects of celecoxib on ion channels, examine mechanistic aspects of drug action and the concomitant changes at the cellular and organ levels, and discuss these findings in the therapeutic context. PMID- 24630833 TI - Spermidine improves fear memory persistence. AB - Persistence is the most characteristic attribute of long-term memory (LTM). For memory persistence, a second late event of consolidation, that occurs around 12h after the acquisition, is necessary. Although the N-methyl-d-aspartate (NMDA) receptor has been involved in the persistence of memory, whether endogenous modulators of the NMDA receptor actually modulate memory persistence is unknown. In the current study we investigated whether spermidine and arcaine, respectively agonist and antagonist of polyamine binding site at NMDA receptor, alter the persistence of the memory of contextual fear conditioning task in rats. While 12h post-training administration of spermidine (10 and 30mg/kg, i.p.) facilitated, arcaine (10mg/kg, i.p.) impaired the memory of fear assessed 2 and 7 days after training. Arcaine (0.1mg/kg) prevented the facilitatory effect of spermidine (10mg/kg, i.p.), and spermidine (1mg/kg), prevented the memory impairment induced by arcaine (10mg/kg, i.p.) when tested 2 and 7 days after training. These results suggest that endogenous polyamines improve the persistence of fear memory. PMID- 24630834 TI - ISG54 and ISG56 are induced by TLR3 signaling in U373MG human astrocytoma cells: possible involvement in CXCL10 expression. AB - Toll-like receptor (TLR) 3 is a pattern recognition receptor that recognizes double-stranded RNA (dsRNA). TLR3 signaling in astrocytes leads to the expression of interferon-beta (IFN-beta), and IFN-beta regulates immune and inflammatory reactions by inducing IFN-stimulated genes (ISGs). We demonstrated in the present study that polyinosinic-polycytidylic acid (poly IC), an authentic dsRNA, up regulated the expression of ISG54 and ISG56 in U373MG human astrocytoma cells. This reaction was confirmed to be mediated via the TLR3/IFN-beta pathway. We also found that ISG56 positively regulates the expression of ISG54, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). In addition, positive feedback loops were found between ISG54 and ISG56, and also between ISG54 and RIG-I. RNA interference experiments revealed that all of ISG54, ISG56, RIG-I and MDA5 were involved in the poly IC-induced expression of a chemokine CXCL10. These results suggest that ISG54 and ISG56 are involved in the induction of CXCL10 in TLR3/IFN-beta signaling at least partly by co-operating with RIG-I and MDA5. ISG54 and ISG56 may contribute to immune and inflammatory reactions elicited by the TLR3/IFN-beta signaling pathway in astrocytes, and may play an important role both in antiviral immunity and in neuroinflammatory diseases. PMID- 24630835 TI - Level-I trauma centre treatment effects on return to work in teaching hospitals. AB - BACKGROUND: Previous research found a positive effect of Level-I trauma centres on return to work outcomes for patients 18-64 years old who were mainly working before injury. Trauma centres were compared to hospitals that differed on average in characteristics such as size and staffing, among others. Thus, a portion of the effect found could be due to general differences in hospital variables rather than the special characteristics of Level I trauma centres. Comparing Level I trauma centres to other Teaching hospitals provides a more refined test of the effect of these centres on return-to-work outcomes. METHODS: The National Study on the Costs and Outcomes of Trauma (NSCOT) is the main source of data for our empirical investigation. We used non-linear instrumental variables methods to control for unobserved characteristics and restrict the sample to teaching hospitals. The first method is the two-stage residual inclusion model in which we identify the effect using the proportion of resident population served by Helicopter Ambulance Services (at the state level) as an instrumental variable. The second method is a recursive bivariate probit model. RESULTS: We found that treatment at Level-I trauma centres has a positive effect on return to work outcomes three months after injury. The estimated effect is statistically significant and positive, but lower than the estimate that did not focus on teaching hospitals. CONCLUSIONS: A previous study found positive effects of treatment at a Level-I trauma centre on return-to-work outcomes, however, a portion of the effect found was due to general differences in hospital variables. PMID- 24630836 TI - Advancing age and trauma: triage destination compliance and mortality in Victoria, Australia. AB - OBJECTIVE: To describe the association between increasing age, pre-hospital triage destination compliance, and patient outcomes for adult trauma patients. METHODS: A retrospective data review was conducted of adult trauma patients attended by Ambulance Victoria (AV) between 2007 and 2011. AV pre-hospital data was matched to Victorian State Trauma Registry (VSTR) hospital data. Inclusion criteria were adult patients sustaining a traumatic mechanism of injury. Patients sustaining secondary traumatic injuries from non-traumatic causes were excluded. The primary outcomes were destination compliance and in-hospital mortality. These outcomes were evaluated using multivariable logistic regression. RESULTS: There were 326,035 adult trauma patients from 2007 to 2011, and 18.7% met the AV pre hospital trauma triage criteria. The VSTR classified 7461 patients as confirmed major trauma (40.9%>55 years). Whilst the trauma triage criteria have high sensitivity (95.8%) and a low under-triage rate (4.2%), the adjusted odds of destination compliance for older trauma patients were between 23.7% and 41.4% lower compared to younger patients. The odds of death increased 8% for each year above age 55 years (OR: 1.08; 95% CI: 1.07, 1.09). CONCLUSIONS: Despite effective pre-hospital trauma triage criteria, older trauma patients are less likely to be transported to a major trauma service and have poorer outcomes than younger adult trauma patients. It is likely that the benefit of access to definitive trauma care may vary across age groups according to trauma cause, patient history, comorbidities and expected patient outcome. Further research is required to explore how the Victorian trauma system can be optimised to meet the needs of a rapidly ageing population. PMID- 24630837 TI - Differentiation of endothelial progenitor cells into endothelial cells by heparin modified supramolecular pluronic nanogels encapsulating bFGF and complexed with VEGF165 genes. AB - Specific genes and growth factors are involved in stem cell differentiation. In this study, we fabricated a delivery carrier for both protein and gene delivery that was introduced into human endothelial progenitor cells (EPCs). The highly negative charge carried by the heparin-modified pluronic nanogels allowed for binding to growth factors and localization in the core of nanogels. The residues of negatively charged heparin can complex with positively charged cationic materials, making it suitable for gene delivery. Supramolecular nanogels can be easily encapsulated the hydrophilic drugs and highly positive surfaces can be complexed with negative charge carrying plasmid DNA (pDNA). The size distribution, gel retardation, and denaturation of encapsulated growth factors and supramolecular nanogels modified with heparin were evaluated. The supramolecular nanogels containing basic fibroblast growth factors and complexing VEGF165 pDNA internalized into EPCs have been well formed vascular formation in matrigel gels. Proteins and genes introduced into EPCs using nanogels promoted neovascularization in an animal model of limb ischemia. EPCs that differentiated into endothelial cells both in vitro and in vivo were tested. PMID- 24630839 TI - Selective inhibition of breast cancer stem cells by gold nanorods mediated plasmonic hyperthermia. AB - Cancer stem cells (CSCs) have been identified in a variety of cancers and emerged as a new target for cancer therapy. CSCs are resistant to many current cancer treatments, including chemotherapy and radiation therapy. Therefore, eradication of this cell population is a primary objective in cancer therapy. Here, we report gold nanorods (AuNRs) mediated photothermal treatment can selectively eliminate CSCs in MCF-7 breast cancer cells. It significantly reduced the aldehyde dehydrogenase positive (ALDH(+)) cells subpopulation and the mammosphere formation ability of treated cells. Also, the gene expression of stem cell markers was decreased. Cellular uptake assay revealed that polyelectrolyte conjugated AuNRs could be internalized by CSCs much more and faster than non cancer stem cells (NCSCs), which might be the main reason for the selective elimination of CSCs. We further loaded salinomycin (SA), a CSCs inhibitor with polyelectrolyte conjugated AuNRs to get a synergistic CSCs inhibition. Enhanced inhibition of CSCs was obtained by NIR light triggered drug release and hyperthermia. This CSCs-targeted thermo-chemotherapy platform provides a new combinatorial strategy for efficient inhibition of CSCs, which is promising to improve cancer treatment and may overcome the chemoresistance and recurrence of cancer. PMID- 24630838 TI - Cytotoxicity, oxidative stress, apoptosis and the autophagic effects of silver nanoparticles in mouse embryonic fibroblasts. AB - With the advancement of nanotechnology, nanomaterials have been comprehensively applied in our modern society. However, the hazardous impacts of nanoscale particles on organisms have not yet been thoroughly clarified. Currently, there exist numerous approaches to perform toxicity tests, but common and reasonable bio-indicators for toxicity evaluations are lacking. In this study, we investigated the effects of silver nanoparticles (AgNPs) on NIH 3T3 cells to explore the potential application of these nanoparticles in consumer products. Our results demonstrated that AgNPs were taken up by NIH 3T3 cells and localized within the intracellular endosomal compartments. Exposure to AgNPs is a potential source of oxidative stress, which leads to the induction of reactive oxygen species (ROS), the up-regulation of Heme oxygenase 1 (HO-1) expression, apoptosis and autophagy. Interestingly, AgNPs induced morphological and biochemical markers of autophagy in NIH 3T3 cells and induced autophagosome formation, as evidenced by transmission electron microscopic analysis, the formation of microtubule associated protein-1 light chain-3 (LC3) puncta and the expression of LC3-II protein. Thus, autophagy activation may be a key player in the cellular response against nano-toxicity. PMID- 24630840 TI - Tribulus terrestris versus placebo in the treatment of erectile dysfunction: A prospective, randomized, double blind study. AB - OBJECTIVES: To evaluate the possible effects of Tribulus terrestris herbal medicine in the erectile dysfunction treatment and to quantify its potential impact on serum testosterone levels. DESIGN AND METHODS: Prospective, randomized, double-blind and placebo-controlled study including thirty healthy men selected from 100 patients who presented themselves spontaneously complaining of erectile dysfunction, >= 40 years of age, nonsmokers, not undergoing treatment for prostate cancer or erectile dysfunction, no dyslipidemia, no phosphodiesterase inhibitor use, no hormonal manipulation and, if present hypertension and/or diabetes mellitus should be controlled. International Index of Erectile Function (IIEF-5) and serum testosterone were obtained before randomization and after 30 days of study. Patients were randomized into two groups of fifteen subjects each. The study group received 800 mg of Tribulus terrestris, divided into two doses per day for thirty days and the control group received placebo administered in the same way. RESULTS: The groups were statistically equivalent in all aspects evaluated. The mean (SD) age was 60 (9.4) and 62.9 (7.9), P = .36 for intervention and placebo groups, respectively. Before treatment, the intervention group showed mean IIEF-5 of 13.2 (5-21) and mean total testosterone 417.1 ng/dl (270.7-548.4 ng/dl); the placebo group showed mean IIEF-5 of 11.6 (6-21) and mean total testosterone 442.7 ng/dl (301-609.1 ng/dl). After treatment, the intervention group showed mean IIEF-5 of 15.3 (5-21) and mean total testosterone 409.3 ng/dl (216.9-760.8 ng/dl); the placebo group showed mean IIEF-5 of 13.7 (6 21) and mean total testosterone 466.3 ng/dl (264.3-934.3 ng/dl). The time factor caused statistically significant changes in both groups for IIEF-5 only (P = .0004), however, there was no difference between the two groups (P = .7914). CONCLUSIONS: At the dose and interval studied, Tribulus terrestris was not more effective than placebo on improving symptoms of erectile dysfunction or serum total testosterone. PMID- 24630841 TI - Micropercutaneous nephrolithotomy. A new therapeutic option for pediatric renal lithiasis. AB - INTRODUCTION: Micropercutaneous nephrolithotomy is an evolution from the conventional percutaneous surgery in which pyelocaliceal access is obtained through minimum bore holes. Its objective is the complete removal of the calculi, lowering the morbidity associated with larger bore percutaneous tracts. MATERIAL AND METHODS: We present the case of a micropercutaneous nephrolithotomy performed in a 14-year-old female patient with a 35 mm diameter kidney stone located in the renal pelvis. Surgery was performed in the Galdakao-modified supine Valdivia position. Puncture was done under ultrasound and fluoroscopic guidance. The 4.85 Ch needle of the Microperc((r)) set was used, completing the procedure through the 8 Ch working shaft. Lasertripsy was done with the Ho:YAG laser. An indwelling double J stent was placed at the end of the procedure. RESULTS: Operating time was 170 minutes. Hospital stay was one day. She suffered renal colic after 72 hours, which was resolved with oral analgesic treatment at home (Clavien I). She returned to school on the fifth postoperative day. The double J was removed at 2 weeks. At one month of the surgery, the patient is asymptomatic, a 4mm lower calyx residual stone being observed in the abdominal ultrasound. CONCLUSION: Micropercutaneous nephrolithotomy is a step forward towards the search for a less invasive kidney stone treatment. It is a safe and effective technique in the pediatric population, and it can be performed in the supine position, even in orthotropic kidneys. Future studies and collaborative works will help to better define its indications, to optimize its technique and to analyze its cost effectiveness compared with other treatment options. PMID- 24630842 TI - Transrectal doppler ultrasound during prostate biopsy: clinical utility and limitations. AB - OBJECTIVE: To determine the clinical utility and limitations of guided prostate biopsy Power Doppler in patients with elevated serum PSA levels. MATERIALS AND METHOD: Prospective study. From April 2012 to May 2013, 111 men over 45 years of age with serum PSA level greater than 4.0ng/dl who underwent a transrectal prostate biopsy were included. The hypoechoic nodules in the peripheral region were considered positive on the gray scale. Subsequently, the study was conducted with the Power Doppler, where the vascularization of suspicious images was analyzed for sampling. In addition, samples were taken from the suspected areas when performing the digital rectal examination. We calculated sensitivity, specificity, positive predictive value and negative predictive value of the three tests (digital rectal examination, standard gray scale ultrasound and power Doppler). RESULTS: Prostate cancer was diagnosed in 48 of the 111 patients (43%). Fifty-nine cases (53%) were defined as positive with the Power Doppler. Of these, 39 (66%) corresponded to a diagnosis of prostate adenocarcinoma. The Power Doppler was positive in 39 cases of the 48 patients diagnosed with cancer and the gray scale ultrasound was positive in 31 cases. Overall sensitivity of the power Doppler was 81%, specificity 68%, PPV 66% and NPV 82%, which was higher compared to the other methods (P<.05). CONCLUSION: Currently, prostate biopsy using Power Doppler does not seem to identify prostate cancer with sufficient accuracy to omit the guided systematic biopsy gray scale, the combined use of these methods being preferable. PMID- 24630844 TI - Crossing boundaries. PMID- 24630843 TI - Modelling hormonal response and development. AB - As our knowledge of the complexity of hormone homeostasis, transport, perception, and response increases, and their outputs become less intuitive, modelling is set to become more important. Initial modelling efforts have focused on hormone transport and response pathways. However, we now need to move beyond the network scales and use multicellular and multiscale modelling approaches to predict emergent properties at different scales. Here we review some examples where such approaches have been successful, for example, auxin-cytokinin crosstalk regulating root vascular development or a study of lateral root emergence where an iterative cycle of modelling and experiments lead to the identification of an overlooked role for PIN3. Finally, we discuss some of the remaining biological and technical challenges. PMID- 24630846 TI - Open access--reasons to be cheerful: a reply to Agrawal. PMID- 24630845 TI - Plant salt-tolerance mechanisms. AB - Crop performance is severely affected by high salt concentrations in soils. To engineer more salt-tolerant plants it is crucial to unravel the key components of the plant salt-tolerance network. Here we review our understanding of the core salt-tolerance mechanisms in plants. Recent studies have shown that stress sensing and signaling components can play important roles in regulating the plant salinity stress response. We also review key Na+ transport and detoxification pathways and the impact of epigenetic chromatin modifications on salinity tolerance. In addition, we discuss the progress that has been made towards engineering salt tolerance in crops, including marker-assisted selection and gene stacking techniques. We also identify key open questions that remain to be addressed in the future. PMID- 24630847 TI - Genetic origins of lactase persistence and the spread of pastoralism in Africa. AB - In humans, the ability to digest lactose, the sugar in milk, declines after weaning because of decreasing levels of the enzyme lactase-phlorizin hydrolase, encoded by LCT. However, some individuals maintain high enzyme amounts and are able to digest lactose into adulthood (i.e., they have the lactase-persistence [LP] trait). It is thought that selection has played a major role in maintaining this genetically determined phenotypic trait in different human populations that practice pastoralism. To identify variants associated with the LP trait and to study its evolutionary history in Africa, we sequenced MCM6 introns 9 and 13 and ~2 kb of the LCT promoter region in 819 individuals from 63 African populations and in 154 non-Africans from nine populations. We also genotyped four microsatellites in an ~198 kb region in a subset of 252 individuals to reconstruct the origin and spread of LP-associated variants in Africa. Additionally, we examined the association between LP and genetic variability at candidate regulatory regions in 513 individuals from eastern Africa. Our analyses confirmed the association between the LP trait and three common variants in intron 13 (C-14010, G-13907, and G-13915). Furthermore, we identified two additional LP-associated SNPs in intron 13 and the promoter region (G-12962 and T 956, respectively). Using neutrality tests based on the allele frequency spectrum and long-range linkage disequilibrium, we detected strong signatures of recent positive selection in eastern African populations and the Fulani from central Africa. In addition, haplotype analysis supported an eastern African origin of the C-14010 LP-associated mutation in southern Africa. PMID- 24630848 TI - Variability in response to transcranial direct current stimulation of the motor cortex. AB - BACKGROUND: Responses to a number of different plasticity-inducing brain stimulation protocols are highly variable. However there is little data available on the variability of response to transcranial direct current stimulation (TDCS). OBJECTIVE: We tested the effects of TDCS over the motor cortex on corticospinal excitability. We also examined whether an individual's response could be predicted from measurements of onset latency of motor evoked potential (MEP) following stimulation with different orientations of monophasic transcranial magnetic stimulation (TMS). METHODS: Fifty-three healthy subjects participated in a crossover-design. Baseline latency measurements with different coil orientations and MEPs were recorded from the first dorsal interosseous muscle prior to the application of 10 min of 2 mA TDCS (0.057 mA/cm2). Thirty MEPs were measured every 5 min for up to half an hour after the intervention to assess after-effects on corticospinal excitability. RESULTS: Anodal TDCS at 2 mA facilitated MEPs whereas there was no significant effect of 2 mA cathodal TDCS. A two-step cluster analysis suggested that approximately 50% individuals had only a minor, or no response to TDCS whereas the remainder had a facilitatory effect to both forms of stimulation. There was a significant correlation between the latency difference of MEPs (anterior-posterior stimulation minus latero-medial stimulation) and the response to anodal, but not cathodal TDCS. CONCLUSIONS: The large variability in response to these TDCS protocols is in line with similar studies using other forms of non-invasive brain stimulation. The effects highlight the need to develop more robust protocols, and understand the individual factors that determine responsiveness. PMID- 24630849 TI - Inter-individual variability in response to non-invasive brain stimulation paradigms. AB - BACKGROUND: Non-invasive Brain Stimulation (NIBS) paradigms are unique in their ability to safely modulate cortical plasticity for experimental or therapeutic applications. However, increasingly, there is concern regarding inter-individual variability in the efficacy and reliability of these paradigms. HYPOTHESIS: Inter individual variability in response to NIBS paradigms would be better explained if a multimodal distribution was assumed. METHODS: In three different sessions for each subject (n = 56), we studied the Paired Associative Stimulation (PAS25), Anodal transcranial DC stimulation (AtDCS) and intermittent theta burst stimulation (iTBS) protocols. We applied cluster analysis to detect distinct patterns of response between individuals. Furthermore, we tested whether baseline TMS measures (such as short intracortical inhibition (SICI), resting motor threshold (RMT)) or factors such as time of day could predict each individual's response pattern. RESULTS: All three paradigms show similar efficacy over the first hour post stimulation--there is no significant effect on excitatory or inhibitory circuits for the whole sample, and AtDCS fares no better than iTBS or PAS25. Cluster analysis reveals a bimodal response pattern--but only 39%, 45% and 43% of subjects responded as expected to PAS25, AtDCS, and iTBS respectively. Pre stimulation SICI accounted for 10% of the variability in response to PAS25, but no other baseline measures were predictive of response. Finally, we report implications for sample size calculation and the remarkable effect of sample enrichment. CONCLUSION: The implications of the high rate of 'dose-failure' for experimental and therapeutic applications of NIBS lead us to conclude that addressing inter-individual variability is a key area of concern for the field. PMID- 24630850 TI - Effect of texture and grain shape on ultrasonic backscattering in polycrystals. AB - An ultrasonic backscattering model is developed for textured polycrystalline materials with orthotropic or trigonal grains of ellipsoidal shape. The model allows us to simulate realistic microstructures and orthotropic macroscopic material textures resulting from thermomechanical processing for a broad variety of material symmetries. The 3-D texture is described by a modified Gaussian orientation distribution function (ODF) of the crystallographic orientation of the grains along the macroscopic texture direction. The preferred texture directions are arbitrary relative to the axes of the ellipsoidal grains. The averaged elastic covariance and the directional anisotropy of the backscattering coefficient are obtained for a wave propagation direction arbitrary relative to the texture and grain elongation directions. One particular application of this analysis is the backscattering solution for cubic crystallites with common textures such as Cube, Goss, Brass and Copper. In our analysis, in the texture defined coordinates the matrix of elastic constants for cubic crystallites takes the form of orthotropic or trigonal symmetry. Numerical results are presented, discussed and compared to the experimental data available in the literature illustrating the dependence of the backscattering coefficient on texture and grain shape. PMID- 24630851 TI - Feasibility of non-invasive temperature estimation by the assessment of the average gray-level content of B-mode images. AB - This paper assesses the potential of the average gray-level (AVGL) from ultrasonographic (B-mode) images to estimate temperature changes in time and space in a non-invasive way. Experiments were conducted involving a homogeneous bovine muscle sample, and temperature variations were induced by an automatic temperature regulated water bath, and by therapeutic ultrasound. B-mode images and temperatures were recorded simultaneously. After data collection, regions of interest (ROIs) were defined, and the average gray-level variation computed. For the selected ROIs, the AVGL-Temperature relation were determined and studied. Based on uniformly distributed image partitions, two-dimensional temperature maps were developed for homogeneous regions. The color-coded temperature estimates were first obtained from an AVGL-Temperature relation extracted from a specific partition (where temperature was independently measured by a thermocouple), and then extended to the other partitions. This procedure aimed to analyze the AVGL sensitivity to changes not only in time but also in space. Linear and quadratic relations were obtained depending on the heating modality. We found that the AVGL Temperature relation is reproducible over successive heating and cooling cycles. One important result was that the AVGL-Temperature relations extracted from one region might be used to estimate temperature in other regions (errors inferior to 0.5 degrees C) when therapeutic ultrasound was applied as a heating source. Based on this result, two-dimensional temperature maps were developed when the samples were heated in the water bath and also by therapeutic ultrasound. The maps were obtained based on a linear relation for the water bath heating, and based on a quadratic model for the therapeutic ultrasound heating. The maps for the water bath experiment reproduce an acceptable heating/cooling pattern, and for the therapeutic ultrasound heating experiment, the maps seem to reproduce temperature profiles consistent with the pressure field of the transducer, and in agreement with temperature maps developed by COMSOL(r)MultiPhysics simulations. PMID- 24630852 TI - Public beliefs and knowledge about risk and protective factors for Alzheimer's disease. AB - BACKGROUND: The purpose of this study was to assess public beliefs and knowledge about risk and protective factors for Alzheimer's disease (AD). METHODS: A brief survey module was added to the Health and Retirement Study, a longstanding national panel study of the U.S. population over the age of 50. RESULTS: Respondents were 1641 adults (mean age=64.4 years, 53.6% female, 81.7% White). Most (60.1%) indicated interest in learning their AD risk, with 29.4% expressing active worry. Many failed to recognize that medications to prevent AD are not available (39.1%) or that having an affected first-degree relative is associated with increased disease risk (32%). Many respondents believed that various actions (e.g., mental activity, eating a healthy diet) would be effective in reducing AD risk. CONCLUSION: Older and middle-aged adults are interested in their AD risk status and believe that steps can be taken to reduce disease risk. Tailored education efforts are needed to address potential misconceptions about risk and protective factors. PMID- 24630853 TI - Acute renal failure after ingestion of guaifenesin and dextromethorphan. AB - BACKGROUND: Guaifenesin is a common nonprescription medication that has been implicated in drug-induced nephrolithiasis. Dextromethorphan, a nonprescription antitussive found in some guaifenesin-containing preparations, is increasingly recognized as a substance of abuse by many youth and young adults. Renally excreted medications known to have poor solubility in urine have the potential to precipitate when ingested in large quantity, leading to acute obstruction of the ureters and renal failure. OBJECTIVE: We describe the case of a 22-year-old male who developed severe bilateral flank pain, hematuria, and oliguria after an isolated recreational ingestion of guaifenesin and dextromethorphan. CASE REPORT: The patient was found to have bilateral ureteral obstruction and acute renal failure, suspected to be secondary to precipitation of medication metabolites in the urine. CONCLUSIONS: This case highlights the potential for acute renal failure secondary to guaifenesin and dextromethorphan abuse. PMID- 24630854 TI - The modified "Wunderer" osteotomy for stabilization of the cleft-premaxilla--a new operative technique. AB - The operative closure of bilateral cleft lip and palate is a difficult procedure that requires in most cases secondary corrections. Besides aesthetic improvements of lip and nose also the rehabilitation of the teeth, in particular of the maxillary arch is important for the improvement of the chewing function and also for the well being of the patient. One of the most disturbing factors for the construction of any type of prosthetic devices, like removable denture, fixed bridge or dental implants is the mobility and often also malposition of the premaxilla. This problem can only be solved by the insertion of bone grafts into the bilateral gaps of the anterior maxillary arch. This procedure however, is difficult due to the narrowness and poor overview that complicates the closure of the nasal mucosa, which is the precondition for the success. For facilitating the operation the premaxilla is osteotomized and reflected anteriorly according to the method of Wunderer (1962). Then, after the much easier closure of the nasal mucosa the bony defects can be filled with autogenous cancellous bone and finally the oral mucosa can be closed. A preoperatively prepared palatal acrylic plate helps to protect the palatal tissue and also stabilizes the position of the premaxilla. The blood supply to the osteotomized premaxilla is secured by a sound soft tissue pedicle of the buccal muco-periosteum. The effectiveness of the blood supply of the premaxilla was examined in experimental studies by several authors. Also investigations of the growth impediments of the premaxilla and the midface revealed that early osteotomies will interfere with the development of this region. Therefore it is advisable to carry out this procedure not before the patient has reached the age of 12-14 years, which is also depending on the race and the gender of the patient. PMID- 24630855 TI - Is there a role for palmitoylethanolamide in the treatment of depression? AB - Depression is a common brain disorder affecting about 350 million people worldwide. Although the pharmacological treatment currently available can produce benefits in the majority of cases, residual depressive symptoms, cognitive deficits, functional impairment, and increase in frequency of relapses are frequently present in unipolar and bipolar depressed patients correctly treated. In the last years, numerous evidences have demonstrated the involvement of endocannabinoid system in the pathophysiology of mood disorders. Considering the recent findings about the antidepressant effect of palmitoylethanolamide in animal model, we have hypothesized the potential antidepressant effect of this fatty acid amide in unipolar and bipolar depressed patients. PMID- 24630856 TI - Operator training in recombinant protein production using a structured simulator model. AB - Model-based operator training simulators (OTS) could be powerful tools for virtual training of operational procedures and skills of production personnel in recombinant protein processes. The applied model should describe critical events in the bioprocess so accurately that the operators' ability to observe and alertly act upon these events is trained with a high degree of efficiency. In this work is shown how this is accomplished in a structured multi-compartment model for the production of a recombinant protein in an Escherichia coli fed batch process where in particular the induction procedure, the stress effects and overflow metabolism were highlighted. The structured model was applied on the OTS platform that virtually simulated the operational bioreactor procedures in real or accelerated time. Evaluation of training using the model-based OTS showed that trained groups of operators exhibited improved capability compared with the untrained groups when subsequently performing real laboratory scale cultivations. The results suggest that this model-based OTS may provide a valuable resource for enhancing operator skills in large scale recombinant protein manufacturing. PMID- 24630857 TI - Cardiac myxoma in diabetic pregnancy. PMID- 24630858 TI - Vaginal agenesis treated by coital dilatation in 20 patients. PMID- 24630859 TI - FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. PMID- 24630860 TI - Comparison of cardiac allograft vasculopathy in heart and heart-lung transplantations: a 15-year retrospective study. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major factor limiting long term survival after heart transplantation (HTx). Specific determinants of CAV and long-term outcome after CAV occurrence have been poorly investigated after heart lung transplantation (HLTx). METHODS: Between January 1996 and December 2006, 79 patients underwent HLTx (36.3 +/- 12.2 years old; 47% men) and 141 patients underwent HTx (49.2 +/- 12.3 years old; 77% men) at two different institutions. CAV grading was reviewed in both groups according to the 2010 standardized nomenclature of the International Society for Heart and Lung Transplantation. The mean post-transplant follow-up was 94 (1 to 181) months. RESULTS: Overall 10-year survival rate was 58% after HTx and 43% after HLTx (p = 0.11). The Grade 1 (or higher) CAV-free survival rate was 95% at 4 years and 69% at 10 years after HLTx, and 77% and 39%, respectively, after HTx (p < 0.01). Mean cyclosporine blood levels were similar between the groups at 3, 6, 12, 24 and 36 months. The main causes of mortality beyond 5 years after HTx and HLTx were malignancies and bronchiolitis obliterans, respectively. By multivariate analysis, recipients who developed >3 acute myocardial rejections during the first year post-transplant were exposed to a higher risk of CAV (95% CI 1.065 to 2.33, p = 0.02). Episodes of acute pulmonary rejection and bronchiolitis obliterans were not associated with an increased risk of CAV (p = 0.52 and p = 0.30). CONCLUSION: HLTx recipients appeared protected from CAV compared with HTx patients in this retrospective study. Repeated acute cardiac rejections were independent predictors of CAV. Unlike bronchiolitis obliterans, CAV had a very low impact on long-term survival after HLTx. PMID- 24630861 TI - Survival and quality of life in rheumatoid arthritis-associated interstitial lung disease after lung transplantation. AB - BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have increased mortality with limited treatment options. We set out to examine post-transplant survival in RA-ILD patients compared with patients with idiopathic pulmonary fibrosis (IPF) and scleroderma-associated ILD (SSc ILD). We also describe post-transplant quality of life (QoL) outcomes in RA-ILD. METHODS: A retrospective review was performed on lung transplantation (1989 to 2011) among patients with RA-ILD, IPF (group-matched for age and transplant year) and SSc-ILD. Cumulative survival after transplantation was estimated by the Kaplan-Meier method and compared between groups using the log-rank test. The 36 item Medical Outcomes Survey Short Form (SF-36) and the St. George's Respiratory Questionnaire (SGRQ) scores, before and after lung transplantation, were analyzed. RESULTS: Overall, 10 patients with RA-ILD, 53 with IPF and 17 with SSc ILD underwent lung transplantation with ages (mean +/- SD) of 59.4 +/- 5.6, 61.0 +/- 4.0 and 45.4 +/- 12.7 years, respectively. Cumulative survival rates at 1 year post-transplant for the RA-ILD, IPF and SSc-ILD groups were 67%, 69% and 82%, respectively, and there was no significant difference among groups in age- and gender-adjusted analyses. Among the RA-ILD patients, mean SF-36 physical component summary scores improved from 22.4 +/- 8.1 to 32.2 +/- 12.9 (p = 0.1), SF-36 mental component summary scores improved from 44.7 +/- 15.3 to 54.9 +/- 4.8 (p = 0.19) and SGRQ total scores improved from 70.4 +/- 16.1 to 36.0 +/- 18.5 (p = 0.03). CONCLUSIONS: After lung transplantation, RA-ILD and IPF patients have similar survival rates. Further, in RA-ILD patients, lung transplantation appears to result in a significant improvement in QoL with regard to respiratory symptoms. These data suggest that lung transplantation should be considered in patients with end-stage RA-ILD. PMID- 24630862 TI - Spontaneous microbubbles in the aortic root and thrombosis of a continuous-flow left ventricular assist device. PMID- 24630863 TI - Continuous-flow left ventricular assist devices and gastrointestinal bleeding: potential role of danazol. PMID- 24630864 TI - A simplified preservation method for lungs donated after cardiac death. AB - The shortage of donor lungs restricts the number of lung transplantations that can be performed. However, extension of the donor pool using organs donated after cardiac death (DCD) could potentially increase the number of patients who undergo transplantation. To establish acceptance among hospital personnel and the donor's next of kin for the uncontrolled DCD procedure we proposed a simplified preservation regime for intrapleural cooling of the donor lungs. METHODS: In an uncontrolled DCD model, 12 pigs were randomized to intrapleural lung cooling using either a standard method with two bilateral chest tubes and intermittent pleural fluid exchanges, or a simplified, less-invasive method with a single bilateral chest tube and filling of the pleural space without fluid exchange. Lungs were explanted and graft function was assessed during ex vivo lung perfusion (EVLP) and by histologic examination. RESULTS: Although the mean temperature after 120 minutes of intrapleural cooling was significantly higher in the lungs cooled using the simplified method (25.9 degrees C vs 13.5 degrees C), this did not affect the oxygenation capacity, pulmonary vascular resistance or dynamic compliance of the lungs, as recorded during EVLP. Furthermore, no differences were found between the lungs preserved by the two methods with respect to the wet/dry ratio, levels of myeloperoxidase in bronchoalveolar lavage, or at histologic examination. CONCLUSIONS: The simplified technique for DCD lung cooling results in a higher preservation temperature but does not affect lung function during EVLP, which implies that this less invasive method can be used in the uncontrolled DCD setting. This is another step forward in the development of a simplified preservation routine for DCD. PMID- 24630865 TI - The calpain system and diabetes. AB - Diabetes mellitus is recognized as a clinical syndrome that is characterized by hyperglycemia due to deficiency of insulin. The global prevalence of diabetes has been estimated to increase from 4% (1995) to 5.4% by the year 2025. Insulin dependent diabetes mellitus (IDDM/Type-1) in human, generating hyperglycemia due to insulin deficiency as a consequence of destructing beta cells in the pancreatic islets. Non-insulin dependent diabetes mellitus (NIDDM/Type-II), is a multifactorial, exact biochemical and genetic defect which has not yet been elucidated completely. Calpains seem to play a role in NIDDM and IDDM. Positional cloning experiments revealed that there is a NIDDM susceptibility to calpain 10 (CAPN10). Increased calpain activity and leukocyte trafficking were noticed in the microcirculation in ZDF (Zuker diabetic fatty) rats. Exercise and low body weight play a significant role in reducing calpains expression or elevating the calpains degradation in the skeletal muscle of NIDDM rats. Numerous investigations have been reported that non-coding polymorphisms in CAPN10 proteins might be involved in the NIDDM. Calpain and its mRNA presence had been reported in tissues from many mammalian species. CAPN10 and other calpains seem to be linked to glucose metabolism, insulin secretion and action pathways. This review will give an overview of the role of calpain in NIDDM and IDDM. PMID- 24630866 TI - Occurrence and levels of polybrominated diphenyl ethers (PBDEs) in house dust and hair samples from Northern Poland; an assessment of human exposure. AB - Polybrominated diphenyl ethers (PBDEs) are among most ubiquitous compounds to be found in indoor environment and ingestion of household dust is considered an important route of exposure to PBDEs, especially in toddlers and young children. The present work reported concentration levels of PBDE congeners (PBDE-28, -47, 99, -100, -153, -154, -183 and -209) in hair and dust samples from selected households from Northern Poland. The concentrations of PBDEs in dust ranged from 10MUg/ml (long term threshold) 6 months after immunization may reflect the proportion protected over at least a 4 year period. CONCLUSION: The current assignment of an anti-Vi IgG protective level may be of value when evaluating vaccine performance of future Vi conjugate vaccines. PMID- 24630870 TI - Therapeutic site selection is important for the successful development of collateral vessels. AB - BACKGROUND: Induction of collateral development to improve tissue perfusion is a promising approach for the treatment of arterial occlusive diseases. Several growth factors and cells have been reported to increase collateral circulation; however, the appropriate site for the delivery of these factors and cells is unclear. In this study, we identified the delivery site for growth factor in a rabbit model of limb ischemia and evaluated whether specific delivery of basic fibroblast growth factor (bFGF) to this site enhanced collateral augmentation. METHODS: The left femoral artery of Japanese white rabbits was excised to induce limb ischemia. Twenty-eight days thereafter, angiograms were obtained to identify the typical pattern of collateral development in this model. Subsequently, bFGF (100 MUg) was selectively injected into the left coccygeofemoral muscle (coccygeo group) or adductor muscle (adductor group), major thigh muscles in proximity. Collateral development was evaluated at 28 days after injection, and its mechanism was assessed by immunologic and morphometric analyses of muscle samples. RESULTS: Angiographic evaluation of this model revealed that after femoral artery excision, collateral vessels generally developed in the left coccygeofemoral muscle, whereas few collateral vessels were detected in the left adductor muscle. At 28 days after injection, calf blood pressure ratio, defined as left pressure to right pressure, was significantly higher in the coccygeo group than in the adductor group (0.85 +/- 0.05 vs 0.69 +/- 0.05, respectively; P < .01). Similar results were observed in blood flow through the internal iliac artery (resting: 24.6 +/- 6.1 vs 17.4 +/- 8.0 mL/min, P < .01; maximum: 47.4 +/- 12.3 vs 33.2 +/- 10.7 mL/min, P < .01) and in the angiographic score (0.67 +/- 0.13 vs 0.39 +/- 0.11; P < .01). Immunologic analyses of the coccygeofemoral muscle at day 3 showed marked expressions of Ki-67, monocyte chemotactic protein 1, and FGF receptor 1 in the coccygeo group compared with the adductor group. Morphometric analyses of the same muscle at day 14 also revealed that collateral vessel density and wall thickness were significantly increased in the coccygeal group compared with the adductor group. CONCLUSIONS: These findings demonstrated that selective bFGF delivery to the coccygeofemoral muscle markedly improved collateral development and limb perfusion compared with delivery to the adductor muscle, suggesting that site selection is important in increasing therapeutic efficacy. PMID- 24630871 TI - Outcomes reported by the Vascular Quality Initiative and the National Surgical Quality Improvement Program are not comparable. AB - OBJECTIVE: The Vascular Quality Initiative (VQI) and National Surgical Quality Improvement Program (NSQIP) have emerged as the primary vascular surgery quality measurement tools with the purpose of evaluating perioperative outcomes and assessing hospital and physician quality. VQI uses self-reporting to capture all index vascular procedures during the inpatient period. NSQIP employs nurse abstractors to capture a sample of procedures and covers 30-day events. We hypothesize that patients undergoing lower extremity bypass (LEB) will exhibit high concordance for preoperative variables and low concordance for postoperative variables between these data sets. METHODS: All patients undergoing LEB for peripheral arterial disease at the University of Massachusetts captured in both VQI and NSQIP databases were reviewed (2007-2012). Concordance between categorical variables was assessed by kappa correlation coefficient. All postoperative variables were compared during equivalent inpatient stay. Events between discharge and 30 days postoperatively were tabulated with use of the NSQIP data set. RESULTS: We identified 240 patients undergoing LEB captured in both VQI and NSQIP. Comparison of this identical patient cohort between VQI and NSQIP revealed a moderate to strong agreement for most preoperative variables except for congestive heart failure (kappa = 0.14) and hypertension (kappa = 0.35), which showed poor agreement. Concordance for inpatient postoperative variables was high for mortality (kappa = 1.0) and myocardial infarction (kappa = 0.86) but moderate for pulmonary complications (kappa = 0.57) and poor for unplanned return to the operating room (kappa = 0.41), wound infection (kappa = 0.01), and change in renal function (kappa = -0.01). A majority of postoperative events (71%) occurred between discharge and 30 days postoperatively, with a significantly higher incidence of wound infections in the outpatient setting (4.2% vs 95.8%; P < .0001). CONCLUSIONS: VQI and NSQIP demonstrate substantial concordance for most preoperative variables and poor concordance for most postoperative variables, even at identical collection periods. This discordance is a result of differences in data collection methods and variable definitions. On the basis of these findings, VQI and NSQIP data sets cannot be used to directly compare risk-adjusted patient outcomes between institutions. PMID- 24630873 TI - Embodiment and language comprehension: reframing the discussion. AB - The debate on whether language comprehension involves the manipulation of abstract symbols or is grounded in perception and action has reached an impasse, with authors from different theoretical persuasions unable to agree on the diagnostic value of empirical findings. To escape this impasse, I propose a pluralist view of cognition that encompasses abstract and grounded symbols. The contributions of these symbol types to language comprehension vary as a function of the degree to which language use is embedded in the environment. I distinguish five levels of embeddedness: demonstration, instruction, projection, displacement, and abstraction. Only through a closer analysis of context will we make significant progress toward understanding language comprehension and cognition in general. PMID- 24630872 TI - Attention in the real world: toward understanding its neural basis. AB - The efficient selection of behaviorally relevant objects from cluttered environments supports our everyday goals. Attentional selection has typically been studied in search tasks involving artificial and simplified displays. Although these studies have revealed important basic principles of attention, they do not explain how the brain efficiently selects familiar objects in complex and meaningful real-world scenes. Findings from recent neuroimaging studies indicate that real-world search is mediated by 'what' and 'where' attentional templates that are implemented in high-level visual cortex. These templates represent target-diagnostic properties and likely target locations, respectively, and are shaped by object familiarity, scene context, and memory. We propose a framework for real-world search that incorporates these recent findings and specifies directions for future study. PMID- 24630874 TI - Alcohol ablation of right ventricular outflow tract obstruction. PMID- 24630875 TI - Effect of catheter-based patent foramen ovale closure on the occurrence of arterial bubbles in scuba divers. AB - OBJECTIVES: This study sought to evaluate the effect of catheter-based patent foramen ovale (PFO) closure on the occurrence of arterial bubbles after simulated dives. BACKGROUND: PFO is a risk factor of decompression sickness in divers due to paradoxical embolization of bubbles. To date, the effectiveness of catheter based PFO closure in the reduction of arterial bubbles has not been demonstrated. METHODS: A total of 47 divers (age 35.4 +/- 8.6 years, 81% men) with a PFO (PFO group) or treated with a catheter-based PFO closure (closure group) were enrolled in this case-controlled observational trial. All divers were examined after a simulated dive in a hyperbaric chamber: 34 divers (19 in the PFO group, 15 in the closure group) performed a dive to 18 m for 80 min, and 13 divers (8 in the PFO group, 5 in the closure group) performed a dive to 50 m for 20 min. Within 60 min after surfacing, the presence of venous and arterial bubbles was assessed by transthoracic echocardiography and transcranial color-coded sonography, respectively. RESULTS: After the 18-m dive, venous bubbles were detected in 74% of divers in the PFO group versus 80% in the closure group (p = 1.0), and arterial bubbles were detected in 32% versus 0%, respectively (p = 0.02). After the 50-m dive, venous bubbles were detected in 88% versus 100%, respectively (p = 1.0), and arterial bubbles were detected in 88% versus 0%, respectively (p < 0.01). CONCLUSIONS: No difference was observed in the occurrence of venous bubbles between the PFO and closure groups, but the catheter-based PFO closure led to complete elimination of arterial bubbles after simulated dives. (Nitrogen Bubble Detection After Simulated Dives in Divers With PFO and After PFO Closure; NCT01854281). PMID- 24630876 TI - Self-expanding stent peeling away from overlapping balloon-expandable stent causing late acquired aneurysm formation and stent malapposition. PMID- 24630877 TI - Covered stents for coarctation of the aorta: treating the interventionalist or the patient? PMID- 24630878 TI - Pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in prasugrel-treated patients. AB - OBJECTIVES: The purpose of this study was to assess the in vitro P2Y12 receptor inhibitory effects of cangrelor on platelets from patients on maintenance prasugrel therapy treated with 2 reloading dose regimens. BACKGROUND: Despite its more potent and rapid antiplatelet effects compared with clopidogrel, recent studies have shown variability in prasugrel-mediated P2Y12 receptor inhibition, particularly in high-risk settings. Cangrelor is a potent intravenous P2Y12 receptor inhibitor. METHODS: A total of 60 patients with coronary artery disease on maintenance prasugrel (10 mg/day) therapy were randomized to a 30- or 60-mg reload of prasugrel. The platelet reactivity index (PRI), as assessed by whole blood vasodilator-stimulated phosphoprotein, was measured with and without in vitro incubation of cangrelor (500 nM) at baseline, and at 1 and 4 h after reload. RESULTS: In the absence of cangrelor, prasugrel reloading reduced PRI (p < 0.001 for both doses), although a 60-mg reload had greater platelet inhibition compared with a 30-mg reload at 4 h (p = 0.001). Cangrelor was associated with a reduction in PRI values during the overall study time course in patients reloaded with 30 mg (p = 0.001) and 60 mg (p < 0.001) of prasugrel. In patients reloaded with 30 mg prasugrel, cangrelor decreased PRI at each time point (baseline, p < 0.001; 1 h, p = 0.013; 4 h, p = 0.001). In patients reloaded with 60 mg prasugrel, cangrelor decreased PRI at baseline (p < 0.001) and 1 h (p = 0.002); levels of platelet reactivity comparable to those achieved with cangrelor were observed only at 4 h (p = 0.325). The intergroup comparisons with cangrelor were not significant at any time point. CONCLUSIONS: In patients on maintenance prasugrel therapy exposed to a reloading dose (30 or 60 mg) of prasugrel, in vitro cangrelor is associated with further platelet P2Y12 receptor inhibitory effects. PMID- 24630879 TI - Current status of rotational atherectomy. AB - Rotational atherectomy facilitates percutaneous coronary intervention for complex de novo lesions with severe calcification. A strategy of routine rotational atherectomy has not, however, conferred reduction in restenosis or major adverse cardiac events. As it is technically demanding, rotational atherectomy is also uncommon. At this 25-year anniversary since the introduction of rotational atherectomy, we sought to review the current state-of-the-art in rotational atherectomy technique, safety, and efficacy data in the modern era of drug eluting stents, strategies to prevent and manage complications, including slow flow/no-reflow and burr entrapment, and appropriate use in the context of the broader evolution in the management of stable ischemic heart disease. Fundamental elements of optimal technique include use of a single burr with burr-to-artery ratio of 0.5 to 0.6-rotational speed of 140,000 to 150,000 rpm, gradual burr advancement using a pecking motion, short ablation runs of 15 to 20 s, and avoidance of decelerations >5,000 rpm. Combined with meticulous technique, optimal antiplatelet therapy, vasodilators, flush solution, and provisional use of atropine, temporary pacing, vasopressors, and mechanical support may prevent slow-flow/no-reflow, which in contemporary series is reported in 0.0% to 2.6% of cases. On the basis of the results of recent large clinical trials, a subset of patients with complex coronary artery disease previously assigned to rotational atherectomy may be directed instead to medical therapy alone or bypass surgery. For patients with de novo severely calcified lesions for which rotational atherectomy remains appropriate, referral centers of excellence are required. PMID- 24630880 TI - Comparison between covered and bare Cheatham-Platinum stents for endovascular treatment of patients with native post-ductal aortic coarctation: immediate and intermediate-term results. AB - OBJECTIVES: This study sought to evaluate the outcomes of endovascular treatment with covered versus bare Cheatham-platinum stents (NuMed, Hopkinton, New York) in coarctation of aorta (CoA) patients. BACKGROUND: Covered stenting has been newly recognized as a useful therapeutic method for patients with native CoA, but there has been no study comparing the use of covered stents with bare stents for treating CoA. METHODS: In this randomized clinical trial, 120 patients with a mean age of 23.60 +/- 10.99 years (range 12 to 58 years, 79 men), with post ductal, short-segment, severe native CoA underwent implantation of bare Cheatham Platinum (bCP) (n = 60) or covered Cheatham-Platinum (cCP) (n = 60) stents. Patients were followed clinically at 1, 3, 6, and 12 months after the stenting and yearly thereafter. During follow-up, multislice computed tomography (64 slices) was scheduled to assess any complications. RESULTS: The procedural success rate was 100% in both groups. Patients were followed for 31.1 +/- 19.2 months. Although recoarctation was seen only in the bCP group during follow-up, the difference between groups did not reach statistical significance (6.7% vs. 0%; p = NS). Two cases of pseudoaneurysm (3.3%) occurred in the cCP group, but none was observed in the bCP group (p = NS). Normotensive status significantly increased during follow-up in both groups (from 15% to 73.3% in the bCP group and 16.7% to 78.3% in the cCP group, p < 0.001 for each group and not significant between groups). CONCLUSIONS: Implanting bCP and cCP stents have very high success rates with remarkable hemodynamic effects in severe native CoA patients. Patients undergoing cCP stent implantation experienced a nonsignificantly lower recoarctation rate and a higher occurrence of pseudoaneurysm formation with respect to bCP stenting during follow-up. These findings indicate that CoA stenting is a safe procedure. (Endovascular Stenting With Covered CP Stent Compared With Bare CP Stent for Adult Patients With Coarctation: The Initial and Intermediate-Term Follow-Up Results; IRCT201012045311N1). PMID- 24630881 TI - Impact of cigarette smoking on extent of coronary artery disease and prognosis of patients with non-ST-segment elevation acute coronary syndromes: an analysis from the ACUITY Trial (Acute Catheterization and Urgent Intervention Triage Strategy). AB - OBJECTIVES: This study sought to evaluate the short- and long-term outcomes for smokers with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). BACKGROUND: Smoking has been associated with the "paradox" of reduced mortality after acute myocardial infarction (MI). This is thought to be due to favorable baseline characteristics and less diffuse coronary artery disease (CAD) among smokers. METHODS: In the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, 13,819 patients (29.1% smokers) with moderate- to high risk NSTE-ACS underwent angiography and, if indicated, revascularization. RESULTS: Smokers were significantly younger and had fewer comorbidities than nonsmokers. Incidence of death and MI were comparable at 30 days, although smokers had significantly reduced risks of 30-day major bleeding (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.67 to 0.96; p = 0.016) and 1-year mortality (HR: 0.797, 95% CI: 0.65 to 0.97; p = 0.027). After correction for baseline and clinical differences, smoking was no longer predictive of major bleeding (odds ratio: 1.06, 95% CI: 0.86 to 1.32; p = 0.56) and was associated with higher 1-year mortality (HR: 1.37, 95% CI: 1.07 to 1.7; p = 0.013). This pattern of reversed risk after multivariable correction held true for those smokers requiring percutaneous coronary intervention. Core laboratory angiographic analysis showed that smokers and nonsmokers were comparable in terms of the extent of CAD, Thrombolysis In Myocardial Infarction flow, myocardial blush, and the presence of thrombi. CONCLUSIONS: In contrast to the paradox previously described in ST-segment elevation MI, our analysis finds smoking to be an independent predictor of higher 1-year mortality in patients presenting with NSTE-ACS, and our angiographic study demonstrates CAD in smokers that is comparable to that in nonsmokers but evident ~1 decade earlier. (Acute Catheterization and Urgent Intervention Triage Strategy [ACUITY]; NCT00093158). PMID- 24630882 TI - The PFO gets blamed again...perhaps this time it is real. PMID- 24630883 TI - Efficacy of a minicourse in radiation-reducing techniques in invasive cardiology: a multicenter field study. AB - OBJECTIVES: Our goal was to validate an educational 90-min minicourse in lower irradiating cardiac invasive techniques. BACKGROUND: Despite comprehensive radiation safety programs, patient radiation exposure in invasive cardiology remains considerable. METHODS: Before and at a median period of 3.7 months after the minicourse at 32 German cardiac centers, 177 interventionalists consistently documented radiation parameters for 10 coronary angiographies: dose area product (DAP), radiographic and fluoroscopic fractions, fluoroscopy time, and number of radiographic frames and runs. RESULTS: A total of 154 cardiologists attended the minicourse and achieved significant (p < 0.001) decrease in patients' median overall DAP (-48.4%), from baseline 26.5 to 13.7 Gy * cm(2). They reduced fluoroscopy times (-20.8%), radiographic runs (-9.1%), frames/run (-18.6%) and frames (-29.6%), and both radiographic DAP/frame (-27.4%) and fluoroscopic DAP/s (-39.3%), which indicate improved collimation, reduced-irradiation angulations, or adequate image quality. Dose-related parameters for the remaining 23 invited cardiologists unable to attend the workshop did not change significantly in univariate comparison. Multilevel analysis (p < 0.001) confirmed the efficacy of the minicourse itself (-14.7 Gy * cm(2)) and revealed higher DAP for increasing body mass index (+1.5 Gy * cm(2) per kg/m(2)), male sex (+5.8 Gy * cm(2)), age (+1.5 Gy * cm(2)/decade), and-owing to different settings during image acquisition-for advanced flat-panel detector systems (+9.0 Gy * cm(2)) versus older, traditional image intensifier systems. CONCLUSIONS: Despite significant required training in radiation safety for all interventional cardiologists, the presented additional 90-min minicourse significantly reduced patient dose. PMID- 24630884 TI - Drug-eluting balloons for the treatment of the superficial femoral artery in stent restenosis: 2-year follow-up. AB - OBJECTIVES: The aim of this prospective registry was to evaluate the safety and efficacy at 2-year follow-up of the use of drug-eluting balloons (DEBs) for the treatment of superficial femoral artery (SFA) in-stent restenosis (ISR). BACKGROUND: The use of DEBs for the treatment of SFA ISR is associated with a satisfactory primary patency rate at 1 year, but no data are available for longer follow-up. Unfortunately, when DEBs were used to treat SFA de novo lesions, the occurrence of restenosis increased by 50% between the first and the second years of follow-up. METHODS: From December 2009 to December 2010, 39 consecutive patients underwent percutaneous transluminal angioplasty of SFA ISR at our institution (Clinica Montevergine, Mercogliano, Italy). All patients underwent conventional SFA percutaneous transluminal angioplasty and final post-dilation with paclitaxel-eluting balloons (IN.PACT, Medtronic Inc., Minneapolis, Minnesota). Patients were evaluated for up to 24 months. RESULTS: During follow up, 1 patient died of heart failure and another of sudden death, for a 2-years rate of cardiovascular mortality rate of 5.12 %. The primary patency rate at 2 years was 70.3% (11 of 37 patients experienced restenosis recurrence at 2-year follow-up). The treatment of complex ISR lesions (classes II and III) was associated with an increased rate of recurrent restenosis compared with class I (33.3 % and 36.3 % vs. 12.5%; p = 0.05). CONCLUSIONS: The data suggest that adjunctive use of DEBs for the treatment of SFA ISR is a safe and effective therapeutic strategy up to 2 years of follow-up. PMID- 24630885 TI - Mandatory radiation safety training for fluoroscopy imaging: a quality improvement priority or unnecessary oversight? PMID- 24630887 TI - MitraClip therapy in surgical high-risk patients: identification of echocardiographic variables affecting acute procedural outcome. AB - OBJECTIVES: The aim of the study was to assess predictors of acute procedural failure in surgical high-risk patients undergoing MitraClip (Abbott Vascular, Abbott Park, Illinois) therapy. BACKGROUND: MitraClip implantation is a novel percutaneous option to treat significant mitral regurgitation (MR). METHODS: In 300 patients (75 +/- 9 years of age, 190 [63%] men), of whom 32 (10.7%) had been unsuccessfully treated (discharge MR grade of >2+), baseline clinical and echocardiographic variables were evaluated by exact logistic regression and classification tree analyses to assess their impact on acute procedural failure. Acute procedural failure was differentiated into aborted procedure (no MitraClip implanted; n = 11) and "clip failure" (inadequate MR reduction despite MitraClip implantation; n = 21). RESULTS: Multivariate logistic regression identified effective regurgitant orifice area (EROA), mitral valve orifice area (MVOA), and mean transmitral pressure gradient (TMPG) as independent predictors of overall acute procedural failure. Classification tree analysis revealed that an EROA >70.8 mm(2) (n = 28) was associated with a high rate (25%) of clip failures, whereas the combination of an MVOA <=3.0 cm(2) and a TMPG >=4 mm Hg (n = 16) was associated with a high rate (37.5%) of aborted procedures. Failure rates of <=10% were observed in all patients with an EROA <=70.8 mm(2) and either an MVOA >3.0 cm(2) (n = 217) or an MVOA <=3.0 cm(2) in concert with a TMPG <=3 mm Hg (n = 39). Multinomial logistic regression identified an EROA >70.8 mm(2) and a TMPG >=4 mm Hg as independently predictive of clip failure, but an MVOA <=3.0 cm(2) and a TMPG >=4 mm Hg as independently predictive of procedure abortion. CONCLUSIONS: In surgical high-risk patients undergoing MitraClip therapy, a TMPG >=4 mm Hg, an EROA >=70.8 mm(2), and an MVOA <=3.0 cm(2) carry an increased risk of procedural failure. PMID- 24630888 TI - Follow-up improvement of distal vessel diameter after successful chronic total coronary occlusion recanalization. PMID- 24630886 TI - Long-term clinical outcomes after percutaneous coronary intervention versus coronary artery bypass grafting for ostial/midshaft lesions in unprotected left main coronary artery from the DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment. AB - OBJECTIVES: The aim of this study was to report the long-term clinical outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) for ostial/midshaft lesions in an unprotected left main coronary artery (ULMCA). BACKGROUND: Data regarding outcomes in these patients are limited. METHODS: Of a total of 2,775 patients enrolled in the DELTA multinational registry, 856 patients with isolated ostial/midshaft lesions in an ULMCA treated by PCI with DES (n = 482) or CABG (n = 374) were analyzed. RESULTS: At a median follow-up period of 1,293 days, there were no significant differences in the propensity score-adjusted analyses for the composite endpoint of all-cause death, myocardial infarction (MI), and cerebrovascular accident (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.79 to 1.86; p = 0.372), all-cause death (HR: 1.35, 95% CI: 0.80 to 2.27; p = 0.255), the composite endpoint of all-cause death and MI (HR: 1.33, 95% CI: 0.83 to 2.12; p = 0.235) and major adverse cardiac and cerebrovascular events (HR: 1.34, 95% CI: 0.93 to 1.93; p = 0.113). These results were sustained after propensity-score matching. However, a higher incidence of target vessel revascularization (HR: 1.94, 95% CI: 1.03 to 3.64; p = 0.039) was observed in the PCI compared with the CABG group, with a trend toward higher target lesion revascularization (HR: 2.00, 95% CI: 0.90 to 4.45; p = 0.090). CONCLUSIONS: This study demonstrates that PCI for ostial/midshaft lesions in an ULMCA is associated with clinical outcomes comparable to those observed with CABG at long-term follow up, despite the use of older first-generation DES. PMID- 24630889 TI - MCM2/TOP2A (ProExC) immunohistochemistry as a predictive marker in head and neck mucosal biopsies. AB - Mucosal biopsies from the head and neck are often small and poorly oriented, which impedes diagnostic interpretation, especially in patients with a history of cancer, being monitored for recurrence. A cocktail of antibodies targeted against DNA topoisomerase IIA and mini-chromosome maintenance protein 2 (MCM2/TOP2A, ProExC), markers of aberrant S-phase induction, have been used with success as a diagnostic adjunct in the evaluation of squamous dysplasia of the uterine cervix. We tested the utility in head and neck biopsies to see if ProExC could be used to discriminate reactive/inflammatory from true pre-neoplasia. Sixty-four archival biopsies were selected from patients who presented to the surgeon with an indication for biopsy to "rule out" dysplasia. Histologically, all biopsies showed nonspecific atypia that was difficult to discriminate from dysplasia. Twenty-three of the patients progressed to squamous carcinoma and the rest remained benign over five years follow-up. Cases stained with ProExC by IHC methods showed a significant pattern of expression (p=0.026). The staining was greatest in patients without a history of prior head and neck cancer but was not significant. Our results show that ProExC, used in conjunction with the H&E slide, can enhance the predictive power of a mucosal biopsy in a cohort of patients. PMID- 24630890 TI - Bloodstream infections among solid organ transplant recipients: epidemiology, microbiology, associated risk factors for morbility and mortality. AB - Bloodstream infections (BSIs) remain important causes of morbidity and mortality among solid organ transplant (SOT) recipients and still threaten the success of SOT. In general, among SOT recipients, risk factors for BSIs are associated with prior ICU admission, catheterization, older recipient or donor age...etc. Pulmonary focus, nosocomial source of BSIs, lack of appropriate antibiotic therapy and other variables have significant impacts on BSIs-related mortality in SOT. Most of BSIs in SOT are caused by gram-negative bacteria. However, all aspects including microbiological spectrum, morbidity and mortality rates, risk factors of BSIs and BSIs-related death depend on the type of transplantation. The purpose of this review is to summarize the epidemiology, microbiologic features including antimicrobial resistance of organisms, and associated risk factors for morbidity and mortality of BSIs according to different type of transplantation to better understand the characteristics of BSIs and improve the outcomes after SOT. PMID- 24630891 TI - Analysis of helicase domain mutations in the hepatitis E virus derived from patients with fulminant hepatic failure: effects on enzymatic activities and virus replication. AB - Fulminant hepatic failure (FHF) is the severe form of hepatitis E virus infection. Virus sequence analyses from severe cases have shown presence of unique and highly conserved mutations in the helicase domain of genotype 1, 3 and 4 viruses. We evaluated role of two amino acid replacements (L1110F) and (V1120I); found to be frequent in genotype 1 FHF-E viruses from India. Three mutant helicase proteins (two with single point mutations and one with dual mutations) were expressed in Escherichia coli and evaluated for their ATPase and RNA unwinding activities. Both L1110F and V1120I helicase mutants showed marginal decrease in ATPase activity, while L1110F/V1120I dual mutant showed normal ATPase activity. All three mutants proteins showed RNA unwinding activities comparable to wild type protein. Corresponding mutations were made in the helicase domain of HEV RLuc replicon and replication efficiencies were tested in the S10-3 (Huh 7) cells. The mutant replicon V1120I showed lower replication as compared to L1110F and L1110F/V1120I mutants. However, all three replicon mutants showed lower replication efficiencies as compared to the wild type replicon. Walker A and Walker B motif mutant HEV replicons were unable to replicate indicating essential role of the virus encoded helicase domain during HEV replication. FHF-E associated helicase mutations resulted in only marginal decrease in the virus replication suggesting alternate function/s of the helicase protein. Mutations in the helicase domain of FHF-E viruses may be responsible for changing virus or host-virus protein-protein interactions, causing alterations in the host responses, eventually leading to more severe disease manifestations. PMID- 24630892 TI - Embedding integrated mental health assessment and management in general hospital settings: feasibility, acceptability and the prevalence of common mental disorder. AB - OBJECTIVE: To assess the feasibility and acceptability of routine web-based screening in general hospital settings, and describe the level of common mental disorder. METHOD: A service development platform to integrate mental and physical healthcare was implemented in six specialties (rheumatology, limb reconstruction, hepatitis C, psoriasis, adult congenital heart disease (ACHD), chronic pain) across three general hospitals in London, UK. Under service conditions, patients completed a web-based questionnaire comprising mental and physical patient reported outcome measures, whilst waiting for their appointment. Feasibility was quantified as the proportion of patients who completed the questionnaire. Acceptability was quantified as the proportion of patients declining screening, and the proportion requiring assistance completing the questionnaire. The prevalence of probable depression and anxiety was expressed as the percentage of cases determined by the Patient Health Questionnaire-9 and Generalised Anxiety Disorder Questionnaire-7. RESULTS: The proportion of patients screened varied widely across specialties (40.1-98.2%). The decline rate was low (0.6-9.7%) and the minority required assistance (11.7-40.4%). The prevalence of probable depression ranged from 60.9% in chronic pain to 6.6% in ACHD. The prevalence of probable anxiety ranged from 25.1% in rheumatology to 11.4% in ACHD. CONCLUSION: Web-based screening is acceptable to patients and can be effectively embedded in routine practice. General hospital patients are at increased risk of common mental disorder, and routine screening may help identify need, inform care and monitor outcomes. PMID- 24630893 TI - Psychosis in neurosyphilis: an association of poor prognosis. AB - The spectrum of neurosyphilis includes asymptomatic patients, those with variable neurologic deficit, and those with complex cognitive, psychotic and mood dysfunction. Although the neurologic symptoms of neurosyphilis can remit with penicillin treatment, the psychiatric symptoms may persist. We identify two neurosyphilis cases characterized by prominent psychoses and describe commonalities that might assist clinicians in identifying neurosyphilis early. PMID- 24630894 TI - The different faces of Creutzfeldt-Jacob disease CJD in psychiatry. AB - OBJECTIVE: Creutzfeldt-Jacob Disease (CJD) is a rapidly progressive spongiform disease of the central nervous system. Psychiatric symptoms, though considered rare, can be the presenting symptoms of CJD and impose diagnosis difficulties. We reviewed prospectively our database to identify the frequency of psychiatric symptoms as identifying symptoms among our community. METHODS: We included all patients in Sheba Medical Center who were diagnosed with CJD between the years 2006 and 2012. Data were collected retrospectively. RESULTS: Twenty-three patients with CJD were admitted to our hospital during this 6-year period. Among them, 10 (44%) were diagnosed first as "psychiatric patients" due to psychiatric presenting symptoms. CONCLUSION: In our series, the frequency of misleading psychiatric symptom was 44%. Clinicians should therefore include CJD in their differential diagnoses of new onset dementia, particularly when associated psychosis and depression symptoms persist and worsen, despite standard psychiatric treatments. PMID- 24630895 TI - Prevalence of suicide attempts in pathological gamblers in a nationwide Austrian treatment sample. AB - BACKGROUND: For pathological gambling (PG), a 12-month prevalence rate of up to 0.66% has been reported. Multiple financial, occupational and relationship problems and losses, humiliation of the person and the environment are possible side effects and may lead to hopelessness, suicidal ideation and suicidal behavior. Suicide attempt rates among pathological gamblers of between 4% and 40% and suicidal ideation of between 12% and 92% have been reported. AIM: This study aims at assessing the prevalence of suicide attempts in PG and at elucidating differences between the patients with and without suicide attempt history (SAH) in a large nationwide Austrian sample. METHODS: Between 2002 and 2011, the Austrian Society for the Research of Non-Substance Related Addiction collected 862 questionnaires of pathological gamblers undergoing outpatient and inpatient treatment for PG in Austria. RESULTS: (a) Of all pathological gamblers, 9.7% had an SAH. (b) The SAH group suffered significantly more from a comorbid disorder and was more often in previous inpatient treatments. (c) The SAH patients had a longer time of an abstinence period in their PG career. DISCUSSION: One in 10 pathological gamblers has an SAH, demonstrating the relevance of suicidality in this population. Significant differences for several parameters were found for PG with and without SAH. However, a regression analysis only explained 15% of the variance. This suggests that suicidality must be considered in pathological gamblers in general. PMID- 24630896 TI - Chronic disease self-management interventions for adults with serious mental illness: a systematic review of the literature. AB - OBJECTIVE: While there is strong evidence in support of chronic disease self management programs, much less is available with regard to individuals living with serious mental illness (SMI). The objectives of this review are to identify and appraise chronic disease self-management studies tested with samples of US adults living with SMI. We include an appraisal of methodological quality of the chronic disease self-management (CDSM) studies that met our final criteria. METHODS: Systematic search methods were utilized to identify intervention studies published before 2012 that describe CDSM outcomes for adults with SMI. RESULTS: Eighteen unduplicated articles were identified that included outcomes of CDSM studies, while 10 met all inclusion criteria. Favorable treatment effects were observed for adults with SMI across 10 studies that took place in different types of clinical settings. CDSM studies that met all search criteria had a wide range of methodological quality, indicating that this is a nascent field of study. CONCLUSIONS: Given the high chronic disease burden experienced by individuals with SMI combined with our nations health care reform, emphasis on self management to improve population health, coupled with advancing the quality of research to evaluate CDSM programs for adults with SMI, is critically needed. PMID- 24630897 TI - Management and treatment of eating disorders with severe medical complications on a psychiatric ward: a study of 9 inpatients in Japan. AB - OBJECTIVE: To describe eating disorders inpatients with severe medical complications and elucidate the problems in managing them on a psychiatric ward. METHOD: Of the 111 eating disorders patients hospitalized on our psychiatric ward from January 2005 to December 2012, 9 had eating disorders with severe medical complications. Through chart review and computerized data collection, we retrospectively evaluated patient clinical data. RESULT: All 9 patients were women, with a mean age of 22.4+/-5.7 years, mean body weight of 26.2+/-3.0 kg, and mean body mass index of 10.5+/-1.5 on admission. Severe medical complications commonly seen were severe hypoglycemia, refeeding syndrome, coagulation abnormality, and severe liver dysfunction. Three patients died during hospitalization. All patients were managed mainly on the psychiatric ward despite their abnormally low body weight and severe medical complications. CONCLUSIONS: Patients with eating disorders, although physically serious, often need to be managed on a psychiatric ward, even at the risk of providing less than ideal care for their physical complications. It is important to assess patient status both physically and psychologically and to select an appropriate therapeutic environment for safe and effective treatment. PMID- 24630898 TI - [Phylogenetic interpretation of aortic arches and outflow tract partitioning]. AB - The great thoracic and cervical vessels come from the complex metameric system, formed of the dorsal and ventral aortas and aortic arches. From the branchial respiratory system of fish to the mammalian configuration, numerous changes have occurred in parallel with the evolution of cardiac septation, which imposes constraints on the vascular system. In addition, an important cell population is involved with the partioning of the arterial bulb: the cardiac neural crests originating from the head. The examination of abnormalities of arterial bulb septation, considered as neurocristopathies, within certain limitations, demonstrates an association of abnormal features with ancestral configurations. Some aortic arch malformations can be considered as a continuation of ancient embryonic transient vessels, which should have disappeared. Exemplative malformations, such as the "tetralogy of Fallot", are similar to reptilian configuration of great vessels, associated with incomplete partition of both ventricles with an absence of sub-endocardial cushions. However, the presence in reptiles of two systemic arches and a pulmonary artery (in fact, 3 vessels arising from the arterial bulb) has no malformative equivalent in mammals. Arteria lusoria, double aortic arch, dextroaortia, corresponds to the persistence of aortic arches intended to disappear, and could be considered as a haemodynamic response to the early and untimely regression of another arch. PMID- 24630900 TI - Resection of early oral squamous cell carcinoma with positive or close margins: relevance of adjuvant treatment in relation to local recurrence: margins of 3 mm as safe as 5 mm. AB - OBJECTIVES: The treatment strategy of early stage oral squamous cell carcinoma's (OSCC) resected with close or involved margins is a returning point of discussion. In this study we reviewed the consequences of re-resection (RR), postoperative radiotherapy (PORT) or watchful waiting (WW). PATIENTS AND METHODS: Two-hundred patients with a primary resected Stage 1-2 OSCC of the tongue, floor of the mouth and cheek were included and retrospectively analysed. Local recurrence ratio was related to margin status, unfavourable histological parameters (spidery infiltrative, peri-neural and vascular-invasive growth) and postoperative treatment modality. 3-year overall survival (OS) and disease specific survival (DSS) was calculated in relation to margin status. RESULTS: Twenty-two of 200 (11%) patients had pathological positive margins (PM), 126 (63%) close margins (CM), and 52 (26%) free margins (FM). OS and DSS were not significantly different between these groups. Nine of 200 (4.5%) patients developed local recurrent disease. Two (9.1%) had a PM, five (4.0%) a CM and two (3.8%) a FM. Of the nine recurrences, five patients had undergone PORT, one a RR, and three follow-up. Watchful waiting for CM ?3 mm with ?2 unfavourable histological parameters showed, besides margin status no significant differences with the FM group. CONCLUSION: With this treatment strategy, the local recurrence rate was 4.5%. No evidence was found for local adjuvant treatment in case of close margins ?3 mm with ?2 unfavourable histological parameters. Current data do not support the use of one treatment modality above any other. PMID- 24630901 TI - Analysis of surgical margins in oral cancer using in situ fluorescence spectroscopy. AB - Oral cancer is a public health problem with high prevalence in the population. Local tumor control is best achieved by complete surgical resection with adequate margins. A disease-free surgical margin correlates with a lower rate of local recurrence and a higher rate of disease-free survival. Fluorescence spectroscopy is a noninvasive diagnostic tool that can aid in real-time cancer detection. The technique, which evaluates the biochemical composition and structure of tissue fluorescence, is relatively simple, fast and, accurate. OBJECTIVES: This study aimed to compare oral squamous cell carcinoma lesions to surgical margins and the mucosa of healthy volunteers by fluorescence spectroscopy. MATERIALS AND METHODS: The sample consisted of 56 individuals, 28 with oral squamous cell carcinoma and 28 healthy volunteers with normal oral mucosa. Thirty six cases (64.3%) were male and the mean age was 60.9 years old. The spectra were classified and compared to histopathology to determine fluorescence efficiency for diagnostic discrimination of tumors. RESULTS: In the analysis of the other cases we observed discrimination between normal mucosa, injury and margins. At two-year follow up, three individuals had local recurrence, and in two cases investigation fluorescence in the corresponding area showed qualitative differences in spectra between the recurrence area and the area without recurrence at the same anatomical site in the same patient. CONCLUSION: In situ analysis of oral mucosa showed the potential of fluorescence spectroscopy as a diagnostic tool that can aid in discrimination of altered mucosa and normal mucosa. PMID- 24630902 TI - Criminal gunshot wound and iatrogenic tension pneumothorax detected by post mortem computed tomography. AB - Post-mortem imaging at autopsy is gradually increasing in popularity among forensic practitioners. The objective of the present paper was to demonstrate that it is essential to survey the cadaver using computed tomography (CT) before autopsy. This case report presents an iatrogenic tension pneumothorax caused by left subclavian vein puncture undertaken during treatment for a gunshot-related wound. The victim, a 64-year-old woman, was shot by her husband at home, and transferred to the hospital emergency unit. Before surgical procedures were carried out, left subclavian vein puncture was performed; however, during the operation, the victim experienced sudden cardiac arrest. Subsequent intensive resuscitation was unsuccessful. The clinical cause of death was recorded as traumatic shock caused by the gunshot injury. However, before the legal autopsy took place, CT clarified the existence of tension pneumothorax not on the same side as the gunshot wound, but on the side of the iatrogenic subclavian vein puncture. Because of this information gained prior to legal dissection, a typical dissection procedure for tension pneumothorax could be performed. Post-mortem imaging prior to regular dissection is essential as an adjunct diagnostic tool. PMID- 24630899 TI - Nonhomologous end joining: a good solution for bad ends. AB - Double strand breaks pose unique problems for DNA repair, especially when broken ends possess complex structures that interfere with standard DNA transactions. Nonhomologous end joining can use multiple strategies to solve these problems. It further uses sophisticated means to ensure the strategy chosen provides the ideal balance of flexibility and accuracy. PMID- 24630903 TI - Molecular mechanism of 2-APB-induced Ca2+ influx in external acidification in PC12. AB - 2-Aminoethoxydiphenyl borate (2-APB) is used as a pharmacological tool because it antagonizes inositol 1,4,5-trisphosphate receptors and store-operated Ca(2+) (SOC) channels, and activates some TRP channels. Recently, we reported that 2-APB enhanced the increase in cytotoxic [Ca(2+)]i, resulting in cell death under external acidic conditions in rat pheochromocytoma cell line PC12. However, the molecular mechanism and functional role of the 2-APB-induced Ca(2+) influx in PC12 have not been clarified. In this study, to identify the possible target for the action of 2-APB we examined the pharmacological and molecular properties of [Ca(2+)]i and secretory responses to 2-APB under extracellular low pH conditions. 2-APB dose-dependently induced a [Ca(2+)]i increase and dopamine release, which were greatly enhanced by the external acidification (pH 6.5). [Ca(2+)]i and secretory responses to 2-APB at pH 6.5 were inhibited by the removal of extracellular Ca(2+) and SOC channel blockers such as SK&F96365, La(3+) and Gd(3+). PC12 expressed all SOC channel molecules, Orai 1, Orai 2 and Orai 3. When we used an siRNA system, downregulation of Orai 3, but not Orai 1 and Orai 2, attenuated both [Ca(2+)]i and secretory responses to 2-APB. These results suggest that 2-APB evokes external acid-dependent increases of [Ca(2+)]i and dopamine release in PC12 through the activation of Orai 3. The present results indicate that 2-APB may be a useful pharmacological tool for Orai channel-related signaling. PMID- 24630904 TI - [Assessment of medical students using a script concordance test at the end of their internship in pediatric gastroenterology]. AB - The Script Concordance Test (SCT) is a tool used to evaluate clinical reasoning in complex medical situations. Our aim was to create the first SCT in pediatric gastroenterology in order to objectively assess medical students. We elaborated a SCT including 31 items divided into ten clinical cases. Topics were chosen within the list comprising the national academic exam. In order to assess medical students, a reference panel was made up of ten residents to establish the scoring process. Answers were noted on a Likert scale, ranging from -2 to +2. Scores were calculated based on the modal response. Depending on the variation of the experts' answers to each item, we classified the questions as correct, incorrect, or uncertain. The SCT was also taken by five GI pediatricians. The results were given as mean/20 +/- SEM. The Student t-test was used for the statistical analysis. The scores were 15.35 +/- 0.38 and 12.44 +/- 0.58 (P=0.0006), respectively, for the reference panel and the students. Scores were unchanged by removing incorrect and uncertain questions. However, the score of the GI pediatricians was 13.37 +/- 0.69, significantly lower than the reference panel (P=0.01). The reliability of this SCT is subject to debate. This was the first time the students had taken a SCT, but they considered that this tool was appropriate and in concordance with the objectives. Although the SCT is a useful method, its elaboration can be difficult. It seems important to create a group of teachers to validate the process and eliminate the wide variability. PMID- 24630905 TI - Impact of a nursing education program about caring for patients in Japan with malignant pleural mesothelioma on nurses' knowledge, difficulties and attitude: a randomized control trial. AB - PURPOSE: In Japan nursing care lags behind the growing population of patients with malignant pleural mesothelioma. This study evaluated an educational program for nurses about caring for patients with malignant pleural mesothelioma in Japan. METHOD: In this randomized controlled study relative to care for malignant pleural mesothelioma, Knowledge, Difficulties and Attitude were measured at baseline, at post-test and at follow-up one month later. The two-day program with a half-day follow-up program included lectures, group work, role-playing and group discussion. 188 participants were randomly assigned to the intervention group (program, n=96) and control group (n=92; self-study by a similar content handbook). At baseline the groups showed no statistical differences in Knowledge (p=0.921), Difficulty (p=0.458) and Attitude (p=0.922). Completing the study were 177 participants yielding 88 in the intervention group and 89 in the control group. Human rights and privacy of participants were protected. RESULTS: The Knowledge score was significantly higher in the intervention post-test (t=14.03, p=0.000) and follow-up test (t=8.98, p=0.000). Difficulty score was significantly lower in the intervention at post-test (t=-3.41, p=0.001) and follow-up test (t= 3.70, p=0.000). The Attitude score was significantly higher in the intervention post-test (t=7.11, p=0.000) and follow-up test (t=4.54, p=0.000). The two-way analysis of variance with repeated measures on time showed an interaction between time and group; the subsequent simple main effect test found significant differences (p=0.000-0.001) between groups for after-program and at follow-up and a significant difference (p=0.000) in time only within the intervention group. CONCLUSION: The educational program was effective in improving the nurses' knowledge and attitude toward malignant pleural mesothelioma care and decreasing the difficulty in MPM care, therefore this program has potential for nurses' in service education throughout Japan. PMID- 24630906 TI - Too many men: the violence problem? AB - There is a strong intuitive expectation in both popular lore and conventional evolutionary thinking that more males lead to more violence. Here, we untangle the logic behind this widely held notion with a specific focus on humans. We first review the relation between the intensity of sexual selection in human populations and the adult sex ratio (ASR), and find that it is more in line with recent reformulations of sexual selection theory than with conventional models. We then turn directly to the patterning of violence across human societies in relation to the sex ratio. Although the 'more men, more violence' expectation is not met, it is clear that the patterning of violence is undertheorized and we offer recommendations for steps forward. PMID- 24630907 TI - A predictive model of early mortality in trauma patients. AB - BACKGROUND: Rapid thrombelastography (rTEG) is a real-time whole-blood viscoelastic coagulation assay. We hypothesized that admission rTEG and clinical data are independent predictors of trauma-related mortality. METHODS: Prospective observational data (patient demographics, admission vital signs, laboratory studies, and injury characteristics) from trauma patients enrolled within 6 hours of injury were collected. Mann-Whitney U test and analysis of variance test assessed significance (P <= .05). Logistic regression analyses determined the association of the studied variables with 24-hour mortality. RESULTS: Seven hundred ninety-five trauma patients were enrolled, of which 55 died within 24 hours of admission. Admission variables which independently predicted 24-hour mortality were as follows: Glasgow Coma Scale <=8, hemoglobin <11 g/dL, international normalized ratio >1.5, Ly30 >8%, and penetrating injury (P < .05). This 5-variable model's area under the receiver operator characteristic curve was .88. The Hosmer-Lemeshow goodness-of-fit test was .90. CONCLUSIONS: This 5 variable model provides a rapid prediction of 24-hour mortality. The inclusion of rTEG Ly30 demonstrates the association of fibrinolysis with outcome and may support the early use of antifibrinolytic therapies. PMID- 24630908 TI - A proposal to reroute and reform the healthcare money trail. AB - Without fundamental changes healthcare costs will continue to accelerate faster than the gross domestic product while consuming larger portions of individual and corporate incomes. Although the problems are widely acknowledged, we believe that there is an underappreciated defect driving these undesirable events. The essence of that defect is that the major portion of the money is outside the control of the patients and competitive pricing is outside the control of the providers. We propose that the patients have virtual, dynamically allocated, evidence-based budgets grounded on their medical conditions and the patients authorize the transfer of funds to the providers while the providers compete on quality and price. Furthermore, we advocate all funding of healthcare be via taxes linked to expenditures to replace and reduce the total healthcare "premiums" and decouple health care from employment as it is archaic and hinders employment. This proposal reassigns the control of money from the government and special interest groups and returns it to the control of the patients. PMID- 24630909 TI - Advantages and limitations of navigation-based multicriteria optimization (MCO) for localized prostate cancer IMRT planning. AB - Efficacy of inverse planning is becoming increasingly important for advanced radiotherapy techniques. This study's aims were to validate multicriteria optimization (MCO) in RayStation (v2.4, RaySearch Laboratories, Sweden) against standard intensity-modulated radiation therapy (IMRT) optimization in Oncentra (v4.1, Nucletron BV, the Netherlands) and characterize dose differences due to conversion of navigated MCO plans into deliverable multileaf collimator apertures. Step-and-shoot IMRT plans were created for 10 patients with localized prostate cancer using both standard optimization and MCO. Acceptable standard IMRT plans with minimal average rectal dose were chosen for comparison with deliverable MCO plans. The trade-off was, for the MCO plans, managed through a user interface that permits continuous navigation between fluence-based plans. Navigated MCO plans were made deliverable at incremental steps along a trajectory between maximal target homogeneity and maximal rectal sparing. Dosimetric differences between navigated and deliverable MCO plans were also quantified. MCO plans, chosen as acceptable under navigated and deliverable conditions resulted in similar rectal sparing compared with standard optimization (33.7 +/- 1.8 Gy vs 35.5 +/- 4.2 Gy, p = 0.117). The dose differences between navigated and deliverable MCO plans increased as higher priority was placed on rectal avoidance. If the best possible deliverable MCO was chosen, a significant reduction in rectal dose was observed in comparison with standard optimization (30.6 +/- 1.4 Gy vs 35.5 +/- 4.2 Gy, p = 0.047). Improvements were, however, to some extent, at the expense of less conformal dose distributions, which resulted in significantly higher doses to the bladder for 2 of the 3 tolerance levels. In conclusion, similar IMRT plans can be created for patients with prostate cancer using MCO compared with standard optimization. Limitations exist within MCO regarding conversion of navigated plans to deliverable apertures, particularly for plans that emphasize avoidance of critical structures. Minimizing these differences would result in better quality treatments for patients with prostate cancer who were treated with radiotherapy using MCO plans. PMID- 24630910 TI - A volumetric approach to path-length measurements is essential when treating radiotherapy with modulated beams. AB - The established dosimetric benefits of intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy have lead to their increased use in prostate radiotherapy. Complimenting these techniques, volumetric image guidance has supported increased positional accuracy. In addition, 3-dimensional image guidance has also allowed for assessment of potential dosimetric variation that can be attributed to a deformation of either internal or external structures, such as rectal distension or body contour. Compounding these issues is the variation of tissue density through which the new field position passes and also the variation of dose across a modulated beam. Despite the growing level of interest in this area, there are only a limited number of articles that examine the effect of a variation in beam path length, particularly across a modulated field. IMRT and volumetric-modulated radiation therapy (VMAT) fields are dynamic in nature, and the dose gradient within these fields is variable. Assessment of variation of path length away from the beam's central axis and across the entire field is vital where there is considerable variation of dose within the field, such as IMRT and VMAT. In these cases, reliance on the traditional central axis to focus skin distances is no longer appropriate. This article discusses these more subtle challenges that may have a significant clinical effect if left unrecognized and undervalued. PMID- 24630911 TI - The radiation oncology workforce: a focus on medical dosimetry. AB - The 2012 Radiation Oncology Workforce survey was conducted to assess the current state of the entire workforce, predict its future needs and concerns, and evaluate quality improvement and safety within the field. This article describes the dosimetrist segment results. The American Society for Radiation Oncology (ASTRO) Workforce Subcommittee, in conjunction with other specialty societies, conducted an online survey targeting all segments of the radiation oncology treatment team. The data from the dosimetrist respondents are presented in this article. Of the 2573 dosimetrists who were surveyed, 890 responded, which resulted in a 35% segment response rate. Most respondents were women (67%), whereas only a third were men (33%). More than half of the medical dosimetrists were older than 45 years (69.2%), whereas the 45 to 54 years age group represented the highest percentage of respondents (37%). Most medical dosimetrists stated that their workload was appropriate (52%), with respondents working a reported average of 41.7 +/- 4 hours per week. Overall, 86% of medical dosimetrists indicated that they were satisfied with their career, and 69% were satisfied in their current position. Overall, 61% of respondents felt that there was an oversupply of medical dosimetrists in the field, 14% reported that supply and demand was balanced, and the remaining 25% felt that there was an undersupply. The medical dosimetrists' greatest concerns included documentation/paperwork (78%), uninsured patients (80%), and insufficient reimbursement rates (87%). This survey provided an insight into the dosimetrist perspective of the radiation oncology workforce. Though an overwhelming majority has conveyed satisfaction concerning their career, the study allowed a spotlight to be placed on the profession's current concerns, such as insufficient reimbursement rates and possible oversupply of dosimetrists within the field. PMID- 24630912 TI - Kilovoltage cone-beam CT imaging dose during breast radiotherapy: a dose comparison between a left and right breast setup. AB - The purpose of this study was to investigate the delivered dose from a kilovoltage cone-beam computed tomography (kV-CBCT) acquired in breast treatment position for a left and right breast setup. The dose was measured with thermoluminescent dosimeters positioned within a female anthropomorphic phantom at organ locations. Imaging was performed on an Elekta Synergy XVI system with the phantom setup on a breast board. The image protocol involved 120kVp, 140mAs, and a 270 degrees arc rotation clockwise 0 degrees to 270 degrees for the left breast setup and 270 degrees to 180 degrees for the right breast setup (maximum arc rotations possible). The dose delivered to the left breast, right breast, and heart was 5.1mGy, 3.9mGy, and 4.0mGy for the left breast setup kV-CBCT, and 6.4mGy, 6.0mGy, and 4.8mGy for the right breast setup kV-CBCT, respectively. The rotation arc of the kV-CBCT influenced the dose delivered, with the right breast setup kV-CBCT found to deliver a dose of up to 4mGy or 105% higher to the treated breast's surface in comparison with the left breast setup. This is attributed to the kV-CBCT source being more proximal to the anterior of the phantom for a right breast setup, whereas the source is more proximal to the posterior of the patient for a left-side scan. PMID- 24630913 TI - Macronutrient contributions of insects to the diets of hunter-gatherers: a geometric analysis. AB - We present a geometric model for examining the macronutrient contributions of insects in the diets of pre-agricultural humans, and relate the findings to some contemporary societies that regularly eat insects. The model integrates published data on the macronutrient composition of insects and other foods in the diets of humans, recommended human macronutrient intakes, and estimated macronutrient intakes to examine the assumption that insects provided to pre-agricultural humans an invertebrate equivalent of vertebrate-derived meats, serving primarily as a source of protein. Our analysis suggests that insects vary more widely in their macronutrient content than is likely to be the case for most wild vertebrate meats, spanning a broad range of protein, fat and carbohydrate concentrations. Potentially, therefore, in terms of their proportional macronutrient composition, insects could serve as equivalents not only of wild meat, but of a range of other foods including some shellfish, nuts, pulses, vegetables and even fruits. Furthermore, humans might systematically manipulate the composition of edible insects to meet specific needs through pre-ingestive processing, such as cooking and selective removal of body parts. We present data suggesting that in modern societies for which protein is the more limiting macronutrient, pre-ingestive processing of edible insects might serve to concentrate protein. It is likely, however, that the dietary significance of insects was different for Paleolithic hunter-gatherers who were more limited in non-protein energy. Our conclusions are constrained by available data, but highlight the need for further studies, and suggest that our model provides an integrative framework for conceiving these studies. PMID- 24630914 TI - Metabolomics using GC-TOF-MS followed by subsequent GC-FID and HILIC-MS/MS analysis revealed significantly altered fatty acid and phospholipid species profiles in plasma of smokers. AB - Mass spectrometry is an ideal tool for investigations of the metabolome in human plasma. To investigate the impact of smoking on the human metabolome, we performed an untargeted metabolic fingerprinting using GC-TOF-MS with EDTA-plasma samples from 25 smokers and 25 non-smokers. The observed elevated levels in the monounsaturated fatty acids (MUFAs) in smokers were verified by a targeted analysis using GC-FID, which revealed also significantly alterations in saturated and polyunsaturated fatty acids in smokers (p<0.05, Mann-Whitney U test). Since the main fraction of fatty acids in plasma is esterified to phospholipids, we analyzed phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species composition in the plasma samples of the same subjects. The profiles of 39 PC and 40 PE species were analyzed with a newly developed and validated HILIC-ESI-MS/MS method. We were able to baseline separate the two lipid classes (PC from PE) by maintaining co-elution of individual lipid species of each class. The method shows a linear range from 0.5MUM to 2000MUM and an inter- and intraday coefficient of variation (CV)<20% across all analytes. Application of the validated method to the plasma samples of smokers and non-smokers, derived from a diet-controlled smoking study, revealed significantly elevated levels of PC and PE species containing MUFAs in smokers. In summary, we could demonstrate that there is a significantly altered total fatty acid profile, with increased MUFAs, in the plasma of smokers compared to non-smokers. Results obtained with the new HILIC-MS/MS method indicate that the altered fatty acid profile is also reflected in the PC and PE profile of smokers. PMID- 24630915 TI - Chronic fatigue syndrome and personality: a case-control study using the Alternative Five Factor Model. AB - Neuroticism is the personality dimension most frequently associated with chronic fatigue syndrome (CFS). Most studies have also shown that CFS patients are less extraverted than non-CFS patients, but results have been inconsistent, possibly because the facets of the extraversion dimension have not been separately analyzed. This study has the following aims: to assess the personality profile of adults with CFS using the Alternative Five-Factor Model (AFFM), which considers Activity and Sociability as two separate factors of Extraversion, and to test the discriminant validity of a measure of the AFFM, the Zuckerman-Kuhlman Personality Questionnaire, in differentiating CFS subjects from normal-range matched controls. The CFS sample consisted of 132 consecutive patients referred for persistent fatigue or pain to the Department of Medicine of a university hospital. These were compared with 132 matched normal population controls. Significantly lower levels of Activity and significantly higher levels of Neuroticism-Anxiety best discriminated CFS patients from controls. The results are consistent with existing data on the relationship between Neuroticism and CFS, and clarify the relationship between Extraversion and CFS by providing new data on the relationship of Activity to CFS. PMID- 24630916 TI - Paranoia and self-concepts in psychosis: a systematic review of the literature. AB - The purpose of the present study was to review systematically, research exploring the relationship between self-concepts and paranoia in psychosis. A literature search was performed by two independent raters in relevant databases (MedLine, PsychInfo and Web of Science) and articles meeting the inclusion criteria were cross-referenced. Following scrutiny according to inclusion criteria, 18 studies were selected for review. A narrative synthesis of findings, in which methodological variability is discussed, is presented relative to three key areas: the nature of the relationship between paranoia and self-concepts; the association between paranoia and discrepancies in self-concepts; the nature of the relationship between paranoia and self-concepts when other, dimensional aspects of these constructs are taken into account. The systematic literature review indicated relatively consistent findings, that paranoia is associated with more negative self-concepts when measured cross-sectionally. Results are somewhat more mixed in regards to research on paranoia and self-concept discrepancies. Studies investigating dimensional aspects of self-concepts and paranoia yield findings of particular interest, especially in regards to the association indicated between instability of self-concepts and paranoia. Limitations in research and of the present systematic review are discussed. Clinical and theoretical implications of findings are outlined and possible directions for future research are suggested. PMID- 24630917 TI - Open access publication & the International Journal of Nursing Studies: all that glitters is not gold. PMID- 24630918 TI - Comparability of nurse staffing measures in examining the relationship between RN staffing and unit-acquired pressure ulcers: a unit-level descriptive, correlational study. AB - BACKGROUND: Various staffing measures have been used in examining the relationship between nurse staffing and patient outcomes. Little research has been conducted to compare these measures based on their explanatory power as predictors of nursing-sensitive outcomes. In this study, both administrative and nurse-reported measures were examined. Administrative measures included registered nurse (RN) skill mix and three versions of nursing hours per patient day (HPPD); nurse-reported measures included RN-reported number of assigned patients and RN-perceived staffing adequacy. OBJECTIVES: To examine correlations among six nurse staffing measures and to compare their explanatory power in relation to unit-acquired pressure ulcers (UAPUs). DESIGN: Descriptive, correlational study. SETTINGS: 2397 nursing units in 409 U.S. acute care hospitals. METHODS: Random-intercept logistic regression analyses were performed using 2011 data from a national database. Relationships between nurse staffing measures and UAPU occurrences were examined in eight models, each with one or more staffing measures as predictors. Characteristics of nursing units (RN workgroup education level and RN workgroup unit tenure) and hospitals (size, teaching status, and Magnet status) were included as control variables. RESULTS: Two versions of HPPD (total nursing HPPD and RN HPPD) and RN skill mix were significantly correlated with RN-reported number of assigned patients (r range= 0.87 to -0.75). These staffing measures had weaker correlations with RN-perceived staffing adequacy (r range=0.16 to 0.23). Of the six staffing variables, only RN perceived staffing adequacy and RN skill mix were significantly associated with UAPU odds, the former being the better predictor. CONCLUSIONS: Although RN perceived staffing adequacy was not highly correlated with administrative measures of HPPD and RN skill mix, it was the strongest predictor of UAPU occurrences. RN-perceived staffing adequacy can serve as a more appropriate measure of staffing for nursing-sensitive outcomes research than administrative measures, as it reflects relevant aspects of staffing and involves an implicit adjustment for patient acuity. PMID- 24630919 TI - Patterns of relapse or progression after bortezomib-based salvage therapy in patients with relapsed/refractory multiple myeloma. AB - INTRODUCTION: Bortezomib-based therapy is commonly used in treatment for relapsed or refractory multiple myeloma (MM). Unfortunately, many patients show relapse or progression in heterogeneous patterns. PATIENTS AND METHODS: In this study, we retrospectively evaluated patterns of relapse or progression after bortezomib based salvage therapy in patients with MM and analyzed prognostic significance according to patterns of relapse or progression. One hundred forty-eight patients were treated with bortezomib-based therapy between November 2004 and April 2012. Of these patients, 104 (70.3%) patients relapsed or progressed after bortezomib based salvage therapy. We divided the patterns of relapse or progression to the 2 groups: (1) the isoform relapse or progression (group A) in 89 (85.6%) patients as disease findings at initiation of bortezomib-based therapy; and (2) transformed relapse or progression (group B) in 15 (14.4%) patients (plasmacytoma, n = 7; light chain escape, n = 6; and plasma cell leukemia, n = 2) different from initial disease findings. RESULTS: Median overall survival in group A and group B were 32.7 months (95% confidence interval [CI], 21.3-44.1) and 10.7 months (95% CI, 2.0-19.4) (P < .001), respectively. CONCLUSION: MM patients who relapsed or progressed as the transformed pattern for bortezomib based salvage therapy have an extremely poor prognosis and might require new innovative approaches. PMID- 24630920 TI - Pernicious anemia with spuriously normal vitamin B12 level might be misdiagnosed as myelodysplastic syndrome. PMID- 24630921 TI - Small lymphocytic lymphoma presenting as a paraneoplastic syndrome with acute central nervous system demyelination. PMID- 24630922 TI - Nutrient deficiencies in patients with obesity considering bariatric surgery: a cross-sectional study. AB - BACKGROUND: Nutritional deficiencies are common after bariatric surgery, but few studies have examined them preoperatively. The objective of this study was to evaluate several vitamins, nutrients, and nutritional markers and their determinants in patients with obesity considering bariatric surgery. METHODS: Preoperative values of fasting plasma glucose, insulin, lipid profile, 25 hydroxyvitamin D (25(OH)D), parathyroid hormone, thyroid-stimulating hormone, calcium, phosphate, albumin, magnesium, total proteins, liver function tests, iron, ferritin, folate, vitamin A, vitamin B12, selenium, and zinc were evaluated in 267 Caucasian outpatients (74.2% women, aged 40.5+/-12.6 years) who were considering bariatric surgery. The determinants of nutrient variability were analyzed by linear regression for nutrients with a prevalence of deficiency>10%, i.e., serum 25(OH)D, iron, phosphate, magnesium, and vitamin A. RESULTS: Prevalence of inadequate concentrations was high for 25(OH)D (67.9% with values <= 20 ng/mL), magnesium (35.4%), phosphate (21.6%), iron (18.8%), and vitamin A (16.9%). Multiple deficiencies were common; 28.5%, 12.1%, and 6.3% of patients had 2, 3, and 4 deficiencies, respectively. In multivariate analyses, metabolic characteristics had an important impact on deficiencies, with lower values of 25(OH)D and vitamin A with increasing body mass index, lower values of 25(OH)D and magnesium with increasing fasting plasma glucose, and a positive correlation between vitamin A and triglycerides. Elevated TSH was associated with low iron concentrations. CONCLUSION: At all ages, micronutrient deficiencies were common, with high prevalence of concentration inadequacies for 25(OH)D, magnesium, phosphate, iron, and vitamin A. High body mass index and high fasting plasma glucose increased the risk of deficiencies, particularly for 25(OH)D. Preoperative screening and correction of deficiencies should be advised. PMID- 24630923 TI - Treatment of ovarian metastases of colorectal and appendiceal carcinoma in the era of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - AIM: To compare outcome of women with ovarian metastasis who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to outcome of women without ovarian metastasis who underwent CRS-HIPEC. METHODS: A prospective CRS-HIPEC database was searched to identify women with surgically treated colorectal carcinoma between 2000 and 2012. Patients with ovarian metastasis were identified and patients with peritoneal carcinomatosis but without ovarian metastasis were included as control cases. RESULTS: 75 patients with macroscopic ovarian metastasis underwent CRS-HIPEC with curative intent, while 50 female patients without ovarian metastasis were identified who underwent CRS-HIPEC. Patients with ovarian metastasis more often had a primary appendiceal tumour and had a more extensive intra-abdominal tumour load compared to patients without ovarian metastases. Median follow-up time was 45 months (95% confidence interval (CI): 37-53 months). Overall survival (OS) did not differ significantly between the two groups with a median OS in the ovarian metastasis group of 40 months (95% CI 26-54) compared to 64 months (95% CI 17-111, P = 0.478) in the non ovarian metastasis group. Recurrence patterns did not differ significantly between groups (p = 0.183). CONCLUSIONS: Patients with ovarian metastasis of colorectal and appendiceal origin who underwent CRS-HIPEC had similar outcome compared to patients without ovarian metastasis. Given the findings of high coincidence of peritoneal metastases with ovarian metastases and ovarian metastases not being an independent factor for survival after CRS-HIPEC, this procedure should be recommended for patients with peritoneal metastases and ovarian metastases of colorectal and appendiceal carcinoma. PMID- 24630924 TI - Evaluation of user adoption during three module deployments of region-wide electronic patient record systems. AB - BACKGROUND: In Sweden there are modular region-wide EPR systems that are implemented at various health organisations in the region. The market is dominated by four IT systems that have been procured and deployed in 18 out of 21 regions. METHODS: In a 2.5-year research study, deployments of three region-wide EPR modules: a patient administration system, eReferral module and eMedication module were followed and evaluated. Health professionals, EPR maintenance organisation, IT and health care managers were observed, interviewed and responded to questionnaires. RESULTS: Although the same deployment process was used during the three deployments, large variations in the units' adoptions were observed. The variations were due to: (1) expectation and attitude, (2) management and steering, (3) end-user involvement, (4) EPR learning, and (5) usability and the possibility of changing and improving the EPR. CONCLUSIONS: If changes in work processes are not considered in development and deployment, the potential benefits will not be achieved. It is therefore crucial that EPR deployment is conceived as organisational development. Users must be supported not just before and during the go-live phase, but also in the post-period. A problem often encountered is that it is difficult to make late changes in a region-wide EPR, and it is an open question whether it is possible to talk about a successful deployment if the usability of the introduced system is low. PMID- 24630925 TI - Comment on Numao et al.: Clinical correlates of serum insulin-like growth factor 1 in patients with Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. PMID- 24630926 TI - H-RN, a novel antiangiogenic peptide derived from hepatocyte growth factor inhibits inflammation in vitro and in vivo through PI3K/AKT/IKK/NF-kappaB signal pathway. AB - H-RN, a novel antiangiogenic peptide derived from the kringle 1 domain of hepatocyte growth factor (HGF), consists of the sequence RNPRGEEGGPW (molecular weight: 1254.34Da). Emerging evidence indicates that HGF and the kringle domain exhibit anti-inflammatory effects in inflammatory diseases. In the present study, we assessed the anti-inflammatory effect of H-RN in models of experimental ocular inflammation, including endotoxin-induced uveitis (EIU) and experimental autoimmune uveitis (EAU). The results demonstrated that intravitreal treatment of H-RN concentration-dependently suppressed clinical manifestation, inhibited ocular inflammatory cytokine production and improved histopathologic scores. Moreover, H-RN attenuated the LPS-induced mRNA and protein expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in RAW 264.7 cells and inhibited cell chemotactic migration toward LPS. We also demonstrated that H-RN suppressed TNF-alpha-induced adhesion molecule expression in HUVECs, including ICAM-1, VCAM-1 and E-selectin, which contributed to its suppressive effect on adherence of U937 cells to endothelial cells. We also demonstrated the possible anti-inflammation mechanism of H-RN. Western blot and immunofluorescence staining analyses revealed that H-RN significantly suppressed LPS-induced phosphorylation of nuclear factor (NF)-kappaB-p65 at Ser276. Based on examination of upstream pathways, we found that H-RN inhibited PI3K-p85 and AKT(Ser473) phosphorylation, which may result in the attenuation of LPS-induced IKK complex activation and IkappaB degradation. Thus, our studies suggest that the 11-amino-acid peptide H RN exhibits anti-inflammatory effects in vitro and in vivo and may represent a promising candidate for ocular inflammatory diseases. PMID- 24630927 TI - Cardiac glycoside ouabain induces autophagic cell death in non-small cell lung cancer cells via a JNK-dependent decrease of Bcl-2. AB - Cardiac glycosides are Na/K-ATPase inhibitors, clinically used for congestive heart failure and cardiac arrhythmias. Epidemiological studies have reported that patients on cardiac glycosides treatment are protected from some types of cancers. This evidence together with the demonstration that cardiac glycosides show selective cytotoxicity against cancer cells has raised new interest on the anticancer properties of these drugs. This study examines the mechanism involved in the anticancer effect of ouabain in non-small cell lung cancer cells lines (A549 and H1975). Ouabain inhibited cell proliferation and induced cell death in a concentration-dependent manner. Cell death was caspase-independent and showed classical patterns of autophagic cell death: conversion of LC3-I to LC3-II, increase of LC3 puncta and increase of autophagic flux. Moreover, cell death was completely blocked by the class III phosphatidylinositol-3 kinase inhibitor 3 methyladenine. Here we show that ouabain caused the reduction of Bcl-2 protein levels, with no change in the expression of the autophagic protein Beclin 1. Early signalling events of ouabain exposure were ERK1/2 and JNK activation, however only JNK inhibition with SP600125 or JNK knockdown by shRNA were able to prevent Bcl-2 decrease, conversion of LC3-I to LC3-II and cell death. We propose that JNK activation by ouabain leads to a decrease of Bcl-2 levels, resulting in disruption of the inhibitory interaction of Bcl-2 with Beclin 1, that promotes autophagy. These findings indicate that pharmacological modulation of autophagy by cardiac glycosides could be exploited for anticancer therapy. PMID- 24630928 TI - Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: evidence for its ability to support follicular development and ovulation. AB - FSH signalling through its cognate receptor is critical for follicular development and ovulation. An earlier study had documented thiazolidinone derivatives to activate FSH receptor expressed in CHO cells and rat granulosa cells; however development of this compound for clinical use was halted for unobvious reasons. The objective of the current study is to extend the previous investigations in detail on the ability of thiazolidinone derivative (henceforth referred to as Compound 5) to activate FSH signalling and learn the barriers that preclude development of this derivative for clinical purposes. Our results demonstrate that the Compound 5 in a dose-dependent manner stimulated cAMP production, activated AKT and ERK signalling pathways and induced estradiol production in cultured rat granulosa cells. Compound 5 also caused dose-dependent increase in estradiol production from human granulosa cells. In increasingly more complex in vitro systems, Compound 5 was able to induce the expansion of mouse cumulus-oocyte-complex and support in vitro development of mouse preantral follicle to preovulatory stage and release of oocyte from the follicle. In vivo, the compound stimulated preovulatory follicular development and ovulation in immature rats. Pharmacokinetic and safety investigations reveal poor oral availability and genotoxicity. Together, our results document Compound 5 to act as a FSHR allosteric modulator but have poor pharmacological properties for development of an oral FSH receptor modulator. PMID- 24630929 TI - Adenanthin targets proteins involved in the regulation of disulphide bonds. AB - Adenanthin has been recently shown to inhibit the enzymatic activities of peroxiredoxins (Prdx) I and II through its functional alpha,beta-unsaturated ketone group serving as a Michael acceptor. A similar group is found in SK053, a compound recently developed by our group to target the thioredoxin-thioredoxin reductase (Trx-TrxR) system. This work provides evidence that next to Prdx I and II adenanthin targets additional proteins including thioredoxin-thioredoxin reductase system as well as protein disulfide isomerase (PDI) that contain a characteristic structural motif, referred to as a thioredoxin fold. Adenanthin inhibits the activity of Trx-TR system and PDI in vitro in the insulin reduction assay and decreases the activity of Trx in cultured cells. Moreover, we identified Trx-1 as an adenanthin binding protein in cells incubated with biotinylated adenanthin as an affinity probe. The results of our studies indicate that adenanthin is a mechanism-selective, rather than an enzyme-specific inhibitor of enzymes containing readily accessible, nucleophilic cysteines. This observation might be of importance in considering potential therapeutic applications of adenanthin to include a range of diseases, where aberrant activity of Prdx, Trx-TrxR and PDI is involved in their pathogenesis. PMID- 24630930 TI - Catalase expression in MCF-7 breast cancer cells is mainly controlled by PI3K/Akt/mTor signaling pathway. AB - Catalase is an antioxidant enzyme that catalyzes mainly the transformation of hydrogen peroxide into water and oxygen. Although catalase is frequently down regulated in tumors the underlying mechanism remains unclear. Few transcription factors have been reported to directly bind the human catalase promoter. Among them FoxO3a has been proposed as a positive regulator of catalase expression. Therefore, we decided to study the role of the transcription factor FoxO3a and the phosphatidylinositol-3 kinase (PI3K) signaling pathway, which regulates FoxO3a, in the expression of catalase. To this end, we developed an experimental model of mammary breast MCF-7 cancer cells that acquire resistance to oxidative stress, the so-called Resox cells, in which catalase is overexpressed as compared with MCF-7 parental cell line. In Resox cells, Akt expression is decreased but its phosphorylation is enhanced when compared with MCF-7 cells. A similar profile is observed for FoxO3a, with less total protein but more phosphorylated FoxO3a in Resox cells, correlating with its higher Akt activity. The modulation of FoxO3a expression by knockdown and overexpression strategies did not affect catalase expression, neither in MCF-7 nor in Resox cells. Inhibition of PI3K and mTOR by LY295002 and rapamycin, respectively, decreases the phosphorylation of downstream targets (i.e. GSK3beta and p70S6K) and leads to an increase of catalase expression only in MCF-7 but not in Resox cells. In conclusion, FoxO3a does not appear to play a critical role in the regulation of catalase expression in both cancer cells. Only MCF-7 cells are sensitive and dependent on PI3K/Akt/mTOR signaling. PMID- 24630931 TI - The anti-lung cancer activity of SEP is mediated by the activation and cytotoxicity of NK cells via TLR2/4 in vivo. AB - Strongylocentrotus nudus egg polysaccharide (SEP) has been reported to display antitumor activity. However, the effects of SEP and its underlying mechanism in the treatment of lung cancer remain unclear, particularly with an immunodeficient mouse model of human non-small cell lung cancer (NSCLC). In the present study, we investigated the anti-lung cancer effects of SEP and its underlying mechanism of action in both Lewis lung cancer (LLC)-bearing C57/BL6J mice and human NSCLC H460 bearing nude mice. Although SEP showed no inhibitory effects on tumor cells in vitro, it markedly stimulated the percentage of CD3-NK1.1(+) cells and natural killer (NK) cell cytotoxicity in the spleens of nude mice and C57/BL6J mice. In LLC-bearing mice, SEP not only inhibited tumor growth but also promoted NK mediated cytotoxicity, the NK1.1(+) cell population, and IL-2 and IFN-gamma secretion. SEP significantly suppressed H460 growth in nude mice, which was abrogated by the selective depletion of NK cells via the intraperitoneal injection of anti-asialo GM-1 antibodies. Furthermore, anti-TLR2/4 antibodies blocked both SEP and NK cell binding and SEP-induced perforin secretion. SEP induced proliferation and IFN-gamma secretion by NK cells in wild type mice were partially impaired in TLR2 or TLR4 knockout mice. These results suggest that SEP promoted NK cytotoxicity, which was partially mediated via TLR2 and TLR4, was the main contributing factor to lung cancer inhibition in vivo and that SEP may be a potential immunotherapy candidate for the treatment of lung cancer. PMID- 24630932 TI - Assent in research: the voices of adolescents. AB - PURPOSE: Adolescents join clinical research after investigators obtain their positive agreement or "assent." Although intended to respect adolescents, little is known about the views of adolescents or their parents regarding assent or research enrollment decisions. This study aimed to better understand perspectives of adolescent research participants and their parents about assent and parental permission. METHODS: Structured interviews were conducted with 13- through 17 year-old teens, enrolled in clinical research at the National Institutes of Health or Seattle Children's Hospital, and separately with one parent. RESULTS: One hundred and seventy-seven adolescent-parent pairs were interviewed. Teens were well distributed by age and gender, represented a wide variety of research and illnesses ranging in severity from mild to life threatening; 20% were healthy volunteers. Teens and parents were generally satisfied with the assent/permission process. Normally, they made the enrollment decision together and teens wanted parents' input and support. About 25% of teens reported pressure to enroll, not only from parents or relatives but also from doctors/nurses/research teams. Only 2% of teens preferred not to sign a consent form. CONCLUSIONS: Despite some differing views about how decisions should be made, the current assent/permission process is perceived as satisfactorily respectful by most teens in research. Many teens want to sign consent forms, and teens' signatures should generally be sought. Flexible guidance allows research teams and Institutional Review Boards to customize the assent process for teens in particular studies in order to facilitate an appropriate balance between giving teens a voice reflective of their emerging independence and enabling supportive collaboration with parents. PMID- 24630933 TI - Conversion factors for determining organ doses received by paediatric patients in high-resolution single slice computed tomography with narrow collimation. AB - Estimations of organ doses DT received during computed tomographic examinations are usually performed by applying conversion factors to basic dose indicators like the computed tomography dose index (CTDI) or the dose-length-product (DLP). In addition to the existing conversion factors for beam apertures of 5 mm or 10 mm, we present new DLP-DT conversion factors adapted to high-resolution CT (HRCT) examinations of infants and young children with beam apertures of the order of 1 mm and under consideration of bow tie filtration. Calculations are performed on mathematical MIRD phantoms for an age range from 0, 1, 5, 10, 15 up to (for comparison) 30 years by adapting PCXMC, a Monte Carlo algorithm originally developed by STUK (Helsinki, Finland) for dose reconstructions in projection radiography. For this purpose, each single slice CT examination is approximated by a series of corresponding virtual planar radiographies comprising all focus positions. The transformation of CT exposure parameters into exposure parameters of the series of corresponding planar radiographies is performed by a specially developed algorithm called XCT. The DLP values are evaluated using the EGSRay code. The new method is verified at a beam aperture of 10 mm by comparison with formerly published conversion factors. We show that the higher spatial resolution leads to an enhanced DLP-DT conversion factor if a small organ (e. g. thyroid gland, mammae, uterus, ovaries, testes) is exactly met by the chosen CT slice, while the conversion factor is drastically reduced if the chosen CT slice is positioned above or below the organ. This effect is utilized for dose-saving examinations with only a few single slices instead a full scan, which technique is applied in about 10% of all paediatric chest CT examinations. PMID- 24630935 TI - Capsaicin increases sensation of fullness in energy balance, and decreases desire to eat after dinner in negative energy balance. AB - Addition of capsaicin (CAPS) to the diet has been shown to increase satiety; therefore, CAPS is of interest for anti-obesity therapy. We investigated the effects of CAPS on appetite profile and ad libitum energy intake in relation to energy balance. Fifteen subjects (seven women and eight men, age: 29.7 +/- 10.8yrs, BMI: 23.3 +/- 2.9 kg/m(2)) underwent four conditions in a randomized crossover design in 36 hour sessions in a respiration chamber; they received 100% of their daily energy requirements in the conditions "100%Control" and "100%CAPS", and 75% of their daily energy requirements in the conditions "75%Control" and "75%CAPS", followed by an ad libitum dinner. In the 100%CAPS and 75%CAPS conditions, CAPS was given at a dose of 2.56 mg (1.03 g of red chili pepper, 39,050 Scoville heat units) with every meal. Satiety (P < 0.05) and fullness (P = 0.01) were measured every waking hour and before and after every meal using visual analogue scales, and were higher in the 100%CAPS versus 100%Control condition. After dinner desire to eat, satiety and fullness did not differ between 75%CAPS and 100%Control, while desire to eat was higher (P < 0.05) and satiety (P = 0.06) and fullness (P = 0.06) tended to be lower in the 75%Control versus 100%Control condition. Furthermore, ad libitum intake (P = 0.07) and overconsumption (P = 0.06) tended to decrease in 100%CAPS versus 100%Control. In energy balance, addition of capsaicin to the diet increases satiety and fullness, and tends to prevent overeating when food intake is ad libitum. After dinner, capsaicin prevents the effects of the negative energy balance on desire to eat. PMID- 24630934 TI - Parental role modeling of fruits and vegetables at meals and snacks is associated with children's adequate consumption. AB - Research has shown that parental role modeling of healthful eating behaviors is positively correlated to children's dietary intake and fruit and vegetable (F&V) preferences. The purpose of this study is to (1) examine associations between parent and child report of parental role modeling of F&V consumption at snacks and dinner and (2) determine whether parental role modeling is associated with children meeting daily F&V recommendations. Parent-child dyads (N = 160) participating in the HOME Plus study completed baseline surveys on parental role modeling of F&V at snacks and dinner. Children also completed 24-hour dietary recalls. Spearman correlations and chi-square/Fisher's exact tests were used to examine relationships between parent and child report of parental role modeling of F&V at snacks and dinner and whether children met daily recommendations. On average, children consumed less than three daily servings of F&V with only 23% consuming the recommended servings. Statistically significant correlations were seen between parent and child report of parental role modeling fruit at dinner and green salad at dinner. Children who reported parental role modeling of vegetables at snack and salad at dinner were significantly more likely, than those who did not, to meet daily F&V recommendations. Parents who reported role modeling fruit at snack were significantly more likely to have children who met daily F&V recommendations. Results indicate that children are aware of their parents' eating behaviors and on occasion report this behavior similarly to their parents. Parents should be encouraged to utilize the opportunity to role model healthful dietary intake, especially at snacks, where consumption of F&V appears low. PMID- 24630936 TI - Implicit affective associations predict snack choice for those with low, but not high levels of eating disorder symptomatology. AB - The central purpose of the current study was to examine whether eating disorder symptomatology moderates the extent to which implicitly and explicitly measured affective associations with fruits, or the feelings individuals associate with them, predict food choice. Participants (N = 107) completed both implicit and explicit measures of affective associations with fruits, a self-report of eating disorder symptomatology. In a subsequent snack selection task, they selected either a granola bar or fruit as a measure of their food choice behavior. Logistic regression analyses revealed that eating disorder symptomatology moderated the relation of implicit affective associations on behavior, OR = 0.27, p = .024, 95% CI (0.085, 0.84). A test of the simple effects indicated that implicit affective associations predicted snack choice at or below mean symptomatology levels [OR = 2.073, p = .02, 95% CI (1.12, 3.84)], but not at high levels [OR = 0.56, p = .28, 95% CI (0.18, 1.74)]. The effects of explicit measures on eating behavior were not moderated by eating disorder symptomatology (ps > .05). These findings advance our understanding of both the relation of implicit affective associations on behavior, as well as the ways in which eating disorder symptomatology may impact the decision-making process, thereby perpetuating disorder-related eating behavior. As such, they have implications for both health decision-making theory, as well as for the study and treatment of eating disorders. PMID- 24630937 TI - Factors influencing U.S. consumer support for genetic modification to prevent crop disease. AB - This study examines support for the genetic modification (GM) of crops in the context of preventing "late blight," a devastating potato and tomato disease that caused the Irish Potato Famine in the 1850s and results in substantial crop loss today. We surveyed U.S. adults who do the primary grocery shopping in their household (n = 859). Half of the respondents were randomly assigned to read a vignette describing late blight before responding to questions about GM, whereas the other half read a vignette about generic crop disease before responding to questions. We also examine how the perceived fairness of decision makers relates to GM support and the perceived legitimacy of GM decision making. We found that disease specificity mattered less to support and legitimacy than the perceived fairness of decision makers. The perceived risks of GM to human and environmental health negatively related to GM support and legitimacy, whereas the perceived benefits (e.g. reduced threats to crops and a more secure food supply) positively related to support and legitimacy. Objective knowledge about GM had a small, negative relationship with legitimacy whereas self-assessed familiarity with GM had a positive relationship. Overall, the results offer additional confirmation of past findings from more localized settings that perceived fairness of decision makers matters to support for GM and underscore the importance of considering how risk managers' behaviors and actions are perceived alongside individuals' perceptions about the risks and benefits. PMID- 24630938 TI - Differential influence of the 5-HTTLPR genotype, neuroticism and real-life acute stress exposure on appetite and energy intake. AB - Stress or negative mood often promotes energy intake and overeating. Since the serotonin transporter-linked polymorphic region (5-HTTLPR) is found to mediate stress vulnerability as well as to influence energy intake, this gene may also influence the negative effects of stress exposure on overeating. Moreover, since stress proneness also reflects cognitive stress vulnerability - as often defined by trait neuroticism - this may additionally predispose for stress-induced overeating. In the present study it was investigated whether the 5-HTTLPR genotype interacted with neuroticism on changes in mood, appetite and energy intake following exposure to a real-life academic examination stressor. In a balanced-experimental design, homozygous S-allele and L-allele carriers (N = 94) with the lowest and highest neuroticism scores were selected from a large database of 5-HTTLPR genotyped students. Mood, appetite and energy intake were measured before and after a 2-hour academic examination and compared with a control day. Examination influenced appetite for particular sweet snacks differently depending on 5-HTTLPR genotype and neuroticism. S/S compared with L/L subjects reported greater examination stress, and this was accompanied by a more profound post-stress increase in appetite for sweet snacks. Data also revealed a 5-HTTLPR genotype by trait neuroticism interaction on energy intake, regardless of examination. These results consolidate previous assumptions of 5-HTTLPR involvement in stress vulnerability and suggest 5-HTTLPR and neuroticism may influence stress-induced overeating depending on the type of food available. These findings furthermore link previous findings of increased risk for weight gain in S/S-allele carriers, particularly with high scores on trait neuroticism, to increased energy intake. PMID- 24630939 TI - Food addiction as a causal model of obesity. Effects on stigma, blame, and perceived psychopathology. AB - The present study examined the impact of the food-addiction model of obesity on weight stigma directed at obese people. Participants (n = 625) were randomly assigned to four experimental conditions. They were asked to read either a food addiction explanatory model of obesity or a nonaddiction model, and subsequently read a vignette describing a target person who met the characteristics of one of these models and was either obese or of normal weight. Questionnaires assessed participants' stigmatization and blame of targets and their attribution of psychopathology toward targets. Additional questionnaires assessed stigma and blame directed toward obese people generally, and personal fear of fat. A manipulation check revealed that the food-addiction experimental condition did significantly increase belief in the food-addiction model. Significant main effects for addiction showed that the food-addiction model produced less stigma, less blame, and lower perceived psychopathology attributed to the target described in vignettes, regardless of the target's weight. The food-addiction model also produced less blame toward obese people in general and less fear of fat. The present findings suggest that presenting obesity as an addiction does not increase weight bias and could even be helpful in reducing the widespread prejudice against obese people. PMID- 24630940 TI - Consumption of organic and functional food. A matter of well-being and health? AB - Health is an important motivation for the consumption of both organic and functional foods. The aim of this study was to clarify to what extent the consumption of organic and functional foods are characterized by a healthier lifestyle and a higher level of well-being. Moreover, the influence of social desirability on the respondents' response behavior was of interest and was also analyzed. Well-being and health was measured in a sample of 555 German consumers at two levels: the cognitive-emotional and the behavioral level. The results show that although health is an important aspect for both functional food and organic food consumption, these two forms of consumption were influenced by different understandings of health: organic food consumption is influenced by an overall holistic healthy lifestyle including a healthy diet and sport, while functional food consumption is characterized by small "adjustments" to lifestyle to enhance health and to increase psychological well-being. An overlap between the consumption of organic and functional food was also observed. This study provides information which enables a better characterization of the consumption of functional food and organic food in terms of well-being and health. PMID- 24630941 TI - Distal radius volar locking plate design and associated vulnerability of the flexor pollicis longus. AB - PURPOSE: Flexor pollicis longus (FPL) tendon rupture is a well-documented complication related to the use of distal radius volar locking plates (VLPs). The final common pathway of flexor tendon rupture appears to involve implants prominent at the watershed line. We hypothesized that significant differences in VLP prominence exist between various plate designs. METHODS: Ten fresh frozen specimens were dissected to identify the path of the FPL in relationship to the distal radius at the watershed line. Five VLP designs were fixed to each specimen based on their anatomic fit, and slid distally until the distal edge of the plate reached the watershed line. The position of each fixed plate was evaluated by fluoroscopy. We used a 3-dimensional laser scanner to create computer models. The total surface area of plate prominence volar to the watershed line and the prominent area beneath the FPL were measured in the axial plane using computer software. RESULTS: At the watershed line, the FPL was located at 54% of the maximal width of the radius, as measured from its volar-ulnar corner. There were no significant differences in the location of plate fixation on lateral view radiographs according to the classification of Soong et al. The mean total surface area of plate prominence was 36 mm(2). The mean prominent area beneath the FPL was 10 mm2. Significant differences in plate prominence were noted for various designs. CONCLUSIONS: Despite optimal plate placement, various VLP designs were observed to have prominent profiles volar to the watershed line, to varying extents. CLINICAL RELEVANCE: The results raise concerns regarding interference between all of the analyzed VLP designs and the FPL. This study may help guide both implant design considerations and assist the surgeon in better understanding implant morphology as it relates to iatrogenic flexor tendon injury. PMID- 24630942 TI - The effect of asymmetric core suture purchase on gap resistance of tendon repair in linear cyclic loading. AB - PURPOSE: To evaluate the biomechanical properties of an asymmetric core suture for tendon repair. METHODS: Sixty porcine flexor tendons were repaired with 3 different 4-strand sutures using different core suture purchases: 2 sets of identical purchases of 10 mm, 2 sets of asymmetric purchases (8 mm proximal/distal stump and 12 mm distal/proximal stump), and 2 sets of identical purchases of 12 mm. The tendons were subjected to the cyclic loading for 20 cycles. The number of tendons with gaps at each cycle, elongation of gap area between tendon ends and tendon segment, gap formation forces, and ultimate strengths were recorded. RESULTS: Tendons repaired with the asymmetric core suture purchases had the smallest gaps during cyclic loading. The elongation of gaps and tendon segments were significantly smaller than those with symmetric suture purchase of 10 or 12 mm. The asymmetric core suture repair had significant higher gap resistance forces than the symmetric suture repair at the final loading cycle. CONCLUSIONS: A 4-strand core suture repair with asymmetric purchases on the tendon stumps generated greater gapping resistance than that with an equal length of suture purchase. CLINICAL RELEVANCE: The asymmetric core suture purchase may be a practical measure to improve gapping resistance and fatigue strength when the suture purchase meets essential length requirements. PMID- 24630944 TI - Partial lacerations of peripheral nerves. PMID- 24630945 TI - Towards optimal clinical and epidemiological registration of haematological malignancies: Guidelines for recording progressions, transformations and multiple diagnoses. AB - Haematological malignancies (HM) represent over 6% of the total cancer incidence in Europe and affect all ages, ranging between 45% of all cancers in children and 7% in the elderly. Thirty per cent of childhood cancer deaths are due to HM, 8% in the elderly. Their registration presents specific challenges, mainly because HM may transform or progress in the course of the disease into other types of HM. In the context of cancer registration decisions have to be made about classifying subsequent notifications on the same patient as the same tumour (progression), a transformation or a new tumour registration. Allocation of incidence date and method of diagnosis must also be standardised. We developed European Network of Cancer Registries (ENCR) recommendations providing specific advice for cancer registries to use haematology and molecular laboratories as data sources, conserve the original date of incidence in case of change of diagnosis, make provision for recording both the original as well as transformed tumour and to apply precise rules for recording and counting multiple diagnoses. A reference table advising on codes which reflect a potential transformation or a new tumour is included. This work will help to improve comparability of data produced by population-based cancer registries, which are indispensable for aetiological research, health care planning and clinical research, an increasing important area with the application of targeted therapies. PMID- 24630946 TI - Inflammation goes with the flow: implications for non-invasive identification of high-risk plaque. PMID- 24630947 TI - Adherence to AASLD guidelines for the treatment of hepatocellular carcinoma in clinical practice: experience of the Bologna Liver Oncology Group. AB - BACKGROUND: Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. METHODS: 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005 2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. RESULTS: Early hepatocellular carcinomas were theoretically eligible for resection (n=27), liver transplantation (n=36), and percutaneous treatment (n=63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). CONCLUSION: Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were "under-treated" and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments. PMID- 24630949 TI - Acute Epstein-Barr virus pancreatitis with thoracic-abdominal abscess and portal compression. PMID- 24630948 TI - Influence of K-ras status and anti-tumour treatments on complications due to colorectal self-expandable metallic stents: a retrospective multicentre study. AB - BACKGROUND: This study aimed to explore the relationship between K-ras status, anti-tumour treatments, and the complications of colorectal self-expandable metallic stenting in colorectal cancer. METHODS: This is a retrospective, multicentre study of 91 patients with obstructive advanced colorectal cancer palliated with enteral stents between 2007 and 2011. RESULTS: K-ras wild-type tumours were diagnosed in 44 patients (48.4%); 82 (90.1%) received chemotherapy and 45 (49.4%) had additional biological therapy (34 bevacizumab, 11 cetuximab). Twenty-one (23.1%) experienced stent-related complications: 11 (52.4%) occurred in the K-ras mutant group (P=0.9). K-ras wild-type patients were not less likely to develop adverse events than K-ras mutant patients (OR, 0.99; 95% CI: 0.4-2.7). Overall mean time to complication was 167.6 days (range 4-720 days), with no difference between the two groups (141 vs. 197 days; P=0.5). Chemotherapy did not influence the risk of complications (OR, 0.56; 95% CI: 0.14-2.9), and there was no evidence that patients treated with chemotherapy and cetuximab were more likely to experience stent-related complications than patients treated with chemotherapy alone, or untreated (OR, 1.2; 95% CI: 0.2-5.9). Although perforation rates were higher with bevacizumab-based treatment (11.8% vs. 7%), this result was not statistically significant (P=0.69). CONCLUSIONS: K-ras mutation status, chemotherapy, and biological treatments should not influence colorectal stent related complication rates. PMID- 24630950 TI - Electrophysiological and metabolic effects of CHF5074 in the hippocampus: protection against in vitro ischemia. AB - CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia. PMID- 24630951 TI - Climate change impacts on mass movements--case studies from the European Alps. AB - This paper addresses the current knowledge on climate change impacts on mass movement activity in mountain environments by illustrating characteristic cases of debris flows, rock slope failures and landslides from the French, Italian, and Swiss Alps. It is expected that events are likely to occur less frequently during summer, whereas the anticipated increase of rainfall in spring and fall could likely alter debris-flow activity during the shoulder seasons (March, April, November, and December). The magnitude of debris flows could become larger due to larger amounts of sediment delivered to the channels and as a result of the predicted increase in heavy precipitation events. At the same time, however, debris-flow volumes in high-mountain areas will depend chiefly on the stability and/or movement rates of permafrost bodies, and destabilized rock glaciers could lead to debris flows without historic precedents in the future. The frequency of rock slope failures is likely to increase, as excessively warm air temperatures, glacier shrinkage, as well as permafrost warming and thawing will affect and reduce rock slope stability in the direction that adversely affects rock slope stability. Changes in landslide activity in the French and Western Italian Alps will likely depend on differences in elevation. Above 1500 m asl, the projected decrease in snow season duration in future winters and springs will likely affect the frequency, number and seasonality of landslide reactivations. In Piemonte, for instance, 21st century landslides have been demonstrated to occur more frequently in early spring and to be triggered by moderate rainfalls, but also to occur in smaller numbers. On the contrary, and in line with recent observations, events in autumn, characterized by a large spatial density of landslide occurrences might become more scarce in the Piemonte region. PMID- 24630952 TI - Advances in swine immunology help move vaccine technology forward. AB - In veterinary animal species, vaccines are the primary tool for disease prevention, a key tool for treatment of infection, and essential for helping maintain animal welfare and productivity. Traditional vaccine development by trial-and-error has achieved many successes. However, effective vaccines that provide solid cross-protective immunity with excellent safety are still needed for many diseases. The path to development of vaccines against difficult pathogens requires recognition of uniquely evolved immunological interactions of individual animal hosts and their specific pathogens. Here, general principles that currently guide veterinary immunology and vaccinology research are reviewed, with an emphasis on examples from swine. Advances in genomics and proteomics now provide the community with powerful tools for elucidation of regulatory and effector mechanisms of protective immunity that provide new opportunities for successful translation of immunological discoveries into safe and effective vaccines. PMID- 24630953 TI - Analysis of a potential cluster of rhinovirus infections in patients and staff on two haemato-oncology wards. AB - BACKGROUND: Human rhinoviruses (HRV) cause the common cold, increased mortality in patients attending elderly care facilities and significant morbidity as well as mortality in the post-transplantation setting. OBJECTIVES: The aim of the study was to determine if there had been a breakdown in infection control practice in a large haemato-oncology centre. Molecular techniques had detected increased numbers of HRV in respiratory samples from patients and staff over a 6 week period. Typing was performed to investigate the possibility of transmission between individuals. STUDY DESIGN: This was a retrospective study having detected HRV RNA in combined nose and throat swab samples that were collected from 13 individuals: 8 patients and 5 staff members, in the haemato-oncology wards of a tertiary referral centre in January and February 2011. The 5'NTR and the VP4/VP2 region were used for HRV typing. RESULTS: All 3 HRV species were detected with 7 HRV-A, 1 HRV-B, 4 HRV-C and 1 untyped. None of the individuals were infected by the same HRV serotype. Three individuals had multiple samples collected: 1 patient had an HRV-B infection over a 4-week period, 1 patient had an HRV-A infection over 3 months and 1 staff member had an HRV-C infection over 1 week, each shedding an unchanged serotype throughout the whole period. CONCLUSION: Nucleotide sequence analysis confirmed that there was no breakdown in infection control measures. No transmission incidents had occurred between patients and/or between staff and patients. PMID- 24630954 TI - Merkel cell carcinoma arising in inguinal lymph node in a patient with von Willebrand disease after multiple blood transfusions. AB - Merkel cell carcinoma (MCC) is an uncommon neuroendocrine tumour of the skin; rare cases have been reported within the lymph nodes without a primary site. The detection of Merkel cell polyomavirus (MCPyV) DNA, integrated within the genome of MCC, suggests its role for the onset of this tumour. We report a case of MCC in an inguinal lymph node of a patient with Von Willebrand disease (VWD), who underwent multiple blood transfusions following haemorrhoidectomy. The diagnosis was performed on the bases of morphology and immunohistochemistry; genomic sequences of LT and VP1 regions of MCPyV were amplified from MCC using a quantitative polymerase chain reaction (qPCR) assay. High levels of MCPyV antibodies were detected in the patient's serum by ELISA method. We discuss the role of MCPyV in the development of this tumour, the use of viral DNA detection for confirming the diagnosis of MCC in unusual sites and the possibility of MCPyV transmission from blood donors. PMID- 24630955 TI - Serum calcium level used as a prognostic predictor in patients with resectable pancreatic ductal adenocarcinoma. AB - BACKGROUND AND OBJECTIVE: There is a relative scarcity of reports to evaluate the associations between serum calcium level and the prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to determine whether serum calcium level is a significant predictor for survival in PDAC patients. METHODS: This is a retrospective cohort study. The clinicopathological characteristics, preoperative serum calcium levels and the survival data of 114 patients who underwent surgery for PDAC between January 1, 2009 and January 31, 2012 were collected. The associations between serum calcium level and overall survival were evaluated using the multivariate Cox proportional hazards model. RESULTS: The median age of the patients was 60 years, and 64 (56.1%) of them were male. Eighty-one cases (71.1%) were dead at the last follow up. Forty-four patients (38.6%) died within the first year after surgery. The receiver operating characteristics (ROC) curve indicated a significant result for serum calcium level in predicting one-year death after surgery [area under the curve (AUC), 0.629; 95% CI 0.527-0.730, P=0.021]. In multivariate analysis, higher serum calcium levels [hazard ratio (HR), 1.922; P=0.036], diabetes (HR, 1.820; P=0.017), histologically poorly-differentiated tumor (HR, 3.342; P=0.001) and vessel invasion (HR, 1.729; P=0.023) were independent predictors of poor prognosis. Similarly, the albumin-adjusted albumin level was also an independent prognostic factor. CONCLUSIONS: The higher serum calcium level is associated with poor prognosis in patients with resectable PDAC and the level of serum calcium can predict death within one year after surgery. PMID- 24630956 TI - Is quadriceps tendon a better graft choice than patellar tendon? a prospective randomized study. AB - PURPOSE: The purpose of this randomized controlled study was to compare knee stability, kneeling pain, harvest site pain, sensitivity loss, and subjective clinical outcome after primary anterior cruciate ligament (ACL) reconstruction with either bone-patellar tendon-bone (BPTB) or quadriceps tendon-bone (QTB) autografts in a noninferiority study design. METHODS: From 2005 to 2009, a total of 51 patients were included in the present study. Inclusion criteria were isolated ACL injuries in adults. Twenty-five patients were randomized to BPTB grafts and 26 to QTB grafts. An independent examiner performed follow-up evaluations 1 and 2 years postoperatively. Anteroposterior knee laxity was measured with a KT-1000 arthrometer (MEDmetric, San Diego, CA). Anterior knee pain was assessed clinically and by knee-walking ability. Knee Injury and Osteoarthritis Outcome Score (KOOS) and subjective International Knee Documentation Committee (IKDC) score were used for patient-evaluated outcome. RESULTS: Anterior knee laxity was equal between the 2 groups with KT-1000 values of 1.1 +/- 1.4 mm and 0.8 +/- 1.7 mm standard deviation (SD) at follow-up in QTB and BPTB groups, respectively (P = .65), whereas positive pivot shift test results were seen less frequently (14% compared with 38%, respectively; P = .03). Anterior kneeling pain, evaluated by the knee walking ability test, was significantly less in the QTB group, with only 7% of patients grading knee walking as difficult or impossible compared with 34% in the BPTB group. At 1 and 2 years' follow-up, there was no difference between the 2 groups in subjective patient-evaluated outcome. The IKDC score was 75 +/- 13 patients and 76 +/- 16 SD at 1-year follow-up in QTB and BPTB groups, respectively (P = .78). At 2 years, 12 patients were lost to follow-up, resulting in 18 in the BPTB group and 21 in the QTB group. CONCLUSIONS: The use of the QTB graft results in less kneeling pain, graft site pain, and sensitivity loss than seen with BPTB grafts; however, similar anterior knee stability and subjective outcomes are seen. The results of this study show that QTB is a viable option for ACL reconstruction. LEVEL OF EVIDENCE: Level II, randomized controlled clinical trial. PMID- 24630957 TI - Complete Fatty infiltration of intact rotator cuffs caused by suprascapular neuropathy. AB - Suprascapular neuropathy is generally considered to be a diagnosis of exclusion, although it has been described in association with several activities and conditions. To our knowledge, this is the first description of suprascapular neuropathy with complete neurogenic fatty replacement in patients with intact rotator cuff tendons in the absence of traction or compression mechanisms. We present 4 cases of patients who presented with complete fatty infiltration of the supraspinatus (1 patient), infraspinatus (2 patients), and both (1 patient) resulting from suprascapular neuropathy. Each of these patients underwent arthroscopic suprascapular nerve decompression and subsequently had immediate improvement in pain and subjective shoulder value. PMID- 24630958 TI - Clinical outcome and repair integrity after rotator cuff repair in patients older than 70 years versus patients younger than 70 years. AB - PURPOSE: The purpose of this study was to evaluate and compare the clinical and structural outcomes of rotator cuff repairs in patients older than 70 years and those younger than 70 years and to analyze a correlation between patient factors and retear rate. METHODS: Two hundred thirty-eight patients between the ages of 60 and 79 who underwent rotator cuff repair between 2006 and 2011 and were available for postoperative magnetic resonance imaging (MRI) evaluation at least 6 months after surgery were enrolled in this study. They were divided into 2 groups, one group (n = 191) included patients aged between 60 and 69 years, and the other group (n = 47) included patients aged between 70 and 79 years. The mean follow-up period was 14.6 months (range, 12-63 months) and 13.2 months (range, 12 62 months) for patients in their 60s and 70s, respectively. RESULTS: The mean visual analog scale (VAS), University of California Los Angeles (UCLA), and Constant scores significantly improved from 5.4, 18.1, and 57.4 preoperatively to 1.0, 31.2, and 75.0 at the final follow-up, respectively (P < .001), in the 60s group and from 5.9, 17.0, and 53.6 to 1.3, 30.1, and 72.7, respectively (P < .001), in the 70s group. There were no significant differences between the 2 groups (P > .05). Instead, intraoperative tear size was correlated with the clinical scores with Pearson correlation coefficients of -0.161 and -0.211 for patients in their 60s and 70s, respectively. There were 76 (39.8%) retears among patients in their 60s and 24 (51.1%) retears among patients in their 70s, with no significant difference between the 2 groups (P = .161). The retear rate increased significantly with increasing preoperative tear size (P < .001; odds ratio [OR], 7.1 in large tears; P < .0001; OR, 17.2 in massive tears). Age and sex were not significantly correlated with the retear rate. CONCLUSIONS: Both patients in their 60s and 70s showed significant improvement in clinical outcomes after rotator cuff repair, without a significant difference between the 2 populations. The retear rate increased significantly with increasing intraoperative tear size but not with increasing age. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 24630960 TI - Molecular characterization and differential expression of the myostatin gene in Coilia nasus. AB - Estuarine tapertail anchovy (Coilia nasus, junior synonym C. ectenes) is a widely distributed and commercially important aquaculture species, although its growth in aquaculture settings is so slow as to pose a serious practical problem. In order to understand the molecular mechanisms of growth, we cloned the myostatin gene in C. nasus (CnMSTN) by homologous cloning methods. Its full-length cDNA is 2252 bp, with a 1125-bp open reading frame (ORF) that encodes a 374-amino acid protein. The CnMSTN protein is predicted to contain domains typical of MSTN, including a TGFb-propeptide domain and a TGFB domain. Gene expression patterns were detected by RT-qPCR. CnMSTN is expressed strongly in the muscle and brain, and comparatively lower in the gills, liver, spleen, intestine, trunk kidney and head kidney. The effects of stress on the muscle and brain MSTN levels were evaluated by RT-qPCR. CnMSTN in the muscle was positively regulated by loading and transport stress, but brain CnMSTN expression was not affected. We found NaCl could reduce the death rate caused by loading and transporting stress, and in this group, CnMSTN mRNA expression in the muscle revealed increased, but decreased in the brain. Further, in the fasting experiment, the CnMSTN mRNA revealed decrease in the muscle, on the contrary, it showed increase in the brain. Selection upon variants of the MSTN gene has shown great potential in breeding work for mammals, and our results provide the basic knowledge for breeding of C. nasus. PMID- 24630959 TI - Generation and analysis of a large-scale expressed sequence tags from a full length enriched cDNA library of Siberian tiger (Panthera tigris altaica). AB - In this study, a full-length enriched cDNA library was successfully constructed from Siberian tiger, the world's most endangered species. The titers of primary and amplified libraries were 1.28*10(6)pfu/mL and 1.59*10(10)pfu/mL respectively. The proportion of recombinants from unamplified library was 91.3% and the average length of exogenous inserts was 1.06kb. A total of 279 individual ESTs with sizes ranging from 316 to 1258bps were then analyzed. Furthermore, 204 unigenes were successfully annotated and involved in 49 functions of the GO classification, cell (175, 85.5%), cellular process (165, 80.9%), and binding (152, 74.5%) are the dominant terms. 198 unigenes were assigned to 156 KEGG pathways, and the pathways with the most representation are metabolic pathways (18, 9.1%). The proportion pattern of each COG subcategory was similar among Panthera tigris altaica, P. tigris tigris and Homo sapiens, and general function prediction only cluster (44, 15.8%) represents the largest group, followed by translation, ribosomal structure and biogenesis (33, 11.8%), replication, recombination and repair (24, 8.6%), and only 7.2% ESTs classified as novel genes. Moreover, the recombinant plasmid pET32a-TAT-COL6A2 was constructed, coded for the Trx-TAT COL6A2 fusion protein with two 6* His-tags in N and C-terminal. After BCA assay, the concentration of soluble Trx-TAT-COL6A2 recombinant protein was 2.64+/ 0.18mg/mL. This library will provide a useful platform for the functional genome and transcriptome research of for the P. tigris and other felid animals in the future. PMID- 24630961 TI - Identification and characterization of Tube in the Chinese mitten crab Eriocheir sinensis. AB - As a key component of the Toll signaling pathway, Tube plays central roles in many biological activities, such as survival, development and innate immunity. Tube has been found in shrimps, but has not yet been reported in the crustacean, Eriocheir sinensis. In this study, we cloned the full-length cDNA of the adaptor Tube for the first time from E. sinensis and designated the gene as EsTube. The full-length cDNA of EsTube was 2247-bp with a 1539-bp open reading frame (ORF) encoding a 512-amino acid protein. The protein contained a 116-residue death domain (DD) at its N-terminus and a 272-residue serine/threonine-protein kinase domain (S_TKc) at its C-terminus. Phylogenetic analysis clustered EsTube initially in one group with other invertebrate Tube and Tube-like proteins, and then with the vertebrate IRAK-4 proteins, finally with other invertebrate Pelle proteins. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis results showed that EsTube was highly expressed in the ovary and testis, and moderately expressed in the thoracic ganglia and stomach. EsTube was expressed at all selected stages and was highly expressed in the spermatid stage (October, testis) and the stage III-2 (November, ovary). EsTube was differentially induced after injection of lipopolysaccharides (LPS), peptidoglycan (PG) or zymosan (beta 1,3-glucan). Our study indicated that EsTube might possess multiple functions in immunity and development in E. sinensis. PMID- 24630962 TI - Genomic analysis of the aconidial and high-performance protein producer, industrially relevant Aspergillus niger SH2 strain. AB - Aspergillus niger is usually regarded as a beneficial species widely used in biotechnological industry. Obtaining the genome sequence of the widely used aconidial A. niger SH2 strain is of great importance to understand its unusual production capability. In this study we assembled a high-quality genome sequence of A. niger SH2 with approximately 11,517 ORFs. Relatively high proportion of genes enriched for protein expression related FunCat items verify its efficient capacity in protein production. Furthermore, genome-wide comparative analysis between A. niger SH2 and CBS513.88 reveals insights into unique properties of A. niger SH2. A. niger SH2 lacks the gene related with the initiation of asexual sporulation (PrpA), leading to its distinct aconidial phenotype. Frame shift mutations and non-synonymous SNPs in genes of cell wall integrity signaling, beta 1,3-glucan synthesis and chitin synthesis influence its cell wall development which is important for its hyphal fragmentation during industrial high-efficiency protein production. PMID- 24630963 TI - Dietary vitamin E affects alpha-TTP mRNA levels in different tissues of the Tan sheep. AB - The alpha-tocopherol transfer protein (alpha-TTP) is a ~32kDa cytosolic protein that plays an important role in the efficient circulation of plasma alpha tocopherol in the body, a factor with great relevance in reproduction. The alpha TTP gene has been studied in a number of tissues; however, its expression and function in some ovine tissues remain unclear. A previous study from our laboratory has demonstrated alpha-TTP expression in sheep liver. In the present study we determined whether alpha-TTP is expressed in non-liver tissues and investigated the effects of dietary vitamin E on the alpha-TTP mRNA levels. Thirty-five male Tan sheep with similar body weight were randomly allocated into five groups and supplemented 0, 20, 100, 200 and 2000IUsheep(-1)day(-1) vitamin E, for four months, respectively. At the end of the study, the animals were slaughtered and tissue samples from the heart, spleen, lung, kidney, longissimus dorsi muscle and gluteus muscle were immediately collected. We found that the alpha-TTP gene is expressed in sheep tissues other than the liver. Moreover, dietary vitamin E levels had influenced the expression levels of alpha-TTP gene in these tissues in a tissue-specific way. The technique of immunohistochemistry was used to detect alpha-TTP in tissues of the heart, spleen, lung, and kidney and we found that alpha-TTP was mainly located in the cytoplasm while no alpha TTP immunoreactivity was detected in the cytoplasm of longissimus dorsi and gluteus muscle samples. Importantly, our findings lay the foundation for additional experiments focusing on the absorption and metabolism of vitamin E in tissues other than the liver. PMID- 24630964 TI - Integration of gene expression data with network-based analysis to identify signaling and metabolic pathways regulated during the development of osteoarthritis. AB - Osteoarthritis (OA) is characterized by remodeling and degradation of joint tissues. Microarray studies have led to a better understanding of the molecular changes that occur in tissues affected by conditions such as OA; however, such analyses are limited to the identification of a list of genes with altered transcript expression, usually at a single time point during disease progression. While these lists have identified many novel genes that are altered during the disease process, they are unable to identify perturbed relationships between genes and gene products. In this work, we have integrated a time course gene expression dataset with network analysis to gain a better systems level understanding of the early events that occur during the development of OA in a mouse model. The subnetworks that were enriched at one or more of the time points examined (2, 4, 8, and 16 weeks after induction of OA) contained genes from several pathways proposed to be important to the OA process, including the extracellular matrix-receptor interaction and the focal adhesion pathways and the Wnt, Hedgehog and TGF-beta signaling pathways. The genes within the subnetworks were most active at the 2 and 4 week time points and included genes not previously studied in the OA process. A unique pathway, riboflavin metabolism, was active at the 4 week time point. These results suggest that the incorporation of network-type analyses along with time series microarray data will lead to advancements in our understanding of complex diseases such as OA at a systems level, and may provide novel insights into the pathways and processes involved in disease pathogenesis. PMID- 24630965 TI - Lentivirus-mediated RNAi knockdown of LMP2A inhibits the growth of nasopharyngeal carcinoma cell line C666-1 in vitro. AB - Latent membrane protein 2A (LMP2A) is found to play a key role in the development of nasopharyngeal carcinoma (NPC). However, the role of LMP2A silencing in the inhibition of cell growth of NPC has not been clarified. In this study, we inhibited LMP2A gene expression by lentivirus-mediated RNAi, to explore the effects of LMP2A silencing on the growth of NPC cell line in vitro. A lentivirus mediated RNAi technology was employed to specifically knock down the LMP2A gene in NPC cell line C666-1. Quantitative real-time polymerase chain reaction, Western blot, flow cytometry and colony formation assays were performed to evaluate the expression of LMP2A and biological behavior of cell line C666-1 in vitro. We successfully construct a highly efficient and stable lentivirus vector, which efficiently downregulate the expression of LMP2A gene in infected cell line C666-1. Down-regulation of the expression of LMP2A significantly inhibits the proliferation and colony formation of C666-1 cells. In addition, the specific down-regulation of LMP2A arrests cells in G0/G1 phase of cell cycle and increases apoptosis rate. Our findings suggest that lentivirus-mediated RNAi knockdown of LMP2A inhibits the growth of NPC cell line C666-1 in vitro, and LMP2A may be a potential target for gene therapy in treatment of NPC. PMID- 24630966 TI - MicroRNA-145: a promising biomarker for hepatocellular carcinoma (HCC). AB - It has been demonstrated that microRNA-145 (miR-145) is downregulated in patients with hepatocellular carcinoma (HCC) compared with healthy controls. The mechanisms for miR-145 in HCC will become potential in future researches. PMID- 24630967 TI - Decreased telomere length in metaphase and interphase cells from newborns with trisomy 21. PMID- 24630968 TI - Rapid quantitative detection of Human immunodeficiency virus type 1 by a reverse transcription-loop-mediated isothermal amplification assay. AB - Accurate and rapid quantitation of Human immunodeficiency virus type 1 (HIV-1) RNA levels is a critical aspect in estimating the effect of antiviral therapy and establishing therapeutic schedule. Thus, for the first time, a rapid quantitative reverse transcription-loop-mediated isothermal amplification (RT-LAMP) was designed to quantitate HIV-1 RNA. The results showed that the dynamic range was from 2.5*10(2) to 10(7) copies with a coefficient of determination (R(2)) of 0.991, and the limit of detection of RT-LAMP by Probit analysis at the 95% detection level was 196 copies. The intra-assay coefficient of variation (CV) ranged from 0.67% to 2.08% at 10(7) copies and 7.25% to 12.97% at 250 copies. The CVs of inter-assay were 2.39% and 13.93% for the high and low copy numbers, respectively. No cross-reaction with Human immunodeficiency virus type 2 (HIV-2), Human T lymphotrophic virus type 1 (HTLV-1) and Hepatitis C virus (HCV) was observed and a good agreement between the RT-LAMP method and the real-time reverse transcription-polymerase chain reaction (qRT-PCR) test was achieved. This proposed RT-LAMP method could be useful for rapid diagnosis of high risk group and pharmacodynamic assessment of anti-HIV drug, especially in less-equipped laboratories of impoverished areas. PMID- 24630969 TI - Protective effect of tea polyphenols on renal ischemia/reperfusion injury via suppressing the activation of TLR4/NF-kappaB p65 signal pathway. AB - Tea polyphenols (TP) was investigated in rats for its protective effect on renal ischemia/reperfusion injury (RIRI). Rats were randomized into groups as follows: (I) sham group (n=10); (II) RIRI group (n=10); (III) RIRI+TP (100mg/kg) group (n=5); (IV) RIRI+TP (200mg/kg) group (n=5); (V) RIRI+TP+ Astragalus mongholicus aqueous extract (AMAE) (300 mg/kg+100mg/kg) group (n=5). For the IRI+TP groups, rats were orally given with tea polyphenols (100, 200 and 300 mg/kg body weight) once daily 10 days before induction of ischemia, followed by renal IRI. For the sham group and RIRI group, rats were orally given with equal volume of saline once daily 10 days before induction of ischemia, followed by renal IRI. Results showed that tea polyphenol pretreatment significantly suppressed ROS level and MDA release. On the other hand, in rats subjected to ischemia-reperfusion, the activities of endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSH Px) showed recovery, whereas the levels of urea nitrogen and serum creatinine were reduced by administration of tea polyphenols orally for 10 days prior to ischemia-reperfusion. Moreover, tea polyphenol pretreatment significantly decreased TLR4 and NF-kappaB p65 protein expression levels in RIRI rats. At the same time, tea polyphenol pretreatment attenuated the increased level of serum IL 1beta, IL-6, ICAM-1 and TNF-alpha, and enhanced IL-10 production in RIRI rats. Furthermore, tea polyphenol pretreatment significantly decreased renal epithelial tubular cell apoptosis induced by renal ischemia/reperfusion, alleviating renal ischemia/reperfusion injury. These results cumulatively indicate that tea polyphenol pretreatment could suppress the TLR4/NF-kappaB p65 signaling pathway, protecting renal tubular epithelial cells against ischemia/reperfusion-induced apoptosis, which implies that antioxidants may be a potential and effective agent for prevention of the ischemic/reperfusion injury through the suppression extrinsic apoptotic signal pathway induced by TLR4/NF-kappaB p65 signal pathway. Moreover, supplement of AMAE can increased renal protection effect of TP. PMID- 24630970 TI - Core promoter regulates the expression of cathepsin B gene in the fat body of Bombyx mori. AB - Bombyx mori cathepsin B (BmCatB) is involved in the programmed cell death of the fat body during B. mori metamorphosis. For a better understanding of the functional regulatory mechanism, the promoter region of BmCatB in the transcriptional regulation has been identified and analyzed in the present study. BmCatB promoter region performed by the 5' truncation or mutagenesis of EcREs was inserted in the pFA3Luc-A3RL double fluorescence expression vector to activate the fireflies luciferase (FLuc) gene. The results indicated that the dual luciferase activity of BmCatB gene in the silkworm larval fat body is regulated by the length of promoter. Site-directed mutagenesis of EcRE experiment has shown that the EcREs are up-regulated significantly in the regulation of the BmCatB promoter. A 142bp region (-1165 to -1023) and EcREs are the mainly fat-body tissue-specificity related region and could function as a core promoter element. PMID- 24630971 TI - Dispositional optimism. AB - Optimism is a cognitive construct (expectancies regarding future outcomes) that also relates to motivation: optimistic people exert effort, whereas pessimistic people disengage from effort. Study of optimism began largely in health contexts, finding positive associations between optimism and markers of better psychological and physical health. Physical health effects likely occur through differences in both health-promoting behaviors and physiological concomitants of coping. Recently, the scientific study of optimism has extended to the realm of social relations: new evidence indicates that optimists have better social connections, partly because they work harder at them. In this review, we examine the myriad ways this trait can benefit an individual, and our current understanding of the biological basis of optimism. PMID- 24630973 TI - Analysis of interaction of phenolic compounds with the cholecystokinin signaling pathway to explain effects on reducing food intake. AB - Previous animal experiments demonstrated that phenolic compounds can reduce weight and food intake, but the exact mechanism(s) behind these effects remain unknown. For regulation of food intake, the cholecystokinin (CCK) hormone signaling pathway plays an important role as it induces satiety by binding on its specific receptor (CCK1R), hereby reducing food intake. In this study, we investigated the possible interactions of eight phenolic compounds of different classes (tannic acid, gallic acid, benzoic acid, hydroxybenzoic acid, protocatechuic acid, quercetin, kaempferol and resveratrol) with the CCK1R signaling pathway. As major results, the tested phenolic compounds could not activate the CCK1R in a specific cell-based bioassay. In contrast, we observed an anti-CCK1R activity. This antagonistic action might be explained by blocking of the functioning of the CCK1R receptor, although the exact mechanism of interaction remains unknown. For tannic acid, we also measured a sequestration activity of the CCK hormone in vitro. In conclusion, the reported activity of phenolic compounds against food intake and weight is not based on an activation of the CCK1R. Taking into account the complex regulation of food intake, further work is necessary to unravel other essential mechanisms involved to explain the reported effects of phenolic compounds against food intake. PMID- 24630972 TI - Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. AB - Amyloid-beta (Abeta) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by beta (Bace1) and gamma-secretases. The accumulation and aggregation of Abeta as amyloid plaques is the hallmark pathology of Alzheimer's disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Abeta after injury is not well understood, several studies have reported a negative correlation between Abeta formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and gamma-secretase), and Abeta are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Abeta after SCI, we reduced or inhibited Abeta in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for Abeta after SCI. PMID- 24630974 TI - Protective effect of oxytocin on ovarian ischemia-reperfusion injury in rats. AB - Oxytocin (OT), a neurohypophysial nonapeptide, plays dual role as a neurotransmitter/neuromodulator and a hormone. It has also well known protective properties against ischemia/reperfusion organ damage. This study investigated the effect of OT on experimentally induced ovarian torsion/de-torsion ischemia/reperfusion (I/R) injury in rats. Sprague-Dawley rats were assigned to five treatment groups (n=7/group): Group 1, sham-operated; Group 2, torsion; Group 3, 80 IU/kg of OT administration 30 min prior to torsion; Group 4, torsion/de-torsion; and Group 5, torsion followed by 80 IU/kg of OT administration 30 min prior to de-torsion. OT administration significantly decreased the tissue malondialdehyde (MDA) levels in both the torsion and OT group (Group 3), and torsion/de-torsion OT group (Group 5) in comparison with the torsion-only group (Group 2) and torsion/de-torsion group (Group 4). Histopathological finding scores including follicular degeneration, edema, hemorrhage, vascular congestion, and infiltration by inflammatory cells were found to be significantly decreased in the torsion and OT group (Group 3), and torsion/de-torsion OT group (Group 5) when compared with the torsion-only group (Group 2) and torsion/de-torsion group (Group 4). In conclusion, these results, verified with histopathologic evaluation and biochemical assays, suggest a probable protective role for OT in ischemia and I/R injury in rat ovaries. PMID- 24630975 TI - 9-Hydroxy-6,7-dimethoxydalbergiquinol inhibits osteoclast differentiation through down-regulation of Akt, c-Fos and NFATc1. AB - Recently, natural plant-derived products have been recognized as one of the main sources for drug discovery and development in human disease. 9-Hydroxy-6,7 dimethoxydalbergiquinol (HDDQ) isolated from the heart wood of Dalbergia odorifera is widely used in oriental medicine, however, the pharmacological effect of HDDQ in osteoclast-associated diseases remains unknown. In this study, HDDQ dose-dependently inhibited the early stage of RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without cytotoxicity. HDDQ strongly inhibited Akt phosphorylation in RANKL-stimulated BMMs and did not show any effects on p38, JNK, and IkappaB phosphorylation and IkappaB degradation. Interestingly, we found that HDDQ down-regulated the induction by RANKL of c-Fos protein by suppressing its translation. Also, ectopic overexpression of c-Fos and NFATc1 rescued the inhibition of osteoclast differentiation by HDDQ. Furthermore, the Akt/c-Fos/NFATc1-regulated expression of genes required for osteoclastogenesis, such as OSCAR and TRAP, was inhibited by HDDQ. These findings suggest that HDDQ prevents osteoclast differentiation via down-regulation of Akt, c-Fos, and NFATc1 signaling molecules, suggesting a potential therapeutic value of HDDQ for bone disorders associated with increased bone resorption. PMID- 24630976 TI - Primary aldosteronism and essential hypertension: assessment of cardiovascular risk at diagnosis and after treatment. AB - BACKGROUND AND AIMS: Primary aldosteronism (PA), the most frequent form of secondary hypertension, is characterized by a higher rate of cardiovascular (CV) events than essential hypertension (EH). Aim of the study was to evaluate the cardiovascular risk according to the ESH/ESC 2007 guidelines, in patients with PA and with EH, at diagnosis and after treatment. METHODS AND RESULTS: We prospectively studied 102 PA patients (40 with aldosterone producing adenoma-APA and 62 with idiopathic hyperaldosteronism-IHA) and 132 essential hypertensives at basal and after surgical or medical treatment (mean follow-up period 44 months for PA and 42 months for EH). At baseline evaluation the stratification of CV risk was significantly different: the predominant risk category was the high CV risk (50% in total PA, 53% in PA matched for blood pressure values and 55% in EH), but the very high risk category was twice in PA than in EH patients (36% in total PA and 33% in matched PA vs. 17% in EH, p < 0.05). The worse risk profile of PA was due to a higher prevalence of glycemic alterations, metabolic syndrome and left ventricular hypertrophy (LVH) (p < 0.05). After adequate treatment, the CV risk was significantly reduced becoming comparable in PA and in EH patient due to a reduction of hypertension grading, prevalence of metabolic syndrome, hypertension persistence and LVH (p < 0.05). CONCLUSION: Patients with PA present a high CV risk, which is in part reversible after specific treatment, due both to the reduced blood pressure values and to the improvement of end-organ damage. PMID- 24630977 TI - Microbore liquid chromatography ultraviolet detection for quantification of total peptide amount and its application for assessing sample quality in shotgun proteome analysis of hundreds of cells. AB - Mass spectrometric profiling of the proteome of a small number of cells requires not only a sensitive instrument for protein/peptide separation and detection, but also a robust sample preparation protocol to process a very small amount of proteins (<1MUg) present in few cells. We have developed and evaluated the performance of a microbore liquid chromatography (LC) UV detection system for quantifying the total amount of peptides in a shotgun proteome analysis workflow that is tailored for the analysis of hundreds of cancer cells. Upon the sample injection into a 1-mm-diameter reversed phase column, a step-gradient was used to first remove salts and other impurities and then elute the peptides quickly without much separation. The UV absorbance of eluted peptides at 214nm was used for peptide quantification with the aid of a calibration curve of a tryptic digest of a mixture of four standard proteins. Two linear calibration regions could be obtained in the peptide amount ranging from 0.03MUg to 0.3MUg and from 0.6MUg to 5MUg. The limit of quantification (LOQ) was determined to be 30ng (or 39ng in the linear calibration range). However, the presence of background proteins, mainly keratins, introduced during the sample preparation process was found to be the limiting factor in quantifying a lower amount of peptides from a cell lysate digest. With background absorbance from the digest of contaminant proteins in a solution, the LOQ was found to be 200ng. This nondestructive microbore LC-UV method should be useful in assessing sample quality during the development and applications of an efficient sample preparation method for proteome analysis of a small number of cells. As an example, this method was used for quantifying the peptides generated from breast cancer MCF-7 cell extracts with a limited number of cells: 250, 500 and 1000 cells. Using capillary LC quadrupole time-of-flight mass spectrometry, 81-126, 122-154 and 256-282 proteins could be identified from 250, 500, and 1000 cells, respectively, in duplicate experiments. This method was also applied for the analysis of biological triplicate samples of MCF-7 cells. The average numbers of peptides and proteins detected from the experimental triplicate analyses of biological triplicate samples were 400+/-71 (9 datasets) and 124+/-14, respectively, from 250 cells, and 531+/-44 and 162+/-16, respectively, from 500 cells. PMID- 24630978 TI - Indirect photometric detection of boron cluster anions electrophoretically separated in methanol. AB - 3,5-Dinitrobenzoate and picrate are light absorbing anions pertinent to indirect photometric detection of boron cluster anions in buffered methanolic background electrolytes (BGEs). Tris(hydroxymethyl)aminomethane and morpholine have been used as buffering bases, which eliminated baseline steps, and minimized the baseline noise. In methanolic BGEs, mobilities of boron cluster anions depend on both ionic constituents of the BGE buffer. This dependence can be explained by ion pair interaction of detected anions with BGE cations, which are not bonded into ion pairs with the BGE anions. The former ion pair interaction decreases sensitivity of the indirect photometric detection. PMID- 24630979 TI - Retrospective analysis by data processing tools for comprehensive two-dimensional gas chromatography coupled to high resolution time-of-flight mass spectrometry: a challenge for matrix-rich sediment core sample from Tokyo Bay. AB - Data processing tools for non-target analysis using comprehensive two-dimensional gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GC*GC-HRTOFMS) were developed and applied to a sediment core in Tokyo Bay, focusing on chlorinated compounds in this study. The processing tools were classified in two different methods: (1) the consecutive use of mass defect filter followed by artificial neutral loss scan (MDF/artificial NLS) as a qualitative non-target screening method and (2) Entire Domain Combined Spectra Extraction and Integration Program (ComSpec) and two-dimensional peak sentinel (T SEN) as a semi-quantitative target screening method. MDF/artificial NLS as a non target screening approach revealed that PCBs, followed by octachlorodibenzo dioxin (OCDD), were the main chlorinated compounds present in all sediment layers. Furthermore, unknown peaks thought to be chlorinated compounds were found in increasing numbers, some in increasing amounts. T-SEN and ComSpec as a target screening approach were adapted for automatic semi-quantitative analysis showed that, in decreasing concentration order, PCBs, OCDD, and dichlorodiphenyltrichloroethane and its metabolites (DDEs, DDDs) were the main chlorinated pollutants in the sediments. The complementary use of both techniques allows us to extract significant chlorinated pollutants, including non-targeted compounds. This retrospective analysis by this approach performed well even on matrix-rich sediment samples and provided us an interesting insight of historical trends of pollution in Tokyo Bay. PMID- 24630980 TI - Development of a capillary high performance liquid chromatography-ion trap-mass spectrometry method for the determination of VLIVP antihypertensive peptide in soybean crops. AB - Soybean peptide VLIVP presents a very high antihypertensive activity (IC50 value 1.69MUM), even higher than extensively studied IPP and VPP peptides from milk. Nevertheless, no much attention has been paid to this peptide and there is no method enabling its determination in soybeans. The aim of this work was the development of an analytical methodology for this purpose. A methodology consisting of the extraction of soybean proteins, their digestion with Protease P enzyme, their chromatographic separation using capillary-HPLC, and IT-MS detection was optimized. Protein extraction was performed by the use of high intensity focused ultrasounds to obtain a reduced extraction time. Optimization of chromatographic and mass spectrometry parameters enabled the separation of VLIVP peptide within just 7min and its sensitive detection. The analytical characteristics of the capillary-HPLC-IT-MS method were evaluated through the study of linearity, LOD, LOQ, study of the presence of matrix interferences, precision, and recovery. The method enabled to detect as low as 3.6ng of peptide and to determine as low as 12ng of peptide in 1g of soybean (as dry basis). Finally, the developed method was applied to the determination of the antihypertensive peptide VLIVP in different soybean varieties. The results showed the highest yield of VLIVP peptide in variety Mazowiecka II from Poland. PMID- 24630981 TI - Novel calibration model maintenance strategy for solving the signal instability in quantitative liquid chromatography-mass spectrometry. AB - In this contribution, a multiplicative effects model with a parameter accounting for the variations in overall sensitivity over time was proposed to reduce the effects of signal instability on quantitative results of LC-MS/MS. This method allows the use of calibration models constructed from large standard sets without having to repeat their measurement even though variations occur in sensitivity and baseline signal intensity. The performance of the proposed method was tested on two proof-of-concept model systems: the determination of the target peptide in two sets of peptide digests mixtures and the quantification of melamine and metronidazole in two sets of milk powder samples. Experimental results confirmed that multiplicative effects model could provide quite satisfactory concentration predictions for both systems with average relative predictive error values far lower than the corresponding values of various models investigated in this paper. Considering its capability in solving the problem of signal instability across samples and over time in LC-MS/MS assays and its implementation simplicity, it is expected that the multiplicative effects model can be developed and extended in many application areas such as the quantification of specific protein in cells and human plasma and other complex systems. PMID- 24630983 TI - The association between serum vitamin D level and immunoglobulin E in Korean adolescents. AB - OBJECTIVE: Vitamin D has immune modulatory functions, and thus its relationship with allergic disease has been evaluated in a number of studies. However, no concrete link between serum IgE level and vitamin D has been established. Thus, the purpose of study was to confirm the association of serum vitamin D level with the serum IgE (total and Dematophagoides farinae specific IgE) in Korean adolescents. METHODS: A total of 365 subjects between 10 and 18 years of age were enrolled through the Korea National Health and Nutrition Examination Survey (KNHANES). Serum levels of vitamin D, total IgE, and Dermatophagoides farinae (Df) specific IgE were measured, and data for potential confounding variables were collected. Multivariate regression analyses were used to determine the independent effects of these variables. RESULTS: Levels of both total and Df specific IgE were positively correlated with serum concentration of vitamin D (Spearman's rho (R)=0.126, p=0.016; R=0.152, p=0.004, respectively). These results were confirmed by multivariate linear regression analysis after adjusting for sex, age, and body mass index (coefficient (B): 10.45 95% confidence interval (CI): 0.59-20.31; B: 1.06, 95% CI: 0.31-1.80, respectively). And, the association between serum vitamin D and IgE showed the different results depending on the presence or absence of Df sensitization. CONCLUSIONS: Serum concentration of vitamin D was positively associated with levels of both total IgE and Df-specific IgE in Korean adolescents. PMID- 24630982 TI - Evaluation of capillary chromatographic supports for immobilized human purine nucleoside phosphorylase in frontal affinity chromatography studies. AB - The aim of this work was to optimize the preparation of a capillary human purine nucleoside phosphorylase (HsPNP) immobilized enzyme reactor (IMER) for characterization and affinity screening studies of new inhibitors by frontal affinity chromatography coupled to mass spectrometry (FAC-MS). For this purpose two monolithic supports, a Chromolith Speed Rod (0.1mm I.D.*5cm) and a methacrylate-based monolithic epoxy polymeric capillary column (0.25mm I.D.*5cm) with epoxy reactive groups were considered and compared to an IMER previously developed using an open fused silica capillary. Each HsPNP-IMER was characterized in terms of catalytic activity using Inosine as standard substrate. Furthermore, they were also explored for affinity ranking experiments. Kd determination was carried out with the based fused silica HsPNP-IMER and the results are herein discussed. PMID- 24630984 TI - The impact of palatal repair before and after 6 months of age on speech characteristics. AB - OBJECTIVE: Optimal timing of palatal repair is still subject of discussion. Although literature provides some evidence that palatal closure prior to 6 months positively influence speech outcome in children with clefts, only few studies verified this hypothesis. The purpose of this study was to describe and compare articulation and resonance characteristics following early (<=6 months) and later (>6 months) palatal repair, performed using the Sommerlad technique. METHODS: Comparison was made between 12 Ugandan children with isolated cleft (lip and) palate following early palatal repair (mean age: 3.3 m) and 12 Belgian patients with later palatal repair (mean age: 11.1 m), matched for cleft type, age and gender. A Ugandan and Belgian age- and gender-matched control group without clefts was included to control for language, culture and other environmental factors. Articulation assessments consisted of consonant inventories and phonetic and phonological analyses that were based on consensus transcriptions. In addition, resonance was evaluated by perceptual consensus ratings and objective mean nasalance values. RESULTS: The Belgian and Ugandan control groups were comparable for the majority of the variables. Comparison of cleft palate groups revealed no clinically relevant significant group differences for consonant inventory or phonological processes. Phonetic analysis showed significantly more distortions in the Belgian cleft palate group due to higher occurrence frequencies for (inter)dental productions of apico-alveolar consonants. Neither perceptual consensus ratings of hypernasality, hyponasality, cul-de-sac resonance and nasal emission/turbulence, nor objective mean nasalance values for oral speech samples revealed significant group differences (p>0.05). CONCLUSION: Articulation and resonance characteristics of young children following palatal repair before and after 6 months of age seem to be at least comparable. PMID- 24630985 TI - Multi-level gene expression signatures, but not binary, outperform Ki67 for the long term prognostication of breast cancer patients. AB - Proliferation-related gene signatures have been proposed to aid breast cancer management by providing reproducible prognostic and predictive information on a patient-by-patient basis. It is unclear however, whether a less demanding assessment of cell division rate (as determined in clinical setting by expression of Ki67) can function in place of gene profiling. We investigated agreement between literature-, distribution-based, as well as signature-derived values for Ki67, relative to the genomic grade index (GGI), 70-gene signature, p53 signature, recurrence score (RS), and the molecular subtype models of Sorlie, Hu, and Parker in representative sets of 253 and 159 breast cancers with a median follow-up of 13 and 14.5 years, respectively. The relevance for breast cancer specific survival was also addressed in uni- and bivariate Cox models. Taking both cohorts into account, our broad approach identified ROC optimized Ki67 cutoffs in the range of 8-28%. With optimum signature-reproducing cutoffs, similarity in classification of individual tumors was higher for binary signatures (72-85%), than multi-level signatures (67-73%). Consistent with strong agreement, no prognostic superiority was noted for either Ki67 or the binary GGI, 70-gene and p53 signatures in the Uppsala dataset by bivariate analyses. In contrast, Ki67-independent prognostic capacity could be demonstrated for RS and molecular subtypes according to Sorlie, Hu and Parker in both datasets. Our results show that the added prognostic value of binary proliferation-related gene signatures is limited for Ki67-assessed breast cancers. More complex, multi-level descriptions have a greater potential in short- and long-term prognostication for biologically relevant breast cancer subgroups. PMID- 24630986 TI - Plk1-targeted therapies in TP53- or RAS-mutated cancer. AB - Despite advances in treatment, prognosis for many types of carcinoma remains poor. Polo-like kinase 1 (Plk1) has been explored as a target for the development of anticancer drugs. As a mitotic master Ser/Thr kinase, Plk1 is involved in centrosomal maturation, microtubule nucleation, chromosomal segregation, and cytokinesis. Additional functions in interphase and in response to DNA damage have been revealed. The multiple locations of Plk1 correspond to distinct functions, mediated by phosphorylation of multiple substrates. Since it is highly expressed in several carcinomas, and expression of Plk1 is inversely correlated with the survival rate of patients in non-small cell lung, head and neck, and esophageal cancer, Plk1 is recognized as a valid prognostic marker. Connections between Plk1 and p53 or KRAS in carcinoma provide a rationale and several possible routes to the development of therapies. Tumors with both p53-deficiency and high Plk1 expression may be particularly sensitive to Plk1 inhibitors, although some controversial data exist. In KRAS-mutant cancers, on the other hand, Plk1 may be essential for tumor cell survival, but detailed studies as to whether Plk1 inhibitors are more effective in KRAS-mutant cancers must be performed in order to determine whether this is the case. Here, we present evidence for Plk1 as a prognostic marker and potentially effective target for the treatment of patients with carcinoma, to demonstrate the value of Plk1 as a target for the development of cancer treatment, especially for patients with solid tumors. In addition, the effects of Plk1 inhibition in p53- or KRAS-mutated cancer are discussed with respect to clinical implications. Structural specifics of Plk1 are presented, as well as current strategies for discovering new Plk1 inhibitors by targeting the conserved ATP binding site or polo-box domain of Plk1, in order to develop Plk1-specific anticancer drugs. PMID- 24630987 TI - Tribocorrosion and oral and maxillofacial surgical devices. AB - The release of metal ions or material particles, or both, into tissues that surround implanted medical or dental devices can create postimplantation complications. These rare but disturbing events are mainly caused by the mechanical movements of the components of the implant against each other, coupled with the influences of local biochemical and electrochemical factors. Mechanical movement of the components of implants against each other results in friction and wear, the study of which is called tribology. The tribology of an implanted device depends on the patient's activity and is affected by variables such as load, frequency, and the surface properties of the components of the implant that are in contact. Local biochemical and electrochemical factors include the ambient pH, and concentrations of protein and oxygen. The effect on local tissues and extracellular fluid can produce biochemical or electrochemical responses to the implant material in the surrounding solution, which is termed corrosion. The combined effect of these mechanical, biochemical, and electrochemical factors is known as tribocorrosion. In this paper we will provide a brief overview of the basic principles of tribocorrosion, and its current status and future perspectives, to create awareness and interest, and to inspire research into its effects on implantable devices in oral and maxillofacial surgery. The information garnered from such investigations, appropriately applied, will not only improve present devices but also will lead to the development of superior ones, ultimately improving care and outcomes for patients. PMID- 24630988 TI - miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment. AB - The miR-34 family was originally found to be a direct target of p53 and is a group of putative tumor suppressors. Surprisingly, mice lacking all mir-34 genes show no increase in cancer formation by 18 months of age, hence placing the physiological relevance of previous studies in doubt. Here, we report that mice with prostate epithelium-specific inactivation of mir-34 and p53 show expansion of the prostate stem cell compartment and develop early invasive adenocarcinomas and high-grade prostatic intraepithelial neoplasia, whereas no such lesions are observed after inactivation of either the mir-34 or p53 genes alone by 15 months of age. Consistently, combined deficiency of p53 and miR-34 leads to acceleration of MET-dependent growth, self-renewal, and motility of prostate stem/progenitor cells. Our study provides direct genetic evidence that mir-34 genes are bona fide tumor suppressors and identifies joint control of MET expression by p53 and miR 34 as a key component of prostate stem cell compartment regulation, aberrations in which may lead to cancer. PMID- 24630989 TI - Caspase-11 controls interleukin-1beta release through degradation of TRPC1. AB - Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1beta (IL-1beta) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1beta without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1beta secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase 1. PMID- 24630990 TI - S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3. AB - S1PR1 signaling has been shown to restrain the number and function of regulatory T (Treg) cells in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8(+) T cell recruitment and activation, and promotes tumor growth. T-cell intrinsic S1PR1 affects Treg cells, but not CD8(+) T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. An increase in S1PR1 in CD4(+) T cells promotes STAT3 activation and JAK/STAT3 dependent Treg tumor migration, whereas STAT3 ablation in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast between the consequences of S1PR1 signaling in Treg cells in the periphery versus tumors. PMID- 24630991 TI - The Marburg virus VP24 protein interacts with Keap1 to activate the cytoprotective antioxidant response pathway. AB - Kelch-like ECH-associated protein 1 (Keap1) is a ubiquitin E3 ligase specificity factor that targets transcription factor nuclear factor (erythroid-derived 2) like 2 (Nrf2) for ubiquitination and degradation. Disrupting Keap1-Nrf2 interaction stabilizes Nrf2, resulting in Nrf2 nuclear accumulation, binding to antioxidant response elements (AREs), and transcription of cytoprotective genes. Marburg virus (MARV) is a zoonotic pathogen that likely uses bats as reservoir hosts. We demonstrate that MARV protein VP24 (mVP24) binds the Kelch domain of either human or bat Keap1. This binding is of high affinity and 1:1 stoichiometry and activates Nrf2. Modeling based on the Zaire ebolavirus (EBOV) VP24 (eVP24) structure identified in mVP24 an acidic loop (K-loop) critical for Keap1 interaction. Transfer of the K-loop to eVP24, which otherwise does not bind Keap1, confers Keap1 binding and Nrf2 activation, and infection by MARV, but not EBOV, activates ARE gene expression. Therefore, MARV targets Keap1 to activate Nrf2-induced cytoprotective responses during infection. PMID- 24630992 TI - Marburgvirus hijacks nrf2-dependent pathway by targeting nrf2-negative regulator keap1. AB - Marburg virus (MARV) has a high fatality rate in humans, causing hemorrhagic fever characterized by massive viral replication and dysregulated inflammation. Here, we demonstrate that VP24 of MARV binds Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear transcription factor erythroid-derived 2 (Nrf2). Binding of VP24 to Keap1 Kelch domain releases Nrf2 from Keap1-mediated inhibition promoting persistent activation of a panoply of cytoprotective genes implicated in cellular responses to oxidative stress and regulation of inflammatory responses. Increased expression of Nrf2-dependent genes was demonstrated both during MARV infection and upon ectopic expression of MARV VP24. We also show that Nrf2-deficient mice can control MARV infection when compared to lethal infection in wild-type animals, indicating that Nrf2 is critical for MARV infection. We conclude that VP24-driven activation of the Nrf2-dependent pathway is likely to contribute to dysregulation of host antiviral inflammatory responses and that it ensures survival of MARV-infected cells despite these responses. PMID- 24630993 TI - Single-molecule fluorescence reveals the unwinding stepping mechanism of replicative helicase. AB - Bacteriophage T7 gp4 serves as a model protein for replicative helicases that couples deoxythymidine triphosphate (dTTP) hydrolysis to directional movement and DNA strand separation. We employed single-molecule fluorescence resonance energy transfer methods to resolve steps during DNA unwinding by T7 helicase. We confirm that the unwinding rate of T7 helicase decreases with increasing base pair stability. For duplexes containing >35% guanine-cytosine (GC) base pairs, we observed stochastic pauses every 2-3 bp during unwinding. The dwells on each pause were distributed nonexponentially, consistent with two or three rounds of dTTP hydrolysis before each unwinding step. Moreover, we observed backward movements of the enzyme on GC-rich DNAs at low dTTP concentrations. Our data suggest a coupling ratio of 1:1 between base pairs unwound and dTTP hydrolysis, and they further support the concept that nucleic acid motors can have a hierarchy of different-sized steps or can accumulate elastic energy before transitioning to a subsequent phase. PMID- 24630995 TI - Structural basis of SOSS1 complex assembly and recognition of ssDNA. AB - The SOSS1 complex comprising SOSSA, SOSSB1, and SOSSC senses single-stranded DNA (ssDNA) and promotes repair of DNA double-strand breaks (DSBs). But how SOSS1 is assembled and recognizes ssDNA remains elusive. The crystal structure of the N terminal half of SOSSA (SOSSAN) in complex with SOSSB1 and SOSSC showed that SOSSAN serves as a scaffold to bind both SOSSB1 and SOSSC for assembly of the SOSS1 complex. The structures of SOSSAN/B1 in complex with a 12 nt ssDNA and SOSSAN/B1/C in complex with a 35 nt ssDNA showed that SOSSB1 interacts with both SOSSAN and ssDNA via two distinct surfaces. Recognition of ssDNA with a length of up to nine nucleotides is mediated solely by SOSSB1, whereas neither SOSSC nor SOSSAN are critical for ssDNA binding. These results reveal the structural basis of SOSS1 assembly and provide a framework for further study of the mechanism governing longer ssDNA recognition by the SOSS1 complex during DSB repair. PMID- 24630994 TI - The Rac-FRET mouse reveals tight spatiotemporal control of Rac activity in primary cells and tissues. AB - The small G protein family Rac has numerous regulators that integrate extracellular signals into tight spatiotemporal maps of its activity to promote specific cell morphologies and responses. Here, we have generated a mouse strain, Rac-FRET, which ubiquitously expresses the Raichu-Rac biosensor. It enables FRET imaging and quantification of Rac activity in live tissues and primary cells without affecting cell properties and responses. We assessed Rac activity in chemotaxing Rac-FRET neutrophils and found enrichment in leading-edge protrusions and unexpected longitudinal shifts and oscillations during protruding and stalling phases of migration. We monitored Rac activity in normal or disease states of intestinal, liver, mammary, pancreatic, and skin tissue, in response to stimulation or inhibition and upon genetic manipulation of upstream regulators, revealing unexpected insights into Rac signaling during disease development. The Rac-FRET strain is a resource that promises to fundamentally advance our understanding of Rac-dependent responses in primary cells and native environments. PMID- 24630996 TI - Helicase and polymerase move together close to the fork junction and copy DNA in one-nucleotide steps. AB - By simultaneously measuring DNA synthesis and dNTP hydrolysis, we show that T7 DNA polymerase and T7 gp4 helicase move in sync during leading-strand synthesis, taking one-nucleotide steps and hydrolyzing one dNTP per base-pair unwound/copied. The cooperative catalysis enables the helicase and polymerase to move at a uniformly fast rate without guanine:cytosine (GC) dependency or idling with futile NTP hydrolysis. We show that the helicase and polymerase are located close to the replication fork junction. This architecture enables the polymerase to use its strand-displacement synthesis to increase the unwinding rate, whereas the helicase aids this process by translocating along single-stranded DNA and trapping the unwound bases. Thus, in contrast to the helicase-only unwinding model, our results suggest a model in which the helicase and polymerase are moving in one-nucleotide steps, DNA synthesis drives fork unwinding, and a role of the helicase is to trap the unwound bases and prevent DNA reannealing. PMID- 24630997 TI - Asymmetric reprogramming capacity of parental pronuclei in mouse zygotes. AB - It has been demonstrated that reprogramming factors are sequestered in the pronuclei of zygotes after fertilization, because zygotes enucleated at the M phase instead of interphase of the first mitosis can support the development of cloned embryos. However, the contribution of the parental pronucleus derived from either the sperm or the oocyte in reprogramming remains elusive. Here, we demonstrate that the parental pronuclei have asymmetric reprogramming capacities and that the reprogramming factors reside predominantly in the male pronucleus. As a result, only female pronucleus-depleted (FPD) mouse zygotes can reprogram somatic cells to a pluripotent state and support the full-term development of cloned embryos; male pronucleus-depleted (MPD) zygotes fail to support somatic cell reprogramming. We further demonstrate that fusion of an additional male pronucleus into a zygote greatly enhances reprogramming efficiency. Our data provide a clue to further identify critical reprogramming factors in the male pronucleus. PMID- 24630998 TI - [Importance of long-term follow-up of diabetes insipidus; from lymphocytic hypophysitis to germinoma]. AB - A case is presented of a 10-year old boy who had a hypothalamic-pituitary axis disorder. He initially presented with diabetes insipidus that progressed to panhypopituitarism. A hidden hypothalamic lesion should be suspected in all these cases, and should be followed up. New lesions were found in the pituitary stem three years later. Although tumor markers were negative, there was an increase in size, and a biopsy was performed. The histopathology reported a Lymphocytic Hypophysitis. There were increases in the tumor markers during the follow-up, thus a second biopsy was performed, with the diagnosis of Germinoma. Lymphocytic Hypophysitis is an uncommon diagnosis in children. Few cases have been reported, and in some cases, they were later diagnosed with Germinoma. We believe this case highlights the importance of the follow-up of children with Central Diabetes Insipidus with a normal MRI, as well as not taking the diagnosis of Lymphocytic Hypophysitis/lymphocytic Infundibular neurohypophysitis as definitive, as it is a rare diagnosis at this age, and could mask a Germinoma, as recorded in some cases. PMID- 24630999 TI - 3D cryo-electron reconstruction of BmrA, a bacterial multidrug ABC transporter in an inward-facing conformation and in a lipidic environment. AB - ABC (ATP-binding cassette) membrane exporters are efflux transporters of a wide diversity of molecule across the membrane at the expense of ATP. A key issue regarding their catalytic cycle is whether or not their nucleotide-binding domains (NBDs) are physically disengaged in the resting state. To settle this controversy, we obtained structural data on BmrA, a bacterial multidrug homodimeric ABC transporter, in a membrane-embedded state. BmrA in the apostate was reconstituted in lipid bilayers forming a mixture of ring-shaped structures of 24 or 39 homodimers. Three-dimensional models of the ring-shaped structures of 24 or 39 homodimers were calculated at 2.3 nm and 2.5 nm resolution from cryo electron microscopy, respectively. In these structures, BmrA adopts an inward facing open conformation similar to that found in mouse P-glycoprotein structure with the NBDs separated by 3 nm. Both lipidic leaflets delimiting the transmembrane domains of BmrA were clearly resolved. In planar membrane sheets, the NBDs were even more separated. BmrA in an ATP-bound conformation was determined from two-dimensional crystals grown in the presence of ATP and vanadate. A projection map calculated at 1.6 nm resolution shows an open outward facing conformation. Overall, the data are consistent with a mechanism of drug transport involving large conformational changes of BmrA and show that a bacterial ABC exporter can adopt at least two open inward conformations in lipid membrane. PMID- 24631000 TI - Assembly of robust bacterial microcompartment shells using building blocks from an organelle of unknown function. AB - Bacterial microcompartments (BMCs) sequester enzymes from the cytoplasmic environment by encapsulation inside a selectively permeable protein shell. Bioinformatic analyses indicate that many bacteria encode BMC clusters of unknown function and with diverse combinations of shell proteins. The genome of the halophilic myxobacterium Haliangium ochraceum encodes one of the most atypical sets of shell proteins in terms of composition and primary structure. We found that microcompartment shells could be purified in high yield when all seven H. ochraceum BMC shell genes were expressed from a synthetic operon in Escherichia coli. These shells differ substantially from previously isolated shell systems in that they are considerably smaller and more homogeneous, with measured diameters of 39+/-2nm. The size and nearly uniform geometry allowed the development of a structural model for the shells composed of 260 hexagonal units and 13 hexagons per icosahedral face. We found that new proteins could be recruited to the shells by fusion to a predicted targeting peptide sequence, setting the stage for the use of these remarkably homogeneous shells for applications such as three dimensional scaffolding and the construction of synthetic BMCs. Our results demonstrate the value of selecting from the diversity of BMC shell building blocks found in genomic sequence data for the construction of novel compartments. PMID- 24631001 TI - General and substance-specific predictors of young adult nicotine dependence, alcohol use disorder, and problem behavior: replication in two samples. AB - BACKGROUND: This paper presents two replications of a heuristic model for measuring environment in studies of gene-environment interplay in the etiology of young adult problem behaviors. METHODS: Data were drawn from two longitudinal, U.S. studies of the etiology of substance use and related behaviors: the Raising Healthy Children study (RHC; N=1040, 47% female) and the Minnesota Twin Family Study (MTFS; N=1512, 50% female). RHC included a Pacific Northwest, school-based, community sample. MTFS included twins identified from state birth records in Minnesota. Both studies included commensurate measures of general family environment and family substance-specific environments in adolescence (RHC ages 10-18; MTFS age 18), as well as young adult nicotine dependence, alcohol and illicit drug use disorders, HIV sexual risk behavior, and antisocial behavior (RHC ages 24, 25; MTFS age 25). RESULTS: Results from the two samples were highly consistent and largely supported the heuristic model proposed by Bailey et al. (2011). Adolescent general family environment, family smoking environment, and family drinking environment predicted shared variance in problem behaviors in young adulthood. Family smoking environment predicted unique variance in young adult nicotine dependence. Family drinking environment did not appear to predict unique variance in young adult alcohol use disorder. CONCLUSIONS: Organizing environmental predictors and outcomes into general and substance-specific measures provides a useful way forward in modeling complex environments and phenotypes. Results suggest that programs aimed at preventing young adult problem behaviors should target general family environment and family smoking and drinking environments in adolescence. PMID- 24631002 TI - Impacts of drinking-age laws on mortality in Canada, 1980-2009. AB - BACKGROUND: Given the recent international debates about the effectiveness and appropriate age setpoints for legislated minimum legal drinking ages (MLDAs), the current study estimates the impact of Canadian MLDAs on mortality among young adults. Currently, the MLDA is 18 years in Alberta, Manitoba and Quebec, and 19 years in the rest of Canada. METHODS: Using a regression-discontinuity approach, we estimated the impacts of the MLDAs on mortality from 1980 to 2009 among 16- to 22-year-olds in Canada. RESULTS: In provinces with an MLDA of 18 years, young men slightly older than the MLDA had significant and abrupt increases in all-cause mortality (14.2%, p=0.002), primarily due to deaths from a broad class of injuries [excluding motor vehicle accidents (MVAs)] (16.2%, p=0.008), as well as fatalities due to MVAs (12.7%, p=0.038). In provinces/territories with an MLDA of 19 years, significant jumps appeared immediately after the MLDA among males in all-cause mortality (7.2%, p=0.003), including injuries from external causes (10.4%, p<0.001) and MVAs (15.3%, p<0.001). Among females, there were some increases in mortality following the MLDA, but these jumps were statistically non significant. CONCLUSIONS: Canadian drinking-age legislation has a powerful impact on youth mortality. Given that removal of MLDA restrictions was associated with sharp upturns in fatalities among young men, the MLDA likely reduces population level mortality among male youth under the constraints of drinking-age legislation. Alcohol-control policies should target the transition across the MLDA as a pronounced period of mortality risk, especially among males. PMID- 24631003 TI - [Interaction between hypnotic agents and the hypothalamic-pituitary adrenocorticotropic axis during surgery]. AB - During stress, the relationship between the central nervous system and the immune system is essential to maintain homeostasis. The main neuroendocrine system involved in this interaction is the hypothalamic-pituitary-adrenal axis (HPA), which via the synthesis of glucocorticoids will modulate the intensity of the inflammatory response. Anaesthetic agents could be interacting with the HPA axis during surgery. Although etomidate currently remains in the center of the discussions, it seems, at least experimentally, that most hypnotics have the capacity to modulate the synthesis of adrenal steroids. Nevertheless, with the large literature on this subject, etomidate seems to be the most deleterious hypnotic agent on the HPA axis function. Its use should be limited when HPA axis is already altered. PMID- 24631004 TI - A survey of percutaneous chest drainage practice in French university surgical ICU's. AB - OBJECTIVE: Percutaneous chest drainage guidelines were published in 2010 by the British Thoracic Society. On several points (insertion technique, drain size), they seem to differ from French practices. Our objectives were to evaluate practice of pleural drainage in French University surgical intensive care units (ICU's), and to compare it with the British guidelines. STUDY DESIGN: National phone survey. METHODS: Physicians working in 58 ICU's were surveyed first in 2007, and subsequently in 2012. They were read a questionnaire to evaluate the demographic characteristics of their units, their indication for pleural drainage, how they quantified pleural effusion, and their technique for drain insertion. Data from the two surveys were compared to detect an evolution in practice following the publication of the British guidelines. Results are expressed as the mean response. RESULTS: In 2007, pleural drainage indications relied on various respiratory criteria in 91% of cases (versus 95% in 2012) and/or on pleural effusion volume in 71% of cases (versus 59% in 2012). Trocars (Monod or Joly) were used in 68% of the procedures in 2007. In the rest, either blunt dissection, a Pleurocath(r) or the Seldinger technique was utilized. From 2007 to 2012, the Seldinger technique increased in frequency (10% versus 22%, P=0.005) while Monod trocar usage decreased (41% vs 29%, P=0.012). Ultrasound before pleural effusion drainage became nearly systematic in 2012 (60% vs 86%, P<0.001). CONCLUSION: The frequent use of trocar (and therefore of large drains) for pleural drainage in French ICU's differs significantly from the British guidelines. PMID- 24631005 TI - [Use of the intraosseous access in adult patients in France in 2012]. AB - OBJECTIVES: To evaluate theoretical and practical knowledges of intraosseous (IO) access in adults patients in France in 2012. STUDY DESIGN: National observational descriptive transversal study as survey of opinion and practices. MATERIALS AND METHODS: An email, with an URL to online computerized quiz, was sent to residents and medical doctors who were working, in France, in anesthesiologist units, intensive care units or emergency units. Several questions were asked about theoretical and practical knowledges concerning IO access. RESULTS: After 1359 responses, 396 (29%) practitioners have used an IO kit mainly in case of cardiopulmonary arrest in adults (68%). The insurance of operators in this technique and the rate of physicians who has even put an IO catheter increased with the years of experience of physicians. The reasons given for not using an IO access were no trouble placing a peripheral vein (77%) and unfamiliarity with the equipment and technology (32%). Most of practitioners (753 [55%]) have been trained and 90% (n=265) of untrained doctors believe that training was necessary. The powered system was the most used (71%). CONCLUSION: Only 29% of practitioners have ever used an IO kit. With the new IO kits, a theoretical and practical training is needed to ensure IO kit used. PMID- 24631006 TI - [Contribution of ultrasonography for the preoperative assessment of gastric contents]. AB - The assessment of the risk of pulmonary aspiration of gastric contents may be difficult in the preoperative period, apart from typical circumstances. The development of ultrasonography in anesthesia and critical care has led to consider ultrasonic imaging of gastric contents for preoperative risk assessment of "full" stomach in clinical practice. Ultrasonography of the body of the stomach allows direct visualization of the gastric contents. However, the stomach is often difficult to identify, particularly when it is empty. Moreover, quantitative assessment of gastric volume is delicate, and no standardized method of ultrasonography of the body of the stomach for preoperative assessment of gastric contents was described. On the contrary, ultrasonography of the antral cross-sectional area, which was initially described for the assessment of gastric emptying as an alternative method to repeated measurements of the variations of antropyloric volume after ingestion of a test meal, is easy to perform and is highly reproducible through using the aorta and the left lobe of the liver as internal landmarks. Qualitative assessment of the gastric antrum allows easily diagnosis of a "full" stomach. The measurement of antral area may allow a more accurate estimate of the presence or absence of gastric contents at risk of lung injury in the event of regurgitation and aspiration (gastric volume >0.8 ml/kg and/or with solid particles), defining the "risk" stomach. The use of antral ultrasonography may help the anesthesiologist to assess the risk of pulmonary aspiration according to clinical history of the patient, in order to choose an appropriate strategy minimizing the occurrence of this complication. PMID- 24631007 TI - [Cardiac arrest secondary to pacemaker dysfunction during general anesthesia in a young adult patient]. AB - The number of patients with cardiac pacemaker is continuously increasing. The anesthetic management of these patients is often trivialized, particularly during minor surgery. However there is always a potential risk of dysfunction during anesthesia. Perioperative management of these patients must be careful and standardized to avoid accidents. We report a case of cardiac arrest during general anesthesia for a day-surgery secondary to pacemaker dysfunction by increasing pacing thresholds in a young adult patient. Rapid onset after induction, without any surgical stimulation, has raised the question of the involvement of anesthetic drugs like propofol. PMID- 24631008 TI - Cortical sources of resting-state EEG rhythms in "experienced" HIV subjects under antiretroviral therapy. AB - OBJECTIVE: Treatment-naive patients with human immunodeficiency virus (HIV) are characterized by diffuse abnormalities of resting-state cortical electroencephalographic (EEG) rhythms (Babiloni et al., 2012a). Here, we tested the hypothesis that these EEG rhythms vary as a function of the systemic immune activity and antiretroviral therapy (ART) in HIV patients. METHODS: Resting-state eyes-closed EEG data were recorded in 68 ART-HIV patients (mini mental state evaluation (MMSE) of 27.5 +/- 0.3 SEM), in 60 treatment-naive HIV subjects (MMSE of 27.5 +/- 0.4 SEM) and in 75 age-matched cognitively normal subjects (MMSE of 29.3 +/- 0.1 SEM). Based on the CD4 lymphocytes' count, we divided ART-HIV subjects into two subgroups: those with CD4>500 cells/MUl (ART-HIV+) and those with CD4<500 cells/MUl (ART-HIV-). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-12 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG sources were estimated by LORETA software. RESULTS: Widespread theta, alpha, and beta sources were lower in ART-HIV subjects than in control subjects. Furthermore, occipital and temporal alpha 1 sources were lower in treatment-naive HIV than in ART-HIV subjects. Moreover, the opposite was true for widespread pathological delta sources. Finally, parietal, occipital, and temporal alpha 1 sources were lower in ART-HIV- than in ART-HIV+ subjects. CONCLUSIONS: In ART-HIV subjects, cortical sources of resting-state alpha rhythms are related to systemic immune activity and cART. SIGNIFICANCE: This EEG procedure may produce biomarkers of treatment response in patients' brain compartments for longitudinal clinical studies. PMID- 24631009 TI - Is interictal EEG activity a biomarker for mood disorders in temporal lobe epilepsy? AB - OBJECTIVE: Psychiatric comorbidities are frequent in temporal lobe epilepsy (TLE), and symptoms of these comorbidities may be related to epilepsy activity. Here we evaluated interictal EEG activity in TLE patients with or without psychiatric comorbidities. METHODS: A cohort study of 78 patients with TLE, with evaluation of wake/sleep interictal scalp EEG. All subjects were submitted to a psychiatric structured clinical interview (SCID) for the diagnosis of lifetime psychiatric comorbidities. Three major diagnostic categories were studied: mood disorders, anxiety disorders, and psychosis. We then evaluated differences in interictal EEG activity between patients with and without these psychiatric comorbidities. RESULTS: Infrequent EEG interictal spikes, defined as less than one event per minute, were significantly associated with mood disorders in TLE (p=0.02). CONCLUSIONS: Low intensity seizure disorder has been associated with a decrease in interictal EEG discharges and with an increase in psychiatric symptoms in TLE, a phenomenon known as forced normalization. In our study, we observed a low interictal spike frequency on EEG in TLE patients with mood disorders. SIGNIFICANCE: A low spike index might be a neurophysiological marker for depression in temporal lobe epilepsy. PMID- 24631010 TI - Spatial Analytic Phase Difference of EEG activity during anesthetic-induced unconsciousness. AB - OBJECTIVE: A number of studies provide supporting evidence for changes in synchronization during anesthetic-induced unconsciousness. This study investigates how anesthetic administration affects the widespread patterns of phase synchrony. METHODS: The recently introduced method of Spatial Analytic Phase Difference (SAPD) was used to measure changes in synchrony in the electroencephalogram (EEG) activity of 29 patients undergoing routine surgery. Analysis was performed over 9 frequency bands: (i) delta (1.5-3.5Hz); (ii) theta (3.5-7.5Hz); (iii) alpha1 (8-10Hz); (iv) alpha2 (10.5-12Hz); (v) beta1 (12.5 18Hz); (vi) beta2 (18.5-21Hz); (vii) beta3 (21.5-30Hz); (viii) gamma1 (30.5 40Hz); and (ix) gamma2 (60-80Hz). RESULTS: Anesthesia was characterized by (a) large and localized synchrony increases in mid-frequency bands (8-12Hz), (b) smaller and widespread synchrony increases in higher frequency bands (30.5-40Hz, 60-80Hz), and (c) both increase and decrease of synchrony in low frequency bands (1.5-7.5Hz). CONCLUSIONS: This study supports anesthetic-induced changes in synchrony, with the inducement of persistent and reversible widespread gamma synchrony being most prominent. SIGNIFICANCE: Our findings have implications in the study of consciousness, support existing literature in the field and contribute towards the theoretical understanding of the mechanisms behind loss of consciousness. Future investigations could result in a synchrony-based measure for monitoring the level of hypnosis of patients during surgery. PMID- 24631011 TI - EEG in delirium: Increased spectral variability and decreased complexity. PMID- 24631012 TI - Line length as a robust method to detect high-activity events: automated burst detection in premature EEG recordings. AB - OBJECTIVE: EEG is a valuable tool for evaluation of brain maturation in preterm babies. Preterm EEG constitutes of high voltage burst activities and more suppressed episodes, called interburst intervals (IBIs). Evolution of background characteristics provides information on brain maturation and helps in prediction of neurological outcome. The aim is to develop a method for automated burst detection. METHODS: Thirteen polysomnography recordings were used, collected at preterm postmenstrual age of 31.4 (26.1-34.4)weeks. We developed a burst detection algorithm based on the feature line length and compared it with manual scorings of clinical experts and other published methods. RESULTS: The line length-based algorithm is robust (84.27% accuracy, 84.00% sensitivity, 85.70% specificity). It is not critically dependent on the number of measurement channels, because two channels still provide 82% accuracy. Furthermore, it approximates well clinically relevant features, such as median IBI duration 5.45 (4.00-7.11)s, maximum IBI duration 14.02 (8.73-18.80)s and burst percentage 48.89 (35.45-60.12)%, with a median deviation of respectively 0.65s, 1.96s and 6.55%. CONCLUSION: Automated assessment of long-term preterm EEG is possible and its use will optimize EEG interpretation in the NICU. SIGNIFICANCE: This study takes a first step towards fully automatic analysis of the preterm brain. PMID- 24631013 TI - Characterizing the phenotypes of obstructive sleep apnea: clinical, sleep, and autonomic features of obstructive sleep apnea with and without hypoxia. AB - OBJECTIVE: The pathophysiological basis of obstructive sleep apnea (OSA) is not completely understood and likely varies among patients. In this regard, some patients with OSA do not exhibit hypoxemia. We aimed to analyze the clinical, sleep, and autonomic features of a group of patients with severe OSA without hypoxia (OSA-h) and compare to OSA patients with hypoxia (OSA+h) and controls. METHODS: Fifty-six patients with OSA-h, 64 patients with OSA+h, and 44 control subjects were studied. Clinical and sleep features were analyzed. Besides, time- and frequency-domain heart rate variability (HRV) measures comprising the mean R R interval, the standard deviation of the RR intervals (SDNN), the low frequency (LF) oscillations, the high frequency (HF) oscillations, and the LF/HF ratio, were calculated across sleep stages during a one-night polysomnography. RESULTS: OSA-h patients had a lower body mass index, a lower waist circumference, lower apnea duration, and a higher frequency of previous naso-pharyngeal surgery when compared to OSA+h patients. In terms of heart rate variability, OSA+h had increased LF oscillations (i.e., baroreflex function) during N1-N2 and rapid eye movement (REM) sleep when compared to OSA-h and controls. Both OSA+h and OSA-h groups had decreased HF oscillations (i.e., vagal inputs) during N1-N2, N3 and REM sleep when compared to controls. The LF/HF ratio was increased during N1-N2 and REM sleep, only in patients with OSA+h. CONCLUSIONS: Patients with OSA-h exhibit distinctive clinical, sleep, and autonomic features when compared to OSA with hypoxia. SIGNIFICANCE: OSA is a heterogeneous entity. These differences must be taken into account in future studies when analyzing therapeutic approaches for sleep apnea patients. PMID- 24631014 TI - Motor cortex plasticity and excitability in Parkinson's disease. PMID- 24631015 TI - Modern scleral contact lenses: A review. AB - Scleral contact lenses (ScCL) have gained renewed interest during the last decade. Originally, they were primarily used for severely compromised eyes. Corneal ectasia and exposure conditions were the primary indications. However, the indication range of ScCL in contact lens practices seems to be expanding, and it now increasingly includes less severe and even non-compromised eyes, too. All lenses that partly or entirely rest on the sclera are included under the name ScCL in this paper; although the Scleral Lens Education Society recommends further classification. When a lens partly rests on the cornea (centrally or peripherally) and partly on the sclera, it is called a corneo-scleral lens. A lens that rests entirely on the sclera is classified as a scleral lens (up to 25 mm in diameter maximum). When there is full bearing on the sclera, further distinctions of the scleral lens group include mini-scleral and large-scleral lenses. This manuscript presents a review of the current applications of different ScCL (all types), their fitting methods, and their clinical outcomes including potential adverse events. Adverse events with these lenses are rare, but the clinician needs to be aware of them to avoid further damage in eyes that often are already compromised. The use of scleral lenses for non-pathological eyes is discussed in this paper. PMID- 24631017 TI - Psychogenic non-epileptic events: does the truth lie at the tip of the tongue? PMID- 24631016 TI - The value of home video with ambulatory EEG: a prospective service review. AB - PURPOSE: The demand for long term EEG monitoring is increasing with the emphasis on recording patients' attacks. Outpatient ambulatory EEG is relatively inexpensive and widely available. The main disadvantage of the technique is the lack of video which can make interpretation of an ictus difficult. We investigated whether patients, if offered home video equipment, would take it, if this resulted in simultaneous EEG-video capture of an ictus and if interpretation of the recording was facilitated by the video. METHOD: All ambulatory EEG patients, adults and children, were offered a camcorder to take home during a 17 month study period. RESULTS: 130 patients/carers were offered a camcorder (93 adults, 37 children), 45 patients (35%) accepted; the main reason for not accepting was that attacks were considered too brief to record. An ictal event occurred in 34 patients (76%) with a camcorder; in 17 (50%) of these an attack was captured successfully on video. The main reasons for failure to capture events were that attacks were too brief, or that the camcorder was not operated successfully. Attacks were captured with greater success in children (14/23, 61%) than adults (3/11, 27%). Of the 17 video recordings, 14 (82%) were helpful in aiding interpretation of the ambulatory EEG. CONCLUSION: In our study, home video facilities aided interpretation of ambulatory EEG recordings in approximately one third of patients. Technological advances and familiarity with portable recording devices will improve this figure and patients and their carers should be encouraged to use such facilities when available. PMID- 24631018 TI - Immunomodulatory activity of zinc peroxide (ZnO2) and titanium dioxide (TiO2) nanoparticles and their effects on DNA and protein integrity. AB - Nanoparticles that are made from zinc and titanium oxide have found widespread applications, including their use in sunscreens. However, there is little information regarding their effects on immune cells. In the current study, we synthesized charge stabilized and "ligand free" colloid stable ZnO2 and TiO2 nanoparticles. Most previous published studies commonly used ZnO and TiO2 nanoparticles. In the current study we investigated the comparative toxicity of ZnO2 and TiO2 nanoparticles. Therefore, our results based on ZnO2 which is more oxidative than ZnO provides novel data on the possible toxicity of this species of nanoparticles. First, we investigated the immunomodulatory action of these nanoparticles on human peripheral blood mononuclear cells and their effects on DNA and protein integrity. A minimum concentration of ZnO2 nanoparticles of 1 MUg/mL inhibited the production of two inflammatory cytokines: interleukin-1-beta and interleukin 6 by peripheral blood mononuclear cells in the presence of lipopolysaccharides. On the other hand, TiO2 nanoparticles at a concentration range of 0.1-100 MUg/mL did not present apparent toxicity to the peripheral blood mononuclear cells. ZnO2 nanoparticles at a minimum concentration of 2 MUg/mL caused DNA damage in vitro. TiO2 nanoparticles at a concentration range of 25-100 MUg/mL only caused marginal DNA damage. ZnO2 nanoparticles at a minimum concentration of 5 MUg/mL were capable of promoting aggregation of malate dehydrogenase, and facilitated its degradation at higher concentrations. Exposure of malate dehydrogenase to TiO2 at a concentration range of 2.5-15 MUg/mL did not alter the solubility of malate dehydrogenase. Altogether, our findings suggest that charge stabilized ZnO2 nanoparticles are nascent and interact with DNA and protein and may be harmful to immune cells. In addition, the propensity of ZnO2 nanoparticles to promote protein aggregation could facilitate the production of protein complexes that may interfere with normal immune functions. PMID- 24631019 TI - Identification of the proteins related to SET-mediated hepatic cytotoxicity of trichloroethylene by proteomic analysis. AB - Trichloroethylene (TCE) is an effective solvent for a variety of organic materials. Since the wide use of TCE as industrial degreasing of metals, adhesive paint and polyvinyl chloride production, TCE has turned into an environmental and occupational toxicant. Exposure to TCE could cause severe hepatotoxicity; however, the toxic mechanisms of TCE remain poorly understood. Recently, we reported that SET protein mediated TCE-induced cytotoxicity in L-02 cells. Here, we further identified the proteins related to SET-mediated hepatic cytotoxicity of TCE using the techniques of DIGE (differential gel electrophoresis) and MALDI TOF-MS/MS. Among the 20 differential proteins identified, 8 were found to be modulated by SET in TCE-induced cytotoxicity and three of them (cofilin-1, peroxiredoxin-2 and S100-A11) were validated by Western-blot analysis. The functional analysis revealed that most of the identified SET-modulated proteins are apoptosis-associated proteins. These data indicated that these proteins may be involved in SET-mediated hepatic cytotoxicity of TCE in L-02 cells. PMID- 24631020 TI - Effectiveness and safety of infliximab and adalimumab for ambulatory Crohn's disease patients in primary gastroenterology centres. AB - BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are the key treatments for Crohn's Disease (CD), unresponsive to standard treatments. Our aim was to compare the efficacy and safety of IFX and ADA in treating CD in clinical practice. METHODS: One hundred and twenty-six patients (61 M, 65 F, mean age 36.2 years, range 19-67 years), affected by CD, were treated with infliximab (IFX, 59 patients) or adalimumab (ADA, 66 patients). Clinical efficacy, mucosal healing (MH), histological healing (HH), and safety were assessed. MH was defined complicated if healing of ulcers occurred with deformation of bowel profile and/or complete colonoscopy was impossible because of scars. RESULTS: Patients were followed-up for 36 months. No difference was found between IFX and ADA in maintaining long-term clinical remission, MH and HH. Complicated MH was present in 17 (28.8%) patients in IFX group and in 7 (10.6%) patients in ADA group (p=0.012). In 9 (15.2%) patients in IFX group and 2 (3.0%) patients in ADA group colonoscopy was incomplete without cecal intubation or terminal ileum exploration (p=0.024). Side effects were similar in both groups. CONCLUSIONS: Both IFX and ADA seem to be effective and safe in long-term outpatient treatment of CD in clinical practice. PMID- 24631021 TI - UPLC-MS(E) application in disease biomarker discovery: the discoveries in proteomics to metabolomics. AB - In the last decade, proteomics and metabolomics have contributed substantially to our understanding of different diseases. Proteomics and metabolomics aims to comprehensively identify proteins and metabolites to gain insight into the cellular signaling pathways underlying disease and to discover novel biomarkers for screening, early detection and diagnosis, as well as for determining prognoses and predicting responses to specific treatments. For comprehensive analysis of cellular proteins and metabolites, analytical methods of wider dynamic range higher resolution and good sensitivity are required. Ultra performance liquid chromatography-mass spectrometry(Elevated Energy) (UPLC-MS(E)) is currently one of the most versatile techniques. UPLC-MS(E) is an established technology in proteomics studies and is now expanding into metabolite research. MS(E) was used for simultaneous acquisition of precursor ion information and fragment ion data at low and high collision energy in one analytical run, providing similar information to conventional MS(2). In this review, UPLC-MS(E) application in proteomics and metabolomics was highlighted to assess protein and metabolite changes in different diseases, including cancer, neuropsychiatric pharmacology studies from clinical trials and animal models. In addition, the future prospects for complete proteomics and metabolomics are discussed. PMID- 24631022 TI - The fungal metabolite galiellalactone interferes with the nuclear import of NF kappaB and inhibits HIV-1 replication. AB - Galiellalactone (GL) is a metabolite produced by the fungus Galiella rufa that presents antitumor and immunomodulatory activities. GL interferes with the binding to DNA of signal transducer and activator of transcription (STAT)-3 and also inhibits other signal pathways such as NF-kappaB, but the mechanism of action in this pathway remains unknown. In this study we report that GL inhibits vesicular stomatitis virus-recombinant HIV-1 infection and the NF-kappaB dependent transcriptional activity of the HIV-LTR promoter. We found that GL prevents the binding of NF-kappaB to DNA but neither affects the phosphorylation and degradation of NF-kappaB inhibitory protein, IkappaBalpha, nor the phosphorylation and acetylation of the NF-kappaB p65 subunit. However, GL prevents the association of p65 with the importin alpha3 impairing the nuclear translocation of this transcription factor. Using a biotinylated probe we found that GL binds to p65 but not to importin alpha3. Therefore, GL is a dual NF kappaB/STAT3 inhibitor that could serve as a lead compound for the development of novel drugs against HIV-1, cancer and inflammatory diseases. PMID- 24631023 TI - Bortezomib partially improves laminin alpha2 chain-deficient muscular dystrophy. AB - Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin alpha2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin alpha2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin alpha2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin alpha2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted. PMID- 24631024 TI - Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation. AB - In acute kidney injury, which is a significant cause of morbidity and mortality, cytokines and leukocytes promote inflammation and injury. We examined the pathogenic role of IL-17A in cisplatin-induced acute kidney injury. Intrarenal IL 17A mRNA transcription and protein expression were increased in wild-type mice after cisplatin-induced renal injury. An important role for IL-17A in the nephrotoxicity of cisplatin was demonstrated by observing protection from cisplatin-induced functional and histological renal injury in Il17a(-/-) and Rorgammat(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1beta and IL-17A production were attenuated in Asc(-/-) and Tlr2(-/-) mice, suggesting that cisplatin induces endogenous TLR2 ligand production and activates the ASC-dependent inflammasome complex, resulting in IL-1beta and injurious IL-17A production. Neutrophils and natural killer cells are the likely targets of these pathways, because combined depletion of these cells was strongly protective; anti-IL-17A antibodies had no additional effect in this setting. Although IL-17A can also be produced by CD4(+) and gammadelta T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in gammadelta T-cell-deficient mice, whereas Il17a(-/-) CD4(+) T cells induced similar injury as did wild-type CD4(+) T cells on transfer to cisplatin-injected Rag1(-/-) mice. These studies demonstrate an important role for TLR2, the ASC inflammasome, and IL-17A in innate leukocytes in cisplatin-induced renal injury. PMID- 24631025 TI - Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the middle aged and elderly with a prevalence of one million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli, creating a reticular network that leads to death by asphyxiation. Lung fibroblasts from patients with IPF have phenotypic hallmarks, distinguishing them from their normal counterparts: pathologically activated Akt signaling axis, increased collagen and alpha-smooth muscle actin expression, distinct gene expression profile, and ability to form fibrotic lesions in model organisms. Despite the centrality of these fibroblasts in disease pathogenesis, their origin remains uncertain. Here, we report the identification of cells in the lungs of patients with IPF with the properties of mesenchymal progenitors. In contrast to progenitors isolated from nonfibrotic lungs, IPF mesenchymal progenitor cells produce daughter cells manifesting the full spectrum of IPF hallmarks, including the ability to form fibrotic lesions in zebrafish embryos and mouse lungs, and a transcriptional profile reflecting these properties. Morphological analysis of IPF lung tissue revealed that mesenchymal progenitor cells and cells with the characteristics of their progeny comprised the fibrotic reticulum. These data establish that the lungs of patients with IPF contain pathological mesenchymal progenitor cells that are cells of origin for fibrosis-mediating fibroblasts. These fibrogenic mesenchymal progenitors and their progeny represent an unexplored target for novel therapies to interdict fibrosis. PMID- 24631026 TI - Islet inflammation, hemosiderosis, and fibrosis in intrauterine growth-restricted and high fat-fed Sprague-Dawley rats. AB - Prenatal and postnatal factors such as intrauterine growth restriction (IUGR) and high-fat (HF) diet contribute to type 2 diabetes. Our aim was to determine whether IUGR and HF diets interact in type 2 diabetes pathogenesis, with particular attention focused on pancreatic islet morphology including assessment for inflammation. A surgical model of IUGR (bilateral uterine artery ligation) in Sprague-Dawley rats with sham controls was used. Pups were fed either HF or chow diets after weaning. Serial measures of body weight and glucose tolerance were performed. At 25 weeks of age, rat pancreases were harvested for histologic assessment. The birth weight of IUGR pups was 13% lower than that of sham pups. HF diet caused excess weight gain, dyslipidemia, hyperinsulinemia, and mild glucose intolerance, however, this was not aggravated further by IUGR. Markedly abnormal islet morphology was evident in 0 of 6 sham-chow, 5 of 8 sham-HF, 4 of 8 IUGR-chow, and 8 of 9 IUGR-HF rats (chi-square, P = 0.007). Abnormal islets were characterized by larger size, irregular shape, inflammation with CD68-positive cells, marked fibrosis, and hemosiderosis. beta-Cell mass was not altered by IUGR. In conclusion, HF and IUGR independently contribute to islet injury characterized by inflammation, hemosiderosis, and fibrosis. This suggests that both HF and IUGR can induce islet injury via converging pathways. The potential pathogenic or permissive role of iron in this process of islet inflammation warrants further investigation. PMID- 24631028 TI - Ventricular arrhythmias are not a short-term reproducible phenomenon--why long recording monitoring is necessary. AB - BACKGROUND: The variability of ventricular arrhythmias (VA) among different days of the week is not well detected by one-day Holter monitoring. AIMS: To evaluate whether there are differences in VA distribution pattern during long recording period. METHODS: The EKG was recorded for 14 h per day during 7 days by Holter system in 34 consecutive pat ventricular couplets and non-sustained ventricular tachycardia (NSVT) recording from patients provided graphic data. We applied the Hurst method (H Coefficient) which evaluates whether a repetitive phenomenon is random or not. When the H is >0.5 and <1 means it is not random and implies a long-term memory effect. Considering the arrhythmic variability, the data were also analyzed by repetitive ANOVA comparing incidence of arrhythmias among the days. RESULTS: Isolated PVCs and ventricular couplets during 98 h recording provided graphic of the occurrence. A trend of increasing and decreasing of arrhythmias was observed which looks erratic. The H coefficient, however, was significantly >0.5 for all patients. Repeated ANOVA showed statistic difference among days in 31 patients with isolated PVCs; in 26 with ventricular couplets and 19 with NSVT when analyzed per hour during week days (p < 0.05). CONCLUSION: PVCs, ventricular couplets and NSVT are not a random phenomenon. Our data suggest the occurrence of ventricular arrhythmias had no similarity among the days, making unlikely that a single Holter recording for 24h may capture this phenomenon. PMID- 24631027 TI - Endothelial NLRP3 inflammasome activation and enhanced neointima formation in mice by adipokine visfatin. AB - Inflammasomes serve as an intracellular machinery to initiate inflammatory response to various danger signals. The present study tested whether an inflammasome centered on nucleotide oligomerization domain-like receptor protein 3 (NLRP3) triggers endothelial inflammatory response to adipokine visfatin, a major injurious adipokine during obesity. NLRP3 inflammasome components were abundantly expressed in cultured mouse microvascular endothelial cells, including NLRP3, apoptosis-associated speck-like protein, and caspase-1. These NLRP3 inflammasome molecules could be aggregated to form an inflammasome complex on stimulation of visfatin, as shown by fluorescence confocal microscopy and size exclusion chromatography. Correspondingly, visfatin significantly increased caspase-1 activity and IL-1beta release in microvascular endothelial cells, indicating an activation of NLRP3 inflammasomes. In animal experiments, direct infusion of visfatin in mice with partially ligated left carotid artery were found to have significantly increased neointimal formation, which was correlated with increased NLRP3 inflammasome formation and IL-1beta production in the intima. Further, visfatin-induced neointimal formation, endothelial inflammasome formation, and IL-1beta production in mouse partially ligated left carotid artery were abolished by caspase-1 inhibition, local delivery of apoptosis-associated speck-like protein shRNA or deletion of the ASC gene. In conclusion, the formation and activation of NLRP3 inflammasomes by adipokine visfatin may be an important initiating mechanism to turn on the endothelial inflammatory response leading to arterial inflammation and endothelial dysfunction in mice during early stage obesity. PMID- 24631029 TI - Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. AB - BACKGROUND: Increased intestinal permeability seems to play a major role in non alcoholic liver disease development and progression. AIM: To investigate the prevalence of altered intestinal permeability in children with non-alcoholic fatty liver disease, and to study its potential association with the stage of liver disease. METHODS: We performed a case-control study examining intestinal permeability in children using the lactulose-mannitol bowel permeability test. RESULTS: Overall, 39 consecutive patients (30 males, median age 12 years) and 21 controls (14 males, median age 11.8 years) were included. The lactulose/mannitol ratio resulted impaired in 12/39 patients (31%) and none of the controls. Intestinal permeability was higher in children with non-alcoholic fatty liver disease (lactulose/mannitol ratios: 0.038+/-0.037 vs. 0.008+/-0.007, p<0.05). Within the non-alcoholic fatty liver disease group, intestinal permeability was increased in children with steatohepatitis compared to those with steatosis only (0.05+/-0.04 vs. 0.03 vs. 0.03, p<0.05). Pathological lactulose/mannitol ratio correlated with portal inflammation (p=0.02), fibrosis (p=0.0002), and ballooning of hepatocytes (p=0.003). Blood lipopolysaccharides levels were higher in children with steatohepatitis (2.27+/-0.68 vs. 2.80+/-0.35, p<0.05). CONCLUSIONS: Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with the severity of the disease. PMID- 24631030 TI - A case of hepatocellular carcinoma: spontaneous regression? PMID- 24631031 TI - Lactoferrin prevents invasion and inflammatory response following E. coli strain LF82 infection in experimental model of Crohn's disease. AB - BACKGROUND: Crohn's disease is a multifactorial disease in which an aberrant immune response to commensal intestinal microbiota leads to chronic inflammation. The small intestine of patients with Crohn's disease is colonized by a group of adherent-invasive Escherichia coli strongly able to adhere and invade intestinal epithelial cells lactoferrin is an iron-binding glycoprotein known to have anti bacterial and anti-inflammatory activities. AIMS: We explore the ability of bovine lactoferrin to modulate the interactions between the adherent-invasive E. coli strain LF82 and intestinal epithelial cells as well as the inflammatory response. METHODS: Bacterial adhesion and invasion assays were used to assess the antimicrobial activity of lactoferrin. Electron microscopy was used to characterize bacteria-cell interactions. The mRNA expression of pro-inflammatory cytokines was measured both in cultured cells and in biopsies taken from intestine of patients affected by Crohn's disease. RESULTS: Lactoferrin inhibited bacterial invasion through minimally affecting adhesion. This divergence was due to a mannose-dependent lactoferrin binding to the bacterial type 1 pili and consequent bacterial aggregation on the intestinal epithelial cell surface. Expression of pro-inflammatory cytokines, such as TNF-alpha, IL-8, and IL-6, was markedly inhibited by lactoferrin both in cultured and Crohn-derived intestinal cells. CONCLUSIONS: Bovine lactoferrin might function via an antibacterial and/or anti-inflammatory mechanism in the treatment of Crohn's disease. PMID- 24631032 TI - Oesophageal capsule endoscopy versus oesophago-gastroduodenoscopy for the diagnosis of recurrent varices: a prospective multicentre study. AB - BACKGROUND: Oesophago-gastroduodenoscopy is the standard method for the diagnosis of recurrent oesophago-gastric varices after endoscopic treatment and eradication. The aim of this study was to evaluate the PillCam Eso capsule endoscopy in this setting. METHODS: Prospective, multicentre study in which patients with history of oesophageal varices treated by band ligation underwent PillCam Eso capsule and oesophago-gastroduodenoscopy. Capsule recordings were blindly read by two endoscopists. Indication for a new prophylactic treatment and patient satisfaction were determined for both procedures. RESULTS: 80 patients (80% males, mean age: 57+/-12 years) were included, after a median delay of 16 months from last endoscopic treatment. Recurrent oesophageal varices requiring a new prophylactic treatment were detected in 26 patients (32.5%). The mean oesophageal transit time of the capsule was 153 s (range 2-930 s). Capsule sensitivity, specificity, negative and positive predictive values for indication of new prophylactic treatments were 65%, 83%, 83%, and 65%, respectively. Capsule adequately classified 77.5% of the patients for prophylaxis indication. Inter observer concordance for capsule readings was 88% for the prophylaxis indication. CONCLUSION: This study demonstrates that accuracy of PillCam Eso capsule for the diagnosis of recurrent oesophageal varices after endoscopic eradication is suboptimal. PillCam Eso capsule might therefore be proposed in patients unable or unwilling to undergo oesophago-gastroduodenoscopy. PMID- 24631033 TI - Diversity of astroglial functions alludes to subcellular specialisation. AB - Rapid signal exchange between astroglia and neurons has emerged as an essential element of neural circuits of the brain. However, the increasing variety of mechanisms contributing to this signalling appears to be facing a conceptual stalemate. The communication medium of astroglia involves intracellular [Ca(2+)] waves, which until recently have been associated with slow, global [Ca(2+)] rises. How such a uniform trigger could handle fast and diverse molecular messages remains unexplained. Recent studies have, however, revealed a variety of apparently independent Ca(2+) activities within individual astrocytic compartments, also indicating the prevalence of subcellular segregation for some signalling mechanisms. These signs of intracellular compartmentalisation might provide the key to the multitude of adaptive roles played by astroglia. PMID- 24631034 TI - Wide area detector CT perfusion: can it differentiate osteoid osteomas from other lytic bone lesions? AB - PURPOSE: To compare the enhancement dynamics of osteoid osteomas with other benign and malignant lytic bone lesions using CT perfusion. PATIENTS AND METHODS: CT perfusion parameters of 15 patients with a final diagnosis of osteoid osteoma, 15 patients with lesions that mimic osteoid osteomas and 26 patients with other bone lytic lesions were compared. RESULTS: Enhancement curve morphology of the osteoid osteomas was significantly different from its mimickers. All osteoid osteomas had an early enhancement with a delay between nidus and arterial peak below 30 seconds. Eighty percent of the mimickers demonstrated a slow and progressive enhancement. The perfusion parameters of the other lytic bone lesions were similar to those of the osteoid osteomas in 46.1% of the patients. CONCLUSION: Early enhancement is suggestive but not pathognomonic of osteoid osteomas. Absent or delayed enhancement in similar lesions should evoke an alternative diagnosis. The same contrast enhancement dynamics of osteoid osteomas can be seen in other bone lesions, both malignant and benign. PMID- 24631035 TI - Umbilical vein varix: Importance of ante- and post-natal monitoring by ultrasound. AB - Foetal intra-abdominal umbilical vein varix is rare. Colour Doppler ultrasonography helps distinguish this vascular anomaly. A detailed anatomic scan must be performed to exclude associated anomalies: forms associated with additional complications are found in 29 to 35% of the cases. Intra-uterine foetal demise (IUFD) is a complication of umbilical vein varix. However, recent studies are more reassuring. When foetal intra-abdominal umbilical vein varix is isolated, there is no reason to change the management of the pregnancy. Foetal sonographic follow-up is recommended, focusing on an increase in the size of the varix and the appearance of a clot. A particular clinical form, connecting the umbilicus to the extra-hepatic portal vein should be known, because of a high risk of thrombosis. On the basis of this finding, postnatal monitoring by ultrasound is necessary. PMID- 24631036 TI - High intensity focused ultrasound: imaging is the key! PMID- 24631037 TI - Unilateral testicular vasculitis in polyarteritis nodosa mimicking a testicular torsion. PMID- 24631038 TI - Endovascular treatment in patients with acute ischemic stroke: technical aspects and results. AB - Ischemic stroke is the primary cause of acquired disability in the world and its treatment is still a challenge. Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA) administered within 41/2 hours of the onset of the symptoms is the only approved medical treatment in the acute phase of cerebral infarction. However, its efficacy is limited where there is proximal intracranial arterial occlusion, and there are many contraindications. The endovascular approach, combined or not with IV thrombolysis, allows high rates of recanalization to be achieved within a short period of time, with a low rate of procedural complications when thrombolysis is less effective (internal carotid artery, M1 segment of the middle cerebral artery). In these situations, endovascular techniques are playing an increasing role in the treatment of these patients even though there is still no indisputable scientific proof of their efficacy. The priority at present is to finish the French THRACE study, but it is already time to think about the next one. PMID- 24631039 TI - CT imaging of peritoneal carcinomatosis and its mimics. AB - Invasive peritoneal disease includes more than just peritoneal carcinomatosis. Although this is the most common aetiology, especially when a primary is found, other conditions may be responsible for peritoneal invasion. A rigorous analysis of CT features taken together with the clinical and biological context usually allows the main differential diagnoses, which entail different types of management, to be drawn out. Pseudomyxoma peritonei, peritoneal lymphomatosis, tuberculosis, peritoneal mesothelioma, diffuse peritoneal leiomyomatosis, and benign splenosis are the main differential diagnoses. PMID- 24631040 TI - Differential expression and anti-oxidant function of glutathione peroxidase 3 in mouse uterus during decidualization. AB - Glutathione peroxidase 3 (GPX3) is an important member of antioxidant enzymes for reducing reactive oxygen species and maintaining the oxygen balance. Gpx3 mRNA is strongly expressed in decidual cells from days 5 to 8 of pregnancy. After pregnant mice are treated with GPX inhibitor for 3 days, pregnancy rate is significantly reduced. Progesterone stimulates Gpx3 expression through PR/HIF1alpha in mouse endometrial stromal cells. In the decidua, the high level of GPX3 expression is closely associated with the reduction of hydrogen peroxide (H2O2). Based on our data, GPX3 may play a major role in reducing H2O2 during decidualization. PMID- 24631041 TI - Ultrasound-guided facet joint injection to treat a spinal cyst. AB - Lumbar spinal cysts often present with backache and may be accompanied by lower extremity weakness as well as radiation pain if root compression occurs. The treatment regimens include anti-inflammatory drugs, physical therapy, procedures guided by fluoroscopy or computed tomography, and surgery. We report the case of a patient with a symptomatic lumbar spinal cyst at the L4-L5 facet joint. The symptoms immediately remitted after ultrasound-guided steroid-lidocaine injection into the L4-L5 facet joint. Magnetic resonance imaging follow up 4 months after injection showed complete resolution of the cyst. PMID- 24631042 TI - Efficacy and safety of Abelmoschus manihot for primary glomerular disease: a prospective, multicenter randomized controlled clinical trial. AB - BACKGROUND: Abelmoschus manihot, a single medicament of traditional Chinese medicine, has been widely used to treat kidney disease. This is the first randomized controlled clinical trial to assess its efficacy and safety in patients with primary glomerular disease. STUDY DESIGN: Prospective, open-label, multicenter, randomized, controlled, clinical trial. SETTING & PARTICIPANTS: From May 2010 to October 2011, a total of 417 patients with biopsy-proven primary glomerular disease from 26 hospitals participated in the study. INTERVENTIONS: A manihot in the form of a huangkui capsule, 2.5 g, 3 times per day; losartan potassium, 50mg/d; or combined treatment, a huangkui capsule at 2.5 g 3 times per day, was combined with losartan potassium, 50mg/d. The duration of intervention was 24 weeks. OUTCOMES & MEASUREMENTS: The primary outcome was change in 24-hour proteinuria from baseline after treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after treatment was a secondary outcome. The 24-hour proteinuria was measured every 4 weeks and eGFR was measured at 0, 4, 12, and 24 weeks. RESULTS: Mean baseline urine protein excretion was 1,045, 1,084, and 1,073 mg/d in the A manihot, losartan, and combined groups, respectively, and mean eGFR was 108, 106, and 106 mL/min/1.73 m2, respectively. After 24 weeks of treatment, mean changes in proteinuria were protein excretion of -508, -376, and 545 mg/d, respectively (P=0.003 for A manihot vs losartan and P<0.001 for the combined treatment vs losartan). Mean eGFR did not change significantly. The incidence of adverse reactions was not different among the 3 groups (P>0.05), and there were no severe adverse events in any group. LIMITATIONS: Results cannot be generalized to those with nephrotic syndrome or reduced eGFR. CONCLUSIONS: A manihot is a promising therapy for patients with primary kidney disease (chronic kidney disease stages 1-2) with moderate proteinuria. PMID- 24631043 TI - Fragility fractures and osteoporosis in CKD: pathophysiology and diagnostic methods. AB - Both chronic kidney disease (CKD) and osteoporosis are major public health problems associated with an aging population. Osteoporosis is characterized by reduced bone mineral density, while CKD results in qualitative changes in bone structure; both conditions increase the predisposition to fragility fractures. There is a significant coprevalence of osteoporotic fractures and CKD, particularly in the elderly population. Not only is the risk of fracture higher in the CKD population, but clinical outcomes are significantly worse, with substantial health care costs. Management of osteoporosis in the CKD population is particularly complex given the impact of renal osteodystrophy on bone quality and the limited safety and hard outcome data for current therapy in patients with severe CKD or on dialysis therapy. In this review, we discuss the pathophysiology of osteoporosis, the impact of CKD on bone strength, and the role of novel imaging techniques and biomarkers in predicting underlying renal osteodystrophy on bone histomorphometry in the context of CKD. PMID- 24631044 TI - The effect of ex vivo lung perfusion on microbial load in human donor lungs. AB - BACKGROUND: Ex vivo lung perfusion (EVLP) has emerged as a technique to potentially recondition unusable donor lungs for transplantation. Beneficial effects of EVLP on physiologic function have been reported, but little is known about the effect of normothermic perfusion on the infectious burden of the donor lung. In this study, we investigated the effect of EVLP on the microbial load of human donor lungs. METHODS: Lungs from 18 human donors considered unusable for transplantation underwent EVLP with a perfusate containing high-dose, empirical, broad-spectrum anti-microbial agents. Quantitative cultures of bacteria and fungi were performed on bronchoalveolar lavage fluid from the donor lung before and after 3 to 6 hours of perfusion. The identification of any organisms and changes in number of colony forming units before and after EVLP were assessed and anti microbial susceptibilities identified. RESULTS: Thirteen out of 18 lungs had positive cultures, with bacterial loads significantly decreasing after EVLP. Yeast loads increased when no anti-fungal treatment was given, but were reduced when prophylactic anti-fungal treatment was added to the circuit. Six lungs were ultimately transplanted into patients, all of whom survived to hospital discharge. There was 1 death at 11 months. CONCLUSIONS: Our study shows that EVLP with high-dose, empirical anti-microbial agents in the perfusate is associated with an effective reduction in the microbial burden of the donor lung, a benefit that has not previously been demonstrated. PMID- 24631045 TI - Intrinsic correlation of oligonucleotides: a novel genomic signature for metagenome analysis. AB - Because a vast majority (99%) of microbes in a given community is likely to be non-cultivable, metagenomics has gradually entered the mainstream of microbial research methods. With the development of high-throughput sequencing techniques, an increasing number of sequencing read data sets of metagenomes from various microbial communities have become available. For these data sets, metagenomic analysis based on mapping reads to microbial genomes has been hampered by the limited number of microbial genomes that are available. Further, this type of analysis is computationally intensive. Thus alignment-free methods, which characterize the sequencing reads with a genomic signature instead of with genomic alignments, can be applied. However, the main requirement of these alignment-free methods is a stable genomic signature that performs reliably. Here, we propose a novel genomic signature of microbial genomes called the intrinsic correlation of oligonucleotides (ICOs). This signature represents the quantification of an intrinsic relationship between any two oligonucleotides. We analyzed microbial genomes at different taxonomic levels using ICO profiles and confirmed the wide availability of useful ICOs. We used intra-genomic and inter genomic distances and relational grades to evaluate the performance of ICOs as a genomic signature. The results of these experiments showed that ICOs can characterize microbial genomes well, and ICOs were better at distinguishing species than tetranucleotide composition, not only in terms of whole genomes but also in terms of sequence fragments. In addition, we evaluated the performance of a hybrid feature that combined ICOs and tetranucleotide composition. The experimental results showed that the hybrid feature performed better than ICOs or tetranucleotide composition alone. ICOs can characterize microbial genomes successfully and are capable of distinguishing organisms at different taxonomic levels. ICOs perform better than tetranucleotide composition in characterizing microbial genomes. The hybrid feature that used a combination of the two kinds of sequence features had advantages over a single sequence feature. PMID- 24631046 TI - Evolutionary branching in deme-structured populations. AB - Adaptive dynamics shows that a continuous trait under frequency dependent selection may first converge to a singular point followed by spontaneous transition from a unimodal trait distribution into a bimodal one, which is called "evolutionary branching". Here, we study evolutionary branching in a deme structured population by constructing a quantitative genetic model for the trait variance dynamics, which allows us to obtain an analytic condition for evolutionary branching. This is first shown to agree with previous conditions for branching expressed in terms of relatedness between interacting individuals within demes and obtained from mutant-resident systems. We then show this branching condition can be markedly simplified when the evolving trait affect fecundity and/or survival, as opposed to affecting population structure, which would occur in the case of the evolution of dispersal. As an application of our model, we evaluate the threshold migration rate below which evolutionary branching cannot occur in a pairwise interaction game. This agrees very well with the individual-based simulation results. PMID- 24631047 TI - Refining network reconstruction based on functional reliability. AB - Reliable functioning is crucial for the survival and development of the genetic regulatory networks in living cells and organisms. This functional reliability is an important feature of the networks and reflects the structural features that have been embedded in the regulatory networks by evolution. In this paper, we integrate this reliability into network reconstruction. We introduce the concept of dependency probability to measure the dependency of functional reliability on network edges. We also propose a method to estimate the dependency probability and select edges with high contributions to functional reliability. We use two real examples, the regulatory network of the cell cycle of the budding yeast and that of the fission yeast, to demonstrate that the proposed method improves network reconstruction. In addition, the dependency probability is robust in calculation and can be easily implemented in practice. PMID- 24631048 TI - [Long-term macrolide treatment in adult chronic bronchial diseases: benefits and limits]. AB - Decreased frequency of pulmonary exacerbations, mainly related to immunomodulatory effects of macrolide antibiotics, has been demonstrated in bronchiectasis and chronic obstructive pulmonary diseases (COPD). Due to its tolerance, azithromycin is the antibiotic of choice for maintenance therapy at the dose of 250 mg per day or 500 mg * 3 per week (for body weight >55 kg). Maintenance therapy with macrolide could be proposed in selected patients with bronchiectasis or COPD with more than 3 acute exacerbations in the previous year or decreased lung function despite compliance with optimum treatment. The risk of sudden cardiac death with azithromycin is rare and controversial. It should be avoided in patients with a high baseline risk of cardiovascular disease, QT>450 msec, pulse rate>100 bpm and potential drug interactions, particularly those known to cause QT prolongation. It is recommended to search for hearing deficit (audiometry) and sputum culture positive for mycobacteria. Patients must also be aware that it can rapidly lead to macrolide resistance in commensal or pathogenic flora. Follow-up evaluation every 3 month can be proposed with medical history (hearing deficit) and electrocardiography. After one year, the treatment should be stopped in the absence of reduction in the frequency of exacerbations. PMID- 24631049 TI - [Family history of sudden death due to idiopathic ventricular fibrillation]. PMID- 24631051 TI - [Arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement and intracavitary thrombus: diagnosis with cardiac magnetic resonance]. PMID- 24631052 TI - Drug-resistant tuberculosis in the WHO European Region: an analysis of surveillance data. AB - To review the latest information about levels of anti-tuberculosis (TB) drug resistance in the European Region of the World Health Organization (WHO) and time trends in multidrug-resistant TB (resistance to isoniazid and rifampicin; MDR-TB) over the past fifteen years. We analysed data on drug resistance among new and previously treated TB cases reported from 1997 to 2012. Data are collected in surveys of representative samples of TB patients or from surveillance systems based on diagnostic drug susceptibility testing. A total of 15.7% (95% confidence limits (CI): 9.5-21.9) of new and 45.3% (95%CI: 39.2-51.5) of previously treated TB cases are estimated to have MDR-TB in the Region. Extensively drug-resistant TB (MDR-TB and resistance to fluoroquinolones and second-line injectables; XDR TB) had been reported by 38 of the 53 countries of the region (72%). The proportion of MDR-TB cases with XDR-TB is 11.4% (95%CI: 8.6-14.2). Between 1997 and 2012, population rates of MDR-TB declined in Estonia, Latvia and Germany and increased in the United Kingdom, Sweden and Tomsk Oblasts of the Russian Federation. Surveillance of drug resistance has been strengthened in the WHO European Region, which has the highest proportions of MDR-TB and XDR-TB ever reported globally. More complete data are needed particularly from the Russian Federation. PMID- 24631054 TI - Influences of process and formulation parameters on powder flow properties and immunogenicity of spray dried polymer particles entrapping recombinant pneumococcal surface protein A. AB - Particle size, antigen load and its release characteristic are the three the main attributes of polymer particles based vaccine delivery systems. The present studies focus on the formulation of spray dried polylactide microparticles entrapping pneumococcal surface protein A (PspA). Influence of process variables during polymer particle formation were optimized by using half-factorial design. Feed rate and atomization pressure during spray drying were found to be the most important parameters for achieving uniform size particles. Spray drying of preformed particles from different stages of solvent evaporation method resulted in formation of particle having different porosity and protein release profile. Presence of polyvinyl alcohol in the external aqueous phase not only contributed towards regulating the size of particles but also influenced the burst release of protein from particles. Polymer particles entrapping PspA elicited robust IgG responses both in mice and in rats. Antigen load in microparticles correlated with the antibody titer indicating the maintenance of protein integrity during particle formation using spray drying. Both, process engineering and formulation parameters during spray drying influenced the particles in terms of size, load and antigen release characteristics. PMID- 24631053 TI - Synthesis and characterization of polyaspartamide copolymers obtained by ATRP for nucleic acid delivery. AB - Nucleic acid molecules such as small interfering RNAs (siRNAs) and plasmidic DNAs (pDNAs) have been shown to have the potential to be of therapeutic value in different human diseases. Their practical use is however compromised by the lack of appropriate release systems. Delivered as naked molecules, siRNAs/pDNAs are rapidly degraded by extracellular nucleases thus considerably reducing the amount of molecule which can reach the target cells. Additionally, the anionic charge of the phosphate groups present on the siRNAs/pDNAs backbone, disfavors the interaction with the negatively charged surface of the cell membrane. In this paper we describe the generation of a novel polymer able to deliver both siRNAs and pDNAs. The combined release of these molecules is used in many different experimental settings such as the evaluation of the silencing efficiency of a given siRNA targeted against a given RNA, encoded by the pDNA. The possibility to use the same delivery system is very convenient from the technical point of view and it allows minimizing possible artifacts introduced by the use of different delivery agents for siRNAs and pDNA. The copolymer described here is based on alpha,beta-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) bearing positively chargeable side oligochains, with diethylamino ethyl methacrylate (DEAEMA) as monomer. Monomer polymerization has been obtained by atom transfer radical polymerization (ATRP), a technique which allows the precise polymerization of the monomer. In addition to the chemical-physical characterization of the polymer, we provide evidences of the polymer ability to delivery both siRNAs and pDNA to cultured cells. Whereas additional investigations are necessary to study the delivery mechanisms of this polyplex, the polymer generated represents a novel and convenient device for the delivery of both siRNAs and pDNA. PMID- 24631055 TI - Enhanced recovery from obstetric surgery: a U.K. survey of practice. AB - BACKGROUND: In the UK earlier discharge of patients following elective caesarean section would require that more patients are discharged the day after surgery. The introduction of enhanced recovery in other specialties has resulted in shorter postoperative stay. We surveyed current U.K. practice to find whether this was consistent with enhanced recovery and what changes units would need to introduce to establish such a programme. METHODS: We conducted an Obstetric Anaesthetists' Association approved electronic survey of all the U.K. lead obstetric anaesthetists between March and May 2013. RESULTS: A response rate of 81% was achieved with 96% of those who responded supporting the concept of enhanced recovery. Only 4% of units routinely discharged their patients on day one. There were a number of practices consistent with enhanced recovery. Postoperative pain was controlled by regular paracetamol (97%) and non-steroidal anti-inflammatory drugs (100% when not contraindicated), with oral opioids (68%) being used for breakthrough pain. Over 70% of units allowed minimal interruption of perioperative oral intake and 72% of units mobilised their patients within 12h of surgery or when the neuraxial block had worn off. In contrast, a minority of units monitored patient temperature in theatre (27%) or used active warming (18%), and 28% routinely removed the urinary catheter within 12h of surgery or when the neuraxial block had worn off. Regarding neonatal recovery, only 23% reported using delayed cord clamping and 53% used skin-to-skin contact in theatre. CONCLUSION: Most obstetric units support the concept of enhanced recovery following caesarean section and many could introduce a programme for elective surgery with relatively small changes in patient care. PMID- 24631056 TI - Relaxant effects of metoclopramide and magnesium sulfate on isolated pregnant myometrium: an in vitro study. AB - BACKGROUND: Metoclopramide and magnesium sulfate are extensively used agents in obstetrics. In this study, the relaxant properties of metoclopramide and magnesium sulfate on pregnant myometrium, together with the possible reversing influences of oxytocin and cabergoline (a dopamine D2 receptor agonist), were investigated. METHODS: Myometrial strips from 24 parturients were randomly allocated to four groups: control (Group CON), magnesium sulfate and oxytocin (Group MSO), metoclopramide and oxytocin (Group MEO), and metoclopramide and cabergoline (Group MEC). Myometrial strips were mounted on a myograph bathed in Krebs buffer. Saline (Group CON) and five incremental doses of magnesium sulfate (Group MSO) or metoclopramide (Groups MEO and MEC) were sequentially microinjected into the bath. Subsequently, oxytocin (Groups CON, MSO and MEO) or cabergoline (Group MEC) was microinjected into the bath. The myometrial contractile characteristics after each drug injection, including contractile force, interval and duration, were analyzed. RESULTS: Magnesium sulfate was more potent for prolonging myometrial contractile interval than reducing contractile force. Metoclopramide relaxed myometrial contractions by inhibiting contractile force and prolonging contractile interval in a concentration-dependent manner. Oxytocin reversed both the inhibited contractile force and the prolonged contractile interval caused by a high concentration of magnesium sulfate but accelerated the contractile interval and had no significant effect on the contractile force suppressed by metoclopramide. The relaxant effects of metoclopramide were completely reversed by cabergoline. CONCLUSIONS: Both magnesium sulfate and metoclopramide relaxed myometrial contractions, and exhibited different responses to subsequent oxytocin treatment. The relaxant mechanism of metoclopramide may be via blockade of dopamine D2 receptor, which requires further investigation. PMID- 24631057 TI - The effect of intravenous ondansetron on maternal haemodynamics during elective caesarean delivery under spinal anaesthesia: a double-blind, randomised, placebo controlled trial. AB - BACKGROUND: Spinal anaesthesia for caesarean delivery is frequently associated with adverse effects such as maternal hypotension and bradycardia. Prophylactic administration of ondansetron has been reported to provide a protective effect. We studied the effect of different doses of ondansetron in obstetric patients. METHODS: This prospective double-blind, randomised, placebo-controlled study included 128 healthy pregnant women scheduled for elective caesarean delivery under spinal anaesthesia. Women were randomly allocated into four groups (n=32) to receive either placebo or ondansetron 2, 4 or 8 mg intravenously before induction of spinal anaesthesia. Demographic, obstetric, intraoperative timing and anaesthetic variables were assessed at 16 time points. Anaesthetic variables assessed included blood pressure, heart rate, oxygen saturation, nausea, vomiting, electrocardiographic changes, skin flushing, discomfort or pruritus and vasopressor requirements. RESULTS: There were no differences in the number of patients with hypotension in the placebo (43.8%) and ondansetron 2mg (53.1%), 4 mg (56.3%) and 8 mg (53.1%) groups (P=0.77), nor the percentage of time points with systolic hypotension (7.3% in the placebo group and 11.1%, 15.7% and 12.6% in the ondansetron 2, 4 and 8 mg groups, respectively, P=0.32). There were no differences between groups in ephedrine (P=0.11) or phenylephrine (P=0.89) requirements and the number of patients with adverse effects. CONCLUSIONS: In our study, prophylactic ondansetron had little effect on the incidence of hypotension in healthy parturients undergoing spinal anaesthesia with bupivacaine and fentanyl for elective caesarean delivery. PMID- 24631058 TI - Effects of a head elevated ramped position during elective caesarean delivery after combined spinal-epidural anaesthesia. AB - BACKGROUND: Elevating the torso in a Head Elevated Ramped Position during caesarean delivery benefits the mother by improving comfort and ventilation while reducing reflux symptoms and providing a better airway position. We hypothesised that using an elevation pillow for an elective caesarean delivery under combined spinal-epidural anaesthesia would not significantly increase the time to achieve a T4 block. METHODS: Following ethical approval and informed consent, 60 women undergoing elective caesarean delivery under combined spinal-epidural anaesthesia were randomised to one of three groups: Control - horizontal with a small pillow under the head; Head Elevated Ramped Position - torso on an elevation pillow; and Head Elevated Ramped Position with initial position horizontal. Data collected were time to T4, block height at 30 and 120 min, adequate block at 12 min, need for epidural supplementation, maternal comfort and airway position assessment. RESULTS: Time to T4 among the three groups was not significantly different (P=0.14). However, there was a significant difference in achievement of block height of T4 at 12 min and greater need for epidural supplementation in the intervention groups compared to the control group (P=0.021). Non-inferiority analyses of time to T4 of both head elevated ramped positions were inconclusive about inferiority relative to the control. Head Elevated Ramped Position was significantly more comfortable than control (P=0.007). Using the level of the external auditory meatus to the sternal notch as an indicator for ease of laryngoscopy, Head Elevated Ramped Position provided a significantly better position than control (P<0.001). CONCLUSION: Elevating the parturient undergoing elective caesarean delivery into the Head Elevated Ramped Position immediately or once the block had been established did not appear to significantly alter time to an adequate block height of T4; however, the need for epidural supplementation was greater in the intervention groups. Cautious use of this novel position change can provide a more comfortable experience and provide a better airway position should conversion to general anaesthesia be required. PMID- 24631059 TI - Brachial plexus block in a parturient. AB - We report a novel circumstance of brachial plexus anesthesia in a parturient. A 25-year-old woman at 34 weeks of gestation presented with a pathologic proximal right humerus fracture from an intramedullary mass. She was scheduled for tumor biopsy which was performed using a two-site ultrasound-guided brachial plexus block to maximize odds of complete anesthesia while minimizing the risk of phrenic nerve paresis. After a supraclavicular block with 0.5% ropivacaine 20 mL, we translated our ultrasound probe cephalad, inferior to the root of C7 where the divisions of the superior trunk could be seen in a tightly compact arrangement. An additional injection of 0.5% ropivacaine 20 mL was administered at this site, and the patient subsequently underwent successful biopsy without sedatives or analgesics, aside from local anesthetics. In the post-anesthesia care unit, she had normal respirations and oxygen saturations breathing room air, denied any shortness of breath or difficulty breathing, and was discharged shortly after her arrival. While we did not pursue radiologic examination to rule out hemidiaphragm paralysis, we assumed, as evidenced in a previous case report, that unlike most healthy patients, a parturient would demonstrate some clinical signs and/or symptoms of hemidiaphragm paralysis, given that the diaphragm is almost totally responsible for inspiration in the term parturient. This represents only the second brachial plexus block in a parturient reported in the literature; the first using ultrasound guidance and without respiratory embarrassment. PMID- 24631060 TI - Concealed paracetamol overdose treated as HELLP syndrome in the presence of postpartum liver dysfunction. AB - Paracetamol is the most frequently used analgesic during pregnancy and the most common drug involved in suicidal overdose in the UK. Manifestation of toxicity classically occurs over four phases with clinical and laboratory features resembling HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome. We report a case that was erroneously managed as HELLP syndrome before a paracetamol overdose was diagnosed. This case highlights current practice in managing paracetamol overdose and focuses on the importance of addressing mental health issues to mitigate the risk of self-harm in pregnancy. PMID- 24631061 TI - Anesthetic considerations in a parturient with oral-facial-digital syndrome and repaired tetralogy of Fallot with left ventricular dysfunction. AB - Oral-Facial-Digital syndrome or Mohr syndrome is a rare congenital disorder characterized by malformations of face, oral cavity, laryngeal structures, trachea, and digits, muscular-skeletal abnormalities, and congenital cardiac defects. In this case report, we describe the anesthetic management of a parturient with Oral-Facial-Digital syndrome type II and repaired tetralogy of Fallot with left ventricular dysfunction. PMID- 24631062 TI - Observational study of changes in epidural pressure and elastance during epidural blood patch in obstetric patients. AB - BACKGROUND: During an epidural blood patch, we inject blood until the patient describes mild back pressure, often leading to injection of more than 20 mL of blood. We undertook this study to measure the epidural pressures generated during an epidural blood patch and to identify the impact of volume on epidural elastance in obstetric patients. METHODS: This study was performed in postpartum patients who presented for an epidural blood patch with symptoms consistent with a postdural puncture headache. After identification of the epidural space using loss of resistance to air or saline, we measured static epidural pressure after each 5-mL injection of blood. Models were then fitted to the data and the epidural elastance and compliance calculated. RESULTS: Eighteen blood patches were performed on 17 patients. The mean final volume injected was 18.9+/-7.8 mL [range 6-38 mL]. The mean final pressure generated was 13.1+/-13.4 mmHg [range 2 56 mmHg]. A curvilinear relationship existed between volume injected and pressure, which was described by two models: (1) pressure=0.0254*(mL injected)(2)+0.0297 mL, or (2) pressure=0.0679*mL(1.742). The value for r2 was approximately 0.57 for both models. We found no correlation between the final pressure generated and the success of the epidural blood patch. CONCLUSIONS: We found a curvilinear relationship between the volume of blood injected during an epidural blood patch and the pressure generated in the epidural space. However, there was a large variation in both the volume of blood and the epidural pressure generated. The clinical importance of this finding is not known. A larger study would be required to demonstrate whether pressure is a predictor of success. PMID- 24631063 TI - Piroxicam inhibits Masitinib-induced cyclooxygenase 2 expression in oral squamous cell carcinoma cells in vitro. AB - Development and characterization of animal models for human cancers is important for the improvement of diagnosis and therapy. The oral squamous cell carcinoma (OSCC) of domestic animals resembles human OSCC in many aspects; thus, cell lines derived from OSCC of cats and dogs are a valuable model for human OSCC. We characterized 1 feline OSCC (FeOSCC-Sidney) and 1 canine OSCC (K9OSCC-Abby) cell line and compared their characteristics with human OSCC cell line hSCC-25. We calculated the doubling time of the new OSCC cell lines and evaluated the expression profiles of cancer-related markers and cell-cycle proteins such as c kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, epidermal growth factor receptor, cyclooxygenase (COX)-1, COX-2, and p27 by immunocytochemistry and Western blot analysis. We evaluated the effects of novel receptor tyrosine kinase inhibitor (Masitinib, AB1010) and the nonsteroidal anti-inflammatory drug piroxicam on the previously mentioned OSCC cells. Interestingly, AB1010 increased expression levels of COX-2 in all tested OSCCs. Cotreatment of piroxicam with Masitinib significantly inhibited cell proliferation of OSCC as compared to either drug alone through the c-kit and AKT signaling pathways. Piroxicam inhibited Masitinib-induced COX-2 expression in all tested OSCCs. Therefore, targeting these two signaling pathways simultaneously was more efficient for inhibition of OSCCs across these species. PMID- 24631065 TI - Biosensor based on lectin and lipid membranes for detection of serum glycoproteins in infected patients with dengue. AB - In this work, we developed a biosystem based on Concanavalin A (ConA) and lipid membranes to recognize glycoproteins from the serum of patients contaminated with dengue serotypes 1, 2 and 3 (DENV1, DENV2 and DENV3). The modified gold electrode was characterized using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and atomic force microscopy. Morphological analyses of 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), DPPC-ConA, DPPC-ConA-DENV1, DPPC ConA-DENV2 and DPPC-ConA-DENV3 revealed the existence of a non-uniform covering and large globules. EIS and CV measurements have shown that redox probe reactions on the modified gold electrodes were partially blocked due to the adsorption of lipid-ConA system and reveal the interaction response of the immobilized ConA to the presence of glycoproteins of dengue serum. The biosystem exhibited a wide linear response to different concentrations of sera of dengue serotypes 1, 2 and 3. A higher impedimetric response to glycoproteins present in dengue serotype 3 was observed. Our results demonstrate the applicability of lectin and lipid membranes to the development of biosensors for dengue infections. PMID- 24631066 TI - Proatherogenic modification of LDL by surface-bound myeloperoxidase. AB - One of the factors promoting oxidative/halogenating modification of low-density lipoproteins (LDL) is myeloperoxidase (MPO). We have shown previously that MPO binds to the LDL surfaces. The LDL-MPO complex is uncoupled in the presence of peptide EQIQDDCTGDED that corresponds to a fragment of apoB-100 (445-456). In this paper we studied how this peptide, as well as inhibitors and modulators of halogenating activity of MPO such as ceruloplasmin (CP), 4-aminobenzoic acid hydrazide (ABAH) and thiocyanate (SCN(-)) affect the accumulation of cholesterol and its esters in monocytes/macrophages after incubation with LDL subjected to different kinds of MPO-dependent oxidative/halogenating modification. In the presence of H2O2 and halides MPO causes stronger proatherogenic modification of LDL than exogenous reactive halogen species (HOCl and HOBr). Both monocytes, which differentiate into macrophages, and neutrophils secrete MPO in response to the presence of damaged LDL. The peptide EQIQDDCTGDED preventing interaction between MPO and LDL reduces the uptake of modified LDL and MPO by monocytes/macrophages and thus precludes the accumulation of intracellular cholesterol. Our results indicate that binding to MPO is important for LDL to become modified and acquire proatherogenic properties. The peptide EQIQDDCTGDED, CP, ABAH, and SCN(-) can play the role of anti-atherogenic factors reducing the deleterious effect of catalytically active MPO on LDL and accumulation of cholesterol in macrophages. PMID- 24631064 TI - Plasma and serum L-selectin and clinical and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - L-selectin has been suggested to play a role in atherosclerosis. Previous studies on cardiovascular disease (CVD) and serum or plasma L-selectin are inconsistent. The association of serum L-selectin (sL-selectin) with carotid intima-media thickness, coronary artery calcium, ankle-brachial index (subclinical CVD), and incident CVD was assessed in 2403 participants in the Multiethnic Study of Atherosclerosis. Regression analysis and the Tobit model were used to study subclinical disease; Cox proportional hazards regression, for incident CVD. Mean age was 63 +/- 10 years and 47% were male. Mean sL-selectin was significantly different across ethnicities. Within each race/ethnicity, sL-selectin was associated with age and sex; among non-Hispanic whites and African Americans, it was associated with smoking status and current alcohol use. sL-selectin levels did not predict subclinical or clinical CVD after correction for multiple comparisons. Conditional logistic regression models were used to study the association of plasma L-selectin and CVD in 154 incident CVD cases, and 306 age-, sex-, and ethnicity-matched control subjects. The median follow-up time was 8.5 years. L-selectin levels in plasma were significantly lower than in serum and the overall concordance was low. Plasma levels were not associated with CVD. In conclusion, in this large, multiethnic population, soluble L-selectin levels did not predict clinical or subclinical CVD. PMID- 24631067 TI - Molecular and component volumes of N,N-dimethyl-N-alkylamine N-oxides in DOPC bilayers. AB - The volumetric properties of fluid bilayers formed of dioleoylphosphatidylcholine (DOPC) with incorporated N,N-dimethyl-N-alkylamine N-oxides (CnNO, n=6, 10-18 is the even number of carbons in alkyl chain) were studied by vibrating tube densitometry in the temperature interval from 20 degrees C to 50 degrees C. It was found that the DOPC and CnNO mixed ideally in the investigated composition range and hence the molecular volumes of DOPC (VDOPC) and incorporated CnNO (VCnNO) were constant and additive within error limits. From the temperature dependencies of the molecular volumes of DOPC and CnNO their coefficients of isobaric thermal expansivities in the investigated temperature interval were obtained. The VCnNO volumes of CnNO incorporated into DOPC bilayers showed linear dependencies on the CnNO alkyl chain length at all measured temperatures. This allowed to calculate the component volume of the CnNO methylene group (VCH2) at several temperatures and its coefficient of isobaric thermal expansivity. Using the assumption that the component volume of the CnNO methyl group VCH3 = 2VCH2 we also calculated the component volume and the coefficient of isobaric thermal expansivity of the hydrophilic group of CnNO (VNO). We found that the VCH2 volume increases in the whole temperature interval whereas the VNO volume decreases. PMID- 24631068 TI - Impact of immunization with Protein F on pulmonary clearance of nontypeable Haemophilus influenzae. AB - Nontypeable Haemophilus influenzae (NTHi) is one of the main aetiologies of childhood bacterial infections as well as exacerbations in COPD patients. Currently, no licensed NTHi vaccine exists. In the present study, we evaluated the potential of the conserved and ubiquitous surface protein Haemophilus Protein F (PF) as a vaccine candidate. Our results show that incubation of NTHi with anti PF antibodies significantly increased the opsonophygocytosis of human promyelocytic leukemia cell line-derived granulocytes, leading to efficient killing of the bacteria (P<=0.05). The presence of anti-PF IgG titers in healthy adults (n=60) was investigated, and we found that 26% of healthy blood donors carried antibodies with the main antigenic epitope being PF(23-48). Finally, mice immunized with PF(23-48) attained a significantly increased capacity to clear NTHi as compared to a control group immunized with a peptide derived from Moraxella catarrhalis beta-lactamase (P<=0.05). Taken together, our results indicate that PF is a potential NTHi-vaccine candidate. PMID- 24631069 TI - Universal paid leave increases influenza vaccinations among employees in the U.S. AB - OBJECTIVES: We predict the impact of paid leave in increasing influenza vaccinations for employees, thus decreasing workdays lost and healthcare visits resulting from infection. METHODS: Nationally representative data from the 2006 2010 Medical Expenditure Panel Survey were used. We examined working adults aged 18 and above (N=51,471). Logistic regression measured the association of paid leave with flu vaccination. We predicted the impact on labor and healthcare markets if universal paid leave were provided. RESULTS: The proportion of workers receiving vaccination annually was higher for those with paid leave versus without paid leave (34.0% vs. 21.0%, P<0.001). Adjusted odds of having a vaccination increased with paid leave vs. without paid leave (OR=1.42, CI: 1.31 1.53). Universal paid leave is predicted to increase vaccinations by 1.6 million, resulting in 63.8 thousand fewer absences from work and 18.2 thousand fewer healthcare visits for the flu annually. CONCLUSIONS: Our study suggests that employees without paid leave are significantly less likely to have had a flu vaccination. Expanding paid leave could substantially increase flu vaccination, resulting in fewer workdays lost to influenza and savings in healthcare costs. PMID- 24631070 TI - Development of a Rift Valley fever virus viremia challenge model in sheep and goats. AB - Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, causes severe to fatal disease in newborn ruminants, as well as abortions in pregnant animals; both preventable by vaccination. Availability of a challenge model is a pre-requisite for vaccine efficacy trials. Several modes of inoculation with RVFV ZH501 were tested on goats and sheep. Differences in development of infectious viremia were observed between animals inoculated with RVFV produced in mosquito C6/36 cells compared to Vero E6 cell-produced inoculum. Only C6/36-RVFV inoculation led to development of viremia in all inoculated sheep and goats. The C6/36 cell-produced RVFV appeared to be more infectious with earlier onset of viremia, especially in sheep, and may also more closely represent a field situation. Goats were somewhat more resistant to the disease development with lower and shorter infectious virus viremia, and with only some animals developing transient increase in rectal temperature in contrast to sheep. In conclusion, a challenge protocol suitable for goat and sheep vaccine efficacy studies was developed using subcutaneous inoculation of 10(7)PFU per animal with RVFV ZH501 produced in C6/36 cells. PMID- 24631071 TI - Autophagy-targeted vaccine of LC3-LpqH DNA and its protective immunity in a murine model of tuberculosis. AB - The development of more effective antituberculosis vaccines would contribute to the control of the global problem of infection with Mycobacterium tuberculosis (MTB). Recently, the highlighted importance of autophagy in the host immune response against MTB has attracted the attention of researchers. However, the vaccines targeted at autophagy remain to be developed. In this study, we report on an autophagy-targeted vaccine of 19kDa MTB lipoprotein (LpqH) DNA that harbors another gene coding microtubule-associated protein light chain-3(LC3), which transports LpqH to autophagosomes and displays enhanced protective efficacy against MTB. After the transfection of pCMV-LpqH DNA, a significant increase LC3 II was detected in RAW264.7 cells, which was similar to that observed with treatment with rapamycin, a reagent used to induce autophagy. To target autophagy, the gene coding LC3, as a marked protein of autophagosome, was linked to the lpqH gene to express an LC3-LpqH fused protein. Interestingly, LC3-LpqH fused protein was determined to be transported to an autophagosome, which was demonstrated by the co-localization of GFP-LC3 with LC3-LpqH at autophagosomes. Notably, the mice immunized with LC3-LpqH/Ag85B displayed decreased mycobacterial loads in the lungs and spleen when challenged with virulent MTB by intravenous infection, which was consistent with increased IgG2a in serum and IFN-gamma and IL-2 produced by splenocyte. In conclusion, our study demonstrates that an LC3 LpqH DNA vaccine could have autophagy as its target, which contributes to the enhancement of the Th1 immune response and vaccine protective efficacy. PMID- 24631072 TI - Oral delivery of plant-derived HIV-1 p24 antigen in low doses shows a superior priming effect in mice compared to high doses. AB - During early infection with human immunodeficiency virus type 1 (HIV-1), there is a rapid depletion of CD4(+) T-cells in the gut-associated lymphoid tissue (GALT) in the gastrointestinal tract. Therefore, immediate protection at these surfaces is of high priority for the development of an HIV-1 vaccine. Thus, transgenic plants expressing HIV-1 antigens, which are exposed to immune competent cells in the GALT during oral administration, can be interesting as potential vaccine candidates. In the present study, we used two HIV-1 p24 antigen-expressing transgenic plant systems, Arabidopsis thaliana and Daucus carota, in oral immunization experiments. Both transgenic plant systems showed a priming effect in mice and induced humoral immune responses, which could be detected as anti-p24 specific IgG in sera after an intramuscular p24 protein boost. Dose-dependent antigen analyses using transgenic A. thaliana indicated that low p24 antigen doses were superior to high p24 antigen doses. PMID- 24631073 TI - What a pandemic teaches us about vaccination attitudes of parents of children with asthma. AB - BACKGROUND: During the recent pandemic, Influenza A/H1N1 vaccine uptake remained far below the targeted rates. Associated factors regarding vaccine refusal in the general population have been reported in many studies, however the reasons behind refusals for asthmatic children have not yet been identified. We aimed to investigate Influenza A/H1N1 virus vaccine acceptance for children with asthma, to determine the attitudes and beliefs of parents concerning Influenza A/H1N1 disease and vaccine and to identify the association of asthma control parameters with vaccination. METHODS: The parents of asthmatic children aged 6-18 years participated in a cross-sectional survey study in three pediatric allergy outpatient clinics. The survey measured demographic factors, asthma control parameters, vaccination rates, and beliefs and attitudes regarding Influenza A/H1N1 vaccine. RESULTS: Of the 625 asthmatic children, 16.8% (n=105) were immunized with Influenza A/H1N1 and 45.7% (n=286) with seasonal influenza vaccine. Educational background of parents (p<0.001 and p=0.002, for father's and mother's educational level, respectively), previous vaccination with seasonal influenza (p<0.001), and having a family member vaccinated against Influenza A/H1N1 (p<0.001) had a significant influence on vaccine acceptance, while fear of side effects (88.6%) was the major parental reason for refusing the vaccine. Asthma control parameters had no influence on uptake of the vaccine. Physician recommendation (84.8%) was important in the decision-making process for immunization. The statement "Children with asthma should receive swine flu vaccine" increased the likelihood of being vaccinated [OR: 2.160, (95%CI 1.135 4.111), p=0.019]. CONCLUSION: Although asthmatic children are considered to be a high-priority group for Influenza A/H1N1 vaccination, we found low uptake of vaccine among our patients. Beliefs and attitudes rather than asthma control parameters influenced parental decisions for immunization. Understanding the underlying determinants for refusing the vaccine will help to improve vaccine campaigns in advance of a future outbreak. PMID- 24631074 TI - An oral vaccine for type 1 diabetes based on live attenuated Salmonella. AB - Type 1 diabetes (T1D) is a metabolic disease that is initiated by the autoimmune destruction of pancreatic insulin-producing beta cells that is accompanied by the development of antigen-specific antibodies and cytotoxic T lymphocytes (CTLs). Several studies have shown that vaccination with diabetic autoantigens provides some protection against this process. In this report we describe a new oral vaccine that utilizes live attenuated Salmonella for simultaneous delivery of autoantigens in conjunction with immunomodulatory cytokine genes to immune cells in the gut mucosa. Recent data showed that live attenuated Salmonella is a safe, simple and effective vector for expression of antigens and cytokines by antigen presenting cells (APCs) of gut-associated lymphatic tissue (GALT). This novel strategy was tested by fusion of the diabetic autoantigen preproinsulin with Salmonella secretory effector protein (SseF) of pathogenicity island-2 (SPI2). In this way the autoantigen is only expressed inside the host immune cells and translocated to the host cell cytosol. In addition Salmonella was used to deliver the gene for the immunomodulatory cytokine transforming growth factor beta (TGFbeta) for host cell expression. Oral co-vaccination of 8 week-old non-obese diabetic (NOD) mice with three weekly doses of both the autoantigen and cytokine significantly reduced the development of diabetes, improved the response to glucose challenge, preserved beta cell mass, and reduced the severity of insulitis compared with controls and autoantigen alone. Combination therapy also resulted in increased circulating levels of IL10 four weeks post-vaccination and IL2 for 12 weeks post-vaccination, but without effect on proinflammatory cytokines IL6, IL12(p70), IL17 and IFNgamma. However, in non-responders there was a significant rise in IL12 compared with responders. Future studies will examine the mechanism of this vaccination strategy in more detail. In conclusion, Salmonella-based oral vaccines expressing autoantigens combined with imunomodulatory cytokines appears to be a promising therapy for prevention of T1D. PMID- 24631075 TI - Variability of genes encoding surface proteins used as vaccine antigens in meningococcal endemic and epidemic strain panels from Norway. AB - Surface-expressed protein antigens such as factor H-binding protein (fHbp), Neisserial adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and Porin protein A (PorA); all express sequence variability that can affect their function as protective immunogens when used in meningococcal serogroup B vaccines like the recently-approved 4CMenB (Bexsero((r))). We assessed the sequence variation of genes coding for these proteins and two additional proteins ("fusion partners" to fHbp and NHBA) in pathogenic isolates from a recent low incidence period (endemic situation; 2005-2006) in Norway. Findings among strains from this panel were contrasted to what was found among isolates from a historic outbreak (epidemic situation; 1985-1990). Multilocus sequence typing revealed 14 clonal complexes (cc) among the 66 endemic strains, while cc32 vastly predominated in the 38 strain epidemic panel. Serogroup B isolates accounted for 50/66 among endemic strains and 28/38 among epidemic strains. Potential strain-coverage ("sequence match") for the 4CMenB vaccine was identified among the majority (>70%) of the endemic serogroup B isolates and all of the epidemic serogroup B isolates evaluated. Further information about the degree of expression, surface availability and the true cross-reactivity for the vaccine antigens will be needed to fully characterize the clinical strain-coverage of 4CMenB in various geographic and epidemiological situations. PMID- 24631076 TI - Target cells for antibodies detection in rabies vaccine control. AB - Rabies causes one of the most lethal zoonotic diseases, with more than 55,000 deaths reported annually. Prevention is based on pre-exposure vaccination of individuals at high risk of contracting rabies, and mass vaccination of dog, which are the main vector for transmission to humans. Post-exposure prophylaxis includes vaccination and rabies immunoglobulins treatment. The measurement of neutralizing antibodies in sera of vaccinated individuals is a primary concern to determine the efficacy of immunization schedules or the potency of new vaccines. Antibodies against rabies glycoprotein are considered an ideal indicator. In this work we showed the development of a VERO clone that is able to detect by fluorescence microscopy and flow cytometry, the presence of antibodies against the rabies glycoprotein, specifically in its native conformation anchored in the plasma membrane. These cells could trigger the development of a new rapid method for the detection of rabies virus neutralizing antibodies in vaccinated individuals. PMID- 24631077 TI - Rabies virus-like particles expressed in HEK293 cells. AB - Rabies is an infectious viral disease with a mortality rate close to 100%. Currently, there is a need to generate cheaper and more immunogenic vaccines for the effective prevention of rabies, mostly in developing countries. Virus-like particles have been widely used in viral vaccine production due to their high immunogenicity and safety during the production process. Rabies virus glycoprotein is the major antigen to trigger a protective immune response and the only protein capable of generating virus neutralizing antibodies. In this study we describe the development of a recombinant stable cell line for the production of rabies virus-like particles (RV-VLPs) expressing the rabies virus glycoprotein by lentivirus-based transduction of HEK293 cells. Protein expression was analyzed by flow cytometry, fluorescence microscopy, western blot and ELISA. Particles were purified from culture supernatant and their size and morphology were studied. Furthermore, mice were immunized with RV-VLPs, formulated with adjuvant, and these particles were able to produce a specific antibody response, demonstrating that these virus-like particles present a promising rabies vaccine candidate. PMID- 24631078 TI - Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spray dried and electron-beam sterilised vaccines in non-human primates. AB - Currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. To overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza A vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. We evaluated the efficacy of novel antigen stabilizing and protecting solutions (SPS) to protect influenza A(H1N1)pdm09 split virus antigen under experimental conditions in vitro and in vivo. Original or SPS re-buffered vaccine (Pandemrix) was spray-dried and terminally sterilised by irradiation with 25 kGy (e-beam). Antigen integrity was monitored by SDS-PAGE, dynamic light scattering, size exclusion chromatography and functional haemagglutination assays. In vitro screening experiments revealed a number of highly stable compositions containing glycyrrhizinic acid (GA) and/or chitosan. The most stable composition was selected for storage tests and in vivo assessment of seroconversion in non-human primates (Macaca fascicularis) using a prime-boost strategy. Redispersed formulations with original adjuvant were administered intramuscularly. Storage data revealed high stability of protected vaccines at 4 degrees C and 25 degrees C, 60% relative humidity, for at least three months. Animals receiving original Pandemrix exhibited expected levels of seroconversion after 21 days (prime) and 48 days (boost) as assessed by haemagglutination inhibition and microneutralisation assays. Animals vaccinated with spray-dried and irradiated Pandemrix failed to exhibit seroconversion after 21 days whereas spray-dried and irradiated, SPS-protected vaccines elicited similar seroconversion levels to those vaccinated with original Pandemrix. Boost immunisation with SPS-protected vaccine resulted in a strong increase in seroconversion but had only minor effects in animals treated with non SPS-protected vaccine. In conclusion, utilising the SPS formulation technology, spray-drying and terminal sterilisation of influenza A(H1N1)pdm09 split virus vaccine is feasible. Findings indicate the potential utility of such formulated vaccines e.g. for needle-free vaccination routes and delivery to countries with uncertain cold chain facilities. PMID- 24631079 TI - Sensitive methods for evaluation of antibodies for host cell protein analysis and screening of impurities in a vaccine process. AB - BACKGROUND: Host cell proteins (HCP) should be carefully monitored in vaccine production. To achieve a reliable HCP estimation, a mixture of polyclonal antibodies (pAbs) with broad affinity would be of preference. Sensitive evaluations of the pAbs are therefore of value. METHODS: Column purification of specific HCPs with affinity to the anti-HCP pAbs was compared with Western blotting of the anti-HCP pAbs binding to filter bound total lysate. The anti-HCP pAbs were used in an HCP quantification analysis using surface plasmon resonance (SPR). Host cell derived impurities from an influenza vaccine process were analyzed using 2-D DIGE analysis. RESULTS: The Western blotting showed a similar HCP binding pattern of anti-HCP pAbs from immunizations using two adjuvants: CFA/IFA and AbISCO((r)). From the column purification of HCPs, total proteins detectable were similar for all anti-HCP pAbs; however the immune response pattern differed significantly for the anti-HCP pAbs from the AbISCO((r)) immunization. In the SPR HCP quantification assay the standard curve ranged from 0.3 to 40 MUg/ml. The advantage of SPR compared with ELISA was the decreased hands on time and that the sample number was not limiting. The 2-D DIGE showed that most of the HCPs were removed at the clarification and virus capture step. DISCUSSION: Column purification of HCPs with affinity to the anti-HCP pAbs increased the sensitivity of affinity analysis compared with Western blotting and opened the possibility of further analysis. The anti-HCP pAbs did not interact with proteins in the virus; simplifying analysis of process samples using SPR. 2 D DIGE analysis gave a direct study of the impurity profile with the advantage of independence from antibody performance. PMID- 24631080 TI - Development of a membrane adsorber based capture step for the purification of yellow fever virus. AB - Yellow fever (YF) is an endemic disease in some tropical areas of South America and Africa that presents lethality rate between 20 and 50%. There is no specific treatment and to control this disease a highly effective live-attenuated egg based vaccine is widely used for travelers and residents of areas where YF is endemic. However, recent reports of rare, sometimes fatal, adverse events post vaccination have raised concerns. In order to increase safety records, alternative strategies should be considered, such as developing a new inactivated vaccine using a cell culture based technology, capable of meeting the demands in cases of epidemic. With this goal, the production of YF virus in Vero cells grown on microcarriers and its subsequent purification by chromatographic techniques was studied. In this work we investigate the capture step of the purification process of the YF virus. At first, virus stability was studied over a wide pH range, showing best results for the alkaline region. Considering this result and the pI of the envelope protein previously determined in silico, a strong anion exchanger was considered most suitable. Due to the easy scalability, simplicity to handle, absence of diffusional limitations and suitability for virus handling of membrane adsorbers, a Q membrane was evaluated. The amount of antigen adsorbed onto the membrane was investigated within the pH range for virus stability, and the best pH for virus adsorption was considered to be 8.5. Finally, studies on gradient and step elution allowed to determine the most adequate salt concentration for washing (0.15M) and virus elution (0.30 M). Under these operating conditions, it was shown that this capture step is quite efficient, showing high product recovery (93.2+/-30.3%) and efficient DNA clearance (0.9+/ 0.3 ng/dose). PMID- 24631081 TI - Duration of vaccine efficacy against malaria: 5th year of follow-up in children vaccinated with RTS,S/AS02 in Mozambique. AB - A primary concern for the RTS,S malaria vaccine candidate is duration of protection. The ongoing Phase III trial reported evidence of waning efficacy within the first year following vaccination. Multiple Phase IIb trials demonstrated early waning of efficacy. The longest duration of protection for RTS,S recorded to date was in a trial of a cohort of 1605 Mozambican children age 1-4 yr at the time of immunization (C1), which showed an overall efficacy against clinical malaria of 30.5% over 43 subsequent months of surveillance. A significant reduction in parasite prevalence in RTS,S vaccinees indicated that the vaccine continued to protect at the end of this period. Although follow-up for recording incident cases of clinical malaria was stopped at 45 months, we were interested in evidence of further durability of protection, and revisited the cohort at 63 months, recording the secondary trial endpoint, prevalence of asexual Plasmodium falciparum parasitemia, in the RTS,S and comparator vaccine groups as a proxy for efficacy. As a comparator, we also visited the contemporaneous cohort of 417 children (C2), which showed waning efficacy after 6 months of follow-up. We also assessed anti-circumsporozoite antibody titers. These results were compared with those of other Phase IIb trials. Prevalence of parasitemia was not significantly lower in the RTS,S/AS02 group compared to comparator groups in C1 (57 [119%] Vs 62 [128%]; p=0.696) or C2 (30 [226%] Vs 35 [276%]; p=0.391), despite elevated antibody titers, suggesting that protection did not extend to 5 years after vaccination. This is in contrast to the earlier assessment of parasitemia in C1, where a 34% lower prevalence of parasitemia was observed in the RTS,S/AS02 group at month 45. Comparison with other Phase II trials highlights a complex relationship between efficacy, age and transmission intensity. RTS,S/AS02 provided partial protection from clinical malaria for at least 3.5 years in C1. Duration of protection may depend on environmental circumstances, such as changing malaria transmission, and special attention should be given in the Phase III trial to identifying factors that modify longevity of protection. PMID- 24631082 TI - Evaluation of immune response and protective effect of four vaccines against the tick-borne encephalitis virus. AB - Among three main subtypes of the tick-borne encephalitis virus (TBEV), the Siberian subtype is currently dominant in a majority of the endemic regions of Russia. However, inactivated vaccines are based on TBEV strains of the heterologous Far Eastern or the European subtypes isolated 40-77 years ago. To analyze the efficacy of the available vaccines against currently prevailing TBEV isolates of the Siberian subtype, mice were immunized subcutaneously three times (one group per each vaccine). The expression of seven cytokine genes was determined using RT-PCR. Sera were studied using homologous and heterologous ELISA, hemagglutination inhibition (HI) and neutralization tests with TBEV strains of the Far Eastern, Siberian and European subtypes. Cross-protective efficacy of the vaccines was evaluated with the TBEV strain 2689 of Siberian subtype isolated from an ixodid tick from the Novosibirsk, South-Western Siberia, Russia in 2010. The cytokine gene expression profile indicates a predominantly Th2 response due to exogenous antigen presentation. Titers for homologous combinations of vaccine strain and strain in ELISA, HI and neutralization tests exceeded those for heterologous antigen-antibody pairs. Despite antibody detection by means of ELISA, HI and neutralization tests, the mouse protection afforded by the vaccines differed significantly. Complete protection of mice challenged with 100 LD50 virus of the Siberian subtype was induced by the vaccine "Encevir" ("Microgen", Tomsk, Russia). The minimal immunization doze (MID50) of "Encevir" protecting 50% of the mice was less than 0.0016 ml. Partial protective effect of vaccines produced in Moscow, Russia and Austria revealed MID50 within recommended intervals (0.001-0.017 ml). However, the MID50 for the vaccine "Encepur" (Novartis, Germany) 0.04 ml exceeded acceptable limits with total loss of mice immunized with vaccine diluted 32, 100 and 320 fold. These results suggest regular evaluation of TBEV vaccines in regions where heterologous virus subtypes prevail. PMID- 24631083 TI - Cost and sustainability of a successful package of interventions to improve vaccination coverage for children in urban slums of Bangladesh. AB - OBJECTIVE: To estimate the incremental economic costs and explore satisfaction with a highly effective intervention for improving immunization coverage among slum populations in Dhaka, Bangladesh. A package of interventions based on extended clinic hours, vaccinator training, active surveillance, and community participation was piloted in two slum areas of Dhaka, and resulted in an increase in valid fully immunized children (FIC) from 43% pre-intervention to 99% post intervention. METHODS: Cost data and stakeholder perspectives were collected January-February 2010 via document review and 10 key stakeholders interviews to estimate the financial and opportunity costs of the intervention, including uncompensated time, training and supervision costs. RESULTS: The total economic cost of the 1-year intervention was $18,300, comprised of external management and supervision (73%), training (11%), coordination costs (1%), uncompensated staff time and clinic costs (2%), and communications, supplies and other costs (13%). An estimated 874 additional children were correctly and fully immunized due to the intervention, at an average cost of $20.95 per valid FIC. Key stakeholders ranked extended clinic hours and vaccinator training as the most important components of the intervention. External supervision was viewed as the most important factor for the intervention's success but also the costliest. All stakeholders would like to reinstate the intervention because it was effective, but additional funding would be needed to make the intervention sustainable. CONCLUSION: Targeting slum populations with an intensive immunization intervention was highly effective but would nearly triple the amount spent on immunization per FIC in slum areas. Those committed to increasing vaccination coverage for hard-to-reach children need to be prepared for substantially higher costs to achieve results. PMID- 24631085 TI - Testing a new formulation for Peste des Petits Ruminants vaccine in Ethiopia. AB - In this paper extended tests on a new candidate formulation for Peste des Petits Ruminants (PPR) vaccine carried out at National Veterinary Institute (NVI) in Ethiopia are presented. This work was performed in the frame of the VACNADA project from GALVmed which aimed at procuring vaccines against neglected veterinary diseases to African vaccine producing laboratories, in particular PPR. After the eradication of Rinderpest, Peste des Petits Ruminants became the next veterinary disease on target for elimination, requiring an effective and thermostable vaccine. In this work a Tris/Trehalose formulation was evaluated in thermal stability studies in comparison to the current used formulation of the live attenuated PPR vaccine, the Weybridge medium. The extended results presented herein show an increased thermal stability of the vaccine, especially at 37 and 45 degrees C, as expected from previously published results (Silva A.C. et al., 2011). Furthermore, during the course of this project, the NVI teams have clearly demonstrated ability to produce higher quality PPR vaccines after a successful transfer of the technology. These results should significantly enhance the utility of the vaccine in the eradication of PPR. PMID- 24631084 TI - Protective immunity to H7N9 influenza viruses elicited by synthetic DNA vaccine. AB - Despite an intensive vaccine program influenza infections remain a major health problem, due to the viruses' ability to change its envelope glycoprotein hemagglutinin (HA), through shift and drift, permitting influenza to escape protection induced by current vaccines or natural immunity. Recently a new variant, H7N9, has emerged in China causing global concern. First, there have been more than 130 laboratory-confirmed human infections resulting in an alarmingly high death rate (32.3%). Second, genetic changes found in H7N9 appear to be associated with enabling avian influenza viruses to spread more effectively in mammals, thus transmitting infections on a larger scale. Currently, no vaccines or drugs are effectively able to target H7N9. Here, we report the rapid development of a synthetic consensus DNA vaccine (pH7HA) to elicit potent protective immunity against the H7N9 viruses. We show that pH7HA induces broad antibody responses that bind to divergent HAs from multiple new members of the H7N9 family. These antibody responses result in high-titer HAI against H7N9. Simultaneously, this vaccine induces potent polyfunctional effector CD4 and CD8T cell memory responses. Animals vaccinated with pH7HA are completely protected from H7N9 virus infection and any morbidity associated with lethal challenge. This study establishes that this synthetic consensus DNA vaccine represents a new tool for targeting emerging infection, and more importantly, its design, testing and development into seed stock for vaccine production in a few days in the pandemic setting has significant implications for the rapid deployment of vaccines protecting against emerging infectious diseases. PMID- 24631086 TI - Efficacy of different pneumococcal conjugate vaccine schedules against pneumonia, hospitalisation, and mortality: re-analysis of a randomised trial in the Gambia. AB - BACKGROUND: Pneumococcal conjugate vaccines (PCV) reduce disease due to Streptococcus pneumoniae. We aimed to determine the efficacy of different PCV schedules in Gambian children. METHODS: We reanalysed data from a randomised placebo-controlled trial. Infants aged 6-51 weeks were allocated to three doses of nine-valent PCV (n=8718) or placebo (n=8719) and followed until age 30 months. We categorised participants to compare: (a) a first dose at age 6 or 10 weeks, (b) intervals of 1 or 2 months between doses, and (c) different intervals between second and third doses. The primary endpoint was first episode of radiologic pneumonia; other endpoints were hospitalisation and mortality. Using the placebo group as the reference population, Poisson regression models were used with follow-up after the first dose to estimate the efficacy of each schedule and from age 6 weeks to estimate the incidence rate difference between schedules. RESULTS: Predicted efficacy in the groups aged 6 weeks (n=2467, 154 events) or 10 weeks (n=2420, 106 events) at first dose against radiologic pneumonia were 32% (95% CI 19-43%) and 33% (95% CI 21-44%), against hospitalisation 14% (95% CI 3-23%) and 17% (95% CI 7-26%), and against mortality 17% (95% CI -3 to 33%) and 16% (95% CI 3 to 32%) respectively. Predicted efficacy in the groups with intervals of 1 month (n=2701, 133 events) or 2 months (n=1351, 58 events) between doses against radiologic pneumonia were 33% (95% CI 20-44%) and 36% (95% CI 24-46%), against hospitalisation 15% (95% CI 5-24%) and 18% (95% CI 8-27%), and against mortality 17% (95% CI -2 to 33%) and 13% (95% CI -8 to 29%) respectively. Efficacy did not differ by interval between second and third doses, nor did the incidence rate difference between schedules. CONCLUSIONS: We found no evidence that efficacy or effectiveness of PCV9 differed when doses were given with modest variability around the scheduled ages or intervals between doses. PMID- 24631087 TI - Interaction of porcine circovirus type 2 and Mycoplasma hyopneumoniae vaccines on dually infected pigs. AB - The objective of this study was to determine the effects of porcine circovirus type 2 (PCV2) and Mycoplasma hyopneumoniae vaccinations on disease severity in an experimental PCV2-M. hyopneumoniae dual challenge model. Vaccine effectiveness was evaluated using microbiological (PCV2 viremia and M. hyopneumoniae nasal shedding), immunological (neutralizing antibodies and interferon-gamma-secreting cells), and pathological (gross lung lesions, histopathologic pulmonary and lymphoid lesions, and the presence of PCV2 antigen and M. hyopneumoniae DNA within the lesions) evaluations. Although M. hyopneumoniae potentiates the severity of PCV2-associated lesions and lesion-associated PCV2 antigen in dually challenged pigs, vaccination against M. hyopneumoniae alone did not reduce PCV2 viremia, PCV2-induced lesions, or PCV2 antigen in dually challenged pigs. In addition, vaccination against PCV2 did not reduce the nasal shedding of M. hyopneumoniae, the M. hyopneumoniae-induced pulmonary lesions or the lesion associated M. hyopneumoniae DNA in dually challenged pigs. Dual challenge with PCV2 and M. hyopneumoniae did not interfere with the induction of active immunity induced by a previous single vaccination for either PCV2 or M. hyopneumoniae. The results of this study demonstrated that (i) vaccination against M. hyopneumoniae alone did not decrease the potentiation of PCV2-induced lesions by M. hyopneumoniae and (ii) vaccination against PCV2 alone decreased the potentiation of PCV2-induced lesions by M. hyopneumoniae in dually challenged pigs. PMID- 24631088 TI - Early protection against foot-and-mouth disease virus in cattle using an inactivated vaccine formulated with Montanide ESSAI IMS D 12802 VG PR adjuvant. AB - Foot and mouth disease is an acute disease of cattle with a broad distribution around the world. Due to the fast spread of FMDV infections, control measures must be applied immediately after an outbreak, such as the use of vaccines that induce fast protection. Previously, it was shown that mice vaccinated with FMD inactivated virus (iFMDV) formulated with MontanideTM ESSAI IMS D 12802 VG PR adjuvant (802-iFMDV) were protected when they were challenged 4 and 7 days post vaccination (dpv) with homologous virus. In this work, we describe the successful use of this formulation in cattle. In addition, adjuvant MontanideTM IMS 1313 VG NPR was also tested. 802-iFMDV vaccine was able to confer 100% protection against viral challenge at 4 and 7 dpv, while eliciting low antibody levels, at 7 dpv. 1313-iFMDV vaccine induced protection in 60% of cattle. At 4 dpv, 1313-iFMDV vaccinated animals presented increased levels of IFNgamma but not of macrophages. At 4 and 7 dpv, macrophages, IFNgamma, nasal IgA and IgG1 antibodies against FMDV, and opsonophagocytosis were increased in animals vaccinated with 802-iFMDV indicating that these phenomena could be involved in protection.It is the first time that total protection against FMDV at early stages post-vaccination is reported using a single dose of the formulation iFMDV plus MontanideTM ESSAI D IMS 12802 VG PR adjuvant. PMID- 24631089 TI - As a genetic adjuvant, CTA improves the immunogenicity of DNA vaccines in an ADP ribosyltransferase activity- and IL-6-dependent manner. AB - Cholera toxin (CT) and its subunits (A and B) have been intensively investigated as adjuvants for protein-based vaccines. Their underlying mechanisms vary with respect to the inoculation route used. By fusing the CTA gene to either the HIV-1 derived Tat-Rev-Vif-Integrase-Nef fusion gene or the OVA gene, our study showed that the fusion of CTA in these DNA vaccines had no cytotoxic effect in vitro and significantly improved both the quantity and quality of the elicited CD8(+) T cell responses. Further experiments identified that the fusion of CTA in these DNA vaccines augmented the secretion of IL-6 in a manner that was dependent on its ADP-ribosyltransferase activity, and protein kinase A (PKA) was found to be the major mediator of its downstream signaling. By site-directed mutagenesis of the ADP-ribosyltransferase catalytic center and in vivo RNAi, we demonstrated that the ADP-ribosyltransferase activity and the upregulation of IL-6 were required for the CTA gene-mediated adjuvant effect. These findings demonstrate that when fused to an immunogen gene, the CTA gene could serve as a potent genetic adjuvant, providing new insights into the mechanisms of CTA as an adjuvant. PMID- 24631090 TI - Purification of O-specific polysaccharide from lipopolysaccharide produced by Salmonella enterica serovar Paratyphi A. AB - The O specific polysaccharide (OSP) of the lipopolysaccharide (LPS) of Salmonella enterica serovar Paratyphi A is a protective antigen and the target for vaccine development. LPS is the major constituent of the outer membrane of S. Paratyphi A with the OSP exposed on the surface, in addition to the cell associated LPS a large amount of free LPS was present in the fermentation broth. A purification method was developed to take advantage of both sources of LPS and to maximize recovery of OSP. After fermentation the bacterial cells were concentrated and washed, the permeate containing the free LPS was processed separately from the cells. The free LPS was concentrated and washed on a 100kD ultrafiltration membrane to remove low molecular weight impurities. The LPS was then detoxified by separation of the lipid A from the OSP using acid hydrolysis at 100 degrees C, the precipitated lipid A was removed by 0.2MUm membrane filtration. Contaminants were then removed by acid precipitation in the presence of sodium deoxycholate. The OSP was concentrated and washed with 1M NaCl then water using a 10kD ultrafiltration membrane then sterile filtered through a 0.2MUm membrane filter. The cells were treated by acid hydrolysis at 100 degrees C, the remaining cells, cell debris and precipitate was removed by centrifugation. The filtrate was then treated in the same way as described above for the free LPS. The combined yield of purified OSP from free LPS plus the cells was greater than 880mg/L of culture broth. The method developed yields large amounts of OSP, is scalable and compatible with cGMP so would be readily transferrable to developing country vaccine manufacturers for low cost production of vaccine against S. Paratyphi A. PMID- 24631091 TI - Purification of Vero cell derived live replication deficient influenza A and B virus by ion exchange monolith chromatography. AB - We explored the possibilities for purification of various DeltaNS1 live, replication deficient influenza viruses on ion exchange methacrylate monoliths. Influenza A DeltaNS1-H1N1, DeltaNS1-H3N2, DeltaNS1-H5N1 and DeltaNS1-influenza B viruses were propagated in Vero cells and concentrated by tangential flow filtration. All four virus strains adsorbed well to CIM QA and CIM DEAE anion exchangers, with CIM QA producing higher recoveries than CIM DEAE. DeltaNS1 influenza A viruses adsorbed well also to CIM SO3 cation exchanger at the same pH, while DeltaNS1-influenza B virus adsorption to CIM SO3 was not complete. Dynamic binding capacity (DBC) for CIM QA, DEAE and SO3 methacrylate monoliths for influenza A DeltaNS1-H1N1 virus were 1.9E+10 TCID50/ml, 1.0E+10 TCID50/ml and 8.9E+08 TCID50/ml, respectively. Purification of DeltaNS1 viruses on CIM QA was scaled up and reproducibility was confirmed. Yields of infectious virus on CIM QA were between 70.8+/-32.3% and 87+/-30.8%. Total protein removal varied from 93.3+/-0.4% to 98.6+/-0.2% and host cell DNA removal efficiency was ranging from 76.4% to 99.9% and strongly depended on pretreatment with deoxyribonuclease. PMID- 24631092 TI - Recombinant adenoviral vector expressing HCV NS4 induces protective immune responses in a mouse model of Vaccinia-HCV virus infection: a dose and route conundrum. AB - Hepatitis C virus (HCV) leads to chronic infection in the majority of infected patients presumably due to failure or inefficiency of the immune responses generated. Both antibody and cellular immune responses have been suggested to be important in viral clearance. Non-replicative adenoviral vectors expressing antigens of interest are considered as attractive vaccine vectors for a number of pathogens. In this study, we sought to evaluate cellular and humoral immune responses against HCV NS4 protein using recombinant adenovirus as a vaccine vector expressing NS4 antigen. We have also measured the effect of antigen doses and routes of immunization on the quality and extent of the immune responses, especially their role in viral load reduction, in a recombinant Vaccinia-HCV (Vac HCV) infection mouse model. Our results show that an optimum dose of adenovirus vector (2*10(7)pfu/mouse) administered intramuscularly (i.m.) induces high T cell proliferation, granzyme B-expressing CD8(+) T cells, pro-inflammatory cytokines such as IFN-gamma, TNF-alpha, IL-2 and IL-6, and antibody responses that can significantly reduce the Vac-HCV viral load in the ovaries of female C57BL/6 mice. Our results demonstrate that recombinant adenovirus vector can induce both humoral and cellular protective immunity against HCV-NS4 antigen, and that immunity is intricately controlled by route and dose of immunizing vector. PMID- 24631093 TI - Immune response to hepatitis B vaccination in drug using populations: a systematic review and meta-regression analysis. AB - Injecting and non-injecting drug users are at increased risk of contracting HBV infection, and show lower antibody response to hepatitis B vaccination compared to the general population. This systematic review and meta-regression analysis aimed to estimate seroprotection rates and identify host or vaccine factors associated with varying immune response following hepatitis B vaccination in drug using populations. Original research articles were searched using online databases (Medline, PubMed, and Embase) and from reference lists of eligible articles. HBV vaccine intervention studies reporting seroprotection rates in drug users, published in English during or after 1989 were eligible. Of 978 citations reviewed, 11 studies were eligible and included for final analysis. The reported seroprotection rates ranged from 54.5% to 97.1%. The studies were significantly heterogeneous (Q=180.850, p=0.000). Measurement of anti-HBs antibody at 2 months after the third vaccine dose (RR=2.62, 95%CI=1.16-5.94, p=0.026) was significantly associated with higher seroprotection rates compared to measurement at 1 month and 6 month following third vaccine dose. Age, gender, current drug use, vaccine dose and schedule, anti-HBc, anti-HCV and anti-HIV antibody seropositivity, and proportion of IDU study population did not show a significant association with seroprotection rates. Recommendations for future research include the definition of a standardized time point for the measurement of anti HBs antibody levels, to enhance comparability of the immune response between different studies. Studies should strive to accurately report all potentially relevant factors affecting immune response to vaccine. Long-term follow up studies are needed to assess the seroprotection status in drug using populations receiving hepatitis B vaccine by standard or accelerated schedules. PMID- 24631094 TI - Single-dose live-attenuated Nipah virus vaccines confer complete protection by eliciting antibodies directed against surface glycoproteins. AB - BACKGROUND: Nipah virus (NiV), a zoonotic pathogen causing severe respiratory illness and encephalitis in humans, emerged in Malaysia in 1998 with subsequent outbreaks on an almost annual basis since 2001 in parts of the Indian subcontinent. The high case fatality rate, human-to-human transmission, wide ranging reservoir distribution and lack of licensed intervention options are making NiV a serious regional and potential global public health problem. The objective of this study was to develop a fast-acting, single-dose NiV vaccine that could be implemented in a ring vaccination approach during outbreaks. METHODS: In this study we have designed new live-attenuated vaccine vectors based on recombinant vesicular stomatitis viruses (rVSV) expressing NiV glycoproteins (G or F) or nucleoprotein (N) and evaluated their protective efficacy in Syrian hamsters, an established NiV animal disease model. We further characterized the humoral immune response to vaccination in hamsters using ELISA and neutralization assays and performed serum transfer studies. RESULTS: Vaccination of Syrian hamsters with a single dose of the rVSV vaccine vectors resulted in strong humoral immune responses with neutralizing activities found only in those animals vaccinated with rVSV expressing NiV G or F proteins. Vaccinated animals with neutralizing antibody responses were completely protected from lethal NiV disease, whereas animals vaccinated with rVSV expressing NiV N showed only partial protection. Protection of NiV G or F vaccinated animals was conferred by antibodies, most likely the neutralizing fraction, as demonstrated by serum transfer studies. Protection of N-vaccinated hamsters was not antibody-dependent indicating a role of adaptive cellular responses for protection. CONCLUSIONS: The rVSV vectors expressing Nipah virus G or F are prime candidates for new 'emergency vaccines' to be utilized for NiV outbreak management. PMID- 24631095 TI - Concomitant administration of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and measles, mumps, rubella (MMR) vaccine: randomized study in toddlers in Taiwan. AB - BACKGROUND: Japanese encephalitis (JE) is the most important cause of viral encephalitis in Asia. METHODS: In this randomized, open-label, multicenter trial in 550 children aged 12 to 18 months in Taiwan, children received one dose of JE CV and one dose of MMR vaccine. Vaccines were either administered separately 6 weeks apart (Groups 'JE-CV' and 'MMR', named after which vaccine was given first), or concomitantly (Group 'Co-Ad'). JE neutralizing antibody titers were assessed using PRNT50. MMR antibody levels were determined by ELISA. RESULTS: All groups had low seroprotection/seropositivity rates (<10%) before vaccination for all antigens. Forty two days after vaccination, on either Study Day 42 or 84, seroconversion rates for all antigens were high in all groups, irrespective of the order of vaccinations. Seroconversion for JE ranged from 96.9% in Group Co-Ad on D42 to 100% in Group MMR. Non-inferiority was demonstrated for all analyses as the lower bound of the 95% CI of the difference in seroconversion rates between groups was above the pre-defined limit of -10.0%. The immune responses remained high for all antigens and well above the level of protection 12 months after vaccination in all groups. There were no safety concerns. CONCLUSIONS: JE-CV is safe and induces a strong protective immune response which persists over 1 year when co-administered with MMR vaccine. PMID- 24631096 TI - Cold adaptation improves the growth of seasonal influenza B vaccine viruses. AB - Gene reassortment has proved useful in improving yields of influenza A antigens of egg-based inactivated vaccines, but similar approaches have been difficult with influenza B antigens. Current regulations for influenza vaccine seed viruses limit the number of egg passages and as a result resultant yields from influenza B vaccine seed viruses are frequently inconsistent. Therefore, reliable approaches to enhance yields of influenza B vaccine seed viruses are required for efficient vaccine manufacture. In the present study three stable cold-adapted (ca) mutants, caF, caM and caB derived from seasonal epidemic strains, B/Florida/4/2006, B/Malaysia/2506/2004 and B/Brisbane/60/2008 were prepared, which produced high hemagglutinin antigen yields and also increased viral yields of reassortants possessing the desired 6:2 gene constellation. The results demonstrate that consistent improvements in yields of influenza B viruses can be obtained by cold adaptation following extended passage. Taken together, the three ca viruses were shown to have potential as donor viruses for the preparation of high-yielding influenza B vaccine viruses by reassortment. PMID- 24631097 TI - Correlates of general practitioners' recommendations to patients regarding vaccination for the 2009-2010 pandemic influenza (A/H1N1) in France: implications for future vaccination campaigns. AB - BACKGROUND: General practitioners' (GPs) recommendations to their patients regarding influenza vaccination is a key determinant of patient uptake of influenza vaccination. OBJECTIVES: To study factors associated with GPs' recommendations regarding pandemic vaccination (pvaccination) to adults <=65 years of age (hereafter referred to as adults) at risk and not at risk of severe complications of the 2009-2010 A/H1N1 influenza. PATIENTS/METHODS: National cross sectional survey of 1431 French GPs. Pvaccination recommendations by GPs to adults were studied according to three categories: recommended pvaccination to at risk adults only; recommended pvaccination to all adults; recommended against pvaccination or did not provide any advice to any adult. RESULTS: GPs were more likely to recommend pvaccination to at-risk than not-at-risk adults (73.4% vs 40.1%, p<0.01). GPs who consulted official sources of information rather than news media during the pandemic were more likely to recommend pvaccination to at risk adults only (OR=1.78; CI 95%=1.27-2.48) and to all adults (OR=2.03; CI 95%=1.42-2.92) than other GPs. GPs' unfavorable perceptions of the risk/efficacy balance of the pandemic vaccine (pvaccine) together with their perceptions of the low severity of the disease were negatively associated with recommending pvaccination. Hospitalization of GPs' patients because of the influenza was specifically associated with pvaccine recommendation to all adults (OR=2.81; CI 95%=1.98-3.99) but not with pvaccine recommendation to at-risk adults only. CONCLUSION: In the pandemic context, GPs' perceptions of disease severity and the risk/efficacy balance of the pvaccine were the major determinants of French GPs recommending pvaccination or not. To increase the general public's acceptability of vaccination policies, GPs should be adequately informed about the course of the epidemics and the safety of the vaccine. PMID- 24631098 TI - Eliciting youth and adult recommendations through citizens' juries to improve school based adolescent immunisation programs. AB - OBJECTIVES: Completion of adolescent immunisation schedules in Australia is sub optimal despite a well-established school based delivery program. The aim of this study was to seek adolescent and adult views on how existing adolescent school based immunisation policy and program delivery could be improved to increase adolescent immunisation uptake. METHOD: Two citizens' juries held separately, one with adolescent participants and one with adult participants deliberated on recommendations for public policy. Jury members were selected using a stratified sampling technique and recruited from a standing panel of community research participants through a market research company in South Australia. Juries were conducted in Metropolitan South Australia over two days and used university facilities with all meals and refreshments provided. RESULTS: Fifteen adults and 16 adolescents participated in the adult and youth juries respectively. Similar recommendations were made by both juries including increased ensuring the accuracy of information provided to adolescents and parents; employing a variety of formats for information delivery; and greater consideration of students' physical and emotional comfort in order to improve the experience for adolescents. While the youth jury recommended that it should be compulsory for adolescents to receive vaccines through the school based immunisation program, the adult jury recommended an 'opt-out' system of consent. Both juries also recommended the use of incentives to improve immunisation uptake and immunisation course completion. CONCLUSIONS: Eliciting adolescent views and including the perspectives of adolescents in discussions and development of strategies to improve engagement in the school based immunisation program provided valuable insight from the group most impacted by these policies and practices. Specifically, incorporation of adolescent and community views using citizens' juries may lead to greater overall support from the community as their values and needs are more accurately reflected. PMID- 24631099 TI - Staying on track: a cluster randomized controlled trial of automated reminders aimed at increasing human papillomavirus vaccine completion. AB - OBJECTIVES: To evaluate whether automated reminders increase on-time completion of the three-dose human papillomavirus (HPV) vaccine series. METHODS: Ten reproductive health centers enrolled 365 women aged 19-26 to receive dose one of the HPV vaccine. Health centers were matched and randomized so that participants received either routine follow-up (control) or automated reminder messages for vaccine doses two and three (intervention). Intervention participants selected their preferred method of reminders - text, e-mail, phone, private Facebook message, or standard mail. We compared vaccine completion rates between groups over a period of 32 weeks. RESULTS: The reminder system did not increase completion rates, which overall were low at 17.2% in the intervention group and 18.9% in the control group (p=0.881). Exploratory analyses revealed that participants who completed the series on-time were more likely to be older (OR=1.15, 95% CI 1.01-1.31), report having completed a four-year college degree or more (age-adjusted OR=2.51, 95% CI 1.29-4.90), and report three or more lifetime sexual partners (age-adjusted OR=3.45, 95% CI 1.20-9.92). CONCLUSIONS: The study intervention did not increase HPV vaccine series completion. Despite great public health interest in HPV vaccine completion and reminder technologies, completion rates remain low. PMID- 24631100 TI - [Osteosarcoma and ATR-16 syndrome: association or coincidence?]. AB - ATR-16 syndrome is due to alterations on chromosome 16p13.3, and is usually accompanied by alpha-thalassemia, mild-moderate mental retardation, dysmorphic facial features, skeletal and genitourinary malformations. There are no references of the combination of ATR-16 syndrome and osteosarcoma in the literature. Osteosarcoma usually has a complex karyotype, characterized by a high degree of heterogeneity of chromosomal aberrations, among which is the involvement of chromosome 16. We report a case of a patient with ATR-16 syndrome diagnosed with femoral osteosarcoma. PMID- 24631101 TI - [Unilateral VI cranial nerve palsy after vaccination: presentation of a case]. PMID- 24631102 TI - Infectious outcomes of nephrostomy drainage before percutaneous nephrolithotomy compared to concurrent access. AB - PURPOSE: We hypothesized that establishing percutaneous nephrostomy drainage and treating with renal urine culture specific antibiotics would lead to a decreased sepsis rate in patients at increased risk for infection. We analyzed the experience of a single surgeon with sepsis after percutaneous nephrolithotomy following prior nephrostomy drainage compared to percutaneous nephrolithotomy with concurrent percutaneous renal collecting system access. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent percutaneous nephrolithotomy. Pertinent collected data included patient infection history, preoperative urine cultures, renal calculi burden size, renal urine/stone cultures, length of stay and sepsis/systemic inflammatory response syndrome events. RESULTS: Percutaneous nephrolithotomy was performed in 219 patients between September 2007 and June 2012. Of the patients 67 (30.6%) had preplaced nephrostomy drainage (group 1) while 152 (69.4%) had concurrent percutaneous renal access (group 2). Stone culture was positive more often in group 1 than in group 2 (64.2% vs 25.7%, p = 0.0001). The concordance rate of preoperative renal urine culture results with stone culture results was higher than the concordance rates of lower urinary tract urine culture results in groups 1 and 2 (30.6% vs 21.4% and 7.3%, respectively). There was no systemic inflammatory response syndrome/sepsis episode in group 1 but we noted a 5.9% systemic inflammatory response syndrome/sepsis rate in group 2 (p = 0.043). CONCLUSIONS: In this retrospective study our data suggest that in patients at high risk for urosepsis preoperative nephrostomy drainage with renal urine culture and culture specific antibiotic treatment may decrease the risk of postoperative infectious complications. Stone culture is also important since many patients at high risk for infection will have positive stone cultures. A prospective study is needed to confirm these retrospective data findings. PMID- 24631104 TI - Pseudospongioplasty using periurethral vascularized tissue to support ventral buccal mucosa grafts in the distal urethra. AB - PURPOSE: For ventral buccal mucosa graft onlay during bulbar urethroplasty, spongioplasty with advancement and closure of the corpus spongiosum is ordinarily performed to stabilize the graft. In the pendulous and distal bulbar urethra the spongiosum is often too thin to allow complete graft coverage. We describe the results of what to our knowledge is a novel technique for ventral graft coverage using periurethral vascularized tissue. We compared these results to those of conventional spongioplasty. MATERIALS AND METHODS: We retrospectively reviewed all urethroplasties performed by 2 surgeons at separate tertiary care facilities from July 2007 to July 2012. One-stage urethroplasties involving ventral buccal mucosa graft placement were selected for analysis. Conventional spongioplasty was performed when possible. When spongiosal tissue was inadequate for graft coverage, periurethral tissue flaps were mobilized bilaterally and sutured together in the midline as pseudospongioplasty to provide coverage. We compared the outcomes of the 2 techniques. RESULTS: Of 637 urethroplasties performed during the 5-year study period 102 (16%) with a buccal mucosa graft onlay met study inclusion criteria. Pseudospongioplasty was performed in 46 of 102 cases (45%), predominantly in the pendulous urethra (34 of 46 or 74%), with success in 37 of 46 (80%) at a mean followup of 41 months. Conventional spongioplasty had a similar 84% success rate (47 of 56 cases) at a mean followup of 39 months (p = 0.645). For conventional spongioplasty mean stricture length was 4.7 cm compared to 5.8 cm for pseudospongioplasty (p = 0.028). CONCLUSIONS: Ventral buccal mucosa grafts can be applied reliably to various locations throughout the anterior urethra. For distal grafts, flaps of periurethral tissue provide a suitable host bed for revascularization with results equivalent to those of conventional spongioplasty. PMID- 24631105 TI - Microvascular invasion of testicular nonseminomatous germ cell tumors: implications of separate evaluation of lymphatic and blood vessels. AB - PURPOSE: We separately evaluated the lymphatic and blood vascular systems to assess the diagnostic accuracy of microvascular invasion and identify predictive markers for occult metastasis of testicular nonseminomatous germ cell tumors. MATERIALS AND METHODS: Tissue samples of 86 patients treated for testicular nonseminomatous germ cell tumors (stage 1 in 48 and stage greater than 1 in 38) were stained using the lymphatic endothelial cell specific marker LYVE-1 and the blood vessel endothelial cell marker von Willebrand factor. We assessed lymph vessel density in LYVE-1 stained sections and blood vessel density in von Willebrand factor stained sections. Lymphovascular invasion in LYVE-1 stained sections and blood vascular invasion in von Willebrand factor stained sections were documented. Parameters were correlated with standard clinicopathological data. RESULTS: Blood vessel density in von Willebrand factor sections was significantly greater than lymphatic vessel density in LYVE-1 sections (p<0.001). Peritumor and nontumor lymphatic vessel density in LYVE-1 sections was associated with metastasis at diagnosis (OR 1.277/U, p=0.020 and OR 1.113/U, p=0.095). Lymphovascular invasion in LYVE-1 sections was significantly associated with metastasis (OR=4.517, p=0.002) but blood vascular invasion in von Willebrand factor sections was only slightly significant (OR 2.261, p=0.071). Only lymphovascular invasion in LYVE-1 stained sections was significantly associated with metastasis in a multiple logistic regression model. Microvascular invasion in hematoxylin and eosin stained sections was not associated with metastasis but microvascular invasion evaluated in LYVE-1 and von Willebrand factor stained sections was associated with metastasis (OR 3.506, p=0.016). CONCLUSIONS: Lymphovascular invasion in LYVE-1 stained sections was the most important predictive parameter for metastasis at diagnosis, suggesting greater relevance of the lymphatic system in metastatic dissemination of testicular nonseminomatous germ cell tumors. Vascular endothelial cell specific markers provide higher diagnostic accuracy for microvascular invasion. Our results may impact the current concept of microvascular invasion used for risk stratification of clinical stage 1 testicular nonseminomatous germ cell tumors. PMID- 24631106 TI - Predictors of unfavorable disease after radical prostatectomy in patients at low risk by D'Amico criteria: role of multiparametric magnetic resonance imaging. AB - PURPOSE: We identified risk factors predicting unfavorable pathological outcomes after radical prostatectomy in patients with low risk prostate cancer. We also evaluated the role of magnetic resonance imaging. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 1,262 patients who underwent 12 core biopsy, preoperative magnetic resonance imaging and radical prostatectomy at a single center between September 2007 and June 2012. A total of 382 men with low risk prostate cancer by the D'Amico criteria were included in study. Multivariate logistic regression analysis was used to identify factors predicting unfavorable pathological outcomes. RESULTS: Median patient age was 65 years and median preoperative prostate specific antigen was 4.6 ng/ml. Gleason sum was upgraded in 212 patients (55.5%). In 249 patients (65.1%) prostate cancer was identified on 3 Tesla T2-weighted and diffusion-weighted magnetic resonance imaging without dynamic contrast imaging. The lesion was in the anterior and posterior of the prostate in 42.9% and 57.0% of cases, respectively. Unfavorable pathological results were found postoperatively in 29.6% of patients. Multivariate analysis revealed that older age (OR 1.072, p<0.001), number of positive cores (OR 1.373, p<0.001) and an anterior index tumor site on magnetic resonance imaging (OR 2.121, p=0.017) were significant predictors of unfavorable final pathological results (pT3 or greater, or tumor upgrading to Gleason 3+4 plus tumor volume 15% or greater, or upgrading to Gleason 4+3 or greater). CONCLUSIONS: An anterior site of cancer on magnetic resonance imaging was useful for predicting Gleason sum upgrading or an unfavorable pathological outcome after radical prostatectomy in patients with low risk prostate cancer. PMID- 24631107 TI - Feasibility and oncologic control after percutaneous image guided ablation of metastatic renal cell carcinoma. AB - PURPOSE: We assessed the safety, local control and oncologic efficacy of percutaneous ablation in the treatment of metastatic renal cell carcinoma. MATERIALS AND METHODS: A retrospective review was performed of 61 patients who underwent 74 ablation procedures to treat 82 metastatic renal cell carcinoma lesions with the intent of local eradication. Technical success, local tumor control, complications and patient survival were analyzed according to standard criteria. RESULTS: Four (4.9%) technical failures were observed while 2 patients were lost to followup. Time to recurrence was assessed for the subset of 76 (93%) tumors that were followed after ablation. Six (of 76, 7.9%) tumors recurred at a mean of 1.6 years after ablation (median 1.4, range 0.6 to 2.9). Thus, known overall local tumor control was achieved in 70 of 80 (87.5%) tumors. Estimated local recurrence-free survival rates (95% CI, number still at risk) at 1, 2 and 3 years after ablation were 94% (88-100, 41), 94% (88-100, 32) and 83% (70-97, 17), respectively. Estimated overall survival rates (95% CI, number still at risk) at 1, 2 and 3 years after ablation were 87% (79-97, 42), 83% (73-94, 31) and 76% (63 90, 19), respectively. CONCLUSIONS: Image guided ablation of metastatic renal cell carcinoma is a relatively safe procedure with acceptable local control rates. Ablation may offer patients a minimally invasive option of local tumor eradication and warrants a role in the multimodal treatment approach for select patients. PMID- 24631108 TI - Impact of hemiscrotectomy on outcome of patients with embryonal paratesticular rhabdomyosarcoma: results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P. AB - PURPOSE: Children with paratesticular rhabdomyosarcoma have a favorable prognosis. Surgical treatment problems include inadequate primary transscrotal approaches, incomplete tumor resections and the need for secondary hemiscrotectomy. We evaluated the need for hemiscrotectomy regarding local relapse and outcome. MATERIALS AND METHODS: A total of 173 patients with a diagnosis of paratesticular rhabdomyosarcoma were enrolled in the Cooperative Soft Tissue Sarcoma Studies between 1986 and 2008. Of the patients 17 were excluded due to an incomplete data set and alveolar histology. Thus, a total of 156 patients with embryonal subtype were analyzed. All patients were treated according to study protocols, which included multiagent chemotherapy, tumor resection and/or radiotherapy. RESULTS: Mean +/- SD 5-year overall survival rate was 91.5% +/- 2.4% for patients with embryonal rhabdomyosarcoma. A total of 28 patients underwent transscrotal approaches initially. Of these patients 12 were treated with hemiscrotectomy (mean +/- SD 5-year event-free survival 91.7% +/- 8%) and 16 without hemiscrotectomy (93.8% +/- 6.1%). Additionally 13 of 156 patients underwent an inguinal approach with hemiscrotectomy due to suspicious tumor infiltration of the scrotal skin (mean +/- SD 5-year event-free survival 84.6% +/- 10%). Relapse was observed in 3 of 12 patients after transscrotal approach with hemiscrotectomy (locoregional lymph node in 1 and metastasis in 2). One metastatic relapse was observed in the group undergoing a transscrotal approach without hemiscrotectomy. One of 13 patients treated with an inguinal approach and hemiscrotectomy had locoregional relapse and died of disease. CONCLUSIONS: Hemiscrotectomy seems not to be mandatory in patients after transscrotal approaches regarding outcome and local relapse. Nevertheless, hemiscrotectomy probably should be performed if the scrotal skin is infiltrated. PMID- 24631109 TI - Validation of team performance assessment of multidisciplinary tumor boards. AB - PURPOSE: We construct validated the instrument to evaluate assessor learning curves and the feasibility and interrater reliability of MTB-MODe for assessing the decision making process using video recorded multidisciplinary tumor board meetings. MATERIALS AND METHODS: Multidisciplinary tumor boards are becoming standard practice for managing cancer internationally but no standards have been agreed on to assess the efficacy of such teams. The MTB-MODe tool assesses the process of multidisciplinary tumor board decision making by standardized observation (1 to 5 anchored scales) of the quality of information presented at the multidisciplinary tumor board as well as board member contributions to the case review. We assessed 683 multidisciplinary tumor board case discussions using MTB-MODe in a multiphase study, including 332 cases (9 urology boards) by 1 urologist in vivo and 224 cases (6 urology boards) by 2 urologists in vivo. The instrument was refined and subsequently used to rate 127 video recorded case discussions (5 tumor types) by a total of 8 multidisciplinary tumor boards. RESULTS: Good interrater reliability was achieved in vivo and at the video recorded multidisciplinary tumor board meetings (ICC >=0.70). MTB-MODe scores were higher in cases that resulted in a decision than in cases in which no decision was made (mean +/- SD 2.54 +/- 0.47 vs 2.02 +/- 0.65, p <=0.001). CONCLUSIONS: A standardized method to assess the quality of multidisciplinary tumor board discussions can enhance the quality of cancer care and the ability of the boards to self-evaluate performance, thus, promoting good practice. Video recordings offer a feasible, reliable method of assessing how multidisciplinary tumor boards work. PMID- 24631110 TI - Microsatellite markers for direct genotyping of the crayfish plague pathogen Aphanomyces astaci (Oomycetes) from infected host tissues. AB - Aphanomyces astaci is an invasive pathogenic oomycete responsible for the crayfish plague, a disease that has devastated European freshwater crayfish. So far, five genotype groups of this pathogen have been identified by applying random amplified polymorphic DNA analysis on axenic cultures. To allow genotyping of A. astaci in host tissue samples, we have developed co-dominant microsatellite markers for this pathogen, tested them on pure cultures of all genotype groups, and subsequently evaluated their use on tissues of (1) natural A. astaci carriers, i.e., North American crayfish species, and (2) A. astaci-infected indigenous European species from crayfish plague outbreaks. Out of over 200 potential loci containing simple sequence repeat (SSR) motifs identified by 454 pyrosequencing of SSR-enriched library, we tested 25 loci with highest number of repeats, and finally selected nine that allow unambiguous separation of all known RAPD-defined genotype groups of A. astaci from axenic cultures. Using these markers, we were able to characterize A. astaci strains from DNA isolates from infected crayfish tissues when crayfish had a moderate to high agent level according to quantitative PCR analyses. The results support the hypothesis that different North American crayfish hosts carry different genotype groups of the pathogen, and confirm that multiple genotype groups, including the one originally introduced to Europe in the 19th century, cause crayfish plague outbreaks in Central Europe. So far undocumented A. astaci genotype seems to have caused one of the analysed outbreaks from the Czech Republic. The newly developed culture independent approach allowing direct genotyping of this pathogen in both axenic cultures and mixed genome samples opens new possibilities in studies of crayfish plague pathogen distribution, diversity and epidemiology. PMID- 24631111 TI - A review of interventions that promote eating by internal cues. AB - Traditional diet programs that encourage individuals to consciously restrict their dietary intake have not only been ineffective in terms of weight outcomes, but have also been counterproductive, promoting psychological distress and unhealthy eating behaviors. Nondiet approaches shift the focus away from weight outcomes to the improvement of health outcomes and psychological well-being. One such approach, intuitive eating, promotes dietary intake based on internal cues of hunger and fullness, body acceptance, and making behavior choices based on health as well as enjoyment. Several studies have implemented such ideas into intervention programs. The purpose of our review was to examine the physical and psychological effects of these programs. Twenty interventions were identified. Overall, studies had positive results, demonstrating improvements in eating habits, lifestyle, and body image as measured by dietary restraint, restrictive dieting, physical activity, body satisfaction, and drive for thinness. Participants also experienced improved psychological health as measured by depression, ineffectiveness, anxiety, self-esteem, negative affect, and quality of life. Several improvements were sustained through follow-up periods as long as 2 years. Completion rates were as high as 92% in nondieting groups. In addition, improvements in eating behaviors and maintaining a nondiet approach, increased self-esteem, and decreased body dissatisfaction were sustained long-term. Overall, studies that encourage individuals to eat intuitively help participants abandon unhealthy weight control behaviors, improve metabolic fitness, increase body satisfaction, and improve psychological distress. Results from our review favor the promotion of programs that emphasize a nonrestrictive pattern of eating, body acceptance, and health rather than weight loss. PMID- 24631112 TI - A cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs healthy controls. AB - BACKGROUND: Poor diet and a sedentary lifestyle can contribute to nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: Our aim was to compare diet and physical activity of patients with NAFLD and healthy controls with current recommendations. DESIGN: This was a cross-sectional study. PARTICIPANTS/SETTINGS: Seventy-four patients with biopsy-proven NAFLD (33 simple steatosis and 41 steatohepatitis [NASH]) and 27 healthy controls participated between 2003 and 2011. MAIN OUTCOME MEASURES: Food records and activity logs were completed for 7 days. Results were compared with Dietary Reference Intakes and Canadian Physical Activity Guidelines. Plasma vitamin C was measured to assess food record accuracy. STATISTICAL ANALYSES PERFORMED: Intake/activity for each participant was compared with the recommendations and proportion of subjects not meeting the requirements was calculated. Groups were compared by Kruskal-Wallis and Mann Whitney U test or z-test with Bonferroni adjustment. RESULTS: More patients with NASH (58.5%) were obese compared with patients with simple steatosis (24.2%) and healthy controls (7.4%; P<0.01). Patients with NAFLD showed more insulin resistance than healthy controls. The reported energy intake was below estimated requirements in all groups (P<=0.001). The proportion of subjects from each group exceeding acceptable energy intake from fat was as follows: simple steatosis: 27.3%; NASH: 46.3%; healthy controls: 63.0% (simple steatosis vs health controls; P<0.05) and from saturated fat: simple steatosis: 42.4%; NASH: 70.7%; healthy controls: 63.0% (simple steatosis vs. NASH; P<0.05). In each group, >80% of subjects did not consume enough linoleic or linolenic acid, vitamin D, and vitamin E, and >60% exceeded the upper intake level for sodium. Only 53.1% of patients with simple steatosis and 53.8% of patients with NASH, but 84.6% of healthy controls, met recommendations for physical activity (P=0.020). Plasma vitamin C was normal, similar among groups, and correlated with vitamin C intakes. CONCLUSIONS: All participants followed a similar Western diet with high fat and sodium intakes and suboptimal micronutrient intakes. However, physical activity was lower in NAFLD compared with healthy controls and was associated with higher body mass index and insulin resistance. PMID- 24631114 TI - MicroRNA-328 as a regulator of cardiac hypertrophy. AB - Cardiac hypertrophy is a primary predictor of progressive heart disease that often results in heart failure. Growing evidence has demonstrated that microRNAs (miRNAs) play a critical role in regulating cardiac hypertrophy. This study was designed to evaluate the effect of miR-328 on cardiac hypertrophy and the potential molecular mechanisms. We found that transgenic overexpression of miR 328 in the heart induced cardiac hypertrophy in mice, which was accompanied by reduced SERCA2a level increased intracellular calcium concentration and calcineurin protein level, and enhanced NFATc3 nuclear translocation. However, normalization of miR-328 level by its antisense chemically modified with locked nucleic acid (LNA-antimiR-328) reversed the changes. Forced expression of miR-328 resulted in cardiomyocyte hypertrophy in cultured neonatal rat ventricular cells, which was accompanied by downregulation of SERCA2a expression and activation of the calcineurin/NFATc3 signaling pathway. These changes were abolished by LNA antimiR-328. We validated the SERCA2a as a direct target for miR-328. MiR-328 expression was upregulated in cardiomyocyte treated with isoproterenol (ISO) to induce hypertrophy; while knockdown of miR-328 attenuated the hypertrophic responses. The level of miR-328 was significantly elevated in a mouse model of hypertrophy by thoracic aortic banding (TAC). Consistently, SERCA2a was downregulated, whereas calcineurin were upregulated, and NFATc3 nuclear translocation was enhanced. In contrast, hypertrophy in these mice was significantly alleviated when treated with miR-328 antisense. MiR-328 promotes cardiac hypertrophy by targeting SERCA2a. Our study therefore uncovered a novel molecular mechanism for cardiac hypertrophy and indicated miR-328 as a potential therapeutic target for this cardiac condition. PMID- 24631113 TI - Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug eluting stents: an optical coherence tomography study. AB - BACKGROUND: Pathology studies have shown delayed arterial healing in culprit lesions of patients with acute coronary syndrome (ACS) compared with stable coronary artery disease (CAD) after placement of drug-eluting stents (DES). It is unknown whether similar differences exist in-vivo during long-term follow-up. Using optical coherence tomography (OCT), we assessed differences in arterial healing between patients with ACS and stable CAD five years after DES implantation. METHODS AND RESULTS: A total of 88 patients comprised of 53 ACS lesions with 7864 struts and 35 stable lesions with 5298 struts were suitable for final OCT analysis five years after DES implantation. The analytical approach was based on a hierarchical Bayesian random-effects model. OCT endpoints were strut coverage, malapposition, protrusion, evaginations and cluster formation. Uncovered (1.7% vs. 0.7%, adjusted p=0.041) or protruding struts (0.50% vs. 0.13%, adjusted p=0.038) were more frequent among ACS compared with stable CAD lesions. A similar trend was observed for malapposed struts (1.33% vs. 0.45%, adj. p=0.072). Clusters of uncovered or malapposed/protruding struts were present in 34.0% of ACS and 14.1% of stable patients (adj. p=0.041). Coronary evaginations were more frequent in patients with ST-elevation myocardial infarction compared with stable CAD patients (0.16 vs. 0.13 per cross section, p=0.027). CONCLUSION: Uncovered, malapposed, and protruding stent struts as well as clusters of delayed healing may be more frequent in culprit lesions of ACS compared with stable CAD patients late after DES implantation. Our observational findings suggest a differential healing response attributable to lesion characteristics of patients with ACS compared with stable CAD in-vivo. PMID- 24631115 TI - Calponin1 inhibits dilated cardiomyopathy development in mice through the epsilonPKC pathway. AB - BACKGROUND: Calponin1 (CNN1) is involved in the regulation of smooth muscle contraction in physiological situation and it also expresses abnormally in a variety of pathological situations. We found that the expression of CNN1 decreased significantly in the heart tissue of a cTnT(R141W) transgenic dilated cardiomyopathy (DCM) mouse model and an adriamycin (ADR)-induced DCM mouse model, suggesting that CNN1 is involved in the pathogenesis of DCM. However, the role of CNN1 on cardiac function, especially on pathogenesis of DCM, has not been clarified. In this study, we tested whether rescued expression of CNN1 could prevent the development of DCM and investigated its possible mechanisms. METHODS AND RESULTS: The DCM phenotypes were significantly improved with the transgenic expression of CNN1 in the cTnT(R141W)*CNN1 double transgenic (DTG) mice, which was demonstrated by the survival, cardiac geometry and function analyses, as well as microstructural and ultrastructural observations based on echocardiography and histology examination. The expression of CNN1 could also resist the cardiac geometry breakage and dysfunction in the ADR-induced DCM mice model. Meanwhile, the epsilon isoform of protein kinase C (epsilonPKC) activator and inhibitor could reverse the activation of epsilonPKC/ERK/mTOR pathway and DCM phenotypes in the cTnT(R141W) and cTnT(R141W)*CNN1 double transgenic (DTG) mice. CONCLUSIONS: epsilonPKC/ERK/mTOR pathway activation induced by the rescued expression of CNN1 contributed to the improvement of cardiac dysfunction and pathological changes observed in the DTG mice. CNN1 could be a therapeutic target to prevent the development of DCM and heart failure (HF). PMID- 24631116 TI - Prevalence and prognostic implication of restenosis or dilatation at the aortic coarctation repair site assessed by cardiovascular MRI in adult patients late after coarctation repair. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) is ideal for assessing patients with repaired aortic coarctation (CoA). Little is known on the relation between long-term complications of CoA repair as assessed by CMR and clinical outcome. We examined the prevalence of restenosis and dilatation at the repair site and the long-term outcome in patients with repaired CoA. METHODS AND RESULTS: CMR imaging and clinical data for adult CoA patients (247 patients aged 33.0 +/- 12.8 years, 60% male), were analyzed. The diameter of the aorta at the repair site was measured on CMR and its ratio to the aortic diameter at the diaphragm (repair site-diaphragm ratio, RDR) was calculated. Restenosis (RDR<=70%) was present in 31% of patients (and significant in 9% [RDR<50%]), and dilatation (RDR>150%) in 13.0%. A discrete aneurysm at the repair site was observed in 9%. Restenosis was more likely after resection and end-end anastomosis, whereas dilatation after patch repair. Systemic hypertension was present in 69% of patients. Of the hypertensive patients, blood pressure (133 +/- 20/73 +/- 10 mm Hg) was well controlled in 93% with antihypertensive therapy. Mortality rate over a median length of 5.9 years was low (0.69% per year, 95% CI: 0.33-1.26), but significantly higher than age-matched healthy controls (standardised mortality ratio 2.86, CI 1.43-5.72, p<0.001). CONCLUSION: Restenosis or dilatation at the CoA repair site as assessed by CMR is not uncommon. Medium term survival remains good, however, albeit lower than in the general population. Life-long follow-up and optimal blood pressure control are likely to secure a good longer term outlook in these patients. PMID- 24631117 TI - Fulminant VZV infection in an adult AIDS patient treated with steroids: a case report. AB - Varicella zoster virus (VZV) typically causes a benign disease in childhood. However, VZV can lead to severe complication in immunocompromised patients, involving skin and nearly every organ system, with significant morbidity and mortality. VZV infection occurs more frequently in patients treated with steroids. Herein, we describe a case of rapidly fatal disseminated VZV infection with cutaneous and visceral involvement in an adult AIDS patient treated with steroids. PMID- 24631118 TI - Controversies in the oncosurgical management of liver limited stage IV colorectal cancer. AB - Colorectal cancer is the fourth most common cancer diagnosis in the world (around 1.2 million diagnoses each year), and accounts for the second highest number of deaths. Over half of patients with colorectal cancer will develop liver metastases, with one quarter presenting in stage IV. There is growing evidence that patients with liver-limited disease represent a distinct biological cohort who will benefit from aggressive management. Only a minority of patients are technically resectable, but around 40% of patients with resected liver limited disease are alive 5 years after diagnosis compared with less than 1% for those with disseminated disease. Novel surgical techniques have been developed to allow more patients to undergo resection and there is also growing recognition that the chemotherapeutic manipulation of irresectable disease may bring some patients to resection with good long-term outcome. Perioperative chemotherapy can also improve long-term outcome through improved biological selection and destruction of occult micrometastases. This review outlines current oncosurgical treatment strategies for liver-limited stage IV colorectal cancer, and discusses some of the controversies surround the management of these complex patients. PMID- 24631119 TI - Cost analysis of tonsillectomy in children using medicaid data. AB - OBJECTIVE: To evaluate the cost-effectiveness of adenotonsillectomy (T&A) for adenotonsillar hypertrophy and recurrent tonsillitis through the use of Missouri Medicaid data. STUDY DESIGN: Children ages 2-16 years who had a diagnosis of adenotonsillar hypertrophy (based on medical claim codes) in 2006 (n = 4276) were included in this population-based study. The main outcome was direct total costs paid by Medicaid. Costs 2 years before and after T&A were compared in children who underwent surgical intervention with those who did not as well as costs comparison pre- and post-T&A. Wilcoxon rank-sum or Wilcoxon Signed-rank test was used for costs comparisons. RESULTS: Children with adenotonsillar hypertrophy who underwent T&A were significantly less likely to be African American. They had more adenotonsillar infections before undergoing T&A and greater total costs (median costs $2313 vs. $1945; P = .009). The median costs were $1228 pre-T&A, compared with $823 post-T&A (P < .0001). This reduction in costs of $405 (33%) compares with a median cost of the procedure of $1088. The reduction in costs was mostly because of less antibiotic use and outpatient visits. CONCLUSIONS: African American children have fewer T&A procedures for adenotonsillar hypertrophy than white children, which represents an unexplained racial disparity. Children with adenotonsillar hypertrophy who underwent T&A compared with those who did not had more adenotonsillar infections and greater health care costs. T&A leads to a reduction in costs that, after 2 years, is 37% of the costs of the procedure. Future studies should examine the effects of demographics, obesity, and disease severity on health care costs in children with adenotonsillar hypertrophy. PMID- 24631120 TI - Synthetic biology tools for bioprospecting of natural products in eukaryotes. AB - Filamentous fungi have the capacity to produce a battery of natural products of often unknown function, synthesized by complex metabolic pathways. Unfortunately, most of these pathways appear silent, many in intractable organisms, and their products consequently unidentified. One basic challenge is the difficulty of expressing a biosynthesis pathway for a complex natural product in a heterologous eukaryotic host. Here, we provide a proof-of concept solution to this challenge and describe how the entire penicillin biosynthesis pathway can be expressed in a heterologous host. The method takes advantage of a combination of improved yeast in vivo cloning technology, generation of polycistronic mRNA for the gene cluster under study, and an amenable and easily manipulated fungal host, i.e., Aspergillus nidulans. We achieve expression from a single promoter of the pathway genes to yield a large polycistronic mRNA by using viral 2A peptide sequences to direct successful cotranslational cleavage of pathway enzymes. PMID- 24631121 TI - DNA replication is the target for the antibacterial effects of nonsteroidal anti inflammatory drugs. AB - Evidence suggests that some nonsteroidal anti-inflammatory drugs (NSAIDs) possess antibacterial properties with an unknown mechanism. We describe the in vitro antibacterial properties of the NSAIDs carprofen, bromfenac, and vedaprofen, and show that these NSAIDs inhibit the Escherichia coli DNA polymerase III beta subunit, an essential interaction hub that acts as a mobile tether on DNA for many essential partner proteins in DNA replication and repair. Crystal structures show that the three NSAIDs bind to the sliding clamp at a common binding site required for partner binding. Inhibition of interaction of the clamp loader and/or the replicative polymerase alpha subunit with the sliding clamp is demonstrated using an in vitro DNA replication assay. NSAIDs thus present promising lead scaffolds for novel antibacterial agents targeting the sliding clamp. PMID- 24631123 TI - PA28alphabeta reduces size and increases hydrophilicity of 20S immunoproteasome peptide products. AB - The specific roles that immunoproteasome variants play in MHC class I antigen presentation are unknown at present. To investigate the biochemical properties of different immunoproteasome forms and unveil the molecular mechanisms of PA28 activity, we performed in vitro degradation of full-length proteins by 20S, 26S, and PA28alphabeta-20S immunoproteasomes and analyzed the spectrum of peptides released. Notably, PA28alphabeta-20S immunoproteasomes hydrolyze proteins at the same low rates as 20S alone, which is in line with PA28, neither stimulating nor preventing entry of unfolded polypeptides into the core particle. Most importantly, binding of PA28alphabeta to 20S greatly reduces the size of proteasomal products and favors the release of specific, more hydrophilic, longer peptides. Hence, PA28alphabeta may either allosterically modify proteasome active sites or act as a selective "smart" sieve that controls the efflux of products from the 20S proteolytic chamber. PMID- 24631122 TI - Intramolecular conformational changes optimize protein kinase C signaling. AB - Optimal tuning of enzyme signaling is critical for cellular homeostasis. We use fluorescence resonance energy transfer reporters in live cells to follow conformational transitions that tune the affinity of a multidomain signal transducer, protein kinase C (PKC), for optimal response to second messengers. This enzyme comprises two diacylglycerol sensors, the C1A and C1B domains, that have a sufficiently high intrinsic affinity for ligand so that the enzyme would be in a ligand-engaged, active state if not for mechanisms that mask its domains. We show that both diacylglycerol sensors are exposed in newly synthesized PKC and that conformational transitions following priming phosphorylations mask the domains so that the lower affinity sensor, the C1B domain, is the primary diacylglycerol binder. The conformational rearrangements of PKC serve as a paradigm for how multimodule transducers optimize their dynamic range of signaling. PMID- 24631124 TI - Relationship between viscosity of the ankle joint complex and functional ankle instability for inversion ankle sprain patients. AB - OBJECTIVES: Measurement of viscosity of the ankle joint complex is a novel method to assess mechanical ankle instability. In order to further investigate the clinical significance of the method, this study intended to investigate the relationship between ankle viscosity and severity of functional ankle instability. DESIGN: Cross-sectional study. METHODS: 15 participants with unilateral inversion ankle sprain and 15 controls were recruited. Their ankles were further classified into stable and unstable ankles. Ankle viscosity was measured by an instrumental anterior drawer test. Severity of functional ankle instability was measured by the Cumberland Ankle Instability Tool. Unstable ankles were compared with stable ankles. Injured ankles were compared with uninjured ankles of both groups. The spearman's rank correlation coefficient was applied to determine the relationship between ankle viscosity and severity of functional ankle instability in unstable ankles. RESULTS: There was a moderate relationship between ankle viscosity and severity of functional ankle instability (r=-0.64, p<0.0001). Unstable ankles exhibited significantly lower viscosity (p<0.005) and more severe functional ankle instability (p<0.0001) than stable ankles. Injured ankles exhibited significantly lower viscosity and more severe functional ankle instability than uninjured ankles (p<0.0001). CONCLUSIONS: There was a moderate relationship between ankle viscosity and severity of functional ankle instability. This finding suggested that, severity of functional ankle instability may be partially attributed to mechanical insufficiencies such as the degenerative changes in ankle viscosity following the inversion ankle sprain. In clinical application, measurement of ankle viscosity could be a useful tool to evaluate severity of chronic ankle instability. PMID- 24631125 TI - The "July effect" in primary total hip and knee arthroplasty: analysis of 21,434 cases from the ACS-NSQIP database. AB - The "July effect" is the hypothetical increase in morbidity thought to be associated with the training of new residents during the first portion of the academic year. We evaluated for the presence of the July effect in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database among 21,434 patients who underwent primary total hip or knee arthroplasty. There was no association of an interaction term for academic quarter and resident involvement with "serious adverse events" (P = 0.656) or "any adverse events" (P = 0.578). As a result, this study could not demonstrate a July effect. Patients can be reassured that undergoing total joint arthroplasty during the first part of the academic year is without increased risk of adverse events related to the training of residents. PMID- 24631126 TI - Response to "a tale of two approaches": prospective randomized study of direct anterior vs postero-lateral approach for total hip arthroplasty. PMID- 24631127 TI - Factors determining discharge destination for patients undergoing total joint arthroplasty. AB - Discharge destination to skilled nursing facilities (SNF) following total joint arthroplasty (TJA) plays an important role in healthcare costs. The pre operative, intra-operative, and post-operative factors of 50 consecutive patients discharged to an SNF following TJA were compared to that of 50 consecutive patients discharged to home. Patients discharged to SNFs had slower pre-operative Get Up and Go scores (TGUG), lower pre-operative EQ-5D scores, higher ASA scores, increased hospital length of stay, increased self-reported post-operative pain, and decreased physical therapy achievements. We believe that the results of this study indicate that patients who get discharged to SNFs fit a certain criteria and this may be used to guide post-operative discharge destination during pre operative planning, which can help lower costs while helping decrease the length of inpatient stay. PMID- 24631128 TI - Modular necks in primary hip arthroplasty without anatomical deformity: no clear benefit on restoration of hip geometry and dislocation rate. An exploratory study. AB - Modular necks were introduced in total hip arthroplasty (THA) to improve restoration of hip-geometry and reduce dislocation-rates. This presumed advantage was evaluated retrospectively for patients with arthritis in otherwise anatomically normal hips. Restoration of hip-geometry was assessed on preoperative and postoperative calibrated radiographs in 95 consecutive primary THAs with a modular neck design and compared with 95 match controlled THAs with a similar monoblock stem. No significant differences were seen in restoration of body moment arm, leg length and cupangle. Offset restoration revealed a borderline significant difference (P = 0.48) with higher values for the monoblock stem. In both groups 4 dislocations within one year were encountered. In this study modular necks did not reveal a clear benefit in restoring hip geometry and dislocation rate after straightforward THA. PMID- 24631129 TI - Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes. AB - AIMS: Evaluate the efficacy and tolerability of ITCA 650 in subjects with type 2 diabetes treated for up to 48 weeks. METHODS: This was a 24-week extension to a randomized, 24-week, open-label, phase 2 study in subjects with type 2 diabetes inadequately controlled with metformin. Subjects received ITCA 650 mg (20, 40, 60 or 80 MUg/day). Mean changes for HbA1c, weight, and fasting plasma glucose (FPG) were evaluated. RESULTS: Mean changes in HbA1c from baseline to week 48 ranged from -0.85% to -1.51%. At week 48, >=64% of subjects with an HbA1c <=7% at week 24 maintained an HbA1c <=7%. The incidence of adverse events (AEs) was dose related and ranged from 13.3% with 20 MUg/day to 37.5% with 80 MUg/day. Most AEs were mild and transient; the incidence of nausea declined from 12.9% to 9.5% over the 24-week extension. One subject on ITCA 650 80 MUg/day experienced mild intermittent vomiting. Three (3.5%) subjects experienced severe AEs, but none were considered related to study drug. CONCLUSION: Significant changes in HbA1c, body weight, and FPG attained with ITCA 650 were maintained to 48 weeks. The incidence of AEs was lower in the 24-week extension than in the initial 24-week treatment phase. PMID- 24631130 TI - Prefrontal gamma-aminobutyric acid type A receptor insertion controls cue-induced relapse to nicotine seeking. AB - BACKGROUND: Current smoking cessation therapies offer limited success, as relapse rates remain high. Nicotine, which is the major component of tobacco smoke, is thought to be primarily responsible for the addictive properties of tobacco. However, little is known about the molecular mechanisms underlying nicotine relapse, hampering development of more effective therapies. The objective of this study was to elucidate the role of medial prefrontal cortex (mPFC) glutamatergic and gamma-aminobutyric acid (GABA)ergic receptors in controlling relapse to nicotine seeking. METHODS: Using an intravenous self-administration model, we studied glutamate and gamma-aminobutyric acid receptor regulation in the synaptic membrane fraction of the rat mPFC following extinction and cue-induced relapse to nicotine seeking. Subsequently, we locally intervened at the level of GABAergic signaling by using a mimetic peptide of the GABA receptor associated protein interacting domain of GABA type A (GABAA) receptor subunit gamma2 (TAT GABAgamma2) and muscimol, a GABAA receptor agonist. RESULTS: Alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate receptors were not regulated after the 30-min relapse test. However, GABAA receptor subunits alpha1 and gamma2 were upregulated, and interference with GABAA receptor insertion in the cell membrane using the TAT-GABAgamma2 peptide in the dorsal mPFC, but not the ventral mPFC, significantly increased responding during relapse. Increasing GABAA transmission with muscimol in the dorsal and ventral mPFC attenuated relapse. CONCLUSIONS: These data indicate that cue-induced relapse entails a GABAergic plasticity mechanism that limits nicotine seeking by restoring inhibitory control in the dorsal mPFC. GABAA receptor-mediated neurotransmission in the dorsal mPFC constitutes a possible future therapeutic target for maintaining smoking abstinence. PMID- 24631131 TI - Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: relation with inflammatory parameters. AB - BACKGROUND: Subjects with Down syndrome (DS) have an increased susceptibility to infections and autoimmune disorders. ATP, adenosine, and acetylcholine contribute to the immune response regulation, and NTPDase, adenosine deaminase (ADA) and acetylcholinesterase (AChE) are important enzymes in the control of the extracellular levels of these molecules. We evaluated the activities of these enzymes and the cytokine levels in samples of DS individuals. METHODS: The population consisted of 23 subjects with DS and 23 healthy subjects. Twelve milliliters of blood was obtained from each subject and used for lymphocyte and serum preparation. Lymphocytes were separated on Ficoll density gradients. After isolation, NTPDase and AChE activities were determined. RESULTS: The NTPDase activity using ADP as substrate was increased in lymphocytes of DS patients compared to control (P<0.05); however, no alterations were observed in the ATP hydrolysis. An increase was observed in the AChE activity in lymphocytes and in ADA activity in serum of DS patients when compared to healthy subjects (P<0.05). In DS subjects, an increase in the levels of IL-1beta, IL-6, TNF-alpha and IFN gamma and a decrease in the IL-10 levels were also observed (P<0.05). CONCLUSIONS: Alterations in the NTPDase, ADA and AChE activities as well changes in the cytokine levels may contribute to immunological alterations observed in DS. PMID- 24631132 TI - Glycated albumin; clinical usefulness. AB - The main purpose of treating diabetes is to prevent the onset and progression of diabetic chronic complications. Since the mechanism of onset of chronic complications is still not well understood, the main strategy to achieve this purpose is to bring plasma glucose levels as close as possible to those in healthy subjects and maintain good glycemic control over the long term. Since glycation among various proteins is increased in diabetic patients compared with non-diabetic subjects, glycated protein can be used as a glycemic control indicator. Currently, among these glycated proteins, HbA1c is used as the gold standard of glycemic control indicators. However, HbA1c does not accurately reflect the actual status of glycemic control in some conditions with rapid changes in glycemic control and in patients with anemia (hemolytic anemia, iron deficiency anemia, etc.) and variant hemoglobin. In comparison, glycated albumin (GA) more accurately reflects changes in plasma glucose during the short term and postprandial plasma glucose. GA also reflects glycemic control in patients with hematologic disorders whereas GA does not reflect glycemic control in patients with disorder of albumin metabolism. GA is a glycemic control indicator which overcomes most of the disadvantages of HbA1c, and could be therefore expected to replace HbA1c as the standard glycemic control indicator in the near future. However, it is necessary to accumulate more evidences from large research studies on the effective directions for measuring GA. PMID- 24631133 TI - Falsely elevated cyclosporin and tacrolimus concentrations over prolonged periods of time due to reversible adsorption to central venous catheters. AB - Falsely elevated concentrations of immunosuppressants can be caused by reversible adsorption to central venous catheter (CVC) systems. If undetected, this may lead to dose reduction resulting in underdosage which may even entail graft-versus host disease or organ rejection. We analyzed the adsorption and release for cyclosporine A (CsA) and tacrolimus (Tac) in vitro and in vivo. Four types of CVCs were examined in vitro: two made from polyurethane (PU), one from silicone and one from PU with an incorporated silver ion-based antimicrobial agent. All 26 CVCs analyzed in vitro showed significant reversible adsorption of CsA (n=13; p=0.001) and Tac (n=13; p=0.001, Wilcoxon signed rank test). Immediately after infusing the drugs, the mean concentrations of 6420ng/mL of CsA and 250ng/mL of Tac were measured. Flushing with NaCl lowered the drug release. Besides, blood samples of fifteen patients were taken simultaneously from all lumina of the CVC and via venipuncture. The samples from contaminated lumina showed the mean elevations by a factor of 11 for CsA (n=12) and 89 for Tac (n=3). Blood sampling for immunosuppressant monitoring should thus never be performed from lumina previously used for infusing the drug even after prolonged periods of time and extensive rinsing. PMID- 24631134 TI - Thrombin-activatable fibrinolysis inhibitor (TAFI) levels and its polymorphism rs3742264 are associated with dyslipidemia in a cohort of Brazilian subjects. AB - BACKGROUND: Dyslipidemia, a metabolic alteration that affects lipoprotein levels, is considered a major risk factor for atherosclerosis and its complications. Dyslipidemia also affects the hemostatic system, especially impairing fibrinolysis, and increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) have been associated with cardiovascular events. OBJECTIVES AND METHODS: This study evaluated the association of acquired risk factors (hypertension, body mass index - BMI, smoking, sedentary lifestyle, use or not of oral contraceptives and hormone replacement therapy, and post-menopause status), the polymorphisms Thr325Ile (rs1926447), Ala147Thr (rs3742264) and +1542C/G (rs940) in the TAFI gene, and TAFI plasma levels in 109 dyslipidemic and 105 normolipemic individuals. Biochemical analyses and TAFI levels were evaluated by colorimetric/turbidimetric assays and ELISA, respectively. Genotypic and allelic frequencies were determined by polymerase chain reaction (PCR). RESULTS: Hypertension, increased BMI, and menopause were more common in dyslipidemic individuals, who had higher TAFI levels. The alleles 325Ile, Ala147, and C showed association with lower TAFI levels. The rs3742264 polymorphism was associated with dyslipidemia in males. CONCLUSIONS: The results suggest that TAFI levels are independently associated to dyslipidemia and that the polymorphism rs3742264 may be related to cardiovascular risk in male subjects. PMID- 24631135 TI - Cinnamon polyphenols attenuate the hydrogen peroxide-induced down regulation of S100beta secretion by regulating sirtuin 1 in C6 rat glioma cells. AB - AIMS: It is well established that the brain is particularly susceptible to oxidative damage due to its high consumption of oxygen. The objective of this study was to investigate the protective effects of a water soluble polyphenol rich extract of cinnamon and the possible mechanisms, under conditions of oxidative stress-induced by hydrogen peroxide, in rat C6 glioma cells. MAIN METHODS: After 24h of H2O2 incubation, the secretion and intracellular expression of S100beta were determined by immunoprecitation/immunoblotting and immunofluorescence imaging. KEY FINDINGS: Cinnamon polyphenols (CP) counteracted the oxidative effects of H2O2 on S100beta secretion and expression. CP also enhanced the impaired protein levels of sirtuins 1, 2, and 3, which are deacetylases important in cell survival. H2O2 also induced the overexpression of the proinflammatory factors, TNF-alpha, phospho-NF-kappaB p65, as well as of Bcl xl, Bax and Caspase-3, which are all the members of the Bcl-2 family. CP not only suppressed the expression of these proteins but also attenuated the phosphorylation induced by H2O2. CP also upregulated the decreased Bcl-2 protein levels in H2O2 treated C6 cells. The effects of CP on H2O2-induced downregulation of S100beta secretion were blocked by SIRT1 siRNA demonstrating that SIRT1 plays a regulatory role in CP-mediated prevention by H2O2. SIGNIFICANCE: These data demonstrate that Cinnamon polyphenols may exert neuroprotective effects in glial cells by the regulation of Bcl-2 family members and enhancing SIRT1 expression during oxidative stress. PMID- 24631136 TI - MADP, a salidroside analog, protects hippocampal neurons from glutamate induced apoptosis. AB - AIMS: To investigate the anti-apoptotic effect of MADP, an analog of salidroside, against glutamate induced apoptosis in the cultured rat hippocampal neurons. MAIN METHODS: Cytotoxicity was determined by the MTT method and lactate dehydrogenase release to the medium. Cell apoptosis was evaluated by Hoechst 33342 staining, TUNEL assay and flow cytometric analysis. Western blotting was applied for detecting protein levels of cellular signaling molecules. KEY FINDINGS: Our results showed that glutamate exposure significantly induces cell apoptosis, whereas the pretreatment of salidroside or MADP remarkably improves cell viability. Most importantly, the anti-apoptotic effect of MADP against glutamate insult is superior to salidroside. To explore the involved mechanisms, we measured some pro-apoptotic and anti-apoptotic protein levels, and several cell survival signaling pathways were analyzed as well. No visible alterations in Bcl 2 and Bax protein levels were observed by MADP or salidroside. Akt and JNK phosphorylation was robustly stimulated by MADP in the glutamate-treated neurons. Salidroside treatment results in a slight activation in Akt, while no significant alteration in JNK activity was observed. SIGNIFICANCE: MADP exhibits higher capacity to attenuate glutamate induced cell apoptosis in the cultured rat hippocampal neurons, suggesting that MADP might be a better candidate than salidroside for developing novel drugs treating neuron loss associated disorders. PMID- 24631137 TI - Remodeling of white adipose tissue metabolism by physical training prevents insulin resistance. AB - AIM: This study sought to determine the role of white adipose tissue (WAT) metabolism in the prevention of insulin resistance (IR) by physical training (PT). MAIN METHODS: Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n=15), CHOW-TR (chow diet, trained; n=18), CAF-SED (cafeteria diet, sedentary; n=15) and CAF-TR (cafeteria diet, trained; n=18). PT consisted of running sessions of 60 min at 60% of maximal speed conducted five days per week for eight weeks. KEY FINDINGS: PT prevented body weight and fat mass accretion in trained groups and prevented hyperglycemia, hyperinsulinemia, glucose intolerance and IR in the CAF-TR. The CAF-SED group presented higher leptin and free fatty acid and lower adiponectin serum levels compared with other groups. Lipolytic activity (in mmol/10(6) adipose cells) stimulated by isoproterenol increased in CHOW-TR (16347+/-3005), CAF-SED (18110+/-3788) and CAF TR (15837+/-2845) compared with CHOW-SED (8377+/-2284). The CAF-SED group reduced FAS activity compared with CHOW-SED and CHOW-TR, reduced citrate synthase activity and increased DGAT2 content compared with other groups. Both trained groups reduced G6PDH activity and increased the expression of p-AMPK (Thr172) compared with sedentary groups. CAF-SED group had lower levels of AMPK, p-AMPK (Thr172), ACC and p-ACC (Ser79) compared with other groups. SIGNIFICANCE: The prevention of IR by PT is mediated by adaptations in WAT metabolism by improving lipolysis, preventing an increase in enzymes responsible for fatty acid esterification and by activating enzymes that improve fat oxidation instead of fat storage. PMID- 24631138 TI - Gallic acid selectively induces the necrosis of activated hepatic stellate cells via a calcium-dependent calpain I activation pathway. AB - AIMS: The activation of hepatic stellate cells (HSCs) in response to liver injury is critical to the development of liver fibrosis, thus, the blockage of the activation of HSCs is considered as a rational approach for anti-fibrotic treatment. In this report, we investigated the effects and the underlying mechanisms of gallic acid (GA) in interfering with the activation of HSCs. MAIN METHODS: The primary cultured rat HSCs were treated with various doses of GA for different time intervals. The morphology, viability, caspase activity, calcium ion flux, calpain I activity, reactive oxygen species generation and lysosomal functions were then investigated. KEY FINDINGS: GA selectively killed HSCs in both dose- and time-dependent manners, while remained no harm to hepatocytes. Besides, caspases were not involved in GA-induced cell death of HSCs. Further results showed that GA toxicity was associated with a rapid burst of reactive oxygen species (ROS) and a subsequent increase of intracellular Ca(2+) and calpain activity. Addition of calpain I but not calpain II inhibitor rescued HSCs from GA-induced death. In parallel, pretreatment with antioxidants or an intracellular Ca(2+) chelator eradicated GA responses, implying that GA-mediated cytotoxicity was dependent on its pro-oxidative properties and its effect on Ca(2+) flux. Furthermore, application of ROS scavengers also reversed Ca(2+) release and the disruption of lysosomal membranes in GA-treated HSCs. SIGNIFICANCE: These results provide evidence for the first time that GA causes selective HSC death through a Ca(2+)/calpain I-mediated necrosis cascade, suggesting that GA may represent a potential therapeutic agent to combat liver fibrosis. PMID- 24631139 TI - Optimal conditions of LDR to protect the kidney from diabetes: exposure to 12.5 mGy X-rays for 8 weeks efficiently protects the kidney from diabetes. AB - AIMS: We reported the attenuation of diabetes-induced renal dysfunction by exposure to multiple low-dose radiation (LDR) at 25 mGy every other day by suppressing renal oxidative damage. We here explored the optimal conditions of LDR to protect the kidney from diabetes. MAIN METHODS: Male C57BL/6J mice with type 1 diabetes were induced with multiple injections of low-dose streptozotocin. Diabetic mice received whole body X-irradiation at a dose of 12.5, 25 or 50 mGy every other day for either 4 or 8 weeks. Age-matched normal mice were similarly irradiated at the dose of 25 mGy for 4 or 8 weeks. The renal function and histopathological changes were examined at the 4th and 8th weeks of the study. KEY FINDINGS: Diabetes induced renal dysfunction is shown by the decreased creatinine and increased microalbumin in the urine. Renal oxidative damage, detected by protein nitration and lipid oxidation, and remodeling, reflected by increased expression of connective tissue growth factor, collagen IV and fibronectin, were significantly increased in diabetic mice. All these renal pathological and function changes in diabetic mice were significantly attenuated by exposure to LDR at all regimens, among which, however, exposure to LDR at 12.5 mGy for 8 weeks provided the best protective effect on the kidney of diabetic mice. SIGNIFICANCE: Our results suggest that whole-body LDR at 12.5 mGy every other day for 8 weeks is the optimal condition of LDR to protect the kidney from diabetes. PMID- 24631140 TI - Anticancer potential of Hericium erinaceus extracts against human gastrointestinal cancers. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hericium is a genus of mushrooms (fungus) in the Hericiaceae family. Hericium erinaceus (HE) has been used for the treatment of digestive diseases for over 2000 years in China. HE possesses many beneficial functions such as anticancer, antiulcer, antiinflammation and antimicrobial effects, immunomodulation and other activities. The aim of the studies was to evaluate the anticancer efficacy of two extracts (HTJ5 and HTJ5A) from the culture broth of HE against three gastrointestinal cancers such as liver, colorectal and gastric cancers in both of in vitro of cancer cell lines and in vivo of tumor xenografts and discover the active compounds. MATERIALS AND METHODS: Two HE extracts (HTJ5 and HTJ5A) were used for the studies. For the study of chemical constituents, the HTJ5 and HTJ5A were separated using a combination of macroporous resin with silica gel, HW-40 and LH-20 chromatography then purified by semipreparative high-performance liquid chromatography (HPLC) and determined by nuclear magnetic resonance (NMR) spectra. For the in vitro cytotoxicity studies, HepG2 and Huh-7 liver, HT-29 colon, and NCI-87 gastric cancer cell lines were used and MTT assay was performed to determine the in vitro cytotoxicity. For in vivo antitumor efficacy and toxicity studies, tumor xenograft models of SCID mice bearing liver cancer HepG2 and Huh-7, colon cancer HT-29 and gastric cancer NCI-87 subcutaneously were used and the mice were treated with the vehicle control, HTJ5 and HTJ5A orally (500 and 1000 mg/kg/day) and compared to 5-fluorouraci (5-FU) at the maximum tolerated dose (MTD, 25-30 mg/kg/day) intraperitoneally daily for 5 days when the tumors reached about 180 200 mg (mm(3)). Tumor volumes and body weight were measured daily during the first 10 days and 2-3 times a week thereafter to assess the tumor growth inhibition, tumor doubling time, partial and complete tumor response and toxicity. RESULTS: Twenty-two compounds were obtained from the fractions of HTJ5/HTJ5A including seven cycli dipeptides, five indole, pyrimidines, amino acids and derivative, three flavones, one anthraquinone, and six small aromatic compounds. HTJ5 and HTJ5A exhibited concentration-dependent cytotoxicity in vitro against liver cancer HepG2 and Huh-7, colon cancer HT-29, and gastric cancer NCI 87 cells with the IC50 in 2.50+/-0.25 and 2.00+/-0.25, 0.80+/-0.08 and 1.50+/ 0.28, 1.25+/-0.06 and 1.25+/-0.05, and 5.00+/-0.22 and 4.50+/-0.14 mg/ml; respectively. For in vivo tumor xenograft studies, HTJ5 and HTJ5A showed significantly antitumor efficacy against all four xenograft models of HepG2, Huh 7, HT-29 and NCI-87 without toxicity to the host. Furthermore, HTJ5 and HTJ5A are more effective than that of 5-FU against the four tumors with less toxicity. CONCLUSION: HE extracts (HTJ5 and HTJ5A) are active against liver cancer HepG2 and Huh-7, colon cancer HT-29 and gastric cancer NCI-87 cells in vitro and tumor xenografts bearing in SCID mice in vivo. They are more effective and less toxic compared to 5-FU in all four in vivo tumor models. The compounds have the potential for development into anticancer agents for the treatment of gastrointestinal cancer used alone and/or in combination with clinical used chemotherapeutic drugs. However, further studies are required to find out the active chemical constituents and understand the mechanism of action associated with the super in vivo anticancer efficacy. In addition, future studies are needed to confirm our preliminary results of in vivo synergistic antitumor efficacy in animal models of tumor xenografts with the combination of HE extracts and clinical used anticancer drugs such as 5-FU, cisplatin and doxurubicin for the treatment of gastrointestinal cancers. PMID- 24631142 TI - Stereotactic body radiotherapy: an attractive treatment modality for recurrent head and neck carcinoma. (Regarding Lartigau et al.: Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer). PMID- 24631141 TI - Eye closure causes widespread low-frequency power increase and focal gamma attenuation in the human electrocorticogram. AB - OBJECTIVE: We sought to characterize the effects of eye closure on EEG power using electrocorticography (ECoG). Specifically, we sought to elucidate the anatomical areas demonstrating an eye closure effect, and at which frequencies this effect occurs. METHODS: ECoG was recorded from 32 patients undergoing invasive monitoring for seizure focus localization. Patients were instructed to close and open their eyes repeatedly. ECoG power was compared in the epochs following eye closure and opening, for various frequency bands and brain regions. RESULTS: We found that at low frequencies, eye closure causes widespread power increases involving all lobes of the brain. This effect was significant not only in the alpha (8-12 Hz) band but in the delta (2-4 Hz), theta (4-8 Hz), and beta (15-30 Hz) bands as well. At high frequencies, eye closure causes comparatively focal power decreases over occipital cortex and frontal Brodmann areas 8 and 9. CONCLUSIONS: Eye closure (1) affects a broad range of frequencies outside the alpha band and (2) involves a distributed network of neural activity in anatomical areas outside visual cortex. SIGNIFICANCE: This study constitutes the first large-scale, systematic application of ECoG to study eye closure, which is shown to influence a broad range of frequencies and brain regions. PMID- 24631143 TI - Dynamic contrast enhanced CT aiding gross tumor volume delineation of liver tumors: an interobserver variability study. AB - PURPOSE: To evaluate the application of perfusion CT for gross tumor volume (GTV) delineation for radiotherapy of intrahepatic tumors. MATERIALS AND METHODS: 15 radiotherapy patients with confirmed liver tumors underwent contrast enhanced 4D CT (Philips Brilliance Big-bore) as well as dynamic contrast enhanced (DCE) CT (GE 750HD). Perfusion maps were generated with CT perfusion v5 from GE. Five observers delineated GTVs of all intrahepatic foci on the 4D-CT, time-averaged DCE-CT and perfusion CT for every patient. STAPLE consensus contours were generated. Dice's coefficients were compared between GTVs generated by observers on each image set and the corresponding consensus GTVs. Comparisons were also performed with patients stratified by hepatocellular carcinoma (HCC) metastatic tumors, and by tumor volume. RESULTS: Overall, mean Dice's coefficients were 0.81+/-0.14, 0.84+/-0.10, and 0.81+/-0.14 for 4D-CT, DCECT and perfusion. DCE-CT performed significantly better than 4D-CT and perfusion (p=0.005 and p=0.01 respectively). For patients with HCC, DCE-CT reduced interobserver variability significantly compared to 4D-CT (Dice's coefficients 0.87 vs. 0.84, p<0.05). For patients with metastatic disease time-averaged DCE-CT images decreased variability compared to 4D-CT (Dice's coefficient 0.81 vs. 0.76, p<0.05), especially true for tumors<100cc. The smaller tumors results are important to be included here. CONCLUSIONS: DCE-CT imaging of liver perfusion reduced interobserver variability in GTV delineation for both HCC and metastatic liver tumors. PMID- 24631145 TI - A critical approach to the clinical use of deformable image registration software. In response to Meijneke et al. PMID- 24631144 TI - Relationships between bladder dose-volume/surface histograms and acute urinary toxicity after radiotherapy for prostate cancer. AB - BACKGROUND AND PURPOSE: DUE01 is an observational study aimed at developing predictive models of genito-urinary toxicity of patients treated for prostate cancer with conventional (1.8-2Gy/fr, CONV) or moderate hypo-fractionation (2.35 2.7Gy/fr, HYPO). The current analysis focused on the relationship between bladder DVH/DSH and the risk of International Prostate Symptoms Score (IPSS)?15/20 at the end of radiotherapy. MATERIALS AND METHODS: Planning and relevant clinical parameters were prospectively collected, including DVH/DSH, LQ-corrected (DVHc/DSHc) and weekly (DVHw/DSHw) histograms. Best parameters were selected by the differences between patients with/without IPSS?15/20 at the end of radiotherapy. Logistic uni- and backward multi-variable (MVA) analyses were performed. RESULTS: Data of 247 patients were available (CONV: 116, HYPO: 131). Absolute DVHw/DSHw and DVHc/DSHc predicted the risk of IPSS?15 at the end of radiotherapy (n=77/247); an MVA model including baseline IPSS, anti-hypertensive, T stage, the absolute surface receiving ?8.5Gy/week and ?12.5Gy/week was developed (AUC=0.78, 95% CI: 0.72-0.83). Similar AUC values were found if replacing DSHw with DVHw/DVHc/DSHc parameters. The impact of dose-volume/surface parameters remained when excluding patients with baseline IPSS?15 and in HYPO. IPSS?20 at the end of radiotherapy (n=27/247) was mainly correlated to baseline IPSS and T stage. CONCLUSIONS: Although the baseline IPSS was the main predictor, constraining v8.5w<56cc and v12.5w<5cc may significantly reduce acute GU toxicity. PMID- 24631146 TI - Impact of planning target volume margins and rectal distention on biochemical failure in image-guided radiotherapy of prostate cancer. AB - BACKGROUND AND PURPOSE: A previous study in our department demonstrated the negative impact on freedom from biochemical failure (FFBF) of using too narrow planning target volume (PTV) margins during prostate image-guided radiotherapy (IGRT). Here, we investigated the impact of appropriate PTV margins and rectal distention on FFBF. METHODS AND MATERIALS: A total of 50 T1-T3N0M0 prostate cancer patients were treated with daily IGRT by implanted markers. In the first 25 patients, PTV margins were 3mm laterolateral, 5mm anterioposterior and 4mm craniocaudal. The subsequent 25 patients were treated with isotropic margins of 6mm. The rectal cross-sectional area (CSA) was determined on the planning CT. Median follow-up was 61months. RESULTS: The overall 5-year FFBF was 83%. A 6mm PTV margin was related to increased 5-year FFBF on univariate analysis (96% vs 74% with the tighter PTV margins, p=0.04). The 5-year FFBF of patients with a rectal distention on the planning CT was worse compared to those with limited rectal filling (75% for CSA?9cm(2) vs 89% for CSA<9cm(2), p=0.02), which remained significant on multivariate analysis (p=0.04). CONCLUSION: This retrospective study illustrated the positive impact of PTV margin adaptation and addressed the importance of avoiding rectal distention at time of the planning CT. PMID- 24631148 TI - CT-based patient modeling for head and neck hyperthermia treatment planning: manual versus automatic normal-tissue-segmentation. AB - BACKGROUND AND PURPOSE: Clinical trials have shown that hyperthermia, as adjuvant to radiotherapy and/or chemotherapy, improves treatment of patients with locally advanced or recurrent head and neck (H&N) carcinoma. Hyperthermia treatment planning (HTP) guided H&N hyperthermia is being investigated, which requires patient specific 3D patient models derived from Computed Tomography (CT)-images. To decide whether a recently developed automatic-segmentation algorithm can be introduced in the clinic, we compared the impact of manual- and automatic normal tissue-segmentation variations on HTP quality. MATERIAL AND METHODS: CT images of seven patients were segmented automatically and manually by four observers, to study inter-observer and intra-observer geometrical variation. To determine the impact of this variation on HTP quality, HTP was performed using the automatic and manual segmentation of each observer, for each patient. This impact was compared to other sources of patient model uncertainties, i.e. varying gridsizes and dielectric tissue properties. RESULTS: Despite geometrical variations, manual and automatic generated 3D patient models resulted in an equal, i.e. 1%, variation in HTP quality. This variation was minor with respect to the total of other sources of patient model uncertainties, i.e. 11.7%. CONCLUSIONS: Automatically generated 3D patient models can be introduced in the clinic for H&N HTP. PMID- 24631147 TI - Regulation of O2 consumption by the PI3K and mTOR pathways contributes to tumor hypoxia. AB - BACKGROUND: Inhibitors of the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathway are currently in clinical trials. In addition to antiproliferative and proapoptotic effects, these agents also diminish tumor hypoxia. Since hypoxia is a major cause of resistance to radiotherapy, we sought to understand how it is regulated by PI3K/mTOR inhibition. METHODS: Whole cell, mitochondrial, coupled and uncoupled oxygen consumption were measured in cancer cells after inhibition of PI3K (Class I) and mTOR by pharmacological means or by RNAi. Mitochondrial composition was assessed by immunoblotting. Hypoxia was measured in spheroids, in tumor xenografts and predicted with mathematical modeling. RESULTS: Inhibition of PI3K and mTOR reduced oxygen consumption by cancer cell lines is predominantly due to reduction of mitochondrial respiration coupled to ATP production. Hypoxia in tumor spheroids was reduced, but returned after removal of the drug. Murine tumors had increased oxygenation even in the absence of average perfusion changes or tumor necrosis. CONCLUSIONS: Targeting the PI3K/mTOR pathway substantially reduces mitochondrial oxygen consumption thereby reducing tumor hypoxia. These alterations in tumor hypoxia should be considered in the design of clinical trials using PI3K/mTOR inhibitors, particularly in conjunction with radiotherapy. PMID- 24631149 TI - Impact of probe pressure variability on prostate localization for ultrasound based image-guided radiotherapy. AB - PURPOSE: To evaluate the impact of transabdominal probe pressure on prostate positioning with an intramodality ultrasound (US) image-guided-radiotherapy system and to quantify pressure variability over the treatment course. MATERIAL AND METHODS: 8 prostate cancer patients (group A) and 17 healthy volunteers underwent 3 consecutive US images with increasing probe pressure levels, and 1 CT acquisition for the group A only. Prostate positions were compared after manual registration of the first US image contour projected on 2 others. Group A's pressure levels were quantified by measuring skin-to-skin distances between corresponding CT-US images. The same methodology was used on paired CT/CBCT-US images acquired during treatments of 18 prostate cancer patients to determine whether the different pressure levels applied to the group A were close to the clinical practices and to quantify pressure variability along the treatment course. RESULTS: 84% of 3D prostate displacements were above 2mm for at least one pressure level. Probe pressures deliberately applied were similar to the ones observed clinically. The latter drastically varied between sessions. CONCLUSION: Even with an intramodality system, probe pressure can impact prostate localization because of the pressure variability along the treatment course. Therefore, margins should be expanded from 0.5 to 1.2mm to ensure treatment accuracy. PMID- 24631150 TI - Metagenomic analysis of oxygenases from activated sludge. AB - Oxygenases play a key role in degradation of the aromatic compounds in the wastewater. This study explores the oxygenase coding gene sequences from the metagenome of activated biomass. Based on these results, the catabolic capacity of the activated sludge was assessed towards degradation of naphthalene, anthracene, phenol, biphenyl and o-toluidine. Oxygenases found in this study were compared with oxygenases from three other metagenome datasets. Results demonstrate that despite different geographical locations and source, many genes coding for oxygenases were common between treatment plants. 1, 2 Homogentisate dioxygenase and phenylacetate CoA oxygenases were present in all four metagenomes. Metagenomics provides a vast amount of data that needs to be mined with specific targets to harness the potential of the microbial world. PMID- 24631151 TI - Adsorption characteristics of arsenic from micro-polluted water by an innovative coal-based mesoporous activated carbon. AB - An innovative coal-based mesoporous activated carbon (NCPAC) was prepared by re agglomeration, oxidation and two-step activation using coal-blending as precursor. Adsorption capacities of As(III) and As(V) ions (<0.5mg/L) onto NCPAC as a function of pH, adsorbent dose, initial arsenic concentrations, contact time, and adsorption isotherms at 7 degrees C was investigated. The innovative methods promoted total pore volume (1.087cm(3)/g), mesoporosity (64.31%), iodine numbers (1104mg/g), methylene blue (251.8mg/g) and ash contents (15.26%). The adsorption capacities of NCPAC for As(III) and As(V) were found to be strongly dependent on pH and contact time. The optimal pH value was 6. The equilibrium time was 60min for adsorption of As(III) and As(V) by NCPAC. The Langmuir model fitted the experimental data well for both As(III) (R(2)=0.9980) and As(V) (R(2)=0.9988). Maximum adsorption capacities of As(III) and As(V) (C0=0.50mg/L) by NCPAC were 1.491 and 1.760mg/g, respectively. PMID- 24631152 TI - The influences of the recycle process on the bacterial community in a pilot scale microalgae raceway pond. AB - The use of recycled media has been shown to be a necessary step within the lifecycle of microalgal biofuels for economic sustainability and reducing the water footprint. However the impact of the harvesting of microalgae on the bacterial load of the recycled water has yet to be investigated. Within this study PCR-DGGE and real-time PCR was used to evaluate the bacterial community dynamics within the recycled water following harvest and concentration steps for a pilot scale open pond system (120,000L), which was developed for the production of green crude oil from Tetraselmis sp. in hyper saline water. Two stages were used in the harvesting; Stage 1 electroflocculation, and Stage 2 centrifugation. Electroflocculation was shown to have little effect on the bacterial cell concentration. In contrast bacterial diversity and cell concentration within the centrifugation step was greatly reduced. PMID- 24631153 TI - The transcription factor GATA3 is critical for the development of all IL-7Ralpha expressing innate lymphoid cells. AB - Innate lymphoid cells (ILCs) are critical in innate immune responses to pathogens and lymphoid organ development. Similar to CD4(+) T helper (Th) cell subsets, ILC subsets positive for interleukin-7 receptor alpha (IL-7Ralpha) produce distinct sets of effector cytokines. However, the molecular control of IL-7Ralpha(+) ILC development and maintenance is unclear. Here, we report that GATA3 was indispensable for the development of all IL-7Ralpha(+) ILC subsets and T cells but was not required for the development of classical natural killer cells. Conditionally Gata3-deficient mice had no lymph nodes and were susceptible to Citrobactor rodentium infection. After the ILCs had fully developed, GATA3 remained important for the maintenance and functions of ILC2s. Genome-wide gene expression analyses indicated that GATA3 regulated a similar set of cytokines and receptors in Th2 cells and ILC2s, but not in ILC3s. Thus, GATA3 plays parallel roles in regulating the development and functions of CD4(+) T cells and IL 7Ralpha(+) ILCs. PMID- 24631154 TI - Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. AB - Recognition of cell death by the innate immune system triggers inflammatory responses. However, how these reactions are regulated is not well understood. Here, we identify the inhibitory C-type lectin receptor Clec12a as a specific receptor for dead cells. Both human and mouse Clec12a could physically sense uric acid crystals (monosodium urate, MSU), which are key danger signals for cell death-induced immunity. Clec12a inhibited inflammatory responses to MSU in vitro, and Clec12a-deficient mice exhibited hyperinflammatory responses after being challenged with MSU or necrotic cells and after radiation-induced thymocyte killing in vivo. Thus, we identified a negative regulatory MSU receptor that controls noninfectious inflammation in response to cell death that has implications for autoimmunity and inflammatory disease. PMID- 24631155 TI - Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism. AB - The contribution of different DC subsets to effector and memory CD8(+) T cell generation during infection and the mechanism by which DCs controls these fate decisions is unclear. Here we demonstrated that the CD103(+) and CD11b(hi) migratory respiratory DC (RDC) subsets after influenza virus infection activated naive virus-specific CD8(+) T cells differentially. CD103(+) RDCs supported the generation of CD8(+) T effector (Teff) cells, which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11b(hi) RDCs activated CD8(+) T cells characteristic of central memory CD8(+) T (CD8(+) Tcm) cells including retention within the draining lymph nodes. CD103(+) RDCs expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8(+) Teff cell differentiation. Mechanistically, CD24 was shown to regulate CD8(+) T cell activation through HMGB1-mediated engagement of T cell RAGE. Thus, there is distribution of labor among DC subsets in regulating CD8(+) T cell differentiation. PMID- 24631158 TI - Analytical validation of BRAF mutation testing from circulating free DNA using the amplification refractory mutation testing system. AB - BRAF mutation testing from circulating free DNA (cfDNA) using the amplification refractory mutation testing system (ARMS) holds potential as a surrogate for tumor mutation testing. Robust assay validation is needed to establish the optimal clinical matrix for measurement and cfDNA-specific mutation calling criteria. Plasma- and serum-derived cfDNA samples from 221 advanced melanoma patients were analyzed for BRAF c.1799T>A (p.V600E) mutation using ARMS in two stages in a blinded fashion. cfDNA-specific mutation calling criteria were defined in stage 1 and validated in stage 2. cfDNA concentrations in serum and plasma, and the sensitivities and specificities of BRAF mutation detection in these two clinical matrices were compared. Sensitivity of BRAF c.1799T>A (p.V600E) mutation detection in cfDNA was increased by using mutation calling criteria optimized for cfDNA (these criteria were adjusted from those used for archival tumor biopsies) without compromising specificity. Sensitivity of BRAF mutation detection in serum was 44% (95% CI, 35% to 53%) and in plasma 52% (95% CI, 43% to 61%). Specificity was 96% (95% CI, 90% to 99%) in both matrices. Serum contains significantly higher total cfDNA than plasma, whereas the proportion of tumor-derived mutant DNA was significantly higher in plasma. Using mutation calling criteria optimized for cfDNA improves sensitivity of BRAF c.1799T>A (p.V600E) mutation detection. The proportion of tumor-derived cfDNA in plasma was significantly higher than in serum. PMID- 24631156 TI - Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. AB - Follicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4(+) T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of IFN-inducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper 1 (Th1) cell-like effector phenotype. Conversely, IFN-alphabeta receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4(+) T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection. PMID- 24631159 TI - Transition from failing dentition to complete-arch implant rehabilitation with a staged approach: a 3-year clinical report. AB - The transition of patients from failing dentition to complete-arch implant rehabilitation often means that the patient is rendered edentulous and has to wear a removable complete denture for a time. Many patients find this objectionable. A staged treatment approach provides a fixed interim prosthesis for use throughout the rehabilitation process, allowing patient comfort and prosthodontic control. This clinical report describes a staged approach protocol with a new type of interim prosthesis. The prosthesis is supported by hopeless teeth and the soft tissues of the maxillary tuberosities and mandibular retromolar pads for the complete-arch implant rehabilitation of a patient with failing dentition. This protocol allows for a fixed interim prosthesis with combined tooth and mucosa or implant support during the entire rehabilitation process, thus avoiding the use of complete dentures. The implants and prostheses were functioning successfully after 3 years of clinical service. PMID- 24631157 TI - Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and gammadelta T cells. AB - Chitin, a polysaccharide constituent of many allergens and parasites, initiates innate type 2 lung inflammation through incompletely defined pathways. We show that inhaled chitin induced expression of three epithelial cytokines, interleukin 25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP), which nonredundantly activated resident innate lymphoid type 2 cells (ILC2s) to express IL-5 and IL-13 necessary for accumulation of eosinophils and alternatively activated macrophages (AAMs). In the absence of all three epithelial cytokines, ILC2s normally populated the lung but failed to increase IL-5 and IL-13. Although eosinophils and AAMs were attenuated, neutrophil influx remained normal without these epithelial cytokines. Genetic ablation of ILC2s, however, enhanced IL-1beta, TNFalpha, and IL-23 expression, increased activation of IL-17A-producing gammadelta T cells, and prolonged neutrophil influx. Thus, chitin elicited patterns of innate cytokines that targeted distinct populations of resident lymphoid cells, revealing divergent but interacting pathways underlying the tissue accumulation of specific types of inflammatory myeloid cells. PMID- 24631160 TI - Influence of a tungsten metal conditioner on the adhesion and residual stress of porcelain bonded to cobalt-chromium alloy. AB - STATEMENT OF PROBLEM: Cobalt-chromium (CoCr) metal ceramic restorations are known to be more susceptible to cracking and interfacial failures. This is partially related to their high potential for oxidation compared with restorations made with high noble alloys. One approach that may improve their compatibility is the use of bonding agents. PURPOSE: The purpose of this study was to investigate the influence of a tungsten metal conditioner on the adhesion and residual stress of porcelain bonded to a cobalt-chromium alloy. MATERIAL AND METHODS: Eighty-one metal-porcelain bilayered specimens were manufactured and tested with a 4-point bend for adhesion and with Vickers indentation for residual stress determination. The strain energy release rate for adhesion energy and indentation residual stress was evaluated for specimens layered with and without tungsten (W) metal conditioner. Subsequent scanning electron microscopy and energy dispersive spectrometry were performed to identify fracture behavior and chemical and phase compositions. RESULTS: The average strain energy release rate of the specimen group tested without the W metal conditioner was significantly higher (P<.05) (44.70 J/m(2)) than that of the group with the W metal conditioner (28.65 J/m(2)). The average residual stress of the specimen group with (0.1 MPa) and without (1.61 MPa) the W metal conditioner did not differ significantly. Scanning electron microscopy and energy dispersive spectrometry analysis enabled the modes of failure to be determined and indicated the mechanisms by which the W metal conditioner influenced the bond. CONCLUSIONS: The W metal conditioner used in this study significantly lowered the strain energy release rate of the porcelain cobalt-chromium interface and did not have a significant influence on the residual stress state of the porcelain. PMID- 24631161 TI - Development of an emergency nursing training curriculum in Ghana. AB - The formal provision of emergency health care is a developing specialty in many sub-Saharan African countries, including Ghana. While emergency medicine training programs for physicians are on the rise, there are few established training programs for emergency nurses. The results of a unique collaboration are described between a university in the United States, a Ghanaian university and a Ghanaian teaching hospital that has developed an emergency nursing diploma program. The expected outcomes of this training program include: (a) an innovative, interdisciplinary, team-based clinical training model, (b) a unique and low-resource emergency nursing curriculum and (c) a comprehensive and sustainable training program to increase in-country retention of nurses. PMID- 24631163 TI - Fournier's gangrene complicating thrombocytopenia treated with steroids. PMID- 24631162 TI - Differential clinical outcomes after 1 year versus 5 years in a randomised comparison of zotarolimus-eluting and sirolimus-eluting coronary stents (the SORT OUT III study): a multicentre, open-label, randomised superiority trial. AB - BACKGROUND: In head-to-head comparisons of coronary drug-eluting stents, the primary endpoint is traditionally assessed after 9-12 months. However, the optimum timepoint for this assessment remains unclear. In this study, we assessed clinical outcomes at up to 5 years' follow-up in patients who received two different types of drug-eluting stents. METHODS: We undertook this multicentre, open-label, randomised superiority trial at five percutaneous coronary intervention centres in Denmark. We randomly allocated 2332 eligible adult patients (>=18 years of age) with an indication for drug-eluting stent implantation to the zotarolimus-eluting Endeavor Sprint stent (Medtronic, Santa Rosa, CA, USA) or the sirolimus-eluting Cypher Select Plus stent (Cordis, Johnson & Johnson, Warren, NJ, USA). Randomisation of participants was achieved by computer-generated block randomisation and a telephone allocation service. The primary endpoint of the SORT OUT III study was a composite of major adverse cardiac events-cardiac death, myocardial infarction, and target vessel revascularisation-at 9 months' follow-up. In this study, endpoints included the occurrence of major adverse cardiac events and definite stent thrombosis at follow-up times of up to 5 years. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00660478. FINDINGS: We randomly allocated 1162 patients to receive the zotarolimus-eluting stent and 1170 to the sirolimus-eluting stent. At 5-year follow-up, rates of major adverse cardiac events were similar in patients treated with both types of stents (zotarolimus eluting stents 197/1162 [17.0%] vs sirolimus-eluting stents 182/1170 [15.6%]; odds ratio [OR] 1.10, 95% CI 0.88-1.37; p=0.40). This finding was indicative of the directly contrasting results for rates of major adverse cardiac events at 1 year follow up (zotarolimus 93/1162 [8.0%] vs sirolimus 46/1170 [3.9%]; OR 2.13, 95% CI 1.48-3.07; p<0.0001) compared with those at follow-up between 1 and 5 years (104 [9.0%] vs 136 [11.6%]; OR 0.78, 95% CI 0.59-1.02; p=0.071). At 1-year follow-up, definite stent thrombosis was more frequent after implantation of the zotarolimus-eluting stent (13/1162 [1.1%]) than the sirolimus-eluting stent (4/1170 [0.3%]; OR 3.34, 95% CI 1.08-10.3; p=0.036), whereas the opposite finding was recorded for between 1 and 5 years' follow-up (zotarolimus-eluting stent 1/1162 [0.1%] vs sirolimus-eluting stent 21/1170 [1.8%], OR 0.05, 95% CI 0.01 0.36; p=0.003). 26 of 88 (30%) target lesion revascularisations in the zotarolimus-eluting stent group occurred between 1 and 5 years' follow-up, whereas 54 of 70 (77%) of those in the sirolimus-eluting stent group occurred during this follow-up period. INTERPRETATION: The superiority of sirolimus eluting stents compared with zotarolimus-eluting stents at 1-year follow-up was lost after 5 years. The traditional 1-year primary endpoint assessment therefore might be insufficient to predict 5-year clinical outcomes in patients treated with coronary drug-eluting stent implantation. FUNDING: Cordis and Medtronic. PMID- 24631164 TI - Stent performance: never too late to sort it out. PMID- 24631165 TI - Cumulative delivery rates after ICSI with donor spermatozoa in different age groups. AB - This retrospective cohort study followed a total of 364 women from their first fresh, donor intracytoplasmic sperm injection (ICSI) cycle through to up to six ICSI cycles. All patients started their treatment between January 2003 and December 2007. Live delivery after 25 weeks of gestation was the main outcome measure. The overall crude cumulative delivery rate (CDR) after six cycles was 66% while the overall expected CDR was 90%. In women aged 38-39 years, the crude and expected CDR after six cycles were 54% and 82%, respectively. In women aged 30-37 years, the crude and expected CDR after six cycles were 66% and 91%, respectively. In women aged 20-29 years the crude and expected CDR after six cycles were 81% and 93%, respectively. No significant difference was found between the CDR of patients who had a primary ICSI treatment (no previous intrauterine insemination) and patients who had previous intrauterine insemination. This study corroborates the impact of age on ICSI with donor spermatozoa. PMID- 24631166 TI - Laser-assisted hatching improves clinical outcomes of vitrified-warmed blastocysts developed from low-grade cleavage-stage embryos: a prospective randomized study. AB - The aim of this study was to evaluate the effects of quarter zona-pellucida (ZP) opening by laser-assisted hatching (QLAH) on the clinical outcomes following transfer of vitrified-warmed blastocysts developed from low-grade cleavage-stage embryos in patients with all high-grade and fair-grade cleavage-stage embryos transferred without achieving pregnancy. Patients were randomized into two groups: QLAH (n=101) and control (n=102). The implantation and clinical pregnancy rates were significantly higher in the QLAH group compared with the control group (P=0.021 and P=0.034, respectively). The live birth rate of the QLAH group was also higher, although not significantly. When the clinical outcomes according to the day of blastocyst vitrification were compared between the groups, the implantation, clinical pregnancy and live birth rates of the QLAH group were significantly higher (P<0.05) than those of the control group for day 6 blastocysts, but not for day 5 or day 5/day 6 blastocysts. These results suggest that QLAH improves the clinical outcomes of vitrified-warmed blastocysts, especially of day 6 vitrified blastocysts, developed from low-grade cleavage stage embryos. PMID- 24631167 TI - Cumulative success rates following mild IVF in unselected infertile patients: a 3 year, single-centre cohort study. AB - A 3-year, retrospective, single-centre cohort study was conducted in a private infertility centre to determine cumulative live birth rates (LBR) per scheduled oocyte retrieval following minimal ovarian stimulation/natural-cycle IVF in unselected infertile patients. A total of 727 consecutive infertile patients were analysed who underwent 2876 (median 4) cycles with scheduled oocyte retrieval from November 2008 to December 2011. Natural-cycle IVF or clomiphene-based minimal ovarian stimulation was coupled with single-embryo transfer and increased use of delayed vitrified-warmed blastocyst transfer. Main outcome measures were crude and expected age-specific cumulative LBR per scheduled oocyte retrieval. Crude cumulative LBR were 65%, 60%, 39%, 15% and 5% in patients aged 26-34, 35 37, 38-40, 41-42 and 43-44 years, respectively. No live births occurred in patients aged ? 45 years. Dropout rates per cycle were 13-25%. Success rates gradually reached a plateau, with few additional live births after six cycles. Most of the expected success rate was reached within 6 months with almost maximal rates within 15 months of the first oocyte retrieval. Acceptable cumulative LBR are reached with an exclusive minimal ovarian stimulation/single-embryo transfer policy especially in patients aged <38 years but also in intermediate aged patients (38-40 years). PMID- 24631168 TI - Duration of oral endotracheal intubation is associated with dysphagia symptoms in acute lung injury patients. AB - PURPOSE: The purpose of this study is to evaluate demographic and clinical factors associated with self-reported dysphagia after oral endotracheal intubation and mechanical ventilation in patients with acute lung injury (ALI). MATERIALS AND METHODS: This is a prospective cohort study of 132 ALI patients who had received mechanical ventilation via oral endotracheal tube. RESULTS: The primary outcome was binary, whether clinically important symptoms of dysphagia at hospital discharge were reported by patients, using the Sydney Swallowing Questionnaire score 200 or more. Of 132 patients, 29% reported clinically important symptoms of dysphagia. Of 18 relevant demographic and clinical variables, only 2 were found to be independently associated with clinically important symptoms of dysphagia in a multivariable logistic regression model: upper gastrointestinal comorbidity (odds ratio, 2.82; 95% confidence interval, 1.09-7.26) and duration of oral endotracheal intubation (odds ratio, 1.79; [95% confidence interval, 1.15-2.79] per day for first 6 days, after which additional days of intubation were not associated with a further increase in the odds of dysphagia). CONCLUSIONS: In ALI survivors, patient-reported, postexubation dysphagia at hospital discharge was significantly associated with upper gastrointestinal comorbidity and a longer duration of oral endotracheal intubation during the first 6 days of intubation. PMID- 24631169 TI - Associations between child disciplinary practices and bullying behavior in adolescents. AB - OBJECTIVE: to investigate associations between different types of child disciplinary practices and children and adolescents' bullying behavior in a Brazilian sample. METHODS: cross-sectional study, with a school-based sample of 10- to 15-year-old children and adolescents. Child disciplinary practices were assessed using two main subtypes: power-assertive and punitive (psychological aggression, corporal punishment, deprivation of privileges, and penalty tasks) and inductive (explaining, rewarding, and monitoring). A modified version of the Olweus Bully Victim Questionnaire was used to measure the frequency of bullying. RESULTS: 247 children and adolescents were evaluated and 98 (39.7%) were classified as bullies. Power-assertive and punitive discipline by either mother or father was associated with bullying perpetration by their children. Mothers who mostly used this type of discipline were 4.36 (95% CI: 1.87-10.16; p<0.001) times more likely of having a bully child. Psychological aggression and mild forms of corporal punishment presented the highest odds ratios. Overall inductive discipline was not associated with bullying. CONCLUSIONS: bullying was associated to parents' assertive and punitive discipline. Finding different ways of disciplining children and adolescents might decrease bullying behavior. PMID- 24631170 TI - Biventricular diastolic function assessed by Doppler echocardiogram in children vertically infected with human immunodeficiency virus. AB - OBJECTIVE: to determine, by Doppler-echocardiography, the frequency of cardiac diastolic dysfunction in asymptomatic and clinically stable pediatric patients with vertical infection by the human immunodeficiency virus (HIV), from the cardiovascular viewpoint. METHODS: this was an observational, prospective, and cross-sectional study, performed at a regional referral clinic for patients with HIV, in a convenience sample of 94 individuals, assessing biventricular diastolic function by Doppler-echocardiography, and weight, blood hemoglobin, and percentage of lymphocytes T-CD4(+). RESULTS: fifty patients had diastolic dysfunction. Left ventricular dysfunction occurred in 38.7%, and the predominant type of dysfunction was decreased myocardial compliance. Right ventricular dysfunction was observed in 29.4% of the sample, and abnormal relaxation was the most prevalent type. Simultaneous biventricular dysfunction occurred in 14.1% of the individuals. There was no association between dysfunction and the immune status. CONCLUSIONS: diastolic dysfunction occurred, individually or simultaneously, with no association with immune status; decreased myocardial compliance was predominant in the left ventricle, and abnormal relaxation in the right ventricle. PMID- 24631172 TI - The timing of oestrus, the preovulatory LH surge and ovulation in Blanca Andaluza goats synchronised by intravaginal progestagen sponge treatment is modified by season but not by body condition score. AB - The aim of this study was to determine whether a seasonal pattern of reproductive events is followed after synchronisation by intravaginal progestagen sponge treatment in female Blanca Andaluza goats, and whether the timing of these events is affected by body condition score (BCS). During seasonal anoestrus (March), and again during the breeding season (November), the same 32 does were distributed into four subgroups according to their BCS: <=2.25, =2.50, =2.75, and >=3.00 (n=8 in all cases). They were then synchronised using a commercial intravaginal sponge treatment. Every 4h over the 72h following sponge removal, oestrous activity, the LH concentration and each doe's number of follicles were followed by transrectal ultrasonography. The does synchronised during seasonal anoestrus produced more follicles than those synchronised during the breeding season (P<0.01). The time elapsed between sponge removal and the onset of oestrus, the LH surge and time of ovulation, was also shorter in these does (P<0.001). The BCS only modified the number of follicles present in the ovary just before ovulation; this number was significantly lower in the =2.50 BCS subgroup than in the other subgroups (P<0.05). The present results show that the time to ovulation, and all events around it, are modified by the season in which Blanca Andaluza does are synchronised, but not by BCS. PMID- 24631171 TI - Expression and prognostic significance of cancer stem cell markers CD24 and CD44 in urothelial bladder cancer xenografts and patients undergoing radical cystectomy. AB - OBJECTIVES: To evaluate CD24/CD44/CD47 cancer stem cell marker expressions in bladder cancer (BCa) and provide data on their prognostic significance for clinical outcome in patients undergoing radical cystectomy (RC). MATERIAL AND METHODS: Primary BCa tissue was used for xenograft studies. A tissue microarray was prepared using specimens from a cohort of 132 patients. All patients underwent RC for urothelial BCa between 2001 and 2010. Expression of CD24, CD44, and CD47 was examined in primary samples and xenografts by fluorescence-activated cell sorting. Populations of CD24(low)- and CD24(high)-expressing cells were sorted and evaluated for tumorigenicity in vivo. Tissue microarray was analyzed for CD24/CD44 staining intensity and tumor-specific vs. stromal cell staining. Associations with BCa survival, BCa stage, and lymph node status were evaluated by univariate and multivariate analyses. RESULTS: CD24 and CD44/CD47 expressions mark distinct cell populations within the normal urothelium as well as in BCa. CD24(high/low) expression was not sufficient to characterize CD24 as a BCa initiating marker in in vivo primary xenotransplants. CD24 and CD44 expressions correlated with lower cancer-specific survival in patients. However, multivariate analyses of CD24 or CD44 did not demonstrate significantly increased hazards for cancer-specific death if analyzed together with stage, grade, and nodal status of patients. CONCLUSIONS: Cancer stem cell markers CD24/CD44/CD47 are differentially expressed in cells of urothelial BCa in patients undergoing RC and influence cancer-specific survival of patients. Further evaluation of CD24/CD44/CD47 protein expression could be of high therapeutic value in BCa. However, both CD24 and CD44 expressions cannot be regarded as independent prognostic parameters for patients undergoing RC. PMID- 24631173 TI - Calcium influx and release mechanism(s) in histamine-induced myometrial contraction in buffaloes. AB - The present study was undertaken to characterize the presence of histamine H1R using molecular biology tools and unravel the influx and release mechanism(s) involved in calcium signalling cascades in histamine-induced myometrial contraction in buffaloes. The presence of H1R mRNA transcript and immunoreactive membrane protein in buffalo myometrium was confirmed by RT-PCR and Western blot analysis. Further, histamine produced concentration-dependent (1nM-10MUM) contraction in buffalo myometrium with a potency of 7.13+/-0.11. When myometrial strips were pre-incubated either with Ca(2+) free solution or with nifedipine, a L-type Ca(2+) channel blocker, dose response curve (DRC) of histamine was significantly (P<0.05) shifted towards right with decline in maximal contraction (Emax). Reduction in Emax of histamine in the presence of nifedipine (55.75+/ 3.10%) was significantly (P<0.001) greater than that in the presence of ruthenium red (93.61+/-3.43%), a blocker of IP3-gated and RyR-sensitive Ca(2+) channels. Moreover, histamine produced only 26.87+/-1.99% of the maximum contraction in the presence of both nifedipine and CPA (blocker of sarco-endoplasmic reticulum Ca(2+)-ATPase). Interestingly, following concurrent exposure to U-73122 (a PL-C inhibitor) and nifedipine, the DRC of histamine was significantly (P<0.05) shifted towards left with increase in maximal contraction (126.30+/-3.36%). Our findings in buffalo uterus thus suggest that influx of extracellular calcium plays a major role in histamine-induced myometrial contraction, while release of intracellular calcium through calcium-release channels of sarcoplasmic reticulum has a minor role. A possible involvement of non-selective cation channels in histamine-induced myometrial contraction cannot be ruled out, and therefore requires further investigations. PMID- 24631174 TI - Stability of serum and plasma osmolality in common clinical laboratory storage conditions. PMID- 24631175 TI - Increased plasma glucose levels after change of recommendation from NaF to citrate blood collection tubes. AB - OBJECTIVES: To evaluate changes in plasma glucose measurements in an unselected patient population after a change of recommendation from NaF to citrate blood collection vacuum tubes. DESIGN AND METHODS: Glucose (n=460 751) and HbA1c (n=55 190) determinations during a period of approximately three years before and after the tube change were extracted from a laboratory information system. RESULTS: Median values for plasma glucose determinations increased from 6.03 before to 6.28mmol/L after the tube change. The proportion of glucose determinations above the WHO limit for impaired fasting glucose (6.1mmol/L) and the medical decision limit for diabetes (7.0mmol/L) increased from 48.1 to 55.4% after the change. CONCLUSIONS: The change from NaF to citrate tubes caused higher glucose values, and consequently more glucose determinations above the decision limit for diabetes. PMID- 24631176 TI - Gestational thyroid reference intervals in antibody-negative Chinese women. AB - OBJECTIVES: The aim of this study is to establish gestation-specific reference intervals (GRIs) for thyroid function assays in pregnant Chinese women with ARCHITECT and compare them to other GRI studies. DESIGN AND METHOD: Thyroid antibody negative pregnant Chinese women were enrolled and followed to establish GRIs for thyroid function by use of the Abbott ARCHITECT i2000SR analyzer (N=1409). Samples from 360 non-pregnant Chinese women served as controls. RESULTS: GRIs of thyroid-stimulating hormone, free thyroxine and free triiodothyronine for first trimester pregnancies were 0.16-3.78mIU/L, 10.9 17.7pmol/L and 2.9-5.0pmol/L, respectively. GRIs for second trimester pregnancies were 0.34-3.51mIU/L, 9.3-15.2pmol/L and 2.9-4.6pmol/L. GRIs for third trimester pregnancies were 0.34-4.32mIU/L, 7.9-14.1pmol/L and 2.9-4.5pmol/L. CONCLUSIONS: Our thyroid GRIs were different from those in other Chinese studies generated on other analyzers, but were similar to a Swiss study using the same analyzer. These data should prove useful for the interpretation of thyroid function assays among pregnant women measured on the Abbott analyzer. PMID- 24631177 TI - Stochastic differential equations as a tool to regularize the parameter estimation problem for continuous time dynamical systems given discrete time measurements. AB - In this paper we consider the problem of estimating parameters in ordinary differential equations given discrete time experimental data. The impact of going from an ordinary to a stochastic differential equation setting is investigated as a tool to overcome the problem of local minima in the objective function. Using two different models, it is demonstrated that by allowing noise in the underlying model itself, the objective functions to be minimized in the parameter estimation procedures are regularized in the sense that the number of local minima is reduced and better convergence is achieved. The advantage of using stochastic differential equations is that the actual states in the model are predicted from data and this will allow the prediction to stay close to data even when the parameters in the model is incorrect. The extended Kalman filter is used as a state estimator and sensitivity equations are provided to give an accurate calculation of the gradient of the objective function. The method is illustrated using in silico data from the FitzHugh-Nagumo model for excitable media and the Lotka-Volterra predator-prey system. The proposed method performs well on the models considered, and is able to regularize the objective function in both models. This leads to parameter estimation problems with fewer local minima which can be solved by efficient gradient-based methods. PMID- 24631178 TI - Parameter identification for model of T cell proliferation in lymphopenia conditions. AB - The number of T Lymphocytes (T cells) in the body is under homeostatic control. At equilibrium, the majority of naive T cells are non-dividing and express low levels of the surface protein CD44. In conditions of T cell deficiency (lymphopenia), naive T cells enter into a proliferative phase, undergoing cell division accompanied by a subtle change in their surface expression of CD44. In this study, we use a mathematical modelling approach to analyse the proliferative response of transgenic T cells in lymphopenic conditions. Our nonlinear model is composed of ordinary differential equations and partial differential equations structured by age (maturity of cell) and CD44 expression. To better understand the evolution of CD44 expression on the surface of T cells during cell division, we present a numerical analysis to solve a parameter identification problem. Finally, we show the parameters and the simulations that we obtain from the model and compare them to experimental data. PMID- 24631179 TI - Preferential lymphatic growth in bronchus-associated lymphoid tissue in sustained lung inflammation. AB - Lymphatics proliferate, become enlarged, or regress in multiple inflammatory lung diseases in humans. Lymphatic growth and remodeling is known to occur in the mouse trachea in sustained inflammation, but whether intrapulmonary lymphatics exhibit similar plasticity is unknown. We examined the time course, distribution, and dependence on vascular endothelial growth factor receptor (VEGFR)-2/VEGFR-3 signaling of lung lymphatics in sustained inflammation. Lymphatics in mouse lungs were examined under baseline conditions and 3 to 28 days after Mycoplasma pulmonis infection, using prospero heomeobox 1-enhanced green fluorescence protein and VEGFR-3 as markers. Sprouting lymphangiogenesis was evident at 7 days. Lymphatic growth was restricted to regions of bronchus-associated lymphoid tissue (BALT), where VEGF-C-producing cells were scattered in T-cell zones. Expansion of lung lymphatics after infection was reduced 68% by blocking VEGFR-2, 83% by blocking VEGFR-3, and 99% by blocking both receptors. Inhibition of VEGFR 2/VEGFR-3 did not prevent the formation of BALT. Treatment of established infection with oxytetracycline caused BALT, but not the lymphatics, to regress. We conclude that robust lymphangiogenesis occurs in mouse lungs after M. pulmonis infection through a mechanism involving signaling of both VEGFR-2 and VEGFR-3. Expansion of the lymphatic network is restricted to regions of BALT, but lymphatics do not regress when BALT regresses after antibiotic treatment. The lung lymphatic network can thus expand in sustained inflammation, but the expansion is not as reversible as the accompanying inflammation. PMID- 24631180 TI - Hair follicle disruption facilitates pathogenesis to UVB-induced cutaneous inflammation and basal cell carcinoma development in Ptch(+/-) mice. AB - Hairless mice carrying homozygous mutations in hairless gene manifest rudimentary hair follicles (HFs), epidermal cysts, hairless phenotype, and enhanced susceptibility to squamous cell carcinomas. However, their susceptibility to basal cell carcinomas (BCCs), a neoplasm considered originated from HF-localized stem cells, is unknown. To demonstrate the role of HFs in BCC development, we bred Ptch(+/-)/C57BL6 with SKH-1 hairless mice, followed by brother-sister cross to get F2 homozygous mutant (hairless) or wild-type (haired) mice. UVB-induced inflammation was less pronounced in shaved haired than in hairless mice. In hairless mice, inflammatory infiltrate was found around the rudimentary HFs and epidermal cysts. Expression of epidermal IL1f6, S100a8, vitamin D receptor, repetin, and major histocompatibility complex II, biomarkers depicting susceptibility to cutaneous inflammation, was also higher. In these animals, HF disruption altered susceptibility to UVB-induced BCCs. Tumor onset in hairless mice was 10 weeks earlier than in haired littermates. The incidence of BCCs was significantly higher in hairless than in haired animals; however, the magnitude of sonic hedgehog signaling did not differ significantly. Overall, 100% of hairless mice developed >12 tumors per mouse after 32 weeks of UVB therapy, whereas haired mice developed fewer than three tumors per mouse after 44 weeks of long-term UVB irradiation. Tumors in hairless mice were more aggressive than in haired littermates and manifested decreased E-cadherin and enhanced mesenchymal proteins. These data provide novel evidence that disruption of HFs in Ptch(+/-) mice enhances cutaneous susceptibility to inflammation and BCCs. PMID- 24631182 TI - Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing. AB - BACKGROUND: The prevalence of asthma has increased alarmingly in the past 2 to 3 decades. Increased antibiotic use in infancy has been suggested to limit exposure to gastrointestinal microbes and to predispose to asthma in later life. OBJECTIVE: To evaluate the association between antibiotic exposure during the first year of life and the development of asthma up to the age of 7 years. METHODS: A retrospective population-based study of a cohort of children enrolled in a nationwide employer-provided health insurance plan from January 1, 1999, through December 31, 2006, in the United States (n = 62,576). We evaluated the association between antibiotic exposure during the first year of life and subsequent development of 3 asthma phenotypes: transient wheezing (began and resolved before 3 years of age), late-onset asthma (began after 3 years of age), and persistent asthma (began before 3 years of age and persisted through 4-7 years of age). RESULTS: Antibiotic use in the first year of life was associated with the development of transient wheezing (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.9-2.2; P < .001) and persistent asthma (OR, 1.6; 95% CI, 1.5 1.7; P < .001). A dose-response effect was observed. When 5 or more antibiotic courses were received, the odds of persistent asthma doubled (OR, 1.9; 95% CI, 1.5-2.6; P < .001). There is no association between antibiotic use and late-onset asthma. CONCLUSION: Antibiotic use in the first year life is associated with an increased risk of early-onset childhood asthma that began before 3 years of age. The apparent effect has a clear dose response. Heightened caution about avoiding unnecessary use of antibiotics in infants is warranted. PMID- 24631181 TI - miR-199a-3p inhibits aurora kinase A and attenuates prostate cancer growth: new avenue for prostate cancer treatment. AB - Prostate cancer (PCa) is the most common solid tumor malignancy in men that severely influences quality of life. Surgery is most often the recommended treatment for PCa, but radical prostatectomy can cause significant urinary adverse effects. Therefore, finding effective biochemical treatments for PCa remains a necessity. Aurora kinase A has been shown to be involved in PCa progression, thus making it a good target for PCa therapy. miRNAs are important regulators of gene expression, with some miRNAs specifically involved in carcinogenesis. Therefore, herein, we identified miRNAs targeted to aurora kinase A and examined their effects on the growth of PCa. We used primary samples from PCa patients and PCa cell lines as research subjects. We demonstrate that miR 199a-3p is down-regulated in PCa tissues compared with normal prostate tissues, with the expression pattern inversely correlated with the expression pattern of aurora kinase A. We find that miR-199a-3p agomir inhibits aurora kinase A and attenuates xenograft tumor growth of PCa. Moreover, we demonstrate that down regulation of miR-199a-3p results from enhancement of the methylation of miR-199a gene in PCa. Furthermore, we find that the expression level of miR-199a-3p is inversely correlated to tumor stage and Gleason score of PCa. Revealing novel mechanisms for oncogene inhibition by miRNA-mediated pathways offers new avenues for PCa treatment. PMID- 24631183 TI - Systemic reactions to inhalant immunotherapy using 1:1 target dosing. AB - BACKGROUND: The 2007 immunotherapy practice parameters advocate maintenance dosing at 1:1 (1:20 maintenance concentrate). There is limited literature exploring the effect of 1:1 dosing on the rate of systemic reactions to subcutaneous immunotherapy (SRITs). OBJECTIVE: To investigate the effects of 1:1 dosing on SRITs in a large, academic practice. METHODS: We conducted a retrospective cohort study of all nonvenom and noncluster SRITs that occurred between 2005 and 2011. SRITs that occurred from August 2008 through December 2011, postparameter dosing (post-PD) was initiated, were compared to SRITs that occurred from January 2005 to July 2008 with preparameter dosing (pre-PD) using 1:50 as a maintenance concentrate. RESULTS: A total of 269 SRITs occurred in a 7 year period. Significantly more post-PD SRITs (131 of 38,548 injections) occurred than pre-PD SRITs (132 of 52,833 injections) (0.34% vs 0.25%, P = .01). However, when excluding 44 SRITs that occurred in established pre-PD patients transitioned to post-PD, there was no significant difference in SRIT rate (0.25% vs 0.22%), World Allergy Organization (WAO) grade, or SRIT time to onset. Nonred (non-1:1) vials accounted for a significantly larger proportion of all post-PD SRITs compared with all pre-PD SRITs (50.7% vs 31.1%, adjusted P = .009). Prior SRITs were reported less frequently among persons with post-PD SRITs (29.2% vs 70.8%, adjusted P = .009). In an adjusted logistic regression model, male sex (odds ratio, 7.9; 95% CI, 2.4-26) and longer time to reaction onset (odds ratio, 0.94; 95% CI, 0.89-0.99) were associated with higher WAO severity grade reactions. CONCLUSION: Pre-PD vs post-PD SRIT rates were not significantly different, adjusting for patients transitioned from established pre-PD to post-PD. This finding suggests that post-PD is as safe as pre-PD. Male sex and faster time to reaction onset were associated with higher WAO grade reactions. PMID- 24631184 TI - Common variable immunodeficiency associated with birdshot-like chorioretinopathy. PMID- 24631185 TI - Synthesis and antimycobacterial activities of some new thiazolylhydrazone derivatives. AB - This Letter reports the synthesis and evaluation of some thiazolylhydrazone derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. The cytotoxic activities of all compounds were also evaluated. The compounds exhibited promising antimycobacterial activity with MICs of 1.03-72.46 MUM and weak cytotoxicity (8.9-36.8% at 50 MUg/mL). Among them, 1 (4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazine 10 was found to be the most active compound (MIC of 1.03 MUM) with a good safety profile (16.4% at 50 MUg/mL). Molecular modeling studies were done to have an idea for the mechanism of the action of the target compounds. According the docking results it can be claimed that these compounds may bind most likely to TMPK than InhA or CYP121. PMID- 24631186 TI - Synthesis of amino-analogs of bacteriochlorophyll-d and their self-aggregation in an aqueous micelle solution. AB - Zinc methyl 3-aminomethyl- and 3-(1-aminoethyl)-pyropheophorbides-a were prepared by modifying naturally occurring chlorophyll-a. The synthetic amino-analogs of bacteriochlorophyll-d self-aggregated in an aqueous micelle solution to give large oligomers with red-shifted and broadened electronic absorption bands. The spectra of these self-aggregates were similar to those of bacteriochlorophyll self-aggregates in the main light-harvesting antennas of green photosynthetic bacteria. The 3(1)-amino groups were alternative to the 3(1)-hydroxy groups in natural bacteriochlorophylls-c/d/e/f. PMID- 24631187 TI - Synthesis and evaluation of amide side-chain modified Agomelatine analogues as potential antidepressant-like agents. AB - In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood-brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine. PMID- 24631188 TI - Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum. AB - The plasmepsins are specific aspartic proteases of the malaria parasite and a potential target for developing new antimalarial agents. Our previously reported peptidomimetic plasmepsin inhibitor with modified 2-aminoethylamino substituent, KNI-10740, was tested against chloroquine sensitive Plasmodium falciparum, D6, to be highly potent, however, the inhibitor exhibited about 5 times less activity against multi-drug resistant parasite (TM91C235). We hypothesized the potency reduction resulted from structural similarity between 2-aminoethylamino substituent of KNI-10740 and chloroquine. Then, we modified the moiety and finally identified compound 15d (KNI-10823), that could avoid drug-resistant mechanism of TM91C235 strain. PMID- 24631189 TI - Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors. AB - The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties. PMID- 24631190 TI - Synthesis, antiproliferative and antibacterial activity of new amides of salinomycin. AB - A series of 11 novel amides of salinomycin were synthesized for the first time. All the obtained compounds were found to show potent antiproliferative activity against human cancer cell lines including the drug-resistant cancer cells. Four new salinomycin derivatives revealed good antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE). PMID- 24631191 TI - Design, synthesis, and antibacterial activity against rice bacterial leaf blight and leaf streak of 2,5-substituted-1,3,4-oxadiazole/thiadiazole sulfone derivative. AB - A series of 2,5-substituted-1,3,4-oxadiazole/thiadiazole sulfone derivatives were synthesized and evaluated for their antibacterial activities against rice bacterial leaf blight and leaf streak caused by Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicolaby via the turbidimeter test in vitro. Antibacterial bioassay results indicated that most compounds demonstrated good inhibitory effect antibacterial bioactivities against rice bacterial leaf blight and leaf streak. Among the title compounds, compound 6c demonstrated the best inhibitory effect against rice bacterial leaf blight and leaf streak with half maximal effective concentration (EC50) values of 1.07 and 7.14 MUg/mL, respectively, which were even better than those of commercial agents such as Bismerthiazol and Thiediazole Copper. In vivo antibacterial activities tests at greenhouse conditions demonstrated that the controlling effect of compounds 6c (43.5%) and 6g (42.4%) against rice bacterial leaf blight were better than those of Bismerthiazol (25.5%) and Thiediazole Copper (37.5%). PMID- 24631192 TI - Purification and characterization of a novel beta-agarase of Paenibacillus sp. SSG-1 isolated from soil. AB - Agar is a polysaccharide polymer material, generally extracted from seaweed. Most agar degradation strains were isolated from seawater. In order to find new species resources and novel agarase from soil, an agar-degrading bacterium Paenibacillus sp. SSG-1 was isolated from soil. Agarase SSG-1a was purified to homogeneity by 30.2 fold with a yield of 4.8% through ammonium sulfate precipitation, DEAE FF chromatography and native-PAGE separation. The tandem mass spectrometry (MS/MS) results indicated that purified SSG-1a should be a novel beta-agarase. The molecular mass of SSG-1a was estimated to be 77 kDa. The optimal temperature and pH for SSG-1a were 50 degrees C and pH 6.0, respectively. Moreover, SSG-1a was stable in pH range of 4.0-10.0 and at temperature up to 40 degrees C. It could hydrolyze the beta-1,4 linkage of agarose to produce neoagarohexaose (95 mol%) and neoagarooctaose (5 mol%). Metal ion Mn(2+) and reducing reagents (beta-Me and DTT) could increase its activity by 150% and 60%, respectively. PMID- 24631194 TI - Somatosensory amplification and menopausal symptoms in breast cancer survivors and midlife women. AB - OBJECTIVES: Somatosensory amplification is the experience of sensing everyday bodily sensations as intense, agitating, and unpleasant. Using data from menopausal breast cancer survivors and midlife women without cancer, the study purposes were to (1) explore the psychometric properties of the Somatosensory Amplification Scale and (2) to describe somatosensory amplification and its relationship to menopausal symptoms of hot flashes, mood and sleep disturbance. STUDY DESIGN: This was a cross-sectional, descriptive, correlational study using demographic, e-diary, and questionnaire data from 99 breast cancer survivors and 138 midlife women. MAIN OUTCOME MEASURES: Somatosensory amplification, hot flashes (frequency, severity, bother, interference, perceived control), mood, and sleep. RESULTS: Cronbach's alphas for the scale were low. When an 8-item version of the scale was evaluated, alphas improved and item-total correlations remained strong or improved. Midlife women and breast cancer survivors did not have significantly different somatosensory amplification total or item scores after adjusting for group differences in demographics. Somatosensory amplification was significantly correlated with hot flash interference, perceived control over hot flashes, and mood and sleep disturbance in both groups but the patterns of correlations differed slightly between groups and depending on whether the 10 item or 8-item scale was used. CONCLUSION: Somatosensory amplification may be a relevant concept to assess in relation to the menopausal symptom experience of midlife women with and without breast cancer as it may represent a potential intervention target to improve the menopausal symptom experience. PMID- 24631193 TI - Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. AB - The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6. PMID- 24631195 TI - Early life stress and tumor necrosis factor superfamily in crack cocaine withdrawal. AB - BACKGROUND: Both early life stress (ELS) and substance abuse, especially cocaine, have robust effects on the inflammatory system. Considering the role of the tumor necrosis factor system in inflammatory signaling and its association with ELS, the aim of the study was to compare plasma levels of TNF-alpha, its soluble receptors and ligands during early abstinence of crack cocaine. METHODS: This study included 24 crack cocaine-dependent women with (CRACK-ELS) and 20 without (CRACK) a history of ELS. A healthy control group (HC), containing 25 participants, was included to provide reference values. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history of patients. Plasma levels of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), soluble receptors TNFRI (sTNFRI) and TNFRII (sTNFRII) were assessed on the 18th day of treatment. RESULTS: The CRACK-ELS group had higher TNF-alpha and lower TWEAK levels compared to the CRACK and HC groups. sTNFRII was increased, but only in comparison with the crack cocaine group and the controls. TRAIL levels were slightly higher in the CRACK-ELS group, while no differences were found for sTNFRI levels. Also, TNF alpha plasma level was positively predicted by abstinence severity and childhood maltreatment severity, and TWEAK was negatively predicted by childhood maltreatment severity. CONCLUSIONS: This is the first study to evaluate the newly secreted tumor necrosis factor superfamily ligands, TWEAK and TRAIL, during crack cocaine abstinence, supporting the association between early life stress and peripheral pro-inflammatory levels. PMID- 24631196 TI - Stress sensitivity mediates the relationship between traumatic life events and attenuated positive psychotic symptoms differentially by gender in a college population sample. AB - The purpose of this study was to investigate whether stress sensitivity mediates the relationship between traumatic life events and total attenuated positive psychotic symptoms, as well as the relationship between traumatic life events and endorsement of 8 or more attenuated positive psychotic symptoms as distressing (a threshold that has been associated with higher risk for psychosis in clinical groups). Participants (n = 671, aged 17-35, 29% male) were college students who were administered the Prodromal Questionnaire, the Perceived Stress Scale and the Life Events Checklist. Bootstrapping results indicated that stress sensitivity significantly mediated the relationships between traumatic life events and the number of attenuated positive psychotic symptoms endorsed and between traumatic life events and those who endorsed 8 or more distressing attenuated positive psychotic symptoms. Stratified gender analyses indicated the findings were specific to females. Results suggest that stress sensitivity may represent a specific vulnerability factor for risk of attenuated psychotic symptoms in those previously exposed to traumatic life events and that this liability appears stronger in females. PMID- 24631197 TI - Carotid artery atherosclerosis among 65-year-old Swedish men - a population-based screening study. AB - OBJECTIVE: There are limited contemporary epidemiological data on the prevalence of carotid atherosclerosis in the general population. The aim was to determine the prevalence of and risk factors associated with carotid artery atherosclerosis among 65-year-old men. METHODS: This was a population-based screening study. All 65-year-old men in the County of Uppsala, Sweden, who attended screening for abdominal aortic aneurysm (AAA) 2007-2009, were invited for duplex scanning of the carotid arteries. RESULTS: Of 4801 men invited, 4657 (97%) accepted. Carotid plaques (>2 * 6 mm) were observed in 1169 (25%) men, 94 (2.0%) had carotid stenoses (50-99%), and 15 (0.3%) had occluded carotid arteries. In a multivariate logistic regression model, smoking (OR 1.7, 95% CI 1.5-1.9), hypertension (1.5, 95% CI 1.3-1.7), diabetes mellitus (1.2, 95% CI 1.0-1.5), and coronary artery disease (1.5, 95% CI 1.3-1.8) were associated with prevalence of carotid atherosclerosis (plaque and/or stenosis). The use of antiplatelet agents and statins in participants with a carotid plaque was 20% and 29%, respectively. The corresponding figures in participants with a stenosis were 42% and 41%. CONCLUSIONS: This study offers contemporary data on the prevalence of carotid atherosclerosis in a population-based cohort of 65-year-old men. Most of those at risk had no other clinical manifestation of atherosclerosis, and therefore had no secondary prevention. PMID- 24631199 TI - Increased virulence of Mycobacterium tuberculosis H37Rv overexpressing LipY in a murine model. AB - We have investigated the role of Rv3097c-encoded lipase (LipY) on the virulence of Mycobacterium tuberculosis. It has been shown that the overexpression of LipY in strain H37Rv induced increase in virulence of recombinant H37Rv::LipY strain. Compared to H37Rv, infection with H37Rv::LipY caused enhanced mortality, weight loss, bacterial load in lungs, splenomegaly, worsening lung morphology and pathology. Mice immunized with recombinant LipY antigen were protected against challenge with H37Rv::LipY, which correlated with enhanced survival of challenged mice and striking decrease in pathological features observed in unimmunized mice. To probe the cause of increase in virulence of H37Rv::LipY, the immune status of the host infected with H37Rv and H37Rv::LipY was compared. It was found that overexpression of LipY compromised immune responses resulting in attenuation of Th1 and Th17 responses, significant increase in IL-10, decrease in number of macrophages and T cells, and increase in numbers of Treg, and DCs in the lungs whereas in mice immunized with LipY an increased pool of T cells and DCs was observed. This led us to conclude that the increase in the virulence of H37Rv::LipY was due to downregulation of the host's protective immunity and the Rv3097c encoded LipY lipase is a virulence factor of M. tuberculosis. PMID- 24631198 TI - ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans. AB - Mycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1 mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells. PMID- 24631200 TI - Cellular immune responses and phagocytic activity of fishes exposed to pollution of volcano mud. AB - Since May 29, 2006, a mud volcano in the Brantas Delta of the Sidoarjo district has emitted mud that has inundated nearby villages. Pollution in this area has been implicated in detrimental effects on fish health. In fishes, leukocyte and phagocytic cells play a vital role in body defenses. We report for the first time the effect of "LUSI" volcano mud on the immune systems of fish in the Brantas Delta. The aim of this study was to find biomarkers to allow the evaluation of the effects of volcanic mud and anthropogenic pollution on fish health in the Brantas Delta. The study took places at the Brantas Delta, which was polluted by volcano mud, and at reference sites in Karangkates and Pasuruan. Leukocyte numbers were determined using a Neubauer hemocytometer and a light microscope. Differential leukocyte counts were determined using blood smears stained with May Grunwald-Giemsa, providing neutrophil, lymphocyte and monocyte counts. Macrophages were taken from fish kidney, and their phagocytic activity was measured. In vitro analyses revealed that leukocyte and differential leukocyte counts (DLC) were higher in Channa striata and Chanos chanos caught from the polluted area. Macrophage numbers were higher in Oreochromis mossambicus than in the other species, indicating that this species is more sensitive to pollution. In areas close to volcanic mud eruption, all specimens had lower phagocytic activity. Our results show that immune cells were changed and phagocytic activity was reduced in the polluted area indicating cytotoxicity and alteration of the innate immune system in fishes exposed to LUSI volcano mud and anthropogenic pollution. PMID- 24631201 TI - Effect of tamsulosin on iris vasculature and morphology. AB - PURPOSE: To determine whether preoperative iris vasculature and morphology are altered in patients who have taken tamsulosin (Flomax). SETTING: Academic multispecialty practice. DESIGN: Case series. METHODS: Patients with current or past tamsulosin use and age- and sex-matched control patients were included. Anterior segment optical coherence tomography (AS-OCT) and iris fluorescein angiography were performed to measure iris vasculature and thickness before cataract surgery. Data collected at surgery included pupil diameter, clinical signs of intraoperative floppy-iris syndrome, and surgical complications. RESULTS: Tamsulosin was currently used by 16 patients and in the past by 4 patients; the control group comprised 10 patients. Pharmacologically dilated pupil diameter was statistically significantly smaller preoperatively and immediately postoperatively in the tamsulosin group than in the control group (P=.009 and P=.003, respectively). There was a statistically significant decrease in pupil size intraoperatively in the tamsulosin group (P=.05) but not in the control group (P=.3). Iris-vasculature parameters, specifically time to first vessel fill and percentage of vessel fill on iris fluorescein angiography, were not significantly different between the 2 groups. The AS-OCT measurements of iris morphology were not statistically significantly different between the groups. No surgical complications occurred. No fluorescein dye leakage, staining, or other vascular anomalies were observed. CONCLUSIONS: Although there were differences in pupil measurements and intraoperative iris behavior between patients who had been on tamsulosin and control patients, there were no significant differences in iris vasculature on iris fluorescein angiography or in iris morphology on AS-OCT. PMID- 24631202 TI - Straylight before and after phacoemulsification in eyes with preoperative corrected distance visual acuity better than 0.1 logMAR. AB - PURPOSE: To report the outcomes of changes in straylight before and after phacoemulsification in eyes with preoperative corrected distance visual acuity (CDVA) better than 0.1 logMAR. SETTING: Private refractive surgery clinic, Driebergen, the Netherlands. DESIGN: Cohort study. METHODS: Standard phacoemulsification with implantation of a monofocal or multifocal intraocular lens (IOL) was performed. Preoperative and 3-month postoperative straylight values, CDVA, and refractive error were compared. RESULTS: The study enrolled 160 eyes (89 patients). The mean CDVA was 0.02 +/- 0.05 logMAR (range -0.1 to 0.1 logMAR) preoperatively and 0.00 +/- 0.04 logMAR (range -0.1 to 0.2 logMAR) postoperatively. The mean preoperative straylight was 1.21 +/- 0.20 log(s) (range 0.80 to 1.74 log[s]) and 1.11 +/- 1.16 log(s) (range 0.76 to 1.63 log[s]), respectively; the improvement was statistically significant. There was a correlation between high preoperative straylight values and postoperative improvement in straylight values. CONCLUSIONS: In eyes with relatively good CDVA of 0.1 logMAR or better (decimal 0.8 or better; Snellen 20/25 or better), straylight improved by 0.10 log(s) after cataract surgery. A subgroup of 44 eyes had an improvement of more than 0.20 log(s), which is comparable to a 2-line improvement on the vision chart. PMID- 24631203 TI - Improvement in vision with inverted placement of an asymmetric refractive multifocal intraocular lens. AB - We report the case of a 73-year-old man who presented for bilateral cataract surgery. He was noted to have a 0.5 mm corneal scar inferonasally at the pupil margin in his right eye. Uneventful bilateral cataract surgery was performed. An asymmetric toric refractive multifocal intraocular lens (IOL) (LU-313MF30T, Lentis MPlus toric) was implanted in the right eye. Postoperatively, the uncorrected distance visual acuity (UDVA) in that eye was 6/6(-3), the uncorrected intermediate visual acuity at 60 cm was J4, and the uncorrected near visual acuity (UNVA) at 40 cm was J8. The patient was not satisfied with the UNVA. Corneal topography showed 3.0 diopters (D) of corneal flattening over the +3.00 D near segment. The IOL was rotated 180 degrees, which improved the UNVA to J1 while maintaining the UDVA. This study demonstrates that the Lentis Mplus can function even when the near segment is not positioned inferiorly. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 24631204 TI - Birth of a domestic cat kitten produced by vitrification of lipid polarized in vitro matured oocytes. AB - The ability to cryopreserve oocytes is an effective method to retain valuable genetic material of mammals, including that of endangered animals. Embryos of domestic cats are amenable to cryopreservation, whereas their oocytes are much less cryo-tolerant. The capability of oocytes to survive cryopreservation is affected by several factors, one of which has been hypothesized to be the high concentration of intracellular lipids. To test this hypothesis, in this study we polarized lipids of cat oocytes and tested their cooling and freezing sensitivity. We found that the sensitivity of oocytes to cooling and cryopreservation does appear to be related to their high intracellular lipid content, as indicated by higher cryosurvival and development into blastocysts when intracellular lipids of in vitro matured oocytes were polarized before vitrification. However, polarization of all intracellular lipids was detrimental to development of embryos. Cell numbers in blastocysts derived from fully polarized/vitrified oocytes were significantly lower than those of partially polarized/vitrified or non-vitrified/fresh oocytes. Although embryos derived from fully polarized/vitrified oocytes developed to the blastocyst stage at higher rates than those of partially polarized/vitrified or non-centrifuged/vitrified oocytes, their in vivo developmental competence was compromised. When embryos derived from fully polarized/vitrified oocytes were transferred, although two recipients became pregnant, all implanted embryos were reabsorbed. In contrast, when embryos derived from oocytes that were only partially lipid polarized before vitrification and then were transferred, one recipient did become pregnant and produced a live healthy kitten. The present results suggest that other approaches to altering intra-cellular lipid levels in cat oocytes should be evaluated to improve their functional survival after cryopreservation. PMID- 24631205 TI - Impact of long-term exposure to cigarette smoking on skin microvascular function. AB - In order to evaluate the impact of cigarettes smoking and smokers' clinical characteristics on skin microvascular function, we measured the skin forearm blood flux, basally and during post-occlusive reactive hyperaemia, in 100 current smokers (mean age 51+/-11 years; range: 18 to 86 years) and in 66 healthy never smokers matched for age and sex, by using laser Doppler fluximetry (LDF). Basal and post-ischemic LDF tracings were analyzed in the frequency domain within 0.009 0.02 Hz, 0.021-0.06 Hz and 0.061-0.2 Hz ranges, related to endothelial-dependent, sympathetic-dependent and myogenic-dependent vasomotion, respectively, using an adapted version of the Fourier analysis. The post-ischemic percentage change from baseline of the area under the LDF curve (AUC%) was significantly lower in smokers than in never-smokers [162.5% (139.3-183.0) vs 190.1% (156.3-216.8); p=0.00016]. Compared to controls, smokers also showed a reduced basal power spectral density (PSD) in the myogenic-dependent vasomotion (p=0.0034) and a reduced post-ischemic percentage increase in PSD of the endothelial-dependent vasomotion (p=0.0010) and sympathetic-dependent vasomotion (p=0.0016). An inverse relationship was observed in smokers between AUC% and smoking exposure duration (r=0.23, p=0.018), pack-years (r=0.33, p=0.0007), age (r=0.26, p=0.008) and body mass index (r=0.21, p=0.037). In the multiple linear regression model, pack-years was the only variable independently associated with AUC% (r=0.21, p=0.03). This study confirms that smoking is associated with cutaneous microvascular dysfunction and shows that the severity of this impairment is independently related to the duration and intensity of the exposure to smoking. PMID- 24631206 TI - Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3alpha, beta and NR2B in adult offspring during fear extinction in rats. AB - Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3alpha, beta), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3alpha, beta and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain. PMID- 24631207 TI - The developmental pattern of the RAS/RAF/Erk1/2 pathway in the BTBR autism mouse model. AB - BTBR mice exhibit several autistic-like behaviors and are currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Ras/Raf/ERK1/2 signaling has been suggested to play an important role in neural development, learning, memory, and cognition. Two studies reported that a deletion of a locus on chromosome 16 containing the mitogen-activated protein kinase 3 (MAPK3) gene, which encodes ERK1, is associated with autism. In the present study, Ras/Raf/ERK1/2 signaling was found to be up-regulated in BTBR mice relative to matched control B6 mice, to further suggest involvement in the pathogenesis of autism. To further characterize the developmental pattern of Ras/Raf/ERK1/2 signaling, varying stages during development were sampled to reveal an up-regulation in newborn and 2-week old BTBR mice relative to age matched B6 mice. By the age of 3-week, Ras/Raf/ERK1/2 signaling in the brain of BTBR mice was unaltered relative to B6 mice, with this trend maintained in 6-week samples. These results suggest that the alteration of Ras/Raf/ERK signaling in the early developmental stages in mice could contribute to the noted autistic phenotype. Furthermore, these findings support the value of BTBR mice to serve as a human analog for autistic etiological research and aid in a better understanding of the developmental mechanisms of autism. PMID- 24631208 TI - A 19-year-old ambulant Duchenne patient with stunted growth on long-term corticosteroids. PMID- 24631209 TI - Catch and release: how do kinetochores hook the right microtubules during mitosis? AB - Sport fishermen keep tension on their lines to prevent hooked fish from releasing. A molecular version of this angler's trick, operating at kinetochores, ensures accuracy during mitosis: the mitotic spindle attaches randomly to chromosomes and then correctly bioriented attachments are stabilized due to the tension exerted on them by opposing microtubules. Incorrect attachments, which lack tension, are unstable and release quickly, allowing another chance for biorientation. Stabilization of molecular interactions by tension also occurs in other physiological contexts, such as cell adhesion, motility, hemostasis, and tissue morphogenesis. Here, we review models for the stabilization of kinetochore attachments with an eye toward emerging models for other force-activated systems. Although attention in the mitosis field has focused mainly on one kinase-based mechanism, multiple mechanisms may act together to stabilize properly bioriented kinetochores and some principles governing other tension-sensitive systems may also apply to kinetochores. PMID- 24631211 TI - Pain in pigs: how much does it hurt? PMID- 24631210 TI - Environmentally relevant mixing ratios in cumulative assessments: a study of the kinetics of pyrethroids and their ester cleavage metabolites in blood and brain; and the effect of a pyrethroid mixture on the motor activity of rats. AB - National surveys of United States households and child care centers have demonstrated that pyrethroids are widely distributed in indoor habited dwellings and this suggests that co-exposure to multiple pyrethroids occurs in nonoccupational settings. The purpose of this research was to use an environmentally relevant mixture of pyrethroids to assess their cumulative effect on motor activity and develop kinetic profiles for these pyrethroids and their hydrolytic metabolites in brain and blood of rats. Rats were dosed orally at one of two levels (1.5* or 5.0* the calculated dose that decreases rat motor activity by 30%) with a mixture of cypermethrin, deltamethrin, esfenvalerate, cis-/trans permethrin, and beta-cyfluthrin in corn oil. At 1, 2, 4, 8, or 24h after dosing, the motor activity of each animal was assessed and the animals sacrificed. Concentrations of pyrethroids in brain and blood, and the following metabolites: cis-/trans-dichlorovinyl-dimethylcyclopropane-carboxylic acid, 3-phenoxybenzoic acid, 3-phenoxybenzyl alcohol, 4-fluoro-3-phenoxybenzoic acid, and cis dibromovinyl-dimethylcyclopropane-carboxylic acid were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). Using this pyrethroid mixture in rats, the results suggest there is greater metabolism of trans-permethrin prior to entering the systemic circulatory system. All pyrethroids had tissue half-lives (t1/2) of less than 5h, excepting esfenvalerate in brain. At early time points, relative pyrethroid brain concentrations approximated their dose mixture proportions and a sigmoidal Emax model described the relationship between motor activity decrease and total pyrethroid brain concentration. In blood, the t1/2's of the cyclopropane metabolites were longer than the phenoxybenzoic metabolites. However, relative to their respective precursors, concentrations of the phenoxybenzoic acids were much higher than concentrations of the cyclopropane metabolites. Brain concentrations of all metabolites were low relative to blood concentrations. This implies limited metabolite penetration of the blood-brain barrier and little metabolite formation within the brain. IN CONCLUSION: toxicokinetic differences between the pyrethroids did not appear to be important determinants of their relative potency and their effect on motor activity was consistent with a pyrethroid dose additive model. PMID- 24631212 TI - Expression of Chlamydia muridarum plasmid genes and immunogenicity of pGP3 and pGP4 in different mouse strains. AB - Chlamydia muridarum carries a cryptic plasmid (pMoPn) of 7.5kb, which encodes seven genes. Our aims were to describe the transcriptional pattern of the pMoPn genes in C. muridarum-infected mice and to evaluate the host immune responses against pGP3 and pGP4 proteins. BALB/c and C57BL/6N female mice were inoculated intranasally with C. muridarum and sacrificed at different time points, and the total RNA was extracted from the lung suspensions to determine the levels of expression of the different plasmid genes by RT qPCR. The supernatants of the lungs were subjected to the quantitation of recoverable C. muridarum. TCA04 and TCA05, which encode pGP3 and pGP4, respectively, were amplified by PCR and cloned into the pET vector. The proteins were overexpressed in E. coli HB101 and purified. Selected groups of BALB/c and C57BL/6N mice were infected with C. muridarum 1-3 times. The humoral immune responses in the sera of the mice to the proteins encoded by TCA04 and TCA05 were tested by Western blotting, and the cellular immune responses were assessed in lymphocyte proliferation assays. The proteins recognized by the mouse sera were further analysed by a LC/MSMS technique. The kinetics of C. muridarum growth were similar in the mouse strains used, but the pathogen burden was higher in the BALB/c mice in the late phase of infection. All the plasmid genes in the BALB/c mice showed an increased level of expression on day 7, whereas the expression of the same genes did not change on day 7 in the C57BL/6N mice. The levels of expression of the plasmid genes were higher in the C57BL/6N mice at later time points. In Western blot assays, the sera of the singly infected C57BL/6N mice reacted with the monomeric form of pGP3, whereas the sera of the singly infected BALB/c mice reacted with the trimeric form of pGP3. The sera of the multiply infected C57BL/6N mice also recognized pGP4. Similarly to the humoral immune response, cellular immune responses to pGP3 and pGP4 were detected in the C. muridarum-infected C57BL/6N mice, but the spleen cells of BALB/c mice responded with proliferation only to the pGP3 protein. These results suggest that the proteins encoded by pMoPn genes may modulate the host immune response during C. muridarum infection, and that the evolved immune response against plasmid proteins, similarly to that against other chlamydial proteins, depends on the genetic background of the host. PMID- 24631213 TI - In silico tools for the analysis of antibiotic biosynthetic pathways. AB - Natural products of bacteria and fungi are the most important source for antimicrobial drug leads. For decades, such compounds were exclusively found by chemical/bioactivity-guided screening approaches. The rapid progress in sequencing technologies only recently allowed the development of novel screening methods based on the genome sequences of potential producing organisms. The basic principle of such genome mining approaches is to identify genes, which are involved in the biosynthesis of such molecules, and to predict the products of the identified pathways. Thus, bioinformatics methods and tools are crucial for genome mining. In this review, a comprehensive overview is given on programs and databases for the identification and analysis of antibiotic biosynthesis gene clusters in genomic data. PMID- 24631214 TI - Membrane vesicles of Clostridium perfringens type A strains induce innate and adaptive immunity. AB - Vesicle shedding from bacteria is a universal process in most Gram-negative bacteria and a few Gram-positive bacteria. In this report, we isolate extracellular membrane vesicles (MVs) from the supernatants of Gram-positive pathogen Clostridium perfringens (C. perfringens). We demonstrated vesicle production in a variety of virulent and nonvirulent type A strains. MVs did not contain alpha-toxin and NetB toxin demonstrated by negative reaction to specific antibody and absence of specific proteins identified by LC-MS/MS. C. perfringens MVs contained DNA components such as 16S ribosomal RNA gene (16S rRNA), alpha toxin gene (plc) and the perfringolysin O gene (pfoA) demonstrated by PCR. We also identified a total of 431 proteins in vesicles by 1-D gel separation and LC MS/MS analysis. In vitro studies demonstrated that vesicles could be internalized into murine macrophage RAW264.7 cells without direct cytotoxicity effects, causing release of inflammation cytokines including granulocyte colony stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), which could also be detected in mice injected with MVs through intraperitoneal (i.p.) route. Mice immunized with C. perfringens MVs produced high titer IgG, especially IgG1, antibodies against C. perfringens membrane proteins. However, this kind of antibody could not provide protection in mice following challenge, though it could slightly postpone the time of death. Our results indicate that release of MVs from C. perfringens could provide a previously unknown mechanism to induce release of inflammatory cytokines, especially TNF-alpha, these findings may contribute to a better understanding of the pathogenesis of C. perfringens infection. PMID- 24631216 TI - BMP antagonism by Noggin is required in presumptive notochord cells for mammalian foregut morphogenesis. AB - Esophageal atresia with tracheoesophageal fistula (EA/TEF) is a serious human birth defect, in which the esophagus ends before reaching the stomach, and is aberrantly connected with the trachea. Several mouse models of EA/TEF have recently demonstrated that proper dorsal/ventral (D/V) patterning of the primitive anterior foregut endoderm is essential for correct compartmentalization of the trachea and esophagus. Here we elucidate the pathogenic mechanisms underlying the EA/TEF that occurs in mice lacking the BMP antagonist Noggin, which display correct dorsal/ventral patterning. To clarify the mechanism of this malformation, we use spatiotemporal manipulation of Noggin and BMP receptor 1A conditional alleles during foregut development. Surprisingly, we find that the expression of Noggin in the compartmentalizing endoderm is not required to generate distinct tracheal and esophageal tubes. Instead, we show that Noggin and BMP signaling attenuation are required in the early notochord to correctly resolve notochord cells from the dorsal foregut endoderm, which in turn, appears to be a prerequisite for foregut compartmentalization. Collectively, our findings support an emerging model for a mechanism underlying EA/TEF in which impaired notochord resolution from the early endoderm causes the foregut to be hypo cellular just prior to the critical period of compartmentalization. Our further characterizations suggest that Noggin may regulate a cell rearrangement process that involves reciprocal E-cadherin and Zeb1 expression in the resolving notochord cells. PMID- 24631215 TI - prdm12b specifies the p1 progenitor domain and reveals a role for V1 interneurons in swim movements. AB - Proper functioning of the vertebrate central nervous system requires the precise positioning of many neuronal cell types. This positioning is established during early embryogenesis when gene regulatory networks pattern the neural tube along its anteroposterior and dorsoventral axes. Dorsoventral patterning of the embryonic neural tube gives rise to multiple progenitor cell domains that go on to differentiate unique classes of neurons and glia. While the genetic program is reasonably well understood for some lineages, such as ventrally derived motor neurons and glia, other lineages are much less characterized. Here we show that prdm12b, a member of the PR domain containing-family of transcriptional regulators, is expressed in the p1 progenitor domain of the zebrafish neural tube in response to Sonic Hedgehog signaling. We find that disruption of prdm12b function leads to dorsal expansion of nkx6.1 expression and loss of p1-derived eng1b-expressing V1 interneurons, while the adjacent p0 and p2 domains are unaffected. We also demonstrate that prdm12b-deficient fish exhibit an abnormal touch-evoked escape response with excessive body contractions and a prolonged response time, as well as an inability to coordinate swimming movements, thereby revealing a functional role for V1 interneurons in locomotor circuits. We conclude that prdm12b is required for V1 interneuron specification and that these neurons control swimming movements in zebrafish. PMID- 24631218 TI - A novel method for concentration evaluation of reading behaviors with electrical activity recorded on the scalp. AB - In this paper, a concentration evaluation of reading behaviors with electrical signal detection on the head is presented. The electrode signal is extracted by brain-computer-interface (BCI) to monitor the user's degree of concentration, where the user is reminded by sound to concentrate, or teaching staffs are reminded to help users improve reading habits, in order to facilitate the user's ability to concentrate. The digital signal processing methods, such as the Kalman Filter, Fast Fourier Transform, the Hamming window, the average value of the total energy of a frame, correlation coefficient, and novel judgment algorithm are used to obtain the corresponding parameters of concentration evaluation. Users can correct their manner of reading with reminders. The repeated test results may be expected to lie with a probability of 95%. Such model training results in better learning effect. PMID- 24631217 TI - Hipk promotes photoreceptor differentiation through the repression of Twin of eyeless and Eyeless expression. AB - Organogenesis is a complex developmental process, which requires tight regulation of selector gene expression to specify individual organ types. The Pax6 homolog Eyeless (Ey) is an example of such a factor and its expression pattern reveals it is dynamically controlled during development. Ey's paralog Twin of eyeless (Toy) induces its expression during embryogenesis, and the two genes are expressed in nearly identical patterns during the larval stages of development. While Ey must be expressed to initiate retinal specification, it must subsequently be repressed behind the morphogenetic furrow to allow for neuronal differentiation. Thus far, a few factors have been implicated in this repression including the signaling pathways Hedgehog (Hh) and Decapentaplegic (Dpp), and more recently downstream components of the retinal determination gene network (RDGN) Sine oculis (So), Eyes absent (Eya), and Dachshund (Dac). Homeodomain-interacting protein kinase (Hipk), a conserved serine-threonine kinase, regulates numerous factors during tissue patterning and development, including the Hh pathway. Using genetic analyses we identify Hipk as a repressor of both Toy and Ey and show that it may do so, in part, through Hh signaling. We also provide evidence that Ey repression is a critical step in ectopic eye development and that Hipk plays an important role in this process. Because Ey repression within the retinal field is a critical step in eye development, we propose that Hipk is a key link between eye specification and patterning. PMID- 24631219 TI - Rad51C: a novel suppressor gene modulates the risk of head and neck cancer. AB - We conducted a case-control study to investigate the possible association between the head and neck cancer (HNC) and genetic variability of Rad51C tumor suppressor gene. Eight polymorphic sites spanning over non-coding regions of Rad51C promoter, exon 1 and intron 1 were genotyped in 81 HNC cases and 156 healthy controls using the real-time PCR technique. One investigated site turned out to be not polymorphic, while among the remaining seven sites a significant HNC risk increasing effect was found for rs16943176 (c.-118G>A), rs12946397 (c.-26C>T) and rs17222691 (c.145+947C>T) on both allelic (OR=1.8; p<0.05) and genotypic (OR=2.0; p<0.05) level. Furthermore, our data seem to provide marginal evidence, that this effect might possibly be confined to women only (OR=2.8; p=0.05 for allelic and OR=3.7; p=0.05 for genotypic comparisons). These SNPs were found to co-segregate together forming two distinct, HNC risk-modulating haplotypes. The genetic variability of Rad51C might thus be of relevance with respect to HNC risk. PMID- 24631220 TI - Reduced repair capacity of a DNA clustered damage site comprised of 8-oxo-7,8 dihydro-2'-deoxyguanosine and 2-deoxyribonolactone results in an increased mutagenic potential of these lesions. AB - A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase beta, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL. PMID- 24631221 TI - Preventing meningitis and septicaemia: are we nearly there yet? PMID- 24631222 TI - Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. AB - BACKGROUND: Infection with Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae causes substantial mortality and long-term morbidity in children. We know of no study to assess the long-term trends in hospital admission rates for meningitis and septicaemia caused by these pathogens in children in England. We aimed to do such a study using routinely reported data in England. METHODS: In this population-based observational study, we used datasets that include routinely collected administrative statistics for hospital care: the Hospital In-Patient Enquiry (data for England from 1968 to 1985), the Hospital Episode Statistics dataset (data for England from 1989 onwards), and the Oxford record linkage study (data for Oxfordshire and surrounding areas from 1963 to 2011). We analysed annual age-specific and age-standardised admission rates in children younger than 15 years with H influenzae, meningococcal and pneumococcal meningitis, and septicaemia. FINDINGS: We saw a reduction in hospital admission rates for childhood invasive bacterial disease after the introduction of conjugate vaccines against H influenzae, N meningitidis, and S pneumoniae in England. Annual incidence of H influenzae meningitis per 100,000 children decreased from 6.72 admissions (95% CI 6.18-7.26) in 1992 to 0.39 admissions (0.26-0.52) in 1994, after the introduction of routine H influenzae type b vaccination. We saw a small rise in admissions in the early 2000s, peaking at 1.24 admissions per 100,000 children (0.99-1.48) in 2003, which decreased to 0.28 per 100,000 children (0.17-0.39) by 2008 after the introduction of catch-up (2003) and routine (2006) booster programmes for young children. Meningococcal disease increased during the 1990s, reaching a peak in 1999, with 34.54 admissions (33.30-35.78) per 100,000 children. Hospital admissions decreased after the meningococcal serogroup C vaccine was introduced in 1999 and was 12.40 admissions (11.68-13.12) per 100,000 in 2011. Admissions for invasive pneumococcal disease increased from the 1990s reaching a peak in 2006 at 4.45 admissions for meningitis (95% CI 4.0-4.9) per 100,000 children and 2.81 admissions for septicaemia (2.45-3.17) per 100,000 children. A reduction in admissions occurred after the introduction of the pneumococcal conjugate vaccine in 2006: hospital admission rates in 2011 were 2.03 per 100,000 children for meningitis and 1.12 per 100,000 children for septicaemia. INTERPRETATION: Vaccine preventable invasive bacterial disease in children has decreased substantially in England in the past five decades, most notably with the advent of effective conjugate vaccines since the 1990s. Ongoing disease surveillance and continued development and implementation of vaccines against additional pneumococcal serotypes and serogroup B meningococcal disease are important. FUNDING: None. PMID- 24631223 TI - Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID): an extension of the STROBE statement. AB - Molecular data are now widely used in epidemiological studies to investigate the transmission, distribution, biology, and diversity of pathogens. Our objective was to establish recommendations to support good scientific reporting of molecular epidemiological studies to encourage authors to consider specific threats to valid inference. The statement Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID) builds upon the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. The STROME-ID statement was developed by a working group of epidemiologists, statisticians, bioinformaticians, virologists, and microbiologists with expertise in control of infection and communicable diseases. The statement focuses on issues relating to the reporting of epidemiological studies of infectious diseases using molecular data that were not addressed by STROBE. STROME-ID addresses terminology, measures of genetic diversity within pathogen populations, laboratory methods, sample collection, use of molecular markers, molecular clocks, timeframe, multiple-strain infections, non independence of infectious-disease data, missing data, ascertainment bias, consistency between molecular and epidemiological data, and ethical considerations with respect to infectious-disease research. In total, 20 items were added to the 22 item STROBE checklist. When used, the STROME-ID recommendations should advance the quality and transparency of scientific reporting, with clear benefits for evidence reviews and health-policy decision making. PMID- 24631224 TI - Preparing for code silver in the pediatric setting. PMID- 24631225 TI - The child with Graves disease. PMID- 24631226 TI - Heat-related illness: time to update our lexicon. PMID- 24631227 TI - Maximum water temperature limit in open-water swimming events. PMID- 24631228 TI - Poly-L-arginine topical lotion tested in a mouse model for frostbite injury. AB - BACKGROUND: Frostbite injury occurs when exposure to cold results in frozen tissue. We recently reported a novel mouse model for frostbite injury to be used in screening potentially therapeutic drugs and other modalities. OBJECTIVE: We used the mouse skin frostbite model to evaluate the effect of poly-l-arginine contained in lotion (PAL) applied topically to involved skin. METHODS: Sixty mice were studied in a randomized, double-blind method. Standardized 2.9-cm-diameter circles were tattooed on the mouse dorsum. Magnets snap frozen in dry ice (-78.5 degrees C) were used to create a frostbite injury on skin within the circle as a continuous 5-minute freeze. Mice were treated with prefreeze placebo, postthaw placebo, combined prefreeze and postthaw placebo, prefreeze with PAL, postthaw with PAL, or combined prefreeze and postthaw with PAL. Appearance, healing rate, tissue loss, and histology were recorded until the wounds were healed. RESULTS: Application of PAL before inducing frostbite injury resulted in decreased tissue loss as compared with other treatment conditions. CONCLUSIONS: Applying PAL topically to frostbitten mouse skin caused decreased tissue loss. Poly-l-arginine should be studied further to determine whether it is a beneficial therapeutic modality for frostbite injury. PMID- 24631229 TI - Evaluation of fluid bolus administration rates using ruggedized field intravenous systems. AB - OBJECTIVE: The purpose of this study was to evaluate 2 ruggedized field intravenous (IV) systems currently in use by US military medics and to determine their effect on fluid bolus administration rates. METHODS: A series of 500 mL fluid boluses consisting of either Lactated Ringer's solution or Hextend were delivered to 2 artificial intravenous training arms using a standard 18G catheter (control) and 2 separate ruggedized field IV systems. Fluid boluses were delivered under both gravity force and pressure infusion (constant 300 mm Hg), and total bolus times were recorded. RESULTS: Using Lactated Ringer's solution, the standard IV system took a mean time of 9:33 minutes (95% CI: 9:13-9:54) to deliver a 500 mL fluid bolus whereas the 2 ruggedized field systems took mean times of 14:50 minutes (95% CI: 14:00-15:40) and 12:20 minutes (95% CI: 11:54 12:45). Using Hextend, the mean bolus time for the control system was 24:39 minutes (95% CI: 22:47-26:32). The 2 ruggedized field systems required an average of 49:32 minutes (95% CI: 48:07-50:58) and 39:46 minutes (95% CI: 37:30-42:01) to deliver an equivalent bolus. Pressure infusion significantly increased flow rate in all systems. CONCLUSIONS: Ruggedized field IV systems can significantly delay fluid bolus rates. In instances where ruggedized field systems are deemed necessary, pressure infusion devices should be considered to overcome the constrictive effects of the ruggedized system. PMID- 24631230 TI - Acute mountain sickness is not repeatable across two 12-hour normobaric hypoxia exposures. AB - OBJECTIVE: The purposes of this experiment were to determine the repeatability of acute mountain sickness (AMS), AMS symptoms, and physiological responses across 2 identical hypoxic exposures. METHODS: Subjects (n = 25) spent 3 nights at simulated altitude in a normobaric hypoxia chamber: twice at a partial pressure of inspired oxygen (PIO2) of 90mmHg (4000 m equivalent; "hypoxia") and once at a PIO2 of 132 mmHg (1000 m equivalent; "sham") with 14 or more days between exposures. The following variables were measured at hours 0 and 12 of each exposure: AMS severity (ie, Lake Louise score [LLS]), AMS incidence (LLS >=3), heart rate, oxygen saturation, blood pressure, and the fraction of exhaled nitric oxide. Oxygen saturation and heart rate were also measured while subjects slept. RESULTS: The incidence of AMS was not statistically different between the 2 exposures (84% vs 56%, P > .05), but the severity of AMS (ie, LLS) was significantly lower on the second hypoxic exposure (mean [SD], 3.1 [1.8]) relative to the first hypoxic exposure (4.8 [2.3]; P < .001). Headache was the only AMS symptom to have a significantly greater severity on both hypoxic exposures (relative to the sham exposure, P < .05). Physiological variables were moderately to strongly repeatable (intraclass correlation range 0.39 to 0.86) but were not associated with AMS susceptibility (P > .05). CONCLUSIONS: The LLS was not repeatable across 2 identical hypoxic exposures. Increased familiarity with the environment (not acclimation) could explain the reduced AMS severity on the second hypoxic exposure. Headache was the most reliable AMS symptom. PMID- 24631231 TI - CAVES as an environment for astronaut training. PMID- 24631232 TI - Effect of flowable composite liner and glass ionomer liner on class II gingival marginal adaptation of direct composite restorations with different bonding strategies. AB - OBJECTIVES: The purpose of the present study was to comparatively evaluate the effect of flowable composite resin liner and resin modified glass ionomer liner on gingival marginal adaptation of class II cavities restored using three bonding agents (Single Bond 3M ESPE, One Coat Self Etching Bond Coltene Whaledent; Adper Easy Bond Self-Etch Adhesive 3M ESPE) and respective composite resins, under cyclic loading. The marginal adaptation was evaluated in terms of 'continuous margin' (CM) at the gingival margin. MATERIALS AND METHODS: Ninety class II cavities with margins extending 1mm below the cement-enamel junction were prepared in extracted mandibular third molars. The samples were divided into three groups: no liner placement; 0.5-1mm thick flowable resin liner placement (Filtek Z350 XT flowable resin) on gingival floor and; light cure glass ionomer (Ketac N100) liner. The groups were further subdivided into three sub-groups on the basis of the bonding agents used. Cavities were restored with composite resins (Z350 for Single Bond and Adper Easy Bond; and Synergy D6 Universal, for One Coat Self Etching Bond) in 2mm increments and the samples were mechanically loaded (60N, 1,50,000 cycles). Marginal adaptation was evaluated using a low vacuum scanning electron microscope. Statistical analysis was done with two way ANOVA with Holm-Sidak's correction for multiple comparisons. RESULTS: Placement of flowable composite liner significantly improved the CM values of Single Bond (78+/-11%) and One Coat Self Etching Bond (77+/-9%) compared with no liner group, but the values of CM of Adper Easy Bond were not improved (61+/-12%). Placement of glass ionomer liner significantly improved the values of CM in all the sub groups (78+/-9%, 72+/-10% and 77+/-10% for Single Bond, One Coat Self Etching Bond & Adper Easy Bond respectively) compared with no liner group. CONCLUSIONS: Placement of liners improved the values of 'continuous margin' in the gingival floor of the proximal cavities restored with composite resins using different bonding agent. CLINICAL RELEVANCE: Placement of flowable composite liner or glass ionomer liner will improve the marginal integrity of composite restorations using etch-and-rinse and two bottle-two step self etch adhesives. To improve the marginal integrity of a single bottle adhesive, glass ionomer liner should be applied. PMID- 24631233 TI - Upper airway outcomes following midface distraction osteogenesis: a systematic review. AB - The objective of this paper is to systematically review the airway outcomes following distraction osteogenesis of midface with the goal of (1) deriving clinically oriented insights and (2) identifying gaps in knowledge to stimulate future research. Medline, EMBASE and Cochrane databases were searched and studies were included if subjects of any age had midface retrusion/hypoplasia and underwent midface distraction osteogenesis. Outcome measures of interest were any respiratory or airway associated measures, and reports of adverse events. A total of 368 abstracts were generated from the literature searches; 16 studies met the criteria for data extraction and analysis. All 16 studies were observational. Generally, midface distraction osteogenesis was reported to improve respiratory status and was well tolerated. Specifically, favorable outcomes in cephalometry (9 studies), polysomnography (9 studies), and decannulation rates (8 studies) were reported. In conclusion, upper airway status was improved in most patients who underwent midface distraction osteogenesis, yet long-term results and consistent objective measures are lacking. Studies reviewed were retrospective case series and details regarding patients who did not improve were deficient. A standardized prospective multicenter cohort trial with long-term patient follow up is required. PMID- 24631234 TI - Systematic review: anastomotic microvascular device. AB - BACKGROUND: Anastomotic microvascular device has gained popularity in reconstructive microsurgery over the last two decades. A systematic literature search has been carried out in the use of the venous coupler device in microsurgery to assess its impact on patency rate in microsurgery. METHOD: Using key words related to the topic, a literature search of major databases was carried out. Selection was undertaken on two level screening. From the literature search 53 potential articles were identified. Of these 13 met both levels of screening for the final critical analysis. RESULTS: A total of 2976 venous anastomoses with coupler device were carried out in the 13 studies with a combined thrombosis in 46 veins reported, giving an average 98.5% patency and a variation in thrombosis rate ranging from 0 to 3%. CONCLUSION: The venous coupler device serves as a powerful instrument in microsurgery by achieving high patency rate. More importantly the data suggests less variation in thrombosis rate compared to hand-sewn venous anastomosis. PMID- 24631235 TI - Early discharge protocol for regional node dissections for skin cancer: the Frenchay Hospital Lymphadenectomy Algorithm. PMID- 24631236 TI - Delayed cervical esophagogastrostomy: a surgical alternative for patients with ischemia of the gastric conduit at time of esophagectomy. AB - Ischemia of the gastric conduit after esophagectomy represents a setback that increases the risk of anastomotic leak. In order to prevent this severe complication, a surgical alternative has been proposed which consists in delaying the reconstruction until gastric perfusion improves. By adopting this strategy we can avoid two other surgical options that may significantly increase the risk of complications: 1) performing an esophagogastrostomy with a poorly perfused gastric tube and 2) resecting the gastric conduit followed by a complex reconstruction. PMID- 24631237 TI - Inhibitory GEF phosphorylation provides negative feedback in the yeast polarity circuit. AB - Cell polarity is critical for the form and function of many cell types. During polarity establishment, cells define a cortical "front" that behaves differently from the rest of the cortex. The front accumulates high levels of the active form of a polarity-determining Rho-family GTPase (Cdc42, Rac, or Rop) that then orients cytoskeletal elements through various effectors to generate the polarized morphology appropriate to the particular cell type [1, 2]. GTPase accumulation is thought to involve positive feedback, such that active GTPase promotes further delivery and/or activation of more GTPase in its vicinity [3]. Recent studies suggest that once a front forms, the concentration of polarity factors at the front can increase and decrease periodically, first clustering the factors at the cortex and then dispersing them back to the cytoplasm [4-7]. Such oscillatory behavior implies the presence of negative feedback in the polarity circuit [8], but the mechanism of negative feedback was not known. Here we show that, in the budding yeast Saccharomyces cerevisiae, the catalytic activity of the Cdc42 directed GEF is inhibited by Cdc42-stimulated effector kinases, thus providing negative feedback. We further show that replacing the GEF with a phosphosite mutant GEF abolishes oscillations and leads to the accumulation of excess GTP Cdc42 and other polarity factors at the front. These findings reveal a mechanism for negative feedback and suggest that the function of negative feedback via GEF inhibition is to buffer the level of Cdc42 at the polarity site. PMID- 24631238 TI - Axons degenerate in the absence of mitochondria in C. elegans. AB - Many neurodegenerative disorders are associated with mitochondrial defects [1-3]. Mitochondria can play an active role in degeneration by releasing reactive oxygen species and apoptotic factors [4-7]. Alternatively, mitochondria can protect axons from stress and insults, for example by buffering calcium [8]. Recent studies manipulating mitochondria lend support to both of these models [9-13]. Here, we identify a C. elegans mutant, ric-7, in which mitochondria are unable to exit the neuron cell bodies, similar to the kinesin-1/unc-116 mutant. When axons lacking mitochondria are cut with a laser, they rapidly degenerate. Some neurons even spontaneously degenerate in ric-7 mutants. Degeneration can be suppressed by forcing mitochondria into the axons of the mutants. The protective effect of mitochondria is also observed in the wild-type: a majority of axon fragments containing a mitochondrion survive axotomy, whereas those lacking mitochondria degenerate. Thus, mitochondria are not required for axon degeneration and serve a protective role in C. elegans axons. PMID- 24631239 TI - A quantitative genetic signature of senescence in a short-lived perennial plant. AB - The evolution of senescence (the physiological decline of organisms with age) poses an apparent paradox because it represents a failure of natural selection to increase the survival and reproductive performance of organisms. The paradox can be resolved if natural selection becomes less effective with age, because the death of postreproductive individuals should have diminished effects on Darwinian fitness [1, 2]. A substantial body of empirical work is consistent with this prediction for animals, which transmit their genes to progeny via an immortal germline. However, such evidence is still lacking in plants, which lack a germline and whose reproduction is diffuse and modular across the soma. Here, we provide experimental evidence for a genetic basis of senescence in the short lived perennial plant Silene latifolia. Our pedigree-based analysis revealed a marked increase with age in the additive genetic variance of traits closely associated with fitness. This result thus extends to plants the quantitative genetic support for the evolutionary theory of senescence. PMID- 24631240 TI - Mating regulates neuromodulator ensembles at nerve termini innervating the Drosophila reproductive tract. AB - Upon mating, regions of the female reproductive tract mature and alter their function [1-3], for example to facilitate storage of sperm or control the release of eggs [4-6]. The female's nervous system and neuromodulators play important roles in her responses to mating [7-13]. However, it is difficult to reconcile the reproductive tract's many changing but coordinated events with the small set of neuromodulators present [14-18]. We hypothesized that each part of the reproductive tract contains a characteristic combination of neuromodulators that confer unique identities on each region and that postmating changes in these combinations coordinate subsequent actions. We examined the presence, locations, and levels of neuromodulators and related molecules ("signaling molecules") in the reproductive tract of Drosophila melanogaster females before and after mating: the biogenic amine octopamine, which regulates ovulation rate in Drosophila and locusts [7, 14-20]; serotonin, which regulates muscle contraction in locust oviducts [21]; and the FMRF amide dromyosuppressin, which regulates contraction of Drosophila heart muscle [22] and may regulate muscle contractions in the reproductive tract, if it is expressed there. We find that separate aspects of mating (sperm, seminal proteins, and physical effects) independently modulate the release of signaling molecules. Each reproductive tract subregion displays a characteristic combination of signaling molecule release, resulting in a unique functional identity. These patterns, and thus functions, change reproducibly after mating. Thus, one event (mating) promotes new combinations of signaling molecules that endow different parts of the reproductive tract with unique temporal and spatial identities that facilitate many aspects of fertilization. PMID- 24631241 TI - Exceptionally preserved 450-million-year-old ordovician ostracods with brood care. AB - Ostracod crustaceans are the most abundant fossil arthropods and are characterized by a long stratigraphic range. However, their soft parts are very rarely preserved, and the presence of ostracods in rocks older than the Silurian period [1-5] was hitherto based on the occurrence of their supposed shells. Pyritized ostracods that preserve limbs and in situ embryos, including an egg within an ovary and possible hatched individuals, are here described from rocks of the Upper Ordovician Katian Stage Lorraine Group of New York State, including examples from the famous Beecher's Trilobite Bed [6, 7]. This discovery extends our knowledge of the paleobiology of ostracods by some 25 million years and provides the first unequivocal demonstration of ostracods in the Ordovician period, including the oldest known myodocope, Luprisca incuba gen. et sp. nov. It also provides conclusive evidence of a developmental brood-care strategy conserved within Ostracoda for at least 450 million years. PMID- 24631242 TI - Directing eye gaze enhances auditory spatial cue discrimination. AB - The present study demonstrates, for the first time, a specific enhancement of auditory spatial cue discrimination due to eye gaze. Whereas the region of sharpest visual acuity, called the fovea, can be directed at will by moving one's eyes, auditory spatial information is derived primarily from head-related acoustic cues. Past auditory studies have found better discrimination in front of the head [1-3] but have not manipulated subjects' gaze, thus overlooking potential oculomotor influences. Electrophysiological studies have shown that the inferior colliculus, a critical auditory midbrain nucleus, shows visual and oculomotor responses [4-6] and modulations of auditory activity [7-9], and that auditory neurons in the superior colliculus show shifting receptive fields [10 13]. How the auditory system leverages this crossmodal information at the behavioral level remains unknown. Here we directed subjects' gaze (with an eccentric dot) or auditory attention (with lateralized noise) while they performed an auditory spatial cue discrimination task. We found that directing gaze toward a sound significantly enhances discrimination of both interaural level and time differences, whereas directing auditory spatial attention does not. These results show that oculomotor information variably enhances auditory spatial resolution even when the head remains stationary, revealing a distinct behavioral benefit possibly arising from auditory-oculomotor interactions at an earlier level of processing than previously demonstrated. PMID- 24631243 TI - Sexually dimorphic octopaminergic neurons modulate female postmating behaviors in Drosophila. AB - Mating elicits profound behavioral and physiological changes in many species that are crucial for reproductive success. After copulation, Drosophila melanogaster females reduce their sexual receptivity and increase egg laying [1, 2]. Transfer of male sex peptide (SP) during copulation mediates these postmating responses [1, 3-6] via SP sensory neurons in the uterus defined by coexpression of the proprioceptive neuronal marker pickpocket (ppk) and the sex-determination genes doublesex (dsx) and fruitless (fru) [7-9]. Although neurons expressing dsx downstream of SP signaling have been shown to regulate postmating behaviors [9], how the female nervous system coordinates the change from pre- to postcopulatory states is unknown. Here, we show a role of the neuromodulator octopamine (OA) in the female postmating response. Lack of OA disrupts postmating responses in mated females, while increase of OA induces postmating responses in virgin females. Using a novel dsx(FLP) allele, we uncovered dsx neuronal elements associated with OA signaling involved in modulation of postmating responses. We identified a small subset of sexually dimorphic OA/dsx(+) neurons (approximately nine cells in females) in the abdominal ganglion. Our results are consistent with a model whereby OA neuronal signaling increases after copulation, which in turn modulates changes in female behavior and physiology in response to reproductive state. PMID- 24631244 TI - Tension and force-resistant attachment are essential for myofibrillogenesis in Drosophila flight muscle. AB - BACKGROUND: Higher animals generate an elaborate muscle-tendon network to perform their movements. To build a functional network, developing muscles must establish stable connections with tendons and assemble their contractile apparatuses. Current myofibril assembly models do not consider the impact of muscle-tendon attachment on myofibrillogenesis. However, if attachment and myofibrillogenesis are not properly coordinated, premature muscle contractions can destroy an unstable myotendinous system, leading to severe myopathies. RESULTS: Here, we use Drosophila indirect flight muscles to investigate how muscle-tendon attachment and myofibrillogenesis are coordinated. We find that flight muscles first stably attach to tendons and then assemble their myofibrils. Interestingly, this myofibril assembly is triggered simultaneously throughout the entire muscle, suggesting a self-assembly mechanism. By applying laser-cutting experiments, we show that muscle attachment coincides with an increase in mechanical tension before periodic myofibrils can be detected. We manipulated tension buildup within the myotendinous system either by genetically compromising attachment initiation and integrin recruitment to the myotendinous junction or by optically severing tendons from muscle. Both treatments cause strong myofibrillogenesis defects. We find that myosin motor activity is required for both tension formation and myofibril assembly, suggesting that myofibril assembly itself contributes to tension buildup. CONCLUSIONS: Our results demonstrate that force-resistant attachment enables a stark tension increase in the myotendinous system. Subsequently, this tension increase triggers simultaneous myofibril self-assembly throughout the entire muscle fiber. As myofibril and sarcomeric architecture as well as their molecular components are evolutionarily conserved, we propose a similar tension-based mechanism to regulate myofibrillogenesis in vertebrates. PMID- 24631245 TI - Unique feeding morphology in a new prognathous extinct porpoise from the Pliocene of California. AB - Modern porpoises (Odontoceti: Phocoenidae) are some of the smallest cetaceans and usually feed near the seafloor on small fish and cephalopods [1-3]. Within both extinct and extant phocoenids, no evidence for specialized mandibular morphology has been documented [4-7]. Here we describe a new species of extinct porpoise, Semirostrum ceruttii, from the marine Pliocene San Diego (4.2-1.6 mega-annum, Ma) and Purisima (5-2.5 Ma) formations of California. The mandibles comprise a long, fused, and nearly edentulous prognathous symphysis, extending farther beyond the rostrum than in any known mammal. Phylogenetic analyses based on morphology reconstruct Semirostrum ceruttii as sister to extant (crown) porpoise species with moderate support. We describe the spectacularly preserved holotype specimen based on computed tomography (CT) scans, which allowed visualization of the elongate mental and accessory canals within the symphysis. The elongate canals are similar to those found in Rynchops birds [8] and were likely involved in sensory function. Oblique labial wear facets present on numerous small conical mandibular teeth posterior to the symphysis suggest regular contact with benthic substrate. The unique mandibular and dental characteristics, along with robust scapulae, sternum, and unfused cervical vertebrae, support the interpretation that this species employed a form of benthic skim feeding by using its mandible to probe for and obtain prey. PMID- 24631246 TI - A dedicated binding mechanism for the visual control of movement. AB - The human motor system is remarkably proficient in the online control of visually guided movements, adjusting to changes in the visual scene within 100 ms [1-3]. This is achieved through a set of highly automatic processes [4] translating visual information into representations suitable for motor control [5, 6]. For this to be accomplished, visual information pertaining to target and hand need to be identified and linked to the appropriate internal representations during the movement. Meanwhile, other visual information must be filtered out, which is especially demanding in visually cluttered natural environments. If selection of relevant sensory information for online control was achieved by visual attention, its limited capacity [7] would substantially constrain the efficiency of visuomotor feedback control. Here we demonstrate that both exogenously and endogenously cued attention facilitate the processing of visual target information [8], but not of visual hand information. Moreover, distracting visual information is more efficiently filtered out during the extraction of hand compared to target information. Our results therefore suggest the existence of a dedicated visuomotor binding mechanism that links the hand representation in visual and motor systems. PMID- 24631247 TI - The role of integrin alpha2 in cell and matrix therapy that improves perfusion, viability and function of infarcted myocardium. AB - Injectable delivery matrices hold promise in enhancing engraftment and the overall efficacy of cardiac cell therapies; however, the mechanisms responsible remain largely unknown. Here we studied the interaction of a collagen matrix with circulating angiogenic cells (CACs) in a mouse myocardial infarction model. CACs + matrix treatment enhanced CAC engraftment, and improved myocardial perfusion, viability and function compared to cells or matrix alone. Integrin-linked kinase (ILK) was up-regulated in matrix-cultured CACs. Integrin alpha2beta1 blocking prevented ILK up-regulation, significantly reduced the adhesion, proliferation, and paracrine properties of matrix-cultured CACs, and negated the benefits of CACs + matrix therapy in vivo. Furthermore, integrin alpha5 was essential for the angiogenic potential of CACs on matrix. These findings indicate that the synergistic therapeutic effect of CACs + matrix therapy in MI requires the matrix to enhance CAC function via alpha2beta1 and alpha5 integrin signaling mechanisms, rather than simply delivering the cells. PMID- 24631248 TI - The effect of gamma keratose on cell viability in vitro after thermal stress and the regulation of cell death pathway-specific gene expression. AB - When skin is thermally burned, transfer of heat energy into the skin results in the destruction of cells. Some of these cells are damaged but may be capable of self-repair and survival, thereby contributing to spontaneous healing of the wound. Keratin protein-based biomaterials have been suggested as potential treatments for burn injury. Isolation of cortical proteins from hair fibers results in an acid soluble fraction of keratin proteins referred to as "gamma" keratose. In the present study, treatment with this fraction dissolved in media was able to maintain cell viability after thermal stress in an in vitro model using primary mouse dermal fibroblasts. PCR array analysis demonstrated that gamma keratose treatment may assist in the survival and salvage of thermally stressed cells by maintaining their viability through regulation of cell death pathway-related genes. Gamma keratose may be a promising biomaterial for burn treatment that aids in spontaneous wound healing from viable tissue surrounding the burn. PMID- 24631249 TI - In vivo monitoring of neural stem cells after transplantation in acute cerebral infarction with dual-modal MR imaging and optical imaging. AB - Stem cell therapies are promising strategies for the treatment of stroke. However, their clinical translation has not been fully realized due, in part, to insufficient ability to track stem cell migration and survival longitudinally over long periods of time in vivo. In this work, we synthesized a new class of manometer-sized cationic polymersomes loaded with superparamagnetic iron oxide nanoparticles and quantum dots for in vivo dual-modal imaging of stem cells. The results demonstrated that the synthesized cationic polymersomes can act as an effective and safety carrier to transfer image labels into neural stem cells, upon which the distribution and migration of grafted stem cells could be monitored by MR imaging up to 6 weeks and by fluorescence imaging within 4 weeks in the context of ischaemic brain injury. Cationic polymersomes hold great promise in the longitudinal monitoring of transplanted stem cells by using dual modal MRI and optical imaging. PMID- 24631250 TI - Neural differentiation of pluripotent cells in 3D alginate-based cultures. AB - Biomaterial-supported culture methods, allowing for directed three-dimensional differentiation of stem cells are an alternative to canonical two-dimensional cell cultures. In this paper, we evaluate the suitability of alginate for three dimensional cultures to enhance differentiation of mouse embryonic stem cells (mESCs) towards neural lineages. We tested whether encapsulation of mESCs within alginate beads could support and/or enhance neural differentiation with respect to two-dimensional cultures. We encapsulated cells in beads of alginate with or without modification by fibronectin (Fn) or hyaluronic acid (HA). Gene expression analysis showed that cells grown in alginate and alginate-HA present increased differentiation toward neural lineages with respect to the two-dimensional control and to Fn group. Immunocytochemistry analyses confirmed these results, further showing terminal differentiation of neurons as seen by the expression of synaptic markers and markers of different neuronal subtypes. Our data show that alginate, alone or modified, is a suitable biomaterial to promote in vitro differentiation of pluripotent cells toward neural fates. PMID- 24631251 TI - Aqueous cationic, anionic and non-ionic multi-walled carbon nanotubes, functionalised with minimal framework damage, for biomedical application. AB - The use of a thermochemical grafting approach provides a versatile means to functionalise as-synthesised, bulk multi-walled carbon nanotubes (MWNTs) without altering their inherent structure. The associated retention of properties is desirable for a wide range of commercial applications, including for drug delivery and medical purposes; it is also pertinent to studies of intrinsic toxicology. A systematic series of water-compatible MWNTs, with diameter around 12 nm have been prepared, to provide structurally-equivalent samples predominantly stabilised by anionic, cationic, or non-ionic groups. The surface charge of MWNTs was controlled by varying the grafting reagents and subsequent post-functionalisation modifications. The degree of grafting was established by thermal analysis (TGA). High resolution transmission electron microscope (HRTEM) and Raman measurements confirmed that the structural framework of the MWNTs was unaffected by the thermochemical treatment, in contrast to a conventional acid oxidised control which was severely damaged. The effectiveness of the surface modification was demonstrated by significantly improved solubility and stability in both water and cell culture medium, and further quantified by zeta-potential analysis. The grafted MWNTs exhibited relatively low bioreactivity on transformed human alveolar epithelial type 1-like cells (TT1) following 24 h exposure as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium (MTS) and lactate dehydrogenase release (LDH) assays. The exposure of TT1 cells to MWNTs suppressed the release of the inflammatory mediators, interleukin 6 (IL-6) and interleukin 8 (IL-8). TEM cell uptake studies indicated efficient cellular entry of MWNTs into TT1 cells, via a range of mechanisms. Cationic MWNTs showed a more substantial interaction with TT1 cell membranes than anionic MWNTs, demonstrating a surface charge effect on cell uptake. PMID- 24631254 TI - Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions. AB - The ISCD 2007 Pediatric Official Positions define osteoporosis in children on the basis of fracture history and low bone density, adjusted as appropriate for age, gender, and body size. The task force on fracture prediction and osteoporosis definition has reviewed these positions and suggests modifications with respect to vertebral fracture and the definition of a significant fracture history and draws attention to the need to consider degree of trauma as a factor that may modify fracture risk prediction. PMID- 24631255 TI - Baicalein attenuates proteasome inhibition-induced apoptosis by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. AB - Impairment in ubiquitin-proteasome system has been shown to be implicated in the pathogenesis in neurodegenerative disorders, such as Parkinson's disease. Flavonoid baicalein has demonstrated anti-oxidant and anti-inflammatory effects. However, the effect of baicalein on the neuronal cell death due to proteasome inhibition has not been studied. Thus, in the respect of the cell death process, we assessed the effect of baicalein on the proteasome inhibition-induced apoptosis using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, an increase in Bax levels, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), an increase in the tumor suppressor p53 levels and cleavage of PARP-1. Baicalein attenuated the proteasome inhibition-induced changes in the levels of apoptosis-related proteins, formation of reactive oxygen species, depletion of GSH, DNA damage and cell death. The results show that baicalein may attenuate the proteasome inhibition-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH. PMID- 24631256 TI - Antihypertensive effect of caffeic acid and its analogs through dual renin angiotensin-aldosterone system inhibition. AB - Hypertension is a crucial risk factor for cardiovascular diseases and contributes to one third of global mortality. In addition to conventional antihypertensive drugs such as captopril, naturally occurring phytochemicals and their analogs are used for reducing the risk and occurrence of hypertension. Herein, we demonstrate the possible use of caffeic acid and its derivatives in the treatment of hypertension through multi-target modulation of renin-angiotensin-aldosterone system (RAAS). Caffeic acid along with its nineteen novel derivatives, chlorogenic acid, quercetin and captopril were all investigated for the inhibition of renin and angiotensin converting enzyme (ACE) activities and production of aldosterone. Compound 22 with CH2CH(Ph)2 moiety exhibited the strongest renin inhibition (IC50=229uM) among all compounds tested (P<=0.05). Caffeic acid was the weakest renin inhibitor (IC50=5704uM) among all the compounds assayed. Similar to renin inhibition, compound 22 (IC50=9.1uM) also exhibited about 47 times stronger ACE inhibition compared to the parent compound. Analysis of aldosterone revealed that compound 8 with n-Pr moiety was the strongest modulator of aldosterone production among all the derivatives (P<=0.05). Toxicity analysis using human fibroblasts (WI-38 cells) confirmed the non-toxic manifestations of caffeic acid and its derivatives in comparison to clinically used drug captopril. PMID- 24631257 TI - Barium chloride impaired Kir2.1 inward rectification in its stably transfected HEK 293 cell lines. AB - Kir2.1 channel is a typical inward rectified channel with little outward currents when the membrane depolarized. Barium blocks the inward Kir2.1 currents in a voltage-dependent manner. However, in this study we found that barium would impair the rectification and open Kir2.1 outward currents at a depolarized voltage, causing increment of outward current amplitudes by 43+/-7% (n=5, P<0.01) after 200s barium application. In the meanwhile, a higher barium concentration did block the outward currents by 17.5+/-4.3% (n=4, P<0.01) and temporarily twisted current upward tendency. The increment was likely barium specific since both calcium and Kir2.1 specific blocker, Chloroethylclonidine (CEC), did not enhance the current amplitudes. The rectification of Kir2.1 was not recovered by washing barium off, which suggested a non-competitive mechanism. Since the currents occurred at phase 1, 2 of cardiac action potential, it would likely shorten the action potential plateau and it would decrease QT duration in electrocardiography (ECG). PMID- 24631258 TI - Protective effect of geranylgeranylacetone via enhanced induction of HSPB1 and HSPB8 in mitochondria of the failing heart following myocardial infarction in rats. AB - The mechanisms underlying mitochondrial impairment in the failing heart are not yet clear. In a previous study, we found that the levels of small heat shock proteins (HSP) such as mitochondrial HSPB1 and HSPB8 in the failing heart following myocardial infarction were decreased. In the present study, to verify the hypothesis that mitochondrial dysfunction in the failing heart is associated with alterations in mitochondrial small heat shock proteins, we examined the effects of geranylgeranylacetone, a heat shock protein inducer, on the cardiac mitochondrial function after myocardial infarction. When hemodynamic parameters of rats with myocardial infarction were measured at the 8th (8W) week after coronary artery ligation (CAL), the 8W-CAL showed signs of chronic heart failure concomitant with a reduced mitochondrial oxygen consumption rate. HSPB1 and HSPB8 contents in the mitochondrial fraction prepared from the failing heart were decreased, suggesting that an attenuation of mitochondrial translocation of HSPB1 and HSPB8 had led to an impairment of mitochondrial energy-producing ability. Geranylgeranylacetone treatment from the 2nd to 8th week after myocardial infarction attenuated the reduction in mitochondrial HSPB1 and HSPB8 contents. Furthermore, the mitochondrial energy-producing ability and cardiac pump function were preserved by orally administered geranylgeranylacetone during the development of heart failure. These results suggest that the induction of small heat shock proteins in the infarcted heart by geranylgeranylacetone treatment contributed to the preservation of mitochondrial function, leading to an improvement of cardiac contractile function. PMID- 24631259 TI - Emergence of realism: Enhanced visual artistry and high accuracy of visual numerosity representation after left prefrontal damage. AB - Over the last two decades, evidence of enhancement of drawing and painting skills due to focal prefrontal damage has accumulated. It is of special interest that most artworks created by such patients were highly realistic ones, but the mechanism underlying this phenomenon remains to be understood. Our hypothesis is that enhanced tendency of realism was associated with accuracy of visual numerosity representation, which has been shown to be mediated predominantly by right parietal functions. Here, we report a case of left prefrontal stroke, where the patient showed enhancement of artistic skills of realistic painting after the onset of brain damage. We investigated cognitive, functional and esthetic characteristics of the patient's visual artistry and visual numerosity representation. Neuropsychological tests revealed impaired executive function after the stroke. Despite that, the patient's visual artistry related to realism was rather promoted across the onset of brain damage as demonstrated by blind evaluation of the paintings by professional art reviewers. On visual numerical cognition tasks, the patient showed higher performance in comparison with age matched healthy controls. These results paralleled increased perfusion in the right parietal cortex including the precuneus and intraparietal sulcus. Our data provide new insight into mechanisms underlying change in artistic style due to focal prefrontal lesion. PMID- 24631260 TI - The role of the left anterior temporal lobe in semantic composition vs. semantic memory. AB - The left anterior temporal lobe (LATL) is robustly implicated in semantic processing by a growing body of literature. However, these results have emerged from two distinct bodies of work, addressing two different processing levels. On the one hand, the LATL has been characterized as a 'semantic hub' that binds features of concepts across a distributed network, based on results from semantic dementia and hemodynamic findings on the categorization of specific compared to basic exemplars. On the other, the LATL has been implicated in combinatorial operations in language, as shown by increased activity in this region associated with the processing of sentences and of basic phrases. The present work aimed to reconcile these two literatures by independently manipulating combination and concept specificity within a minimal MEG paradigm. Participants viewed simple nouns that denoted either low specificity (fish) or high specificity categories (trout) presented in either combinatorial (spotted fish/trout) or non combinatorial contexts (xhsl fish/trout). By combining these paradigms from the two literatures, we directly compared the engagement of the LATL in semantic memory vs. semantic composition. Our results indicate that although noun specificity subtly modulates the LATL activity elicited by single nouns, it most robustly affects the size of the composition effect when these nouns are adjectivally modified, with low specificity nouns eliciting a much larger effect. We conclude that these findings are compatible with an account in which the specificity and composition effects arise from a shared mechanism of meaning specification. PMID- 24631262 TI - A genome-wide survey of bHLH transcription factors in the Placozoan Trichoplax adhaerens reveals the ancient repertoire of this gene family in metazoan. AB - Basic helix-loop-helix (bHLH) transcription factors play significant roles in multiple biological processes in metazoan cells. To address the evolutionary history of this gene family, comprehensive and detailed characterization in basal metazoans is essential. Here I report a genome-wide survey of bHLH genes in the Placozoan, Trichoplax adhaerens. The present survey revealed ancient origins of two orthologous families, 48-related-1/Fer1 and ASCb, which both belong to high order Group A. Group A factors are mainly involved in neural and mesodermal differentiation. I also identified novel members of a Group E orthologous family previously thought to be unique to Homo sapiens. These were discovered in Trichoplax, Saccoglossus kowalevskii, Euperipatoides kanangrensis, and Crassostrea gigas, but apparently are not found in Drosophila melanogaster, Caenorhabditis elegans, or Nematostella vectensis. Furthermore, as reported previously, many unclassified Group A members were observed in Trichoplax. The present study provides important information to infer the ancestral state of bHLH components in the Metazoa. PMID- 24631261 TI - Understanding discourse-linked elements in aphasia: a threefold study in Russian. AB - BACKGROUND: Agrammatic speakers have problems with grammatical encoding and decoding. However, not all syntactic processes are equally problematic: present time reference, who questions, and reflexives can be processed by narrow syntax alone and are relatively spared compared to past time reference, which questions, and personal pronouns, respectively. The latter need additional access to discourse and information structures to link to their referent outside the clause (Avrutin, 2006). Linguistic processing that requires discourse-linking is difficult for agrammatic individuals: verb morphology with reference to the past is more difficult than with reference to the present (Bastiaanse et al., 2011). The same holds for which questions compared to who questions and for pronouns compared to reflexives (Avrutin, 2006). These results have been reported independently for different populations in different languages. The current study, for the first time, tested all conditions within the same population. AIMS: We had two aims with the current study. First, we wanted to investigate whether discourse-linking is the common denominator of the deficits in time reference, wh questions, and object pronouns. Second, we aimed to compare the comprehension of discourse-linked elements in people with agrammatic and fluent aphasia. METHODS AND PROCEDURES: Three sentence-picture-matching tasks were administered to 10 agrammatic, 10 fluent aphasic, and 10 non-brain-damaged Russian speakers (NBDs): (1) the Test for Assessing Reference of Time (TART) for present imperfective (reference to present) and past perfective (reference to past), (2) the Wh Extraction Assessment Tool (WHEAT) for which and who subject questions, and (3) the Reflexive-Pronoun Test (RePro) for reflexive and pronominal reference. OUTCOMES AND RESULTS: NBDs scored at ceiling and significantly higher than the aphasic participants. We found an overall effect of discourse-linking in the TART and WHEAT for the agrammatic speakers, and in all three tests for the fluent speakers. Scores on the RePro were at ceiling. CONCLUSIONS: The results are in line with the prediction that problems that individuals with agrammatic and fluent aphasia experience when comprehending sentences that contain verbs with past time reference, which question words and pronouns are caused by the fact that these elements involve discourse linking. The effect is not specific to agrammatism, although it may result from different underlying disorders in agrammatic and fluent aphasia. PMID- 24631263 TI - Identification of rice genes associated with cosmic-ray response via co expression gene network analysis. AB - In order to better understand the biological systems that are affected in response to cosmic ray (CR), we conducted weighted gene co-expression network analysis using the module detection method. By using the Pearson's correlation coefficient (PCC) value, we evaluated complex gene-gene functional interactions between 680 CR-responsive probes from integrated microarray data sets, which included large-scale transcriptional profiling of 1000 microarray samples. These probes were divided into 6 distinct modules that contained 20 enriched gene ontology (GO) functions, such as oxidoreductase activity, hydrolase activity, and response to stimulus and stress. In particular, modules 1 and 2 commonly showed enriched annotation categories such as oxidoreductase activity, including enriched cis-regulatory elements known as ROS-specific regulators. These results suggest that the ROS-mediated irradiation response pathway is affected by CR in modules 1 and 2. We found 243 ionizing radiation (IR)-responsive probes that exhibited similarities in expression patterns in various irradiation microarray data sets. The expression patterns of 6 randomly selected IR-responsive genes were evaluated by quantitative reverse transcription polymerase chain reaction following treatment with CR, gamma rays (GR), and ion beam (IB); similar patterns were observed among these genes under these 3 treatments. Moreover, we constructed subnetworks of IR-responsive genes and evaluated the expression levels of their neighboring genes following GR treatment; similar patterns were observed among them. These results of network-based analyses might provide a clue to understanding the complex biological system related to the CR response in plants. PMID- 24631264 TI - Identification of the flavonoid 3'-hydroxylase and flavonoid 3',5'-hydroxylase genes from Antarctic moss and their regulation during abiotic stress. AB - Flavonoids are ubiquitous plant secondary metabolites, and their hydroxylation pattern determines their color, stability, and antioxidant capacity. The hydroxylation pattern of the B-ring of flavonoids is determined by the activity of two members of cytochrome P450 protein (P450) family, the flavonoid 3' hydroxylase (F3'H) and flavonoid 3',5'-hydroxylase (F3',5'H). However, they are still not well documented in lower plants such as bryophytes. We report the identification of gene encoding F3'H, F3',5'H from Antarctic moss Pohlia nutans and their transcriptional regulation under different stress conditions. Totally, sixteen cDNAs were isolated from P. nutans by RT-PCR and RACE techniques, all of which were predicted to code for F3'Hs or F3',5'Hs based on their annotations of Blast results. Amino acid alignment showed that they possessed the featured conserved domains of flavonoid hydroxylase, including proline-rich "hinge" region, EXXR motif, oxygen binding pocket motif, heme binding domain and substrate recognition sites. Phylogenetic analysis indicated that moss F3'Hs and F3',5'Hs were highly conserved and have independent evolution from the monocots, dicots and ferns. Meanwhile, real-time PCR analysis revealed that the expression profiling of flavonoid hydroxylase genes was influenced by diverse abiotic stresses including cold, salinity, drought or UV-B radiation and plant hormone abscisic acid (ABA) or jasmonic acid (JA) treatment. Since 3',4',5'-hydroxylated flavonoid-derivatives may serve a multitude of functions, including antioxidant activity and UV filters, the evolution and expression profile of flavonoid hydroxylase probably reflect the adaptive value of Antarctic moss in the acclimation of polar environment. PMID- 24631265 TI - Entropic Biological Score: a cell cycle investigation for GRNs inference. AB - Inference of gene regulatory networks (GRNs) is one of the most challenging research problems of Systems Biology. In this investigation, a new GRNs inference methodology, called Entropic Biological Score (EBS), which linearly combines the mean conditional entropy (MCE) from expression levels and a Biological Score (BS), obtained by integrating different biological data sources, is proposed. The EBS is validated with the Cell Cycle related functional annotation information, available from Munich Information Center for Protein Sequences (MIPS), and compared with some existing methods like MRNET, ARACNE, CLR and MCE for GRNs inference. For real networks, the performance of EBS, which uses the concept of integrating different data sources, is found to be superior to the aforementioned inference methods. The best results for EBS are obtained by considering the weights w1=0.2 and w2=0.8 for MCE and BS values, respectively, where approximately 40% of the inferred connections are found to be correct and significantly better than related methods. The results also indicate that expression profile is able to recover some true connections, that are not present in biological annotations, thus leading to the possibility of discovering new relations between its genes. PMID- 24631266 TI - Identification of a feather beta-keratin gene exclusively expressed in pennaceous barbule cells of contour feathers in chicken. AB - Feathers are elaborate skin appendages shared by birds and theropod dinosaurs that have hierarchical branching of the rachis, barbs, and barbules. Feather filaments consist of beta-keratins encoded by multiple genes, most of which are located in tandem arrays on chromosomes 2, 25, and 27 in chicken. The expansion of the genes is thought to have contributed to feather evolution; however, it is unclear how the individual genes are involved in feather formation. The aim of the present study was to identify feather keratin genes involved in the formation of barbules. Using a combination of microarray analysis, reverse-transcription polymerase chain reaction, and in situ hybridization, we found an uncharacterized keratin gene on chromosome 7 that was expressed specifically in barbule cells in regenerating chicken feathers. We have named the gene barbule specific keratin 1 (BlSK1). The BlSK1 gene structure was similar to the gene structure of previously characterized feather keratin genes, and consisted of a non-coding leader exon, an intron, and an exon with an open reading frame (ORF). The ORF was predicted to encode a 98 aa long protein, which shared 59% identity with feather keratin B. Orthologs of BlSK1 were found in the genomes of other avian species, including turkey, duck, zebra finch, and flycatcher, in regions that shared synteny with chromosome 7 of chicken. Interestingly, BlSK1 was expressed in feather follicles that generated pennaceous barbules but not in follicles that generated plumulaceous barbules. These results suggested that the composition of feather keratins probably varies depending on the structure of the feather filaments and, that individual feather keratin genes may be involved in building different portions and/or types of feathers in chicken. PMID- 24631267 TI - Prognosis value of HIF-1alpha expression in patients with non-small cell lung cancer. AB - BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays a critical role in the development and progression of tumors. Various studies evaluating the prognostic value of HIF-1alpha in patients with lung cancer (LC) remain controversial. To comprehensively and quantitatively summarize the evidence on the effect of HIF-1alpha expression on the survival of patients with LC, a meta-analysis was carried out. MATERIAL AND METHODS: Electronic databases were used to identify published studies before August 31st, 2013. Studies were assessed for quality using REMARK. Data were collected comparing overall survival in patients with high HIF-1alpha expression with those with low expression. RESULTS: Totally, 13 papers including 1420 patients were subjected to final analysis. The combined hazard ratio (HR) was 1.60 (95% CI: 1.14-2.25, P=0.007), suggesting that high expression of HIF-1alpha was an indicator of poor prognosis. Further, when stratified by LC histological type (SCLC and NSCLC), study region (Asia and Europe), cut-off values (10%), tumor stage (I-III and I IV), antibody for IHC (H1alpha67 and ESEE 122), and HR estimated method (univariate/multivariate analysis), most of the results were statistically significant. CONCLUSIONS: Taken together, this meta-analysis revealed that HIF 1alpha overexpression might be a predicative factor of poor prognosis for NSCLC particularly in Asia. PMID- 24631269 TI - Gauging the impact of Forensic Science International: Genetics--Citation metrics for top articles in the journal. AB - Using the Thomson Reuters' Web of Knowledge bibliometric tool enables the analysis of citation patterns for the articles published in FSI: Genetics since it was launched. This brief survey identifies the most cited articles published by the journal since its inception and amongst these, the most impactful original research articles: those showing the highest citation rates per year since their publication. PMID- 24631268 TI - Permanent draft genomes of four new coccolithoviruses: EhV-18, EhV-145, EhV-156 and EhV-164. AB - Coccolithoviruses infect the marine coccolithophorid microalga Emiliania huxleyi. Here, we describe the genomes of four new coccolithoviruses isolated from UK coastal locations. Of particular interest, EhV-18 and EhV-145 encode serine palmitoyltransferase function via two distinct genes, whereas all other coccolithoviruses have SPT as a gene fusion of LCB1/LCB2 domains. PMID- 24631270 TI - Whole-exome sequence analysis of ataxia telangiectasia-like phenotype. AB - A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum alpha-fetoprotein, were subjected to whole exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjogren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype. PMID- 24631271 TI - The utility of initial and follow-up ultrasound reevaluation for blunt renal trauma in children and adolescents. AB - OBJECTIVE: To discover if renal ultrasound (RUS) can be utilized as the primary follow-up imaging modality in the management of blunt renal injuries in children and adolescents. METHODS: We initiated a protocol utilizing RUS reevaluations for children and adolescents treated for blunt renal injuries. Patients following this protocol (Post) had initial computerized tomography (CT) with RUS reevaluation at day 2 and 2 weeks. We retrospectively compared this group to a 2 year cohort treated between 2007 and 2009 (Pre). RESULTS: In our study, 28 Post protocol patients were retrospectively compared with 22 Pre cohort patients. No significant differences were observed in age, length of stay (LOS), injury severity score (ISS), and utilization of CT reevaluation. Follow-up reevaluation was obtained in 13 Pre patients versus 21 Post patients (p = 0.231). No patients had any evidence of long-term complications in either cohort. CONCLUSION: Our results suggest that RUS can be utilized as the primary surveillance imaging modality in the management of blunt renal injuries in children and adolescents. The lack of benefit of usage of RUS demonstrated in the acute post-injury surveillance period calls into question the benefit of RUS immediately following the blunt trauma. PMID- 24631272 TI - MicroRNAs as regulators of drug transporters, drug-metabolizing enzymes, and tight junctions: implication for intestinal barrier function. AB - Drug transporters, drug-metabolizing enzymes, and tight junctions in the small intestine function as an absorption barrier and sometimes as a facilitator of orally administered drugs. The expression of these proteins often fluctuates and thereby causes individual pharmacokinetic variability. MicroRNAs (miRNAs), which are small non-coding RNAs, have recently emerged as a new class of gene regulator. MiRNAs post-transcriptionally regulate gene expression by binding to target mRNA to suppress its translation or regulate its degradation. They have been shown to be key regulators of proteins associated with pharmacokinetics. Moreover, the role of miRNAs on the expression of some proteins expressed in the small intestine has recently been clarified. In this review, we summarize current knowledge regarding the role of miRNAs in the regulation of drug transporters, drug-metabolizing enzymes, and tight junctions as well as its implication for intestinal barrier function. MiRNAs play vital roles in the differentiation, architecture, and barrier function of intestinal epithelial cells, and directly and/or indirectly regulate the expression and function of proteins associated with drug absorption in intestinal epithelial cells. Moreover, the variation of miRNA expression caused by pathological and physiological conditions as well as genetic factors should affect the expression of these proteins. Therefore, miRNAs could be significant factors affecting inter- and intra-individual variations in the pharmacokinetics and intestinal absorption of drugs. Overall, miRNAs could be promising targets for personalized pharmacotherapy or other attractive therapies through intestinal absorption of drugs. PMID- 24631273 TI - Azithromycin: mechanisms of action and their relevance for clinical applications. AB - Azithromycin is a macrolide antibiotic which inhibits bacterial protein synthesis, quorum-sensing and reduces the formation of biofilm. Accumulating effectively in cells, particularly phagocytes, it is delivered in high concentrations to sites of infection, as reflected in rapid plasma clearance and extensive tissue distribution. Azithromycin is indicated for respiratory, urogenital, dermal and other bacterial infections, and exerts immunomodulatory effects in chronic inflammatory disorders, including diffuse panbronchiolitis, post-transplant bronchiolitis and rosacea. Modulation of host responses facilitates its long-term therapeutic benefit in cystic fibrosis, non-cystic fibrosis bronchiectasis, exacerbations of chronic obstructive pulmonary disease (COPD) and non-eosinophilic asthma. Initial, stimulatory effects of azithromycin on immune and epithelial cells, involving interactions with phospholipids and Erk1/2, are followed by later modulation of transcription factors AP-1, NFkappaB, inflammatory cytokine and mucin release. Delayed inhibitory effects on cell function and high lysosomal accumulation accompany disruption of protein and intracellular lipid transport, regulation of surface receptor expression, of macrophage phenotype and autophagy. These later changes underlie many immunomodulatory effects of azithromycin, contributing to resolution of acute infections and reduction of exacerbations in chronic airway diseases. A sub-group of post-transplant bronchiolitis patients appears to be sensitive to azithromycin, as may be patients with severe sepsis. Other promising indications include chronic prostatitis and periodontitis, but weak activity in malaria is unlikely to prove crucial. Long-term administration of azithromycin must be balanced against the potential for increased bacterial resistance. Azithromycin has a very good record of safety, but recent reports indicate rare cases of cardiac torsades des pointes in patients at risk. PMID- 24631275 TI - A clinical decision framework for the identification of main problems and treatment goals for ambulant children with bilateral spastic cerebral palsy. AB - The primary aim of the study was to investigate how a clinical decision process based on the International Classification of Function, Disability and Health (ICF) and the Hypothesis-Oriented Algorithm for Clinicians (HOAC-II) can contribute to a reliable identification of main problems in ambulant children with cerebral palsy (CP). As a secondary aim, to evaluate how the additional information from three-dimensional gait analysis (3DGA) can influence the reliability. Twenty-two physical therapists individually defined the main problems and specific goals of eight children with bilateral spastic CP. In four children, the results of 3DGA were provided additionally to the results of the clinical examination and the GMFM-88 (gross motor function measure-88). Frequency analysis was used to evaluate the selected main problems and goals. For the main problems, pair-wise agreement was calculated by the number of corresponding problems between the different therapists and using positive and negative agreement per problem. Cluster analysis using Ward's method was used to evaluate correspondence between the main problems and specific goals. The pair-wise agreement revealed frequencies of 47%, 32% and 3% for the identification of one, two or three corresponding main problems. The number of corresponding main problems was higher when additional information of 3DGA was provided. Most of the specific goals were targeting strength (34%), followed by range of motion (15.2%) and GMFM-D (11.8%). In 29.7% of the cases, therapists could not prioritize and exceeded the number of eight specific goals. Cluster analysis revealed a logic connection between the selection of strength as a main problem and as specific goal parameters. Alignment as a main problem was very often associated with specific parameters like ROM and muscle length and with hypertonia as a main problem. The results show a moderate agreement for the selection of main problems. Therapists are able to use the proposed model for a logic and structured clinical reasoning. Setting priorities in the definition of specific goals is revealed as a remaining difficulty. Further research is required to investigate the additional value of 3DGA and to improve priority setting. PMID- 24631276 TI - Transthoracic impedance waveform during cardiopulmonary resuscitation: one size does not fit all! PMID- 24631277 TI - Do emergency nurses and doctors agree in their triage assessment of dyspneic patients? AB - OBJECTIVES: This study investigated the inter-observer agreement (IOA) between doctors and nurses on triaging adult ED dyspneic patients. METHODS: This was a prospective observational study comparing eight trained ED nurses with doctors. Each patient was assessed by a nurse and two doctors (1 and 2) who decided on four-point Patient Acuity Category (PAC) and triage management steps. The primary outcome was the proportion of resuscitation room escalations from consult. Secondary outcomes included proportions and IOA of assigned PAC and steps in triage management. The investigators reported IOA as the k statistic (95% CIs) and percent agreement. DATA/RESULTS: There were 22/302 (7.3%) escalations; one from clinical deterioration. Proportions of assigned PAC status by nurses, Drs 1 and 2 were: PAC 1: 20.2-24.2%; PAC 2: 71.5-72.8%; PAC 3: 4.3-7.0%; PAC 4: 0.0 0.7%. The IOA was at least fair to moderate [k: 0.33 (0.22-0.43) to 1.00] in all steps of management except for electrocardiogram [k: 0.19 (0.10-0.27) to 0.45 (0.35-0.55)] ordering. The percent agreement ranged from 81 to 100% for all management steps except for chest Xray (66-73%) and electrocardiogram (61-71%) ordering. CONCLUSION: Trained ED nurses were safe and managed adult dyspneic patients as well as doctors at triage. PMID- 24631278 TI - Postural sway following cryotherapy in healthy adults. AB - In light of the wide use of cryotherapy and its potential negative effects on postural stability, little is known about how postural sway is affected, particularly when the whole lower limb is immersed. The purpose of this study was to analyze the influence of cryotherapy on postural sway in healthy males. Twenty six subjects were randomly assigned into two intervention groups: control (tepid water at ~26 degrees C) or ice (cold water at ~11 degrees C). Postural sway was measured through the center of pressure (COP) position while they stood on a force plate during bipedal (70 s) and unipedal (40 s) conditions before and after the subjects were immersed in a water tub up to the umbilical level for 20 min. COP standard deviation (SD) and COP velocity were analyzed in the anterior posterior (AP) and medial-lateral (ML) directions. Statistical analysis showed that in the bipedal condition cryotherapy increased the COP SD and COP velocity in the ML direction. During the unipedal condition, a higher COP velocity in the AP and ML directions was also reported. Our findings indicate that cryotherapy by immersing the whole lower limb should be used with caution before engaging in challenging postural control activities. PMID- 24631279 TI - Which method of hip joint centre localisation should be used in gait analysis? AB - Accurate localisation of the hip joint centre is required to obtain accurate kinematics, kinetics and musculoskeletal modelling results. Literature data showed that conclusions drawn from synthetic data, adult normal subjects and cerebral palsy children may vary markedly. This study investigated the localisation accuracy of the hip joint centre against EOS. The EOS system allowed us to register the hip joint centres with respect to the skin markers on standing subjects. A comprehensive set of predictive and functional calibration techniques were tested. For the functional calibration techniques, our results showed that algorithm, range of motion and self-performance of the movement were factors significantly affecting the results. Best results were obtained for comfortable range and self-performance of the movement. The best method in this scenario was the functional geometrical sphere fitting method which localised the hips 1.1cm from the EOS reference in average and 100% of the time within 3 cm. Worst results for functional calibration methods occurred when the movement was assisted with a reduced range of movement. The best method in this scenario was the Harrington et al. regression equations since it does not rely on a functional calibration movement. Harrington et al. equations put the hips 1.7 cm from the EOS reference in average and 97% of the time within 3 cm. We conclude that accurate localisation of the hip joint centre is possible in gait analysis providing that method to localise the hip joint centres are adapted to the population studied: functional geometrical sphere fitting when hip calibration movements are not a problem and Harrington et al. predictive equations otherwise. PMID- 24631280 TI - MRI findings in Duane's ocular retraction syndrome. AB - AIM: To investigate the innervation pattern of extra-ocular muscles in patients with clinically diagnosed Duane's ocular retraction syndrome (DRS) using magnetic resonance imaging (MRI). MATERIALS AND METHODS: The study population consisted of 11 patients. Six patients had type I DRS (eight eyes), four patients had type II DRS (five eyes) and one patient had inverse DRS. Images were acquired using a Siemens 3 T MRI system. The type of DRS, corresponding innervation findings, and condition of the affected muscles were evaluated by two experienced neuroradiologists in consensus. RESULTS: All patients with clinically diagnosed DRS type I showed absence of the abducens nerve (CN6), hypoplasia of the superior oblique muscle (SOM), and aberrant innervation of lateral rectus muscle (LRM) by an extra branch of oculomotor nerve (CN3). All patients with type II DRS show dual-innervation of the LRM (by CN6 and an aberrant CN3 branch) and hypoplasia of SOM. The single patient with inverse DRS showed hypoplasia of CN3, the medial rectus muscle (MRM), the inferior rectus muscle (IRM), and the inferior oblique muscle (IOM). CONCLUSION: Each type of DRS has characteristic MRI appearances. Therefore, MRI is a useful diagnostic tool for the confirmation and classification of suspected cases of DRS. PMID- 24631281 TI - The diagnosis of hemimegalencephaly using in utero MRI. AB - AIM: To review our experience of diagnosing hemimegalencephaly (HME) using in utero magnetic resonance imaging (MRI). MATERIALS AND METHODS: The MRI database in the Academic Unit of Radiology, University of Sheffield was searched using "hemimegalencephaly" and "in utero MR" as search terms. The antenatal histories and reports of ultrasound imaging were reviewed as well as the in utero MRI images. RESULTS: Nine cases of foetal HME were located. One case was referred after ultrasound with the diagnosis of HME, one as a "complex brain malformation", and one as a "mass lesion". The other six were referred as "unilateral ventriculomegaly". A common finding in foetuses imaged in the second trimester was disruption of the normal "transient structures" found in the developing cerebral hemispheres. CONCLUSION: HME is a difficult diagnosis to make using antenatal ultrasound and in utero MRI should be considered in cases of unilateral ventriculomegaly diagnosed at ultrasound. Disruption of the transient structures of the cerebral hemispheres is a common finding on in utero MRI and can sometimes produce mass-like appearances in the region of the germinal matrix/ganglionic eminence. PMID- 24631282 TI - Intercellular adhesion molecule-1 expression in massive chronic intervillositis: implications for the invasion of maternal cells into fetal tissues. AB - INTRODUCTION: Massive chronic intervillositis (MCI), also known as chronic intervillositis of unknown etiology, is a placental lesion associated with massive infiltration of mononuclear cells in the intervillous space, poor perinatal outcome, and high rate of recurrence. Our previous demonstration of increased syncytiotrophoblast (st) intercellular adhesion molecule-1 (ICAM-1) expression in villitis lesions and the finding of extensive monocyte/macrophagic cells in the maternal intervillous space in MCI, led us to further investigate stICAM-1 in MCI. MATERIALS AND METHODS: A cross-sectional study of placentas from the third trimester of pregnancy (34-41 weeks gestation) was conducted to determine stICAM-1 in MCI (n = 7). MCI stICAM-1 expression was compared to stICAM 1 in villitis (n = 7) and in normal villi from placentas with (n = 7) and without (n = 7) villitis. Maternal cells within villi in MCI were identified in placentas mismatched for maternal/fetal human leukocyte antigen (HLA)-DRw52. Villitis was diagnosed with hematoxylin and eosin staining and antibody to CD3 in serial sections, and ICAM-1 in syncytiotrophoblasts was confirmed with antibodies to ICAM-1 and cytokeratin. RESULTS: Placentas with MCI had higher stICAM-1 (79.8%) than placentas with villitis (27.1%), normal villi from placentas with villitis (11.5%), and normal villi from placentas without villitis (0.3%). Maternal cells were identified within villi of placentas (n = 5) mismatched (mothers positive, fetuses negative) for HLA-DRw52. CONCLUSIONS: Placentas with MCI have more stICAM 1 than placentas with or without villitis lacking MCI. The finding that MCI and villitis have prominent stICAM-1 and maternal cells in the villi suggests that MCI and villitis could have a similar pathophysiologic mechanism. PMID- 24631274 TI - GABAergic contributions to alcohol responsivity during adolescence: insights from preclinical and clinical studies. AB - There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the gamma amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol use disorders. PMID- 24631283 TI - The Cdk/cDc14 module controls activation of the Yen1 holliday junction resolvase to promote genome stability. AB - Faithful genome transmission during cell division requires precise, coordinated action of DNA metabolic enzymes, including proteins responsible for DNA damage detection and repair. Dynamic phosphorylation plays an important role in controlling repair enzymes during the DNA damage response (DDR). Cdc14 phosphatases oppose cyclin-dependent kinase (Cdk) phosphorylation and have been implicated in the DDR in several model systems. Here, we have refined the substrate specificity of budding yeast Cdc14 and, using this insight, identified the Holliday junction resolvase Yen1 as a DNA repair target of Cdc14. Cdc14 activation at anaphase triggers nuclear accumulation and enzymatic activation of Yen1, likely to resolve persistent recombinational repair intermediates. Consistent with this, expression of a phosphomimetic Yen1 mutant increased sister chromatid nondisjunction. In contrast, lack of Cdk phosphorylation resulted in constitutive activity and elevated crossover-associated repair. The precise timing of Yen1 activation, governed by core cell-cycle regulators, helps coordinate DNA repair with chromosome segregation and safeguards against genome destabilization. PMID- 24631284 TI - Global analyses of the effect of different cellular contexts on microRNA targeting. AB - MicroRNA (miRNA) regulation clearly impacts animal development, but the extent to which development-with its resulting diversity of cellular contexts-impacts miRNA regulation is unclear. Here, we compared cohorts of genes repressed by the same miRNAs in different cell lines and tissues and found that target repertoires were largely unaffected, with secondary effects explaining most of the differential responses detected. Outliers resulting from differential direct targeting were often attributable to alternative 3' UTR isoform usage that modulated the presence of miRNA sites. More inclusive examination of alternative 3' UTR isoforms revealed that they influence ~10% of predicted targets when comparing any two cell types. Indeed, considering alternative 3' UTR isoform usage improved prediction of targeting efficacy significantly beyond the improvements observed when considering constitutive isoform usage. Thus, although miRNA targeting is remarkably consistent in different cell types, considering the 3' UTR landscape helps predict targeting efficacy and explain differential regulation that is observed. PMID- 24631285 TI - Dual control of Yen1 nuclease activity and cellular localization by Cdk and Cdc14 prevents genome instability. AB - The careful orchestration of cellular events such as DNA replication, repair, and segregation is essential for equal distribution of the duplicated genome into two daughter cells. To ensure that persistent recombination intermediates are resolved prior to cell division, the Yen1 Holliday junction resolvase is activated at anaphase. Here, we show that the master cell-cycle regulators, cyclin-dependent kinase (Cdk) and Cdc14 phosphatase, control the actions of Yen1. During S phase, Cdk-mediated phosphorylation of Yen1 promotes its nuclear exclusion and inhibits catalytic activity by reducing the efficiency of DNA binding. Later in the cell cycle, at anaphase, Cdc14 drives Yen1 dephosphorylation, leading to its nuclear relocalization and enzymatic activation. Using a constitutively activated form of Yen1, we show that uncontrolled Yen1 activity is detrimental to the cell: spatial and temporal restriction of Yen1 protects against genotoxic stress and, by avoiding competition with the noncrossover-promoting repair pathways, prevents loss of heterozygosity. PMID- 24631286 TI - Human mesenchymal stromal cells primed with paclitaxel, apart from displaying anti-tumor activity, maintain their immune regulatory functions in vitro. PMID- 24631287 TI - Aquatic primary production in a high-CO2 world. AB - Here, we provide a review of the direct effect of increasing CO2 on aquatic primary producers through its function as a source of carbon, focusing our analysis on the interpretation of this increase as an increase in the availability of a resource. This provides an interesting context to evaluate ecological and evolutionary theories relating to nutrient availability and leads us to: the assessment of theories about limitation of productivity and the integration of CO2 into the co-limitation paradigm; the prediction of community composition and of change in communities from known changes in the environment; and evaluation of the potential for evolutionary adaptation in conditions that increase growth. PMID- 24631288 TI - Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR. AB - Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of beta-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-beta-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-beta-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib-simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/beta-catenin signaling-dependent down-regulation of survivin and apoptosis induction. PMID- 24631289 TI - Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells. AB - Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7(+) satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of alpha-smooth actin and type I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration. PMID- 24631290 TI - Cell-scaffold interaction within engineered tissue. AB - The structure of a tissue engineering scaffold plays an important role in modulating tissue growth. A novel gelatin-chitosan (Gel-Cs) scaffold with a unique structure produced by three-dimensional printing (3DP) technology combining with vacuum freeze-drying has been developed for tissue-engineering applications. The scaffold composed of overall construction, micro-pore, surface morphology, and effective mechanical property. Such a structure meets the essential design criteria of an ideal engineered scaffold. The favorable cell matrix interaction supports the active biocompatibility of the structure. The structure is capable of supporting cell attachment and proliferation. Cells seeded into this structure tend to maintain phenotypic shape and secreted large amounts of extracellular matrix (ECM) and the cell growth decreased the mechanical properties of scaffold. This novel biodegradable scaffold has potential applications for tissue engineering based upon its unique structure, which acts to support cell growth. PMID- 24631291 TI - Molecular aspects of hereditary spastic paraplegia. AB - Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower limbs spasticity and weakness. What was first thought to be a small group of rare Mendelian disorder has now become a large group that includes many complex syndromes. While large families with defined modes of inheritance were used for the initial HSP gene discovery, new sequencing technologies have recently allowed the study of small families, with the identification of many new disease causative genes. These discoveries are slowly leading to a better understanding of the molecular mechanisms underlying HSP with the identification of precise disease pathways. These insights may lead to new therapeutic strategies for what is a group of largely untreatable diseases. This review looks at the key players involved in HSP and where they act in their specific pathways. PMID- 24631292 TI - Smurf1 plays a role in EGF inhibition of BMP2-induced osteogenic differentiation. AB - It has been demonstrated that epidermal growth factor (EGF) plays a role in supporting the proliferation of bone marrow stromal cells in bone but inhibits their osteogenic differentiation. However, the mechanism underlying EGF inhibition of osteoblast differentiation remains unclear. Smurf1 is an E3 ubiquitin ligase that targets Smad1/5 and Runx2, which are critical transcription factors for bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation. In this study, we investigated the effect of EGF on the expression of Smurf1, and the role of Smurf1 in EGF inhibition of osteogenic differentiation using C2C12 cells, a murine myoblast cell line. EGF increased Smurf1 expression, which was blocked by inhibiting the activity of either JNK or ERK. Chromatin immunoprecipitation and Smurf1 promoter assays demonstrated that c Jun and Runx2 play roles in the EGF induction of Smurf1 transcription. EGF suppressed BMP2-induced expression of osteogenic marker genes, which were rescued by Smurf1 knockdown. EGF downregulated the protein levels of Runx2 and Smad1 in a proteasome-dependent manner. EGF decreased the transcriptional activity of Runx2 and Smurf1, which was partially rescued by Smurf1 silencing. Taken together, these results suggest that EGF increases Smurf1 expression via the activation of JNK and ERK and the subsequent binding of c-Jun and Runx2 to the Smurf1 promoter and that Smurf1 mediates the inhibitory effect of EGF on BMP2-induced osteoblast differentiation. PMID- 24631293 TI - ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. AB - Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy. PMID- 24631294 TI - Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance. AB - PURPOSE: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. METHODS AND RESULTS: DRP1 expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (DeltaPsim) depolarization, exhibited attenuated insulin signaling and 2-deoxy-d-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4 pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H2O2), they increased DRP1 expression and mitochondrial fragmentation, resulting in DeltaPsim depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H2O2-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1 suppression nor TMPyP restored the DeltaPsim depolarization and impaired 2-DG uptake, however they improved insulin signaling. CONCLUSIONS: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate induced insulin resistance. PMID- 24631295 TI - Coordination of tooth morphogenesis and neuronal development through tissue interactions: lessons from mouse models. AB - In addition to being an advantageous model to investigate general molecular mechanisms of organ formation, the tooth is a distinct target organ for peripheral nerve innervation. These nerves are required for the function and protection of the teeth and, as shown in fish, also for their regeneration. This review focuses on recent findings of the local tissue interactions and molecular signaling mechanisms that regulate the early nerve arrival and patterning of mouse mandibular molar tooth sensory innervation. Dental sensory nerve growth and patterning is a stepwise process that is intimately linked to advancing tooth morphogenesis. In particular, nerve growth factor and semaphorin 3A serve as essential functions during and are iteratively used at different stages of tooth innervation. The tooth germ controls development of its own nerve supply, and similar to the development of the tooth organ proper, tissue interactions between dental epithelial and mesenchymal tissues control the establishment of tooth innervation. Tgf-beta, Wnt, and Fgf signaling, which regulate tooth formation, are implicated to mediate these interactions. Therefore, tissue interactions mediated by conserved signal families may constitute key mechanism for the integration of tooth organogenesis and development of its peripheral nerve supply. PMID- 24631297 TI - C-Fos activation in the periaqueductal gray following acute morphine-3beta-D glucuronide or morphine administration. AB - Morphine-3beta-D-glucuronide (M3G), a primary morphine metabolite, evokes hyperalgesia in mice and rats and putatively mediates hyperalgesia associated with morphine (MOR) administration. However, M3G does not act via opioid receptors and its locus of activity in the CNS is unknown. Here we assessed the density of neurons immunoreactive for c-Fos, an immediate early gene regulated by neuronal activity, in the periaqueductal gray (PAG), a midbrain region critical to pain modulation, in male CD-1 mice after MOR and M3G exposure. Mice were injected with acute doses of MOR or M3G following a pre-injection of saline (SAL) or the opioid antagonist naltrexone (NTX), perfused 3 h later, and labeled for c Fos using immunohistochemistry. Labeled image stacks taken from the PAG were then analyzed on a confocal microscope for the number of neurons showing c-Fos expression. Relative to controls, significant but similar increases in the mean density of PAG c-Fos immunoreactive neurons were observed in mice pre-injected with SAL then M3G or morphine. However, NTX pre-injection blocked this increase in MOR but not M3G injected mice. The data demonstrate for the first time a CNS locus for M3G activity. Consistent with previous observations, this M3G activity is not mediated by opioid receptors. PMID- 24631298 TI - The Q223R polymorphism in the leptin receptor associates with objectively measured light physical activity in free-living Japanese. AB - Physical activity (PA) is associated with reductions in the risk of all-cause mortality and in the prevalence of cardiovascular disease and stroke. Nevertheless, a large proportion of the general population may not be sufficiently active. PA level has been reported to be influenced by genetic factors, and we investigated whether Q223R polymorphism in the leptin receptor (LEPR) gene was associated with PA level. A total of 556 Japanese adults aged 24 65years old participated in this cross-sectional study. The duration and intensity of PA were objectively evaluated by triaxial accelerometry. Q223R polymorphism was determined by the TaqMan method. The distribution of Q223R polymorphism was: QQ 0.7%, QR 22.6%, and RR 76.6%. The relation between the LEPR genotype and PA level was analyzed by ANCOVA with age and sex as covariates in the Q dominant genetic model. There were significant differences between LEPR genotypes and the time spent in light PA or inactive time. The subjects with RR genotype showed significantly shorter time spent in light PA (RR genotype: 559.4+/-102.9min/day, QQ/QR genotype: 579.9+/-103.1min/day) and longer inactive time (RR genotype: 815.5+/-107.5min/day, QQ/QR genotype: 792.3+/-107.7min/day) than the subjects with QQ/QR genotype (P<0.05). There were no such differences in the time spent in moderate or vigorous PA. These results suggest that the variety of PA level, especially spontaneous PA in humans, is partly caused by diversity in the LEPR gene. PMID- 24631296 TI - Is fat taste ready for primetime? AB - Mounting evidence suggests that gustation is important for the orosensory detection of dietary fats, and might contribute to preferences that humans, rodents, and possibly other mammals exhibit for fat-rich foods. In contrast to sweet, sour, salty, bitter, and umami, fat is not widely recognized as a primary taste quality. Recent investigations, however, provide a wealth of information that is helping to elucidate the specific molecular, cellular, and neural mechanisms required for fat detection in mammals. The latest evidence supporting a fat taste will be explored in this review, with a particular focus on recent studies that suggest a surprising role for gut-brain endocannabinoid signaling in controlling intake and preference for fats based on their proposed taste properties. PMID- 24631300 TI - Central administration of oleate or octanoate activates hypothalamic fatty acid sensing and inhibits food intake in rainbow trout. AB - If levels of fatty acids like oleate and octanoate are directly sensed through different fatty acid (FA) sensing systems in hypothalamus of rainbow trout, intracerebroventricular (ICV) administration of FA should elicit effects similar to those previously observed after intraperitoneal (IP) treatment. Accordingly, we observed after ICV treatment with oleate or octanoate decreased food intake accompanied in hypothalamus by reduced potential of lipogenesis and FA oxidation, and decreased potential of ATP-dependent inward rectifier potassium channel (K(+)ATP). Those changes support direct FA sensing through mechanisms related to FA metabolism and mitochondrial activity. The FA sensing through binding to FAT/CD36 and subsequent expression of transcription factors appears to be also direct but an interaction with peripheral hormones cannot be rejected. Moreover, decreased expression of NPY and increased expression of POMC were observed in parallel with the activation of FA sensing systems and decreased food intake. These results allow us to suggest the involvement of at least these peptides in controlling the decreased food intake noted after oleate and octanoate treatment in rainbow trout. PMID- 24631301 TI - Food costs, diet quality and energy balance in the United States. AB - The high obesity rates and poor diet quality in the United States, particularly among low income populations, are often attributed to low income, low food access, and high food prices of healthy foods. This paper discusses these associations and questions some of the metrics used to measure food prices. The paper argues that 1. On average, Americans consume diets that need improvement and there is only a very limited relationship between income and diet quality; 2. The way the food price is measured makes a difference in the perception of how expensive healthy and less healthy food is; 3. The way Americans allocate their food budgets between healthy and less healthy foods is not in line with healthy diets; and 4. At any food spending level there are households that purchase healthy (and unhealthy) diets, including budgets at or below the maximum allotment for the Supplemental Nutrition Assistance Program (SNAP) which provides a means for low-income households to purchase food. Our key finding is that healthy foods and diets are affordable, but policy makers, nutrition educators, researchers and the media need to focus on promoting this message, and providing additional guidance on making the changes for Americans to switch to a healthy and affordable diet. PMID- 24631299 TI - Human cognitive function and the obesogenic environment. AB - Evidence is accumulating which suggests that, in addition to leading to unprecedented rates of obesity, the current food environment is contributing to the development of cognitive impairment and dementia. Recent experimental research indicates that many of the cognitive deficits associated with obesity involve fundamental inhibitory processes that have important roles in the control of food intake, implicating these cognitive impairments as a risk factor for weight gain. Here, we review experiments that link obesity with deficits in memory, attentional, and behavioral control and contemplate how these deficits may predispose individuals to overeat. Specifically, we discuss how deficits in inhibitory control may reduce one's ability to resist eating when confronted with the variety of foods and food cues that are ubiquitous in today's environment. Special attention is given to the importance of memory inhibition to the control of eating and appetitive behavior, and the role of the hippocampus in this process. We also discuss the potential etiology of both obesity and obesity related cognitive impairment, highlighting non-human animal research which links both of these effects to the consumption of the modern "Western" diet that is high in saturated fats and simple carbohydrates. We conclude that part of what makes the current food environment "obesogenic" is the increased presence of food cues and the increased consumption of a diet which compromises our ability to resist those cues. Improving control over food-related cognitive processing may be useful not only for combating the obesity epidemic but also for minimizing the risk of serious cognitive disorder later in life. PMID- 24631302 TI - The impact of maternal consumption of cafeteria diet on reproductive function in the offspring. AB - Maternal obesity is a risk factor for the development of metabolic syndrome and childhood obesity, and early overnutrition seems to induce the development of pathologies in adulthood, including insulin resistance, cardiovascular diseases, type 2 diabetes mellitus, and a higher BMI. In addition, it is known that obesity can negatively affect fertility and reproductive function in men. The objective of this work was to investigate the impact of maternal obesity induced by the consumption of cafeteria diet on metabolic, endocrine and reproductive outcomes in the male offspring. Body weight, abdominal fat content and concentrations of insulin, leptin, glucose and total cholesterol were analyzed in dams. The same parameters were evaluated in pups when in adulthood, in addition to the analysis of sexual behavior, followed by measurement of plasma luteinizing hormone, follicle-stimulating hormone, testosterone, and prolactin. Maternal consumption of cafeteria diet affected reproductive hormone regulation in the offspring and such modifications were reflected on sexual performance. Also, these modifications were independent of time and of the reproductive period during which dams consumed the diet. Our results indicate, for the first time, that maternal nutrition may have a deep impact on the reproductive function of the adult male offspring. PMID- 24631303 TI - Prenatal stress produces anxiety prone female offspring and impaired maternal behaviour in the domestic pig. AB - Numerous studies have shown that prenatal stress (PNS) can have profound effects on postnatal well-being. Here, the domestic pig (Sus scrofa) was used to investigate PNS effects owing to the direct relevance for farm animal welfare and the developing status of the pig as a large animal model in translational research. Pregnant primiparous sows were exposed, in mid-gestation, to either a social stressor (mixing with unfamiliar conspecifics) or were kept in stable social groups. The ratio of levels of mRNAs for corticotropin releasing hormone (CRH) receptors 1 and 2 in the amygdala, measured for the first time in the pig, was substantially increased in 10-week-old female, but not male, PNS progeny indicating a neurobiological propensity for anxiety-related behaviour. Mature female offspring were observed at parturition in either a behaviourally restrictive crate or open pen. Such PNS sows showed abnormal maternal behaviour in either environment, following the birth of their first piglet. They spent more time lying ventrally, more time standing and showed a higher frequency of posture changes. They were also more reactive towards their piglets, and spent longer visually attending to their piglets compared to controls. Associated with this abnormal maternal care, piglet mortality was increased in the open pen environment, where protection for piglets is reduced. Overall, these data indicate that PNS females have their brain development shifted towards a pro anxiety phenotype and that PNS can be causally related to subsequent impaired maternal behaviour in adult female offspring. PMID- 24631304 TI - Biofeedback combined with cue-exposure as a treatment for heroin addicts. AB - The aim of this study was to test if cue-exposure therapy (CET) combined with biofeedback therapy (BT) could decrease craving and physiological reactivity to drug-related cues in heroin dependents. Forty-five participants were randomly assigned to usual rehabilitation with or without CET combined with BT. Craving was assessed by a 100-point visual analog scale (VAS). Skin conductance (SC) and muscle electromyography (MEG) were recorded using a biofeedback device. After 2 months of treatment, both the pre-cue exposure craving and the post-cue exposure craving, SC, and MEG were lower in the experimental group than in the control group. Compared to the control group, the experimental group had a greater decrease in craving, SC, and MEG from baseline after the treatment. The results suggest that CET combined with BT treatment is effective in reducing craving and physiology reactivity in heroin dependents and could be used as a component of heroin-dependence rehabilitation. PMID- 24631306 TI - Testosterone, cortisol, and psychopathic traits in men and women. AB - Cortisol and testosterone are theorized to independently and jointly influence antisocial behaviors. The current research examined the independent and interactive effects of baseline testosterone and cortisol on individual differences in psychopathic traits in a relatively large non-clinical sample (N=237). Participants completed the Self-Report Psychopathy - Short Form (SRP; Paulhus, Neumann, & Hare, in press) and provided saliva samples. Analyses indicated that testosterone and cortisol were positively correlated with psychopathic traits in men, but beyond these effects, cortisol moderated the relationship between testosterone and psychopathy in men. The relationship between testosterone and psychopathy within men was positive when cortisol levels were high, but negative when cortisol levels were low. These results have implications for work surrounding the dual hormone hypothesis and suggest that nonclinical variability in psychopathy can be predicted by baseline testosterone and cortisol. PMID- 24631305 TI - Role of nitric oxide in altered nociception and memory following chronic stress. AB - INTRODUCTION: Chronic stress alters sensory and cognitive function of mankind and animals. Sub-chronic swim stress is known to induce a prolonged hyperalgesia which is mediated through the NMDA and opioid systems. Nitric oxide is a soluble gas which acts as a retrograde messenger that modulates the release of the mentioned neurotransmitters. It is also involved in nociception and memory. The objective of the current study was to evaluate the role of NO pathway in nociception and memory impairments induced by sub-chronic swim stress. METHODS AND MATERIALS: A three session forced swimming stress protocol was administered to the rats. Pretreatment with l-NAME (10mg/kg, i.p.), l-Arginine (10mg/kg, i.p.) or saline was made before each swimming session. Anxiety-like behavior, nociception and passive avoidance (PA) learning were evaluated 24h after the last swim stress session. RESULTS: Swim stress altered locomotion and anxiety-like behaviors in the open field test. Reduced thermal threshold was observed in the nociceptive measurement after swim stress. Pretreatment with l-NAME could reverse the reduced threshold. A decreased step through latency was observed in the PA paradigm after swim stress, which could be inhibited by pretreatment with l-NAME. CONCLUSION: The results of this study indicate that sub-chronic swim stress impairs nociception and PA learning. NO pathway seems to have a modulatory role in these alterations. Further studies are suggested to examine the protective effect of NOS inhibitors on stress-induced impairments in sensory and cognitive function. PMID- 24631307 TI - Growing up in the family or growing up alone influences behavior and hormones, but not arginine vasopressin receptor 1a expression in male African striped mice. AB - In many species males display alternative reproductive tactics (ARTs). While males of different tactics differ behaviorally in the field, it is often not known whether these behavioral differences would also occur under standardized laboratory conditions, nor how ARTs are regulated by the brain. In the present study we kept male African striped mice (Rhabdomys pumilio) in captivity either in family groups or solitary, to mimic ARTs observed in the field. This allowed us to study these males behaviorally under standardized conditions, to replicate physiological findings from the field, and to study the expression of the arginine vasopressin 1a receptor (AVPR1a) in their brains. Changes in either peptide release or receptor expression (or both) might regulate ARTs with differential timelines, with peptide secretion being faster than receptor expression. As observed in the field, family living males had higher corticosterone but lower testosterone levels than singly housed males. Surprisingly, singly housed males were less aggressive while at the same time having higher testosterone levels. We found no differences in AVPR1a expression. In a previous study it was shown that singly housed males have higher levels of AVP stored in their brain, which potentially could be secreted when the social situation changes, for example to establish social bonds. Our study on AVPR1a suggests the hypothesis that, given that the receptor distribution and expression of singly housed males do not differ from that of family-living males, the brains of singly-housed males have a similar capacity to be responsive to AVP when given the chance to interact socially. PMID- 24631308 TI - Social support in pigs with different coping styles. AB - The presence of a conspecific during a stressful situation, i.e. social support, can considerably lower the stress response of an individual compared to experiencing the stressful situation alone. Pigs also benefit from social support, but it is not known whether the extent to which they benefit is dependent on their personality or coping style. In this study, therefore, the effect of social support on behavioral and physiological (i.e. salivary cortisol, heart rate and the heart rate variability parameters standard deviation (SDNN) and root mean square of successive differences (RMSSD)) stress responses was studied in pigs with different coping styles. Based on the backtest, piglets were classified as high-resisting (HR) or low-resisting (LR). At 11weeks of age, 12 gilts of each coping style were subjected to a 15min restraint test in a weighing cage without a pen mate present (i.e. no support treatment) and 12 other gilts of each coping style were subjected to this test with a pen mate, a boar with the same coping style, present (i.e. support treatment). With the pen mate present, LR gilts showed less standing alert behavior and they had their ears back less often than without the pen mate present. On the other hand, HR gilts seemed to spend less time on escaping the cage and more HR gilts seemed to urinate in the situation when the pen mate was present than without the pen mate present, but this was not significant. Independently of the test situation, HR gilts grunted more than LR gilts and they were more likely to urinate than LR gilts. Salivary cortisol concentrations were not affected by treatment or coping style, but were increased at 30min after the start of the test after which concentrations decreased again to starting levels. The heart rate and heart rate variability parameters RMSSD and RMSSD/SDNN ratio were not affected by treatment or coping style, but the SDNN was lower in the LR pigs during the first and last 5min of the test when a pen mate was present than without the pen mate present. In addition, heart rate and heart rate variability were increased during the test compared to before and after the test. No differences in behavior and salivary cortisol concentrations were found between the HR and LR accompanying boars. Although effects of social support were not found on all variables measured, the results do indicate that pigs may benefit from social support during a stressful situation and that pigs with a low-resisting coping style will likely benefit more than pigs with a high-resisting coping style. PMID- 24631309 TI - Compaction of functionalized calcium carbonate, a porous and crystalline microparticulate material with a lamellar surface. AB - In the present study, we aimed to characterize the compressibility and compactibility of the novel pharmaceutical excipient, functionalized calcium carbonate (FCC). We studied three FCC modifications and compared the values for compressibility and compactibility with mannitol, microcrystalline cellulose (MCC), and ground calcium carbonate (CC 330) as well as mixtures of paracetamol and MCC or FCC at drug loads of 0%, 25%, 50%, 75%, and 100% (w/w). We used Heckel analysis, modified Heckel analysis, and Leuenberger analysis to characterize the compaction and compression behavior of the mixtures. Compaction analysis of FCC showed this material to markedly differ from ground calcium carbonate, exhibiting properties, i.e. plastic deformability, similar to those of MCC. This effect was attributed to the highly lamellar structure of FCC particles whose thickness is of the order of a single crystal unit cell. According to Leuenberger parameters, we concluded that FCC-based tablet formulations had mechanical properties equal or superior to those formulated with MCC. FCC tablets with high tensile strength were obtained already at low compressive pressures. Owing to these favorable properties (i.e. marked tensile strength and porosity), FCC promises to be suitable for the preparation of solid dosage forms. PMID- 24631310 TI - Sarcoidosis complicating treatment with adalimumab for Crohn's disease. PMID- 24631311 TI - Tailoring Crohn's disease treatment: the impact of small bowel capsule endoscopy. AB - BACKGROUND AND AIMS: Small bowel capsule endoscopy (SBCE) may detect proximal small bowel lesions that have been previously missed by ileocolonoscopy and small bowel imaging in patients with known ileal and/or colonic Crohn's disease (CD). We aimed to evaluate whether the therapeutic management is influenced by SBCE findings. METHODS: Retrospective single center study. Inclusion of consecutive patients with known non-stricturing and non-penetrating ileal and/or colonic CD, submitted to SBCE to evaluate disease extension and activity, with >= 1 year follow-up. Lesions were classified with the Lewis score (LS) as non-significant (LS<135), mild (135<=LS<=790), or moderate-to-severe (LS>790). Therapeutic changes were assessed three months after SBCE. RESULTS: Fifty consecutive patients (35+/-13 years, 52% females) were included. At ileocolonoscopy, disease location was ileal (L1) in 60%, colonic (L2) in 10% and ileocolonic (L3) in 30% of the patients. In 33 patients (66%) SBCE detected significant proximal lesions previously missed by other modalities. The proportion of patients on thiopurines and/or biologics before SBCE was 2/50 (4%); this was significantly higher three months after SBCE, 15/50 (30%), p=0.023. Treatment with thiopurines and/or biologics was started more often in patients with proximal small bowel lesions [13/33 (39%) vs. 1/17 (6%), p=0.011, relative risk (RR) 6.5], particularly when severe (6%, 36% and 45% of patients with non-significant, mild and moderate-to severe inflammation, respectively). CONCLUSIONS: SBCE diagnoses previously undetected lesions and it influences therapeutic management of CD, triggering an earlier introduction of immunomodulators and/or biological therapy. PMID- 24631312 TI - Lung volume reduction surgery since the National Emphysema Treatment Trial: study of Society of Thoracic Surgeons Database. AB - OBJECTIVES: The National Emphysema Treatment Trial demonstrated that lung volume reduction surgery is an effective treatment for emphysema in select patients. With chronic lower respiratory disease being the third leading cause of death in the United States, this study sought to assess practice patterns and outcomes for lung volume reduction surgery on a national level since the National Emphysema Treatment Trial. METHODS: Aggregate statistics on lung volume reduction surgery reported in the Society of Thoracic Surgeons Database from January 2003 to June 2011 were analyzed to assess procedure volume, preoperative and operative characteristics, and outcomes. Comparisons with published data from the National Emphysema Treatment Trial were made using chi-square and 2-sided t tests. RESULTS: In 8.5 years, 538 patients underwent lung volume reduction surgery, with 20 to 118 cases reported in the Society of Thoracic Surgeons Database per year. When compared with subjects in the National Emphysema Treatment Trial, subjects in the Society of Thoracic Surgeons Database were younger (P < .001), a larger proportion underwent the procedure thoracoscopically (P < .001), and forced expiratory volume in 1 second was 31% versus 28% of predicted (P < .001). When mortality was compared between subjects in the Society of Thoracic Surgeons Database and all subjects in the National Emphysema Treatment Trial randomized to surgery, there were no significant differences. However, mortality was 3% higher in subjects in the Society of Thoracic Surgeons Database when compared with the non-high-risk National Emphysema Treatment Trial subset (P = .005). CONCLUSIONS: This study demonstrates the importance of patient selection and the need to develop consensus on appropriate benchmarks for mortality rates after lung volume reduction surgery. It underscores the need for dedicated centers to increasingly address the heavy burden of chronic lower respiratory disease in the United States in a multidisciplinary fashion, particularly for preoperative evaluation and postoperative management of emphysema. PMID- 24631313 TI - Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology. AB - The growing exposure to chemicals in our environment and the increasing concern over their impact on health have elevated the need for new methods for surveying the detrimental effects of these compounds. Today's gold standard for assessing the effects of toxicants on the brain is based on hematoxylin and eosin (H&E) stained histology, sometimes accompanied by special stains or immunohistochemistry for neural processes and myelin. This approach is time consuming and is usually limited to a fraction of the total brain volume. We demonstrate that magnetic resonance histology (MRH) can be used for quantitatively assessing the effects of central nervous system toxicants in rat models. We show that subtle and sparse changes to brain structure can be detected using magnetic resonance histology, and correspond to some of the locations in which lesions are found by traditional pathological examination. We report for the first time diffusion tensor image-based detection of changes in white matter regions, including fimbria and corpus callosum, in the brains of rats exposed to 8 mg/kg and 12 mg/kg trimethyltin. Besides detecting brain-wide changes, magnetic resonance histology provides a quantitative assessment of dose-dependent effects. These effects can be found in different magnetic resonance contrast mechanisms, providing multivariate biomarkers for the same spatial location. In this study, deformation-based morphometry detected areas where previous studies have detected cell loss, while voxel-wise analyses of diffusion tensor parameters revealed microstructural changes due to such things as cellular swelling, apoptosis, and inflammation. Magnetic resonance histology brings a valuable addition to pathology with the ability to generate brain-wide quantitative parametric maps for markers of toxic insults in the rodent brain. PMID- 24631315 TI - Chemically-induced oxidative stress increases the vulnerability of PC12 cells to rotenone-induced toxicity. AB - In vitro models, including the widely used PC12 cell line, can increase insight into cellular and molecular mechanisms underlying neurodegenerative processes. An important determinant for the vulnerability of cells for chemical insults may be the endogenous level of oxidative stress. To test this hypothesis, we induced different degrees of cellular stress in PC12 cells by altering their ROS production using dexamethasone, l-dihydroxyphenylalanine (l-DOPA) and iron. These different PC12 models were subsequently used to investigate whether the degree of cellular stress could increase their susceptibility to environmental pollutants. The characteristics of these stressed PC12 cell subtypes and their vulnerability to the reference pesticide rotenone were investigated using a combination of biochemical (oxidative stress, cell viability, and alpha-synuclein expression) and functional (fluorescent calcium imaging) assays. Our combined data demonstrate that chemically-induced stress in PC12 cells increases the production of reactive oxygen species (ROS) and alters calcium homeostasis and alpha synuclein expression. Moreover, l-DOPA and FeSO4 pre-treated PC12 cells show increased vulnerability to rotenone-induced cytotoxicity. These chemically stressed cell models may therefore prove valuable to investigate how increased cellular stress influences neurotoxic outcome, for example in case of mixture toxicity. PMID- 24631314 TI - Differential inflammatory response to acrylonitrile in rat primary astrocytes and microglia. AB - Acrylonitrile (ACN) is extensively used in the production of plastics, resins, nitriles and other commercial products. Chronic low dose exposures to ACN cause glial cell tumors in rats, primarily microglial in origin. Recently it has been determined that astrocytes and microglia respond to ACN-induced oxidative stress differently, which may influence cell-specific activation of inflammatory and carcinogenic pathways. This study was conducted to compare the inflammatory responses of astrocytes and microglia following ACN treatment in vitro to further characterize differential sensitivities and adaptive responses in these cell types. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and p53 levels were measured along with levels of 12 different cytokines and chemokines in primary rat microglia and astrocytes. Additionally levels of cytochrome P450 2E1 (CYP2E1) were measured to evaluate the cells' ability to metabolize ACN. Results indicate that while both cells upregulate p53 and NF kappaB, the cytokines and chemokines produced differ between the cell types. Astrocytes, but not microglia, upregulated CYP2E1 in response to ACN, which may be due to the astrocytes accumulating more ACN than the microglia. Altogether our data implicate the inflammatory response as an important event in ACN-induced neurotoxicity. PMID- 24631316 TI - Subacute reversible toxic encephalopathy related to treatment with capecitabine: a case report with literature review and discussion of pathophysiology. AB - INTRODUCTION: Capecitabine, a 5-fluorouracil (5FU) pro-drug, is increasingly used in breast and gastrointestinal cancers due to its more convenient oral route of administration when compared to 5FU. Despite its widespread use, there are only a few reports on capecitabine CNS toxicity, while the pathogenic basis of such toxicity remains unclear. CASE: A 69-year-old male presented with recurrent generalized seizures 2.5 months after preoperative chemoradiotherapy with capecitabine in locally advanced rectal cancer. Brain MRI revealed a diffuse, subcortical white matter alteration suggestive of vasogenic edema. The diagnosis of toxic encephalopathy was supported after elimination of alternative causes of the neurological dysfunction and complete resolution of clinical and imaging findings after 3 months of no further chemotherapy. CONCLUSIONS: Given the expanding use of capecitabine, physicians should be aware of this potential complication when a neurological worsening occurs during or after treatment with this chemotherapeutic agent. In our case, as in previously described cases encephalopathy was characterized by a favorable course after cessation of the drug. Vasogenic edema rather than cytotoxic edema may play a pivotal pathogenetic role in this form of encephalopathy. PMID- 24631317 TI - Ocular fundus reference images from optical coherence tomography. AB - Two-dimensional images computed from three-dimensional optical coherence tomography (OCT) data are intrinsically aligned with it, allowing to accurately position a retinal OCT scan within the ocular fundus. In this work, we aim to compute an OCT fundus reference image with improved retinal vasculature extension and contrast over traditional approaches. Based on the shadow casted by hemoglobin on the outer layers of the retina, we compute three independent images from the OCT volumetric data (including the traditional fundus reference image). Combining these images, a fourth one is created that is able to outperform the other three, both quantitatively and qualitatively (as evaluated by retina specialists). The vascular network extension provided by this method was also compared with widely used fundus imaging modalities, showing that it is similar to that achieved with color fundus photography. In this way, the proposed method is an important starting point to the segmentation of the vascular tree and provides users with a detailed fundus reference image. PMID- 24631318 TI - Evaluating dysmenorrhea in a sample of Turkish nursing students. AB - The aim of this study was to determine the prevalence and symptoms of dysmenorrhea, its relevant factors, and the rate of seeking medical help in a group of nursing students. A total of 380 students were included in the study. The demographic data questionnaire, a Daily Menstrual Symptom Rating Scale (DMSR), and the Visual Analog Scale for pain (VASP) were used as tools for data collection. The mean age of the participants was 20.31 +/- 1.10 years. Most students had experienced dysmenorrhea (84.9%). Menstrual pain was frequently initiated on the first day of menstruation (77.8%). The most commonly reported menstrual problems were irregular menstrual cycles (27.2%) and oligomenorrhea (15.1%). Only 24.1% of students consulted their physicians for dysmenorrhea. The participants who had dysmenorrhea had significantly higher symptom scores than the participants who had not had dysmenorrhea, in terms of decreased activities, tension, hip and abdominal pain, backache, headache, and fatigue. Also, having a sister with dysmenorrhea increased the risk of dysmenorrhea. Although dysmenorrhea is a gynecological problem that is commonly seen in young women and that negatively affects daily activities and school life, the rate of seeking medical help is low. Adolescents should, therefore, be educated and counseled to determine the underlying cause and to increase the use of an effective treatment method. Considering that nurses should be better informed about dysmenorrhea causes and treatment options, a study of nursing students was undertaken. PMID- 24631319 TI - Immunohistochemical study of mouse sciatic nerves under various stretching conditions with "in vivo cryotechnique". AB - BACKGROUND: In living animal bodies, some morphological changes of nerve fibers will probably occur when peripheral nerves are stretched or not stretched during various joint exercises. We aimed to capture the dynamic structures of nerves under various stretching conditions and to keep soluble serum proteins in their tissue sections. NEW METHOD: Morphological changes of stretched or non-stretched sciatic nerve fibers were examined with "in vivo cryotechnique" (IVCT). Fibers were directly frozen with liquid isopentane-propane cryogen (-193 degrees C). Immunolocalizations of protein 4.1G and albumin were also examined in the fibers. RESULTS: The structures of IVCT-prepared sciatic nerves under the stretched condition showed a beaded appearance. By immunostaining for membrane skeletal protein 4.1G, Schmidt-Lanterman incisures (SLIs) were clearly identified, and the heights of their circular truncated cones were increased at narrow sites of the nerve fibers under the stretched condition, compared to those of non-stretched nerve fibers. Albumin was immunolocalized in blood vessels and also along endoneurium including regions near the node of Ranvier. COMPARISON WITH EXISTING METHODS: With the conventional perfusion-fixation method (PF), it was difficult to keep stable postures of living mouse limbs for tissue preparation. In nerve fibers after PF, the structures of SLI were easily modified, and albumin was heterogeneously immunolocalized due to diffusion artifacts. CONCLUSIONS: IVCT revealed (1) the structures of peripheral nerve fibers under dynamically different conditions, indicating that the morphological changes of SLIs play a functional role as a bumper structure against mechanical forces, and (2) accurate immunolocalization of serum albumin in the sciatic nerve fibers. PMID- 24631320 TI - A novel semi-automated apparatus for measurement of aggressive biting behavior in mice. AB - BACKGROUND: Currently, behavioral research of aggressiveness is often conducted with intraspecific intermale aggression tests. Intraspecific aggression is not detectable in early stages of psychiatric disorders or in female animals, except during the nursing period. NEW METHOD: We developed a semi-automated apparatus (ARM: Aggression Response Meter) for measurement of aggressive biting behavior (ABB) in mice. The apparatus is loaded with computer-controlled sticks that stimulate the mouse through touch, inducing irritation and anger. When the mouse bites the sticks in anger, a load sensor attached to the sticks detects ABB dynamically. Changes in ABB were assessed with isolation-reared/re-socialized mice using the ARM, and additional isolation-reared mice were tested using both the ARM and the resident-intruder test, and then buspirone, a serotonin 1A receptor agonist, was administered. RESULTS: ABB significantly increased during isolation rearing, and then significantly decreased throughout the re socialization period; both changes were time-dependent. The ARM also detected ABB of female mice after 3 weeks of isolation rearing. Buspirone significantly inhibited aggressive behavior in both tests in a similar manner. COMPARISON WITH EXISTING METHOD: The ARM detects aggressiveness in psychiatric disorders at an earlier stage and in both male and female mice. CONCLUSIONS: ABB toward inanimate objects is a reliable paradigm that makes it possible to detect aggressiveness in the early stage of psychiatric disorders. The ARM is useful for the quantification of aggressiveness using the same individual repeatedly, and for objective evaluation of the effects of drugs on aggressiveness. The ARM can be used with both male and female mice. PMID- 24631321 TI - Multi-trial evoked EEG and independent component analysis. AB - BACKGROUND: Independent component analysis (ICA) is increasingly used to decompose EEG data into components. The analysis is based on the assumption that the hidden components are statistically independent. Here, we investigate the use of ICA on evoked multi-trial non-stationary EEG data. We show that the multi trial data do not fulfill the assumption of the independence of the hidden components. This discrepancy questions the use of ICA in analyzing evoked EEG. NEW METHOD: To overcome the problem with the independence assumption, we introduce a novel way to preprocess multi-trial data. In this preprocessing, the hidden components gain a property which we call the null conditional mean (NCM). We show that this property is sufficient to make the ICA separation to work. The suggested methodology has the additional advantage that it suppresses the stimulus-evoked artifacts, such as the strong muscular artifacts in the transcranial magnetic stimulation (TMS)-evoked EEG, which may otherwise prevent the use of ICA. RESULTS: The theoretical results, which support the mean subtraction method, were proved. We also confirmed the efficiency of the method with several numerical simulations, which resembled TMS-EEG measurement data. COMPARISON WITH EXISTING METHOD: As compared with conventional ICA of multi-trial data, the results substantially improved when using NCM data. CONCLUSIONS: The proposed methodology facilitates in uncovering hidden components that, with other existing methods, easily remain uncovered in evoked EEG or MEG data. PMID- 24631322 TI - Squamous cell carcinoma in enterocutaneous fistula associated with Crohn's disease: first case report. PMID- 24631323 TI - Response to: infliximab three-dose induction regimen in severe corticosteroid refractory ulcerative colitis: early and late outcome and predictors of colectomy. PMID- 24631324 TI - Low-frequency repetitive transcranial magnetic stimulation for dyskinesia and motor performance in Parkinson's disease. AB - Dyskinesias are one of the most frequent and disabling complications of the long term treatment of Parkinson's disease (PD). Although the cause is not completely understood, it appears that an imbalance between excitatory and inhibitory inputs from the basal ganglia to the motor cortex leads to overactivation of motor and premotor areas. Overactivation of the supplementary motor area (SMA) has been observed in neuroimaging studies in dyskinetic PD patients. We investigated the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) of the SMA on levodopa-induced dyskinesias (LID) and motor performance in PD. We tested whether longer duration (10days) and higher number of total pulses (1800 pulses) would enhance the beneficial effect. Seventeen dyskinetic PD patients were randomly assigned to real rTMS or sham (placebo) rTMS, and 1Hz rTMS or sham rTMS was applied over the SMA for 10 consecutive days. Patients were assessed at baseline and 1day after the last rTMS with a levodopa challenge test, and video recordings were taken. Dyskinesias and motor performance were rated off-line by two blinded raters using video recordings. After 10days of treatment with rTMS, we observed that 1Hz rTMS delivered over the SMA had decreased LID lasting for 24hours without a change in motor performance, whereas sham rTMS induced no significant change in dyskinesia scores. These results support a possible therapeutic effect of low-frequency rTMS in LID. However, in order to suggest rTMS as an effective treatment, long-term observations and further investigations with a larger patient population are essential. PMID- 24631325 TI - Effects of plasma D-dimer levels on early mortality and long-term functional outcome after spontaneous intracerebral hemorrhage. AB - The activation of hemostatic systems has been detected in spontaneous intracerebral hemorrhage (ICH) patients. The influence of plasma D-dimer levels on clinical outcome remains unclear. This study aimed to investigate the impact of elevated plasma D-dimer levels on early mortality and long-term functional outcome in spontaneous ICH. A total of 259 spontaneous ICH patients (<24hours from ictus) between November 2010 and October 2011 were included. Clinical information and radiological findings were collected at admission. Spearman correlation analyses revealed that D-dimer concentrations were correlated with midline shift, hematoma volume, intraventricular hemorrhage (IVH) score and Glasgow Coma Scale score. Patients with subarachnoid extension had significantly higher D-dimer levels than those without SAH extension. Comparison of patients with IVH and those without yielded a similar result. Multivariate stepwise backward logistic analysis identified plasma D-dimer levels as an independent risk factor for 7 day mortality (adjusted odds ratio [OR]=1.237, 95% confidence interval [CI] 1.017-1.504, p=0.033) and 3 month poor functional outcome (modified Rankin Scale score >= 3) (adjusted OR=2.279, 95% CI 1.130-6.595, p=0.026). The mechanisms by which elevated D-dimer affects the prognoses of spontaneous ICH patients remain unclear and require clarification in future studies. PMID- 24631326 TI - Traumatic pseudoaneurysms of the superficial temporal artery: case series, anatomy, and multidisciplinary treatment considerations. AB - Pseudoaneurysms of the superficial temporal artery (STA) are rare vascular lesions of the external carotid artery system and are most often incurred after blunt head trauma. Diagnosis can be made on clinical grounds, and is confirmed by ultrasonography (US) or CT angiography. Surgical ligation and excision of the aneurysm remains a definitive treatment modality. Patients with STA pseudoaneurysms are often referred to a neurovascular specialist given the neurovascular origin and gross anatomic location of these lesions. Three patients presented to our neurovascular service several weeks following blunt head injury to the anterolateral skull surface with progressive, palpable, pulsatile masses. Each patient underwent CT angiography, which demonstrated a pseudoaneurysm of the frontal branch of the STA, followed by operative ligation and en bloc excision. The present series highlights the anatomical considerations relevant to STA injury and pseudoaneurysm formation following blunt head trauma and reviews the necessary diagnostic and treatment considerations. PMID- 24631327 TI - The elusive importance of being a mitochondrial Ca(2+) uniporter. AB - The molecular components of the mitochondrial Ca(2+) uptake machinery have been only recently identified. In the last months, in addition to the pore forming subunit and of one regulatory protein (named MCU and MICU1, respectively) other four components of this complex have been described. In addition, a MCU KO mouse model has been generated and a genetic human disease due to missense mutation of MICU1 has been discovered. In this contribution, we will first summarize the recent findings, discussing the roles of the different subunits of the mitochondrial Ca(2+) uptake complex, pointing to the current contradictions in the published data, as well as possible explanations. Finally we will speculate on the recent, totally unexpected, results obtained in the MCU knock-out (KO) mice. PMID- 24631329 TI - [Hair casts and nits]. PMID- 24631328 TI - Observational study of the acceptability of Sayana(r) Press among intramuscular DMPA users in Uganda and Senegal. AB - BACKGROUND: Sayana(r) Press (SP), a subcutaneous formulation of depot medroxyprogesterone acetate (DMPA) in UnijectTM, has potential to be a valuable innovation in family planning (FP) because it may overcome logistic and safety challenges in delivering intramuscular DMPA (DMPA IM). However, SP's acceptability is unknown. We measured acceptability of SP among DMPA IM users. STUDY DESIGN: This open-label observational study was conducted in clinics in three districts in Senegal and community-based distribution services in two districts in Uganda. Experienced DMPA IM users were offered SP by community health workers (CHWs) or clinic-based providers. SP decliners were asked to discuss their reasons. Those who received SP were interviewed pre- and postinjection and 3 months later, when they were asked if they would select SP over DMPA IM if it were available. RESULTS: One hundred twenty women in Uganda and 242 in Senegal received SP (117 and 240 were followed up, respectively). Nine Ugandan and seven Senegalese SP decliners were interviewed. Three months after receiving SP, 84% [95% confidence interval (CI)=75%-93%] of Ugandan participants and 80% (95% CI=74%-87%) of Senegalese participants said they would select SP over DMPA IM. Main reasons for selecting SP were fewer side effects, liking the method, fast administration, less pain and method effectiveness. Thirty-four adverse events were reported but were not serious. No pregnancies were reported. CONCLUSION: Current DMPA IM users in Senegal and Uganda accepted SP, and most preferred SP over DMPA IM. SP can be safely introduced into FP programs and administered by trained CHWs, with expectation of client uptake. IMPLICATIONS: We found SP acceptable and safe in diverse settings among current intramuscular DMPA users, including those who received SP from CHWs. This provides evidence that SP would be used and could therefore reduce unmet family planning needs if introduced into family planning programs. PMID- 24631330 TI - [Acute compartmental syndrome]. PMID- 24631331 TI - Characterization of phenoloxidase from the sea cucumber Apostichopus japonicus. AB - Phenoloxidase (PO) is a crucial immune-related enzyme in invertebrates. In this study, three POs of the sea cucumber Apostichopus japonicus were detected in coelomic fluid using linear-gradient native-PAGE combined with catechol staining and then partially purified by gel excising. The results showed that the three POs had a color of mahogany (AjPO1), yellow (AjPO2) and purple (AjPO3) respectively with molecular weights smaller than 21kDa in native-PAGE after staining with catechol. Enzymatic activities analysis revealed that AjPO1, AjPO2 and AjPO3 had optimal temperature of 45, 95 and 85 degrees C and pH of 5.0, 8.0 and 8.0, respectively. Kinetic analysis showed that the Km values of AjPO1 for catechol, l-DOPA, dopamine and hydroquinone were 3.23, 0.86, 3.98 and 1.20mmol/l, respectively, those of AjPO2 were 0.31, 0.38, 2.05 and 1.30mmol/l, respectively, and those of AjPO3 were 5.95, 1.28, 5.81 and 0.62mmol/l, respectively. These results suggest that the three POs are laccase-type phenoloxidase. The activities of all three A. japonicus POs were significantly promoted by Ca(2+), Mg(2+) and Mn(2+), and strongly inhibited by ethylenediamine tetraacetic acid disodium (EDTA), sodium diethyldithiocarbamate (DETC) and some common antioxidants. The inhibitions by EDTA and DETC suggest that the three A. japonicus POs are copper containing metalloenzymes. Immune-responsive analysis showed that the total PO activities in coelomocytes (TPAC) increased greatly after lipopolysaccharide (LPS) challenge and declined significantly after polyinosinic-polycytidylic acid (PolyI:C) challenge, implying that A. japonicus PO immune system, which is composed of several isoenzymes with different characteristics, is closely involved in the defense against the infection of Gram-negative bacteria and double-stranded RNA viruses. PMID- 24631332 TI - Identification of RNF114 as a novel positive regulatory protein for T cell activation. AB - RNF114 [RING (really interesting new gene) finger protein 114] has been shown to be a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses, though the underlying mechanism was not fully identified. In the present study, to investigate whether RNF114 is involved in T cell activation, a series of fluorescence activated cell sortings (FACS) were performed. The analysis confirmed that RNF114 over-expression had a promotion effect on T cell activation with an average 43.97% increment and the upregulatory roles showed a dose-dependent effect with 18.44% increment. Interestingly, the two C2H2 domains were shown to play important but opposite roles in T cell activation. The deficiency of upstream C2H2 domain increased the efficiency of T cell activation by 12.81%, while the downstream C2H2 domain alone promoted it with an average level 25.12% higher than intact RNF114 protein. Combined with tandem affinity purification (TAP) and mass spectrometry, our investigations found 23 RNF114-interacting proteins that have distinct physiological roles in transcription, translation, DNA repair and signaling pathways. These findings, including recognition of RNF114 as a positive regulatory protein and identification of its interacting proteins, widen the understanding for investigating functions of RNF114 involved in T cell activation. PMID- 24631333 TI - Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP. AB - Progressive accumulation of age related mitochondrial DNA mutations reduce ATP production and increase reactive oxygen species output, leading to oxidative stress, inflammation and degradation. The pace of this is linked to metabolic demand. The retina has the greatest metabolic demand and mitochondrial density in the body and displays progressive age related inflammation and marked cell loss. Near infra-red (670 nm) is thought to be absorbed by cytochrome c oxidase (COX), a key element in mitochondrial respiration and it has been demonstrated that it improves mitochondrial membrane potentials in aged eyes. It also significantly reduces the impact of experimental pathology and ameliorates age related retinal inflammation. We show ATP decline with ageing in mouse retina and brain. Also, in these tissues that ATP is significantly increased by 670 nm exposure in old mice. In the retina this was associated with increased COX and reduced acrolein expression. Acrolein, being a free radical marker of retinal oxidative stress, is up regulated in Alzheimer's and retinal degeneration. This is the first demonstration of ATP manipulation in vivo and may provide a simple non-invasive route to combating age related tissue decline. PMID- 24631334 TI - Capacity of aflibercept to counteract VEGF-stimulated abnormal behavior of retinal microvascular endothelial cells. AB - Members of the vascular endothelial growth factor (VEGF) family differently regulate processes in retinal endothelial cells (REC) which are crucially involved in the pathogenesis of diabetic retinopathy: Both, VEGF-A and placenta growth factor (PlGF), stimulate proliferation of primary and immortalized bovine REC ((i)BREC) but only VEGF-A165 stimulates their migration. Diabetic macular edema is most likely a consequence of an elevated permeability of REC which can be induced by VEGF-A, but not by PlGF. Binding of VEGF-A by the antibody fragment ranibizumab is sufficient to completely restore or prevent VEGF-A-induced disturbance of the iBREC barrier or migration of these cells without affecting the basal processes. This was observed even in the presence of other growth factors when surplus proliferation was only partly blocked. The recombinant protein aflibercept (VEGF-trap) not only binds very strongly to VEGF-A, but - in contrast to ranibizumab - also recognizes PlGF. In this study, we investigated whether this additional targeting of PlGF also results in better inhibition of growth factor-induced proliferation and migration, and disturbance of the iBREC barrier. In addition, uptake of aflibercept by iBREC and potential functional consequences were examined. In accordance with its binding specificity, aflibercept strongly and specifically inhibited iBREC proliferation stimulated with VEGF-A, PlGF or a combination of these factors. By treatment with aflibercept at therapeutically achievable concentrations, VEGF-A-stimulated iBREC migration was reduced not only to normal values but driven below the basal level. However, the VEGF-A binding humanized antibody bevacizumab as well as the unrelated control antibody rituximab also inhibited basal or VEGF-A stimulated migration at clinically relevant concentrations, suggesting an effect of high amounts of IgG domain-containing proteins which does not depend on their binding specificity. However, aflibercept specifically blocked VEGF-A stimulated migration at lower concentration without influencing basal processes. Effects on permeability were determined by measuring transendothelial resistance (TER) of iBREC (+/-VEGF-A165) and their expression of the tight junction protein claudin 1. The VEGF-A-disturbed barrier was completely restored by treatment with <=25 MUg/ml aflibercept of which even much higher concentrations did not interfere with normal barrier function. Uptake of aflibercept by iBREC - analyzed by Western blot - was observed after 1 h of treatment and the amount further increased during prolonged incubation. Most of the internalized aflibercept was present in subcellular fractions of proteins assigned to the membranes and organelles, but it was also detected in the fraction consisting of cytoskeletal proteins. Co-immunofluorescence staining showed aflibercept absorbed by iBREC to be localized in or close to the Golgi apparatus. Aflibercept at high concentrations interferes with an important normal iBREC function, but prevents and restores VEGF-A-induced disturbances at considerably lower concentrations. Therefore, reduction of the doses administered in DR and DME therapy might be considered. PMID- 24631335 TI - Assessment of inner retina dysfunction and progressive ganglion cell loss in a mouse model of glaucoma. AB - The DBA/2J mouse is a model of ocular hypertension and retinal ganglion cell (RGC) degeneration, the main features of which are iris pigment dispersion (IPD) and iris stromal atrophy (ISA). These animals also experience glaucomatous changes, including an increase in intraocular pressure (IOP) beginning at about 9 12 months of age and sectorial RGC death in the retina. The aim of this study was to determine the onset of functional changes exhibited by DBA/2J mice in the inner retina. This was performed by means of electroretinographic recordings (scotopic threshold response, STR) and their correlation with morphological changes (loss of RGCs). To this end, we recorded the scotopic threshold response in control C57BL/6J and in DBA/2J mice at different ages. The RGCs, in both DBA/2J and C57BL/6J animals, were identified at 15 months of age by retrograde tracing with an analogue of fluorogold, hydroxystilbamidine methanesulfonate (OHSt), applied on the superior colliculi. Whole mount retinas were processed to quantify the population of RGCs identified by fluorogold tracing and Brn3a immunodetection, and were counted using image analysis software; an isodensity contour plot was generated for each retina. DBA/2J mice showed a significant reduction in the positive STR (pSTR) amplitudes at 12 months of age, as compared to control C57BL/6J mice of the same age. The pSTR mean amplitude decreased to approximately 27.82% of the values recorded in control mice (p = 0.0058). STR responses decreased in both strains as a result of the natural process of aging, but the decrease was more pronounced in DBA/2J mice. Furthermore, quantification of the total number of RGCs identified by OHSt and Brn3a expression showed a reduced population of RGCs in DBA/2J mice as compared to control mice. Regression analysis revealed significant correlations between the decrease in pSTR and a non homogeneous reduction in the number of RGCs throughout the retina. Our results indicate the existence of a correlation between retinal function impairment and RGC loss. This functional and morphological analysis allows a reliable assessment of the progression of the disease. PMID- 24631336 TI - Synaptic pattern of nicotinic acetylcholine receptor alpha7 and beta2 subunits on the direction-selective retinal ganglion cells in the postnatal mouse retina. AB - Direction-selective retinal ganglion cells (DS RGCs) respond strongly to a stimulus that moves in their preferred direction, but respond weakly or do not respond to a stimulus that moves in the opposite or null direction. DS RGCs are sensitive to acetylcholine, and starburst amacrine cells (SACs) make cholinergic synapses on DS RGCs. We studied the distributions of nicotinic acetylcholine receptor (nAChR) alpha7 and beta2 subunits on the dendritic arbors of DS RGCs to search for anisotropies that contribute to the directional preferences of DS RGCs. The DS RGCs from the retinas of postnatal mice (postnatal day P5, P10, and P15) were injected with Lucifer yellow, and injected cells were identified by their dendritic morphology. The dendrites of the DS RGCs were labeled with antibodies for either the nAChR alpha7 or beta2 subunit as well as postsynaptic density protein-95 (PSD-95), visualized by confocal microscopy, and reconstructed from high-resolution confocal images. The distribution of nAChR subunits on the dendritic arbors in both the ON and OFF layers of the RGCs revealed an asymmetrical pattern on early postnatal day P5. However, the distributions of nAChR subunits on the dendritic arbors were not asymmetric on P10 and P15. Our results therefore provide anatomical and developmental evidence suggesting that the nAChR alpha7 and beta2 subunits may involve in the early direction selectivity formation of DS RGCs in the mouse retina. PMID- 24631337 TI - Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C delta in a mouse model of diabetic retinopathy. AB - Recent studies revealed that Tonicity-responsive enhancer binding protein (TonEBP) directly regulates the transcription of aldose reductase (AR), which catalyzes the first step of the polyol pathway of glucose metabolism. Activation of protein kinase C delta (PKCdelta) is dependent on AR and it has been linked to diabetic complications. However, whether TonEBP affects expressions of AR and PKCdelta in diabetic retinopathy was not clearly shown. In this study, we used TonEBP heterozygote mice to study the role of TonEBP in streptozotocin (STZ) induced diabetic retinopathy. We performed immunofluorescence staining and found that retinal expressions of AR and PKCdelta were significantly reduced in the heterozygotes compared to wild type littermates, particularly in ganglion cell layer. To examine further the effect of TonEBP reduction in retinal tissues, we performed intravitreal injection of TonEBP siRNA and confirmed the decrease in AR and PKCdelta levels. In addition, we found that a proapoptotic factor, Bax level was reduced and a survival factor, Bcl2 level was increased after injection of TonEBP siRNA, indicating that TonEBP mediates apoptotic cell death. In parallel, TonEBP siRNA was applied to the in vitro human retinal pigment epithelial (ARPE 19) cells cultured in high glucose media. We have consistently found the decrease in AR and PKCdelta levels and changes in apoptotic factors for survival. Together, these results clearly demonstrated that hyperglycemia-induced TonEBP plays a crucial role in increasing AR and PKCdelta levels and leading to apoptotic death. Our findings suggest that TonEBP reduction is an effective therapeutic strategy for diabetic retinopathy. PMID- 24631338 TI - Anti-inflammatory effect of tricin 4'-O-(threo-beta-guaiacylglyceryl) ether, a novel flavonolignan compound isolated from Njavara on in RAW264.7 cells and in ear mice edema. AB - Although recent study has shown tricin 4'-O-(threo-beta-guaiacylglyceryl) ether (TTGE), an isolated compound from Njavara rice, to have the most potent anti inflammatory effects, the action mechanism has not been fully understood. Here, we examined the effect of TTGE on the inflammation and elucidated the potential mechanism. We demonstrated that TTGE significantly inhibited LPS-induced NO and ROS generation in RAW264.7 cells, which was correlated with the down-regulating effect of TTGE on the iNOS and COX-2 expression via NF-kappaB and STAT3. TPA induced ear edema was also efficiently inhibited by the TTGE treatment. TTGE blocked the induction of iNOS and COX-2 through the regulation of NF-kappaB and STAT3, which could explain the reduced TPA-induced edema symptoms. Moreover, the introduction of ERK inhibitor abrogated the anti-inflammatory effect of TTGE via the recovery of NF-kappaB and STAT3 signalings. Taken together, these results suggest that TTGE has anti-inflammatory properties through down-regulation of NF kappaB and STAT3 pathways. PMID- 24631339 TI - Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERalpha pathway. AB - Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor alpha (ERalpha), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERalpha-positive MCF-7 cells but not in ERalpha-negative MDA-MB-231 cells. Additionally, leptin increased 4 hydroxyoestradiol in MCF-7 cells. Also, ERalpha knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERalpha-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERalpha at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERalpha activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERalpha phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERalpha pathway as a result of the activation of ERK and Akt in MCF-7 cells. PMID- 24631340 TI - Herb-drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7. AB - Herb-drug interaction strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug metabolizing enzymes (DMEs) has been regarded as one of the most important reasons. The present study aims to investigate the inhibition potential of andrographolide derivatives towards one of the most important phase II DMEs UDP glucuronosyltransferases (UGTs). Recombinant UGT isoforms (except UGT1A4) catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction and UGT1A4 catalyzed trifluoperazine (TFP) glucuronidation were employed to firstly screen the andrographolide derivatives' inhibition potential. High specific inhibition of andrographolide derivatives towards UGT2B7 was observed. The inhibition type and parameters (Ki) were determined for the compounds exhibiting strong inhibition capability towards UGT2B7, and human liver microsome (HLMs)-catalyzed zidovudine (AZT) glucuronidation probe reaction was used to furtherly confirm the inhibition behavior. In combination of inhibition parameters (Ki) and in vivo concentration of andrographolide and dehydroandrographolide, the potential in vivo inhibition magnitude was predicted. Additionally, both the in vitro inhibition data and computational modeling results provide important information for the modification of andrographolide derivatives as selective inhibitors of UGT2B7. Taken together, data obtained from the present study indicated the potential herb-drug interaction between Andrographis paniculata and the drugs mainly undergoing UGT2B7-catalyzed metabolic elimination, and the andrographolide derivatives as potential candidates for the selective inhibitors of UGT2B7. PMID- 24631341 TI - The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis. AB - Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. PMID- 24631342 TI - Temporal genetic structure of major dengue vector Aedes aegypti from Manaus, Amazonas, Brazil. AB - In recent years, high levels of Aedes aegypti infestation and several dengue outbreaks with fatal outcome cases have been reported in Manaus, State of Amazonas, Brazil. This situation made it important to understand the genetic structure and gene flow patterns among the populations of this vector in Manaus, vital pieces of information for their management and development of new control strategies. In this study, we used nine microsatellite loci to examine the effect of seasonality on the genetic structure and gene flow patterns in Ae. aegypti populations from four urban neighborhoods of Manaus, collected during the two main rainy and dry seasons. All loci were polymorphic in the eight samples from the two seasons, with a total of 41 alleles. The genetic structure analyses of the samples from the rainy season revealed genetic homogeneity and extensive gene flow, a result consistent with the abundance of breeding sites for this vector. However, the samples from the dry season were significantly structured, due to a reduction of Ne in two (Praca 14 de Janeiro and Cidade Nova) of the four samples analyzed, and this was the primary factor influencing structure during the dry season. Genetic bottleneck analyses suggested that the Ae. aegypti populations from Manaus are being maintained continuously throughout the year, with seasonal reduction rather than severe bottleneck or extinction, corroborating previous reports. These findings are of extremely great importance for designing new dengue control strategies in Manaus. PMID- 24631343 TI - Low tension breast hydatid cyst--a case report. AB - INTRODUCTION: Features of low tension in breast hydatid cyst and symptoms secondary to cyst dying and disintegration are unique and not yet reported in the literature. MATERIAL AND METHOD: An young woman of 30 years complained about pain and vague swelling in the right breast during follow-up with albendazole therapy following second laparotomy for post-surgical residual cavity of hydatid cyst in the left lobe of the liver. Breast ultrasound was diagnostic. RESULTS: Segmental breast excision revealed a large dead hydatid cyst. Postoperative course was uneventful. CONCLUSIONS: Breast hydatid cyst may become symptomatic and hypotensive after start of albendazole therapy. PMID- 24631344 TI - Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase. AB - Complement receptor 3 (CR3) activation in microglia is involved in neuroinflammation-related brain disorders and pruning of neuronal synapses. Hypoxia, often observed together with neuroinflammation in brain trauma, stroke, and neurodegenerative diseases, is thought to exacerbate inflammatory responses and synergistically enhance brain damage. Here we show that when hypoxia and an inflammatory stimulus (lipopolysaccharide [LPS]) are combined, they act synergistically to trigger long-term synaptic depression (LTD) that requires microglial CR3, activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), and GluA2-mediated A-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR) internalization. Microglial CR3 triggered LTD is independent of N-methyl-D-aspartate receptors (NMDARs), metabotropic glutamate receptors (mGluRs), or patterned synaptic activity. This type of LTD may contribute to memory impairments and synaptic disruptions in neuroinflammation-related brain disorders. PMID- 24631346 TI - Detection of Coconut cadang-cadang viroid (CCCVd) in oil palm by reverse transcription loop-mediated isothermal amplification (RT-LAMP). AB - A reverse transcription loop-mediated isothermal amplification (RT-LAMP) detected Coconut cadang-cadang viroid (CCCVd) within 60 min at 60 degrees C in total nucleic acid extracted from oil palm leaves infected with CCCVd. Positive reactions showed colour change from orange to green in the reaction mix after the addition of fluorescent reagent, and a laddering pattern band on 2% agarose gel electrophoresis. Conventional RT-PCR with LAMP primers produced amplicons with a sequence identical to the 297-nt CCCVd oil palm variant with the primers being specific for CCCVd and not for other viroids such as PSTVd and CEVd. RT-LAMP was found to be rapid and specific for detecting oil palm CCCVd. PMID- 24631345 TI - WIDE AWAKE mediates the circadian timing of sleep onset. AB - How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep. PMID- 24631347 TI - Production of equine herpesvirus 1 recombinant glycoprotein D and development of an agar gel immunodiffusion test for serological diagnosis. AB - Equine herpesvirus 1 and 4 (EHV-1 and 4) infect most of the world's horses, causing serious clinical illness. Viral glycoproteins have been identified as the immunodominant antigens that generate the antiviral serological responses to EHV 1 and EHV-4 in infected horses. Here, glycoprotein D of EHV-1 was expressed by a recombinant baculovirus, purified and evaluated by a simple agar gel immunodiffusion test (AGID). Compared with virus neutralization, serological analysis by AGID showed good specificity (100%) and sensitivity (99.5%). The estimated Kappa values for repeatability and reproducibility were satisfactory. Thus, this rapid, inexpensive, simple and highly specific AGID test seems to be a valuable alternative tool for serological detection of antibodies against both EHV-1 and EHV-4. PMID- 24631348 TI - Re: the prostatic urethral lift for the treatment of lower urinary tract symptoms associated with prostate enlargement due to benign prostatic hyperplasia: the L.I.F.T. Study. C. G. Roehrborn, S. N. Gange, N. D. Shore, J. L. Giddens, D. M. Bolton, B. E. Cowan, B. T. Brown, K. T. McVary, A. E. Te, S. S. Gholami, P. Rashid, W. G. Moseley, P. T. Chin, W. T. Dowling, S. J. Freedman, P. F. Incze, K. S. Coffield, F. D. Borges and D. B. Rukstalis J Urol 2013;190:2161-2167. PMID- 24631349 TI - Re: effect of prior radiotherapy and ablative therapy on surgical outcomes for the treatment of rectourethral fistulas. B. J. Linder, E. C. Umbreit, D. Larson, E. J. Dozois, P. Thapa and D. S. Elliott J Urol 2013;190:1287-1291. PMID- 24631351 TI - Editorial comment. PMID- 24631352 TI - Editorial comment. PMID- 24631353 TI - Predicting all-cause and cause-specific mortality by static and dynamic measurements of allostatic load: a 10-year population-based cohort study in Taiwan. AB - OBJECTIVE: To evaluate the role of allostatic load (AL), either static or dynamic measurements, in predicting all-cause and cause-specific mortality of older people in Taiwan. DESIGN: A prospective cohort study. SETTING: Population-based community study. PARTICIPANTS: One thousand twenty-three community-dwelling older people. MEASUREMENTS: Allostatic load (calculated by systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glycosylated hemoglobin, fasting glucose, waist-to-hip ratio, body mass index, dehydroepiandrosterone sulfate, insulin-like growth factor-1, 12-hour urine cortisol, 12-hour urine epinephrine, 12-hour urine norepinephrine, 12-hour urine dopamine, white blood cell count, neutrophils, interleukin-6, albumin, creatinine) and all-cause and cause-specific mortality from national death registry. INTERVENTION: None. RESULTS: Adjusted for age and sex, each 1-point increase in AL score was associated with 20% incremental risk of mortality [hazard ratio 1.20, 95% confidence interval (CI) 1.09-1.31]. This association can be extended to cause-specific mortality in both sexes in general. In addition, the higher AL score quintile was significantly associated with higher risk of 10-year all-cause mortality (P < .0001). This association was consistent across different cause-specific mortality (ie, malignant neoplasm (P = .008), cardiometabolic diseases (P < .0001), infectious diseases (P < .0001), respiratory diseases (P < .0001), and others (P = .0002), respectively. Compared with AL score decliners, adjusted for age, sex, and baseline AL score in 2000, participants with fast increase had significantly higher mortality (HR 2.68, 95% CI 1.23-5.84, P = .01). The effect was stronger in men (HR 2.83, 95% CI 1.1-7.29, P = .03 in slow increase; HR 4.06, 95% CI 1.56-10.6, P = .001 in fast increase group), but it was insignificant in female participants. CONCLUSIONS: Higher AL score or rapid increase of AL score significantly increased subsequent mortality risk in older adults, either measured statically or dynamically. AL is predictive of 10-year mortality regardless of cause of death, and rapid increase in AL score is associated with higher subsequent mortality. PMID- 24631355 TI - The role of endosomes in innate and adaptive immunity. AB - The regulation of the immune system is critical for the generation of effective immune responses to a range of pathogens, as well as for protection against unwanted responses. The regulation of many immune response pathways are directly dependent on the organisation and activities of intracellular endosomal compartments associated with cargo sorting, membrane trafficking and signalling. Over the last 5-10 years, the appreciation of the important contribution of the endosomal system has expanded dramatically to include antigen presentation of MHC class I, MHC class II and CD1 molecules, as well as the regulation of antigen receptor signalling and pattern recognition receptor signalling of the innate immune system. This review summarises some of the very diverse and key roles played by endosomes in generating effective innate and adaptive immune responses. PMID- 24631354 TI - It takes two to tango, a dance between the cells of origin and cancer stem cells in the Drosophila larval brain. AB - During malignant transformation the cells of origin give rise to cancer stem cells which possess the capacity to undergo limitless rounds of self-renewing division, regenerating themselves while producing more tumor cells. Within normal tissues, a limitless self-renewal capacity is unique to the stem cells, which divide asymmetrically to produce more restricted progenitors. Accumulating evidence suggests that misregulation of the self-renewal machinery in stem cell progeny can lead to tumorigenesis, but how it influences the properties of the resulting tumors remains unclear. Studies of the type II neural stem cell (neuroblast) lineages in the Drosophila larval brain have identified a regulatory cascade that promotes commitment to a progenitor cell identity by restricting their response to the self-renewal machinery. Brain tumor (Brat) and Numb initiate this cascade by asymmetrically extinguishing the activity of the self renewal factors. Subsequently, Earmuff (Erm) and the SWI/SNF complex stably restrict the competence of the progenitor cell to respond to reactivation of self renewal mechanisms. Together, this cascade programs the progenitor cell to undergo limited rounds of division, generating exclusive differentiated progeny. Here we review how defects in this cascade lead to tumor initiation and how inhibiting the self-renewal mechanisms may be an effective strategy to block CSC expansion. PMID- 24631356 TI - From wavy hair to naked proteins: the role of transforming growth factor alpha in health and disease. AB - Since its discovery in 1978 and cloning in 1984, transforming growth factor-alpha (TGF-alpha, TGFA) has been one of the most extensively studied EGF receptor (EGFR) ligands. In this review, we provide a historical perspective on TGFA related studies, highlighting what we consider important advances related to its function in normal and disease states. PMID- 24631358 TI - Antiproliferative activities of halogenated thieno[3,2-d]pyrimidines. AB - The in vitro evaluation of thieno[3,2-d]pyrimidines identified halogenated compounds 1 and 2 with antiproliferative activity against three different cancer cell lines. A structure activity relationship study indicated the necessity of the chlorine at the C4-position for biological activity. The two most active compounds 1 and 2 were found to induce apoptosis in the leukemia L1210 cell line. Additionally, the compounds were screened against a variety of other microbial targets and as a result, selective activity against several fungi was also observed. The synthesis and preliminary biological results are reported herein. PMID- 24631357 TI - Epiregulin: roles in normal physiology and cancer. AB - Epiregulin is a 46-amino acid protein that belongs to the epidermal growth factor (EGF) family of peptide hormones. Epiregulin binds to the EGF receptor (EGFR/ErbB1) and ErbB4 (HER4) and can stimulate signaling of ErbB2 (HER2/Neu) and ErbB3 (HER3) through ligand-induced heterodimerization with a cognate receptor. Epiregulin possesses a range of functions in both normal physiologic states as well as in pathologic conditions. Epiregulin contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation. Deregulated epiregulin activity appears to contribute to the progression of a number of different malignancies, including cancers of the bladder, stomach, colon, breast, lung, head and neck, and liver. Therefore, epiregulin and the elements of the EGF/ErbB signaling network that lie downstream of epiregulin appear to be good targets for therapeutic intervention. PMID- 24631359 TI - N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs. AB - Gemcitabine (dFdC) is a cytidine analog remarkably active against a wide range of solid tumors. Inside a cell, gemcitabine is phosphorylated by deoxycytidine kinase to yield gemcitabine monophosphate, further converted to gemcitabine di- and triphosphate. The most frequent form of acquired resistance to gemcitabine in vitro is the deoxycytidine kinase deficiency. Thus, proper prodrugs carrying the 5'-pdFdC moiety may help to overcome this problem. A series of new derivatives of gemcitabine possessing N-acyl(thio)phosphoramidate moieties were prepared and their cytotoxic properties were determined. N-Acyl-phosphoramidate derivatives of gemcitabine have similar cytotoxicity as gemcitabine itself, and have been found accessible to the cellular enzymes. The nicotinic carboxamide derivative of gemcitabine 5'-O-phosphorothioate occurred to be the best inhibitor of bacterial DNA polymerase I and human DNA polymerase alpha. PMID- 24631360 TI - Camphor-based symmetric diimines as inhibitors of influenza virus reproduction. AB - Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The purpose of the study was synthesis and investigation of antiviral activity of camphor-based symmetric diimines and diamines. A set of C2-symmetric nitrogen-containing camphor derivatives have been synthesized. The antiviral activity of these compounds was studied against rimantadine- and amantadine resistant influenza virus A/California/7/09 (H1N1)pdm09 in MDCK cells. The highest efficacy in virus inhibiting was shown for compounds 2a-e with cage moieties bound by aliphatic linkers. The therapeutic index (selectivity index) for 2b exceeded that for reference compounds amantadine, deitiforin and rimantadine almost 10-fold. As shown by structure-activity analysis, the length of the linker has a dramatic effect on the toxicity of compounds. Compound 2e with -C12H24- linker exhibited the lowest toxicity (CTD50=2216MUM). Derivatives of camphor, therefore, can be considered as prospective antiinfluenza compounds active against influenza viruses resistant to adamantane-based drugs. PMID- 24631361 TI - Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives. AB - In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07MUM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07MUM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies. PMID- 24631362 TI - Expanded potential of seleno-carbohydrates as a molecular tool for X-ray structural determination of a carbohydrate-protein complex with single/multi wavelength anomalous dispersion phasing. AB - Seleno-lactoses have been successfully synthesized as candidates for mimicking carbohydrate ligands for human galectin-9 N-terminal carbohydrate recognition domain (NCRD). Selenium was introduced into the mono- or di-saccharides using p methylselenobenzoic anhydride (Tol2Se) as a novel selenating reagent. The TolSe substituted monosaccharides were converted into selenoglycosyl donors or acceptors, which were reacted with coupling partners to afford seleno-lactoses. The seleno-lactoses were converted to the target compounds. The structure of human galectin-9 NCRD co-crystallized with 6-MeSe-lactose was determined with single/multi-wavelength anomalous dispersion (SAD/MAD) phasing and was similar to that of the co-crystal with natural lactose. PMID- 24631363 TI - Synthesis and evaluation of effective photoaffinity probe molecule of furospinosulin-1, a hypoxia-selective growth inhibitor. AB - The synthesis and evaluation of a photoaffinity probe molecule for furospinosulin 1, a hypoxia-selective growth inhibitor that we identified from marine sponge, was studied. An analogue carrying an alkyne tail showed potent hypoxia-selective inhibitory activity exceeding that of the parent molecule, and exhibited in vivo anti-tumor activity following oral administration. The alkyne moiety in the analogue was also found to be a good anchoring group for the preparation of probe molecules; a photoaffinity probe molecule having an optimized spacer length was selected through the systematic synthesis of several probes and the evaluation of their hypoxia-selective growth inhibitory activity and electrophoretic mobility shift properties. PMID- 24631364 TI - Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations. AB - Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been performed to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6-inhibitor binding affinity are two crucial internuclear distances, that is, the distance between the heme iron atom of CYP2A6 and the coordinating atom of the inhibitor, and the hydrogen-bonding distance between the N297 side chain of CYP2A6 and the pyridine nitrogen of the inhibitor. The combined MD simulations and QM/MM-PBSA calculations have led to dynamic CYP2A6-inhibitor binding structures that are consistent with the observed dynamic behaviors and structural features of CYP2A6-inhibitor binding, and led to the binding free energies that are in good agreement with the experimentally derived binding free energies. The agreement between the calculated binding free energies and the experimentally-derived binding free energies suggests that the combined MD and QM/MM-PBSA approach may be used as a valuable tool to accurately predict the CYP2A6-inhibitor binding affinities in future computational design of new, potent and selective CYP2A6 inhibitors. PMID- 24631365 TI - Synthesis and biological evaluation of new pyrazolone-pyridazine conjugates as anti-inflammatory and analgesic agents. AB - A new series of pyrazolone-pyridazine conjugates 3 and 4a-l were synthesized and characterized by spectroscopic means and elemental analyses. All compounds were tested in vivo for their anti-inflammatory and analgesic properties against diclofenac, as reference compound. The synthesized compounds were also evaluated for their ability to inhibit the production of certain inflammatory cytokines such as TNF-alpha and IL-6 in serum samples. The ulcerogenic potential of the synthesized compounds was also determined. IC50 values for inhibition of COX-1 and COX-2 enzymes were investigated in vitro for the most active candidates. Molecular docking was performed on the active site of COX-2 to predict their mode of binding to the amino acids. Among the synthesized derivatives, compounds 4c and 4e showed good analgesic and anti-inflammatory activities with lower ulcer index than the reference drug. PMID- 24631366 TI - Cloning, characterization, and expression analysis of acyl-acyl carrier protein (ACP)-thioesterase B from seeds of Chinese Spicehush (Lindera communis). AB - Acyl-acyl carrier protein (ACP) thioesterases (TE EC 3.1.2.14) are fatty acid biosynthesis key enzymes that determine fatty acid carbon chain length in most plant tissues. A full-length cDNA corresponding to one of the fatty acyl-ACP thioesterase (Fat) genes, designated LcFatB, was isolated from developing Lindera communis seeds using PCR and RACE with degenerate primers based on conserved sequences of multiple TE gene sequences obtained from GenBank. The 1788 bp cDNA had an open reading frame (ORF) of 1260 bp encoding a protein of 419 amino acids. The deduced amino acid sequence showed 61-73% identity to proteins in the FatB class of plant thioesterases. Real-time quantitative PCR analysis revealed that LcFatB was expressed in all tissues of L. communis, with the highest expression in the developing seeds 75days after flowering. Recombinant pET-MLcFatB was constructed using the pET-30 a vector and transformed into Escherichia coli BL21(DE3)?FadE, a strain that deleted the acyl-CoA dehydrogenase (FadE). SDS-PAGE analysis of proteins isolated from pET-MLcFatB E. coli cells after induction with IPTG revealed a protein band at ~40.5kDa, corresponding to the predicted size of LcFatB mature protein. The decanoic acid and lauric acid contents of the pET MLcFatB transformant were increased significantly. These findings suggest that an LcFatB gene from a non-traditional oil-seed tree could be used to function as a saturated acyl-ACP thioesterase and could potentially be used to modify the fatty acid composition of seed oil from L. communis or other species through transgenic approaches. PMID- 24631368 TI - Sour cherry (Prunus cerasus) seed extract increases heme oxygenase-1 expression and decreases proinflammatory signaling in peripheral blood human leukocytes from rheumatoid arthritis patients. AB - Sour cherry seed extract (SCE) was evaluated for its capacity to inhibit lipopolysaccharide-treated human peripheral blood T cells expressing tumor necrosis factor-alpha, and the chemokine interleukin-8. Both proteins are diagnostic biomarkers for inflammatory pathologies. Peripheral blood leukocytes from 11 rheumatoid arthritis (RA) patients and 8 healthy control subjects were co cultured for 24h in lipopolysaccharide and the extract, then evaluated by flow cytometry for T cell activation and by enzyme-linked immunoassay for lymphocyte associated heme oxygenase-1 (HO-1) expression. There was a dose-dependent decrease in expression of the immunophenotypes: CD3+TNF-alpha+, and CD3+IL8+ in cultures from RA patients to a greater extent than in cells from healthy participants. These results suggest that the extract may have a modulatory roll in RA and other inflammatory disorders via the induction of HO-1, thus abating oxidative stress and strengthening regulation of pro-inflammatory signaling pathways. PMID- 24631367 TI - A novel mechanism for inhibition of lipopolysaccharide-induced proinflammatory cytokine production by valproic acid. AB - The inhibitory effect of valproic acid (VPA) on lipopolysaccharide (LPS)-induced inflammatory response was studied by using mouse RAW 264.7 macrophage-like cells. VPA pretreatment attenuated LPS-induced phosphorylation of phosphatidylinositol 3 kinase (PI3K) and Akt, but not nuclear factor (NF)-kappaB and mitogen-activated protein kinases. VPA reduced phosphorylation of MDM2, an ubiquitin ligase and then prevented LPS-induced p53 degradation, followed by enhanced p53 expression. Moreover, p53 small interfering RNA (siRNA) abolished the inhibitory action of VPA on LPS-induced NF-kappaB p65 transcriptional activation and further LPS induced tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. VPA prevented LPS-induced degradation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) and up-regulated the PTEN expression. Taken together, VPA was suggested to down-regulate LPS-induced NF-kappaB-dependent transcriptional activity via impaired PI3K/Akt/MDM2 activation and enhanced p53 expression. A detailed mechanism for inhibition of LPS-induced inflammatory response by VPA is discussed. PMID- 24631369 TI - Prevalence and risk factors for antibiotic-resistant community-associated bloodstream infections. AB - BACKGROUND: Antibiotic resistance is increasing in many community settings. The purpose of this study was to determine the proportion of antibiotic resistant community-associated bloodstream infections (CA-BSIs) present on hospital admissions to identify risk factors for acquiring resistant versus susceptible CA BSIs and to describe the incidence of concurrent infections with CA-BSIs. METHODS: We conducted a retrospective cohort study of patients discharged from one community, one pediatric, and two tertiary/quaternary care hospitals within an academically affiliated network in the borough of Manhattan in New York, NY, from 2006 to 2008. The CA-BSIs present at hospital admission were defined as BSIs occurring within the first 48h of hospitalization. Infections and patient characteristics were identified using data available from patients' electronic medical records and discharge records. RESULTS: In total, 1677 CA-BSIs were identified. Staphylococcus aureus had the largest proportion of resistance (41.2%), followed by enterococcal species (24.3%), Pseudomonas aeruginosa (20.2%), Streptococcus pneumoniae (16.6%), Acinetobacter baumannii (10.0%), and Klebsiella pneumoniae (9.9%). Significant predictors of resistance were prior residence in a skilled nursing facility (OR, 2.55; 95% CI, 1.39-4.70), advanced age (1.01; 1.002-1.02), presence of malignancy (0.58; 0.37-0.91), prior hospitalization (1.62; 1.17-2.23), a weighted Charlson score (1.09; 1.02-1.17) for S. aureus, presence of malignancy (1.82; 1.004-3.30), prior hospitalizations (2.03; 1.12-3.38) for enterococcal species, and younger age for S. pneumoniae (p=0.02). Urinary tract infections were the most common concurrent infection (n=45/87, 51.7%). CONCLUSION: Over 27% of the CA-BSIs present on admission were antibiotic resistant. Understanding the prevalence and risk factors for CA-BSIs may help improve empiric antibiotic therapy and outcomes for patients with community-onset infections. PMID- 24631370 TI - SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although several clinical characteristics can be associated with worse prognosis, more robust biological markers still remains uncovered. SMYD2, a member of SMYD protein family, regulates the activity of several proteins through methylation. In this study, we performed quantitative real time PCR to compare the expression of SMYD2 in 83 pediatric ALL patients and non-neoplastic bone marrow samples (BMS). The study revealed that SMYD2 expression is altered in ALL BMS and its high expression was correlated with a bad prognosis. Moreover, we also revealed that SMYD2 expression level significantly decreases in patients that respond to chemotherapy treatment. PMID- 24631371 TI - Optimizing treatments in rare diseases: will our evidence come from registry data? PMID- 24631372 TI - [Mycological profile of onychomycosis in Dakar (Senegal)]. AB - OBJECTIVE: Onychomycosis are a mycose of nail due to fungi. According to published data, they stands for half of all nail abnormalities. This survey was carried out to determine the frequency and the fungi involved in onychomycosis in Dakar. MATERIAL AND METHODS: This study was carried out at the laboratory of parasitology and mycology at Le Dantec Hospital, in Senegal from January 2008 to December 2012 and includes 507 patients. RESULTS: Onychomycosis were mycologically proved in 58.78% (298/507) of patients. Patient's age varies between 02 years to 82 years with a mean of 34.24 years. Women were more infected than men (sex-ratio was 2.38). Onychomycosis due to dermatophyte represented 37.92% (113/298) of patients and were essentially located on toes (60.71%). Distal and lateral subungual onychomycosis was the most frequent clinical form. Trichophyton rubrum and Trichophyton interdigitale were isolated respectively in 53.6% and 26.1% on toes. Yeasts represented 59.06% (176/298) of onychomycosis and were essentially located on fingernails (80.11%). Candida albicans represented 90.86% of isolated yeasts. Molds were isolated in nine cases (3.02%) and predominated in toenails. CONCLUSION: Among 507 patients with onychopathy, this study identified 298 cases of onychomycosis. T. rubrum was the main dermatophytes and was isolated on toenails whereas on fingernails C. albicans was more often observed. PMID- 24631373 TI - Recent advances in the understanding of brown spider venoms: From the biology of spiders to the molecular mechanisms of toxins. AB - The Loxosceles genus spiders (the brown spiders) are encountered in all the continents, and the clinical manifestations following spider bites include skin necrosis with gravitational lesion spreading and occasional systemic manifestations, such as intravascular hemolysis, thrombocytopenia and acute renal failure. Brown spider venoms are complex mixtures of toxins especially enriched in three molecular families: the phospholipases D, astacin-like metalloproteases and Inhibitor Cystine Knot (ICK) peptides. Other toxins with low level of expression also present in the venom include the serine proteases, serine protease inhibitors, hyaluronidases, allergen factors and translationally controlled tumor protein (TCTP). The mechanisms by which the Loxosceles venoms act and exert their noxious effects are not fully understood. Except for the brown spider venom phospholipase D, which causes dermonecrosis, hemolysis, thrombocytopenia and renal failure, the pathological activities of the other venom toxins remain unclear. The objective of the present review is to provide insights into the brown spider venoms and loxoscelism based on recent results. These insights include the biology of brown spiders, the clinical features of loxoscelism and the diagnosis and therapy of brown spider bites. Regarding the brown spider venom, this review includes a description of the novel toxins revealed by molecular biology and proteomics techniques, the data regarding three dimensional toxin structures, and the mechanism of action of these molecules. Finally, the biotechnological applications of the venom components, especially for those toxins reported as recombinant molecules, and the challenges for future study are discussed. PMID- 24631374 TI - Increased autophagy reduces endoplasmic reticulum stress after neonatal hypoxia ischemia: role of protein synthesis and autophagic pathways. AB - The endoplasmic reticulum (ER) stress can result from several pathological conditions that perturb ER homeostasis and is characterized by accumulation of unfolded proteins in the ER lumen. To cope with ER stress, cells activate the unfolded protein response (UPR), a protein quality control mechanism aimed at restoring homeostasis. The present study was undertaken to characterize the UPR after neonatal hypoxia/ischemia (HI) and its crosstalk with autophagy. After HI, there was a significant increase of GRP78 and Hsp70 expression, phosphorylation of eIF2alpha, Xbp-1 mRNA splicing and CHOP expression, revealing severe ER stress and UPR. Increasing autophagy with rapamycin (Rap) significantly reduced the UPR. Rap did not further increase the eIF2alpha phosphorylation and p70S6 kinase (p70S6K) inactivation induced by HI. After autophagy activation, however, there was a clear co-localization between monodansylcadaverine (MDC)-positive autophagosome-like structures and the ribosomal protein S6 (RPS6), indicating the presence of ribosomes in autophagosomes (ribophagy). We found that the autophagy inhibitor 3-methyladenine administered after Rap treatment completely reverted the increased phosphorylation of eIF2alpha and p70S6K inactivation, and blocked the formation of autophagosome-like structures restoring the UPR. These results demonstrate that the UPR is strongly activated after neonatal HI. Over-activation of autophagy significantly reduces this response, highlighting the relevance of the cross-talk between ER and the autophagy machinery in this important pathological condition. Furthermore, the presence of ribosome subunits in autophagosome-like structures suggests that increased ribosome turnover through autophagy (ribophagy) may represent an additional mechanism involved in the neuroprotective effect observed after autophagy over-activation. PMID- 24631376 TI - Improving the reliability of venous Doppler flow measurements: relevance of combined ECG, training and repeated measures. AB - The nature of venous Doppler waves is highly variable. An additional electrocardiogram (ECG) improves the interpretation of venous Doppler wave characteristics and allows measurement of venous pulse transit time. The purpose of this study was to assess the reproducibility of ECG-guided repeated measurements of venous Doppler flow characteristics before and after sonographer training and the inter- and intra-observer variability. In four groups of 25 healthy women, venous Doppler flow measurements were performed at the level of the kidneys and liver according to a standardized protocol. Intra-observer Pearson correlation coefficients of the renal interlobar vein Doppler indices were >= 0.80 with the addition of the ECG, which are higher than the results of a former study. The inter-observer correlation between an experienced ultrasonographer and an inexperienced ultrasonographer improved from >= 0.71 to >= 0.91 after training. The correlation range of all parameters between two independent observers improved when values were based on repeated measures. The addition of an ECG to the Doppler image, training and repeated measurements are helpful in improving venous Doppler wave interpretation. PMID- 24631375 TI - Changes in NG2 cells and oligodendrocytes in a new model of intraspinal hemorrhage. AB - Spinal cord injury (SCI) evokes rapid deleterious and reparative glial reactions. Understanding the triggers for these responses is necessary for designing strategies to maximize repair. This study examined lesion formation and glial responses to vascular disruption and hemorrhage, a prominent feature of acute SCI. The specific role of hemorrhage is difficult to evaluate in trauma-induced lesions, because mechanical injury initiates many downstream responses. To isolate vascular disruption from trauma-induced effects, we created a novel and reproducible model of collagenase-induced intraspinal hemorrhage (ISH) and compared glial reactions between unilateral ISH and a hemi-contusion injury. Similar to contusion injuries, ISH lesions caused loss of myelin and axons and became filled with iron-laden macrophages. We hypothesized that intraspinal hemorrhage would also initiate reparative cellular responses including NG2+ oligodendrocyte progenitor cell (OPC) proliferation and oligodendrocyte genesis. Indeed, ISH induced OPC proliferation within 1d post-injury (dpi), which continued throughout the first week and resulted in a sustained elevation of NG2+ OPCs. ISH also caused oligodendrocyte loss within 4h that was sustained through 3d post-ISH. However, oligodendrogenesis, as determined by bromo-deoxyuridine (BrdU) positive oligodendrocytes, restored oligodendrocyte numbers by 7dpi, revealing that proliferating OPCs differentiated into new oligodendrocytes after ISH. The signaling molecules pERK1/2 and pSTAT3 were robustly increased acutely after ISH, with pSTAT3 being expressed in a portion of OPCs, suggesting that activators of this signaling cascade may initiate OPC responses. Aside from subtle differences in timing of OPC responses, changes in ISH tissue closely mimicked those in hemi-contusion tissue. These results are important for elucidating the contribution of hemorrhage to lesion formation and endogenous cell-mediated repair, and will provide the foundation for future studies geared toward identifying the role of specific blood components on injury and repair mechanisms. This understanding may provide new clinical targets for SCI and other devastating conditions such as intracerebral hemorrhage. PMID- 24631377 TI - In silico study of low-frequency transcranial ultrasound fields in acute ischemic stroke patients. AB - Ultrasound in the sub-megahertz range enhances thrombolysis and may be applied transcranially to ischemic stroke patients. The consistency of transcranial insonification needs to be evaluated. Acoustic and thermal simulations based on computed-tomography (CT) scans of 20 patients were performed. An unfocused 120 kHz transducer allowed homogeneous insonification of the thrombus, and positioning based on external landmarks performed similarly to an optimized placement based on CT data. With a weakly focused 500-kHz transducer, the landmark-based positioning underperformed. The predicted inter-patient variation of in situ acoustic pressure was similar with both the 120 and 500-kHz transducers for the optimized placement (18.0-26.4% relative standard deviation). The simulated maximum acoustic pressure in intervening tissues was 2.6 +/- 0.6 and 2.0 +/- 0.7 times the pressure in the thrombus for the 120-kHz and 500-kHz transducers, respectively. A 1 W/cm(2) insonification of the thrombus caused a 3.8 +/- 2.2 degrees C increase in the bone for the 120-kHz transducer, and a 13.4 +/- 3.3 degrees C increase for the 500-kHz transducer. Contralateral local maxima up to 1.1 times the pressure amplitude in the targeted zone were predicted for the 120-kHz transducer. We established two transducer placement approaches, one based on analysis of a head CT and the other using simple external, visible landmarks. Both approaches allowed consistent insonification of the thrombus. PMID- 24631378 TI - Soft-focused extracorporeal shock waves increase the expression of tendon specific markers and the release of anti-inflammatory cytokines in an adherent culture model of primary human tendon cells. AB - Focused extracorporeal shock waves have been found to upregulate the expression of collagen and to initiate cell proliferation in healthy tenocytes and to positively affect the metabolism of tendons, promoting the healing process. Recently, soft-focused extracorporeal shock waves have also been found to have a significant effect on tissue regeneration. However, very few in vitro reports have dealt with the application of this type of shock wave to cells, and in particular, no previous studies have investigated the response of tendon cells to this impulse. We devised an original model to investigate the in vitro effects of soft-focused shock waves on a heterogeneous population of human resident tendon cells in adherent monolayer culture. Our results indicate that soft-focused extracorporeal shock wave treatment (0.17 mJ/mm(2)) is able to induce positive modulation of cell viability, proliferation and tendon-specific marker expression, as well as release of anti-inflammatory cytokines. This could prefigure a new rationale for routine employment of soft-focused shock waves to treat the failed healing status that distinguishes tendinopathies. PMID- 24631379 TI - Intravascular photoacoustic imaging: a new tool for vulnerable plaque identification. AB - The vulnerable atherosclerotic plaque is believed to be at the root of the majority of acute coronary events. Even though the exact origins of plaque vulnerability remain elusive, the thin-cap fibroatheroma, characterized by a lipid-rich necrotic core covered by a thin fibrous cap, is considered to be the most prominent type of vulnerable plaque. No clinically available imaging technique can characterize atherosclerotic lesions to the extent needed to determine plaque vulnerability prognostically. Intravascular photoacoustic imaging (IVPA) has the potential to take a significant step in that direction by imaging both plaque structure and composition. IVPA is a natural extension of intravascular ultrasound that adds tissue type specificity to the images. IVPA utilizes the optical contrast provided by the differences in the absorption spectra of plaque components to image composition. Its capability to image lipids in human coronary atherosclerosis has been shown extensively ex vivo and has recently been translated to an in vivo animal model. Other disease markers that have been successfully targeted are calcium and inflammatory markers, such as macrophages and matrix metalloproteinase; the latter two through application of exogenous contrast agents. By simultaneously displaying plaque morphology and composition, IVPA can provide a powerful prognostic marker for disease progression, and as such has the potential to transform the current practice in percutaneous coronary intervention. PMID- 24631380 TI - Morphokinetic parameters of ICSI tripronucleated embryos observed using time lapse. AB - Time-lapse analysis of tripronucleated zygotes obtained in ICSI cycles showed that 75.4% cleaved into embryos. These embryos subsequently demonstrated slower developmental kinetics than normally fertilized embryos. PMID- 24631381 TI - Oocyte banking for anticipated gamete exhaustion (AGE) is a preventive intervention, neither social nor nonmedical. AB - The scope of female fertility preservation through cryopreservation of oocytes or ovarian cortex has widened from mainly oncological indications to a variety of fertility-threatening conditions. So far, no specific universally accepted denomination name has been given to cryopreservation of oocytes or ovarian cortex for the prevention of age-related fertility decline. We argue that the commonly used phrases 'social' and 'nonmedical freezing' to denote the indication for cryopreservation are not entirely correct. We suggest 'AGE banking', as this has not only the advantage of being catchy but also depicts the exact indication for the strategy, anticipated gamete exhaustion. PMID- 24631382 TI - Including ethical considerations in models for first-trimester screening for pre eclampsia. AB - Recent efforts to develop reliable and efficient early pregnancy screening programmes for pre-eclampsia have focused on combining clinical, biochemical and biophysical markers. The same model has been used for first-trimester screening for fetal aneuploidies i.e. prenatal diagnosis (PD), which is routinely offered to all pregnant women in many developed countries. Some studies suggest combining PD and pre-eclampsia screening, so women can be offered testing for a number of conditions at the same clinical visit. A combination of these tests may be practical in terms of saving time and resources; however, the combination raises ethical issues. First-trimester PD and pre-eclampsia screening entail qualitative differences which alter the requirements for disclosure, non-directedness and consent with regard to the informed consent process. This article explores the differences related to the ethical issues raised by PD and pre-eclampsia in order to elucidate which factors are relevant to deciding the type of information and consent required in each context from the perspective of the ethical principles of beneficence and autonomy. Furthermore, it argues that ensuring respect for patient autonomy is context dependent and, consequently, pre-eclampsia screening and PD should be performed independently of one another. PMID- 24631383 TI - Polymorphism in DNMT1 may modify the susceptibility to oligospermia. AB - As an important methyltransferase, DNMT1 plays a key role in DNA methylation that is essential for normal spermatogenesis, which suggests that it may be involved in male infertility with spermatogenesis impairment. To explore the relationship between DNMT1 and spermatogenesis impairment, polymorphic distributions of single nucleotide polymorphisms (SNP) rs16999593, rs2228612 and rs2228611 in DNMT1 were investigated in 342 infertile patients with idiopathic azoospermia or oligospermia and 232 fertile controls in a Chinese population. As a result, no significant differences in allele and genotype frequencies of the three SNP between total patients and controls were observed. However, after stratifying the patients, significant differences in allele and genotype frequencies were detected between oligospermia subgroup and control group. The frequencies of rs16999593 allele A (83.6% versus 77.6%, P=0.033) and genotype AA (69.2% versus 59.0%, P=0.037) and SNP rs2228611 genotype AA (18.4% versus 9.9%, P=0.016) in patients with oligospermia were significantly higher than those in control group. These findings suggest that the polymorphism in DNMT1 might be associated with oligospermia and could modify the susceptibility of oligospermia. PMID- 24631384 TI - Can omega-3 fatty acids and tocotrienol-rich vitamin E reduce symptoms of neurodevelopmental disorders? AB - The incidence of childhood neurodevelopmental disorders, which include autism, attention-deficit hyperactivity disorders, and apraxia, are increasing worldwide and have a profound effect on the behaviors, cognitive skills, mood, and self esteem of these children. Although the etiologies of these disorders are unclear, they often accompany genetic and biochemical abnormalities resulting in cognitive and communication difficulties. Because cognitive and neural development require essential fatty acids (particularly long-chain omega-3 fatty acids often lacking in mother's and children's diets) during critical growth periods, the potential behavior-modifying effects of these fatty acids as "brain nutrients" has attracted considerable attention. Additionally, there is compelling evidence for increased oxidative stress, altered antioxidant defenses, and neuroinflammation in these children. The purpose of this review is to provide a scientific rationale based on cellular, experimental animal model, observational, and clinical intervention studies for incorporating the combination of omega-3 fatty acids and tocotrienol-rich vitamin E as complementary nutritional therapies in children with neurodevelopmental disorders. Should this nutritional combination correct key clinical or biochemical outcomes and/or improve behavioral patterns, it would provide a safe, complementary option for these children. PMID- 24631385 TI - Fruit and vegetable intake and related nutrients are associated with oxidative stress markers in middle-aged men. AB - OBJECTIVE: The aim of this cross-sectional study was to assess the potential relationships between fruit and vegetable (FV) intake and oxidative stress markers in middle-aged men, with an emphasis on vitamin C, fiber, and magnesium content. METHODS: The study was conducted with 296 healthy men, age 50.5 +/- 5.0 y, and body mass index (BMI) of 25.8 +/- 3.5 kg/m(2). Dietary intake, anthropometry, blood pressure, lifestyle features, and blood and urine biochemical data were assessed with validated procedures. The oxidative stress markers selected were plasma oxidized low-density lipoprotein (ox-LDL), urinary 8 iso-prostaglandin F2 alpha (8-iso-PGF2 alpha) and 8-hydroxy-2'-deoxyguanosine (8 OHdG). RESULTS: The men included in the highest tertile of FV intake (>=341.1 g/d) displayed lower concentrations of ox-LDL, 8-iso-PGF2 alpha and 8-OHdG (P for trend < 0.05), regardless of confounding factors. Concentrations of ox-LDL were negatively associated with fiber from the FV intake (P for trend < 0.05) regardless of confounding factors. ox-LDL and 8-OHdG concentrations tended to be lower in the higher tertile of magnesium (P for trend = 0.06) and vitamin C from FV intake (P for trend = 0.05), respectively. Additionally, concentrations of 8 iso-PGF2 alpha were lower in men in the highest tertile of fiber (>=6.5 g/d; P for trend = 0.034), vitamin C (>=98.0 mg/d; P for trend = 0.007), and magnesium (>=48.9 mg/d; P for trend = 0.018) from the FV-group intake. CONCLUSIONS: Greater FV intake was independently associated with reduced ox-LDL, 8-OHdG, and 8-iso PGF2 alpha in middle-aged men. Fiber, vitamin C, and magnesium from FV seem to contribute to this beneficial relationship. PMID- 24631386 TI - Yacon effects in immune response and nutritional status of iron and zinc in preschool children. AB - OBJECTIVE: The aim of this study was to evaluate the effect of yacon flour on iron and zinc nutritional status and immune response biomarkers in preschool children. METHODS: Preschool children ages 2 to 5 y were selected from two nurseries and were placed into a control group (n = 58) or a yacon group (n = 59). The yacon group received yacon flour in preparations for 18 wk at a quantity to provide 0.14 g of fructooligosaccharides/kg of body weight daily. Anthropometric parameters were measured before and after the intervention and dietary intake was measured during the intervention. To assess iron and zinc status, erythrograms, serum iron, ferritin, and plasma, and erythrocyte zinc were evaluated. Systemic immune response was assessed by the biomarkers interleukin IL 4, IL-10, IL-6, and tumor necrosis factor-alfa (TNF-alpha). Intestinal immune response was analyzed by secretory IgA (sIgA) levels before and after the intervention. Statistical significance was evaluated using the paired t test (alpha = 5%). RESULTS: Before and after the study, the children presented a high prevalence of overweight and an inadequate dietary intake of zinc and fiber. The yacon group presented with lower hemoglobin, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration at the end of the study (P < 0.05). Erythrocyte zinc was reduced in both groups at the end of the study (P < 0.05). Yacon intake increased the serum levels of IL-4 and fecal sIgA (P < 0.05). The control group had lower serum TNF-alpha after the study period (P < 0.05). CONCLUSION: Yacon improved intestinal immune response but demonstrated no effect on the nutritional status of iron and zinc in preschool children. PMID- 24631387 TI - Effects of smell loss (hyposmia) on salt usage. AB - OBJECTIVE: Smell loss (hyposmia) inhibits flavor perception and influences food intake. To compensate for flavor loss, some patients with hyposmia appear to increase salt usage. The purpose of this study was to compare self-reported salt usage in patients with hyposmia with that in normal volunteers. METHODS: Salt usage was compared in 56 patients with hyposmia but with normal taste function with that in 27 normal volunteers. Salt usage was formulated with respect to 1) a standard quantitative salt intake scale, 2) salt addition related to food intake, 3) intake of foods and beverages with high salt content, and 4) salt intake related to presence or absence of hypertension. RESULTS: Eighteen (32%) of the 56 patients self-reported increased salt usage; they were labeled "increased users." The other 38 hyposmic patients (68%) did not report increased salt usage; they were labeled "non-changers." Increased users estimated their salt usage rose an average 2.8 times that experienced before their hyposmia onset. They also reported adding salt to their food before tasting it and ate more highly salted foods than did the non-changers. Salt usage was not increased further among increased users with hypertension but was increased further among non-changers with hypertension. CONCLUSIONS: Salt usage is increased among some patients with hyposmia presumably to enhance flavor perception to compensate for diminished flavor perception related to loss of smell. PMID- 24631388 TI - Massive and long-lasting decrease in vitamin C plasma levels as a consequence of extracorporeal circulation. AB - OBJECTIVE: The use of cardiopulmonary bypass (CPB) is suggested to induce oxidative stress, reflected by an imbalance between prooxidant and antioxidant substances. The majority of studies published have either focused on only one aspect (prooxidant or antioxidant side) or covered only a short observation period. Therefore, the aim of this study was to investigate the long-term effects of CPB on the balance of prooxidative markers and antioxidant substances in one single group of patients, being able to estimate the degree of oxidative stress. METHODS: Blood samples were taken from 29 patients undergoing cardiovascular surgery beginning the day before surgery through postoperative day 6 (discharge). Plasma concentrations of vitamins C (total ascorbic acid) and E and malondialdehyde were measured by high-performance liquid chromatography. Plasma levels of ascorbyl free radical were determined using electron paramagnetic resonance spectroscopy. RESULTS: The study showed a significant decrease in vitamin C plasma levels during CPB without any recovery of vitamin C up to the time of discharge. Furthermore, CPB induced a significant increase in malondialdehyde plasma concentrations immediately after unclamping, accompanied by a significant increase in the ascorbyl free radical to total ascorbic acid ratio. The latter stayed elevated until the end of observation. CONCLUSIONS: Our findings indicate that the oxidative stress event after CPB can be divided into two phases: Immediately after reperfusion, a massive oxidative stress occurs, reflected by the increase in malondialdehyde. During convalescence, there must be an ongoing situation of oxidative stress, especially in the water-soluble compartment, leading to the consumption of vitamin C. Because the main antioxidant substance, vitamin C, did not increase again over the entire observation period, supplementation should be given consideration. PMID- 24631389 TI - Deletion of the prion gene Prnp affects offensive aggression in mice. AB - Prion protein (Prp(c)) is involved in the etiology of prion neurodegenerative diseases in mammals. The biological functions of Prp(c) are still largely unknown despite many studies in recent years. Different studies have shown impairment in locomotion, emotional/social behaviors, sleep disorders and memory impairment in mice lacking the prion gene Prnp (Prnp(-/-)) but its exact functions in the brain are still unclear. In the present study, Zurich I Prnp(-/-) and their littermate wild type (WT) control male mice were behaviorally characterized for offensive aggressive behavior in a resident-intruder paradigm with the aim to establish the possible function of Prp(c) in the regulation of offensive aggressive behavior. Prnp(-/-) mice showed reduced latencies to the first attack and bite, higher percentage of mice biting and higher frequencies of attacks of stimulus males. These results show that Prnp(-/-) mice exhibit altered aggressive behavior in comparison to their WT controls and therefore suggest that lack of the Prnp either directly or indirectly affects brain circuitry responsible for the regulation of offensive aggressive behavior. PMID- 24631390 TI - NMDA receptor activation and PKC but not PKA lead to the modification of the long term potentiation in the insular cortex induced by conditioned taste aversion: differential role of kinases in metaplasticity. AB - It has been reported that training in behavioral tasks modifies the ability to induce long-term potentiation (LTP) in an N-methyl-D-aspartate receptor (NMDAR) dependent manner. This receptor leads to calcium entry into neuronal cells, promoting the activation of protein kinases as protein kinase A (PKA) and protein kinase C (PKC), which contribute significantly to the formation of different types of memories and play a pivotal role in the expression of LTP. Our previous studies involving the insular cortex (IC) have demonstrated that induction of LTP in the basolateral amygdaloid nucleus (BLA)-IC projection prior to conditioned taste aversion (CTA) training enhances the retention of this task. Recently, we showed that CTA training triggers a persistent impairment in the ability to induce subsequent synaptic plasticity on the BLA-IC pathway in a protein synthesis-dependent manner, but the underlying molecular mechanisms remain unclear. In the present study we investigated whether the blockade of NMDAR, as well as the inhibition of PKC and PKA affects the CTA-dependent impairment of the IC-LTP. Thus, CTA-trained rats received high frequency stimulation in the Bla-IC projection in order to induce LTP 48 h after the aversion test. The NMDAR antagonist CPP and the specific inhibitors for PKC (chelerythrine) and PKA (KT 5720) were intracortically administered during the acquisition session. Our results show that the blockade of NMDAR and the inhibition of PKC activity prevent the CTA memory-formation as well as the IC-LTP impairment. Nevertheless, PKA inhibition prevents the memory formation of taste aversion but produces no interference with the CTA-dependent impairment of the IC-LTP. These findings reveal the differential roles of protein kinases on CTA-dependent modification of IC-LTP enhancing our understanding of the effects of memory-related changes on synaptic function. PMID- 24631391 TI - First come, last primed: FN400 reflects post-encoding editing of the memory trace. AB - Explicit associative memory relies on different neural substrates depending on similarity of the items associated. Extant literature dissociates old/new effects elicited by homogeneous and heterogeneous pairs. However, current results scarcely address potential priming effects induced by the presentation sequence. In the present ERP study, participants learned associations between two pictures, which either belonged to the same semantic category (e.g., animal-animal), or to different categories (e.g., animal-scene). Pictures forming a pair were shown sequentially, allowing for investigation of the different neural processes related to presentation of the first and the second item. After the study phase, participants performed a recognition judgment. After recognition, participants were asked to recall the associated picture. During retrieval, between 260 and 350 ms post-stimulus there was a significant frontal effect of category (i.e., same-category versus different-category), but only for items shown first within a pair. In the 350-600 ms time window the parietal old/new effect was unaffected by semantic category, but was modulated by presentation order. Exploratory analyses revealed even earlier effects in the time windows 40-90 ms and 150-200 ms. This evidence supports the priming account of the FN400 and highlights the importance of sequence effects in electrophysiological activity during episodic retrieval. PMID- 24631392 TI - mGluR3 knockout mice show a working memory defect and an enhanced response to MK 801 in the T- and Y-maze cognitive tests. AB - Polymorphisms in the metabotropic glutamate receptor 3 (mGluR3) encoding gene GRM3 have been linked to schizophrenia and cognitive performance in humans. Our aim was to analyze the role of mGluR3 in basal working memory and attentional processes, and also when these functions were distracted by the psychotomimetic N methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801). mGluR3 knockout (KO) mice were used. Spontaneous alternation in a T-maze test was significantly reduced in mGluR3-KO mice compared to wildtype (WT) mice, particularly after a low dose of MK-801 (0.03 mg/kg, i.p., 30 min). In a Y-maze novelty discrimination test, the locomotor stimulatory effect of MK-801 (0.1mg/kg) was enhanced in mGluR3-KO mice. Interestingly, mGluR3-KO mice showed the significantly reduced alternation in the spontaneous alternation T-maze test and the significantly enhanced sensitivity to MK-801 in the Y-maze test only when forced to enter the right arm first, not when the forced arm was on the left. A side-biased response was also found in a rewarded alternation T-maze test, where mGluR3-KO mice made significantly more incorrect visits to the left arm than the right arm after a 25-s delay. No genotype difference was found in the novelty discrimination in the Y-maze test, rewarded alternation with a 5-s delay, preference for left or right when free to enter either arm or in MK-801-induced circling. Our findings indicate cognitive disturbance and left-right asymmetry in certain behavioral responses of mGluR3-KO mice. This novel observation warrants further elucidation, and should also be considered in other studies of mGluR3 in brain functions. PMID- 24631393 TI - Influence of postural threat on postural responses to aversive visual stimuli. AB - Recent research has shown that emotion influences postural control. The objective of the present study was to establish whether or not postural threat influences postural and physiological responses to aversive visual stimuli. In order to investigate the coupling between emotional reactions, motivated behavior and postural responses, we studied the displacement of the subject's center of pressure (COP) and the changes in electrodermal activity (EDA), heart rate (HR) and postural muscle activation. Thirty-two participants (15 males, 17 females; mean +/- SD age: 21.4 +/- 2.3) viewed affective and neutral pictures while standing still on a force platform in the presence or absence of postural threat. The HR and EDA data revealed that the emotional state varied as a function of the postural condition. The mean displacement in the anteroposterior (AP) axis was more rearwards in response to aversive stimuli that in response to neutral stimuli, in both the absence of postural threat (-0.65 mm and +0.90 mm for aversive and neutral stimuli, respectively) and the presence of postural threat ( 0.00 mm vs. +0.89 mm, respectively). An aversive stimulus was associated with a shorter AP COP sway path than a neutral stimulus in the presence of a postural threat (167.26 mm vs. 174.66 mm for aversive and neutral stimuli, respectively) but not in the latter's absence (155.85 mm vs. 154.48 mm, respectively). Our results evidenced withdrawal behavior in response to an aversive stimulus (relative to a neutral stimulus) in the absence of postural threat. Withdrawal behavior was attenuated (but nevertheless active) in the presence of a postural threat. PMID- 24631394 TI - Mongolian gerbils learn to navigate in complex virtual spaces. AB - Virtual reality (VR) environments are increasingly used to study spatial navigation in rodents. So far behavioral paradigms in virtual realities have been limited to linear tracks or open fields. However, little is known whether rodents can learn to navigate in more complex virtual spaces. We used a VR setup with a spherical treadmill but no head-fixation, which permits animals not only to move in a virtual environment but also to freely rotate around their vertical body axis. We trained Mongolian gerbils to perform spatial tasks in virtual mazes of different complexity. Initially the animals learned to run back and forth between the two ends of a virtual linear track for food reward. Performance, measured as path length and running time between the virtual reward locations, improved to asymptotic performance within about five training sessions. When more complex mazes were presented after this training epoch, the animals generalized and explored the new environments already at their first exposure. In a final experiment, the animals also learned to perform a two-alternative forced choice task in a virtual Y-maze. Our data thus shows that gerbils can be trained to solve spatial tasks in virtual mazes and that this behavior can be used as a readout for psychophysical measurements. PMID- 24631395 TI - Peripheral administration of poly I:C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse. AB - Alzheimer's disease (AD) is a progressive disorder characterized by neuronal and behavioral deterioration. Two hallmark pathologies of AD are amyloid-beta (Abeta) plaques and neurofibrillary tangles, and the presence of such pathology can limit cell-to-cell communication, leading to cognitive deficits, and neuronal cell death. Although Abeta plaques were originally thought to cause the cognitive deficits, more simple forms of Abeta, such as monomers, dimers, tetramers and oligomers, have also been shown to be neurotoxic. Moreover, chronic inflammation has also been implicated in the onset and progression of these AD-related pathologies. The current study was designed to further our understanding of peripheral inflammation-induced AD-like pathology, by administering polyinosinic:polycytidylic acid (poly I:C), a viral mimetic. Mice were administered intraperitoneal injections of poly I:C or saline once daily for 7 consecutive days. Hippocampal tissue from animals receiving poly I:C contained significantly higher levels of the Abeta1-42 peptide. Even after ensuring that potential sickness behavior could not confound cognitive testing, we found that animals administered poly I:C displayed significant cognitive deficits in the hippocampus-dependent contextual fear conditioning paradigm. These results confirm our hypothesis that peripheral inflammation can lead to increased levels of hippocampal-Abeta and associated cognitive deficits. PMID- 24631396 TI - The neural correlates of age effects on verbal-spatial binding in working memory. AB - In this study, we investigated the neural correlates of age-related differences in the binding of verbal and spatial information utilizing event-related working memory tasks. Twenty-one right handed younger adults and twenty-one right handed older adults performed two versions of a dual task of verbal and spatial working memory. In the unbound dual task version letters and locations were presented simultaneously in separate locations, while in the bound dual task version each letter was paired with a specific location. In order to identify binding-specific differences, mixed-effects ANOVAs were run with the interaction of age and task as the effect of interest. Although older adults performed worse in the bound task than younger adults, there was no significant interaction between task and age on working memory performance. However, interactions of age and task were observed in brain activity analyses. Older adults did not display the greater unbound than bound task activity that younger adults did at the encoding phase in bilateral inferior parietal lobule, right putamen, and globus pallidus as well as at the maintenance phase in the cerebellum. We conclude that the binding of letters and locations in working memory is not as efficient in older adults as it is in younger adults, possibly due to the decline of cognitive control processes that are specific to working memory binding. PMID- 24631397 TI - Initial uncertainty in Pavlovian reward prediction persistently elevates incentive salience and extends sign-tracking to normally unattractive cues. AB - Uncertainty is a component of many gambling games and may play a role in incentive motivation and cue attraction. Uncertainty can increase the attractiveness for predictors of reward in the Pavlovian procedure of autoshaping, visible as enhanced sign-tracking (or approach and nibbles) by rats of a metal lever whose sudden appearance acts as a conditioned stimulus (CS+) to predict sucrose pellets as an unconditioned stimulus (UCS). Here we examined how reward uncertainty might enhance incentive salience as sign-tracking both in intensity and by broadening the range of attractive CS+s. We also examined whether initially induced uncertainty enhancements of CS+ attraction can endure beyond uncertainty itself, and persist even when Pavlovian prediction becomes 100% certain. Our results show that uncertainty can broaden incentive salience attribution to make CS cues attractive that would otherwise not be (either because they are too distal from reward or too risky to normally attract sign tracking). In addition, uncertainty enhancement of CS+ incentive salience, once induced by initial exposure, persisted even when Pavlovian CS-UCS correlations later rose toward 100% certainty in prediction. Persistence suggests an enduring incentive motivation enhancement potentially relevant to gambling, which in some ways resembles incentive-sensitization. Higher motivation to uncertain CS+s leads to more potent attraction to these cues when they predict the delivery of uncertain rewards. In humans, those cues might possibly include the sights and sounds associated with gambling, which contribute a major component of the play immersion experienced by problematic gamblers. PMID- 24631398 TI - Patient transfer from a rehabilitation hospital to an emergency department : a retrospective study of an American trauma center. AB - OBJECTIVE: To analyze medical indications and conditions for patients transferred from a rehabilitation hospital to an emergency department (ED). Are there differences in terms of which patients go to the ED during their stay and which do not? Specifically, what type of patient is most likely to be transferred? METHODOLOGY: A retrospective study was conducted at an American adult and pediatric urban trauma center that serves 40,000 patients per year. This study compared randomly selected samples of 534 patients having been transferred to the ED from a rehabilitation hospital and 500 patients who were directly admitted to the ED from the community. Variables examined were: demographics, ED diagnosis and level of care, length of hospital stay, costs, discharge condition and return within 60days to the ED. RESULTS: The patients transferred from the rehabilitation hospital were older (P<0.01), differed with regard to ethnicity (83% African American; P<0.01), the reason for hospitalization (P<0.01; the majority presented with cardiovascular disease, respiratory disease or altered mental status), had longer and more expensive stays (average: 4-8days, P<0.01), required a higher level of care (P<0.01), were more often admitted to surgery or telemetry, and, lastly, were more likely to be discharged in a frail or poor condition (P<0.01). CONCLUSIONS: The patients transferred from a rehabilitation hospital had complex, intense medical (and often psychological) issues. These patients' medical needs required a high level of resources in the ED. They frequently left the hospital in sub-optimal conditions, making it likely that they would return to the hospital via the ED prior to completing their treatment within the rehabilitation hospital. PMID- 24631399 TI - Effect of a polybrominated diphenyl ether congener (BDE-47) on growth and antioxidative enzymes of two mangrove plant species, Kandelia obovata and Avicennia marina, in South China. AB - The effects of BDE-47 on the growth and antioxidative responses of the seedlings of Kandelia obovata (Ko) and Avicennia marina (Am) were compared in an 8-week hydroponic culture spiked with different levels of BDE-47, 0.1, 1, 5 and 10 mg l( 1). The two highest BDE-47 levels significantly suppressed the growth and increased the activities of three antioxidative enzymes, superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), of Ko in week 1. However, SOD and POD activities at high levels of BDE-47 became lower than the control in week 8. On the contrary, growth of Am was not affected at all contamination levels, and the activities of three enzymes were enhanced by BDE-47 in weeks 1 and 4, but such stimulatory effect became insignificant in week 8. Avicennia was more tolerant to BDE-47 toxicity than Kandelia, as its antioxidative enzymes could better counter balance the oxidative stress caused by BDE-47. PMID- 24631400 TI - Contamination of polycyclic aromatic hydrocarbons (PAHs) in surface sediments and plants of mangrove swamps in Shenzhen, China. AB - The concentrations of 16 individual and total polycyclic aromatic hydrocarbons (?PAHs) in sediments, roots and leaves of three mangrove swamps in Shenzhen, China, namely Futian, Baguang and Waterlands, were determined. The mean concentration of ?PAHs in Futian (4480 ng g(-1)) was significantly higher than that in Baguang (1262 ng g(-1)) and Waterlands (2711 ng g(-1)). Among the 16 PAHs, the concentration of naphthalene was the highest. Based on the ratios of phenanthrene/anthracene and fluoranthene/pyrene, PAHs in Futian and Waterlands came from petrogenic and pyrolytic sources, while Baguang was mainly from pyrolytic. More PAHs were accumulated in leaves, as reflected by its higher mean concentration of ?PAHs (3697 ng g(-1)) and bioconcentration factor of PAHs (BCF) (>1.5) than that in roots. The BCF values in plants collected from Futian were significantly higher than that from Waterlands. These results indicated that more attention should be paid to the PAH contamination in Futian. PMID- 24631401 TI - Bioaccumulation of heavy metals in commercially important marine fishes from Mumbai Harbor, India. AB - Seventeen commercially important marine fish species were caught in Mumbai Harbor using a trawl net and evaluated using Atomic Absorption Spectroscopy and ICP-OES. It was found that certain species of fish contained lower levels of all metals tested. J. elongatus and C. dussumieri had the highest levels of all 8 metals tested. The heavy metal concentrations were significantly varied within and between the studied fishes (p<0.05). However, a significant correlation among heavy metals was observed. This investigation indicated that various levels of heavy metals exist in the fish species sampled, but those concentrations are within the maximum residual levels recommended by the European Union and FAO/WHO. Therefore, fish caught in Mumbai Harbor can be considered safe for human consumption. PMID- 24631402 TI - Caspase-3 cleavage of dishevelled induces elimination of postsynaptic structures. AB - During the development of vertebrate neuromuscular junction (NMJ), agrin stabilizes, whereas acetylcholine (ACh) destabilizes AChR clusters, leading to the refinement of synaptic connections. The intracellular mechanism underlying this counteractive interaction remains elusive. Here, we show that caspase-3, the effector protease involved in apoptosis, mediates elimination of AChR clusters. We found that caspase-3 was activated by cholinergic stimulation of cultured muscle cells without inducing cell apoptosis and that this activation was prevented by agrin. Interestingly, inhibition of caspase-3 attenuated ACh agonist induced dispersion of AChR clusters. Furthermore, we identified Dishevelled1 (Dvl1), a Wnt signaling protein involved in AChR clustering, as the substrate of caspase-3. Blocking Dvl1 cleavage prevented induced dispersion of AChR clusters. Finally, inhibition or genetic ablation of caspase-3 or expression of a caspase-3 resistant form of Dvl1 caused stabilization of aneural AChR clusters. Thus, caspase-3 plays an important role in the elimination of postsynaptic structures during the development of NMJs. PMID- 24631404 TI - Diet fatty acid profile, membrane composition and lifespan: an experimental study using the blowfly (Calliphora stygia). AB - The membrane pacemaker theory of ageing proposes that the polyunsaturated fatty acid (PUFA) composition of membrane lipids of a species is an important determinant of its maximum lifespan. We report three experiments using the blowfly Calliphora stygia, where this theory was tested by manipulation of dietary fat profile. Although the fat profile of the larval diet resulted in small alterations of individual membrane fatty acids, it had no effect on the peroxidation index (PI) of membrane lipids and furthermore had no effect on maximum lifespan. Similarly, manipulation of the fat profile of the adult diet resulted in small changes in individual fatty acids, but had no effect on the PI of membrane lipids. There was a small increase in maximum lifespan when adult diet was supplemented with PUFA in form of vegetable oils but no effect when diet was supplemented with pure PUFA. This difference is possibly due to antioxidant content of vegetable oils. The relative refractoriness of membrane PI to dramatic changes in response to diet is similar to the situation in the rat. These results also indicate the blowfly is unable to convert 18-carbon PUFA to more highly polyunsaturated 20- and 22-carbon PUFA. PMID- 24631405 TI - The controversy that will not go away. PMID- 24631403 TI - Dedifferentiation of neurons precedes tumor formation in Lola mutants. AB - The ability to reprogram differentiated cells into a pluripotent state has revealed that the differentiated state is plastic and reversible. It is evident, therefore, that mechanisms must be in place to maintain cells in a differentiated state. Transcription factors that specify neuronal characteristics have been well studied, but less is known about the mechanisms that prevent neurons from dedifferentiating to a multipotent, stem cell-like state. Here, we identify Lola as a transcription factor that is required to maintain neurons in a differentiated state. We show that Lola represses neural stem cell genes and cell cycle genes in postmitotic neurons. In lola mutants, neurons dedifferentiate, turn on neural stem cell genes, and begin to divide, forming tumors. Thus, neurons rather than stem cells or intermediate progenitors are the tumor initiating cells in lola mutants. PMID- 24631406 TI - Robot-assisted sacrocolpopexy for pelvic organ prolapse: a systematic review and meta-analysis of comparative studies. AB - CONTEXT: Surgery represents the mainstay of treatment for pelvic organ prolapse (POP). Among different surgical procedures, abdominal sacrocolpopexy (SC) is the gold standard for apical or multicompartmental POP. Research has recently focused on the role of robot-assisted sacrocolpopexy (RASC). OBJECTIVE: To conduct a systematic review on the outcomes of RASC. EVIDENCE ACQUISITION: PubMed, Scopus, and Web of Science databases as well as ClinicalTrials.gov were searched for English-language literature on RASC. A total of 509 articles were screened; 50 (10%) were selected, and 27 (5%) were included. Studies were evaluated per the Grading of Recommendations, Assessment, Development, and Evaluation system and the European Association of Urology guidelines. EVIDENCE SYNTHESIS: Overall, data on 1488 RASCs were collected from 27 studies, published from 2006 to 2013. Objective and subjective cures ranged from 84% to 100% and from 92% to 95%, respectively. Conversion rate to open surgery was <1% (range: 0-5%). Intraoperative, severe postoperative complications, and mesh erosion rates were 3% (range: 0-19%), 2% (range: 0-8%), and 2% (range: 0-8%), respectively. Surgical related outcomes have improved with increased experience, with an estimated learning curve of about 10-20 procedures. Laparoscopic SC is less costly than RASC, although the latter has lower costs than abdominal SC. CONCLUSIONS: RASC is a safe and feasible procedure for POP; it allows the execution of complex surgical steps via minimally invasive surgery without medium- and long-term anatomic detriments. Further prospective studies are needed to confirm these findings. PATIENT SUMMARY: We looked at the outcomes of robotic sacrocolpopexy for prolapse. We found that the use of robotic technology is safe and effective for the treatment of prolapse in women. PMID- 24631407 TI - Targeting vascular endothelial growth factor receptor signaling in renal cancer: the sooner the better? PMID- 24631408 TI - Application of the statistical process control method for prospective patient safety monitoring during the learning phase: robotic kidney transplantation with regional hypothermia (IDEAL phase 2a-b). AB - BACKGROUND: Traditional evaluation of the learning curve (LC) of an operation has been retrospective. Furthermore, LC analysis does not permit patient safety monitoring. OBJECTIVES: To prospectively monitor patient safety during the learning phase of robotic kidney transplantation (RKT) and determine when it could be considered learned using the techniques of statistical process control (SPC). DESIGN, SETTING AND PARTICIPANTS: From January through May 2013, 41 patients with end-stage renal disease underwent RKT with regional hypothermia at one of two tertiary referral centers adopting RKT. Transplant recipients were classified into three groups based on the robotic training and kidney transplant experience of the surgeons: group 1, robot trained with limited kidney transplant experience (n=7); group 2, robot trained and kidney transplant experienced (n=20); and group 3, kidney transplant experienced with limited robot training (n=14). INTERVENTION: We employed prospective monitoring using SPC techniques, including cumulative summation (CUSUM) and Shewhart control charts, to perform LC analysis and patient safety monitoring, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes assessed included post-transplant graft function and measures of surgical process (anastomotic and ischemic times). CUSUM and Shewhart control charts are time trend analytic techniques that allow comparative assessment of outcomes following a new intervention (RKT) relative to those achieved with established techniques (open kidney transplant; target value) in a prospective fashion. RESULTS AND LIMITATIONS: CUSUM analysis revealed an initial learning phase for group 3, whereas groups 1 and 2 had no to minimal learning time. The learning phase for group 3 varied depending on the parameter assessed. Shewhart control charts demonstrated no compromise in functional outcomes for groups 1 and 2. Graft function was compromised in one patient in group 3 (p<0.05) secondary to reasons unrelated to RKT. In multivariable analysis, robot training was significantly associated with improved task-completion times (p<0.01). Graft function was not adversely affected by either the lack of robotic training (p=0.22) or kidney transplant experience (p=0.72). CONCLUSIONS: The LC and patient safety of a new surgical technique can be assessed prospectively using CUSUM and Shewhart control chart analytic techniques. These methods allow determination of the duration of mentorship and identification of adverse events in a timely manner. A new operation can be considered learned when outcomes achieved with the new intervention are at par with outcomes following established techniques. PATIENT SUMMARY: Statistical process control techniques allowed for robust, objective, and prospective monitoring of robotic kidney transplantation and can similarly be applied to other new interventions during the introduction and adoption phase. PMID- 24631409 TI - Effects of cabozantinib on pain and narcotic use in patients with castration resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort. AB - BACKGROUND: Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation. OBJECTIVE: Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: This was a nonrandomized expansion (NRE) cohort (n=144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals. INTERVENTION: Open-label cabozantinib (100mg or 40mg). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The following stringent response definition was used: clinically meaningful pain reduction (>=30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed. RESULTS AND LIMITATIONS: Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported >=6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant (p <= 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design. CONCLUSIONS: Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies. PATIENT SUMMARY: We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well controlled trials are necessary to confirm these findings. PMID- 24631410 TI - Seminal vesicle intraepithelial neoplasia versus basal cell hyperplasia in a seminal vesicle. AB - In the examination of >3000 radical prostatectomy specimens and their seminal vesicles (SVs), we came across a unique case of an intraepithelial abnormality in preexisting ducts and acini in the left SV of a 73-yr-old patient with prostatic adenocarcinoma. At low magnification, the epithelial lining was thicker than the surrounding normal ducts with obliteration of the acinar lumen. At high magnification, there were varying degrees of cell stratification. Prostate specific antigen, prostate-specific acid phosphatase, prostate-specific membrane antigen, prostein (P501S), alpha-methylacyl-CoA racemase, and GATA binding protein 3 (GATA3) were negative; p63, 34betaE12, cytokeratin 5/6, and p53 were positive in cells in basal and suprabasal positions, whereas CA-125 was expressed in the luminal cells. The case shows morphologic and immunohistochemical features similar to those of basal cell hyperplasia of the prostate and is different from the early neoplastic epithelial changes of the SV in the transgenic adenocarcinoma mouse prostate model (ie, SV intraepithelial neoplasia). To the best of our knowledge, there are no previous reports of such a change in a human SV. The clinical significance of this lesion is not known and is overshadowed by the presence of prostate cancer. PMID- 24631411 TI - Obesity, abdominal obesity, physical activity, and caloric intake in US adults: 1988 to 2010. AB - BACKGROUND: Obesity and abdominal obesity are associated independently with morbidity and mortality. Physical activity attenuates these risks. We examined trends in obesity, abdominal obesity, physical activity, and caloric intake in US adults from 1988 to 2010. METHODS: Univariate and multivariate analyses were performed using National Health and Nutrition Examination Survey data. RESULTS: Average body mass index (BMI) increased by 0.37% (95% confidence interval [CI], 0.30-0.44) per year in both women and men. Average waist circumference increased by 0.37% (95% CI, 0.30-0.43) and 0.27% (95% CI, 0.22-0.32) per year in women and men, respectively. The prevalence of obesity and abdominal obesity increased substantially, as did the prevalence of abdominal obesity among overweight adults. Younger women experienced the greatest increases. The proportion of adults who reported no leisure-time physical activity increased from 19.1% (95% CI, 17.3-21.0) to 51.7% (95% CI, 48.9-54.5) in women, and from 11.4% (95% CI, 10.0-12.8) to 43.5% (95% CI, 40.7-46.3) in men. Average daily caloric intake did not change significantly. BMI and waist circumference trends were associated with physical activity level but not caloric intake. The associated changes in adjusted BMIs were 8.3% (95% CI, 6.9-9.6) higher among women and 1.7% (95% CI, 0.68-2.8) higher among men with no leisure-time physical activity compared with those with an ideal level of leisure-time physical activity. CONCLUSIONS: Our analyses highlight important dimensions of the public health problem of obesity, including trends in younger women and in abdominal obesity, and lend support to the emphasis placed on physical activity by the Institute of Medicine. PMID- 24631412 TI - Risky business. PMID- 24631413 TI - Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond. AB - The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D. PMID- 24631414 TI - The role of attachment in the relationship between child maltreatment and later emotional and behavioral functioning. AB - The experience of childhood maltreatment is an important predictor of unfavorable emotional and behavioral outcomes. Because little research examined explanatory variables in the relationship between childhood maltreatment experiences and later outcomes, this study examined the role that attachment serves in this relationship. Four hundred twenty-four participants completed questionnaires assessing the variables of interest for this study. Results indicated that both childhood maltreatment experiences (particularly emotional abuse) and attachment (particularly to mothers and peers) are significant predictors of later emotional and behavioral outcomes. Further, attachment contributed unique and significant variance to the relationship between childhood maltreatment experiences and later outcomes. Such findings suggested that secure attachment may serve as a protective factor against maladaptive emotional and behavioral outcomes as children reach emerging adulthood, even in the context of childhood maltreatment experiences. The importance of studying the relationships among these variables is discussed. PMID- 24631415 TI - Factors affecting disclosure among Israeli children in residential care due to domestic violence. AB - Disclosure of child abuse may enable initiating interventions to end maltreatment and mediate its negative physical and psychological consequences. The present study reviews the field of disclosure and examines factors affecting disclosure among a service population of abused children who were placed in residential care due to various forms of abuse (e.g., physical, sexual, emotional, neglect and witnessing domestic violence). The sample consisted of 286 Israeli (Hebrew and Arabic speaking) children aged 12-17 (mean=14+/-1). Following approval of the Ethics committee of the University and parents' written consent, participants were administered a self-report questionnaire that included the following measures: a Socio-Demographic Questionnaire, the Childhood Trauma Questionnaire (CTQ), the Juvenile Victimization Questionnaire (JVQ), and the Disclosure of Trauma Questionnaire (DTQ). Results indicated that the three key factors enhancing the likelihood of disclosure were: moral factors, external initiatives and intolerable physical pain. The three key factors inhibiting disclosure were feelings of shame, fear of losing social support and uncertainty as to how and to whom to disclose. Results also showed that children preferred to disclose to their nuclear family members (parents and siblings) in comparison with professionals. PMID- 24631416 TI - Reply to comment on "Type II diabetes and metabolic syndrome in relation to head and neck squamous cell carcinoma risk: A SEER-Medicare database study". PMID- 24631418 TI - The association between type 2 diabetes and head and neck squamous cell carcinoma. PMID- 24631417 TI - Risk factors for Kaposi's sarcoma among HIV-positive individuals in a case control study in Cameroon. AB - BACKGROUND: Individuals co-infected with Kaposi's sarcoma herpesvirus (KSHV) and Human Immunodeficiency Virus (HIV) are at greatly increased risk of developing Kaposi's sarcoma (KS). The objective of the current analysis is to identify risk cofactors for KS among HIV-positive individuals. METHODS: We conducted a case control study of KS in Cameroon on 161 HIV-positive and 14 HIV-negative cases and 680 HIV-positive and 322 HIV-negative controls. Participants answered a physician administered questionnaire and provided blood and saliva specimens. Antibodies against KSHV lytic, K8.1, and latent, ORF73, antigens were measured by ELISA to determine KSHV serostatus. Conditional logistic regression was performed to determine multivariate odds ratios (OR) and 95% confidence intervals (CI) for risk factors associated with KS among HIV-positive cases and controls. RESULTS: Overall, 98% (158) of HIV-positive cases, 100% (14) of HIV-negative cases, 81% (550) of HIV-positive controls, and 80% (257) of HIV-negative controls were KSHV seropositive. Risk factors for KS among HIV-positive individuals included KSHV seropositivity (OR=9.6; 95% CI 2.9, 31.5), non-use of a mosquito bed net (OR 1.9; 95% CI 1.2, 2.9), minority ethnicity (OR=3.1; 95% CI 1.1, 9.3), treatment from a traditional healer (OR=2.3; 95% CI 1.5, 3.7), history of transfusion (OR=2.4; 95% CI 1.5, 3.9), and family history of cancer (OR=1.9; 95% CI 1.1, 3.1). CONCLUSION: KSHV seroprevalence of >=80% indicates a high prevalence in the general population in Cameroon. Among HIV-positive individuals, the strong association of KS with non-use of mosquito nets and treatment from traditional healers are compelling findings, consistent with recently reported data from East Africa. PMID- 24631419 TI - Acaricidal activity of 9-oxo-10,11-dehydroageraphorone extracted from Eupatorium adenophorum in vitro. AB - The acaricidal activity of the 9-oxo-10,11-dehydroageraphorone (euptox A), a cadenine sesquiterpene from Eupatorium adenophorum (E. adenophorum) against Sarcoptes scabiei and Psoroptes cuniculi was tested in vitro. A complementary log log (CLL) model was used to analyze the data of the toxicity tests in vitro. The results showed euptox A had strong toxicity against mites, killing all S. scabiei at 3 and 4 mg/ml (m/v) concentration, while 4 mg/ml euptox A was also found to kill all P. cuniculi within a 4 h period. Similarly, 2, 3 and 4 mg/ml concentration of euptox A had strong toxicity against S. scabiei, with median lethal time (LT50) values at 0.687, 0.526, 0.326 h, respectively. 3 mg/ml and 4 mg/ml showed strong acaricidal action against P. cuniculi; the LT50 values were 0.693 and 0.493 h, respectively. The median lethal concentration (LC50) values were 1.068 mg/ml for Scabies mite and 0.902 mg/ml for P. cuniculi in 2 h. The results indicate that euptox A has strong acaricidal activity and may exploit as novel drugs for the effective control of animal acariasis. PMID- 24631420 TI - Reply to letter: Defibrillators can be susceptible to electromagnetic fields from adjacent portable suction units. PMID- 24631421 TI - Is hypothermia beneficial even for the depressed heart after the resumption of spontaneous circulation (ROSC) from out-of-hospital cardiac arrest (OHCA)? PMID- 24631422 TI - Reply to letter: Defibrillators can be susceptible to electromagnetic fields from adjacent portable suction units. PMID- 24631423 TI - A proposal for fs-electron microscopy experiments on high-energy excitations in solids. AB - Recent advances in ultrafast technology enable both the study and the control of materials properties thanks to the ability to record high temporal resolution movies of their transformations, or the ability to generate new states of matter by selecting ad hoc an excitation to drive the system out of equilibrium. The holy grail of this type of experiments is to combine a high tuneability of the excitation with a wide observation window. For example, this is achieved in multidimensional optical spectroscopy where the response to several excitation energies is monitored in a broad energy range by a large bandwidth optical pulse. In this article, the possibility to combine the chemical sensitivity of intense tuneable X-rays pulses from a free electron laser, with the wide range of observables available in an ultrafast transmission electron microscope is discussed. The requirements for such experiments are quantified via estimates based on state of the art experiments and simulations, and it is proposed that ultrafast electron imaging, diffraction and spectroscopy experiments can be performed in combination with a chemically selective X-ray excitation of materials. PMID- 24631424 TI - On a definition of the appropriate timing for surgical intervention in orthognathic surgery. AB - Together with the introduction of new orthodontic techniques and minimally invasive surgery protocols, the emergence of modern patient prototypes has given way to novel timing schemes for the handling of dento-maxillofacial deformities. The aim of this study was to define, justify, and systematize the appropriate timing for orthognathic surgery. A retrospective analysis of orthognathic surgery procedures carried out over a 3-year period was performed. Six timing schemes were defined: 'surgery first', 'surgery early', 'surgery late', 'surgery last', 'surgery only', and 'surgery never'. Gender, age at surgery, main motivation for treatment, orthodontic treatment length, and number of orthodontic appointments were evaluated. A total of 362 orthognathic procedures were evaluated. The most common approach was 'surgery late'. While aesthetic improvement was the leading treatment motivation in 'surgery first', 'surgery early', and 'surgery last' cases, occlusal optimization was the chief aim of 'surgery late'. Sleep disordered breathing was the main indication for treatment in 'surgery only'. Compared to 'surgery late', orthodontic treatment was substantially shorter in 'surgery early' and 'surgery first' cases, but the number of orthodontic appointments was similar. In conclusion, the skilful management of dento maxillofacial deformities requires a comprehensive analysis of patient-, orthodontist-, and surgeon-specific variables. Each timing approach has well defined indications, treatment planning considerations, and orthodontic and surgical peculiarities. PMID- 24631426 TI - Rasch analysis for assessing unidimensionality and identifying measurement biases of malignancy scores in oncology. The example of the Weiss histopathological system for the diagnosis of adrenocortical cancer. AB - PURPOSE: Many malignancy scores have been developed without comprehensive statistical or measurement validation, and in particular without verification of the necessary property of unidimensionality. Here, we used Rasch analysis to assess unidimensionality and identify measurement biases of malignancy scores. METHODS: The Weiss histopathological system (WHS), summing nine items of histopathological alteration, was used to evaluate 247 adrenocortical tumors. Rasch model analysis was implemented and compared to classical factor analytic methods to investigate the validity of item-score summation for both the original and modified WHS, to assess differential functioning of the WHS items across various factors related to patient and tumors, and to identify items or subtypes of tumors that could be considered for removal or exclusion from the WHS with the aims of improving measurement and relieving the burden on pathologists. RESULTS: The WHS does not meet the necessary property of unidimensionality and is severely affected by differential item functioning in relation to size and weight of the tumor. Moreover, items are not well distributed along the spectrum of malignancy, most being located in the upper part and several at the same place. CONCLUSION: The WHS in its present form should be applied only to small or moderate size tumors, and better scoring systems could be developed by using more appropriately distributed items. Rasch analysis is a powerful method for developing, evaluating, refining and simplifying malignancy scores. PMID- 24631425 TI - Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. AB - Individuals carrying DRB1*0401 who smoke cigarettes are at an increased risk of developing severe seropositive RA. To determine how cigarette smoke (CS) interacts with host genetic factors in the induction of RA-associated autoimmunity, we used transgenic mice carrying the RA-susceptible HLA genes DR4 and DQ8, but lacking all endogenous murine class II molecules. Cigarette smoke exposure augmented peptidylarginine deiminase (PAD) enzyme expression, and enhanced immune responses to citrullinated collagen and vimentin. Here we show for the first time that DQ molecules can present citrullinated peptides much more efficiently than native peptides. Interestingly, CS exposure suppressed collagen induced arthritis (CIA) in DRB1*0401 mice although innate immune response was enhanced. On the other hand, CS exposure exacerbated CIA in DQ8 mice, which was accompanied by an increased expression of Th17 gene transcripts in lungs. These observations suggest that cigarette smoke promotes antigen-specific autoimmunity that is profoundly influenced by host genetic factors. PMID- 24631427 TI - [Epidemiologic warnings from studies on alcohol use disorders]. AB - The highest consumption levels of alcohol are found in the developed world, mostly the Northern Hemisphere. After a slight decrease at the beginning of the 1990s, alcohol use in the European Region increased with an average adult per capita consumption amounting to 12.5 litres of pure alcohol per capita for the year 2009. In France, adult consumption was 12.7 litres of pure alcohol per capita for the year 2009, and it is estimated that 1.5 to 2 million of adults are alcohol-dependent (4-5% of the adult population) and 5 million are excessive drinkers. The harmful use of alcohol is one of the world's leading health risks. Alcohol is the direct cause of more than 30 diseases and a causal factor in more than 60 major types of diseases and injuries, resulting in approximately 2.5 million deaths each year. Approximately 4% of all deaths worldwide and 4.5% (7.4% for men and 1.4% for women) of the global burden of disease and injury are attributable to alcohol. In 2004 in the EU, 15.2% of all disability-adjusted life years (DALYs) in men and 3.9% of all DALYs in women were lost due to alcohol. While the impact of alcohol consumption and dependence on mortality and disease is substantial, there are also many psychosocial consequences, including violence, family problems, child neglect and abuse, absenteeism and lost productivity in the workplace. This means that alcohol consumption and dependence have sizable impacts on many people other than the drinker. These effects add up to a staggering number of alcohol-attributable social costs, which can be estimated at ? 155.8 billion a year in Europe. Despite all these consequences, many individuals with alcohol use disorders remain untreated although effective treatments exist. From 37 community-based psychiatric epidemiology studies that used standardized diagnostic instruments and included data on the percentage of individuals receiving care for alcohol abuse or dependence, the median rate of untreated cases of these disorders was calculated across the studies. Alcohol abuse and dependence had the widest treatment gap at 78.1% worldwide, and 92% in Europe. In this context, healthcare systems must adapt to meet the needs of patients who currently do not receive specialized care. PMID- 24631428 TI - Analysis of U3 snoRNA and small subunit processome components in the parasitic protist Entamoeba histolytica. AB - In the early branching parasitic protist Entamoeba histolytica, pre-rRNA synthesis continues when cells are subjected to growth stress, but processing slows down and unprocessed pre-rRNA accumulates. To gain insight into the regulatory mechanisms leading to accumulation, it is necessary to define the pre rRNA processing machinery in E. histolytica. We searched the E. histolytica genome sequence for homologs of the SSU processome, which contains the U3snoRNA, and 72 proteins in yeast. We could identify 57 of the proteins with high confidence. Of the rest, 6 were absent in human, and 4 were non-essential in yeast. The remaining 5 were absent in other parasite genomes as well. Analysis of U3snoRNA showed that the E. histolytica U3snoRNA adopted the same conserved secondary structure as seen in yeast and human. The predicted structure was verified by chemical modification followed by primer extension (SHAPE). Further we showed that the predicted interactions of Eh_U3snoRNA boxes A and A' with pre 18S rRNA were highly conserved both in position and sequence. The predicted interactions of 5'-hinge and 3'-hinge sequences of Eh_U3 snoRNA with the 5'-ETS sequences were conserved in position but not in sequence. Transcription of selected genes of SSU processome was tested by northern analysis, and transcripts of predicted sizes were obtained. During serum starvation, when unprocessed pre RNA accumulated, the transcript levels of some of these genes declined. This is the first report on pre-rRNA processing machinery in E. histolytica, and shows that the components are well conserved with respect to yeast and human. PMID- 24631429 TI - Emotional stress evoked by classical fear conditioning induces yawning behavior in rats. AB - Yawning is often observed not only in a state of boredom or drowsiness but also in stressful emotional situations, suggesting that yawning is an emotional behavior. However, the neural mechanisms for yawning during stressful emotional situations have not been fully determined, though previous studies have suggested that both parvocellular oxytocin (OT) and corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) are responsible for induction of yawning. Thus, using ethological observations and c-Fos immunohistochemistry, we examined whether emotional stress evoked by classical fear conditioning is involved in induction of yawning behavior in freely moving rats. Emotional stress induced yawning behavior that was accompanied by anxiety related behavior, and caused neuronal activation of the central nucleus of the amygdala (CeA), as well as increases in activity of both OT and CRF neurons in the PVN. These results suggest that emotional stress may induce yawning behavior, in which the neuronal activation of the CeA may have a key role. PMID- 24631430 TI - Object memory impairment at post-drug Day 15 but not at Day 1 after a regimen of repeated treatment with oral methylphenidate. AB - Methylphenidate (MPH) is a dopamine and norepinephrine reuptake inhibitor that is widely used for the treatment of attention-deficit/hyperactivity disorder in children and adults. Its similarity to other psychostimulants suggests that, at certain doses, the drug may generate lasting neuroadaptations that can be detrimental to the recipient. Some investigators have found that, in rats, the residual effects of the drug (i.e., following a 10-14 day washout period) can interfere with memory for objects when the retention interval is 3h or more. The present experiment replicated this result and demonstrated the critical importance of the washout period. Long-Evans male rats treated with MPH (5.0mg/kg po b.i.d.) on 21 days (during a post-natal period ranging from Day 29 to Day 57) and then twice-assessed for their performance in an object recognition task were able to recognize a familiar object on Day 1 after the last dose of the drug had been administered, behaving the same as the untreated control group. However, on Day 15 post-drug, the same MPH group failed to distinguish between a familiar and a novel object, exploring both nearly equally, while the control group continued to investigate the novel object to a greater extent than the familiar one. This suggests that, if a test for object recognition is conducted too early after the MPH treatment period ceases, a memory impairment may not be detected. In general, this finding has implications for studies of other behavioral or neurophysiological consequences of MPH that may appear following a drug-free withdrawal period. PMID- 24631431 TI - Preventing repeat pregnancy in adolescents: is immediate postpartum insertion of the contraceptive implant cost effective? AB - OBJECTIVE: The objective of the study was to determine the cost-effectiveness of a hypothetical state-funded program offering immediate postpartum implant (IPI) insertion for adolescent mothers. STUDY DESIGN: Participants in an adolescent prenatal-postnatal program were enrolled in a prospective observational study of IPI insertion (IPI group, n = 171) vs standard contraceptive initiation (comparison group, n = 225). Implant discontinuation, repeat pregnancies and pregnancy outcomes were determined. We compared the anticipated public expenditures for IPI recipients and comparisons at 6, 12, 24, and 36 months postpartum using the actual outcomes of this cohort and Colorado Medicaid reimbursement estimates. Costs were normalized to 1000 adolescents in each arm and included 1 year of well-baby care for delivered pregnancies. RESULTS: At 6 months, the expenditures of the IPI group exceed the comparison group by $73,000. However, at 12, 24, and 36 months, publicly funded IPIs would result in a savings of more than $550,000, $2.5 million, and $4.5 million, respectively. For every dollar spent on the IPI program, $0.79, $3.54, and $6.50 would be saved at 12, 24, and 36 months. Expenditures between the IPI and comparison groups would be equal if the comparison group pregnancy rate was 13.8%, 18.6%, and 30.5% at 12, 24, and 36 months. Actual rates were 20.1%, 46.5%, and 83.7%. CONCLUSION: Offering IPIs to adolescent mothers is cost effective. Payors that do not currently cover IPI should integrate these data into policy considerations. PMID- 24631432 TI - Monitoring childbirth morbidity using hospital discharge data: further development and application of a composite measure. AB - OBJECTIVE: The purpose of this study was to evaluate the use of a childbirth composite morbidity indicator for monitoring childbirth morbidity at hospital and regional levels in California. STUDY DESIGN: Study data were obtained from the 2005 linked maternal and neonatal discharge dataset for California hospitals. The study population was limited to laboring women with singleton, term (>=37 weeks' gestation), inborn, and live births. Women with and without pregnancy complications were stratified into high- and low-risk groups. The composite outcome was defined as any significant morbidity of the mother or newborn infant during the childbirth admission. Submeasures for maternal and neonatal composite morbidity and for severe maternal morbidity were examined with both aggregate and hospital-level analyses. RESULTS: Of 377,869 eligible deliveries, 120,218 (31.8%) were categorized as high risk and 257,651 (68.2%) were categorized as low risk. High-risk women had higher morbidity rates for all comparisons. The mean childbirth composite morbidity rate was 21% overall: 28% for high-risk women and 18% for low-risk women. For high- and low-risk strata, the rates of maternal complications were 18% and 13%, and the rates of severe maternal morbidity were 1.4% and 0.5%, respectively. There was substantial variation across hospitals for all measures. CONCLUSION: The childbirth composite morbidity rate is designed to report childbirth complication rates that combine maternal and neonatal morbidity. This measure and its submeasures met the criteria for quality indicator evaluation as specified by the Agency for Healthcare Research and Quality and can be used for benchmarking or for monitoring childbirth outcomes at regional levels. PMID- 24631434 TI - Doppler parameters of fetal lung hypoplasia and impact of sildenafil. AB - OBJECTIVE: Congenital diaphragmatic hernia (CDH) is clinically challenging because of associated lung hypoplasia (LH). There have been no validated parameters to evaluate fetal LH severity. Sildenafil has been shown to improve LH mass in nitrofen-induced pulmonary artery (PA) models, but the pulmonary vascular tone has not been evaluated in vivo. The aim of this study was to identify the PA Doppler parameter that best predicts LH severity and to investigate the efficacy of antenatal sildenafil treatment in experimental CDH. STUDY DESIGN: Nitrofen (50 60% CDH in offspring) or vehicle on E9.5 and sildenafil or vehicle on E11.5-20.5 were administrated to pregnant rats. On E20.5, PA Doppler indices were investigated with and without maternal hyperoxia. The presence/absence of CDH, lung/body weight ratio and radial saccular count were assessed at E20.5. RESULTS: At baseline, CDH rats had lower PA Doppler acceleration/ejection time ratios and pulsatility index (PI). Maternal hyperoxia resulted in a significant decrease in the PA/PI suggesting pulmonary vasodilation. In contrast, in CDH fetuses, the ipsilateral PA/PI showed little or no response to hyperoxia (P > .05), and in those with LH, PI response to maternal hyperoxia correlated positively with hernia, lung/body weight ratio (r = 0.70, P = .01). Maternal sildenafil therapy significantly improved PA response to hyperoxia and lung growth in CDH fetuses (P < .01). CONCLUSION: Pulmonary vasodilation that occurs in E20.5 fetal rats in response to maternal hyperoxia is blunted in CDH. Change in PA/PI with hyperoxia is a useful predictor of LH severity. Sildenafil improves pulmonary vascular response and lung growth in fetal CDH. PMID- 24631435 TI - Double cervix: clarifying a diagnostic dilemma. AB - OBJECTIVE: Although double cervix is often considered to indicate uterus didelphys, it may be challenging to determine the true associated anomaly as double cervix occurs with other mullerian anomalies. Our purpose is to report the frequency of uterine mullerian anomalies that occur with a double cervix and identify imaging or clinical criteria to help classify the associated anomaly. STUDY DESIGN: After institutional review board approval, an electronic search was performed to identify patients with double cervix and pelvic magnetic resonance imaging (MRI) between 1976-2010 (using International Statistical Classification of Diseases and Related Health Problems, Edition 9 and Hospital International Classification of Diseases Adapted codes). MRIs were reviewed to classify the mullerian anomaly. Clinical characteristics including cervical canal thickness, intercervical distance and orientation were recorded. Kruskal-Wallis and chi(2) tests were used to test for differences in patient and imaging characteristics across mullerian anomalies. RESULTS: There were 64 patients who met inclusion criteria: 32 (50%) septate uterus, 27 (42%) uterus didelphys and 5 (8%) bicornuate uterus. Cervical canal divergence was present in 34% (11/32) with septate uterus, 26% (7/27) with uterus didelphys, and none with bicornuate uterus. Mean intercervical distance was significantly greater (P < .001) in uterus didelphys (12.05 mm) compared with septate (5.43 mm) or bicornuate uterus (5.40 mm). CONCLUSION: Septate uterus is as common as uterus didelphys, and considerably more common than bicornuate uterus, in women with a double cervix. Although a widened intercervical distance may support the MRI diagnosis of uterus didelphys, careful evaluation of the uterine fundus is required for correct diagnosis when encountering a double cervix. PMID- 24631433 TI - Urinary incontinence management costs are reduced following Burch or sling surgery for stress incontinence. AB - OBJECTIVE: The objective of the study was to estimate the effect of Burch and fascial sling surgery on out-of-pocket urinary incontinence (UI) management costs at 24 months postoperatively and identify predictors of change in cost among women enrolled in a randomized trial comparing these procedures. STUDY DESIGN: Resources used for UI management (supplies, laundry, dry cleaning) were self reported by 491 women at baseline and 24 months after surgery, and total out-of pocket costs for UI management (in 2012 US dollars) were estimated. Data from the 2 surgical groups were combined to examine the change in cost for UI management over 24 months. Univariate and bivariate changes in cost were analyzed using the Wilcoxon signed rank test. Predictors of change in cost were examined using multivariate mixed models. RESULTS: At baseline mean (+/-SD) age of participants was 53 +/- 10 years, and the frequency of weekly UI episodes was 23 +/- 21. Weekly UI episodes decreased by 86% at 24 months (P < .001). The mean weekly cost was $16.60 +/- $27.00 (median $9.39) at baseline and $4.57 +/- $15.00 (median $0.10) at 24 months (P < .001), a decrease of 72%. In multivariate analyses, cost decreased by $3.38 +/- $0.77 per week for each decrease of 1 UI episode per day (P < .001) and was strongly associated with greater improvement in Urogenital Distress Inventory and Incontinence Impact Questionnaire scores (P < .001) and decreased 24-hour pad weight (P < .02). CONCLUSION: Following Burch or fascial sling surgery, the UI management cost at 24 months decreased by 72% ($625 per woman per year) and was strongly associated with decreasing UI frequency. Reduced out-of-pocket expenses may be a benefit of these established urinary incontinence procedures. PMID- 24631436 TI - Extended embryo culture is not associated with increased adverse obstetric or perinatal outcome. AB - OBJECTIVE: We sought to compare obstetric and perinatal outcomes of singletons born after extended embryo culture and a single blastocyst stage embryo vs a single cleavage stage embryo transfer. STUDY DESIGN: This was a retrospective cohort study of 1543 fresh single embryo transfers using nondonor oocytes in women <=40 years old from December 2008 through December 2012 at the reproductive unit of McGill University Health Center. The main outcome measures were perinatal outcomes including birthweight, low birthweight, small for gestational age, preterm delivery, preeclampsia, placental abruption, and neonatal complications. Covariates were maternal age, body mass index, smoking, cause of infertility, parity, and sex of the baby. RESULTS: Transfers of 693 fresh single cleavage embryos and 850 fresh single blastocysts resulting in 564 pregnancies and 381 singleton deliveries were analyzed. Blastocyst transfer resulted in a higher clinical pregnancy rate (50.1% and 19.9%) and live birth rate (33.5% and 13.8%) compared to cleavage embryo transfer, respectively (P < .001). Multivariate analyses for pregnancy revealed no increased risk of maternal or neonatal complications in pregnancies resulting from extended embryo culture. CONCLUSION: Live births resulting from extended embryo culture and a single blastocyst transfer are not associated with increased adverse obstetric and perinatal outcome compared to live births from a single cleavage embryo transfer in women <=40 years old. PMID- 24631437 TI - Body image in the Pelvic Organ Prolapse Questionnaire: development and validation. AB - OBJECTIVE: The purpose of this study was to develop and validate a prolapse specific body image questionnaire. STUDY DESIGN: Prolapse-specific body image themes that were identified in our previous work served as a framework for the development of a question pool. After review for face and content validity and reading level, the question pool was reduced to 21 items that represent predominant themes and that form the initial Body Image in Pelvic Organ Prolapse (BIPOP) questionnaire. Women with symptomatic prolapse of Pelvic Organ Prolapse Quantification (POPQ) of more than stage II were enrolled from 2 academic urogynecology practices; they completed questionnaires on pelvic floor symptoms and distress, general body image, depression, self-esteem, and the BIPOP questionnaire, and they underwent the POPQ. We field-tested the BIPOP questionnaire with approximately 200 participants; 10 women completed cognitive interviews, and 100 women repeated the BIPOP questionnaire to assess test-retest reliability. RESULTS: Two hundred eleven participants were enrolled, and 201 women had complete data. Participants had mean age of 60.2 +/- 10.5 years, were predominantly white (98%), were partnered (80%), and had median POPQ stage III. Cognitive interviews confirmed comprehension and clarity of questions and acceptability of length and subject matter. Exploratory factor analysis was performed in an iterative process until a parsimonious, 10-item scale with 2 subscales was identified (subscale 1 represented general attractiveness; subscale 2 represented partner-related prolapse reactions). Cronbach's alpha score for the subscales were 0.90 (partner) and 0.92 (attractiveness). Correlations between related questionnaires and BIPOP subscales were strong and directionally appropriate. Test-retest correlations on both total and subscale measurements were high. CONCLUSION: We developed and validated a prolapse-specific body image measurement that has face and content validity, high internal consistency, strong correlation with general prolapse and body image measures, and strong test-retest reliability. PMID- 24631438 TI - Neonatal outcomes in early term birth. AB - OBJECTIVE: To determine neonatal morbidity rates for early term birth compared with full term birth by precursor leading to delivery. STUDY DESIGN: This was a retrospective study of 188,809 deliveries from 37 0/7 to 41 6/7 weeks of gestation with electronic medical record data from 2002 to 2008. Precursors for delivery were categorized as spontaneous labor, premature rupture of membranes indicated, and no recorded indication. After excluding anomalies, rates of neonatal morbidities by precursor were compared at each week of delivery. RESULTS: Early term births (37 0/7-38 6/7 weeks) accounted for 34.1% of term births. Overall, 53.6% of early term births were due to spontaneous labor, followed by 27.6% indicated, 15.5% with no recorded indication, and 3.3% with premature rupture of membranes. Neonatal intensive care unit admission and respiratory morbidity were lowest at or beyond 39 weeks compared with the early term period for most precursors, although indicated deliveries had the highest morbidity compared with other precursors. The greatest difference in morbidity was between 37 and 39 weeks for most precursors, although most differences in morbidities between 38 and 39 weeks were not significant. Respiratory morbidity was higher at 37 than 39 weeks regardless of route of delivery. CONCLUSION: Given the higher neonatal morbidity at 37 compared with 39 weeks regardless of delivery precursor, our data support recent recommendations for designating early term to include 37 weeks. Prospective data is urgently needed to determine the optimal timing of delivery for common pregnancy complications. PMID- 24631439 TI - The association of body mass index with serum angiogenic markers in normal and abnormal pregnancies. AB - OBJECTIVE: Because obesity is a risk factor for placental dysfunction, we hypothesized that maternal body mass index (BMI) would be associated with alterations in serum angiogenic markers. STUDY DESIGN: We included 2399 singleton pregnancies with and without placental dysfunction in a prospective longitudinal cohort study of angiogenic markers. We modeled the relationship between categorical and continuous BMI, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) over gestation, stratified by pregnancy outcome. RESULTS: In women with normal pregnancies, a higher BMI was associated with lower sFlt-1 values across gestation (P < .0001), lower PlGF in the second and third trimesters (P < .0001), and lower rate of change in PlGF (P < .0001). Similar relationships were seen between maternal BMI, sFlt-1 (P < .0001), and PlGF (P = .0005) in women with clinically evident placental dysfunction. CONCLUSION: The sFlt-1 value is inversely associated with maternal BMI. The pattern of change in PlGF is also dependent on maternal BMI, indicating that obese women may have abnormalities in angiogenesis near term. PMID- 24631440 TI - Maternal and neonatal outcomes in electively induced low-risk term pregnancies. AB - OBJECTIVE: Elective induction of labor has been discouraged over concerns regarding increased complications. We evaluated the mode of delivery and maternal and neonatal morbidities in low-risk patients whose labor was electively induced or expectantly managed at term. STUDY DESIGN: This was a retrospective cross sectional study from 12 US institutions (19 hospitals), 2002 through 2008 (Safe Labor Consortium). Healthy women with viable, vertex singleton pregnancies at 37 41 weeks of gestation were included. Women electively induced in each week were compared with women managed expectantly. The primary outcome was mode of delivery. RESULTS: Of 131,243 low-risk deliveries, 13,242 (10.1%) were electively induced. The risk of cesarean delivery was lower at each week of gestation with elective induction vs expectant management regardless of parity and modified Bishop score (for unfavorable nulliparous patients at: 37 weeks = 18.6% vs 34.2%, adjusted odds ratio, 0.40; [95% confidence interval, 0.18-0.88]; 38 weeks = 28.4% vs 35.4%, 0.65 [0.49-0.85]; 39 weeks = 23.6% vs 38.5%, 0.47 [0.38-0.57]; 40 weeks = 32.3% vs 42.3%, 0.70 [0.59-0.81]). Maternal infections were significantly lower with elective inductions. Major, minor, and respiratory neonatal morbidity composites were lower with elective inductions at >=38 weeks (for nulliparous patients at: 38 weeks = adjusted odds ratio, 0.43; [95% confidence interval, 0.26 0.72]; 39 weeks = 0.75 [0.61-0.92]; 40 weeks = 0.65 [0.54-0.80]). CONCLUSION: Elective induction of labor at term is associated with decreased risks of cesarean delivery and other maternal and neonatal morbidities compared with expectant management regardless of parity or cervical status on admission. PMID- 24631442 TI - First-trimester prediction of small-for-gestational age neonates incorporating fetal Doppler parameters and maternal characteristics. AB - OBJECTIVE: First-trimester screening for subsequent delivery of a small-for gestational-age (SGA) infant typically focuses on maternal risk factors and uterine artery (UtA) Doppler. Our aim is to test if incorporation of fetal umbilical artery (UA) and ductus venosus (DV) Doppler improves SGA prediction. STUDY DESIGN: Prospective screening study of singletons at 11-14 weeks. Maternal characteristics, serum concentrations of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin are ascertained and UtA Doppler, UA, and DV Doppler studies are performed. These parameters are tested for their ability to predict subsequent delivery of a SGA infant. RESULTS: Among 2267 enrolled women, 191 (8.4%) deliver an SGA infant. At univariate analysis women with SGA neonates are younger, more frequently African-American (AA), nulliparous, more likely to smoke, have lower PAPP-A and free beta-human chorionic gonadotropin levels. They have a higher incidence of UtA Doppler bilateral notching, higher mean UtA Doppler-pulsatility index z-scores (P < .001) and UA pulsatility index z-scores (P = .03), but no significant difference in DV pulsatility index z-scores or in the incidence of abnormal qualitative UA and DV patterns. Multivariate logistic regression analysis identifies nulliparity and AA ethnicity (P < .001), PAPP-A multiple of the median and bilateral notching (P < .05) as determinants of SGA infant. Predictive sensitivity was low; receiver operating characteristic curve analysis yields areas under the curve of 0.592 (95% confidence interval, 0.548-0.635) for the combination of UtA Doppler and UA pulsatility index z-scores. CONCLUSION: Delivery of a SGA infant is most frequent in nulliparous women of AA ethnicity. Despite the statistical association with UtA Doppler first-trimester SGA prediction is poor and not improved by the incorporation of fetal Doppler. PMID- 24631443 TI - Degradation of imidacloprid using combined advanced oxidation processes based on hydrodynamic cavitation. AB - The harmful effects of wastewaters containing pesticides or insecticides on human and aquatic life impart the need of effectively treating the wastewater streams containing these contaminants. In the present work, hydrodynamic cavitation reactors have been applied for the degradation of imidacloprid with process intensification studies based on different additives and combination with other similar processes. Effect of different operating parameters viz. concentration (20-60 ppm), pressure (1-8 bar), temperature (34 degrees C, 39 degrees C and 42 degrees C) and initial pH (2.5-8.3) has been investigated initially using orifice plate as cavitating device. It has been observed that 23.85% degradation of imidacloprid is obtained at optimized set of operating parameters. The efficacy of different process intensifying approaches based on the use of hydrogen peroxide (20-80 ppm), Fenton's reagent (H2O2:FeSO4 ratio as 1:1, 1:2, 2:1, 2:2, 4:1 and 4:2), advanced Fenton process (H2O2:Iron Powder ratio as 1:1, 2:1 and 4:1) and combination of Na2S2O8 and FeSO4 (FeSO4:Na2S2O8 ratio as 1:1, 1:2, 1:3 and 1:4) on the extent of degradation has been investigated. It was observed that near complete degradation of imidacloprid was achieved in all the cases at optimized values of process intensifying parameters. The time required for complete degradation of imidacloprid for approach based on hydrogen peroxide was 120 min where as for the Fenton and advance Fenton process, the required time was only 60 min. To check the effectiveness of hydrodynamic cavitation with different cavitating devices, few experiments were also performed with the help of slit venturi as a cavitating device at already optimized values of parameters. The present work has conclusively established that combined processes based on hydrodynamic cavitation can be effectively used for complete degradation of imidacloprid. PMID- 24631444 TI - An efficient enzymatic modification of cordycepin in ionic liquids under ultrasonic irradiation. AB - A comparative study of the immobilized Candida antarctica lipase B (Novozym 435) catalyzed acylation of cordycepin with vinyl acetate in ionic liquids (ILs) under ultrasonic irradiation and shaking was conducted. The application of ultrasonic irradiation instead of shaking during acylation resulted in an enhanced reaction rate and a higher level of substrate conversion. Among the various ILs examined, 1-butyl-3-methylimidazolium tetrafluorobrate ([C4MIm][BF4]) was the best medium for the reaction because it produced the highest substrate conversion. In [C4MIm][BF4], the optimal ultrasonic power, water activity, and reaction temperature were 120 W, 0.33, and 50 degrees C, respectively. The acylation of cordycepin in [C4MIm][BF4] proved to be regioselective under both conditions: the C5'-OH was acylated. Novozym 435 exhibited a much higher operational stability in [C4MIm][BF4], and 58.0% of its original activity was maintained after ten reuse cycles under ultrasonic irradiation. Compared with the cordycepin, the rate of adenosine deaminase-catalyzed deamination was greatly reduced when the 5'-OH was substituted by acetyl group. These results demonstrated that the combined application of ultrasonic irradiation and IL as a medium was an efficient approach for the enzymatic modification of cordycepin. PMID- 24631445 TI - Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone. AB - OBJECTIVE: The objective of this study was to examine SLN evaluation alone in women with squamous cell carcinoma (SCC) of the vulva and evaluate the inguinal recurrence and complication rates. METHODS: An IRB approved prospective study enrolled patients with SCC of the vulva. Peritumoral injection of Tc-99 sulfur colloid and blue dye was used to identify SLNs intraoperatively. Patients with negative SLN for metastasis were followed clinically without further treatment. Patients with metastasis to a SLN underwent full groin node dissection followed by standard treatment protocols. RESULTS: A total of 73 women were enrolled onto protocol with 69 patients undergoing SLN dissection. Mean age was 66.9years (range: 29-91) with 47 stage I, 12 stage II, 9 stage III, 2 stage IV and 3 unstaged patients. SLN dissections were successful in 63 patients. Of the 111 groins evaluated with a SLN dissection 93% had a SLN identified with an average of 2 SLN per groin. There were 92 groins with negative SLN and 11 groins with positive SLN. 57 patients had negative SLN and underwent conservative management with the median follow-up of 58.3months. Three patients experienced groin recurrences (2 unilateral, 1 bilateral) for a recurrence rate of 5.2% (3/57). The complication rate for the inguinal incisions was 17.5% (1 cellulitis, 1 abscess, 2 lymphoceles, 5 lymphedema and leg pain). CONCLUSIONS: Isolated SLN dissection alone has a low inguinal recurrence rate with decreased complications and should be considered as an option for women with SCC of the vulva. PMID- 24631441 TI - Can differences in obstetric outcomes be explained by differences in the care provided? The MFMU Network APEX study. AB - OBJECTIVE: The purpose of this study was to determine whether hospital differences in the frequency of adverse obstetric outcomes are related to differences in care. STUDY DESIGN: The Assessment of Perinatal EXcellence cohort comprises 115,502 women and their neonates who were born in 25 hospitals in the United States between March 2008 and February 2011. Hierarchical logistic regression was used to quantify the amount of variation in postpartum hemorrhage, peripartum infection, severe perineal laceration, and a composite adverse neonatal outcome among hospitals that is explained by differences in patient characteristics, hospital characteristics, and obstetric care provided. RESULTS: The study included 115,502 women. For most outcomes, 20-40% of hospital differences in outcomes were related to differences in patient populations. After adjusting for patient-, provider-, and hospital-level factors, multiple care processes were associated with the predefined adverse outcomes; however, these care processes did not explain significant variation in the frequency of adverse outcomes among hospitals. Ultimately, 50-100% of the interhospital variation in outcomes was unexplained. CONCLUSION: Hospital differences in the frequency of adverse obstetric outcomes could not be explained by differences in frequency of types of care provided. PMID- 24631446 TI - Suberoylanilide hydroxamic acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer. AB - OBJECTIVES: Approximately 50% of serous epithelial ovarian cancers (EOC) contain molecular defects in homologous recombination (HR) DNA repair pathways. Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in HR-deficient, but not in HR-proficient, EOC tumors as a single agent. Our goal was to determine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can sensitize HR-proficient ovarian cancer cells to the PARPi AZD-2281 (olaparib). METHODS: Ovarian cancer cell lines (SKOV-3, OVCAR-8, NCI/ADR-Res, UWB1.289 BRCA1null and UWB1.289+BRCA1 wild-type) were treated with saline vehicle, olaparib, SAHA or olaparib/SAHA. Sulforhodamine B (SRB) assessed cytotoxicity and immunofluorescence and Western blot assays assessed markers of apoptosis (cleaved PARP) and DNA damage (pH2AX and RAD51). Drug effects were also tested in SKOV-3 xenografts in Nude mice. Affymetrix microarray experiments were performed in vehicle and SAHA-treated SKOV-3 cells. RESULTS: In a microarray analysis, SAHA induced coordinated down-regulation of HR pathway genes, including RAD51 and BRCA1. Nuclear co-expression of RAD51 and pH2AX, a marker of efficient HR repair, was reduced approximately 40% by SAHA treatment alone and combined with olaparib. SAHA combined with olaparib induced apoptosis and pH2AX expression to a greater extent than either drug alone. Olaparib reduced cell viability at increasing concentrations and SAHA enhanced these effects in 4 of 5 cell lines, including BRCA1 null and wild-type cells, in vitro and in SKOV-3 xenografts in vivo. CONCLUSIONS: These results provide preclinical rationale for targeting DNA damage response pathways by combining small molecule PARPi with HDACi as a mechanism for reducing HR efficiency in ovarian cancer. PMID- 24631447 TI - Radical surgical cytoreduction in the treatment of ovarian carcinosarcoma. AB - OBJECTIVE: Carcinosarcomas are rare and aggressive ovarian malignancies. Treatment recommendations, which include surgical cytoreduction followed by platinum based chemotherapy, have been based on small amounts of retrospective data or extrapolated from experience with high-grade epithelial ovarian adenocarcinoma. Our objective was to determine the effects of radical primary cytoreduction on progression-free survival (PFS) and overall survival (OS). METHODS: Following IRB approval, records of women with ovarian carcinosarcomas diagnosed between 2000 and 2012 at our institution were reviewed. Demographics, tumor characteristics, treatments, PFS, and OS were collected. Patients were divided into three groups based on the amount of residual disease: >1cm of disease, <= 1 cm of disease, or no visible disease. Chi-square and student's t test were used to compare variables among groups. Kaplan-Meier survival curves were generated and compared with the log-rank test. RESULTS: 51 patients with ovarian carcinosarcoma were identified and all underwent primary cytoreductive surgery. Following surgical cytoreduction, 18 patients (35%) had no visible disease, 20 (39%) had <= 1 cm of disease, and 13 (25%) had >1cm of residual disease. Median PFS varied significantly among groups: 29 vs. 21 vs. 2 months (p=0.036) as did median OS: 57 vs. 32 vs. 11 months (p=0.015). When patients with stage 3 disease were analyzed separately, median OS still varied significantly among groups: 57 versus 31 versus 3 months (p=0.009). CONCLUSION: Degree of surgical cytoreduction appears to correlate with PFS and OS. Radical surgery resulting in no visible disease is recommended for the upfront surgical treatment of ovarian carcinosarcoma. PMID- 24631448 TI - Statins, aspirin and risk of thromboembolic events in ovarian cancer patients. AB - OBJECTIVES: Studies suggest that statins and low dose aspirin reduce risk of VTEs in the general population. We aimed to study the effect of these drugs on the incidence of VTEs in patients with ovarian cancer. METHODS: Patients diagnosed with ovarian cancer between 2000 and 2011 were identified through the Clalit Health Services (CHS) chronic disease registry. Data were extracted from CHS database and from computerized pharmacy records. Use of medications was analyzed as a time dependent covariate in a Cox regression model. RESULTS: Of 1746 patients 175 (10%) had a VTE during a median follow up of 3.13 years. 83 patients (5.6%) had a VTE within 2 years of diagnosis of ovarian cancer. Use of chemotherapy and stage 3 and 4 at presentation were associated with an increased risk for VTEs. Statins were used by 43.5% of the patients, and 32.3% used aspirin. Aspirin use was associated with a marginally significant reduction in incidence of VTEs within 2 years of diagnosis, HR 0.423 (95% CI 0.182-1.012, p value 0.053). Statin use was not associated with risk of VTEs. CONCLUSION: This is the first study looking at the effect of statins and aspirin on the incidence of VTEs in ovarian cancer patients. In our cohort, statins did not decrease the risk for a VTE and aspirin use was associated with a reduced risk which was marginally significant. Our results might be explained by use of low potency statins and by alternate mechanisms for VTE formation in cancer patients. PMID- 24631449 TI - Does risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair gene depend on family history of endometrial cancer or colorectal cancer? AB - OBJECTIVE: To determine whether risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair (MMR) gene depends on family history of endometrial or colorectal cancer. METHODS: We retrospectively followed a cohort of 79,166 women who were recruited to the Colon Cancer Family Registry, after exclusion of women who were relatives of a carrier of a MMR gene mutation. The Kaplan-Meier failure method was used to estimate the cumulative risk of endometrial cancer. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for association between family history of endometrial or colorectal cancer and risk of endometrial cancer. RESULTS: A total of 628 endometrial cancer cases were observed, with mean age at diagnosis of 54.4 (standard deviation: 15.7) years. The cumulative risk of endometrial cancer to age 70 years was estimated to be 0.94% (95% CI 0.83-1.05) for women with no family history of endometrial cancer, and 3.80% (95% CI 2.75-4.98) for women with at least one first- or second-degree relative with endometrial cancer. Compared with women without family history, we found an increased risk of endometrial cancer for women with at least one first- or second-degree relative with endometrial cancer (HR 3.66, 95% CI 2.63-5.08), and for women with one first degree relative with colorectal cancer diagnosed at age <50 years (HR 1.48, 95% CI 1.15-1.91). CONCLUSION: An increased risk of endometrial cancer is associated with a family history of endometrial cancer or early-onset colorectal cancer for women without a MMR gene mutation, indicating for potential underlying genetic and environmental factors shared by colorectal and endometrial cancers other than caused by MMR gene mutations. PMID- 24631450 TI - Liquid-based cytology and human papillomavirus testing: a pooled analysis using the data from 13 population-based cervical cancer screening studies from China. AB - OBJECTIVE: The objective of this study was to evaluate the impact of introducing HR-HPV testing in cytology regarding cervical cancer screening practice. METHODS: A pooled analysis of liquid-based cytology (LBC) and HR-HPV testing using data from 13 population-based cervical cancer screening studies conducted in China was performed. Participants (n=25,404) received LBC and HR-HPV testing. Women found to be positive on screening were referred for colposcopy and biopsy. The effectiveness of screening strategies that use: LBC with HR-HPV triage for atypical squamous cells of undetermined significance (ASC-US), HR-HPV testing with cytology triage for HPV positive tests, or LBC and HPV cotesting was compared with that of LBC screening alone. RESULTS: LBC with HR-HPV triage for ASC-US had similar sensitivity compared with LBC alone, but significantly increased specificity for both cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3 or worse (CIN3+) endpoints, and had the best balance between sensitivity and specificity among the strategies. LBC and HR-HPV cotesting had the highest sensitivity and negative predictive value (NPV) and could permit a safe extension of screening intervals. Through the use of an immediate colposcopy threshold of ASC-US or worse for HR-HPV positive women and the use of a raised threshold of low-grade squamous intraepithelial lesion (LSIL) or worse for HR-HPV negative women, LBC and HR-HPV cotesting could provide the same effectiveness as LBC testing with HR-HPV triage for ASC-US at baseline tests. CONCLUSIONS: The results of the current study support the use of the cervical cancer screening guidelines in China. PMID- 24631451 TI - Recurrent high-grade cervical lesion after primary conization is associated with persistent human papillomavirus infection in Norway. AB - OBJECTIVE: This retrospective registry-based study aimed to assess the human papillomavirus (HPV)-type distribution in primary and recurrent high-grade cervical intraepithelial neoplasia (CIN2+), and to discriminate pre-existing from newly-acquired infections. METHODS: Cervical specimens from 58 women (median age (Q1-Q3): 37.6 (31.7-44.9)) who underwent primary (1998-2003) and repeat conizations were confirmed as CIN2+ during expert pathology review. HPV testing was performed using PCR MP-TS123 Luminex for 16 HPV types. Molecular HPV16 E6 and HPV18 LCR DNA sequencing was performed on specimens with persistent HPV16/18. RESULTS: All 58 paired cones were HPV positive; 49 had CIN3+ in the primary cone. Forty-seven (95.9%) women with primary CIN3+ and recurrent CIN2+ had persistent high-risk (hr) HPV infection, of which 74.5% were HPV16/18. Two women had probable newly-acquired HPV16/52/56 and HPV39 infections. One woman with persistent HPV52 also had a probable new HPV16 E6 variant in the recurrent CIN2+. Median time delay (Q1-Q3) between conizations was 2.0 years (1.1-4.0), being shorter for women older than 40 years: 2.6 years (1.1-3.7) than for women younger than 40 years: 6.0 years (2.0-8.7). Primary conization histology revealed CIN3, cervical adenocarcinoma in situ and microinvasive carcinomas in 43 (87.8%), 5 (10.2%) and 1 (2.0%) women, respectively. Primary HPV16- and HPV18-infected CIN3+ had a shorter delay between conizations: 1.8years (1.2-4.4) and 2.2 years (0.4 NE), respectively, compared to HPV33-: 3.8 years (3.3-7.8) or other HPV type infected: 8.2 years (6.0-NE) CIN3+. CONCLUSIONS: Routine post-conization hr-HPV DNA testing together with cervical cytology may provide a better prediction for potential recurrent disease. Further, primary prevention through adolescent vaccination may prevent CIN2+ and its recurrence. PMID- 24631452 TI - Quality of life of women with lower limb swelling or lymphedema 3-5 years following endometrial cancer. AB - OBJECTIVE: To quantitatively assess and compare the quality of life (QoL) of women with a self-reported diagnosis of lower limb lymphedema (LLL), to women with lower limb swelling (LLS), and to women without LLL or LLS following treatment for endometrial cancer. METHODS: 1399 participants in the Australian National Endometrial Cancer Study were sent a follow-up questionnaire 3-5 years after diagnosis. Women were asked if they had experienced swelling in the lower limbs and, if so, whether they had received a diagnosis of lymphedema by a health professional. The 639 women who responded were categorized as: Women with LLL (n=68), women with LLS (n=177) and women without LLL or LLS (n=394). Multivariable-adjusted generalized linear models were used to compare women's physical and mental QoL by LLL status. RESULTS: On average, women were 65 years of age and 4 years after diagnosis. Women with LLL had clinically lower physical QoL (M=41.8, SE=1.4) than women without LLL or LLS (M=45.1, SE=0.8, p=.07), however, their mental QoL was within the normative range (M=49.6; SE=1.1 p=1.0). Women with LLS had significantly lower physical (M=41.0, SE=1.0, p=.003) and mental QoL (M=46.8; SE=0.8, p<.0001) than women without LLL or LLS (Mental QoL: M=50.6, SE=0.8). CONCLUSION: Although LLL was associated with reductions in physical QoL, LLS was related to reductions in both physical and mental QoL 3-5 years after cancer treatment. Early referral to evidence-based lymphedema programs may prevent long-term impairments to women's QoL. PMID- 24631453 TI - A suggested modification to FIGO stage I endometrial cancer. AB - OBJECTIVE: FIGO stage I endometrial cancers are divided into two substages, regardless of the presence or absence of lymphovascular space invasion (LVSI). The aim of this study was to investigate whether stratification based on the LVSI status would better predict mortality. METHODS: Using a multicentric database, we identified patients who underwent endometrial cancer operations between 2000 and 2010. The staging performance was quantified with respect to discrimination. RESULTS: The study cohort included 508 patients (198 with LVSI-positive tumors and 310 with LVSI-negative tumors). The survival difference between the stage I patients with LVSI-positive and LVSI-negative tumors was highly significant (81% and 97%, respectively P=.009), whereas the difference between the stage I patients with tumors invading greater or less than half of the myometrium was not (87% and 96%, respectively P=0.09). The 5-year OS rates for the patients with LVSI-negative tumors invading less than half of the myometrium, with LVSI negative tumors invading more than half of the myometrium and with LVSI-positive invading more than or less than half of the myometrium were 98%, 95%, and 81%, respectively (P=.03). Separating the LVSI-negative and LVSI-positive tumors would improve discrimination (concordance index, 77% vs. 75%, respectively, using the actual staging system). CONCLUSION: A LVSI-positive status has a significantly worse prognosis. In this study, the distinction by LVSI status appears to be more relevant than the distinction between stages IA and IB for predicting survival in stage I endometrial cancer. This difference in prognosis would favor restaging these two entities. PMID- 24631454 TI - Adjuvant chemotherapy in stage I-II uterine leiomyosarcoma: a multicentric retrospective study of 140 patients. AB - OBJECTIVE: About 50-60% of patients with stage I-II uterine leiomyosarcoma (ULMS), primarily treated with surgery, relapse and die from progressive disease. In this retrospective study we describe the impact of adjuvant chemotherapy in this subset of patients. METHODS: 140 women treated from 1976 to 2011 were included in the study. Univariate and multivariate analysis were used to test the association of clinical features and adjuvant treatments with overall survival (OS) and disease-free survival (DFS). RESULTS: 62 women did not receive any further treatment after hysterectomy, 14 had radiotherapy (RT), 52 chemotherapy and 12 chemo-radiotherapy. Chemotherapy based on doxorubicin and ifosfamide combination was used in 54 cases. After a median follow-up of 63months, 87 women (62%) have relapsed, and 62 (44%) have died. The vast majority of patients who relapsed had distant recurrences (72%). The 5year median DFS and OS were 43% and 64% respectively. After 5years of follow up 68.7% of women treated with chemotherapy (+/-RT) vs 65.6% of patients only observed were alive (p=0.521). In the univariate analysis no factors had a statistical impact on DFS, while number of mitosis (>20*10HPF), age (>60years) and adjuvant radiotherapy were found as negative prognostic factors for OS. In the multivariate analysis only mitosis and age remained significant for OS. CONCLUSION: Adjuvant chemotherapy was not associated with a significant survival benefit and should not be considered as standard of care for patients with stage I-II ULMS until randomized clinical studies will give further information. PMID- 24631455 TI - Grand rounds: Eyelid swelling after nose blowing. PMID- 24631456 TI - Illness course and quality of life in Mexican patients with psychosis. AB - OBJECTIVE: To analyze the differences in the quality of life of patients with psychosis according to the course of the illness. METHOD: Clinical records and SCID-I interviews were used to establish the course of the illness and to categorize it according to 3 criteria: a) relapses, b) residual symptoms, and c) clinical diagnosis. Subjective quality of life was assessed with the Seville Questionnaire. RESULTS: Sixty one patients (56% women) participated, reporting a mostly adequate quality of life. An illness course characterized by the presence of residual symptoms, rather than by the occurrence of any relapse or the progression of a first-episode psychosis into schizophrenia, showed a negative effect on the perceived quality of life of patients. CONCLUSIONS: The clinical services provided to patients with psychosis should focus not only on symptoms remission and relapse prevention, but also achieving a recovery with a satisfactory quality of life. Having identified residual symptoms as a crucial factor negatively affecting quality of life, clinicians must carefully assess them and treat them, in order to achieve the best possible recovery. PMID- 24631457 TI - The role of c-Jun in controlling the EPAC1-dependent induction of the SOCS3 gene in HUVECs. AB - The cyclic AMP sensor, EPAC1, activates AP1-mediated transcription in HUVECs. Correspondingly, induction of the SOCS3 minimal promoter by EPAC1 requires a single AP1 site that constitutively binds phosphorylated (Ser63) c-Jun in DNA pull-down assays. c-Jun (Ser63) becomes further phosphorylated following cyclic AMP stimulation and specific activation of protein kinase A (PKA), but not through selective activation of EPAC1. Moreover, despite a requirement for c-Jun for SOCS3 induction in fibroblasts, phospho-null c-Jun (Ser63/73Ala) had little effect on SOCS3 induction by cyclic AMP in HUVECs. AP1 activation and SOCS3 induction by EPAC1 in HUVECs therefore occur independently of c-Jun phosphorylation on Ser63. PMID- 24631458 TI - Shuttling of information between the mucosal and luminal environment drives intestinal homeostasis. AB - The gastrointestinal tract is a passageway for dietary nutrients, microorganisms and xenobiotics. The gut is home to diverse bacterial communities forming the microbiota. While bacteria and their metabolites maintain gut homeostasis, the host uses innate and adaptive immune mechanisms to cope with the microbiota and luminal environment. In recent years, multiple bi-directional instructive mechanisms between microbiota, luminal content and mucosal immune systems have been uncovered. Indeed, epithelial and immune cell-derived mucosal signals shape microbiota composition, while microbiota and their by-products shape the mucosal immune system. Genetic and environmental perturbations alter gut mucosal responses which impact on microbial ecology structures. On the other hand, changes in microbiota alter intestinal mucosal responses. In this review, we discuss how intestinal epithelial Paneth and goblet cells interact with the microbiota, how environmental and genetic disorders are sensed by endoplasmic reticulum stress and autophagy responses, how specific bacteria, bacterial- and diet-derived products determine the function and activation of the mucosal immune system. We will also discuss the critical role of HDAC activity as a regulator of immune and epithelial cell homeostatic responses. PMID- 24631459 TI - Botulism in Greenland. PMID- 24631460 TI - Charting the dynamics of translation. AB - Codon usage bias (CUB) is the well-known phenomenon that the frequency of synonymous codons is unequal. This is presumably the result of adaptive pressures favouring some codons over others. The underlying reason for this pressure is unknown, although a large number of possible driver mechanisms have been proposed. According to one hypothesis, the decoding time could be such a driver. A tacit assumption of this hypothesis is that faster codons lead to a higher translation rate which in turn is more resource efficient. While it is generally assumed that there is such a link, there are no rigorous studies to establish under which conditions the link between translation speed and rate actually exists. Using a computational simulation model and explicitly calculated codon decoding times, this contribution maps the entire range of dynamical regimes of translation. These simulations make it possible to understand precisely under which conditions translation speed and rate are linked. PMID- 24631461 TI - The structure and assembly mechanism of a novel three-stranded tubulin filament that centers phage DNA. AB - Tubulins are a universally conserved protein superfamily that carry out diverse biological roles by assembling filaments with very different architectures. The underlying basis of this structural diversity is poorly understood. Here, we determine a 7.1 A cryo-electron microscopy reconstruction of the bacteriophage encoded PhuZ filament and provide molecular-level insight into its cooperative assembly mechanism. The PhuZ family of tubulins is required to actively center the phage within infected host cells, facilitating efficient phage replication. Our reconstruction and derived model reveal the first example of a three-stranded tubulin filament. We show that the elongated C-terminal tail simultaneously stabilizes both longitudinal and lateral interactions, which in turn define filament architecture. Identified interaction surfaces are conserved within the PhuZ family, and their mutagenesis compromises polymerization in vitro and in vivo. Combining kinetic modeling of PhuZ filament assembly and structural data, we suggest a common filament structure and assembly mechanism for the PhuZ family of tubulins. PMID- 24631462 TI - Nucleotides and substrates trigger the dynamics of the Toc34 GTPase homodimer involved in chloroplast preprotein translocation. AB - GTPases are molecular switches that control numerous crucial cellular processes. Unlike bona fide GTPases, which are regulated by intramolecular structural transitions, the less well studied GAD-GTPases are activated by nucleotide dependent dimerization. A member of this family is the translocase of the outer envelope membrane of chloroplast Toc34 involved in regulation of preprotein import. The GTPase cycle of Toc34 is considered a major circuit of translocation regulation. Contrary to expectations, previous studies yielded only marginal structural changes of dimeric Toc34 in response to different nucleotide loads. Referencing PELDOR and FRET single-molecule and bulk experiments, we describe a nucleotide-dependent transition of the dimer flexibility from a tight GDP- to a flexible GTP-loaded state. Substrate binding induces an opening of the GDP-loaded dimer. Thus, the structural dynamics of bona fide GTPases induced by GTP hydrolysis is replaced by substrate-dependent dimer flexibility, which likely represents a general regulatory mode for dimerizing GTPases. PMID- 24631464 TI - miRNAs in lung cancer: a link to aging. AB - Lung cancer is a leading cause of cancer deaths worldwide. Development of lung cancer is associated with exposure to carcinogens such as tobacco smoke and some environmental factors. The incidence of lung cancer increases with age, particularly after age 60. It was estimated that less than 2% of all lung cancer cases occurred in patients younger than 45; therefore, this type of tumor can be considered as an aging-related disease. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating expression of over 50% of protein-coding genes. miRNAs were shown to play an extremely important role in cell functioning, affecting all biological processes, as well as development of various diseases. Expression profiles of miRNAs are known to be altered in cancer, including lung cancer, and also exhibit changes during aging. These RNA molecules are stable in tissue sections and blood and reflect tumor origin, histotype, and stage, which make them candidate diagnostic and prognostic biomarkers. miRNA mimetics or inhibitors can be delivered into a cell, with possible therapeutic implications. Here, we review the results obtained during the last several years that demonstrate the aging-related regulation of miRNAs expression, in association with their role in lung cancer initiation, progression, and resistance to anticancer therapy, as well as the possibility to use miRNAs as predictive biomarkers for treatment response. PMID- 24631463 TI - Using a combined computational-experimental approach to predict antibody-specific B cell epitopes. AB - Antibody epitope mapping is crucial for understanding B cell-mediated immunity and required for characterizing therapeutic antibodies. In contrast to T cell epitope mapping, no computational tools are in widespread use for prediction of B cell epitopes. Here, we show that, utilizing the sequence of an antibody, it is possible to identify discontinuous epitopes on its cognate antigen. The predictions are based on residue-pairing preferences and other interface characteristics. We combined these antibody-specific predictions with results of cross-blocking experiments that identify groups of antibodies with overlapping epitopes to improve the predictions. We validate the high performance of this approach by mapping the epitopes of a set of antibodies against the previously uncharacterized D8 antigen, using complementary techniques to reduce method specific biases (X-ray crystallography, peptide ELISA, deuterium exchange, and site-directed mutagenesis). These results suggest that antibody-specific computational predictions and simple cross-blocking experiments allow for accurate prediction of residues in conformational B cell epitopes. PMID- 24631465 TI - Comparison of zotarolimus- and everolimus-eluting stents in patients with ST elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with poor outcomes after percutaneous coronary intervention (PCI). The aim of the study was to compare zotarolimus- and everolimus-eluting stents used during primary PCI in patients with acute myocardial infarction (AMI) and CKD. METHODS: We selected 854 consecutive ST-elevation MI patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) undergoing primary PCI who were followed up for 12 months. They were divided into two groups based on type of stents implanted: (1) zotarolimus-eluting stent (ZES) and (2) everolimus-eluting stent (EES). The study end point was the 12-month major adverse cardiac events (MACE) which included all cause death, non-fatal MI, target lesion revascularization (TLR), and target vessel revascularization (TVR). RESULTS: The average number of stents used per vessel was 1.4 +/- 0.7. A total of 433 patients received ZES and 421 patients received EES. There was no significant difference in the incidence of 12-month MI, TLR, or TVR. All-cause death was found to be borderline significant between two groups (2.8% in ZES vs 0.9% in EES, p=0.05). The incidence of 12-month MACE in ZES and EES was 5.7% and 2.6% respectively, p=0.022. Stent thrombosis did not differ between groups (p=0.677). Kaplan-Meier analysis did not show significant difference for 12-month MACE-free survival between groups (log-rank p=0.158). It remained the same even after propensity adjustment for multiple confounders in Cox model (p=0.326). CONCLUSIONS: Implantation of ZES or EES provided comparable clinical outcomes with similar risk of 12-month MACE and death in STEMI patients with CKD undergoing primary PCI. PMID- 24631466 TI - Homocysteine and metabolic syndrome: from clustering to additional utility in prediction of coronary heart disease. AB - BACKGROUND: The association between homocysteine (Hcy) and metabolic syndrome (MetS)-related disorders remains to be unveiled. First, the role of Hcy-MetS interaction in prediction of coronary heart disease (CHD) was assessed. Next, we investigated whether serum Hcy improves CHD risk-prediction beyond MetS and traditional risk factors (TRFs). DESIGN: A prospective study of 5893 community dwelling participants (two sub-cohorts, 3286 diabetic and 2607 non-diabetic; ~ 8.5 years of follow-up). METHODS: Clustering of Hcy with MetS components was assessed using exploratory factor-analysis. Cox regression hazard ratio (HR) was used to predict CHD using Hcy level and MetS status. Baseline model included MetS and TRFs. Addition of Hcy and hyper-homocysteinemia (HHcy) to the baseline model was evaluated in two separate models. RESULTS: Hcy was correlated with MetS components, especially with systolic blood pressure. The factor linking MetS to CHD is the factor through which Hcy is linked to MetS. HHcy and MetS interacted as risk factors for CHD. CONCLUSION: Hcy adds to the value of MetS and TRFs for CHD risk-prediction by reclassifying around 47.3-49.0% of the overall and 21.6 28.1% of the intermediate-risk population. PMID- 24631467 TI - Higher quality of molecular testing, an unfulfilled priority: Results from external quality assessment for KRAS mutation testing in colorectal cancer. AB - Precision medicine is now a key element in clinical oncology. RAS mutational status is a crucial predictor of responsiveness to anti-epidermal growth factor receptor agents in metastatic colorectal cancer. In an effort to guarantee high quality testing services in molecular pathology, the European Society of Pathology has been organizing an annual KRAS external quality assessment program since 2009. In 2012, 10 formalin-fixed, paraffin-embedded samples, of which 8 from invasive metastatic colorectal cancer tissue and 2 artificial samples of cell line material, were sent to more than 100 laboratories from 26 countries with a request for routine KRAS testing. Both genotyping and clinical reports were assessed independently. Twenty-seven percent of the participants genotyped at least 1 of 10 samples incorrectly. In total, less than 5% of the distributed specimens were genotyped incorrectly. Genotyping errors consisted of false negatives, false positives, and incorrectly genotyped mutations. Twenty percent of the laboratories reported a technical error for one or more samples. A review of the written reports showed that several essential elements were missing, most notably a clinical interpretation of the test result, the method sensitivity, and the use of a reference sequence. External quality assessment serves as a valuable educational tool in assessing and improving molecular testing quality and is an important asset for monitoring quality assurance upon incorporation of new biomarkers in diagnostic services. PMID- 24631468 TI - Peri-operative management of anticoagulation and antiplatelet therapy in gastrointestinal surgery. AB - Peri-operative management of the risks of hemorrhage and thrombosis related to gastrointestinal surgery tailored to patient characteristics are part of daily multidisciplinary practice tasks. The goal of this update is to discuss current practices concerning antithrombosis prophylaxis and the management of recently developed anticoagulants and antiplatelet agents. The duration of prophylaxis is 1 month for oncological surgery. The recommended doses in bariatric surgery are twice daily injections of low-molecular weight heparin without exceeding a total dose of 10,000 IU/day. Dual antiplatelet therapy is necessary for 6 weeks after placement of bare-metal stents, from 6-12 months for drug-eluting stents, and 12 months after an acute coronary artery syndrome. Abrupt discontinuation of antiplatelet therapy exposes the patient to an increased risk of thrombosis. Data are insufficient to make specific recommendations for antiplatelet therapy in gastrointestinal surgery. For major digestive surgery, prescription of daily aspirin should be discussed case by case. If discontinuation of treatment is absolutely necessary, this should be as short as possible (aspirin: 3 days, ticagrelor and clopidogrel: 5 days, prasugrel: 7 days). The modalities for elective management of new oral anticoagulants are similar to those for classical vitamin K antagonists (VKA) therapy, except that any overlapping with heparin administration must be avoided. In the emergency setting, an algorithm can be proposed depending on the drug, the available coagulation tests and the interval before performing surgery. PMID- 24631469 TI - Exit, voice, and radiology. PMID- 24631470 TI - Hemodynamic regulator and mitogenic growth factor: re-visiting the age old question with ACE2 and Jak2. PMID- 24631471 TI - Proteinase-activated receptor-1 (PAR1) and PAR2 mediate relaxation of guinea pig internal anal sphincter. AB - Activation of proteinase-activated receptor-1 (PAR1) and PAR2 stimulates contraction of the rat but relaxation of the guinea pig colon. The aim of the present study was to investigate PAR effects on internal anal sphincter (IAS) motility. We measured relaxation of isolated muscle strips from the guinea pig IAS caused by PAR agonists using isometric transducers. Reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the existence of PAR. In the IAS, thrombin and PAR1 peptide agonists TFLLR-NH2 and SFLLRN-NH2 evoked moderate to marked relaxation in a concentration-dependent manner. In addition, trypsin and PAR2 peptide agonists 2-furoyl-LIGRLO-NH2, SLIGRL-NH2 and SLIGKV-NH2 produced relaxation. In contrast, both PAR1 and PAR2 inactive control peptides did not elicit relaxation. Furthermore, the selective PAR1 antagonist vorapaxar and PAR2 antagonist GB 83 specifically inhibited thrombin and trypsin induced relaxations, respectively. RT-PCR revealed the presence of PAR1 and PAR2 in the IAS. This indicates that PAR1 and PAR2 mediate the IAS relaxation. The relaxant responses of TFLLR-NH2 and trypsin were attenuated by N(omega)-Nitro-L arginine (L-NNA), indicating involvement of NO. These responses were not affected by tetrodotoxin, implying that the PAR effects are not neurally mediated. On the other hand, PAR4 agonists GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2 did not cause relaxation or contraction, suggesting that PAR4 is not involved in the sphincter motility. Taken together, these results demonstrate that both PAR1 and PAR2 mediate relaxation of the guinea pig IAS through the NO pathway. PAR1 and PAR2 may regulate IAS tone and might be potential therapeutic targets for anal motility disorders. PMID- 24631472 TI - Response to the "letter to the editor" by Ramsey et al. [Med. Eng. Phys. 36 (2014) 805]. PMID- 24631473 TI - Predictors of clinical success among a national Veterans Affairs cohort with methicillin-resistant Staphylococcus aureus pneumonia. AB - BACKGROUND: The treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is exceedingly complicated, which is concerning because of the high mortality rate associated with the infection. Identification of independent predictors of clinical success can optimize patient care by assisting clinicians in treatment decisions. OBJECTIVES: Our goal was to identify independent predictors of clinical success in a national Veterans Affairs (VA) cohort of patients with MRSA pneumonia. METHODS: A nested case-control study was conducted among a cohort of VA patients with MRSA pneumonia receiving linezolid or vancomycin between January 2002 and September 2010. Cases included those demonstrating clinical success, defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Control subjects represented nonsuccess, defined as therapy change, intubation, intensive care unit admission, readmission, or death between treatment initiation and day 14. The potential predictors assessed included treatment, patient demographic and admission characteristics, previous health care and medication exposures, comorbidities, and medical history. Odds ratios (ORs) and 95% CIs were calculated from logistic regression. RESULTS: Our study included 2442 cases of clinical success and 1290 control subjects. Demographic characteristics varied between the clinical success and nonsuccess groups, including age, race, and region of facility. A current diagnosis of chronic respiratory disease (46% vs 42%) and diagnosis of pneumonia in the year before the MRSA pneumonia admission (37% vs 32%) were both more common in the clinical success group. Despite these significant differences, only 2 predictors of clinical success were identified in our study: previous complication of an implant or graft, including mechanical complications and infections, in the year before the MRSA pneumonia admission (adjusted OR, 1.55 [95% CI, 1.17-2.06]) and treatment with linezolid (adjusted OR, 1.53 [95% CI, 1.12-2.10]). Predictors of nonsuccess (adjusted OR [95% CI) included diagnosis of concomitant urinary tract infection (0.82 [0.70-0.96]), intravenous line (0.76 [0.66-0.89]), previous coagulopathy (0.74 [0.56-0.96]), previous amputation procedure (0.72 [0.53-0.98]), current coagulopathy diagnosis (0.71 [0.53-0.96]), dialysis (0.54 [0.38-0.76]), multiple inpatient procedures (0.53 [0.45-0.62]), inpatient surgery (0.48 [0.41-0.57]), and previous endocarditis (0.24 [0.07 0.81]). CONCLUSIONS: MRSA pneumonia tends to affect patients with complex care, and identification of the predictors of clinical success is useful when considering different therapeutic approaches. In this national cohort of VA patients with MRSA pneumonia, treatment was the only modifiable variable predicting clinical success. PMID- 24631474 TI - Morphologic characteristics of macular complications of a dome-shaped macula determined by swept-source optical coherence tomography. AB - PURPOSE: To investigate the morphologic characteristics of macular complications of dome-shaped maculas using swept-source optical coherence tomography (OCT). DESIGN: Retrospective observational case series. METHODS: Axial length measurements and swept-source OCT were performed in 49 highly myopic eyes (in 5 male and 30 female subjects) with dome-shaped maculas. We classified the dome patterns and measured the central retinal thickness, central choroidal thickness, central scleral thickness, and the macular bulge height, and assessed the associations of these parameters with macular complications. RESULTS: The central scleral thickness was significantly negatively correlated with age and the axial length. We classified the eyes into 3 groups: 6 with choroidal neovascularization (CNV group), 8 with retinal pigment epithelial detachment (PED group; 5 with serous retinal detachment), and 35 with no complications (no complications group). Nine eyes had a round dome and 40 had horizontally oriented oval-shaped domes. There were no significant differences in the frequency of macular complications between these patterns. The CNV group was significantly older and had a longer axial length than the other groups. The PED group had significantly larger values for both the central scleral thickness and bulge height than the other groups. The central choroidal thickness was significantly thinner in the CNV group than in the no complications group. CONCLUSION: A dome-shaped macula results from relative thickening of the macular sclera, and this may lead to PED. Thinning of the sclera owing to long-term changes and elongation of the axis may develop CNV and cause visual impairment. PMID- 24631475 TI - Management of idiopathic retinal vasoproliferative tumors by slit-lamp laser or endolaser photocoagulation. AB - PURPOSE: To report the efficacy of laser photocoagulation in treating idiopathic (primary) retinal vasoproliferative tumors. DESIGN: Retrospective noncomparative interventional case series. PATIENTS AND METHOD: Thirty eyes of 30 patients (22 women and 8 men) with retinal vasoproliferative tumors. Main outcome measures were best-corrected visual acuity (BCVA), presence of retinal hard exudates, retinal detachment (RD), cystoid macular edema (CME), and epiretinal membrane (ERM). Laser photocoagulation was performed at the slit lamp or during pars plana vitrectomy for telangiectasia visible at the retinal vasoproliferative tumors surface. RESULTS: Fifteen eyes were treated with slit-lamp laser. Mean follow-up was 36.5 months (range 7 months to 11 years). Mean BCVA increased from 20/40 to 20/32 at the end of the follow-up. Hard exudates and CME regressed completely in 15 of 15 and 5 of 6 eyes, respectively. Fifteen eyes underwent vitrectomy owing to the presence of ERM (10 eyes), large exudative RD (4 eyes), or vitreous hemorrhage (1 eye). Mean follow-up was 24 months (9 months to 3.5 years). Mean BCVA increased from 20/125 to 20/40 at the end of the follow-up. No vision loss occurred. The retina reattached in all cases. Hard exudates regressed completely in 14 of 15 eyes and decreased significantly in 1. Postoperative complications were rhegmatogenous RD in 2 eyes, successfully reattached after additional surgery. CONCLUSION: Selective laser photocoagulation of retinal telangiectasia at the retinal vasoproliferative tumors' surface induced the regression of retinal exudation. Slit-lamp laser photocoagulation was sufficient in half of the cases. In more severe conditions, direct endolaser photocoagulation of the telangiectasia was required. PMID- 24631476 TI - Intraocular lens injector-induced stress on the corneal incisions during lens implantation. AB - PURPOSE: To describe a model for calculating induced stress on corneal incisions during intraocular lens implantation, and to compare the nozzles of common injectors using 2 incision sizes. DESIGN: Experimental study. METHODS: A finite element calculation model was developed and used to compare 7 commercially available injectors in widespread clinical use. The injectors' characteristics were measured and correlated for the stress they induced for 2.4- or 2.2-mm corneal incisions. RESULTS: Each injector created a different level of stress on the corneal incision. The stress was highest at the incision margins, and its level correlated with the injector's external circumference. The induced stress on 2.2-mm incision margins was about 9% higher compared to the induced stress on 2.4-mm incision margins. CONCLUSIONS: A model for comparing stress induced on corneal incisions during intraocular lens implantation by 7 injectors revealed different levels of induced stress on the incision margins. It is therefore recommended that the choice of injector be matched to the size of the corneal incision. PMID- 24631477 TI - Laminar resorption in modified osteo-odonto-keratoprosthesis procedure: a cause for concern. AB - PURPOSE: To analyze the cases of lamina resorption following the modified osteo odonto-keratoprosthesis (MOOKP) procedure. DESIGN: Retrospective case series. PATIENTS AND METHODS: Case records of 18 eyes (20 laminae) of 17 patients who showed evidence of lamina resorption out of the 85 eyes (87 laminae) of 82 patients that underwent MOOKP procedure between March 2003 and March 2013 were analyzed. RESULTS: Of the 17 patients (20 laminae), 1 underwent MOOKP procedure following multiple graft failures, 6 (7 laminae) belonged to the chemical injury group, and 10 (12 laminae) to the Stevens-Johnson syndrome (SJS) group. Resorption was noted in 20 out of 87 laminae (22.98%). The need for removal of lamina/extrusion was noted in 3 out of the 7 laminae in the chemical injury group and 8 out of the 12 laminae in the SJS group. The mean duration to the first sign suggestive of resorption among patients of SJS was 36.7 months and among patients of chemical injury was 43 months. Vitritis was the presenting feature (7 of 20 laminae, 35%) indicative of early resorption, and the occurrence of the same in eyes with lamina resorption was noted to be statistically significant in comparison to controls (P<.001). Sixteen out of 20 laminae showed evidence of resorption superiorly. CONCLUSION: Vitritis was the most common presenting feature of lamina resorption and could be an indicator of lamina resorption. Resorption of the laminae was noted to occur along the aspect with thinner bone support in all eyes. Incidence of severe resorption with extrusion of cylinder/requiring lamina removal was noted to be higher among patients with SJS. PMID- 24631478 TI - New testing options for diagnosing and grading dry eye disease. AB - PURPOSE: To describe new options for diagnosis and severity grading of dry eye disease. DESIGN: Perspective on technological advancements to identify tear dysfunction and their value in diagnosing and grading dry eye disease. METHODS: Evidence is presented on new and evolving technologies to measure tear stability, composition, and meniscus height and their role in dry eye diagnosis and therapeutic efficacy grading is assessed. RESULTS: Evolving concepts regarding pathogenesis and new technologies to evaluate the tears and ocular surface have improved the ability to diagnose, classify, and grade the severity of dry eye disease. New technologies include noninvasive imaging of tear stability and tear meniscus height as a measure of tear volume and tear composition (osmolarity, lacrimal factors, inflammatory mediators, growth and differentiation factors). Approved tests, such as tear osmolarity and tear imaging, are being integrated into clinical practice and may eventually supplant certain traditional tests that have greater variability and less sensitivity. Other tests, such as molecular assays of tears and conjunctival cells, are currently being used in studies investigating pathogenesis and therapeutic mechanism of action. They may eventually translate to routine clinical practice. CONCLUSIONS: New technologies have emerged that can noninvasively evaluate the tears and measure disease associated compositional changes. These tests are being integrated into clinical practice and therapeutic trials for diagnosis, classification, and severity grading of dry eye disease. PMID- 24631479 TI - Ghost maculopathy: an artifact on near-infrared reflectance and multicolor imaging masquerading as chorioretinal pathology. AB - PURPOSE: To describe the features of an artifact on near-infrared reflectance and MultiColor imaging, termed "ghost maculopathy," and to illustrate how it may masquerade as true chorioretinal pathology. DESIGN: This was a retrospective, observational case series. METHODS: The authors studied 144 eyes of 72 consecutive patients in a vitreoretinal clinical practice, reviewing multimodal imaging including color and red-free fundus photography, fundus autofluorescence (FAF), near-infrared reflectance, MultiColor imaging, and spectral-domain optical coherence tomography (SD OCT). RESULTS: In 36 of 144 eyes (25%), there was an appearance of a hyper-reflective spot on near-infrared reflectance and MultiColor imaging, located at the macula, nasal or superonasal to the fovea, which did not correspond to any apparent lesion on color and red-free fundus photography, FAF, or SD OCT. This spot was termed the "ghost image" in this phenomenon of "ghost maculopathy." The ghost image was present consistently on near-infrared reflectance and MultiColor imaging in all 36 eyes at every imaging encounter, showing minimal and subtle variability in its shape and location within each eye; however, it showed large interindividual variability in size, shape, location, and reflectivity between different eyes. Nine eyes were found to have a similar hyper-reflective spot resembling that in ghost maculopathy, but corresponding SD OCT images were consistent with diagnoses of choroidal nevus, age-related macular degeneration, and multifocal choroiditis. All eyes with ghost maculopathy were found to be pseudophakic with a posterior chamber intraocular lens. CONCLUSION: Ghost maculopathy is the phenomenon of an imaging artifact appearing at the macula on near-infrared reflectance and MultiColor imaging that occurs predominantly in pseudophakic patients and may be mistaken for true chorioretinal pathology. Awareness of this artifact is prudent to avoid misinterpretation of clinical findings and possible unnecessary over-investigation. PMID- 24631480 TI - Differential miRNA expression defines migration and reduced apoptosis in follicular thyroid carcinomas. AB - The objective of the study was to identify microRNAs (miRs) characteristic for follicular thyroid carcinoma (FTC) and to define their role in tumorigenesis. A miR-microarray study was conducted to identify miRs differentially expressed between FTCs and their surrounding tissues. Selection was further reinforced by a literature review. Four miRs were selected and confirmed by RT-qPCR: miR-146b, 183, -221 were up-regulated, whereas miR-199b down-regulated in FTCs. The influence of these miRs on cell proliferation, cell cycle, apoptosis and migration was studied in HTori and FTC-133 cells. Functional characterization suggests an impact of miR-183 and miR-146b in FTC development. Overexpression of both miRs significantly induces migration. Moreover, overexpression of miR-183 significantly represses apoptosis. MiR-199b and -221 do not have significant effects on proliferation, cell cycle, apoptosis or migration in HTori and FTC-133 cells. Our data suggest that miR-146b and miR-183 may influence FTC development through the induction of migration and apoptosis inhibition. PMID- 24631481 TI - Expression, signaling and function of Egr transcription factors in pancreatic beta-cells and insulin-responsive tissues. AB - Egr-1 and the related zinc finger transcription factors Egr-2, Egr-3, and Egr-4 are stimulated by many extracellular signaling molecules and represent a convergence point for intracellular signaling cascades. Egr-1 expression is induced in insulinoma cells and pancreatic beta-cells following stimulation with either glucose, or pregnenolone sulfate. Moreover, stimulation of Galphaq and Galphas-coupled receptors enhances EGR-1 gene transcription. Functional studies revealed that Egr transcription factors control insulin biosynthesis via regulation of Pdx-1 expression. Glucose homeostasis and pancreatic islet size are regulated by Egr transcription factors, indicating that these proteins control central physiological parameters regulated by pancreatic beta-cells. In addition, Egr-1 is an integral part of the insulin receptor signaling cascade in insulin responsive tissues and influences insulin resistance. PMID- 24631482 TI - Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. AB - Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7-10 mm Hg of goal. It should be noted that the currently approved agents have side effects that include an increased incidence of genital infections, predominantly in women. The approved SGLT2 inhibitors have limited use based on kidney function and should be used only in those with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 for dapagliflozin and >=45 mL/min/1.73 m2 for canagliflozin. Cardiovascular outcome trials are ongoing with these agents and will be completed within the next 4-5 years. PMID- 24631484 TI - The effect of ((-)-2-oxa-4-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268), an mGlu2/3 receptor agonist, on EEG power spectra and coherence in ketamine model of psychosis. AB - In the present study we investigated the potential antipsychotic effects of the mGlu2/3 agonist LY379268 on changes in EEG power spectra and coherence in the ketamine model of psychosis. In order to use behaviorally active drug doses, experiments detecting changes in locomotor activity and sensorimotor gating were also conducted. In EEG experiments, adult male Wistar rats were injected with ketamine 30 mg/kg i.p. and LY379268 3 mg/kg i.p. Cortical EEG was recorded from twelve (2 * 6) electrodes placed homolaterally on each hemisphere. To avoid interference with the behavioral hyperactivity of ketamine challenge, the behavioral activity of animals was simultaneously registered at the time of recording. Subsequent power spectral and coherence analyses were assessed in epochs corresponding to behavioral inactivity. Analysis of segments with behavioral activity compared to inactivity was also performed. The effects of LY379268 3 mg/kg i.p. on the deficits in sensorimotor processing and on hyperlocomotion induced by ketamine were evaluated in the test of prepulse inhibition of acoustic startle reaction (PPI ASR) and in the open field. LY379268 reversed the ketamine-induced hyperlocomotion but had no effect on ketamine induced PPI deficits. In EEG epochs corresponding to behavioral inactivity ketamine decreased the power in the delta band, induced a power increase in the high frequency bands and globally decreased EEG coherence. Pretreatment with the LY379268 completely reversed the ketamine-induced power increase in high frequency bands and had a partial effect on EEG coherence. LY379268 alone induced a decrease of beta, high beta and low-gamma power, and an increase in coherence in high frequency bands. Additional analysis revealed that behavioral activity increases power as well as coherence in most frequency bands. In conclusion, agonism of mGlu2/3 receptors was effective in reversing most of the changes induced by ketamine, however due to the lack of effectiveness on PPI deficits its potential antipsychotic properties remain disputable. PMID- 24631483 TI - Peroxisome proliferator-activated receptor-gamma activation attenuates motor and cognition impairments induced by bile duct ligation in a rat model of hepatic cirrhosis. AB - INTRODUCTION: Hepatic cirrhosis (HC) is a common health problem with long-term consequences. Patients suffering from HC have been shown to have mental and cognitive impairments. Animal models of HC also confirm such impairments. The objective of the current study was to evaluate the possible protective effect of pioglitazone on these impairments in a rat model of HC. METHODS AND MATERIAL: Male Wistar rats were used for the current study. Bile duct ligation (BDL) surgery was performed and pioglitazone (20mg/kg, i.p., once a day) or saline administration was started two weeks after surgery for the next four weeks. Spatial learning (Morris water maze), passive avoidance (PA) learning (shuttle box), balance (rotarod) and muscle strength were evaluated in BDL and sham rats receiving pioglitazone or saline. RESULTS: BDL rats had an increased level of hepatic enzymes and bilirubin. The increase in hepatic enzymes but not bilirubin by BDL was reversed by pioglitazone. BDL rats showed significant decrease in spatial learning which was reversed by pioglitazone. PA learning was also impaired in BDL rats compared to the other three groups; treatment with pioglitazone reversed these impairments in BDL rats. Balance on the rod was significantly reduced in the BDL and BDL+pioglitazone groups compared to the sham and sham+pioglitazone groups. Muscle strength was not altered in the BDL rats compared to the other two groups. CONCLUSION: Results of the current study confirm previous findings regarding the deleterious effect of BDL on cognitive function. Pioglitazone showed promising results against cognitive impairments. Unchanged locomotion indicates that differences observed in spatial and PA learning are not due to motor deficits. PMID- 24631485 TI - Broad-spectrum antiemetic efficacy of the L-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva). AB - The dihydropyridine l-type calcium (Ca(2+)) channel blockers nifedipine and amlodipine reduce extracellular Ca(2+) entry into cells. They are widely used for the treatment of hypertensive disorders. We have recently demonstrated that extracellular Ca(2+) entry via l-type Ca(2+) channels is involved in emesis and that nifedipine has broad-spectrum antiemetic activity. The aim of this study was to evaluate the antiemetic efficacy of the longer-acting l-type Ca(2+) channel blocker, amlodipine. Fully effective emetic doses of diverse emetogens such as the l-type Ca(2+) channel agonist (FPL 64176) as well as selective and/or nonselective agonists of serotonergic 5-HT3 (e.g. 5-HT or 2-Me-5-HT)-, dopamine D2 (e.g. apomorphine or quinpirole)-, cholinergic M1 (e.g. pilocarpine or McN A343)- and tachykininergic NK1 (e.g. GR73632)-receptors, were administered intraperitoneally (i.p.) in the least shrew to induce vomiting. The broad spectrum antiemetic potential of amlodipine was evaluated against these emetogens. Subcutaneous (s.c.) administration of amlodipine (0.5-10mg/kg) attenuated in a dose-dependent and potent manner both the frequency and percentage of shrews vomiting in response to intraperitoneal (i.p.) administration of FPL 64176 (10mg/kg), 5-HT (5mg/kg), 2-Me-5-HT (5mg/kg), apomorphine (2mg/kg), quinpirole (2mg/kg), pilocarpine (2mg/kg), McN-A343 (2mg/kg), or GR73632 (5mg/kg). A combination of non-effective doses of amlodipine (0.5mg/kg, s.c.) and the 5-HT3 receptor antagonist palonosetron (0.05 mg/kg, s.c.) was more effective against FPL 64176-induced vomiting than their corresponding doses tested alone. Amlodipine by itself suppressed the frequency of acute cisplatin (10mg/kg, i.p)-induced vomiting in a dose-dependent manner. Moreover, a combination of a non-effective dose of amlodipine (1mg/kg) potentiated the antiemetic efficacy of a semi-effective dose of palonosetron (0.5mg/kg, s.c.) against acute vomiting caused by cisplatin. We confirm that influx of extracellular Ca(2+/-) ion underlies vomiting due to diverse causes and demonstrate that l-type Ca(2+) channel blockers are a new class of broad-spectrum antiemetics. PMID- 24631487 TI - Asiaticoside attenuates memory impairment induced by transient cerebral ischemia reperfusion in mice through anti-inflammatory mechanism. AB - Asiaticoside (AS) is isolated from Centella asiatica (L.) which has been using for a long time as a memory enhancing drug in India. This study was to investigate the effects of AS on memory impairment and inflammatory cytokines expression induced by transient cerebral ischemia and reperfusion in mice, as well as the potential signaling pathway. Transient bilateral common carotid artery occlusion (tBCCAO) induced severe memory deficits in mice according to the Morris water maze task and the step-down passive avoidance test. Meanwhile the microglial activation and the gene expression of inflammatory cytokines including interleukin (IL)-1beta, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were increased in the hippocampus of the mice with cerebral ischemia and reperfusion. Oral administration of AS (40 and 60 mg/kg, once per day, started the day after surgery and lasted for 7 days) significantly ameliorated the memory impairment and the inflammation. Moreover, AS (20, 40 and 60 mg/kg) markedly reduced the microglial overactivation and the phosphorylation of p38 MAPK in hippocampus compared with the transient cerebral ischemia and reperfusion group. These results suggested that AS showed the neuroprotective effect against transient cerebral ischemia and reperfusion in mice, and this effect might be associated with the anti-inflammation effect of AS via inhibiting overactivation of p38 MAPK pathway. PMID- 24631486 TI - The VGF-derived peptide TLQP62 produces antidepressant-like effects in mice via the BDNF/TrkB/CREB signaling pathway. AB - Recent studies demonstrate that the neuropeptide VGF (nonacronymic)-derived peptide is regulated in the hippocampus by antidepressant therapies. Brain derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), cAMP response element-binding protein (CREB) signaling, and monoamine transmitter pathways mediate the behavioral effects of antidepressants, but it is not known if these pathways also contribute to the antidepressant-like effects of VGF derived peptide TLQP62. Here the antidepressant-like effects of TLQP62 were evaluated by measuring immobility time in the forced swimming and tail suspension tests (FST and TST) following acute microinjection of the TLQP62 (0.25, 0.5 and 1 nmol/side) into the hippocampal CA1 regions. This treatment dose-dependently reduced immobility in the FST and TST compared to phosphate-buffered saline (PBS) infusion without affecting locomotor activity in the open field test (OFT). In addition, daily intrahippocampal microinfusion of TLQP62 (1 nmol/side/day; 21 days) also upregulated the expression of BDNF and the phosphorylation of CREB (pCREB) and TrkB (pTrkB) without altering CREB or TrkB. Blocking tissue plasminogen activator (tPA) by microinfusion of tPASTOP or TrkB activation by microinfusion of K252a 60 min prior to TLQP62 infusion almost completely abolished TLQP62-induced antidepressant-like effects, BDNF upregulation, and CREB/TrkB phosphorylation. In contrast, none of these effects were diminished by pretreatment with the non-specific 5-HT receptor antagonist metergoline, the selective 5-HT1A receptor antagonist NAN-190, the 5-HT synthase inhibitor parachlorophenylalanine, the selective alpha1-adrenoceptor antagonist prazosin, the beta receptor antagonist propranolol, or the D2 receptor antagonist raclopride. Moreover, our study was also to investigate the antidepressant-like effects of TLQP62 (50, 250 and 500 nmol/kg; i.p.) on depression-related behaviors in comparison with fluoxetine (10mg/kg; i.p.). While TLQP62 and fluoxetine showed similar antidepressant-like behavioral effects in the FST of mice. Our present results strongly suggest that activation of BDNF/TrkB/CREB signaling may be involved in the antidepressant-like effects of TLQP62. PMID- 24631488 TI - Detection of radicals in single droplets of oil-in-water emulsions with the lipophilic fluorescent probe BODIPY(665/676) and confocal laser scanning microscopy. AB - Lipid oxidation is a widespread phenomenon in foods and other systems of biological origin. Detection methods for early stages of lipid oxidation are in demand to understand the progress of oxidation in space and time. The fluorescence spectrum of the nonpolar fluorescent probe BODIPY(665/676) changes upon reacting with peroxyl radicals originating from 2,2'-azobis(2,4 dimethyl)valeronitrile and tert-butoxyl radicals generated from di-tert butylperoxide. The excitation wavelength of the main peak of BODIPY(665/676) was 675 nm in the fluorometer, and 670 nm under the microscope, and the optimum excitation wavelength for the secondary peak of BODIPY(665/676) was 580 nm. Advantages of using BODIPY(665/676) are fewer problems with autofluorescence and the possibility of combining several fluorescent probes that are excited and emitted at lower wavelengths. However, because of the spectrum of the probe, specific lasers and detectors are needed for optimal imaging under the microscope. Furthermore, BODIPY(665/676) is resistant to photobleaching at both excitation wavelengths, 670 and 580 nm. In diffusion studies, BODIPY(665/676) is highly lipophilic, remaining in the lipid phase and not diffusing into the aqueous phase or between lipid droplets. PMID- 24631489 TI - Biochanin A and prunetin improve epithelial barrier function in intestinal CaCo-2 cells via downregulation of ERK, NF-kappaB, and tyrosine phosphorylation. AB - The single-layered gut epithelium represents the primary line of defense against environmental stressors; thereby monolayer integrity and tightness are essentially required to maintain gut health and function. To date only a few plant-derived phytochemicals have been described as affecting intestinal barrier function. We investigated the impact of 28 secondary plant compounds on the barrier function of intestinal epithelial CaCo-2/TC-7 cells via transepithelial electrical resistance (TEER) measurements. Apart from genistein, the compounds that had the biggest effect in the TEER measurements were biochanin A and prunetin. These isoflavones improved barrier tightness by 36 and 60%, respectively, compared to the untreated control. Furthermore, both isoflavones significantly attenuated TNFalpha-dependent barrier disruption, thereby maintaining a high barrier resistance comparable to nonstressed cells. In docking analyses exploring the putative interaction with the tyrosine kinase EGFR, these novel modulators of barrier tightness showed very similar values compared to the known tyrosine kinase inhibitor genistein. Both biochanin A and prunetin were also identified as potent reducers of NF-kappaB and ERK activation, zonula occludens 1 tyrosine phosphorylation, and metalloproteinase-mediated shedding activity, which may account for the barrier-improving ability of these isoflavones. PMID- 24631491 TI - Prevalence of plasmid-mediated quinolone resistance determinants in extended spectrum beta-lactamase-producing and -non-producing enterobacteria in Spain. PMID- 24631490 TI - Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids. AB - Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency. PMID- 24631492 TI - Patient compliance and suboptimal bowel preparation with split-dose bowel regimen in average-risk screening colonoscopy. AB - BACKGROUND: Although split-dose bowel regimen is recommended in colon cancer screening and surveillance guidelines, implementation in clinical practice has seemingly lagged because of concerns of patient compliance. OBJECTIVES: To assess patient compliance with the split-dose bowel regimen and assess patient- and preparation process-related factors associated with compliance and bowel preparation adequacy. DESIGN: Prospective survey cohort. SETTING: Tertiary care setting. PATIENTS: Average-risk patients undergoing colonoscopy for colorectal cancer screening between August 2011 and January 2013. MAIN OUTCOME MEASUREMENTS: Split-dose bowel regimen patient-reported compliance and bowel preparation adequacy with the Boston Bowel Preparation Scale score. RESULTS: Surveys and Boston Bowel Preparation Scale score data were completed in 462 participants; 15.4% were noncompliant with the split-dose bowel regimen, and suboptimal bowel preparation (score <5) was reported in 16% of all procedures. White (P = .009) and married (P = .01) subjects were least likely to be noncompliant, whereas Hispanic subjects and those who reported incomes of US$75,000 or less were most likely to be noncompliant (P = .004). Participants who were noncompliant with split-dosing were less likely to follow the other laxative instructions and more likely to have their colonoscopy appointment before 10:30 am. Compliance differed by bowel preparation type (P = .003, chi(2) test), with those who used MiraLAX showing the highest compliance, followed by polyethylene glycol electrolyte solution and other bowel preparations. Noncompliance with split-dose bowel preparation (odds ratio 6.7; 95% confidence interval, 3.2-14.2) was the strongest predictor of suboptimal bowel preparation. LIMITATIONS: Patient self-report, performed at tertiary care center. CONCLUSIONS: Overall, 1 in 7 patients do not comply with a split-dose bowel regimen. Ensuring compliance with the split-dose bowel regimen will reduce the risk of a suboptimal bowel preparation. PMID- 24631493 TI - The intestinal metabolome: an intersection between microbiota and host. AB - Recent advances that allow us to collect more data on DNA sequences and metabolites have increased our understanding of connections between the intestinal microbiota and metabolites at a whole-systems level. We can also now better study the effects of specific microbes on specific metabolites. Here, we review how the microbiota determines levels of specific metabolites, how the metabolite profile develops in infants, and prospects for assessing a person's physiological state based on their microbes and/or metabolites. Although data acquisition technologies have improved, the computational challenges in integrating data from multiple levels remain formidable; developments in this area will significantly improve our ability to interpret current and future data sets. PMID- 24631494 TI - Increased levels of the long intergenic non-protein coding RNA POU3F3 promote DNA methylation in esophageal squamous cell carcinoma cells. AB - BACKGROUND & AIMS: Thousands of long intergenic non-protein coding RNAs (lincRNAs) have been identified in mammals via genome-wide sequencing studies. Many are functional, but are expressed aberrantly by cancer cells. We investigated whether levels of lincRNAs are altered during the development of esophageal squamous cell carcinoma (ESCC). METHODS: We used quantitative real time polymerase chain reaction to measure levels of 26 highly conserved lincRNAs in ESCC and surrounding nontumor tissues. A total of 182 ESCC and paired adjacent nontumor tissue samples were collected from patients undergoing tylectomy at The First Affiliate Hospital of Soochow University from 2001 through 2009; another 178 ESCC tissue pairs were collected from Guangzhou Medical University from 2002 through 2009. LincRNAs were expressed from lentiviral vectors or knocked down with small hairpin RNAs in Eca-109 and TE-1 cells. RESULTS: Levels of a lincRNA encoded by a gene located next to POU3F3 (linc-POU3F3) were significantly higher in ESCC than neighboring nontumor tissues. In RNA immunoprecipitation assays, linc-POU3F3 was associated with the EZH2 messenger RNA (mRNA). Overexpression of linc-POU3F3 in cell lines increased their proliferation and ability to form colonies, and reduced the expression of POU3F3 mRNA, whereas knockdown of linc POU3F3 increased the levels of POU3F3 mRNA. CpG islands in POU3F3 were densely hypermethylated in cell lines that overexpressed linc-POU3F3; methylation at these sites was reduced by knockdown of linc-POU3F3. Pharmacologic inhibition of EZH2 increased the levels of POU3F3 mRNA and significantly reduced binding of DNA methyltransferase (DNMT)1, DNMT3A, and DNMT3B to POU3F3. ESCC cells with knockdown of linc-POU3F3 formed xenograft tumors more slowly in mice than control ESCC cells. CONCLUSIONS: Levels of linc-POU3F3 are increased in ESCC samples from patients compared with nontumor tissues. This noncoding RNA contributes to the development of ESCC by interacting with EZH2 to promote methylation of POU3F3, which encodes a transcription factor. PMID- 24631495 TI - New hepatitis C therapies: the toolbox, strategies, and challenges. AB - Therapy for hepatitis C is undergoing a revolution. Several new drugs against the hepatitis C virus (HCV) have reached the market and many others, including direct acting antivirals and host-targeted agents, are in phase II or III clinical development. All-oral, interferon-free combinations of drugs are expected to cure more than 90% of infections. A vast amount of data from clinical trials are presented regularly at international conferences or released to the press before peer-review, creating confusion in the viral hepatitis field. The goal of this review is to clarify the current stage of HCV therapy and drug development. This review describes the different classes of drugs and their mechanisms and properties, as well as treatment strategies in development, including those that are interferon-based and interferon-free. HCV treatment options that will be available in 2014-2015 are presented for each genotype. A number of unanswered questions and challenges remain, such as how to treat special populations, the role of ribavirin in interferon-free regimens, the role of HCV resistance in treatment failures, and how to best re-treat patients who failed on treatment. Strategic choices, cost issues, HCV screening, and improving access to care in resource-constrained areas also are discussed. PMID- 24631496 TI - The effect of manuring on cereal and pulse amino acid delta(15)N values. AB - Amino acid delta(15)N values of barley (Hordeum vulgare) and bread wheat (Triticum aestivum) grains and rachis and broad bean (Vicia faba) and pea (Pisum sativum) seeds, grown in manured and unmanured soil at the experimental farm stations of Rothamsted, UK and Bad Lauchstadt, Germany, were determined by GC-C IRMS. Manuring was found to result in a consistent (15)N-enrichment of cereal grain amino acid delta(15)N values, indicating that manuring did not affect the metabolic routing of nitrogen (N) into cereal grain amino acids. The increase in cereal grain delta(15)N values with manuring is therefore due to a (15)N enrichment in the delta(15)N value of assimilated inorganic-N. Greater variation was observed in the (15)N-enrichment of rachis amino acids with manuring, possibly due to enhanced sensitivity to changes in growing conditions and higher turnover of N in rachis cells compared to cereal grains. Total amino acid delta(15)N values of manured and unmanured broad beans and peas were very similar, indicating that the legumes assimilated N2 from the atmosphere rather than N from the soil, since there was no evidence for routing of (15)N-enriched manure N into any of the pulse amino acids. Crop amino acid delta(15)N values thus provide insights into the sources of N assimilated by non N2-fixing and N2 fixing crops grown on manured and unmanured soils, and reveal an effect of manure on N metabolism in different crop species and plant parts. PMID- 24631497 TI - Nutrient content of school meals before and after implementation of nutrition recommendations in five school districts across two U.S. counties. AB - OBJECTIVE: To compare changes in nutrient levels of school meals before and after implementation of nutrition interventions at five school districts in two, large U.S. counties. School menu changes were compared against national school meal recommendations. METHODS: A large urban school district in Los Angeles County (LAC), California and four school districts in suburban Cook County (SCC), Illinois implemented school meal nutrition interventions. Nutrition analyses were conducted for school breakfast and lunch before and after changes were made to the meal programs. Means, % change, and net calories (kilocalories or kcal) offered as a result of the nutrition interventions were calculated. RESULTS: School districts in both counties made district-wide changes in their school breakfast and lunch menus. Menu changes resulted in a net reduction of calories, sugar, and sodium content offered in the meals. Net fewer calories offered as a result of the nutrition interventions were estimated to be about 64,075kcal per student per year for LAC and 22,887kcal per student per year for SCC. CONCLUSIONS: Nutrition interventions can have broad reach through changes in menu offerings to school-aged children and adolescents. However, further research is needed to examine how these changes affect student food selection and consumption. PMID- 24631498 TI - The behavioral and health consequences of sleep deprivation among U.S. high school students: relative deprivation matters. AB - OBJECTIVE: To evaluate whether the strength of the association between sleep deprivation and negative behavioral and health outcomes varies according to the relative amount of sleep deprivation experienced by adolescents. METHODS: 2011 Youth Risk Behavior Survey data of high school students (N=15,364) were analyzed. Associations were examined on weighted data using logistic regression. Twelve outcomes were examined, ranging from weapon carrying to obesity. The primary independent variable was a self-reported measure of average number of hours slept on school nights. RESULTS: Participants who reported deprivations in sleep were at an increased risk of a number of negative outcomes. However, this varied considerably across different degrees of sleep deprivation. For each of the outcomes considered, those who slept less than 5h were more likely to report negative outcomes (adjusted odds ratios ranging from 1.38 to 2.72; p<.05 across all models) relative to sleeping 8 or more hours. However, less extreme forms of sleep deprivation were, in many instances, unrelated to the outcomes considered. CONCLUSIONS: Among U.S. high school students, deficits in sleep are significantly and substantively associated with a variety of negative outcomes, and this association is particularly pronounced for students achieving fewer than 5h of sleep at night. PMID- 24631499 TI - Americans' opinions about policies to reduce consumption of sugar-sweetened beverages. AB - OBJECTIVE: Strategies to reduce consumption of sugar-sweetened beverages are a key component of public health promotion and obesity prevention, yet the introduction of many of these policies has been met with political controversy. The objective of this study is to assess the levels of and determinants of U.S. public support for policies to reduce consumption of sugar-sweetened beverages. METHODS: An Internet-based survey (N=1319) was fielded with a nationally representative sample of U.S. adults aged 18-64 during fall 2012. RESULTS: Respondents have the highest support for calorie labeling (65%) and removing drinks from schools (62%), and the lowest support for taxes (22%) or portion size restrictions (26%). Examining several determinants of support simultaneously, Democrats and those with negative views of soda companies are more likely to support these policies. CONCLUSIONS: The results provide policymakers and advocates with insights about the political feasibility of policy approaches to address the prevalent consumption of sugar-sweetened beverages, as well as the role of attitudes toward soda companies as an independent predictor of the public's opinions. PMID- 24631500 TI - International association of Parkinsonism & Related Disorders--Annual Report 2013. PMID- 24631501 TI - Comparing clinical features of young onset, middle onset and late onset Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) affects 1-2% of the population over 65 years. There is evidence that the clinical features differ with age at symptom onset, but published information is scarce. METHODS: We reviewed the charts of 593 PD patients and divided them into young onset (<=49 years), middle onset (50 69 years) and late onset (>=70 years) groups. Data collected included age at symptom onset, year of onset, family history of Parkinson's disease in first and second degree relatives, predominant first symptom, first anti parkinsonian medication prescribed, frequency of levodopa-induced dyskinesia, therapy related dystonia, therapy related gastrointestinal side effects, hallucination, dementia, depression and apathy. RESULTS: The middle onset was the largest group (51%), followed by the late onset (39%) and the young onset (10%) groups. Young onset patients had a more frequent family history of Parkinson's disease and a longer survival. Symptoms other than tremor were more frequent as the initial symptom of the young onset group, and the frequency of tremor as the first symptom increased with advancing age at onset. Depression was more frequent in the young onset group. The frequency of treatment related dyskinesia or dystonia decreased with advancing age at onset. CONCLUSION: We have identified specific clinical differences in Parkinson's disease related to the patient's age at onset and added to the existing knowledge of the variability of disease presentation. We suggest an age of onset of 49 years or less for the definition of young onset PD. PMID- 24631502 TI - Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs. AB - Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 MUg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes. PMID- 24631503 TI - Curative and preventive efficacy of orally administered afoxolaner against Ctenocephalides canis infestation in dogs. AB - The efficacy of orally administered afoxolaner against adult dog fleas, Ctenocephalides canis, was evaluated in a controlled, blinded study. A total of 32 dogs were infested with 100 adult unfed fleas approximately 24h prior to treatment and then at weekly intervals for 5 weeks after treatment. Live fleas were counted upon removal at 12h (for 16 dogs) and 24h (for the remaining 16 dogs) after treatment (for counts performed the first week) or after infestation (for counts performed on subsequent weeks). In addition, flea eggs were collected from each pen and counted for the dogs with flea removal at 24h. Dosing of individual dogs was achieved using a combination of the chewable tablets to be as close as possible to the minimum effective dose of 2.5mg/kg. The percent efficacy of the afoxolaner treatment was >= 99.0% for all 24-h flea counts. For flea counts performed 12h after treatment or infestations, the percent efficacy was >= 94.1% up to Day 21. After Day 1, no flea eggs were recovered from the afoxolaner treated group, providing 100% reduction in numbers of flea eggs recovered versus untreated control group. This study confirmed that a single oral treatment with afoxolaner provided excellent efficacy against infestations by C. canis within 12 24h after treatment, prevented re-infestations, and completely prevented egg production from new flea infestations for up to 5 weeks. PMID- 24631504 TI - Peroxisome proliferator-activated receptor gamma-mediated induction of microRNA 145 opposes tumor phenotype in colorectal cancer. AB - MicroRNAs (miRNAs) regulate diverse biological processes by inhibiting translation or inducing degradation of target mRNAs. miR-145 is a candidate tumor suppressor in colorectal carcinoma (CRC). Colorectal carcinogenesis involves deregulation of cellular processes controlled by a number of intertwined chief transcription factors, such as PPARgamma and SOX9. Since PPAR family members are able to modulate complex miRNAs networks, we hypothesized a role of miRNA-145 in the interaction between PPARgamma and SOX9 in colorectal carcinogenesis. To address this issue, we evaluated gene expression in tissue specimens of CRC patients and we took advantage of invitro models represented by CRC derived cell lines (CaCo2, SW480, HCT116, and HT-29), employing PPARgamma activation and/or miRNA-145 ectopic overexpression to analyze how their interplay impact the expression of SOX9 and the development of a malignant phenotype. RESULTS: PPARgamma regulates the expression of miR-145 by directly binding to a PPAR response element (PPRE) in its promoter at -1207/-1194bp from the transcription start site. The binding is essential for miR-145 upregulation by PPARgamma upon rosiglitazone treatment. Ectopic expression of miR-145, in turn, regulates SOX9 expression through the binding to specific seed motifs. The PPARgamma-miR-145 SOX9 axis overarches cell cycle progression, invasiveness and differentiation of CRC derived cell lines. Together, these results suggest that miR-145 is a novel target of PPARgamma, acts as a tumor suppressor in CRC cell lines and is a key regulator of intestinal cell differentiation by directly targeting SOX9, a marker of undifferentiated progenitors in the colonic crypts. PMID- 24631505 TI - Reversible acetylation of Lin28 mediated by PCAF and SIRT1. AB - Lin28 is a small RNA-binding protein that plays an important role in regulating developmental timing, stem cell reprogramming, and oncogenesis. However, the significance of the effect of post-translational modifications on Lin28 activity is not fully understood. In this study, we demonstrated that PCAF directly interacted with and acetylated Lin28. We also showed that the acetylation of Lin28 can be specifically reversed by the deacetylase SIRT1. These findings suggest that the PCAF/SIRT1 balance plays an important role in regulating Lin28 activity. Furthermore, we found that the cold shock domain of Lin28 is the major target of PCAF-mediated acetylation, which leads to a severe reduction in the Lin28 protein levels and an increase in the level of mature let-7a. This study provides the first demonstration that post-translational modification regulates Lin28 activity during let-7a biogenesis and sheds light on the regulation of Lin28 in ES cells and carcinogenesis. PMID- 24631506 TI - Non-classical testosterone signaling is mediated by a G-protein-coupled receptor interacting with Gnalpha11. AB - Testosterone is known to mediate its effects by two different mechanisms of action. In the so-called "classical" pathway testosterone binds to cytosolic androgen receptors (AR), which essentially function as ligand-activated transcription factors. Once activated, these receptors bind to DNA and activate the expression of target genes. In the "non-classical" pathway, the steroid hormone binds to receptors associated with the plasma membrane and induces signaling cascades mediated through activation of Erk1/2. The precise nature of the membrane-associated AR, however, remains controversial. Although some assume that the membrane and cytosolic AR are identical, others propose that the AR of the membrane is a G-protein-coupled receptor (GPCR). To evaluate these two possibilities we first searched for testosterone-induced signaling cascades in the spermatogenic cell line GC-2. Testosterone was found to cause phosphorylation (activation) of Erk1/2, CREB, and ATF-1, consistent with its non-classical mechanism of action. Silencing of AR expression by means of siRNA did not influence testosterone-induced activation of Erk1/2, CREB, or ATF-1, indicating that this pathway is not activated by the classical cytosolic/nuclear AR. In contrast, when the expression of the G-protein Gnalpha11 is suppressed, the activation of these signaling molecules is abolished, suggesting that these responses are elicited through a membrane-bound GPCR. The results presented here and the identification of the testosterone-specific GPCR in future investigations will help to reveal and characterize new testosterone-mediated mechanisms associated not only with fertility and reproduction but perhaps also with other physiological processes. PMID- 24631507 TI - Diagnostic value of PET-measured longitudinal flow gradient for the identification of coronary artery disease. AB - OBJECTIVES: The purpose of this study was to evaluate the diagnostic value of a positron emission tomography (PET)/computed tomography (CT)-determined longitudinal decrease in myocardial blood flow (MBF) gradient during hyperemia and myocardial flow reserve (MFR) for the identification of epicardial stenosis >=50%. BACKGROUND: Although PET-determined reductions in MFR are increasingly applied to identify epicardial lesions in coronary artery disease (CAD), it may be seen as a suboptimal approach due to the nonspecific origin of decreases in MFR. METHODS: In 24 patients with suspected or known CAD, MBF was measured with (13)N-ammonia and PET/CT in ml/g/min at rest, during dipyridamole stimulation, and the corresponding MFR was calculated. MBF was also determined in the mid and mid-distal myocardium of the left ventricle (LV). A decrease in MBF from mid to mid-distal LV myocardium was defined as longitudinal MBF gradient. MBF parameters were determined in the myocardial region with stress-induced perfusion defect and with stenosis >=50% (territory 1), without defect but with stenosis >=50% (territory 2), or without stenosis >=50% (territory 3). RESULTS: In territories 1 and 2 with focal stenosis >=50%, the severity of epicardial artery stenosis correlated with the Deltalongitudinal MBF gradient (stress-rest) (r = 0.52; p < 0.0001), while this association was less pronounced for corresponding MFR (r = 0.40; p < 0.003). On a vessel-based analysis, the sensitivity and specificity of the Deltalongitudinal MBF gradient in the identification of epicardial lesions was higher than those for MFR (88% vs. 71%, p <= 0.044; and 81% vs. 63%, p = 0.134, respectively). Combining both parameters resulted in an optimal sensitivity of 100% and intermediate specificity of 75%. The diagnostic accuracy was highest for the combined analysis than for the Deltalongitudinal MBF gradient or MFR alone (94% vs. 86%, p <= 0.003; and 94% vs. 70%, p <= 0.0002). CONCLUSIONS: The combined evaluation of a Deltalongitudinal MBF gradient and MFR may evolve as a new promising analytic approach to further optimize the identification of CAD lesions. PMID- 24631508 TI - 3D echocardiographic location of implantable device leads and mechanism of associated tricuspid regurgitation. AB - OBJECTIVES: This study sought to: 1) determine the feasibility of using 3 dimensional transthoracic echocardiography (3D TTE) in patients with implantable cardiac resynchronization devices, pacemakers, and defibrillators to visualize the device leads in the right heart and their position relative to the tricuspid valve leaflets; 2) determine the prevalence of different lead positions; and 3) study the relationship between lead location and tricuspid regurgitation (TR) severity. BACKGROUND: Pacemaker, defibrillator, and cardiac resynchronization device implantation is currently guided by fluoroscopy, not allowing targeted lead positioning relative to the tricuspid valve leaflets. These leads have been reported to cause TR of variable degrees, but echocardiography is not routinely used to elucidate the mechanisms of lead interference with tricuspid valve leaflets in individual patients. METHODS: 3D TTE full-volume images of the right ventricle and/or zoomed images of the tricuspid valve were obtained in 121 patients with implanted devices. Images were viewed offline to determine the position of the device-lead relative to the tricuspid valve leaflets. Severity of TR was estimated on the basis of vena contracta measurements. RESULTS: 3D TTE clearly depicted lead position in 90% of patients. The right ventricular lead was impinging on either the posterior (20%) or septal (23%) leaflet or was not interfering with leaflet motion (53%) when positioned near the posteroseptal commissure or in the central portion of the tricuspid valve orifice. In the remaining patients, leads were impinging on the anterior leaflet (4%) or positioned in either the anteroposterior or anteroseptal commissure (3%). Leads interfering with normal leaflet mobility were associated with more TR than nonimpinging leads (vena contracta: median 0.62 cm [1st and 3rd quartiles: 0.51, 0.84 cm] vs. 0.27 cm [1st and 3rd quartiles: 0.00, 0.48 cm]; p < 0.001). CONCLUSIONS: 3D TTE showed a clear association between device lead position and TR. To minimize TR induced by device-leads, 3D TTE guidance should be considered for placement in a commissural position. PMID- 24631509 TI - Additional value of transluminal attenuation gradient in CT angiography to predict hemodynamic significance of coronary artery stenosis. AB - OBJECTIVES: The current study evaluates the incremental value of transluminal attenuation gradient (TAG), TAG with corrected contrast opacification (CCO), and TAG with exclusion of calcified coronary segments (ExC) over coronary computed tomography angiogram (CTA) alone using fractional flow reserve (FFR) as the gold standard. BACKGROUND: TAG is defined as the contrast opacification gradient along the length of a coronary artery on a coronary CTA. Preliminary data suggest that TAG provides additional functional information. Interpretation of TAG is hampered by multiple heartbeat acquisition algorithms and coronary calcifications. Two correction models have been proposed based on either dephasing of contrast delivery by relating coronary density to corresponding descending aortic opacification (TAG-CCO) or excluding calcified coronary segments (TAG-ExC). METHODS: Eighty-five patients with intermediate probability of coronary artery disease were prospectively included. All patients underwent step-and-shoot 256 slice coronary CTA. TAG, TAG-CCO, and TAG-ExC analyses were performed followed by invasive coronary angiography in conjunction with FFR measurements of all major coronary branches. RESULTS: Thirty-four patients (40%) were diagnosed with hemodynamically-significant coronary artery disease (i.e., FFR <=0.80). On a per vessel basis (n = 253), 59 lesions (23%) were graded as hemodynamically significant, and the diagnostic accuracy of coronary CTA (diameter stenosis >=50%) was 95%, 75%, 98%, and 54% for sensitivity, specificity, negative predictive value, and positive predictive value, respectively. TAG and TAG-ExC did not discriminate between vessels with or without hemodynamically significant lesions (-13.5 +/- 17.1 HU [Hounsfield units] * 10 mm(-1) vs. -11.6 +/- 13.3 HU * 10 mm(-1), p = 0.36; and 13.1 +/- 15.9 HU * 10 mm(-1) vs. -11.4 +/- 11.7 HU * 10 mm(-1), p = 0.77, respectively). TAG-CCO was lower in vessels with a hemodynamically-significant lesion (-0.050 +/- 0.051 10 mm(-1) vs. -0.036 +/- 0.034 10 mm(-1), p = 0.03) and TAG-ExC resulted in a slight improvement of the net reclassification index (0.021, p < 0.05). CONCLUSIONS: TAG did not provide incremental diagnostic value over 256-slice coronary CTA alone in assessing the hemodynamic consequences of a coronary stenosis. Correction for temporal nonuniformity of contrast delivery or exclusion of calcified coronary segments slightly enhanced the results. PMID- 24631510 TI - Prediction of high-risk plaque development and plaque progression with the carotid atherosclerosis score. AB - OBJECTIVES: The goal of this prospective study was to evaluate the carotid atherosclerosis score (CAS) for predicting the development of high-risk plaque features and plaque burden progression. BACKGROUND: Previous studies have shown that carotid intraplaque hemorrhage (IPH) and a disrupted luminal surface (DLS), as identified by using magnetic resonance imaging, are associated with greater risk for cerebrovascular events. On the basis of data from a large cross sectional study, a scoring system was developed to determine which plaque features are associated with the presence of IPH and DLS. However, the predictive value of CAS has not been previously tested in a prospective, longitudinal study. METHODS: A total of 120 asymptomatic subjects with 50% to 79% carotid stenosis underwent carotid magnetic resonance imaging scans at baseline and 3 years thereafter. Presence of IPH and DLS, wall volume, maximum wall thickness, and maximum percent lipid-rich necrotic core area were measured at both time-points. Baseline CAS values were calculated on the basis of previously published criteria. RESULTS: Of the 73 subjects without IPH or DLS at baseline, 9 (12%) developed 1 or both of these features during follow-up. There was a significant increasing trend between CAS and the development of new DLS (p < 0.001) and with plaque burden progression (p = 0.03) but not with the development of new IPH (p = 0.3). Percent carotid stenosis was not significantly associated with new DLS (p = 0.2), new IPH (p = 0.1), or plaque progression (p = 0.6). CONCLUSIONS: CAS was found to have a significant increasing relationship with incident DLS and plaque progression in this prospective study. CAS can potentially provide improved risk stratification beyond luminal stenosis. PMID- 24631511 TI - Clinical outcome of nonculprit plaque ruptures in patients with acute coronary syndrome in the PROSPECT study. AB - OBJECTIVES: The aim of this study was to report the frequency, patient and lesion related characteristics, and outcomes of subclinical, nonculprit plaque ruptures in the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. BACKGROUND: Plaque rupture and subsequent thrombosis is the most common cause of acute coronary syndrome (ACS). Secondary, subclinical, nonculprit plaque ruptures have been seen in both stable patients and patients with ACS; however, reports of the natural history of these secondary plaque ruptures are limited. METHODS: After successful stenting in 697 patients with ACS, 3-vessel grayscale and intravascular ultrasound virtual histology (IVUS-VH) was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective multicenter study. RESULTS: Among 660 patients with complete IVUS data, 128 plaque ruptures were identified in 105 nonculprit lesions in 100 arteries from 93 patients (14.1%). Although the minimum lumen area (MLA) was similar, the plaque burden was significantly greater in nonculprit lesions with a plaque rupture compared with nonculprit lesions without a plaque rupture (66.0% [95% confidence interval: 64.5% to 67.4%] vs. 56.0% [95% confidence interval: 55.6% to 56.4%]; p < 0.0001). IVUS-VH analysis revealed that a nonculprit lesion with a plaque rupture was more often classified as a fibroatheroma than a nonculprit lesion without a plaque rupture (77.1% vs. 51.4%; p < 0.0001). Independent predictors of a plaque rupture were lesion length (per 10 mm; odds ratio: 1.30; p < 0.0001), plaque burden at the MLA site (per 10%; odds ratio: 2.56; p < 0.0001), vessel area at the MLA site (per 1 mm(2); odds ratio: 1.13; p < 0.0001), and VH-thin-cap fibroatheroma (odds ratio: 1.80; p = 0.016). During 3 years of follow-up, the incidence of overall major adverse cardiac events did not differ significantly between the patients with and patients without subclinical, nonculprit plaque ruptures. CONCLUSIONS: Secondary, nonculprit plaque ruptures were seen in 14% of patients with ACS and were associated with a fibroatheroma phenotype with a residual necrotic core but not with adverse outcomes if patients were treated with optimal medical therapy as part of a multicenter study. (Providing Regional Observations to Study Predictors of Events in the Coronary Tree [PROSPECT]; NCT00180466). PMID- 24631512 TI - Impaired resting myocardial annular velocities are independently associated with mental stress-induced ischemia in coronary heart disease. AB - OBJECTIVES: The aim of this study was to investigate the association between resting myocardial function as assessed by tissue Doppler myocardial velocities and the propensity to develop mental stress-induced ischemia (MSIMI). BACKGROUND: Tissue Doppler myocardial velocities detect preclinical cardiac dysfunction and clinical outcomes in a range of conditions. However, little is known about the interrelationship between myocardial velocities and the propensity to develop MSIMI compared with exercise stress-induced myocardial ischemia. METHODS: Resting annular myocardial tissue Doppler velocities were obtained in 225 patients with known coronary heart disease who were subjected to both conventional exercise stress testing as well as a battery of 3 mental stress tests. Diastolic early (e') and late (a') as well as systolic (s') velocities were obtained, and the eas index, an integrated measure of myocardial velocities, was calculated as e'/(a' * s'). MSIMI was defined as: 1) the development or worsening of regional wall motion abnormality; 2) a reduction in left ventricular ejection fraction >= 8%; and/or 3) ischemic ST-segment changes during 1 or more of the 3 mental stress tests. RESULTS: A total of 98 of 225 patients (43.7%) exhibited MSIMI. Patients developing MSIMI had significantly lower s' (7.0 +/- 1.7 vs. 7.5 +/- 1.2, p = 0.016) and a' (8.9 +/- 1.8 vs. 10.0 +/- 1.9, p < 0.001) at baseline, whereas e' did not differ (6.5 +/- 1.7 vs. 6.5 +/- 1.8, p = 0.85). Furthermore, the eas index was significantly higher (0.11 +/- 0.04 vs. 0.09 +/- 0.03, p < 0.0001). The eas index remained significantly associated with the propensity to develop MSIMI (odds ratio per 0.05-U increase: 1.85; 95% confidence interval: 1.21 to 2.82; p = 0.004) after adjustment for resting left ventricular ejection fraction, resting wall motion index score, sex, and social circumstances of living. There was no association between resting eas index and exercise stress-induced myocardial ischemia. CONCLUSIONS: MSIMI but not exercise stress-induced myocardial ischemia is independently associated with resting abnormalities in myocardial systolic and late diastolic velocities as well as the integrated measure of the eas index in patients with known coronary artery disease. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847). PMID- 24631513 TI - Effect of chemical modification on the ability of pyrrolidinium fullerene to induce apoptosis of cells transformed by JAK2 V617F mutant. AB - JAK2 V617F mutant, a gene responsible for human myeloproliferative neoplasms (MPNs), causes not only cellular transformation but also resistance to various anti-cancer drugs. We previously reported that pyrrolidinium fullerene markedly induced the apoptosis of JAK2 V617F mutant-induced transformed cells through the reduction of apoptosis signal-regulating kinase 1 (ASK1), following inhibition of the c-Jun N-terminal kinase (JNK) pathway. In the current study, we found that the replacement of the 2-hydrogen atom (H) or N-methyl group (CH3) by the butyl group (C4C9) caused the more than 3-fold potent cytotoxic effects on cells transformed by the JAK2 V617F mutant. Strikingly, these chemical modification of pyrrolidinium fullerene resulted in more marked reduction of ASK1 protein and a more potent inhibitory effect on the JNK signaling cascade. On the other hand, when modified with a longer alkyl group, the derivatives lacked their cytotoxicity. These observations clearly indicate that the modification of pyrrolidinium fullerene with a suitable length of alkyl group such as butyl group enhances its apoptotic effect through inhibition of the ASK1-MKK4/7-JNK pathway. PMID- 24631514 TI - Oral administration of baicalin and geniposide induces regression of atherosclerosis via inhibiting dendritic cells in ApoE-knockout mice. AB - Atherosclerosis is a systemic inflammatory disease characterized by the accumulation of dendritic cells (DCs) and other types of immune cells in atherosclerotic plaque. In this study, baicalin and geniposide were isolated from Scutellaria baicalensis Georgi and Gardenia jasminoids Ellis, which are the plants used in traditional Chinese medicine to treat a variety of inflammatory diseases. We then investigated whether baicalin and geniposide could induce regression of atherosclerotic lesions in ApoE-/- mice fed a high cholesterol diet and used as a model of atherosclerosis. Following model induction, these mice were treated with baicalin (100mg/kg), geniposide (100mg/kg), and then a mixture containing baicalin (100mg/kg) and geniposide (100mg/kg) administered daily by gavage for a period of 12weeks. The combined administration of baicalin and geniposide significantly reduced atherosclerotic lesions, and modulated the phenotype of dendritic cells in bone marrow and atherosclerotic plaque. Geniposide lowered both plasma lipid levels and DC numbers, while baicalin administered either alone or in combination with geniposide did not decrease plasma lipids. Our results suggest that baicalin and geniposide may have immune regulatory effects and prevent the formation of atherosclerotic lesions by decreasing the DC numbers, and inhibit DC maturation in bone marrow and infiltration into lesions. PMID- 24631515 TI - TGF-beta/Smad signaling pathway regulates Th17/Treg balance during Echinococcus multilocularis infection. AB - Alveolar echinococcosis (AE) is a severe parasitic disease caused by the infection of Echinococcus multilocularis (Em). Very little is known on the relationship between TGF-beta/Smad signaling pathway and Treg/Th17 balance in the infected liver at different periods after Em infection. Using qRT-PCR, immunohistochemistry, flow cytometry and CBA assay, we measured the expression levels of TGF-beta, Smad2/3/7, ROR-gammat, Foxp3, IL-17, IL-10 and percentages of Th17 cells and Treg cells in mouse AE model, from day 2 to day 270 after infection. In the early stage of infection (day 2 to day 30), Smad7 was up regulated and the TGF-beta pathway was inactivated. In the middle stage of infection (day 30 to day 90), TGF-beta and Smad2/3 were up-regulated. And levels of Treg cells, Foxp3, Th17 cells, RORgammat, IL-17, IL-10 and IL-6 were significantly increased. In the late stage of infection (day 90 to day 270), Treg cells, Foxp3, TGF-beta and IL-10 maintained at high levels whereas Th17 cells and IL-17 decreased significantly. TGF-beta/Smad signaling pathway was activated during the chronic infection. Our data suggest that there were Treg/Th17 imbalance in the middle and especially in the late stage of Em infection and that Treg/Th17 imbalance may be regulated by TGF-beta/Smad signaling pathway. Treg and Th17 subsets may be involved in regulating immune tolerance and tissue inflammation, and facilitating the long-term survival of Em in the host. PMID- 24631516 TI - Madecassoside prevents Abeta(25-35)-induced inflammatory responses and autophagy in neuronal cells through the class III PI3K/Beclin-1/Bcl-2 pathway. AB - Inflammatory responses and autophagy have been implicated in the amyloid-beta (Abeta) aggregation in Alzheimer's disease (AD) due to recycling cellular waste and eliminating toxic protein aggregates. Madecassoside (Mad), a triterpenoid saponin compound, has been found to improve impaired cognitive function. However, little was known about the protection of Mad nerve cells against inflammation response and autophagy, as well as their underlying mechanism. In the present study, we investigated whether Mad could prevent Abeta25-35-induced inflammatory responses and autophagy, as well as the possible mechanism. Transmission electron microscopy results showed that Mad could significantly reduce Abeta25-35-induced autophagosomes in neural cells. Mad could also increase cell viability whereas decrease remarkably LDH leakage in Abeta25-35-induced neural cells. Both ELISA assay and western blot showed that Mad attenuated inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-6 and COX-2 production. Moreover, western blot results showed that Mad could block the conversion of light chain3-I (LC3-I) to light chain3-II (LC3-II), reduce Beclin 1, whereas increase anti-apoptotic protein Bcl-2 level. The levels of Beclin-1 and hVps34 in control vector-transfected NG108-15 neural cells but not in Bcl-2 transfected NG108-15 neural cells were reduced by Mad. The levels of inflammatory cytokines including TNF-alpha and IL-6 productions decreased significantly by the treatment with Mad. These results demonstrated that Mad protected neural cells against inflammation and autophagy induced by Abeta25-35 through the class III PI3K/Beclin-1/Bcl-2 pathway. Our findings provide evidences for the beneficial effect of Mad on the treatment of AD. PMID- 24631517 TI - Broad specific enzyme-linked immunosorbent assay for determination of residual phenothiazine drugs in swine tissues. AB - In this study, a novel generic hapten of phenothiazine drugs was synthesized by derivatization of 2-chlorophenothiazine with sodium bromoacetate. Then the hapten was coupled to bovine serum albumin for production of the monoclonal antibody. Results showed that the obtained monoclonal antibody recognized five phenothiazine drugs simultaneously: chlorpromazine, promethazine, acepromazine, perphenazine, and fluphenazine. After evaluation of different coating antigens, a heterologous competitive indirect enzyme-linked immunosorbent assay was developed to determine the residues of the five phenothiazine drugs in swine tissues (muscle, liver, and kidney). The cross-reactivities to the five analytes were in the range of 71 to 98%, and the limits of detection were in the range of 0.2 to 0.4 ng/ml, depending on the drug. Their recoveries from the fortified blank samples were in the range of 73.8 to 96.2%, with coefficients of variation in the range of 4.1 to 14.3%. This is the first study reporting a broad specific immunoassay for multi-determination of the residues of five phenothiazine drugs in animal-derived foods. PMID- 24631518 TI - DNA counterstaining for methylation and hydroxymethylation immunostaining in bovine zygotes. AB - Immunostaining is the preferred technique to assess differences in methylation and hydroxymethylation status of both pronuclei in single zygotes. DNA counterstaining is needed to delimitate the pronuclear area for quantification purposes. For a correct epitope retrieval of 5-methylcytosine and 5 hydroxymethylcytosine in bovine zygotes, 1h of denaturation with 4N HCl is needed. However, DNA stains are sensitive to denaturation. Therefore, four DNA stains were tested after 1h of denaturation with 4N HCl in this study. After this treatment, DAPI (4',6-diamidino-2-phenylindole) and Hoechst failed to bind DNA, but both propidium iodide and ethidium homodimer-2 successfully bound it and both pronuclei were stained. PMID- 24631519 TI - Validation of high-throughput single cell analysis methodology. AB - High-throughput quantitative polymerase chain reaction (qPCR) approaches enable profiling of multiple genes in single cells, bringing new insights to complex biological processes and offering opportunities for single cell-based monitoring of cancer cells and stem cell-based therapies. However, workflows with well defined sources of variation are required for clinical diagnostics and testing of tissue-engineered products. In a study of neural stem cell lines, we investigated the performance of lysis, reverse transcription (RT), preamplification (PA), and nanofluidic qPCR steps at the single cell level in terms of efficiency, precision, and limit of detection. We compared protocols using a separate lysis buffer with cell capture directly in RT-PA reagent. The two methods were found to have similar lysis efficiencies, whereas the direct RT-PA approach showed improved precision. Digital PCR was used to relate preamplified template copy numbers to Cq values and reveal where low-quality signals may affect the analysis. We investigated the impact of calibration and data normalization strategies as a means of minimizing the impact of inter-experimental variation on gene expression values and found that both approaches can improve data comparability. This study provides validation and guidance for the application of high-throughput qPCR workflows for gene expression profiling of single cells. PMID- 24631520 TI - Glucopsychosine increases cytosolic calcium to induce calpain-mediated apoptosis of acute myeloid leukemia cells. AB - To identify novel anti-cancer agents, we created and screened a unique nutraceutical library for activity against acute myeloid leukemia (AML) cells. From this screen, we determined that glucopsychosine was selectively toxic toward AML cell lines and primary AML patient samples with no effect toward normal hematopoietic cells. It delayed tumor growth and reduced tumor weights in mouse xenograft models without imparting toxicity. Glucopsychosine increased cytosolic calcium and induced apoptosis through calpain enzymes. Extracellular calcium was functionally important for glucopsychosine-induced AML cell death and surface calcium channel expression is altered in AML cells highlighting a unique mechanism of glucopsychosine's selectivity. PMID- 24631521 TI - Plasmodium knowlesi in travellers, update 2014. AB - OBJECTIVES: Since the initial discovery of Plasmodium knowlesi in Malaysia, cases have been reported from several neighbouring countries. Tourism has also resulted in an increasing number of cases diagnosed in Europe, America, and Oceania. In this review we focus on the risk of the travel-associated acquisition of P. knowlesi malaria. METHODS: A search of the literature in PubMed was carried out to identify articles and literature on the distribution of P. knowlesi infections in Southeast Asia and details of its acquisition and importation by travellers to other continents. The cut-off date for the search was December 1, 2013. Search words used were: "Plasmodium knowlesi", "Plasmodium knowlesi infections", "Plasmodium knowlesi travellers", "Plasmodium knowlesi prevalence", "Plasmodium knowlesi host", "Plasmodium knowlesi vector" "Plasmodium knowlesi RDT", and "Plasmodium knowlesi Malaysia". Traveller numbers to Malaysia were obtained from the Tourism Malaysia website. RESULTS: A total of 103 articles were found. Using a selection of these and others identified from the reference lists of the papers, we based our review on a total of 66 articles. RESULTS: P. knowlesi malaria appears to be the most common malaria species in Malaysian Borneo and is also widely distributed on the Malaysian mainland. Furthermore, locally transmitted cases of P. knowlesi malaria have been reported in Thailand, the Philippines, Vietnam, Singapore, Myanmar, Indonesian Borneo, and Cambodia. Two cases have been reported from non-endemic countries in Asia (Japan and Taiwan) in people with a history of travel to Malaysia and the Philippines. Twelve cases were imported to their home countries by travellers from other continents: two from the USA, two from the Netherlands, two from Germany, and one each from Spain, France, Sweden, Finland, Australia, and New Zealand. In most cases, the infection was associated with a trip to or near forested areas. The symptoms were fever (n=12), headache (n=6), chills (n=6), nausea (n=4), myalgia (n=3), back pain (n=3), abdominal problems (n=1), anorexia (n=2), fatigue (n=2), malaise (n=1), arthralgia (n=1), sore throat (n=1) vomiting (n=2), and jaundice (n=1). All patients were treated successfully with currently available antimalaria treatments. The identification of the pathogen by microscopy can be problematic due to the morphological similarity of P. knowlesi to Plasmodium malariae. CONCLUSION: P. knowlesi appears to be a threat not only to the local population in Malaysia, but also to the estimated 25 million annual tourists and occupational travellers to Malaysia, especially those who visit rural, forested areas of the country. The P. knowlesi risk is not limited to Malaysia, and travellers from Southeast Asia presenting with possible malaria should be considered for a diagnostic work-up that includes P. knowlesi. PMID- 24631522 TI - Systematic review of the birth prevalence of congenital cytomegalovirus infection in developing countries. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is the leading infectious cause of congenital hearing loss and neurodevelopmental disability in developed countries. Information on congenital CMV infection in developing countries appears to be lacking. METHODS: We conducted a systematic literature review to identify studies from developing countries with population-based samples of at least 300 infants that used laboratory methods established as reliable for the diagnosis of congenital CMV infection. RESULTS: Most studies were excluded due to biased samples or inadequate diagnostic methods; consequently the search identified just 11 studies that were from Africa, Asia, and Latin America. The number of newborns tested ranged from 317 to 12 195. Maternal CMV seroprevalence ranged from 84% to 100%. CMV birth prevalence varied from 0.6% to 6.1%. CMV associated impairments were not documented in most studies. CONCLUSIONS: Birth prevalence ranges were higher than for Europe and North America, as expected based on the higher maternal CMV seroprevalence. With very limited data available on sequelae, the disease burden of congenital CMV in developing countries remains largely unknown at this time. PMID- 24631524 TI - The police, social services and psychiatry cooperation in Denmark--a new model of working practice between governmental sectors. A description of the concept, process, practice and experience. AB - In 2004 a new model of working practice between three public sectors, the local Police Department, Social Services and Psychiatry/Mental Health Services (PSP) was introduced in the municipality of Frederiksberg, Denmark. The aim of this cooperation was to enhance support to vulnerable citizens, who do not belong solely to one of the three sectors and thereby often get lost in the system. The PSP cooperation was introduced to ensure that relevant information concerning vulnerable citizens was shared between the three sectors and to improve collaboration between the sectors involved in order to provide the needed support to the individual citizen. Due to the success of the PSP cooperation in Frederiksberg, the PSP model was implemented by law in Denmark in 2009. In order to evaluate the model, a qualitative study based on structured interviews, focus group discussions and observations, was performed in four selected municipalities in Denmark: Frederiksberg, Odense, Amager and Esbjerg. The evaluation was undertaken by the Danish National Centre for Social Research. It is concluded that the PSP cooperation draws attention to marginalized groups of citizens and helps to prevent social downfall and crime. Participants of the PSP cooperations further highlight positive changes in the cooperation between the involved sectors, which is thought to further improve the support to vulnerable citizens and thereby enhance both prevention and follow up of cases. Furthermore, the recommendations drawn from the evaluation are to adapt PSP cooperations to local conditions, avoid unnecessary red-tape, keep a constant focus on citizens' ethics, as well as involve the frontline workers in the individual sectors, i.e. those who are actually in contact with marginalized citizens. PMID- 24631523 TI - Vitamin D status and hypertensive disorders in pregnancy. AB - PURPOSE: Several studies have reported increased risk of preeclampsia when 25 hyrdoxyvitamin D (25[OH]D) levels are low. The extent to which 25(OH)D may lower risk for hypertensive disorder during pregnancy remains unclear. METHODS: Among women enrolled in the Project Viva prenatal cohort in Massachusetts, we examined associations of 25(OH)D levels obtained at 16.4-36.9 weeks of gestation (mean 27.9 weeks) with hypertensive disorders of pregnancy, including preeclampsia (56/1591, 3.5%) and gestational hypertension (109/1591, 6.9%). RESULTS: We did not detect an association between plasma 25(OH)D concentration (mean 58, standard deviation 22 nmol/L) and preeclampsia. For each 25 nmol/L increase in 25(OH)D, the adjusted odds ratio for preeclampsia was 1.14 (95% confidence interval, 0.77 1.67). By contrast and contrary to hypothesis, higher 25(OH)D concentrations were associated with higher odds of gestational hypertension: adjusted odds ratio for gestational hypertension was 1.32 (95% confidence interval, 1.01-1.72) per each 25 nmol/L increment in 25(OH)D. Vitamin D intake patterns suggest that this association was not because of reverse causation. Although the elevated hypertension risk may be due to chance, randomized trials of vitamin D supplementation during pregnancy should monitor for gestational hypertension. CONCLUSIONS: These data do not support the hypothesis that higher 25(OH)D levels lower the overall risk of hypertensive disorders of pregnancy. PMID- 24631525 TI - Predictors of length of stay in forensic psychiatry: the influence of perceived risk of violence. AB - This study describes the prevalence of adverse events and length of stay in forensic psychiatric patients with and without a restriction order. Detailed clinical and administrative information from medical records and written court decisions was gathered retrospectively from admission until discharge for a Swedish population-based, consecutive cohort of forensic psychiatric patients (n=125). The median length of stay for the whole cohort was 951 days, but patients with a restriction order stayed in hospital almost five times as long as patients without. Restriction orders were related to convictions for violent crime, but not for any other differences in demographic or clinical variables. The majority of the patients (60%) were involved in adverse events (violence, threats, substance abuse, or absconding) at some time during their treatment. Patients with restriction orders were overrepresented in violent and threat events. Previous contact with child and adolescence psychiatric services, current violent index crime, psychotic disorders, a history of substance, and absconding during treatment predicted longer length of stay. Being a parent, high current Global Assessment of Functioning scores, and mood disorders were all significantly related to earlier discharge. In a stepwise Cox regression analysis current violent index crime and absconding remained risk factors for a longer hospital stay, while a diagnosis of mood disorder was significantly related to a shorter length of stay. PMID- 24631526 TI - Forensic mental health assessment in France: recommendations for quality improvement. AB - The quality of forensic mental health assessment has been a growing concern in various countries on both sides of the Atlantic, but the legal systems are not always comparable and some aspects of forensic assessment are specific to a given country. This paper describes the legal context of forensic psychological assessment in France (i.e. pre-trial investigation phase entrusted to a judge, with mental health assessment performed by preselected professionals called "experts" in French), its advantages and its pitfalls. Forensic psychiatric or psychological assessment is often an essential and decisive element in criminal cases, but since a judiciary scandal which was made public in 2005 (the Outreau case) there has been increasing criticism from the public and the legal profession regarding the reliability of clinical conclusions. Several academic studies and a parliamentary report have highlighted various faulty aspects in both the judiciary process and the mental health assessments. The heterogeneity of expert practices in France appears to be mainly related to a lack of consensus on several core notions such as mental health diagnosis or assessment methods, poor working conditions, lack of specialized training, and insufficient familiarity with the Code of Ethics. In this article we describe and analyze the French practice of forensic psychologists and psychiatrists in criminal cases and propose steps that could be taken to improve its quality, such as setting up specialized training courses, enforcing the Code of Ethics for psychologists, and calling for consensus on diagnostic and assessment methods. PMID- 24631527 TI - Mental disorder and probation policy and practice: a view from the UK. AB - This article is concerned with the manner in which offenders with mental illnesses serving community sentences are identified and treated by the probation service in the UK. It presents the results of recent research examining the prevalence levels of current and lifetime mental illness, substance misuse, and dual diagnosis and suicide rates amongst those serving community sentences in the UK. These high levels of mental disorder are not being addressed by probation policy or practice in a manner that is effective or sensitive. The article concludes by considering the relevance of innovative approaches to the treatment of offenders with mental illnesses in the community currently being adopted in the US to the UK. PMID- 24631528 TI - CCN1 enables Fas ligand-induced apoptosis in cardiomyoblast H9c2 cells by disrupting caspase inhibitor XIAP. AB - Cell proliferation from pre-existing cardiomyocytes is a major source of cells for normal mammalian myocardial renewal or for regeneration after myocardial injury. These proliferative cardiomyocytes may act differently from the postmitotic cardiomyocytes in a stressed heart. Extracellular matrix molecule CCN1 is produced to promote Fas ligand (FasL)-induced cardiomyocyte apoptosis in mice with stress-induced cardiac injury. We aimed to investigate the effect of CCN1 on the proliferative cardiomyocytes. We used rat embryonic cardiomyoblast H9c2 cells to study the cardiotoxicity of CCN1. We found that FasL dose dependently increased the X-linked inhibitor of apoptosis protein (XIAP) levels to prevent the progression of apoptosis in H9c2 cells. CCN1, though it did not induce apoptosis by itself, sensitized H9c2 cells to FasL-induced apoptosis. CCN1 functions by engaging its cell-surface receptor integrin alpha6beta1 and elevating reactive oxygen species levels, which leads to mitogen-activated protein kinase p38 activation, cytosolic Bax translocation to mitochondria, and the release of mitochondrial Smac and HtrA2 to cytosol. These elevated cytosolic Smac and HtrA2 dismantle the inhibition of XIAP, thereby facilitating the activation of caspase-3 and the apoptosis-induced by FasL. In summary, we demonstrated a novel mechanism underlying the resistance of cardiomyoblasts to FasL-induced apoptosis, and the pro-apoptotic function of CCN1 by disrupting this resistance. PMID- 24631529 TI - Galpha12gep oncogene inhibits FOXO1 in hepatocellular carcinoma as a consequence of miR-135b and miR-194 dysregulation. AB - The high mortality rate of hepatocellular carcinoma (HCC) is associated with its fast-growing malignancy. In tumor microenvironments, certain GPCRs are coupled to Galpha12 for signal transduction. Given the role of forkhead box O1 (FOXO1) in the inhibition of various tumors, this study investigated whether increase of Galpha12 in HCC causes FOXO1 repression, and if so, whether this event occurs through microRNA dysregulation. Overexpression of an active mutant of Galpha12 (Galpha12QL) decreased FOXO1 levels, whereas knockdown of Galpha12 had the opposite effect. Of the microRNAs targeting FOXO1, miR-135b levels were markedly increased by Galpha12 signaling, which led to FOXO1 repression as shown by the experiments using mimic, antisense oligonucleotide or siRNA. Galpha12QL increased the primary form of miR-135b by activating JunB (or c-Jun)/AP-1. Consistently, knockdown of JunB (or c-Jun) decreased miR-135b levels, thereby increasing FOXO1. Moreover, Galpha12QL induced MDM2, the deficiency of which facilitated FOXO1 accumulation. In addition, Galpha12QL repressed miR-194 cluster gene products (194/192/215), which contributed to MDM2-mediated FOXO1 repression. In functional assays, Galpha12QL facilitated tumor cell growth with alterations in cell cycle associated protein levels, which was antagonized by enforced expression of FOXO1. In human HCCs, FOXO1 levels were decreased as compared with the surrounding liver tissue. Moreover, decrease of FOXO1 or miR-194 was statistically significant between stages T1 and T2, whereas increase of miR-135b discriminated tumor stage T3a versus T1/T2. In conclusion, Galpha12gep oncogene inhibits FOXO1, which may result from the inhibition of FOXO1 de novo synthesis by miR-135b in conjunction with MDM2-mediated destabilization of FOXO1. PMID- 24631530 TI - C5L2 is required for C5a-triggered receptor internalization and ERK signaling. AB - C5L2 is a receptor that binds to C5a and belongs to the family of G protein coupled receptors, but its role in physiological C5a-mediated responses remains under debate. Here we show that, like the canonical C5a receptor C5aR, C5L2 plays a pro-inflammatory role in a murine model of acute experimental colitis. We demonstrate that C5L2 physically interacts with C5aR and is required for optimal C5a-mediated C5aR internalization and associated ERK activation. Abrogation of C5a-induced receptor internalization by treatment with the dynamin inhibitor dynasore(TM) impaired C5a-induced MEK and ERK signaling. Although the presence of C5aR alone was sufficient to recruit the scaffold protein beta-arrestin1 to the cell membrane in response to C5a stimulation, it was inadequate to mediate AP2 recruitment and subsequent C5aR internalization. Expression of C5L2 allowed normal internalization of C5aR in response to C5a stimulation, followed by normal ERK signaling. Thus, our work reveals an essential role for C5L2 in C5a triggered, AP2-dependent C5aR internalization and downstream ERK signaling. PMID- 24631531 TI - MicroRNA-363-mediated downregulation of S1PR1 suppresses the proliferation of hepatocellular carcinoma cells. AB - S1PR1 plays a crucial role in promoting proliferation of hepatocellular carcinoma (HCC). Over expression of S1PR1 is observed in HCC cell lines. The mechanisms underlying the aberrant expression of S1PR1 are not known well. MircroRNAs are important regulators of gene expression and disproportionate microRNAs can result in dysregulation of oncogenes in cancer cells. In this study, we found that miR 363, a potential tumor suppressor microRNA, downregulated the expression of S1PR1 and inhibited the proliferation of HCC cells. Bioinformatic analysis predicted a putative binding site of miR-363 within the 3'-UTR of S1PR1 mRNA. Luciferase reporter assay showed that miR-363 directly targeted the 3'-UTR of S1PR1 mRNA. Transfection of miR-363 mimics suppressed S1PR1 expression in HCC cells, followed by the repression of the activation of ERK and STAT3. Moreover, we found that the expression of downstream genes of ERK and STAT3, including PDGF-A, PDGF-B, MCL-1 and Bcl-xL, was suppressed after miR-363 transfection. Taken together, the present study demonstrated that miR-363 was a negative regulator of S1PR1 expression in HCC cells and inhibited cell proliferation, suggesting that the miR 363/S1PR1 pathway might be a novel target for the treatment of HCC. PMID- 24631533 TI - Recent findings in evolution and function of insect innexins. AB - The past decade has seen significant advances in the field of innexin biology, particularly in the model invertebrate organisms, the nematode Caenorhabditis elegans and the fly Drosophila melanogaster. However, advances in genomics and functional techniques during this same period are ushering in a period of comparative innexin biology. Insects are the most diverse metazoan taxa in terms of species number, as well as in developmental, physiological, and morphological processes. Combined with genomics data, the study of innexins should rapidly advance. In this review, we consider the current state of knowledge regarding innexins in insects, focusing on innexin diversity, both evolutionary and functional. We also consider an unusual set of innexins, known as vinnexins, that have been isolated from mutualistic viruses of some parasitoid wasps. We conclude with a call to study insect innexins from a broader, evolutionary perspective. Knowledge derived from such comparative studies will offer significant insight into developmental and evolutionary physiology, as well as specific functional processes in a taxon that has huge biomedical and ecological impact on humans. PMID- 24631532 TI - MiR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET. AB - Dysregulation of the REarranged during Transfection proto-oncogene (RET) pathway and microRNA (miRNAs) are crucial for the development of medullary thyroid carcinomas (MTC). Here we demonstrate that miR-129-5p is down-regulated in MTC tissues and cell lines and inhibits RET expression by directly binding its 3' untranslated regions. Ectopic expression of miR-129-5p significantly decreases cell growth, induces apoptosis and suppresses migration ability in MTC cells through decreasing the phosphorylated AKT, thus functioning as a tumor suppressor. These findings give new clues for understanding MTC carcinogenesis and may help in developing a therapeutic approach for the treatment of RET activated MTC. PMID- 24631534 TI - Hunting for connexin hemichannels. AB - Connexin hemichannels (connexons) are building blocks of gap junctions but also function as free unapposed channels, which has become an active field of research. Defining functions of hemichannels and their involvement in any biological event requires ruling out possible participation of other channels that share biophysical and regulatory properties, for example pannexins, CALHM1 and P2X receptors. The lack of specific inhibitors for these channels has become an obstacle in elucidating the role of connexin hemichannels. Several experimental approaches are now available to identify hemichannels at the cell surface and to characterize their electrophysiological, permeability and regulatory properties. The use of connexin knockout/knockdown, and the development of peptides that target intracellular connexin domains and specific antibodies directed to extracellular domains have helped to dissect the role of hemichannels in endogenously expressing systems. Moreover, studies of connexin mutants in exogenous expression systems have provided convincing evidence on hemichannels in the pathogenesis of several human genetic diseases. We here present a brief overview of connexin hemichannels as functional channels and itemize a list of aspects to consider when concluding on their involvement. PMID- 24631535 TI - A new angle on blood-CNS interfaces: a role for connexins? AB - Neuronal signaling in the CNS depends on the microenvironment around synapses and axons. To prevent fluctuations in blood composition affecting the interstitial fluid and CSF, two barriers, the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are interposed between the blood and the brain/CSF compartment. Brain capillary endothelial cells (ECs) constitute the BBB whereas choroid plexus epithelial (CPE) cells form the BCSFB. The anatomical basis of these barriers is located at the level of an intercellular junctional complex that impedes paracellular diffusion. Tight and adherens junctions are known as the principal constituents of this junctional complex. Transmembrane connexins (Cxs) are the prime building blocks of plasma membrane hemichannels that combine to form intercellular gap junctions (GJ). Although Cxs co-exist within the junctional complex, their influence on tight/adherens junctions and their role in barrier function of BBB ECs and CPE has been mostly ignored. Here, we review current knowledge on the role of Cxs in the BBB, BCSFB and other interfaces that subside within the CNS. We conclude that Cxs are a rather unexplored but promising target for influencing CNS barrier function. PMID- 24631536 TI - GDSL lipase 1 regulates ethylene signaling and ethylene-associated systemic immunity in Arabidopsis. AB - Arabidopsis GDSL lipase 1 (GLIP1) has been shown to modulate systemic immunity through the regulation of ethylene signaling components. Here we demonstrate that the constitutive triple response mutant ctr1-1 requires GLIP1 for the ethylene response, gene expression, and pathogen resistance. The glip1-1 mutant was defective in induced resistance following primary inoculation of necrotrophic pathogens, whereas GLIP1-overexpressing plants showed resistance to multiple pathogens. Necrotrophic infection triggered the downregulation of EIN3 and the activation of ERF1 and SID2 in a GLIP1-dependent manner. These results suggest that GLIP1 positively and negatively regulates ethylene signaling, resulting in an ethylene-associated, necrotroph-induced immune response. PMID- 24631537 TI - Connexins in respiratory and gastrointestinal mucosal immunity. AB - The mucosal lining forms the physical and chemical barrier that protects against pathogens and hostile particles and harbors its own population of bacteria, fungi and archea, known as the microbiota. The immune system controls tolerance of this population of microorganisms that have proven to be beneficial for its host. Keeping its physical integrity and a correct balance with the microbiota, the mucosa preserves its homeostasis and its protective function and maintains host's health. However, in some conditions, pathogens may succeed in breaching mucosal homeostasis and successfully infecting the host. In this review we will discuss the role the mucosa plays in the defense against bacterial pathogens by considering the gap junction protein connexins. We will detail their implication in mucosal homeostasis and upon infection with bacteria in the respiratory and the gastrointestinal tracts. PMID- 24631538 TI - Type 2 ryanodine receptors are highly sensitive to alcohol. AB - Exposure to ethanol levels reached in circulation during alcohol intoxication (>10mM) constricts cerebral arteries in rats and humans. Remarkably, targets and mechanisms underlying this action remain largely unidentified. Artery diameter is regulated by myocyte Ca(2+) sparks, a vasodilatory signal contributed to by type 2 ryanodine receptors (RyR2). Using laser confocal microscopy in rat cerebral arteries and bilayer electrophysiology we unveil that ethanol inhibits both Ca(2+) spark and RyR2 activity with IC50<20 mM, placing RyR2 among the ion channels that are most sensitive to ethanol. Alcohol directly targets RyR2 and its lipid microenvironment, leading to stabilization of RyR2 closed states. PMID- 24631539 TI - Ubiquitin ligase Cbl-b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability. AB - Discoidin domain receptor 2 (DDR2), a collagen receptor tyrosine kinase, initiates signal transduction upon collagen binding, but little is known as to how DDR2 signaling is negatively regulated. Herein we demonstrate that Cbl family member Cbl-b predominantly promotes the ubiquitination of DDR2 upon collagen II stimulation. Cbl-b-mediated ubiquitination accelerates the degradation of activated DDR2. Finally, the production of MMP-13, a downstream target of DDR2, is enhanced in Cbl-b-knocked down MC3T3-E1 cells and Cbl-b-deficient mouse primary synovial fibroblasts. Thus, Cbl-b, by promoting the ubiquitination and degradation of DDR2, functions as a negative regulator in the DDR2 signaling pathway. PMID- 24631540 TI - The two common polymorphic forms of human NRH-quinone oxidoreductase 2 (NQO2) have different biochemical properties. AB - There are two common forms of NRH-quinone oxidoreductase 2 (NQO2) in the human population resulting from SNP rs1143684. One has phenylalanine at position 47 (NQO2-F47) and the other leucine (NQO2-L47). Using recombinant proteins, we show that these variants have similar steady state kinetic parameters, although NQO2 L47 has a slightly lower specificity constant. NQO2-L47 is less stable towards proteolytic digestion and thermal denaturation than NQO2-F47. Both forms are inhibited by resveratrol, but NQO2-F47 shows negative cooperativity with this inhibitor. Thus these data demonstrate, for the first time, clear biochemical differences between the variants which help explain previous biomedical and epidemiological findings. PMID- 24631541 TI - Detection and quantification of alternative splice sites in Arabidopsis genes AtDCL2 and AtPTB2 with highly sensitive surface enhanced Raman spectroscopy (SERS) and gold nanoprobes. AB - Alternative splicing (AS) increases the size of the transcriptome and proteome to enhance the physiological capacity of cells. We demonstrate surface enhanced Raman spectroscopy (SERS) in combination with a DNA hybridization analytical platform to identify and quantify AS genes in plants. AS in AtDCL2 and AtPTB2 were investigated using non-fluorescent Raman probes using a 'sandwich assay'. Utilizing Raman probes conjugated to gold nanoparticles we demonstrate the recognition of RNA sequences specific to AtDCL2 and AtPTB2 splice junction variants with detection sensitivity of up to 0.1 fM. PMID- 24631542 TI - Self-assembly of proteins into a three-dimensional multilayer system: investigation of the surface of the human fungal pathogen Aspergillus fumigatus. AB - Hydrophobins are small surface active proteins that fulfil a wide spectrum of functions in fungal growth and development. The human fungal pathogen Aspergillus fumigatus expresses RodA hydrophobins that self-assemble on the outer conidial surface into tightly organized nanorods known as rodlets. AFM investigation of the conidial surface allows us to evidence that RodA hydrophobins self-assemble into rodlets through bilayers. Within bilayers, hydrophilic domains of hydrophobins point inward, thus making a hydrophilic core, while hydrophobic domains point outward. AFM measurements reveal that several rodlet bilayers are present on the conidial surface thus showing that proteins self-assemble into a complex three-dimensional multilayer system. The self-assembly of RodA hydrophobins into rodlets results from attractive interactions between stacked beta-sheets, which conduct to a final linear cross-beta spine structure. A Monte Carlo simulation shows that anisotropic interactions are the main driving forces leading the hydrophobins to self-assemble into parallel rodlets, which are further structured in nanodomains. Taken together, these findings allow us to propose a mechanism, which conducts RodA hydrophobins to a highly ordered rodlet structure. The mechanism of hydrophobin assembly into rodlets offers new prospects for the development of more efficient strategies leading to disruption of rodlet formation allowing a rapid detection of the fungus by the immune system. PMID- 24631544 TI - The self-association of the giant hemoglobin from the earthworm, Lumbricus terrestris. AB - BACKGROUND: The crystallographic structure of the gigantic hemoglobin (erythrocruorin) of the annelid worm, Lumbricus terrestris, provides a molar mass of 3.6MDa for the hexagonal bilayer structure. Prior to this determination, some light-scattering and ultracentrifugal measurements indicated higher masses: 4.1 4.4MDa. Values of 3.6MDa were attributed to dissociation or subunit loss. However, early electron microscopy of the giant hemoglobin from a related annelid, Eumenia crassa by Oster Levin, showed that the hexagonal bilayer molecules were present mostly as oligomers; few were monomeric. METHODS: Measurements by light-scattering of solutions of Lumbricus hemoglobin resolved by size-exclusion chromatography have been used to determine the weight-average molar mass of self-associating proteins. The X-ray structure has been re examined. RESULTS: Our measurements show that both 3.6MDa monomers and self association products are present as a mixture. Analysis of the X-ray structure indicates several different kinds of monomer-monomer interactions. CONCLUSIONS: We propose that the measured masses of Lumbricus hemoglobin as high as 4.4MDa, result from oligomerization. These masses would result from the presence of an array of oligomers of various sizes together with monomers of 3.6MDa. Furthermore, several different kinds of monomer-monomer interactions are clearly evident in the X-ray structure as well as in solution. GENERAL SIGNIFICANCE: The results demonstrate that self-association of monomers of the hemoglobin of Lumbricus terrestris explains the high molar masses of 4.1-4.4MDa previously observed. PMID- 24631545 TI - Responsiveness of four gender-specific genes, figla, foxl2, scp3 and sox9a to 17alpha-ethinylestradiol in adult rare minnow Gobiocypris rarus. AB - Proteins encoded by figla, foxl2, scp3 and sox9a play important roles in gonad differentiation and reproduction. In the present study, we aimed to determine the responsiveness of figla, foxl2, scp3 and sox9a to 17alpha-ethinylestradiol (EE2) in the gonads of adult Gobiocypris rarus. Full-length cDNAs of figla, scp3 and sox9a were cloned and characterized by RT-PCR and RACE methods. Expression patterns in adult tissues were investigated. Results indicated that figla was predominantly expressed in adult ovaries and scp3 was restrictively expressed in the male testes and sox9a was principally expressed in the brains of both genders and the testes of males. Gene expression profiles of figla, foxl2, scp3 and sox9a were analyzed in the gonads of adult G. rarus exposed to EE2 at 1, 5, 25, and 125ng/L for 3 and 6days. Three-day EE2 treatment at 1-125ng/L all caused a significant increase of figla transcript in testes and foxl2 transcript in ovaries. However, six-day EE2 exposure at 1-125ng/L repressed figla and scp3 transcript in testes and foxl2 transcript in ovaries. The present study indicates that the testicular transcripts of figla and scp3 in males and the ovarian foxl2 transcript in females have high responsiveness to EE2 and they can be used as sensitive molecular biomarkers for early warning to monitor the environmental estrogenic chemicals in fresh water environment. The present study also suggests that the effective EE2 dosage for feminization in male G. rarus might be at least 25ng/L. PMID- 24631543 TI - Pyrrolysyl-tRNA synthetase: an ordinary enzyme but an outstanding genetic code expansion tool. AB - The genetic incorporation of the 22nd proteinogenic amino acid, pyrrolysine (Pyl) at amber codon is achieved by the action of pyrrolysyl-tRNA synthetase (PylRS) together with its cognate tRNA(Pyl). Unlike most aminoacyl-tRNA synthetases, PylRS displays high substrate side chain promiscuity, low selectivity toward its substrate alpha-amine, and low selectivity toward the anticodon of tRNA(Pyl). These unique but ordinary features of PylRS as an aminoacyl-tRNA synthetase allow the Pyl incorporation machinery to be easily engineered for the genetic incorporation of more than 100 non-canonical amino acids (NCAAs) or alpha-hydroxy acids into proteins at amber codon and the reassignment of other codons such as ochre UAA, opal UGA, and four-base AGGA codons to code NCAAs. PMID- 24631546 TI - Cholecystokinin: how many functions? Observations in seabreams. AB - A short overview on the regional distribution of the gastro-intestinal peptide hormone cholecystokin (CCK) in fish is presented. In particular, the results of molecular and immunological studies on seabreams, Diplodus puntazzo and Diplodus sargus, are reported, which, by demonstrating CCK in the hindgut, open new questions regarding the functional role of this hormone in that part of the intestine. The putative involvement of hindgut CCK in the feedback control of digestive processes was tested by measuring CCK gene and protein expression in fed and fasted fish. The results of this study led to hypothesize different roles for the two CCK isoforms in D. sargus, one of which related to regulation of digestive processes from pyloric caeca through hindgut. On the other hand, a functional role alternative to regulation of digestive processes may be inferred for the other isoform. PMID- 24631547 TI - Structural characterization and antioxidant activities of polysaccharides from Citrus aurantium L. AB - Three polysaccharide fractions were obtained from Citrus aurantium L. (CAL) by sequential extraction with cold water, hot water, and 1.0M NaOH, respectively. The fractions were denoted CALA, CALB, and CALC. Structural characterization was conducted by physicochemical property, FTIR, and SEM analyses. Antioxidant activities in vivo and in vitro were also evaluated. CALB, which showed the highest activity, was further isolated to afford four purified polysaccharides (CALB-1-4) by various ion exchange and gel-filtration chromatography. Meanwhile, the purified polysaccharides were subjected to composition analysis and screened by antioxidant activity in vitro. Among the four purified polysaccharides, CALB-3 had the highest antioxidant activity and its structure was analyzed by FTIR, SEM and AFM microscopy. Overall, these results indicated that polysaccharides from CAL had potential therapeutic applications in the medical and food industries because of their antioxidant activities. PMID- 24631549 TI - Effect of sugars and salts on rheological properties of Balangu seed (Lallemantia royleana) gum. AB - The effect of different sugars (sucrose, glucose, fructose, and lactose) and salts (NaCl and CaCl2) at various concentrations on rheological properties of Balangu seed gum (BSG, 1% w/w) was investigated. The apparent viscosity was influenced by the sugars and salts concentration and shear rate. Synergistic interaction between BSG gum and sugars improved the viscosity of solutions, whereas addition of salts decreased viscosity of gum solutions. The Power law and Herschel-Bulkley models were fitted to shear stress-shear rate data to obtain the consistency coefficient (K) and flow behavior index (n) for BSG solutions. Power law model well described non-Newtonian pseudoplastic behavior of BSG. Both K and n were sensitive to sugars and salts concentration. Highest values (0.45-0.49) of flow behavior index were observed for glucose at all concentrations. Addition of sucrose, fructose, lactose and salts to BSG led to more pseudoplastic solutions, whereas glucose decreased pseudoplasticity of solutions. PMID- 24631548 TI - Structural characterization and bioactivity of released exopolysaccharides from Lactobacillus plantarum 70810. AB - Two released exopolysaccharides (r-EPS1 and r-EPS2) were isolated from the culture supernatant of Lactobacillus plantarum 70810 by ethanol precipitation, anion exchange and gel filtration chromatography and characterization of the structures were conducted. The r-EPS1 and r-EPS2 were homogenous polysaccharides with average molecular weights of, respectively, 204.6 and 202.8kDa, and composed of glucose, mannose and galactose with molar ratios of 18.21:78.76:3.03 and 12.92:30.89:56.19, respectively. Methylation and NMR analysis revealed r-EPS1 was consisted of alpha configuration sugar residues, whereas r-EPS2 contained both alpha and beta configuration sugar residues. Antioxidant and antitumor activities of the two exopolysaccharides were evaluated in vitro. The results showed that r EPS1 and r-EPS2 exhibited potent antioxidant activities regarding hydroxyl and DPPH radicals scavenging and reducing power assays, and possessed antitumor activities against Caco-2, BGC-823 and HT-29 cells, which suggested that they could be potential sources of antioxidant and antitumor drug. PMID- 24631550 TI - Development of biodegradable antibacterial cellulose based hydrogel membranes for wound healing. AB - Cellulose-based hydrogels have wide applications in tissue engineering and controlled delivery systems. In this study, chloramphenicol (CAP) loaded 2,3 dialdehyde cellulose (DABC) hydrogel membranes were prepared, characterized and their antibacterial efficacy was evaluated. Bacterial cellulose (BC) secreted by Acetobacter xylinum was modified to become DABC by oxidation via the sodium metaperiodate method. CAP-BC and CAP-DABC interactions were illustrated via ATR FTIR analysis. Water retention capacity of BC and DABC membranes were determined as 65.6+/-1.6% and 5.3+/-0.3%, respectively. CAP release profiles were determined via HPLC analysis. The drug-loading capacities of BC and DABC membranes were 5mg/cm(2) and 0.1mg/cm(2), respectively. Membranes released 99-99.5% of the contained CAP within 24h and an initial burst release effect was not observed. In vitro antibacterial tests of BC and DABC, both CAP-loaded, demonstrated their ability to inhibit bacterial growth for a prolonged duration. Antimicrobial effect against bacteria was still prevalent after 3 days of incubation period with disc diffusion tests. The MTT test results reveal that fibroblast adhesion and proliferation on CAP-loaded DABC membranes were noticeably higher than CAP loaded BC membrane. This newly developed drug containing DABC membranes seem to be highly suitable for wound healing due to its unique properties of biodegradability, biocompatibility, and antimicrobial effectiveness. PMID- 24631551 TI - The properties of different cultivars of Jinhai sweet potato starches in China. AB - IR, (13)C NMR, X-ray diffraction and DSC applied to study the physicochemical properties of starches from six different cultivars of Jinhai (I-VI) sweet potato strains in China. Jinhai II showed the highest rate of retrogradation while Jinhai III showed the lowest in all studied cultivars. The hydrolysis rates of those starches by alpha-amylase were from 98.1% in Jinhai II to 99.9% in Jinhai VI with a mean value of 99.3%. The ratio of R (1158/991cm(-1)) in IR spectra of those six different sweet potato starches could be the feature to identify them. All of the six studied Jinhai sweet potato starches showed strong peak at diffraction angle (2theta) of 17 degrees , 15 degrees and 23 degrees , meanwhile an extremely weak peak at 2theta around 5.5 degrees was also identical. XRD pattern of Jinhai II and IV starch also gave strong diffraction peaks at 26.6 degrees , which could be the characteristics of them. The enthalpy and Tp of Jinhai II were especially lower than other cultivars. Jinhai IV revealed two Tp of 128.0 degrees C and 140 degrees C, respectively. The second Tp was maybe the characteristic of Jinhai IV starch. IR and DSC were the most effective methods to distinguish different cultivars of sweet potato. PMID- 24631552 TI - NCS-1 deficiency causes anxiety and depressive-like behavior with impaired non aversive memory in mice. AB - Sensing and regulating intracellular levels of calcium are essential for proper cellular function. In neurons, calcium sensing plays important roles in neuronal plasticity, neurotransmitter release, long-term synapse modification and ion channel activity. Neuronal calcium sensor-1 (NCS-1) is a member of the highly conserved neuronal calcium sensor family. Although NCS-1 has been associated with psychiatric conditions including autism, bipolar disorder and schizophrenia, it is unclear which role NCS-1 plays in behavior. To understand the involvement of NCS-1 in psychiatric conditions, we provided a comprehensive behavioral characterization of NCS-1 knockout (KO) mice. These mice grow and develop normally without apparent abnormalities in comparison to wild type littermates. However, open field showed that NCS-1 deficiency impairs novelty-induced exploratory activity in both KO and heterozygote (HT) mice. Moreover, NCS-1 deficiency also resulted in anxiety- and depressive-like behaviors as demonstrated by elevated plus maze, large open field, forced swim and tail suspension tasks. Furthermore, based on spontaneous object recognition test, non aversive long-term memory was impaired in NCS-1 KO mice. In contrast, neither social behavior nor a kind of aversive memory was affected under NCS-1 deficiency. These data implicate NCS-1 in exploratory activity, memory and mood related behaviors, suggesting that NCS-1 gene ablation may result in phenotypic abnormalities associated with neuropsychiatric disorders. PMID- 24631555 TI - Diagnosis and treatment experience of rectal carcinoid (a report of 312 cases). AB - OBJECTIVE: To explore the diagnosis of rectal carcinoid tumors and to adopt the best method of treatment. PATIENTS AND METHODS: A group of 312 cases of pathologically confirmed rectal carcinoid were analyzed retrospectively. Data were obtained retrospectively from a database of all colorectal malignancies at Qilu Hospital from January 2004 to December 2012. 4072 colorectal malignant tumors and 312 rectal carcinoid tumors were diagnosed. Endoscopic resection was performed on 44 patients, while the other 248 underwent anus partial extended radical polypectomy. We evaluated the clinical manifestations, diagnosis, treatment and follow-ups regarding carcinoids and the relation between tumor diameter and the rate of recurrence or metastasis after surgery. RESULTS: There is no recurrence or metastasis after the transanal local resection in 284 cases with the tumor diameter less than 2 cm, 6 months to 7 years' follow-up. While, in 12 cases with the tumor diameter more than 2 cm radical surgery was performed, 8 cases had liver metastases at the time of the diagnosis of rectal carcinoid, 4 cases had no recurrence or metastasis after two and a half years' of follow ups, there is no recurrence or metastasis in 4 cases of multiple rectal carcinoids, whom all underwent radical surgery, follow ups continued for 2 years. CONCLUSION: Early diagnosis and treatment is important for rectal carcinoids, local resection is a simple, safe and effective treatment for carcinoids with a tumor diameter less than 2 cm. PMID- 24631554 TI - Preoperative prediction of the extrathyroidal extension of papillary thyroid carcinoma with ultrasonography versus MRI: a retrospective cohort study. AB - BACKGROUND: The purpose of this study was to assess the diagnostic performance of preoperative ultrasonography (US) for the prediction of extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) and to compare the diagnostic performances of US and magnetic resonance imaging (MRI) for predicting ETE. METHODS: 75 patients with PTC who underwent preoperative US and MRI were retrospectively reviewed in this study. Two radiologists independently evaluated the US and MR findings to assess minimal or extensive ETE of PTC. These results were compared with the histopathologic findings. The diagnostic performances of US and MRI in the evaluation of ETE were compared. RESULTS: US was more accurate than MRI in the prediction of minimal ETE (p < 0.05) and the accuracies were not significantly different between US and MRI in extensive ETE. US showed higher sensitivity, negative predictive value and accuracy than MRI (p < 0.001) in the prediction of overall ETE. CONCLUSION: US provided higher accuracy for assessing overall ETE and higher sensitivity for minimal ETE than MR imaging in preoperative evaluation of ETE of PTC. There was no significant difference in evaluating extensive ETE of PTC between US and MRI. PMID- 24631553 TI - Estrogen receptor beta and oxytocin interact to modulate anxiety-like behavior and neuroendocrine stress reactivity in adult male and female rats. AB - The hypothalamic-pituitary-adrenal (HPA) axis is activated in response to stressors and is controlled by neurons residing in the paraventricular nucleus of the hypothalamus (PVN). Although gonadal steroid hormones can influence HPA reactivity to stressors, the exact mechanism of action is not fully understood. It is known, however, that estrogen receptor beta (ERbeta) inhibits HPA reactivity and decreases anxiety-like behavior in rodents. Since ERbeta is co expressed with oxytocin (OT) in neurons of the PVN, an ERbeta-selective agonist was utilized to test the whether ERbeta decreases stress-induced HPA reactivity and anxiety-like behaviors via an OTergic pathway. Adult gonadectomized male and female rats were administered diarylpropionitrile, or vehicle, peripherally for 5days. When tested for anxiety-like behavior on the elevated plus maze (EPM), diarylpropionitrile-treated males and females significantly increased time on the open arm of the EPM compared to vehicle controls indicating that ERbeta reduces anxiety-like behaviors. One week after behavioral evaluation, rats were subjected to a 20minute restraint stress. Treatment with diarylpropionitrile reduced CORT and ACTH responses in both males and females. Subsequently, another group of animals was implanted with cannulae directed at the lateral ventricle. One week later, rats underwent the same protocol as above but with the additional treatment of intracerebroventricular infusion with an OT antagonist (des Gly-NH2 d(CH2)5 [Tyr(Me)(2), Thr(4)] OVT) or VEH, 20min prior to behavioral evaluation. OT antagonist treatment blocked the effects of diarylpropionitrile on the display of anxiety-like behaviors and plasma CORT levels. These data indicate that ERbeta and OT interact to modulate the HPA reactivity and the display of anxiety-like behaviors. PMID- 24631556 TI - Heterologous expression of a lectin from Pleurocybella porrigens (PPL) in Phanerochaete sordida YK-624. AB - Pleurocybella porrigens is a mushroom-forming fungus, which had been consumed as a traditional food in Japan. However, in 2004, 55 people got poisoned by eating the mushroom and 17 people among them died of acute encephalopathy. We have already reported the purification, characterization, and cDNA cloning of a lectin from the mushroom (PPL) which might have caused the poisoning. Here, we report the heterologous expression of recombinant PPL by basidiomycete Phanerochaete sordida YK-624. The glyceraldehyde 3-phosphate dehydrogenase gene promoter was used to drive the expression of the PPL gene (ppl) in P. sordida YK-624. Furthermore, the signal peptide of lignin peroxidase which is an extracellular protein was used to secrete rPPL into extracellular region. Fifteen regenerated clones were cultured on Kirk HNHC broth, and the presence of lectin activity in the culture broth was checked by agglutination assays. The results indicated that the culture broth of rPPL-6 clone showed the strongest hemagglutination activity, and it was therefore used for subsequent analysis. The heterologous expression of rPPL by P. sordida YK-624 was confirmed by SDS-PAGE, lectin activity by the hemagglutination assay, and mass of rPPL by MALDI-TOF respectively, indicating that the extracellular secretion of rPPL as active form was successful. PMID- 24631557 TI - Differentiation of Klebsiella pneumoniae carbapenemase (KPC) variants by pyrosequencing. AB - A fast and reliable protocol using the pyrosequencing technique was developed to identify 11 different types of the KPC enzyme. A total of 65 blaKPC positive bacterial isolates were tested and characterized. In the end, the pyrosequencing proved to be a powerful tool for epidemiological studies of KPC producer isolates. PMID- 24631558 TI - Development of multilocus variable-number tandem repeat analysis (MLVA) for Xanthomonas arboricola pathovars. AB - Xanthomonas arboricola is an important bacterial species, the pathovars of which are responsible for bacterial blight diseases on stone fruit, hazelnut, Persian walnut, poplar, strawberry, poinsettia and banana. In this study, we evaluated variable number tandem repeats (VNTR) as a molecular typing tool for assessing the genetic diversity within pathovars of X. arboricola. Screening of the X. arboricola pv. pruni genome sequence (CFBP5530 strain) predicted 51 candidate VNTR loci. Primer pairs for polymerase chain reaction (PCR) amplification of all 51 loci were designed, and their discriminatory power was initially evaluated with a core collection of 8 X. arboricola strains representative of the different pathovars. Next, the 26 polymorphic VNTR loci present in all strains were used for genotyping a collection of 61 strains. MLVA is a typing method that clearly differentiates X. arboricola strains. The MLVA scheme described in this study is a rapid and reliable molecular typing tool that can be used for further epidemiological studies of bacterial diseases caused by X. arboricola pathovars. PMID- 24631559 TI - Increased population of oligodendroglia-like cells in pediatric intractable epilepsy. AB - Pediatric focal epilepsies often involve more extratemporal regions than adult epilepsies. This study aims to investigate the population of oligodendroglia-like cells (OLCs) in the pediatric focal epilepsy patients requiring surgery. We hypothesize that OLCs are one of the factors that extend the pediatric epileptic network in intractable epilepsy. Thirty (18 female) patients (1.8-16.9 years old with a mean of 9.7 years), who underwent resective surgery for the intractable epilepsy from 2010 to 2012 were retrospectively studied. Seizure types consisted of epileptic spasms in nine patients, partial seizures in 17 patients and partial seizure with secondary generalization in four patients. Eight autopsy cases without neurological disease served as controls. The neuropathology examination utilized the H&E/LFB stain and immunohistochemical staining for NeuN, GFAP and Olig2 as a marker of OLCs. OLCs were counted in three sites: (a) gray matter, (b) junction of gray/white matter, and (c) white matter. We also examined the correlation between the density of OLC among the three sites and the clinical features. Fifteen (50%) patients underwent multiple lobe resections, consisting of both temporal and extratemporal lobe resections in 12 patients and extratemporal lobe resections in 3 patients. The other 15 (50%) patients underwent single lobe resection including 3 (10%) patients with temporal lobectomy sparing hippocampus. Pathological diagnosis of epilepsy patients was as follows: 14 (47%) patients=focal cortical dysplasia (type I, 4; II, 9; III, 1); 6 (20%)=oligodendrogliosis; 6 (20%)=astrocytic gliosis; 2 (7%)=hyaline protoplasmic astrocytopathy and 2 (7%)=tuberous sclerosis complex. The numbers of OLCs at all three sites in epilepsy group were significantly higher than those of control group (p<0.001). In the epilepsy group, there was a significant difference among the number of OLCs at gray matter, junction of gray and white matter, and white matter (p<0.001). The number of OLCs significantly increased from gray matter and junction of gray/white matter to white matter. In the control group, there was no difference among the number of OLCs at three sites. There was no significant difference in the numbers of OLCs between focal cortical dysplasia types I and II. The significantly increased OLCs, especially in the white matter may contribute to the extensive epileptic network in children with intractable focal epilepsy. PMID- 24631561 TI - No association between genetic variants of the LRRK2 gene and schizophrenia in Han Chinese. AB - Mitochondrial dysfunction was widely reported in schizophrenia patients in recent studies. Leucine-rich repeat kinase 2 (LRRK2) is a mitochondrial protein, and mutations in the LRRK2 gene can induce mitochondrial dysfunction. LRRK2 mutations have been reported to be the most frequent genetic cause of Parkinson's disease (PD). We were interested in whether LRRK2 variants also play a role in schizophrenia. In this study, we genotyped 12 genetic variants (including 4 tag SNPs and 8 disease-associated variants) in the LRRK2 gene in a total of 2449 samples composed of two independent Han Chinese schizophrenia case-control cohorts (486 schizophrenia patients and 480 healthy controls from Hunan Province; 624 schizophrenia patients and 859 healthy controls from Shanghai). We compared the genotype, allele and haplotype frequencies of those SNPs between cases and controls. Statistical analyses revealed no association between LRRK2 variants/haplotypes and schizophrenia in these two schizophrenia case-control cohorts and the combined samples. Our results indicated that the LRRK2 variants are unlikely to be actively involved in schizophrenia in Han Chinese. PMID- 24631560 TI - Suppression of spinal connexin 43 expression attenuates mechanical hypersensitivity in rats after an L5 spinal nerve injury. AB - Activation of spinal astrocytes may contribute to neuropathic pain. Adjacent astrocytes can make direct communication through gap junctions formed by connexin 43 (Cx43) in the central nervous system. Yet, the role of spinal astroglial gap junctions in neuropathic pain is not fully understood. Since Cx43 is the connexin isoform expressed preferentially in astrocytes in the spinal cord, we used a small interfering RNA (siRNA) approach to examine whether suppression of spinal Cx43 expression inhibits mechanical hypersensitivity in rats after an L5 spinal nerve ligation (SNL). SNL rats were administered intrathecal Cx43 siRNA (3MUg/15MUl, twice/day) or an equal amount of mismatch siRNA (control) on days 14 17 post-SNL. Cx43 siRNA, but not mismatch siRNA, alleviated mechanical hypersensitivity in SNL rats. Furthermore, Western blot analysis showed that the pain inhibition induced by Cx43 siRNA correlated with downregulation of Cx43 expression, but not that of Cx36 (the neuronal gap junction protein) or glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) in the spinal cord of SNL rats. Western blot analysis and immunohistochemistry also showed that SNL increased GFAP expression, but decreased Cx43 expression, in spinal cord. Our results provide direct evidence that selective suppression of spinal Cx43 after nerve injury alleviates neuropathic mechanical hypersensitivity. These findings suggest that in the spinal cord, the enhanced function of astroglial gap junctions, especially those formed by Cx43, may be important to neuropathic pain in SNL rats. PMID- 24631562 TI - Association analysis of STK39, MCCC1/LAMP3 and sporadic PD in the Chinese Han population. AB - With the completion of the Human Genome Project, GWAS have been widely used in exploring the genetic studies of complex diseases. A meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe found 11 loci that surpassed the threshold for genome-wide significance (p<5*10(-8)), and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11 and CCDC62/HIP1R). Another GWAS of the Ashkenazi Jewish population also identified loci in STK39 and LAMP3. Because the association between the STK39 and MCCC1/LAMP3 genes and PD was confirmed in different populations, we conducted a case-control cohort to clarify the association between the four single nucleotide polymorphism (SNP) loci (rs2102808 and rs3754775 in the STK39; rs11711441 and rs12493050 in the MCCC1/LAMP3) and PD in the Chinese Han population. Polymerase chain reaction and direct DNA sequencing analyses were used to detect the four variations in a case control cohort comprised of 993 ethnic Chinese subjects. We found that in the detection of the rs11711441, there was a significant difference between ungrouped populations, early-onset PD, late-onset PD, male PD, female PD and the corresponding control group in allele and genotype frequency (p<0.001, OR<1). In the detection of the rs2102808, rs3754775 and rs12493050, ungrouped populations, early-onset PD, late-onset PD, male PD or female PD with the corresponding control group showed no significant difference in allele and genotype frequency (p>0.0125). Our findings suggested that the allele G of rs11711441 of the MCCC1/LAMP3 gene can decrease the risk of PD in Chinese population. No statistically significant difference in genotype frequency between cases and controls was observed for the other three SNPs. PMID- 24631563 TI - Differential expression of hippocampal EphA4 and ephrinA3 in anhedonic-like behavior, stress resilience, and antidepressant drug treatment after chronic unpredicted mild stress. AB - Stress exposure is one of the major risk factors of depression, but the mechanism is not understood. While some individuals show resilience to stress exposure, antidepressants only partially reduce stress-induced depression in both humans and rodents. Stress could dysregulate the remodeling of neuronal dendrites and spines in hippocampus while antidepressants could recover the deficiency induced by stress. EphA4 and its ligand ephrinA3 are critical in the remodeling of neuronal dendrites and spines, but the relationship between ephrinA3/EphA4, stress-induced depression and antidepressants treatment is largely unknown. Based on a rat chronic unpredicted mild stress (CUMS) model, we investigated ephrinA3/EphA4 expression in stress susceptibility, stress resilience, treatment response and treatment resistance in rats. CUMS led to downregulation of EphA4 expression and upregulation of ephrinA3 expression in the hippocampus of stress susceptible rats, but not in stress-resilient rats. Dysregulated EphA4 and ephrinA3 can be rescued by fluoxetine administration in drug responders, but not in fluoxetine resistant rats. These data provide insights into the potential role of EphA4 and ephrinA3 after stressor exposure, stress adaptation, fluoxetine response and drug treatment refraction. PMID- 24631564 TI - Spatial location and pathway memory compared in the reaching vs. walking domains. AB - Spatial information processing is influenced by the space in which an individual acts and the nature of the stimulus. This distinction is also present in spatial memory, where stimuli are processed differently because of their nature and the space in which they are released. The aim of the present study was to compare college students' performance on spatial location and pathway memory tasks in two different domains (reaching and walking). Reaching space refers to the portion of space within "grasping distance" and walking space to that beyond arm's reach. Research results indicate that it is easier to remember a pathway in the walking than the reaching domain and to remember single spatial locations in the reaching domain. Women are more able to perform the task in the walking domain than the reaching domain and men perform equally well in both domains. PMID- 24631565 TI - [Nosological and functional justifications for sick leave: a cross-sectional study in the Rhone district]. AB - BACKGROUND: Although sick leave has significant medical and economic stakes, justifications for sick leave are poorly known in France. Our objective was to describe the medical justifications for sick leave, in nosological, functional and contextual terms. METHODS: Cross-sectional study, based on 1,143 sick leave certificates collected by the Health Insurance Fund of the Rhone district in February 2011. The medical justifications for sick leave were classified and coded in nosological terms according to the International Classification of Primary Care (ICPC-2) and in functional and contextual terms according to the "AT CIF questionnaire", derived from the International Classification of Functioning (ICF). RESULTS: Among the 1,073 sick leaves containing a medical justification (93.9%), 757 (70.5%) could be classified only according to the ICPC-2 and 316 (29.5%) according to both the ICPC-2 and the AT-CIF questionnaires. The health problems most frequently reported in sick leave justifications concerned, in order of decreasing frequency: respiratory (26.9%), psychological (13.7%), or digestive (12.1%) systems; general problems (10.7%); pregnancy (3.5%); the neurological system (2.9%). Furthermore, 346 functional deficiencies, five restrictions of activity and one environmental barrier were identified. CONCLUSION: Sick leave certificates almost always provide justifications for sick leave in nosological terms, but in less than one third of certificates provide information in functional or contextual terms. Training practitioners to make functional and contextual assessments may allow them to more optimally decide on the indication and the duration of sick leave, and facilitate communication around the patient. PMID- 24631566 TI - Simultaneous detection of IgG antibodies associated with viral hemorrhagic fever by a multiplexed Luminex-based immunoassay. AB - Viral hemorrhagic fevers (VHFs) are worldwide diseases caused by several kinds of viruses. With the emergence of new viruses, advanced diagnostic methods are urgently needed for identification of VHFs. Based on Luminex xMAP technology, a rapid, sensitive, multi-pathogen and high-throughput method which could simultaneously detect hemorrhagic fever viruses (HFVs) specific IgG antibodies was developed. Recombinant antigens of nine HFVs including Hantaan virus (HTNV), Seoul virus (SEOV), Puumala virus (PUUV), Andes virus (ANDV), Sin Nombre virus (SNV), Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus (RVFV), Severe fever with thrombocytopenia syndrome bunyavirus (SFTSV) and dengue virus (DENV) were produced and purified from a prokaryotic expression system and the influence of the coupling amount was investigated. Cross-reactions among antigens and their rabbit immune sera were evaluated. Serum samples collected from 51 laboratory confirmed hemorrhagic fever with renal syndrome (HFRS) patients, 43 confirmed SFTS patients and 88 healthy donors were analyzed. Results showed that recombinant nucleocapsid protein of the five viruses belonging to the genus Hantavirus, had serological cross-reactivity with their corresponding rabbit immune sera, but not apparent with immune sera of other four viruses. Evaluation of this new method with clinical serum samples showed 98.04% diagnostic sensitivity for HFRS, 90.70% for SFTS detection and the specificity was ranging from 66.67% to 100.00%. The multiplexed Luminex-based immunoassay has firstly been established in our study, which provides a potentially reliable diagnostic tool for IgG antibody detection of VHFs. PMID- 24631567 TI - Combination of transcranial direct current stimulation and methylphenidate in subacute stroke. AB - Noninvasive transcranial direct current stimulation (tDCS) and methylphenidate (MP) are associated with motor recovery after stroke. Based on the potentially complementary mechanisms of these interventions, we examined whether there is an interactive effect between MP and tDCS. In this preliminary study, we randomized subacute stroke subjects to receive tDCS alone, MP alone or combination of tDCS and MP. A blinded rater measured safety, hand function, and cortical excitability before and after treatment. None of the treatments caused any major or severe adverse effects or induced significant differences in cortical excitability. Analysis of variance of gain score, as measured by Purdue pegboard test, showed a significant between-group difference (F(2,6)=12.167, p=0.008). Post hoc analysis showed that the combination treatment effected greater Purdue pegboard gain scores than tDCS alone (p=0.017) or MP alone (p=0.01). Our preliminary data with nine subjects shows an interesting dissociation between motor function improvement and lack of motor corticospinal plasticity changes as indexed by transcranial magnetic stimulation in subacute stroke subjects. PMID- 24631568 TI - Venlafaxine protects methylglyoxal-induced apoptosis in the cultured human brain microvascular endothelial cells. AB - It was reported that venlafaxine protects microvascular endothelial cells injury in several models. But the mechanisms of venlafaxine protects cell injury still poor understanding. Here, we shows that in the cultured human brain microvascular endothelial cells (HBMEC), we found that venlafaxine protects methylglyoxal (MGO) induced cell injury, and the venlafaxine significant reduction in the level of reactive oxygen species, down-regulated expression of pro-apoptotic activated caspase-3 and Bax, increased BDNF release and expression of anti-apoptotic Bcl-2 in the cultured HBMEC. Furthermore, we found that venlafaxine inhibits MGO induced phosphorylation of JNK. Moreover, venlafaxine increased AKT phosphorylation and the protective effects of venlafaxine was inhibited by PI3K/AKT inhibitor. These findings suggest that venlafaxine protects MGO-induced HBMEC injury through PI3K/AKT and JNK pathway as the potential underlying mechanisms of HBMEC injury in diabetes. PMID- 24631569 TI - Inhibition of calpains fails to improve regeneration through a peripheral nerve conduit. AB - Intramuscular injection of the calpain inhibitor leupeptin promotes peripheral nerve regeneration in primates (Badalamente et al., 1989 [13]), and direct positive effects of leupeptin on axon outgrowth were observed in vitro (Hausott et al., 2012 [12]). In this study, we applied leupeptin (2mg/ml) directly to collagen-filled nerve conduits in the rat sciatic nerve transection model. Analysis of myelinated axons and retrogradely labeled motoneurons as well as functional 'CatWalk' video analysis did not reveal significant differences between vehicle controls and leupeptin treated animals. Therefore, leupeptin does not improve nerve regeneration via protease inhibition in regrowing axons or in surrounding Schwann cells following a single application to a peripheral nerve conduit suggesting indirect effects on motor endplate integrity if applied systemically. PMID- 24631570 TI - Psychiatric morbidity in Egyptian children with acute lymphoblastic leukemia and their care providers. AB - AIM OF THE STUDY: To evaluate the psychological morbidity of acute lymphoblastic leukemia (ALL) on children and their parents at different stages of illness and to assess the crucial contribution of the psychologist in the pediatric oncology team. METHODS: We recruited 103 children with ALL and their 96 parents, and divided them into five groups according to disease phase: diagnosis, initial remission, active treatment, survival and relapsing. We compared these to 22 healthy controls and their parents. Patients and controls were subjected to clinical assessments, the symptoms checklist of the International Classification of Disease ICD (ICD-10), and the Wechsler Intelligence Scale for Children The parents of patients and controls underwent a general health questionnaire, the ICD-10 symptoms checklist, rating scales for anxiety and depression, post traumatic stress disorder (PTSD) assessment scale, and the physical cognitive affective social economic ego problems (PCASEE) questionnaire for quality of life (QOL) rating. RESULTS: Psychiatric morbidity was evident in nearly 60% of leukemic children and their parents and was significantly increased in comparison to controls. Children mostly suffered from adjustment and oppositional defiant disorders. The most common discriminators between patient groups were conduct and attention problems being lowest in newly diagnosed patients, and social aggression being lowest in patients in remission. The three parameters were highest in relapsed patients whose parents mostly had adjustment and depressive disorders. Risk factors for child psychopathology were older age, female gender, and parental psychopathology. Mothers and parents with lower education and professional level were found to be vulnerable. Performance and total intelligence quotient (IQ) were significantly lower in leukemic children, and these were most pronounced in the survivor group. Risk factors for cognitive dysfunction were younger age, longer chemotherapy duration, and lower parental education level. CONCLUSION: Most patients and their caregivers suffered from significant psychiatric morbidity, highlighting the need for routine screening to improve psychological outcomes in such cases. PMID- 24631571 TI - Cellular and molecular mechanisms in liver fibrogenesis. AB - Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process, potentially reversible, that drives the progression of chronic liver diseases (CLD) towards liver cirrhosis and hepatic failure. Hepatic myofibroblasts (MFs), the pro-fibrogenic effector cells, originate mainly from activation of hepatic stellate cells and portal fibroblasts being characterized by a proliferative and survival attitude. MFs also contract in response to vasoactive agents, sustain angiogenesis and recruit and modulate activity of cells of innate or adaptive immunity. Chronic activation of wound healing and oxidative stress as well as derangement of epithelial-mesenchymal interactions are "major" pro-fibrogenic mechanisms, whatever the etiology. However, literature has outlined a complex network of pro-fibrogenic factors and mediators proposed to modulate CLD progression, with some of them being at present highly debated in the field, including the role of epithelial to mesenchymal transition and Hedgehog signaling pathways. Hypoxia and angiogenesis as well as inflammasomes are recently emerged as ubiquitous pro-inflammatory and pro-fibrogenic determinants whereas adipokines are mostly involved in CLD related to metabolic disturbances (metabolic syndrome and/or obesity and type 2 diabetes). Finally, autophagy as well as natural killer and natural killer-T cells have been recently proposed to significantly affect fibrogenic CLD progression. PMID- 24631572 TI - The myofilament elasticity and its effect on kinetics of force generation by the myosin motor. AB - The half-sarcomere is the functional unit of striated muscle, in which, according to a "linear" mechanical model, myosin motors are parallel force generators with an average strain s acting between the opposing myosin and actin filaments that behave as a series elastic element with compliance Cf. Thus the definition of the mechanism of force generation by myosin motors in muscle requires integration of the crystallographic model of the working stroke with the mechanical constraints provided by the organization of motors in the half-sarcomere. The relation between half-sarcomere compliance and force (Chs-T) during the development of isometric contraction deviates, at low forces, from that predicted by the linear model, indicating the presence of an elastic element in parallel with the myosin motors, which may influence the estimate of s. A working stroke model, kinetically constrained by the early phase of the isotonic velocity transient following a force step, predicts that the rate of quick force recovery following a length step is reduced to the observed value by a Cf of 12.6nm/MPa. With this value of Cf, the fit of Chs-T relation during the isometric force rise gives s=1.8-1.9nm, similar to the values estimated using the linear model. PMID- 24631573 TI - Reduced cellular Mg2+ content enhances hexose 6-phosphate dehydrogenase activity and expression in HepG2 and HL-60 cells. AB - We have reported that Mg(2+) dynamically regulates glucose 6-phosphate entry into the endoplasmic reticulum and its hydrolysis by the glucose 6-phosphatase in liver cells. In the present study, we report that by modulating glucose 6 phosphate entry into the endoplasmic reticulum of HepG2 cells, Mg(2+) also regulates the oxidation of this substrate via hexose 6-phosphate dehydrogenase (H6PD). This regulatory effect is dynamic as glucose 6-phosphate entry and oxidation can be rapidly down-regulated by the addition of exogenous Mg(2+). In addition, HepG2 cells growing in low Mg(2+) show a marked increase in hexose 6 phosphate dehydrogenase mRNA and protein expression. Metabolically, these effects on hexose 6-phosphate dehydrogenase are important as this enzyme increases intra reticular NADPH production, which favors fatty acid and cholesterol synthesis. Similar effects of Mg(2+) were observed in HL-60 cells. These and previously published results suggest that in an hepatocyte culture model changes in cytoplasmic Mg(2+) content regulates glucose 6-phosphate utilization via glucose 6 phosphatase and hexose-6 phosphate dehydrogenase in alternative to glycolysis and glycogen synthesis. This alternative regulation might be of relevance in the transition from fed to fasted state. PMID- 24631574 TI - Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice. AB - Nosocomial respiratory infections caused by methicillin-resistant Staphylococcus aureus (MRSA) can progress to lethal systemic infections. Bacteriophage (phage) therapy is expected to be effective against these critical infections. Previously, phage S13' was proposed as a potential therapeutic phage. We here examined phage treatment in a mouse model of lung-derived septicemia using phage S13'. Intraperitoneal phage administration at 6 h postinfection reduced the severity of infection and rescued the infected mice. Phage S13' can efficiently lyse hospital-acquired MRSA strains causing pneumonia-associated bacteremia in vitro. Thus, phage therapy may be a possible therapeutic intervention in staphylococcal lung-derived septicemia. PMID- 24631575 TI - IV. Tools and methods for studying cell migration and cell rearrangement in tissue and organ development. AB - A vast diversity of biological systems, ranging from prokaryotes to multicellular organisms, show cell migration behavior. Many of the basic cellular and molecular concepts in cell migration apply to diverse model organisms. Drosophila, with its vast repertoire of tools for imaging and for manipulation, is one of the favorite organisms to study cell migration. Moreover, distinct Drosophila tissues and organs offer diverse cell migration models that are amenable to live imaging and genetic manipulations. In this review, we will provide an overview of the fruit fly toolbox that is of particular interest for the analysis of cell migration. We provide examples to highlight how those tools were used in diverse migration systems, with an emphasis on tracheal morphogenesis, a process that combines morphogenesis with cell migration. PMID- 24631576 TI - Cryorecanalization for in-stent recanalization in the esophagus. PMID- 24631577 TI - Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. AB - BACKGROUND & AIMS: Nonselective beta blockers (NSBBs) reduce portal pressure and the risk for variceal hemorrhage in patients with cirrhosis. However, development of spontaneous bacterial peritonitis (SBP) in these patients could preclude treatment with NSBBs because of their effects on the circulatory reserve. We investigated the effects of NSBBs in patients with cirrhosis and ascites with and without SBP. METHODS: We performed a retrospective analysis of data from 607 consecutive patients with cirrhosis who had their first paracentesis at the Medical University of Vienna from 2006 through 2011. Cox models were calculated to investigate the effect of NSBBs on transplant-free survival time and adjusted for Child-Pugh stage and presence of varices. RESULTS: NSBBs increased transplant free survival in patients without SBP (hazard ratio = 0.75; 95% confidence interval: 0.581-0.968; P = .027) and reduced days of nonelective hospitalization (19.4 days/year for patients on NSBBs vs 23.9 days/year for patients not taking NSBBs). NSBBs had only moderate effects on systemic hemodynamics at patients' first paracentesis. However, at the first diagnosis of SBP, the proportion of hemodynamically compromised patients with systolic arterial pressure <100 mm Hg was higher among those who received NSBBs (38% vs 18% of those not taking NSBBs; P = .002), as was the proportion of patients with arterial pressure <82 mm Hg (64% of those taking NSBBs vs 44% of those not taking NSBBs; P = .006). Among patients with SBP, NSBBs reduced transplant-free survival (hazard ratio = 1.58; 95% confidence interval: 1.098-2.274; P = .014) and increased days of nonelective hospitalization (29.6 days/person-year in patients on NSBBs vs 23.7 days/person year in those not taking NSBBs). A higher proportion of patients on NSBBs had hepatorenal syndrome (24% vs 11% in those not taking NSBBs; P = .027) and grade C acute kidney injury (20% vs 8% for those not taking NSBBs; P = .021). CONCLUSIONS: Among patients with cirrhosis and SBP, NSBBs increase the proportion who are hemodynamically compromised, time of hospitalization, and risks for hepatorenal syndrome and acute kidney injury. They also reduce transplant-free survival. Patients with cirrhosis and SBP should not receive NSBBs. PMID- 24631578 TI - Severity mapping of the proximal femur: a new method for assessing hip osteoarthritis with computed tomography. AB - OBJECTIVE: Plain radiography has been the mainstay of imaging assessment in osteoarthritis for over 50 years, but it does have limitations. Here we present the methodology and results of a new technique for identifying, grading, and mapping the severity and spatial distribution of osteoarthritic disease features at the hip in 3D with clinical computed tomography (CT). DESIGN: CT imaging of 456 hips from 230 adult female volunteers (mean age 66 +/- 17 years) was reviewed using 3D multiplanar reformatting to identify bone-related radiological features of osteoarthritis, namely osteophytes, subchondral cysts and joint space narrowing. Scoresheets dividing up the femoral head, head-neck region and the joint space were used to register the location and severity of each feature (scored from 0 to 3). Novel 3D cumulative feature severity maps were then created to display where the most severe disease features from each individual were anatomically located across the cohort. RESULTS: Feature severity maps showed a propensity for osteophytes at the inferoposterior and superolateral femoral head neck junction. Subchondral cysts were a less common and less localised phenomenon. Joint space narrowing <1.5 mm was recorded in at least one sector of 83% of hips, but most frequently in the posterolateral joint space. CONCLUSIONS: This is the first description of hip osteoarthritis using unenhanced clinical CT in which we describe the co-localisation of posterior osteophytes and joint space narrowing for the first time. We believe this technique can perform several important roles in future osteoarthritis research, including phenotyping and sensitive disease assessment in 3D. PMID- 24631579 TI - A novel Toll like receptor with two TIR domains (HcToll-2) is involved in regulation of antimicrobial peptide gene expression of Hyriopsis cumingii. AB - Animal Toll-like receptors (TLRs) are involved in innate immunity. Toll proteins are generally transmembrane proteins. In this study, an atypical Toll-like receptor (HcToll-2) was identified from the triangle-shell pearl mussel Hyriopsis cumingii, which belongs to phylum Mollusca. Unlike the typical Toll like receptors with extracellular leucine-rich repeats (LRRs), transmembrane, and intracellular Toll/interleukin-1 receptor (TIR) domains, HcToll-2 has two homologous TIR domains located at the C-terminal (designated as HcTIR1 and HcTIR2) and lacks a transmembrane domain. Phylogenetic analysis showed that HcTIR1 was clustered with TIR of sea anemone Toll, and HcTIR2 was clustered with TIR of Drosophila Toll. HcToll-2 mRNA could be detected in the hepatopancreas and was upregulated after challenge with Escherichia coli and Staphylococcus aureus. Recombinant HcLRR protein with GST tag could bind to bacteria and also to LPS and PGN. Over-expression of both HcTIR1 and HcTIR2 induced drosomycin genes in Drosophila S2 cells. RNAi analysis showed that HcToll-2 was required for the expression of theromacin, which is a cysteine-rich antimicrobial peptide (AMP) gene. This research is the first report of an atypical Toll-like receptor HcToll 2 involved in antibacterial immunity through induction of AMP expression. PMID- 24631580 TI - Identification, characterization and immunological response analysis of stimulator of interferon gene (STING) from grass carp Ctenopharyngodon idella. AB - Stimulator of interferon gene (STING), an important adapter responsible for RLR pathway, plays a pivotal role in both viral RNA- and DNA-triggered induction of IFNs in mammals. To understand the roles of STING in piscine immune system, STING gene (CiSTING) was identified from grass carp (Ctenopharyngodon idella). The genomic sequence of CiSTING was of 8548 base pairs (bp), including 899 bp 5' flank region, 7 exons and 6 introns. Promoter region was predicted and promoter activity was verified. The CiSTING cDNA was of 1358 bp with an open reading frame of 1185 bp, encoding a polypeptide of 394 amino acids with a signal peptide and three transmembrane motifs in the N-terminal region. mRNA expression of CiSTING was widespread in fifteen tissues investigated, and was up-regulated by GCRV in vivo and in vitro. Meanwhile, the transcription of CiSTING was inhibited at early stage, and then up-regulated at late phase upon poly(I:C) or PGN stimulation in vitro. Interestingly, CiSTING had little impact on LPS in vitro. In CiSTING over expression cells, CiTBK1, CiIRF3 and CiIRF7 were significantly up-regulated post GCRV or viral/bacterial PAMPs stimulation. In addition, post GCRV or PGN stimulation, the transcription of CiIFN-I was remarkably inhibited while CiMx1 was up-regulated; as for poly(I:C) stimulation, mRNA expressions of CiIFN-I and CiMx1 were inhibited at early stage while enhanced at late phrase; after LPS stimulation, both CiIFN-I and CiMx1 were inhibited. Furthermore, antiviral activity of CiSTING was manifested by the inhibition of GCRV yield. Taken together, these results demonstrated that CiSTING may be involved in board innate immune responses via the TBK1-IRF3/IRF7 cascade, responding to not only dsRNA analogue in an IFN-dependent pathway, but also virus and bacterial PAMPs in an IFN-independent pathway. This study provided novel insights into the essential role of STING in innate immunity. PMID- 24631582 TI - Identification of IRAK-4 in grouper (Epinephelus coioides) that impairs MyD88 dependent NF-kappaB activation. AB - Interleukin 1 (IL-1) receptor-associated kinase (IRAK) family members are crucial signal transducer in the Toll-like receptor/IL-1R signal pathway, which mediates downstream signal cascades involved in the innate and adaptive immune responses. In this study, we identified an IRAK-4 protein (EcIRAK-4) in the orange-spotted grouper (Epinephelus coioides), with an N-terminal death domain, a proST domain, and a central kinase domain, similar to that of other fishes and mammals. A sequence alignment and phylogenic analysis demonstrated that full-length EcIRAK-4 shares a high degree of sequence identity with those of other fishes, especially the roughskin sculpin, and their death domains and kinase domains share greater identity than their proST domains. A conservation analysis indicated that most of the functional sites in mammalian IRAK-4 are conserved in IRAK-4 of the grouper and other fishes, with the exception of the sites of interaction with IRAK-2 and one autophosphorylation site within the activation loop. EcIRAK-4 is broadly expressed in all the tissues examined, with highest expression in the head kidney and liver. After infection with Cryptocaryon irritans, EcIRAK-4 expression was significantly upregulated, especially in the skin, which suggests that this molecule is involved in the host's defense against parasitic infection. Surprisingly, after cotransfection with grouper MyD88, EcIRAK-4 significantly impaired the NF-kappaB activity induced by MyD88. EcIRAK-4 was uniformly distributed throughout the cytoplasm in HeLa cells. These findings suggest that although IRAK-4 is evolutionarily conserved between fish and mammals, its signal transduction function is markedly different. PMID- 24631581 TI - The MHC class I genes of zebrafish. AB - Major histocompatibility complex (MHC) molecules play a central role in the immune response and in the recognition of non-self. Found in all jawed vertebrate species, including zebrafish and other teleosts, MHC genes are considered the most polymorphic of all genes. In this review we focus on the multi-faceted diversity of zebrafish MHC class I genes, which are classified into three sequence lineages: U, Z, and L. We examine the polygenic, polymorphic, and haplotypic diversity of the zebrafish MHC class I genes, discussing known and postulated functional differences between the different class I lineages. In addition, we provide the first comprehensive nomenclature for the L lineage genes in zebrafish, encompassing at least 15 genes, and characterize their sequence properties. Finally, we discuss how recent findings have shed new light on the remarkably diverse MHC loci of this species. PMID- 24631583 TI - Decreased circulating leptin and increased neuropeptide Y gene expression are implicated in food deprivation-induced hyperactivity in striped hamsters, Cricetulus barabensis. AB - Physiological and behavioral adjustments of small mammals are important strategies in response to variations in food availability. Although numerous of studies have been carried out in rodents, behavioral patterns in response to food deprivation and re-feeding (FD-RF) are still inconsistent. Here we examined effects of a 24h FD followed by RF on general activity, serum leptin concentrations and gene expression of orexigenic and anorexigenic hypothalamic neuropeptides in striped hamsters (Cricetulus barabensis) with/without leptin supplements. The time spent on activity was increased by 2.5 fold in FD hamsters compared with controls fed ad libitum (P<0.01). Body mass, fat mass as well as serum leptin concentrations were significantly decreased in FD hamsters in comparison with ad libitum controls, which were in parallel with hyperactivity. During re-feeding, leptin concentrations increased rapidly to pre-deprivation levels by 12h, but locomotor activity decreased gradually and did not return to pre-deprivation levels until 5days after re-feeding. Leptin administration to FD hamsters significantly attenuated the increased activity. Gene expression of hypothalamic neuropeptide Y (NPY) was upregulated in FD hamsters and fell down to control levels when hamsters were re-fed ad libitum, similar to that observed in activity behavior. Leptin supplement induced increases in serum leptin concentrations (184.1%, P<0.05) in FD hamsters and simultaneously attenuated the increase in activity (45.8%, P<0.05) and NPY gene expression (35%, P<0.05). This may allow us to draw a more generalized conclusion that decreased leptin concentrations function as a starvation signal in animals under food shortage; to induce an increase in activity levels, leading animals to forage and/or migrate, and consequently increasing the chance of survival. Decreased concentrations of serum leptin in animals subjected to food shortage may induce an upregulation of gene expression of hypothalamus NPY, consequently driving a significant increase in foraging behavior. PMID- 24631584 TI - Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood. AB - There are indications that exposing adolescent rodents to oxytocin (OT) may have positive "trait-changing" effects resulting in increased sociability and decreased anxiety that last well beyond acute drug exposure and into adulthood. Such findings may have relevance to the utility of OT in producing sustained beneficial effects in human psychiatric conditions. The present study further examined these effects using an intermittent regime of OT exposure in adolescence, and using Long Evans rats, that are generally more sensitive to the acute prosocial effects of OT. As OT has substantial affinity for the vasopressin V1a receptor (V1aR) in addition to the oxytocin receptor (OTR), we examined whether a more selective peptidergic OTR agonist - [Thr4, Gly7]-oxytocin (TGOT) - would have similar lasting effects on behavior. Male Long Evans rats received OT or TGOT (0.5-1mg/kg, intraperitoneal), once every three days, for a total of 10 doses during adolescence (postnatal day (PND) 28-55). Social and anxiety-related behaviors were assessed during acute administration as well as later in adulthood (from PND 70 onwards). OT produced greater acute behavioral effects than TGOT, including an inhibition of social play and reduced rearing, most likely reflecting primary sedative effects. In adulthood, OT but not TGOT pretreated rats displayed lasting increases in social interaction, accompanied by an enduring increase in plasma OT. These findings confirm lasting behavioral and neuroendocrine effects of adolescent OT exposure. However, the absence of such effects with TGOT suggests possible involvement of the V1aR as well as the OTR in this example of developmental neuroplasticity. PMID- 24631585 TI - An aminoglycoside sensing riboswitch controls the expression of aminoglycoside resistance acetyltransferase and adenyltransferases. AB - The emergence of antibiotic resistance in human pathogens is an increasing threat to public health. The fundamental mechanisms that control the high levels of expression of antibiotic resistance genes are not yet completely understood. The aminoglycosides are one of the earliest classes of antibiotics that were introduced in the 1940s. In the clinic aminoglycoside resistance is conferred most commonly through enzymatic modification of the drug although resistance through enzymatic modification of the target rRNA through methylation or the overexpression of efflux pumps is also appearing. An aminoglycoside sensing riboswitch has been identified that controls expression of the aminoglycoside resistance genes that encode the aminoglycoside acetyltransferase (AAC) and aminoglycoside nucleotidyltransferase (ANT) (adenyltransferase (AAD)) enzymes. AAC and ANT cause resistance to aminoglycoside antibiotics through modification of the drugs. Expression of the AAC and ANT resistance genes is regulated by aminoglycoside binding to the 5' leader RNA of the aac/aad genes. The aminoglycoside sensing RNA is also associated with the integron cassette system that captures antibiotic resistance genes. Specific aminoglycoside binding to the leader RNA induces a structural transition in the leader RNA, and consequently induction of resistance protein expression. Reporter gene expression, direct measurements of drug RNA binding, chemical probing and UV cross-linking combined with mutational analysis demonstrated that the leader RNA functioned as an aminoglycoside sensing riboswitch in which drug binding to the leader RNA leads to the induction of aminoglycoside antibiotic resistance. This article is part of a Special Issue entitled: Riboswitches. PMID- 24631586 TI - General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression. AB - Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low- and high-intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high-intensity, but not low-intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low-intensity stimulation, too, induces a reversible cephalic allodynia, and high-intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high-intensity stimulation. Fos expression reveals that a single high-intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition-induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine. PMID- 24631587 TI - Severity of pediatric pain in relation to school-related functioning and teacher support: an epidemiological study among school-aged children and adolescents. AB - The current cross-sectional study examined child and adolescent pain severity in relation to various domains of school functioning and, in line with self determination theory, the potentially protective role of perceived teacher support of child/adolescent autonomy and competence. Data from a large representative sample of Flemish school children and adolescents (N=10650; 50.8% boys; age range 10-21years; mean age=14.33) was collected as part of the World Health Organization (WHO) collaborative Health Behaviour in School-Aged Children (HBSC) survey. Child/adolescent pain severity was graded based on a pediatric pain classification system adapted from that of Von Korff et al. The current study thus provided insight regarding the prevalence of pain among Flemish children/adolescents and, extending the limitations of existing literature, examined the specific role of pain severity across various domains of school functioning. Findings indicated that a sizeable proportion of children reported moderate to severe pain problems (ie, about 14% of children and adolescents were classified in the highest pain grades: ie, grade III or IV). Furthermore, higher pain grades were associated with poorer outcomes across all indices of school functioning (ie, school absenteeism, school-related pressure and satisfaction, and bullying experiences), with the exception of academic performance. However, the association between pain grade and school absenteeism was less pronounced when children perceived their teachers to be highly supportive of competence and autonomy. Furthermore, teacher support of competence appeared to buffer against the harmful effects of severe pain upon instances of bullying experiences at school. Future research directions and implications for school-based interventions are discussed. PMID- 24631589 TI - Results from clinical trials of a selective ionotropic glutamate receptor 5 (iGluR5) antagonist, LY5454694 tosylate, in 2 chronic pain conditions. AB - This article reports results of 2 studies investigating LY545694 in pain due to osteoarthritis (OA) of the knee and diabetic peripheral neuropathic pain (DPNP). Study I randomized patients to either of 2 doses of LY545694 or to placebo, and study II randomized patients to either of 3 doses of LY545694, to pregabalin, or to placebo. No significant differences between LY545694 groups and placebo were observed on the primary (average pain severity) or secondary efficacy measures in either study. Notably, study I lacked an active control, and, in study II, pregabalin, did not separate from placebo. Treatment-emergent nausea, vomiting, and dizziness were significantly more frequent in the LY545694 groups in both trials (P?.05), and significantly more LY545694-treated patients discontinued because of adverse events (P<.001). Steady-state concentrations of LY545694 were comparable in patients in both studies but were lower than exposures required for efficacy in animal models of pain behavior. Because the active control did not separate from placebo in the DPNP study, the study was potentially failed, rather than negative. Without an active control, it is unknown whether the OA study was negative or failed. Consequently, efficacy of selective ionotropic glutamate receptor antagonism in chronic pain conditions may warrant further investigation. Future trials should consider different pain conditions, contain a positive control with larger patient numbers per arm, and be conducted within a single region. PMID- 24631588 TI - Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: potential roles in acute inflammatory pain. AB - PI3-kinases (PI3Ks) participate in nociception within spinal cord, dorsal root ganglion (DRG), and peripheral nerves. To extend our knowledge, we immunohistochemically stained for each of the 4 class I PI3K isoforms along with several cell-specific markers within the lumbar spinal cord, DRG, and sciatic nerve of naive rats. Intrathecal and intraplantar isoform specific antagonists were given as pretreatments before intraplantar carrageenan; pain behavior was then assessed over time. The alpha-isoform was localized to central terminals of primary afferent fibers in spinal cord laminae IIi to IV as well as to neurons in ventral horn and DRG. The PI3Kbeta isoform was the only class I isoform seen in dorsal horn neurons; it was also observed in DRG, Schwann cells, and axonal paranodes. The delta-isoform was found in spinal cord white matter oligodendrocytes and radial astrocytes, and the gamma-isoform was seen in a subpopulation of IB4-positive DRG neurons. No isoform co-localized with microglial markers or satellite cells in naive tissue. Only the PI3Kbeta antagonist, but none of the other antagonists, had anti-allodynic effects when administered intrathecally; coincident with reduced pain behavior, this agent completely blocked paw carrageenan-induced dorsal horn 2-amino-3-(3-hydroxy-5 methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor trafficking to plasma membranes. Intraplantar administration of the gamma-antagonist prominently reduced pain behavior. These data suggest that each isoform displays specificity with regard to neuronal type as well as to specific tissues. Furthermore, each PI3K isoform has a unique role in development of nociception and tissue inflammation. PMID- 24631590 TI - Novel role of the Candida albicans ferric reductase gene CFL1 in iron acquisition, oxidative stress tolerance, morphogenesis and virulence. AB - Ferric reductase catalyzes the reduction of ferric iron into ferrous iron and plays an essential role in high-affinity iron acquisition. In this study, we found that the cfl1Delta/Delta (orf19.1263) mutant was not defective in iron acquisition. However, deletion of CFL1 increased cellular iron accumulation by elevating surface ferric reductase activity in Candida albicans, revealing that there existed functional redundancy and/or a compensatory upregulation mechanism among ferric reductase genes. The absence of CFL1 resulted in increased expression levels of other alternative ferric reductase genes, including FRP1, CFL2 and FRE10. In addition, CFL1 played an important role in the response to different oxidative stresses. Further research revealed that the cfl1Delta/Delta mutant exhibited higher levels of both ROS production and SOD activity under oxidative conditions. Moreover, deletion of CFL1 led to a profound defect in filamentous development in an iron-independent manner at both 30 and 37 degrees C. The cfl1Delta/Delta mutant exhibited highly attenuated virulence and reduced fungal burdens in the mouse systemic infection model, indicating that CFL1 might be a potential target for antifungal drug development. In summary, our results provide new insights into the roles of ferric reductase gene in C. albicans. PMID- 24631591 TI - A mutation in rcsB, a gene encoding the core component of the Rcs cascade, enhances the virulence of Edwardsiella tarda. AB - Edwardsiella tarda, a Gram-negative bacterium of the family Enterobacteriaceae, is the causative agent of the systemic disease edwardsiellosis, which is a major problem in aquaculture industry worldwide. Many virulence-related genes in E. tarda have been investigated, but the Rcs phosphorelay, a two-component pathway, which regulates several cell-surface-associated structures related to invasion and survival in host cells, has not yet been thoroughly studied. In the present study, an rcsB in-frame deletion mutant DeltarcsB was constructed through double crossover allelic exchange. To complement the rcsB mutation, the DeltarcsB (pACYC184K-rcsB) mutant was constructed by transformation of a low-copy plasmid carrying the intact rcsB into the DeltarcsB mutant of E. tarda. Several virulence associated characters of the mutants and wild-type strain were tested. Compared with wild-type strain EIB202, biofilm formation decreased significantly in DeltarcsB, while DeltarcsB (pACYC184K-rcsB) recovered the phenotype to some extent. In addition, the capacity for autoagglutination, the percentage of adherence and internalization to Epithelioma papulosum cyprini cells and lethality toward zebrafish embryos significantly increased in DeltarcsB. All these phenomena displayed by mutant DeltarcsB showed a certain degree of recovery, though incomplete, in strain DeltarcsB (pACYC184K-rcsB). Present results indicate that rcsB is involved in regulating the gene expression of virulence factors in E. tarda, as shown in other members of Enterobacteriaceae. PMID- 24631592 TI - Induction of HT-29 cells apoptosis by lactobacilli isolated from fermented products. AB - A total of 138 lactobacillus strains were obtained from the traditional fermented foods of minority nationalities or infant faeces, respectively. The lactobacillus strains were screened for anticancer effects and probiotic potential. The results showed that 10 strains exerted anti-proliferative activity and higher adhering capability on HT-29 cells. They were then screened for resistance to biological barriers (acid and bile salts), and the four most promising strains were selected. Further analysis revealed that the 4 strains (cell walls and cytoplasm extracts) displayed the high anti-proliferative activity and the large extent of DNA strand breakage in individual cells. Through the selected procedure, cell walls that were extracted from X12, M5 and K14 strains induced apoptosis in HT-29 cells. Further investigation confirmed that apoptosis-inducing ability of cell wall extracts was attributed to the breakdown of mitochondrial membrane potential, which is a known initiation of apoptotic mitochondrial pathway. Cell walls from X12, M5 and K14 strains, were determined to be less harmful to noncancerous Vero cells than to human colon cancer HT-29 cells. These findings suggested that X12, M5 and K14 strains opposing the ability to induce HT-29 cells apoptosis, and cell wall extracts were involved in this apoptosis induction. PMID- 24631593 TI - Efficacy and safety of photodynamic therapy for cervical intraepithelial neoplasia: a systemic review. AB - BACKGROUND: The current treatment of cervical intraepithelial neoplasia (CIN) is primarily based on surgical excision using laser, a loop electrosurgical procedure, or a cold knife technique. Unfortunately, these treatments often lead to obstetrical problems during the subsequent pregnancy, particularly in young women. Photodynamic therapy (PDT), which uses a topical or intravenous photosensitizer (PS) activated by a light source to ablate abnormal tissue, offers a minimally invasive alternative. The purpose of this study was to comprehensively assess the effectiveness and safety of PDT in the treatment of CIN. METHODS: Following Cochrane guidelines, a comprehensive systematic review of all clinical studies and reports examining the use of PDT for CIN was conducted. Study quality was assessed using the Oxford Levels of Evidence Scale. RESULTS: The 14 studies included two randomized control trials (RCTs), one case-control study, and 11 case series. Among the 506 patients studied, 472 were included to study the effectiveness of PDT on CIN and 10 were lost to follow-up. An assessment of clinical effectiveness included the response of the lesion to treatment (may include lesion recurrence) reported by all 14 studies. The complete response rate (CRR) of PDT on CIN ranged from 0% to 100%. HPV eradication rate (HER) was reported in seven studies, with rates ranging from 53.4% to 80.0%. CONCLUSIONS: PDT is a safe and tolerable treatment for CIN. Evidence regarding the efficacy of PDT for CIN is conflicting, which may, in part, be explained by the limited number of controlled comparative clinical trials. PMID- 24631595 TI - Is the migraine brain super-active? PMID- 24631594 TI - Variation in pediatric traumatic brain injury outcomes in the United States. AB - OBJECTIVE: To ascertain the degree of variation, by state of hospitalization, in outcomes associated with traumatic brain injury (TBI) in a pediatric population. DESIGN: A retrospective cohort study of pediatric patients admitted to a hospital with a TBI. SETTING: Hospitals from states in the United States that voluntarily participate in the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project. PARTICIPANTS: Pediatric (age <= 19 y) patients hospitalized for TBI (N=71,476) in the United States during 2001, 2004, 2007, and 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary outcome was proportion of patients discharged to rehabilitation after an acute care hospitalization among alive discharges. The secondary outcome was inpatient mortality. RESULTS: The relative risk of discharge to inpatient rehabilitation varied by as much as 3 fold among the states, and the relative risk of inpatient mortality varied by as much as nearly 2-fold. In the United States, approximately 1981 patients could be discharged to inpatient rehabilitation care if the observed variation in outcomes was eliminated. CONCLUSIONS: There was significant variation between states in both rehabilitation discharge and inpatient mortality after adjusting for variables known to affect each outcome. Future efforts should be focused on identifying the cause of this state-to-state variation, its relationship to patient outcome, and standardizing treatment across the United States. PMID- 24631596 TI - Cyclical changes of cortical excitability and metaplasticity in migraine: evidence from a repetitive transcranial magnetic stimulation study. AB - The primary brain dysfunctions leading to the onset of a migraine attack remain largely unknown. Other important open questions concern the mechanisms of initiation, continuation, and termination of migraine pain, and the changes in brain function underlying migraine transformation. Brief trains of high-frequency repetitive transcranial magnetic stimulation (rTMS), when applied to the primary motor cortex at suprathreshold intensity (?120% of resting motor threshold [RMT]), elicit in healthy subjects a progressive, glutamate-dependent facilitation of the motor evoked potentials (MEP). Conversely, in conditions of increased cortical excitability, the rTMS trains induce inhibitory MEP responses likely mediated by cortical homeostatic mechanisms. We enrolled 66 migraine without-aura patients, 48 migraine-with-aura patients, 14 patients affected by chronic migraine (CM), and 20 healthy controls. We assessed motor cortical response to 5-Hz rTMS trains of 10 stimuli given at 120% RMT. Patients with episodic migraine were studied in different phases of the migraine cycle: interictal, preictal, ictal, and postictal states. Results showed a facilitatory MEP response during the trains in patients evaluated in the preictal phase, whereas inhibitory responses were observed during and after a migraine attack, as well as in CM patients. In the interictal phase, different responses were observed, depending on attack frequency: facilitation in patients with low and inhibition in those with high attack recurrence. Our findings suggest that changes in cortical excitability and fluctuations in the threshold for inhibitory metaplasticity underlie the migraine attack recurrence, and could be involved in the process of migraine transformation. PMID- 24631597 TI - Partial transcriptomic profiling of toxins from the venom gland of the scorpion Parabuthus stridulus. AB - Since it is an apocrine secretion, scorpion venom is a complex mixture that contains a variety of low-molecular-weight basic proteins (neurotoxins), mucus, salts, as well as a large number of other constituents. Diversity of scorpion venom peptides exists also at the transcript level. Two kinds of venom peptides are typically considered: the neurotoxins and the antimicrobial peptides. We constructed a cDNA library and carried an EST (Expressed Sequence Tag) approach to overview the different peptides in the transcriptome of the telson from Parabuthus stridulus. P. stridulus are psammophilous and highly venomous scorpions endemic to Namibia (Prendini 2004) with medical relevance because of important human envenomation occurrence. We obtained 111 ESTs, 20% of them corresponding to cellular process transcripts, 7% to hypothetical proteins and 17% were sequences without good matches, but the majority of ESTs, 56%, corresponds to transcripts encoding for different venom components, including voltage-gated sodium, potassium and calcium channel toxins, antimicrobial peptides and other venom and cell proteins. To the best of our knowledge this report contains the first transcriptome analysis of genes transcribed by the venomous gland of the scorpion species P. stridulus, belonging to the family of medically important Buthidae scorpions. One hundred and eleven ESTs were analyzed, showing an important number of genes that encode for products similar to known scorpion venom components. In total, 17 unique and novel sequences were indentified. The identification and characterization of these compounds will be a good source of novel pharmacological tools for studying ion channels and the understanding of the physiological effects of toxins in P. stridulus envenomations at a molecular level. PMID- 24631598 TI - Contribution of sediments in the removal of microcystin-LR from water. AB - Microcystins are produced by several species of cyanobacteria and can harm aquatic organisms and human beings. Sediments have the potential to contribute to the removal of dissolved microcystins from the water body through either adsorption to sediment particles or biodegradation by the sediment's bacterial community. However, the relative contribution of these two removal processes remains unclear and little is known about the significance of sediment's overall contribution. To study this, changes in the concentration of microcystin-LR (MCLR) in the presence of sediment, sediment with microbial inhibitor, and non sterile lake water were quantified in a laboratory experiment. Our results show that, in the presence of sediment, MCLR concentration decreased significantly in an exponential way without a lag phase, with an average degradation rate of 9 MUg d(-1) in the first 24 h. This indicates that sediment can contribute to the removal of MCLR from the water immediately and effectively. Whilst both, the biodegradation and adsorption ability of the sediment contributed significantly to the removal of MCLR from the water body, biodegradation was shown to be the dominant removal process. Also, the sediment's ability to degrade MCLR from the water was shown to be faster than the biodegradation through the bacterial community in the water. The present study emphasizes the importance of sediments for the removal of microcystins from a water body. This will be especially relevant in shallow systems where the interaction between the water and the sediment is naturally high. Our results are also useful for the application of sediments to remove microcystins at water treatment facilities. PMID- 24631599 TI - Fungal ribotoxins: Natural protein-based weapons against insects. AB - Ribotoxins are fungal extracellular ribonucleases highly toxic due to their ability to enter host cells and their effective ribonucleolytic activity against the ribosome. The natural role of these proteins in the producing fungi is still unsolved. Nevertheless, recent studies showing the insecticidal properties of two ribotoxins from different origin support their involvement in defense mechanisms. Thus, it seems that not just the entomopathogen Hirsutella thompsonii expresses the ribotoxin hirsutellin A as a virulence factor but also Aspergillus, the main ribotoxin producer, does so. In this review we focus on this little known aspect of this family of proteins, their toxicity against insects, from the point of view of its biological relevance and its potential biotechnological applications. PMID- 24631600 TI - Prediction of treatment response in head and neck carcinomas using IVIM-DWI: Evaluation of lymph node metastasis. AB - PURPOSE: To obtain diffusion and microperfusion measures in lymph node metastases of head and neck squamous cell carcinomas (HNSCC) using intravoxel incoherent motion (IVIM) imaging. The obtained IVIM parameters were used to characterize lymph nodes in the staging phase and longitudinal follow-up was performed to evaluate the potential predictive value of these parameters considering therapy response. METHODS: Fifteen patients with lymph node metastases of histologically confirmed locally advanced HNSCC were examined using diffusion weighted imaging (DWI) before a nonsurgical organ preserving therapy. DWI imaging was performed at 3T using eight different b-values ranging from 0 to 800s/mm(2). Using the IVIM approach, the perfusion fraction f and the diffusion coefficient D were extracted using a biexponential fit. A follow-up period of 13.5 months was available for all patients. One patient with a macroscopically necrotic lymph node was excluded from analyses. A region of interest (ROI)-analysis was performed in all patients. RESULTS: Locoregional failure (LRF) was present in 3 of 15 patients within 13.5 months follow-up. The initial f-value was significantly higher (p=0.01) in patients with LRF (14.5+/-0.6% vs. 7.7+/-2.6%) compared to patients with locoregional control (LRC). The initial diffusion coefficient D did not differ significantly (p=0.30) between the two groups (0.97+/-0.15*10(-3)mm(2)/s vs. 0.88+/-0.13*10(-3)mm(2)/s). CONCLUSIONS: Our results indicate that a high initial perfusion fraction f in lymph nodes may predict poor treatment response in patients with HNSCC due to locoregional failure. PMID- 24631601 TI - The evolving use of higher risk grafts is associated with an increased incidence of acute kidney injury after liver transplantation. AB - BACKGROUND & AIMS: The growing discrepancy between supply and demand for liver transplantation has necessitated a greater use of higher risk grafts. Donation after Circulatory Death (DCD) liver transplant recipients have an increased frequency of acute kidney injury (AKI). We hypothesised that other higher risk grafts might also impact negatively on renal function. Our aim was to examine the effect of the evolving use of higher risk grafts on the incidence of post liver transplant AKI. METHODS: Single-centre study of 1152 patients undergoing first single-organ liver transplantation for chronic liver disease 01/2000-12/2011. To assess the impact of the evolution of graft quality over time; donor/graft/recipient variables were compared over three 4-year periods. RESULTS: Pretransplant recipient renal function improved during follow-up (p<0.001), and the median postoperative day-1 (p<0.001), -2 (p<0.001), and -3 (p<0.001) tacrolimus trough levels fell. The proportion of patients receiving a higher risk graft was 31.8% in 2000-2003, 40.9% in 2004-2007, and 59.1% in 2008-2011 (p<0.001). There was a progressive increase in AKI (2000-2003, OR 1.00; 2004 2007, OR 1.43; 2008-2011, OR 2.40, p<0.001). After adjusting for recipient variables increasing recipient warm ischaemic time (p=0.019), DCD transplantation (p<0.001), donor age >=60 years (p=0.020), and donor body mass index >=30 kg/m(2) (p<0.001) were independent predictors of AKI. CONCLUSIONS: The increasing use of higher risk liver grafts is associated with an increased incidence of AKI. These findings support the need for therapies that minimise the hepatic ischaemia reperfusion injury. PMID- 24631602 TI - The origin of cancer stem cells. PMID- 24631603 TI - Nutrient concentrations in tree leaves on brown and gray reclaimed mine soils in West Virginia. AB - Surface mining in Appalachia disrupts large areas of forested land. Federal and state laws require disturbed lands be reclaimed by re-constructing the landscape and replacing soil materials to provide a rooting medium. If insufficient quantities of native topsoil are available, substitute materials derived from the overburden may be used as soil media. This study examined soil and foliar nutrient concentrations of three hardwood tree species on areas where brown and gray sandstone overburden were applied as substitute growth media at the Birch River mine in West Virginia. Soil and foliar nutrient concentrations found in four experimental plots were compared to soil and foliar nutrient concentrations found in a nearby native Appalachian forest. Many foliar nutrients such as phosphorus and potassium were lower in all three tree species on most mine soils compared to trees growing in nearby native forest soils and to tree nutrient concentrations from the literature. Foliar and soil nutrient concentrations in the Brown mine soil were similar to those found in native forest soil, while the Gray mine soil provided significantly lower levels of nutrients. Overall, low nutrient availability in mine soils translates into generally lower foliar nutrient concentrations in trees growing on mine soils. After six years, amended topsoil substitutes and Brown mine soil produced higher foliar nutrient concentrations than Gray mine soil. PMID- 24631604 TI - Transformation of the artificial sweetener acesulfame by UV light. AB - The transformation of the artificial sweetener acesulfame by direct photolysis was investigated at various pH values, in different water types and at various concentration levels. Main photodegradation products of acesulfame were elucidated and analyzed both in laboratory experiments and in a full-scale waterworks using UV treatment for disinfection purposes. The degradation of acesulfame was found to be independent of the pH (range 5-11) and followed pseudo first order kinetics in a concentration range between 1 MUg?L(-1) and 10 mg?L( 1). Calculated rate constants were in the range between 5.4.10(-3)s(-1) and 7.4.10(-3)s(-1). The main photodegradation products of acesulfame were separated by ion exchange chromatography and high performance liquid chromatography and were identified as hydroxylated acesulfame and iso-acesulfame by high resolution mass spectrometry and fragmentation experiments. In the case of iso-acesulfame an intramolecular rearrangement is assumed as the transformation product has a higher polarity and different product ions after MS fragmentation compared to acesulfame. Minor transformation products were identified as amidosulfonic acid and sulfate by comparison with analytical standards. The transformation pathway was found to be transferable to drinking water production as the identified transformation products were also detected to a similar extent in fortified tap water. In a Swiss full-scale waterworks acesulfame concentrations were reduced by approximately 30% and one of the main UV transformation products could be qualitatively detected. PMID- 24631605 TI - Acute effects of black carbon and PM2.5 on children asthma admissions: a time series study in a Chinese city. AB - Epidemiologic evidence for an association between black carbon (BC) and health outcomes is limited. We estimated associations and exposure-response relationships between childhood asthma admission and concentration of BC and PM2.5 (particle less than 2.5mm in aerodynamic diameter) in ambient air in Shanghai using a lag distributed model. The PM2.5 and the BC were significantly associated with childhood asthma admissions in single-pollution model. However, the effects of BC on asthma attacks were slightly stronger than those of PM2.5 after adjusting or not adjusting for NO2 and SO2. In conclusion, our study suggests combustion-associated particles are important in China. Black carbon should be considered as one of the air quality indicators in China. PMID- 24631606 TI - Prenatal exposure to PM10 and NO2 and children's neurodevelopment from birth to 24 months of age: mothers and Children's Environmental Health (MOCEH) study. AB - INTRODUCTION: Previous studies have suggested adverse effects of maternal exposure to air pollution on neurodevelopment in early childhood. OBJECTIVES: We aimed to investigate the association between prenatal exposure to particulates of less than 10 MUm in diameter (PM10) and nitrogen dioxide (NO2) and neurodevelopment in children during the first 24 months of their lives. METHODS: The MOCEH study is a prospective birth cohort study in South Korea. Average exposure levels to PM10 and NO2 during the entire pregnancy were estimated using the inverse distance weighting (IDW) method. A total of 520 mother-child pairs who completed neurodevelopmental assessments using the Korean Bayley Scale of Infant Development II (K-BSID-II) more than once at ages of 6, 12 and 24 months were included. Mental developmental index (MDI) and psychomotor developmental index (PDI) from the K-BSID-II were used as outcome variables. RESULTS: There were negative associations between maternal exposure to PM10 and MDI (beta=-2.83; p=0.003) and PDI (beta=-3.00; p=0.002) throughout the first 24 months of life as determined by the generalized estimating equation (GEE) model. Maternal NO2 exposure was related with impairment of psychomotor development (beta=-1.30; p=0.05) but not with cognitive function (beta=-0.84; p=0.20). In a multiple linear regression model, there were significant effects of prenatal air pollution exposure on MDI (PM10: beta=-4.60; p<0.001, NO2: beta=-3.12; p<0.001) and PDI (PM10: beta=-7.24; p<0.001, NO2: beta=-3.01; p<0.001) at 6 months, but no significant association was found at 12 and 24 months of age. CONCLUSIONS: The findings suggest that exposure to air pollution may result in delayed neurodevelopment in early childhood. PMID- 24631607 TI - Impact of selenium on mortality, bioaccumulation and feeding deterrence in the invasive Argentine ant, Linepithema humile (Hymenoptera: Formicidae). AB - Ants are known for the important roles they play in processes contributing to ecosystem functioning in many habitats. However, pollutants can impact the ecosystem services provided by ants. The Argentine ant, an invasive species in North America, was investigated for the potential impact selenium (Se) may have on ants residing within a contaminated habitat. Mortality tests were conducted using worker ants fed an artificial nectar source containing 1-of-4 environmentally common Se compounds (forms): seleno-l-methionine, methylselenocysteine, selenate or selenite. Accumulation of Se in ant bodies at the end of two weeks was quantified with the use of hydride generation atomic absorption spectroscopy. Lastly, we conducted choice tests using dyes to determine whether ants might avoid a carbohydrate diet containing Se by providing them a choice between sucrose with or without Se. Choice tests also tested the responses of ants to selenium when provided in different background sucrose concentrations. The results of this study indicated that form and quantity of Se, as well as time of exposure, impact mortality in Argentine ant workers. Methylselenocysteine and selenate were found to be the most toxic among the 4 chemical forms when presented in sucrose solutions, whereas seleno-l-methionine and selenite caused greater Se body burdens. Furthermore, choice tests showed that ants did not prefer control sucrose solution to sucrose treated with Se regardless of the background sucrose concentration. These findings serve as first look into the possible detrimental impacts these contaminants may pose for ants that frequent sugary nectar sources. PMID- 24631608 TI - Determinants of stomatal sluggishness in ozone-exposed deciduous tree species. AB - Our knowledge of ozone effects on dynamic stomatal response is still limited, especially in Asian tree species. We thus examined ozone effects on steady-state leaf gas exchange and stomatal dynamics in three common tree species of China (Ailanthus altissima, Fraxinus chinensis and Platanus orientalis). Seedlings were grown and were exposed to three levels of ozone in open-top chambers (42, 69, 100 nmol mol(-1) daylight average, from 09:00 to 18:00). At steady-state, ozone exposure induced an uncoupling of photosynthesis and stomatal conductance, as the former decreased while the latter did not. Dynamic stomatal response was investigated by cutting the leaf petiole after a steady-state stomatal conductance was reached. Ozone exposure increased stomatal sluggishness, i.e., slowed stomatal response after leaf cutting, in the following order of sensitivity, F. chinensis>A. altissima>P. orientalis. A restriction of stomatal ozone flux reduced the ozone-induced sluggishness in P. orientalis. The ozone induced impairment of stomatal control was better explained by stomatal ozone flux per net photosynthesis rather than by stomatal ozone flux only. This suggests that ozone injury to stomatal control depends both on the amount of ozone entering a leaf and on the capacity for biochemical detoxification or repair. Leaf mass per area and the density of stomata did not affect stomatal sluggishness. PMID- 24631610 TI - Effects of calcite and magnesite application to a declining Masson pine forest on strongly acidified soil in Southwestern China. AB - Liming of strongly acidified soil under a Masson pine (Pinus massoniana Lamb.) forest was studied through a seven-year field manipulation experiment at Tieshanping, Chongqing in Southwestern China. To distinguish between the individual effects of Ca(2+) and Mg(2+) addition, we separately applied calcite (CaCO3) and magnesite (MgCO3), rather than using dolomite [CaMg(CO3)2]. Both calcite and magnesite additions caused a significant increase in pH and a decrease in dissolved inorganic monomeric aluminium (Ali) concentration of soil water. Ecological recovery included increases of herb biomass (both treatments) and Mg content in Masson pine needles (magnesite treatment only). However, the growth rate of Masson pine did not increase under either treatment, possibly because of nutrient imbalance due to phosphorus (P) deficiency or limited observation period. In China, acid deposition in forest ecosystems commonly coincides with large inputs of atmogenic Ca(2+), both enhancing Mg(2+) leaching. Calcite addition may further decrease the Mg(2+) availability in soil water, thereby exacerbating Mg(2+) deficiency in the acidified forest soils of southern and southwestern China. The effect of anthropogenic acidification of naturally acid forest soils on P availability needs further study. PMID- 24631609 TI - Occurrence of eight household micropollutants in urban wastewater and their fate in a wastewater treatment plant. Statistical evaluation. AB - The occurrence in urban wastewater of eight micropollutants (erythromycin, ibuprofen, 4-nonylphenol (4-NP), ofloxacin, sucralose, triclosan, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS)) originating from household activities and their fate in a biological wastewater treatment plant (WWTP) were investigated. Their concentrations were assessed in the liquid and solid phases (sewage particulate matter and wasted activated sludge (WAS)) by liquid chromatography-tandem mass spectrometry. The analysis of sewage from two different urban catchments connected to the WWTP showed a specific use of ofloxacin in the mixed catchment due to the presence of a hospital, and higher concentrations of sucralose in the residential area. The WWTP process removed over 90% of ibuprofen and triclosan from wastewater, while only 25% of ofloxacin was eliminated. Erythromycin, sucralose and PFOA were not removed from wastewater, the influent and effluent concentrations remaining at about 0.7 MUg/L, 3 MUg/L and 10 ng/L respectively. The behavior of PFOS and 4-nonylphenol was singular, as concentrations were higher at the WWTP outlet than at its inlet. This was probably related to the degradation of some of their precursors (such as alkylphenol ethoxylates and polyfluorinated compounds resulting in 4-NP and PFOS, respectively) during biological treatment. 4-NP, ofloxacin, triclosan and perfluorinated compounds were found adsorbed on WAS (from 5 ng/kg for PFOA to 1.0mg/kg for triclosan). The statistical methods (principal component analysis and multiple linear regressions) were applied to examine relationships among the concentrations of micropollutants and macropollutants (COD, ammonium, turbidity) entering and leaving the WWTP. A strong relationship with ammonium indicated that some micropollutants enter wastewater via human urine. A statistical analysis of WWTP operation gave a model for estimating micropollutant output from the WWTP based on a measurement of macropollution parameters. PMID- 24631611 TI - Noise annoyance is related to the presence of urban public transport. AB - BACKGROUND: The association between noise annoyance and public transport as a source of noise has not been studied previously. The aim was to study noise annoyance in an urban population due to the presence, the type and the number of public transport vehicles, in relation to other acoustical and non-acoustical parameters. METHOD: The study sample comprised 5861 adults residing in 118 streets in the city center of Belgrade. The presence, the type and the number of public transport vehicles were assessed using official transport maps and matched with residential addresses. Noise annoyance was assessed by a questionnaire including a self-report five-graded scale. 'High noise annoyance' was defined by merging 'very' and 'extremely' annoyed answers. RESULTS: Significant predictors of high noise annoyance were the presence of public transport at daytime (yes vs. no) (odds ratio=1.47, 95% confidence interval=1.28-1.70), and at night (yes vs. no) (OR=1.39, 95% CI=1.20-1.61). Residing in the streets with more than 79 public transport vehicles per hour (3rd tercile vs. 1st tercile) predicted high noise annoyance at daytime (OR=1.64, 95% CI=1.18-2.27). Residing in the streets with buses and trams at night ('bus and tram' vs. no public transport) increased the risk of high noise annoyance (OR=2.67, 95% CI=1.78-4.09). These associations were independent from noise sensitivity, orientation of bedroom windows, floor level, and equivalent noise levels. Living in the apartment with bedroom windows facing the street was the strongest confounder for the association between noise annoyance, noise levels and public transport. CONCLUSION: The study has identified the presence of public transport at daytime and at night as a significant and independent predictor of high noise annoyance. Future intervention measures should concern the presence, the type and the number of public transport vehicles in order to reduce noise annoyance reactions in urban areas. PMID- 24631612 TI - Seasonal patterns of polycyclic aromatic hydrocarbons in digestive gland and arm of octopus (Octopus vulgaris) from the Northwest Atlantic. AB - Among organic pollutants existing in coastal areas, polycyclic aromatic hydrocarbons (PAHs) are of great concern due to their ubiquity and carcinogenic potential. The aim of this study was to evaluate the seasonal patterns of PAHs in the digestive gland and arm of the common octopus (Octopus vulgaris) from the Northwest Atlantic Portuguese coast. In the different seasons, 18 PAHs were determined and the detoxification capacity of the species was evaluated. Ethoxyresorufin O-deethylase (EROD) and ethoxycoumarin O-deethylase (ECOD) activities were measured to assess phase I biotransformation capacity. Individual PAH ratios were used for major source (pyrolytic/petrogenic) analysis. Risks for human consumption were determined by the total toxicity equivalence approach. Generally, low levels of PAHs were detected in the digestive gland and in the arm of octopus, with a predominance of low molecular over high molecular weight compounds. PAHs exhibited seasonality in the concentrations detected and in their main emission sources. In the digestive gland, the highest total PAH levels were observed in autumn possibly related to fat availability in the ecosystem and food intake. The lack of PAH elimination observed in the digestive gland after captivity could be possibly associated to a low biotransformation capacity, consistent with the negligible/undetected levels of EROD and ECOD activity in the different seasons. The emission sources of PAHs found in the digestive gland varied from a petrogenic profile observed in winter to a pyrolytic pattern in spring. In the arm, the highest PAH contents were observed in June; nevertheless, levels were always below the regulatory limits established for food consumption. The carcinogenic potential calculated for all the sampling periods in the arm were markedly lower than the ones found in various aquatic species from different marine environments. The results presented in this study give relevant baseline data for environmental monitoring of organic pollution in coastal areas. PMID- 24631613 TI - Trace element concentrations in leachates and mustard plant tissue (Sinapis alba L.) after biochar application to temperate soils. AB - Biochar application to agricultural soils has been increasingly promoted worldwide. However, this may be accompanied by unexpected side effects in terms of trace element (TE) behavior. We used a greenhouse pot experiment to study the influence of woodchip-derived biochar (wcBC) on leaching and plant concentration of various TEs (Al, Cd, Cu, Pb, Mn, As, B, Mo, Se). Three different agricultural soils from Austria (Planosol, Cambisol, Chernozem) were treated with wcBC at application rates of 1 and 3% (w/w) and subsequently planted with mustard (Sinapis alba L.). Soil samples were taken 0 and 7 months after the start of the pot experiment, and leachate water was collected twice (days 0 and 54). The extractability (with NH4NO3) of cationic TEs was decreased in the (acidic) Planosol and Cambisol after wcBC application, whereas in the (neutral) Chernozem it hardly changed. In contrast, anionic TEs were mobilized in all three soils, which resulted in higher anion concentrations in the leachates. The application of wcBC had no effect on Al and Pb in the mustard plants, but increased their B and Mo concentrations and decreased their Cd, Cu and Mn concentrations. A two-way analysis of variance showed significant interactions between wcBC application rate and soil type for most TEs, which indicates that different soil types may react differently upon wcBC application. Correlation and partial correlation analyses revealed that TE behavior was primarily related to soil pH, whereas the involvement of other factors such as electrical conductivity (EC), organic carbon (OC) content and dissolved organic carbon (DOC) was found to be more soil and TE specific. The application of wcBC may be a useful strategy for the remediation of soils with elevated levels of cationic TEs, but could lead to deficiencies of cationic micronutrients and enhance short-term translocation of anionic TEs towards the groundwater at high leaching rates. PMID- 24631614 TI - Persisting impact of historical mining activity to metal (Pb, Zn, Cd, Tl, Hg) and metalloid (As, Sb) enrichment in sediments of the Gardon River, Southern France. AB - In this study, we assessed past and present influence of ancient mining activity on metal(loid) enrichment in sediments of a former mining watershed (Gardon River, SE France), that is now industrialized and urbanized. A sedimentary archive and current sediments were characterized combining geochemical analyses, zinc isotopic analyses and sequential extractions. The archive was used to establish local geochemical background and recorded (i) increasing enrichment factors (EFs) for Pb, Zn, Cd, Tl, Hg, As and Sb throughout the industrial era, (ii) a contamination peak in 1976 attributed to a tailings dam failure, and (iii) current levels in 2002 and 2011 similar to those of 1969, except for Sb and Hg, reflecting a persisting contamination pattern. Inter-element relationships and spatial distribution of EF values of current sediments throughout the watershed suggested that both ancient and current contamination had a common origin for Pb, Zn, Cd, Tl and As related to the exploitation of Pb/Zn mineralization while old Sb mines and coal extraction area were the main sources for Sb and Hg respectively. This prevailing mining origin was reflected for Zn by a relatively uniform isotopic composition at delta(66)Zn=0.23 +/- 0.030/00, although slight decrease from 0.230/00 to 0.180/00 was recorded from upstream to downstream sites along the river course in relation with the contribution of the lighter delta(66)Zn signature (~0.080/00) of acid mine drainage impacted tributaries. Results from sequential extractions revealed that the potential mobility of the studied metal(loid)s varied in the order Sb75 years) may indicate a continuous development in the human gut methanogenic flora throughout lifetime. However, when subjects were compared on 5 year age intervals, an interruption in the percentage of methane producers in the sixth and seventh decade was noted. We further revealed an age dependence on the ratio of female to male producers. This is shown by a dominance in female breath methane producers during the first half of life which afterwards is replaced by a dominance in male breath methane producers with an approximately linear decrease in the ratio between 20 and 65 years (R(2)=0.926). These observations might suggest a relationship between methanogenic activity and hormonal factors. Using our data, we predict that the percentage of breath CH4 producers within the German population will increase from its current value of 30% (2013) to 35% by 2050. PMID- 24631622 TI - Modeling cumulative effects in life cycle assessment: the case of fertilizer in wheat production contributing to the global warming potential. AB - This paper aims at presenting a dynamic indicator for life cycle assessment (LCA) measuring cumulative impacts over time of greenhouse gas (GHG) emissions from fertilizers used for wheat cultivation and production. Our approach offers a dynamic indicator of global warming potential (GWP), one of the most used indicator of environmental impacts (e.g. in the Kyoto Protocol). For a case study, the wheat production in France was selected and considered by using data from official sources about fertilizer consumption and production of wheat. We propose to assess GWP environmental impact based on LCA method. The system boundary is limited to the fertilizer production for 1 ton of wheat produced (functional unit) from 1910 to 2010. As applied to wheat production in France, traditional LCA shows a maximum GWP impact of 500 kg CO2-eq for 1 ton of wheat production, whereas the GWP impact of wheat production over time with our approach to dynamic LCA and its cumulative effects increases to 18,000 kg CO2-eq for 1 ton of wheat production. In this paper, only one substance and one impact assessment indicator are presented. However, the methodology can be generalized and improved by using different substances and indicators. PMID- 24631623 TI - Polychlorinated biphenyls (PCBs) in air, soil, and cereal crops along the two tributaries of River Chenab, Pakistan: concentrations, distribution, and screening level risk assessment. AB - This study reports the first systematic data on PCB levels and their risk assessments by consumption of cereal food crops from Pakistan. Polychlorinated biphenyls (PCB) including dioxin-like PCBs (dl-PCBs) were analyzed in wheat (n=28), rice (n=28), air (n=6), and soil (n=28) samples to assess the levels, spatial distribution pattern, and their risk assessments along with the two tributaries of River Chenab, Pakistan. ?33PCB concentrations ranged between 0.15 2.22 ng g(-1)dW, 0.05-9.21 ng g(-1)dW, 0.70-30.5 ng g(-1)dW and 41-299 pg m(-3) in the wheat, rice, soil, and air samples, respectively. In the current study, comparatively lower dioxin toxicity equivalency (TEQ) values were calculated from the previously reported data. Hazardous ratio (HR) for human health risk assessment allied to non-cancer was found lower than integrity. PMID- 24631624 TI - Comparison of the direct burst pressure and the ring tensile test methods for mechanical characterization of tissue-engineered vascular substitutes. AB - Tissue engineering provides a promising alternative for small diameter vascular grafts, especially with the self-assembly method. It is crucial that these grafts possess mechanical properties that allow them to withstand physiological flow and pressure without being damaged. Therefore, an accurate assessment of their mechanical properties, especially the burst pressure, is essential prior to clinical release. In this study, the burst pressure of self-assembled tissue engineered vascular substitutes was first measured by the direct method, which consists in pressurizing the construct with fluid until tissue failure. It was then compared to the burst pressure estimated by Laplace's law using data from a ring tensile test. The major advantage of this last method is that it requires a significantly smaller tissue sample. However, it has been reported as overestimating the burst pressure compared to a direct measurement. In the present report, it was found that an accurate estimation of the burst pressure may be obtained from a ring tensile test when failure internal diameter is used as the diameter parameter in Laplace's law. Overestimation occurs with the method previously reported, i.e. when the unloaded internal diameter is used for calculations. The estimation of other mechanical properties was also investigated. It was demonstrated that data from a ring tensile test provide an accurate estimate of the failure strain and the stiffness of the constructs when compared to measurements with the direct method. PMID- 24631625 TI - The effect of collagen crosslinking on the biphasic poroviscoelastic cartilage properties determined from a semi-automated microindentation protocol for stress relaxation. AB - Given the important role of the collagenous structure in cartilage mechanics, there is considerable interest in the relationship between collagen crosslinking and the mechanical behavior of the cartilage matrix. While crosslink-induced alterations to the elastic modulus of cartilage have been described, changes to time-dependent behavior have not yet been determined. The objective of the study was to quantify changes to cartilage material properties, including viscoelastic coefficients, with crosslinking via indentation. To accomplish this, a semi autonomous microindentation stress relaxation protocol was first developed, validated and then applied to cartilage specimens before and after crosslinking. The change in mechanical properties with crosslinking was analyzed both in the unloading portions of the test via the Oliver-Pharr method and in the holding portion with an inverse iterative finite element model that represented cartilage as a biphasic poroviscoelastic material. Although both techniques suggested a similar increase in equilibrium modulus in the crosslinked specimens as compared to the controls, distinct differences in the control specimens were apparent, suggesting that the two different techniques may be capturing different aspects of the material behavior. No differences in time-dependent properties were observed between the crosslinked and the control specimens. These results give further insight into the effects of crosslinking in cartilage mechanical behavior. Additionally, the microindentation stress relaxation protocol may enable increased automation for high-throughput testing. PMID- 24631626 TI - A versatile bacterial expression vector designed for single-step cloning of multiple DNA fragments using homologous recombination. AB - Production of recombinant proteins is the starting point for biochemical and biophysical analyses and requires methodology to efficiently proceed from gene sequence to purified protein. While optimized strategies for the efficient cloning of single-gene fragments for bacterial expression is available, efficient multiple DNA fragment cloning still presents a challenge. To facilitate this step, we have developed an efficient cloning strategy based on yeast homologous recombination cloning (YHRC) into the new pET-based bacterial expression vector pSUMO-YHRC. The vector supports cloning for untagged expression as well as fusions to His6-SUMO or His6 tags. We demonstrate that YHRC from single PCR products of 6 independent genes into the vector results in virtually no background. Importantly, in a quantitative assay for functional expression we find that single-step YHRC of 7 DNA fragments can be performed with very high cloning efficiencies. The method and reagents described in this paper significantly simplifies the construction of expression plasmids from multiple DNA fragments, including complex gene fusions, chimeric genes and polycistronic constructs. PMID- 24631627 TI - Obsessive-compulsive disorder: a "sensory-motor" problem? AB - Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. Although its pathophysiology is not completely understood, neurophysiologic and neuroimaging data have disclosed functional abnormalities in the networks linking frontal cortex, supplementary motor and premotor areas, striatum, globus pallidus, and thalamus (CSPT circuits). By means of transcranial magnetic stimulation (TMS) it is possible to test inhibitory and excitatory circuits within motor cortex. Previous studies on OCD patients under medication have demonstrated altered cortical inhibitory circuits as tested by TMS. On the other hand there is growing evidence suggesting an alteration of sensory-motor integration. Therefore, the aim of the present study was to evaluate sensory motor integration (SAI and LAI), intracortical inhibition, and facilitation in drug-naive OCD patients, using TMS. In our sample, we have demonstrated a significant SAI reduction in OCD patients when compared to a cohort of healthy individuals. SAI abnormalities may be related to a dysfunction of CSPT circuits which are involved in sensory-motor integration processes. Thus, it can be speculated that hypofunctioning of such system might impair the ability of OCD patients to suppress internally triggered intrusive and repetitive movements and thoughts. In conclusion, our data suggest that OCD may be considered as a sensory motor disorder where a dysfunction of sensory-motor integration may play an important role in the release of motor compulsions. PMID- 24631628 TI - Focussed microarray analysis of apoptosis in periodontitis and its potential pharmacological targeting by carvacrol. AB - OBJECTIVE: The objective of this study was to perform a landscape analysis of apoptosis-related genes/proteins and to study the differential gene expression by analysing array data from periodontitis patients and, second, to evaluate the anti-apoptotic effects of carvacrol, a monoterpenoid phenol, in vitro. DESIGN: A gene/protein interaction network model 'APOP' was developed by using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) version 9.05. Differential gene expression was determined by using the limma package from R and false discovery rate (FDR). With ViaComplex software, gene expression was plotted over the network. The anti-apoptotic effect of carvacrol was tested on sorbitol treated HaCaT cells, by using a commercial kit for caspase-3 activity. RESULTS: The 'APOP' model characterised the landscape of interactions between apoptosis related genes/proteins in silico. Forty-nine out of 70 genes from this model, such as CSF2RB, NFKBIE, ENDOG, CASP10 and CASP3, were differentially expressed (corrected p-value<0.05) in periodontitis samples when compared to those of healthy controls. In addition, carvacrol (0.43%) was able to inhibit the pro apoptotic effects induced by sorbitol (0.3M), as seen by the reduction in caspase 3 activity on HaCaT cells. CONCLUSION: Our results suggest that caspase-3 can be a target protein to inhibit periodontitis-associated apoptosis of epithelial cells and that carvacrol has therapeutic potential as an anti-apoptotic agent. PMID- 24631629 TI - Evaluation of peri-implant mucosa: clinical, histopathological and immunological aspects. AB - OBJECTIVE: The aim was to compare the inflammatory response in peri-implant mucosa between patients with peri-implantitis (PP-group) and patients with healthy peri-implant tissues (HP-group). MATERIALS AND METHODS: Two fragments of peri-implant mucosa of 18 patients were collected and serial sections were performed for histological and immunohistochemical analysis. RESULTS: When compared with HP-group, PP-group showed higher immunostained cell density for TGF beta, IL-17 and CD31, beyond greater density of red cells, leukocytes, mast cells chymase (MCC) and mast cell tryptase (MCT). HP-group patients showed higher IL-13 expression and increased amount of collagen fibres when compared with PP-group. In PP-group there was significant positive correlation between MCT density and density of blood vessels immunostained, and between MCC density and density of blood vessels immunostained. There was significant negative correlation between the IL-17 density and collagen percentage. CONCLUSIONS: This study demonstrated that in patients with peri-implantitis there was higher of TGF-beta and IL-17, indicating that these cytokines are directly involved in the inflammatory process. Thus, understanding the influence of cytokines in the peri-implantitis installation, new therapies could be developed in order to inhibit the synthesis of IL-17 and induce synthesis of IL-13 in peri-implant tissue, contributing to increase the longevity of the implant. PMID- 24631630 TI - Erk1/2 signalling is involved in the differentiation of periodontal ligament stem cells to Schwann cells in dog. AB - Periodontal ligament stem cells (PDLSCs) show a multi-differentiation potential, however, the mechanism of its neural differentiation is still unclear. We aim to explore the potential role of Erk1/2 signalling pathway in the differentiation of PDLSCs to Schwann cells (SCs). When PDLSCs were induced to differentiate to SCs, the cells were treated with U0126, an Erk1/2 pathway specific inhibitor, and its potential effect on SC differentiation was appraised using Western-blotting, immunostaining, and reverse transcriptase PCR. Specifically inhibiting the Erk1/2 signalling pathway reduced the expression of SC-specific marker genes, S100, GFAP, and P75 and SC differentiation regulators, krox-20, Oct-6, and P0 in the cells undergoing induced differentiation from PDLSCs. From these results, we conclude that the Erk1/2 signalling pathway is involved in the induced differentiation of PDLSCs to SCs. PMID- 24631631 TI - The expression of MCP-1 and CCR2 in induced rats periapical lesions. AB - OBJECTIVE: Monocyte chemotatic protein-1 (MCP-1) has been found to promote chemotaxis, differentiation, and activation of osteoclasts. The aim of this study is to detect and localize the expressions of MCP-1 and its receptor CCR2 in a rat model of apical periodontitis. DESIGN: After exposing the pulp of the first mandibular molars, 25 Wistar rats were killed on days 0, 7, 14, 21, 28, and 35. Rat jaws containing the first molar were obtained and routinely prepared for histological analysis, immunohistochemistry, enzyme histochemistry and immunofluorescence staining. RESULTS: Lesions expanded from day 0 to day 28, and stabilized thereafter. Most of the MCP-1-positive cells were inflammatory cells, and their amount increased from day 7 to day 28. Aside from inflammatory cells, CCR2 was also detected in osteoclasts in the lesions. From day 7 to day 14, the number of osteoclasts increased. From day 21 to day 35, fewer osteoclasts could be observed, and the number of osteoclast was negatively correlated with positive MCP-1 expression. CONCLUSION: These findings showed that MCP-1/CCR2 could be observed and might possibly be involved in the development of periapical lesions. PMID- 24631632 TI - The different effects on cranial and trunk neural crest cell behaviour following exposure to a low concentration of alcohol in vitro. AB - Embryonic neural crest cells give rise to large regions of the face and peripheral nervous system. Exposure of these cells to high alcohol concentrations leads to cell death in the craniofacial region resulting in facial defects. However, the effects of low concentrations of alcohol on neural crest cells are not clear. In this study, cranial neural crest cells from Xenopus laevis were cultured in an ethanol concentration approximately equivalent to one drink. Techniques were developed to study various aspects of neural crest cell behaviour and a number of cellular parameters were quantified. In the presence of alcohol, a significant number of cranial neural crest cells emigrated from the explant on fibronectin but the liberation of individual cells was delayed. The cells also remained close to the explant and their morphology changed. Cranial neural crest cells did not grow on Type 1 collagen. For the purposes of comparison, the behaviour of trunk neural crest cells was also studied. The presence of alcohol correlated with increased retention of single cells on fibronectin but left other parameters unchanged. The behaviour of trunk neural crest cells growing on Type 1 collagen in the presence of alcohol did not differ from controls. Low concentrations of alcohol therefore significantly affected both cranial and trunk neural crest cells, with a wider variety of effects on cells from the cranial as opposed to the trunk region. The results suggest that low concentrations of alcohol may be more detrimental to early events in organ formation than currently suspected. PMID- 24631633 TI - Contributions of sigma(B) and PrfA to Listeria monocytogenes salt stress under food relevant conditions. AB - Listeria monocytogenes is well known to survive and grow under several stress conditions, including salt stress, which is important for growth in certain foods as well as for host infection. To characterize the contributions, to salt stress response, of transcriptional regulators important for stress response and virulence (i.e., sigma(B) and PrfA), we analyzed three L. monocytogenes parent strains and isogenic mutants (DeltasigB, DeltaprfA, and DeltasigBDeltaprfA), representing different serotypes and lineages, for their ability to grow, at 25 degrees C, in BHI with 1.9 M NaCl. With regard to growth rate, only the lineage IV strain presented a significant difference between the parent strain and both of its respective mutants lacking prfA (DeltaprfA and DeltasigBDeltaprfA). Conversely, the lineage I and II parent strains showed significantly shorter lag phase in comparison to their respective DeltasigB mutant strains. Intestinal epithelial cell invasion assay and hemolytic activity assays showed a significant role for sigma(B) in the former and for PrfA in the latter. To explore the mechanism that may contribute to the extended lag phase in the DeltasigB mutant strain and survival and growth of the parent strain upon salt shock, whole genome transcription profiling was performed to compare transcript levels between the lineage I, serotype 1/2b, parent strain and its isogenic DeltasigB mutant after 30 min of lag phase growth at 25 degrees C in the presence of 1.9M NaCl (salt shock) without aeration. Microarray data showed significantly higher transcript levels for 173 genes in the parent strain as compared to the DeltasigB strain. Overall, 102 of the 173 sigma(B) up-regulated genes had been identified in previous studies, indicating that 71 genes were newly identified as being up regulated by sigma(B) in this study. We hypothesize that, among these genes newly identified as sigma(B) up-regulated, four genes (lmo2174, lmo0530, lmo0527 and lmo0529) may play a major role in response to salt stress. Lmo2174 contains domains that facilitate sensing and producing a transduction signal in the form of cyclic di-GMP, which may activate the enzymes Lmo0527, Lmo0529 and Lmo0530, which encode proteins similar to those responsible for synthesis of exopolysaccharides that may protect the cell by changing the cell wall structure during salt stress. Overall, our data showed that sigma(B), but not PrfA, contributes to growth under salt stress. Moreover, we show that the sigma(B) regulon of a L. monocytogenes lineage I strain challenged with salt shock includes salt stress-specific as well as previously unidentified sigma(B) up regulated genes. PMID- 24631634 TI - Diversity and activities of yeasts from different parts of a Stilton cheese. AB - Blue cheeses are very complex food matrices presenting significant spatial differentiation between sections and the Stilton variety also has a hard brown crust making its matrix even more complex. The mycobiota communities in the three sections (blue veins, white core and outer crust) of a Stilton blue cheese were studied by employing culture-independent (TRFLP, DGGE) and culture-dependent analyses. Yeasts isolated from the cheese were studied for aroma production in a dairy model system with and without the starter Lactococcus lactis and filamentous fungus Penicillium roqueforti using SPME GC-MS. Significant qualitative and quantitative differences were observed in the yeast communities between the cheese sections with all the techniques. Yarrowia lipolytica presented strong synergistic activity with P. roqueforti enhancing the production of ketone aroma compounds, characteristic of blue cheeses. Culture techniques allowed the observation of the presence and uneven distribution of two different morphological groups of Debaryomyces hansenii in the different sections and of Trichosporon ovoides but failed to isolate Candida catenulata which dominated some parts of the cheese in the culture-independent analysis. This suggests that this species may be an important early coloniser but fails to survive into the final cheese. The study indicated that the yeast flora in the cheese sections differ including isolates that could affect their aroma profiles. PMID- 24631635 TI - Real-time loop-mediated isothermal amplification (LAMP) assay for group specific detection of important trichothecene producing Fusarium species in wheat. AB - Trichothecene mycotoxins such as deoxynivaneol (DON), nivalenol (NIV) and T2 Toxin are produced by a variety of Fusarium spp. on cereals in the field and may be ingested by consumption of commodities and products made thereof. The toxins inhibit eukaryotic protein biosynthesis and may thus impair human and animal health. Aimed at rapid and sensitive detection of the most important trichothecene producing Fusarium spp. in a single analysis, a real-time duplex loop-mediated isothermal amplification (LAMP) assay was set up. Two sets of LAMP primers were designed independently to amplify a partial sequence of the tri6 gene in Fusarium (F.) graminearum and of the tri5 gene in Fusarium sporotrichioides, respectively. Each of the two sets detected a limited number of the established trichothecene producing Fusarium-species. However, combination of the two sets in one duplex assay enabled detection of F. graminearum, Fusarium culmorum, Fusarium cerealis, F. sporotrichioides, Fusarium langsethiae and Fusarium poae in a group specific manner. No cross reactions were detected with purified DNA from 127 other fungal species or with cereal DNA. To demonstrate the usefulness of the assay, 100 wheat samples collected from all over the German state of Bavaria were analyzed for the trichothecene mycotoxin DON by HPLC and for the presence of trichothecene producers by the new real-time duplex LAMP assay in parallel analyses. The LAMP assay showed positive results for all samples with a DON concentration exceeding 163ppb. The major advantage of the duplex LAMP assay is that the presence of six of the major trichothecene producing Fusarium spp. can be detected in a rapid and user-friendly manner with only one single assay. To our knowledge this is the first report of the use of a multiplex LAMP assay for fungal organisms. PMID- 24631636 TI - New insights into the advantages of ammonium as a winemaking nutrient. AB - Nitrogen limitation is the most common cause for stuck or sluggish fermentation in winemaking, and it is usually dealt with by supplementing grape juice with either ammonium salts or organic nutrients. These practices have a direct impact on both fermentation kinetics and the sensorial features of the final product. The aim of this work is to provide a detailed characterization of yeast physiology in response to ammonium supplementation during alcoholic fermentation. This is done by determining changes in metabolic rates on a high frequency basis, as a sensitive way to detect the impact of fermentation conditions on yeast physiology. Our results indicate that the choice of supplementation strategy has an impact on several enological parameters like fermentation length, volatile acidity, final glycerol content, and aroma profile. Interestingly, a higher proportion of ammonium relates with improved glycerol and volatile acidity, for the same global yeast assimilable nitrogen content. However, ammonium over supplementation has a negative impact on quality related parameters, notably on volatile acidity and aroma complexity. Production kinetics and final content of several volatile compounds are also differentially influenced by standard or excess ammonium supplementation. PMID- 24631637 TI - Genetic influences on dietary variety - results from a twin study. AB - The heritability of variety seeking in the food domain was estimated from a large sample (N = 5,543) of middle age to elderly monozygotic and dizygotic twins from the "Virginia 30,000" twin study. Different dietary variety scores were calculated based on a semi-quantitative food choice questionnaire that assessed consumption frequencies and quantities for a list of 99 common foods. Results indicate that up to 30% of the observed variance in dietary variety was explained through heritable influences. Most of the differences between twins were due to environmental influences that are not shared between twins. Additional non genetic analyses further revealed a weak relationship between dietary variety and particular demographic variables, including socioeconomic status, age, sex, religious faith, and the number of people living in the same household. PMID- 24631638 TI - Dose-response effect of a novel functional fibre, PolyGlycopleX((r)), PGX((r)), on satiety. AB - The objective of this research was to determine the dose-response effects of a palatable, viscous and gel forming fibre, PolyGlycopleX((r)) (PGX((r))), [(alpha D-glucurono-alpha-manno-beta-D-manno-beta-D-gluco), (alpha-Lgulurono-beta-D mannurono), (beta-D-gluco-beta-D-mannan)] on satiety, and to gain insight into the underlying mechanisms that lead to appetite inhibition. Healthy subjects (n = 10), aged between 20.3 and 29.2 years, consumed PGX((r)), in granular form at 2.5, 5.0 and 7.5 g, and a 5g inulin control, with a standard breakfast. The PGX((r)) doses of 2.5 and 7.5 g mixed with water at the start of breakfast increased satiety (iAUC of 140.0 and 157.7, P = 0.025 and 0.001, respectively) compared to the control. The most effective dose (7.5g) was palatable and corresponded to a 34% increase in fullness, measured using a visual analogue scale and incremental area under the curve, and resulted in a delayed postprandial glycaemic response when compared with the control. PMID- 24631639 TI - Large, binge-type meals of high fat diet change feeding behaviour and entrain food anticipatory activity in mice. AB - Male C57BL/6 mice fed ad libitum on control diet but allowed access to a palatable high fat diet (HFD) for 2 h a day during the mid-dark phase rapidly adapt their feeding behaviour and can consume nearly 80% of their daily caloric intake during this 2 h-scheduled feed. We assessed food intake microstructure and meal pattern, and locomotor activity and rearing as markers of food anticipatory activity (FAA). Schedule fed mice reduced their caloric intake from control diet during the first hours of the dark phase but not during the 3-h period immediately preceding the scheduled feed. Large meal/binge-like eating behaviour during the 2-h scheduled feed was characterised by increases in both meal number and meal size. Rearing was increased during the 2-h period running up to scheduled feeding while locomotor activity started to increase 1 h before, indicating that schedule-fed mice display FAA. Meal number and physical activity changes were sustained when HFD was withheld during the anticipated scheduled feeding period, and mice immediately binged when HFD was represented after a week of this "withdrawal" period. These findings provide important context to our previous studies suggesting that energy balance systems in the hypothalamus are not responsible for driving these large, binge-type meals. Evidence of FAA in HFD dark phase schedule-fed mice implicates anticipatory processes in binge eating that do not involve immediately preceding hypophagia or regulatory homeostatic signalling. PMID- 24631641 TI - Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium. AB - Long non-coding RNAs (lncRNAs) have emerged recently as key regulatory molecules with diverse roles at almost every level of the regulation of gene expression. The roles of these RNAs in the pathogenesis of cystic fibrosis (CF); a lethal multisystem, autosomal recessive disorder have yet to be explored. Our aim was to examine the expression profile of lncRNA, in the airway epithelium of people with CF. We examined the expression of 30,586 lncRNAs by microarray (Human LncRNA Array v3.0, Arraystar, Inc.), in vivo in bronchial cells isolated from endobronchial brushings obtained from CF and non-CF individuals. In total, we identified 1,063 lncRNAs with differential expression between CF and non-CF individuals (fold change >=3, p<=0.001). The microarray also contained probes for ~26,109 protein coding transcripts, of which 720 were differentially expressed between CF and non-CF brush samples (fold change >=3, p<=0.001). Confirmation of a selection of differentially expressed coding mRNA and lncRNA transcripts such as XIST and TLR8 was achieved using qRT-PCR. Gene ontology bioinformatics analysis highlighted that many processes over-represented in the CF bronchial epithelium are related to inflammation. These data show a significantly altered lncRNA and mRNA expression profile in CF bronchial cells in vivo. Dysregulation of some of these lncRNAs may play important roles in the chronic infection and inflammation that exists in the lungs of people with CF. PMID- 24631640 TI - Placental and embryonic tissues exhibit aromatase activity in the viviparous lizard Niveoscincus metallicus. AB - Aromatase is a key regulator of circulating testosterone (T) and 17-beta oestradiol (E2), two steroids which are critical to the development, maintenance and function of reproductive tissues. The role of aromatase in sexual differentiation in oviparous (egg-laying) reptiles is well understood, yet has never been explored in viviparous (live-bearing) reptiles. As a first step towards understanding the functions of aromatase during gestation in viviparous reptiles, we measured aromatase activity in maternal and embryonic tissues at three stages of gestation in the viviparous skink, Niveoscincus metallicus. Maternal ovaries and adrenals maintained high aromatase activity throughout gestation. During the early phases of embryonic development, placental aromatase activity was comparable to that in maternal ovaries, but declined significantly at progressive stages of gestation. Aromatase activity in the developing brains and gonads of embryos was comparable with measurements in oviparous reptiles. Aromatase activity in the developing brains peaked mid development, and declined to low levels in late stage embryos. Aromatase activity in the embryonic gonads was low at embryonic stage 29-34, but increased significantly at mid-development and then remained high in late stage embryos. We conclude that ovarian estrogen synthesis is supplemented by placental aromatase activity and that maternal adrenals provide an auxiliary source of sex steroid. The pattern of change in aromatase activity in embryonic brains and gonads suggests that brain aromatase is important during sexual differentiation, and that embryonic gonads are increasingly steroidogenic as development progresses. Our data indicate vital roles of aromatase in gestation and development in viviparous lizards. PMID- 24631643 TI - Proliferating cell unclear antigen-associated factor (PAF15): a novel oncogene. AB - Proliferating cell nuclear antigen (PCNA)-Associated Factor (PAF15) is a small protein containing a PCNA interacting motif and sequences for association with ubiquitin enzymes. In interaction with PCNA, PAF15 plays a key role in recruiting DNA replicative polymerase by double monoubiquitination at Lys(15) and Lys(24). Under DNA damage conditions, PAF15 regulates the switch from DNA replicative polymerase to translesion synthesis polymerase in order to bypass the replication blocking lesions. Overexpression of PAF15 promotes the repair of ultraviolet induced DNA damage and prevents cell death, whereas attenuation of PAF15 decreases DNA replication and cell survival. Ectopic expression of PAF15 in mouse fibroblasts increases colony formation and tumourigenicity. PAF15 is aberrantly increased in various human malignancies with poor prognosis. Collectively, PAF15 may contribute to carcinogenesis and represents one of the potential therapeutic targets in the treatment of cancer. PMID- 24631642 TI - Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies. AB - Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an epithelial anion channel. Since the identification of the disease in 1938 and up until 2012, CF patients have been treated exclusively with medications aimed at bettering their respiratory, digestive, inflammatory and infectious symptoms. The identification of the CFTR gene in 1989 gave hopes of rapidly finding a cure for the disease, for which over 1950 mutations have been identified. Since 2012, recent approaches have enabled the identification of small molecules targeting either the CFTR protein directly or its key processing steps, giving rise to novel promising therapeutic tools. This review presents the current CFTR mutation classifications according to their clinical consequences and to their effect on the structure and function of the CFTR channel. How these classifications are essential in the establishment of mutation-targeted therapeutic strategies is then discussed. The future of CFTR-targeted treatment lies in combinatory therapies that will enable CF patients to receive a customized treatment. PMID- 24631644 TI - Controversies on the role of 5-HT(2C) receptors in the mechanisms of action of antidepressant drugs. AB - Evidence from the various sources indicates alterations in 5-HT2C receptor functions in anxiety, depression and suicide, and other stress-related disorders treated with antidepressant drugs. Although the notion of a 5-HT2C receptor desensitization following antidepressant treatments is rather well anchored in the literature, this concept is mainly based on in vitro assays and/or behavioral assays (hypolocomotion, hyperthermia) that have poor relevance to anxio depressive disorders. Our objective herein is to provide a comprehensive overview of the studies that have assessed the effects of antidepressant drugs on 5-HT2C receptors. Relevant molecular (second messengers, editing), neurochemical (receptor binding and mRNA levels), physiological (5-HT2C receptor-induced hyperthermia and hormone release), behavioral (5-HT2C receptor-induced changes in feeding, anxiety, defense and motor activity) data are summarized and discussed. Setting the record straight about drug-induced changes in 5-HT2C receptor function in specific brain regions should help to determine which pharmacotherapeutic strategy is best for affective and anxiety disorders. PMID- 24631645 TI - Role of glutamate receptors of central and basolateral amygdala nuclei on retrieval and reconsolidation of taste aversive memory. AB - There are a number of experiments showing an important involvement of amygdala N methyl-d-aspartate (NMDA) glutamate receptors on consolidation of conditioned taste aversion (CTA) memory. Interestingly, recent evidence has shown that alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors are particularly involved in CTA retrieval. Memory reconsolidation has been proposed as a destabilization and re-stabilization process induced by memory reactivation. We have recently suggested that reconsolidation could be enabled in the absence of retrieval. Hence, we decided to analyze the participation of AMPA and NMDA receptors of the central (CeA) and basolateral amygdala (BLA) in CTA memory retrieval and reconsolidation. To do so, we tested whether administrations of an AMPA receptor blocker (NBQX) or an NMDA receptor blocker (APV) 15 min before a second acquisition trial could have effects on taste aversion. We found that administration of NBQX in the BLA blocked retrieval, whereas APV blocked reconsolidation in the BLA, and consolidation in the CeA. When we administered both NBQX and APV into the BLA before the second acquisition trial, results showed impairment of both retrieval and reconsolidation. These results further support the idea that reconsolidation is independent of retrieval, since retrieval blockade in the BLA did not impair memory reconsolidation. These results suggest that glutamate receptors have different participation on retrieval and reconsolidation of CTA and further support the hypothesis that these two processes could be independent. PMID- 24631646 TI - Development of hydrogel biochip for in vitro allergy diagnostics. AB - A hydrogel biochip was developed for the simultaneous quantitative determination of sIgE for 21 allergens and total IgE in human serum. The biochips are manufactured by photoinduced copolymerization of different molecules (allergens and antibodies) with gel-forming monomers resulting in the formation of three dimensional hydrogel elements (1nl gel drops). After incubation of the biochip with the serum, the results are visualized using fluorescently labeled anti-IgE antibodies. Using biochips, serum samples from allergic patients and healthy donors were analyzed and good correlation with the results obtained using commercial EIA test systems of generally recognized quality (Dr. Fooke Laboratorien GmbH, Germany) was observed. PMID- 24631648 TI - Why not decompress early? The cauda equina syndrome. PMID- 24631647 TI - Mouse models of hepatitis B and delta virus infection. AB - Liver disease associated to persistent infection with the hepatitis B virus (HBV) continues to be a major health problem of global impact. Therapeutic regimens currently available can efficiently suppress HBV replication; however, the unique replication strategies employed by HBV permit the virus to persist within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment with polymerase inhibitors. Among the HBV chronically infected patients, more than 15million patients are estimated to be co-infected with the hepatitis delta virus (HDV), a defective satellite virus that needs the HBV envelope for propagation. No specific drugs are currently available against HDV, while nucleos(t)ide analogs are not effective against HDV replication. Since chronic HBV/HDV co-infection leads to the most severe form of chronic viral hepatitis in men, a better understanding of the molecular mechanisms of HDV-mediated pathogenesis and the development of improved therapeutic approaches is urgently needed. The obvious limitations imposed by the use of great apes and the paucity of robust experimental models of HBV infection have hindered progresses in understanding the complex network of virus-host interactions that are established in the course of HBV and HDV infections. This review focuses on summarizing recent advances obtained with well-established and more innovative experimental mouse models, giving emphasis on the strength of infection systems based on the reconstitution of the murine liver with human hepatocytes, as tools for elucidating the whole life cycle of HBV and HDV, as well as for studies on interactions with the infected human hepatocytes and for preclinical drug evaluation. PMID- 24631649 TI - Hemangiopericytoma of meninges--a "malignant" challenge. PMID- 24631650 TI - The timing of decompressive spinal surgery in cauda equina syndrome. PMID- 24631651 TI - G-quadruplex-mediated regulation of telomere binding protein POT1 gene expression. AB - BACKGROUND: Telomere is protected by its G-quadruplex, T-loop structure, telomerase, and binding protein complex. Protein POT1 (protection of telomeres 1) is one subunit of telomere binding protein complex Shelterin. POT1 acts as a regulator of telomerase-dependent telomere length, and it can help telomere to form D-loop structure to stabilize telomere. POT1 protects telomere ends from ATR dependent DNA damage response as well. METHODS: Extensive methods were used, including CD, EMSA, ITC, PCR stop assay, luciferase reporter assay, quantitative real-time PCR, Western blot, chromatin immunoprecipitation (Ch-IP), cloning, expression and purification of proteins. RESULTS: We found a new G-rich 30-base pair long sequence (P-pot1 G18) located from -165 to -136 base pairs upstream of the translation starting site of protein POT1. This sequence in the promoter region of pot1 gene formed G-quadruplex resulting in down-regulation of pot1 gene transcription. This G-rich sequence is close to a binding site "TCCC" for transcription factor hnRNP K (heterogeneous nuclear ribonucleoprotein K), and its conversion to G-quadruplex prevented the access of hnRNP K to this binding site. The binding of hnRNP K could up-regulate pot1 gene transcription. TMPyP4 (meso tetra(N-methyl-4-pyridyl)porphine) has been widely used as G-quadruplex binding ligand, which stabilized the G-quadruplex in vitro and in cellulo, resulting in down-regulation of pot1 gene transcription. CONCLUSIONS: This G-quadruplex might become a potentially new drug target for antitumor agents. GENERAL SIGNIFICANCE: Our results first demonstrated that G-quadruplex formation can affect the binding of transcription factor to its nearby binding site, and thus making additional influence to gene transcription. PMID- 24631652 TI - Injured cardiomyocytes promote dental pulp mesenchymal stem cell homing. AB - BACKGROUND: The heart is unable to regenerate its tissues after severe injuries. Stem cell therapy appears to be one of the most promising approaches, though preclinical results are hitherto contradictory and clinical trials scanty and/or limited to phase-I. The limited knowledge about stem cell early homing in infarcted cardiac tissues can concur to this scenario. METHODS: The stem cell migration was assessed in in-vitro and ex-vivo models of heart ischemia, employing a rat dental pulp stem cell line (MUR-1) that shares the same ontogenic progenitors with portions of the heart, expresses markers typical of cardiac/vascular-like progenitors and is able to differentiate into cardiomyocytes in-vitro. RESULTS: Here, we demonstrated that the MUR-1 can reach the injured cells/tissue and make contacts with the damaged cardiomyocytes, likely through Connexin 43, N-cadherin and von Willebrand Factor mediated cell cell interactions, both in in-vitro and ex-vivo models. Furthermore, we found that SDF-1, FGF-2 and HGF, but not VEGF are involved as chemotactic factors in MUR-1 migration, notifying a similarity with neural crest cell behavior during the organogenesis of both the splanchnocranium and the heart. CONCLUSIONS: Herein we found a similarity between what happens during the heart organogenesis and the early migration and homing of MUR-1 cells in ischemic models. GENERAL SIGNIFICANCE: The comprehension of molecular aspects underlying the early phases of stem cell migration and interaction with damaged organ contributes to the future achievement of the coveted stem cell-mediated organ regeneration and function preservation in-vivo. PMID- 24631654 TI - Cyclic GMP catabolism up-regulation in MRL/lpr lupus-prone mice is associated with organ remodeling. AB - Production of high titer of antibodies against nuclear components is a hallmark of systemic lupus erythematosus, an autoimmune disease characterized by the progressive chronic inflammation of multiple joints and organs. Organ damage and dysfunction such as renal failure are typical clinical features in lupus. Cell hypermetabolism and hypertrophy can accelerate organ dysfunction. In this study we focus on a specific murine model of lupus, the MRL/lpr strain, and investigated the role of cyclic guanosine monophosphate (cGMP) catabolism in organ remodeling of main target tissues (kidney, spleen and liver) in comparison with age-matched control mice. In MRL/lpr-prone mice, the cGMP-phosphodiesterase (PDE) activities were significantly increased in the kidney (3-fold, P<0.001), spleen (2-fold, P<0.001) and liver (1.6-fold, P<0.05). These raised activity levels were paralleled by both an increased activity of PDE1 in the kidney (associated with nephromegaly) and in the liver, and PDE2 in the spleen of lupus prone mice. The up-regulation of PDE1 and PDE2 activities were associated with a decrease in intracellular cGMP levels. This underlines an alteration of cGMP-PDE signaling in the kidney, spleen and liver targeting different PDEs according to organs. In good agreement with these findings, a single intravenous administration to MRL/lpr mice of nimodipine (PDE1 inhibitor) but not of EHNA (PDE2 inhibitor) was able to significantly lower peripheral hypercellularity (P=0.0401), a characteristic feature of this strain of lupus-prone mice. Collectively, our findings are important for generating personalized strategies to prevent certain forms of the lupus disease as well as for understanding the role of PDEs and cGMP in the pathophysiology of lupus. PMID- 24631655 TI - Role of the nucleolus in human diseases. Preface. PMID- 24631653 TI - Neuroprotective effect of PEP-1-peroxiredoxin2 on CA1 regions in the hippocampus against ischemic insult. AB - BACKGROUND: Oxidative stress is a leading cause of various diseases, including ischemia and inflammation. Peroxiredoxin2 (PRX2) is one of six mammalian isoenzymes (PRX1-6) that can reduce hydrogen peroxide (H2O2) and organic hydroperoxides to water and alcohols. METHODS: We produced PEP-1-PRX2 transduction domain (PTD)-fused protein and investigated the effect of PEP-1-PRX2 on oxidative stress-induced neuronal cell death by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, Western blot, immunofluorescence microscopy, and immunohistochemical analysis. RESULTS: Our data showed that PEP-1 PRX2, which can effectively transduce into various types of cells and brain tissues, could be implicated in suppressing generation of reactive oxygen species, preventing depolarization of the mitochondrial membrane, and inhibiting the apoptosis pathway in H2O2-stimulated HT22, murine hippocampal neuronal cells, likely resulting in protection of HT22 cells against H2O2-induced toxicity. In addition, we found that in a transient forebrain ischemia model, PEP-1-PRX2 inhibited the activation of astrocytes and microglia in the CA1 region of the hippocampus and lipid peroxidation and also prevented neuronal cell death against ischemic damage. CONCLUSIONS: These findings suggest that the transduced PEP-1 PRX2 has neuroprotective functions against oxidative stress-induced cell death in vitro and in vivo. GENERAL SIGNIFICANCE: PEP-1-PRX2 could be a potential therapeutic agent for oxidative stress-induced brain diseases such as ischemia. PMID- 24631656 TI - Alternating Hemiplegia of Childhood mutations have a differential effect on Na(+),K(+)-ATPase activity and ouabain binding. AB - De novo mutations in ATP1A3, the gene encoding the alpha3-subunit of Na(+),K(+) ATPase, are associated with the neurodevelopmental disorder Alternating Hemiplegia of Childhood (AHC). The aim of this study was to determine the functional consequences of six ATP1A3 mutations (S137Y, D220N, I274N, D801N, E815K, and G947R) associated with AHC. Wild type and mutant Na(+),K(+)-ATPases were expressed in Sf9 insect cells using the baculovirus expression system. Ouabain binding, ATPase activity, and phosphorylation were absent in mutants I274N, E815K and G947R. Mutants S137Y and D801N were able to bind ouabain, although these mutants lacked ATPase activity, phosphorylation, and the K(+)/ouabain antagonism indicative of modifications in the cation binding site. Mutant D220N showed similar ouabain binding, ATPase activity, and phosphorylation to wild type Na(+),K(+)-ATPase. Functional impairment of Na(+),K(+)-ATPase in mutants S137Y, I274N, D801N, E815K, and G947R might explain why patients having these mutations suffer from AHC. Moreover, mutant D801N is able to bind ouabain, whereas mutant E815K shows a complete loss of function, possibly explaining the different phenotypes for these mutations. PMID- 24631657 TI - Amphiphilic degradable polymers for immobilization and sustained delivery of sphingosine 1-phosphate. AB - Controlled delivery of the angiogenic factor sphingosine 1-phosphate (S1P) represents a promising strategy for promoting vascularization during tissue repair and regeneration. In this study, we developed an amphiphilic biodegradable polymer platform for the stable encapsulation and sustained release of S1P. Mimicking the interaction between amphiphilic S1P and its binding proteins, a series of polymers with hydrophilic poly(ethylene glycol) core and lipophilic flanking segments of polylactide and/or poly(alkylated lactide) with different alkyl chain lengths were synthesized. These polymers were electrospun into fibrous meshes, and loaded with S1P in generally high loading efficiencies (>90%). Sustained S1P release from these scaffolds could be tuned by adjusting the alkyl chain length, blockiness and lipophilic block length, achieving 35-55% and 45-80% accumulative releases in the first 8h and by 7 days, respectively. Furthermore, using endothelial cell tube formation assay and chicken chorioallantoic membrane assay, we showed that the different S1P loading doses and release kinetics translated into distinct pro-angiogenic outcomes. These results suggest that these amphiphilic polymers are effective delivery vehicles for S1P and may be explored as tissue engineering scaffolds where the delivery of lipophilic or amphiphilic bioactive factors is desired. PMID- 24631658 TI - Polymerization- and solvent-induced phase separation in hydrophilic-rich dentin adhesive mimic. AB - Current dental resin undergoes phase separation into hydrophobic-rich and hydrophilic-rich phases during infiltration of the over-wet demineralized collagen matrix. Such phase separation undermines the integrity and durability of the bond at the composite/tooth interface. This study marks the first time that the polymerization kinetics of model hydrophilic-rich phase of dental adhesive has been determined. Samples were prepared by adding varying water content to neat resins made from 95 and 99 wt.% hydroxyethylmethacrylate and 5 and 1 wt.% (2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl1]-propane prior to light curing. Viscosity of the formulations decreased with increased water content. The photopolymerization kinetics study was carried out with a time-resolved Fourier transform infrared spectrometer. All of the samples exhibited two-stage polymerization behavior which has not been reported previously for dental resin formulation. The lowest secondary rate maxima were observed for water contents of 10-30 wt.%. Differential scanning calorimetry (DSC) showed two glass transition temperatures for the hydrophilic-rich phase of dental adhesive. The DSC results indicate that the heterogeneity within the final polymer structure decreased with increasing water content. The results suggest a reaction mechanism involving both polymerization-induced phase separation and solvent-induced phase separation for the model hydrophilic-rich phase of dental resin. PMID- 24631659 TI - Characterization of hLF1-11 immobilization onto chitosan ultrathin films, and its effects on antimicrobial activity. AB - hLF1-11 (GRRRRSVQWCA) is an antimicrobial peptide (AMP) with high activity against methicillin-resistant Staphylococcus aureus (MRSA), the most prevalent species in implant-associated infection. In this work, the effect of the surface immobilization on hLF1-11 antimicrobial activity was studied. Immobilization was performed onto chitosan thin films as a model for an implant coating due to its reported osteogenic and antibacterial properties. Chitosan thin films were produced by spin-coating on gold surfaces. hLF1-11 was immobilized onto these films by its C-terminal cysteine in an orientation that exposes the antimicrobial activity-related arginine-rich portion of the peptide. Two levels of exposure (with and without a polyethylene glycol (PEG) spacer) were analyzed. Covalent immobilization was further compared with the AMP physical adsorption onto chitosan films. Surfaces were characterized using ellipsometry, contact angle measurements, atomic force microscopy, infrared and X-ray photoelectron spectroscopies and using a fluorimetric assay for hLF1-11 quantification. Surface antimicrobial activity was assessed through surface adhesion and viability assays using an MRSA (S. aureus ATCC 33591). The incorporation of hLF1-11 increased significantly bacterial adhesion to chitosan films. However, the presence of hLF1 11, namely when immobilized through a PEG spacer, decreased the viability of adherent bacteria with regard to the control surface. These results demonstrated that hLF1-11 after covalent immobilization by its cysteine can maintain activity, particularly if a spacer is applied. However, further studies, exploring the opposite orientation or the same C-terminal orientation, but non-cysteine related, can help to clarify the potential of the hLF1-11 immobilization strategy. PMID- 24631660 TI - Biotribology of a vitamin E-stabilized polyethylene for hip arthroplasty - Influence of artificial ageing and third-body particles on wear. AB - The objective of our study was to evaluate the influence of prolonged artificial ageing on oxidation resistance and the subsequent wear behaviour of vitamin E stabilized, in comparison to standard and highly cross-linked remelted polyethylene (XLPE), and the degradation effect of third-body particles on highly cross-linked remelted polyethylene inlays in total hip arthroplasty. Hip wear simulation was performed with three different polyethylene inlay materials (standard: gamma-irradiation 30 kGy, N2; highly cross-linked and remelted: gamma irradiation 75 kGy, EO; highly cross-linked and vitamin E (0.1%) blended: electron beam 80 kGy, EO) machined from GUR 1020 in articulation with ceramic and cobalt-chromium heads. All polyethylene inserts beneath the virgin references were subjected to prolonged artificial ageing (70 degrees C, pure oxygen at 5 bar) with a duration of 2, 4, 5 or 6 weeks. In conclusion, after 2 weeks of artificial ageing, standard polyethylene shows substantially increased wear due to oxidative degradation, whereas highly cross-linked remelted polyethylene has a higher oxidation resistance. However, after enhanced artificial ageing for 5 weeks, remelted XLPE also starts oxidate, in correlation with increased wear. Vitamin E-stabilized polyethylene is effective in preventing oxidation after irradiation cross-linking even under prolonged artificial ageing for up to 6 weeks, resulting in a constant wear behaviour. PMID- 24631661 TI - Rhodopirellula lusitana sp. nov. and Rhodopirellula rubra sp. nov., isolated from the surface of macroalgae. AB - Twenty two strains of Rhodopirellula were isolated from the epiphytic community of several marine macroalgae and separated into two groups, designated as group B and group C. In this study, we characterized these groups as two novel species belonging to the genus Rhodopirellula. These strains were represented by pleomorphic cells that were arranged in rosettes and formed pink- or red pigmented colonies. The organisms were chemoorganotrophic and required vitamin B12 for growth. Their optimal temperature for growth was around 25 degrees C. Major fatty acids were C18:1 omega9c, C16:0 and C16:1 omega7c/C16:1 omega6c. Phosphatidylcholine and phosphatidylglycerol were the major polar lipids. Unidentified phospholipids were also present. The 16S rDNA sequence analysis confirmed the affiliation of these organisms to the order Planctomycetales, genus Rhodopirellula, with R. baltica as the closest phylogenetic relative. The analysis of a partial sequence of the gene encoding the beta-subunit of RNA polymerase (rpoB) confirmed the phylogenetic separation of the isolates into two different species of the genus Rhodopirellula. The 16S rRNA sequences from strains of group B revealed their widespread occurrence across the world, whereas strains of group C were not observed before. On the basis of physiological, biochemical, chemotaxonomic and genetic characteristics we propose that our isolates represent two new species of Rhodopirellula, Rhodopirellula rubra sp. nov. (type strain is LF2(T)=DSM 25,459=CECT 8075) and Rhodopirellula lusitana sp. nov. (type strain is UC17(T)=DSM 25,457=LMG 27,777). PMID- 24631662 TI - Matrix metalloproteinases in inflammation. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are a family of ubiquitously expressed zinc-dependent endopeptidases with broad substrate specificity and strictly regulated tissue specific expression. They are expressed in physiological situations and pathological conditions involving inflammation. MMPs regulate several functions related to inflammation including bioavailability and activity of inflammatory cytokines and chemokines. There is also evidence that MMPs regulate inflammation in tumor microenvironment, which plays an important role in cancer progression. SCOPE OF REVIEW: Here, we discuss the current view on the role of MMPs in the regulation of inflammation. MAJOR CONCLUSIONS: MMPs modulate inflammation by regulating bioavailability and activity of cytokines, chemokines, and growth factors, as well as integrity of physical tissue barriers. MMPs are also involved in immune evasion of tumor cells and in regulation of inflammation in tumor microenvironment. GENERAL SIGNIFICANCE: There is increasing evidence for non-matrix substrates of MMPs that are related to regulation of inflammatory processes. New methods have been employed for identification of the substrates of MMPs in inflammatory processes in vivo. Detailed information on the substrates of MMPs may offer more specific and effective ways of inhibiting MMP function by blocking the cleavage site in substrate or by inhibition of the bioactivity of the substrate. It is expected, that more precise information on the MMP-substrate interaction may offer novel strategies for therapeutic intervention in inflammatory diseases and cancer without blocking beneficial actions of MMPs. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. PMID- 24631663 TI - A trained perceptual bias that lasts for weeks. AB - Classical (Pavlovian) conditioning procedures can be used to bias the appearance of physical stimuli. Under natural conditions this form of perceptual learning could cause perception to become more accurate by changing prior belief to be in accord with what is statistically likely. However, for learning to be of functional significance, it must last until similar stimuli are encountered again. Here, we used the apparent rotation direction of a revolving wire frame (Necker) cube to test whether a learned perceptual bias is long lasting. Apparent rotation direction was trained to have a different bias at two different retinal locations by interleaving the presentation of ambiguous cubes with presentation of cubes that were disambiguated by disparity and occlusion cues. Four groups of eight subjects were subsequently tested either 1, 7, 14, or 28 days after initial training, respectively, using a counter-conditioning procedure. All four groups showed incomplete re-learning of the reversed contingency relationship during their second session. One group repeated the counter-conditioning and showed an increase in the reverse bias, showing that the first counter-conditioning session also had a long-lasting effect. The fact that the original learning was still evident four weeks after the initial training is consistent with the operation of a mechanism that ordinarily would improve the accuracy and efficiency of perception. PMID- 24631664 TI - Strong dimerization of wild-type ErbB2/Neu transmembrane domain and the oncogenic Val664Glu mutant in mammalian plasma membranes. AB - Here, we study the homodimerization of the transmembrane domain of Neu, as well as an oncogenic mutant (V664E), in vesicles derived from the plasma membrane of mammalian cells. For the characterization, we use a Forster resonance energy transfer (FRET)-based method termed Quantitative Imaging-FRET (QI-FRET), which yields the donor and acceptor concentrations in addition to the FRET efficiencies in individual plasma membrane-derived vesicles. Our results demonstrate that both the wild-type and the mutant are 100% dimeric, suggesting that the Neu TM helix dimerizes more efficiently than other RTK TM domains in mammalian membranes. Furthermore, the data suggest that the V664E mutation causes a very small, but statistically significant change in dimer structure. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID- 24631665 TI - Utilizing zeta potential measurements to study the effective charge, membrane partitioning, and membrane permeation of the lipopeptide surfactin. AB - The effective charge of membrane-active molecules such as the fungicidal lipopeptide surfactin (SF) is a crucial property governing solubility, membrane partitioning, and membrane permeability. We present zeta potential measurements of liposomes to measure the effective charge as well as membrane partitioning of SF by utilizing what we call an equi-activity analysis of several series of samples with different lipid concentrations. We observe an effective charge of 1.0 for SF at pH8.5 and insignificantly lower at pH7.4, illustrating that the effective charge may deviate strongly from the nominal value (-2 for 1 Asp, 1 Glu). The apparent partition coefficient decreases from roughly 100 to 20/mM with increasing membrane content of SF in agreement with the literature. Finally, by comparing zeta potentials measured soon after the addition of peptide to liposomes with those measured after a heat treatment to induce transmembrane equilibration of SF, we quantified the asymmetry of partitioning between the outer and inner leaflets. At very low concentration, SF binds exclusively to the outer leaflet. The onset of partial translocation to the inner leaflet occurs at about 5mol-% SF in the membrane. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID- 24631666 TI - Headspace sorptive extraction for the detection of combustion accelerants in fire debris. AB - A novel method for separation and identification of ignitable liquid residues in fire debris by gas chromatography and mass spectrometry is presented. Preconcentration of the analytes was carried out using the simple headspace sorptive extraction (HSSE) technique. Polydimethylsiloxane stir bars were used as the enrichment phase, and parameters affecting both the adsorption and desorption stages were carefully optimized. Extraction was carried out at 50 degrees C for 1h. Stir bars were desorbed thermally in the GC injection port, thus avoiding the use of organic solvents. The results for five ignitable liquids, including gasoline and diesel fuel, using HSSE were compared with those obtained with a solid-phase microextraction method, with HSSE appearing as a more sensitive alternative. PMID- 24631668 TI - Free energy landscape for glucose condensation and dehydration reactions in dimethyl sulfoxide and the effects of solvent. AB - The mechanisms and free energy surfaces (FES) for the initial critical steps during proton-catalyzed glucose condensation and dehydration reactions were elucidated in dimethyl sulfoxide (DMSO) using Car-Parrinello molecular dynamics (CPMD) coupled with metadynamics (MTD) simulations. Glucose condensation reaction is initiated by protonation of C1--OH whereas dehydration reaction is initiated by protonation of C2--OH. The mechanisms in DMSO are similar to those in aqueous solution. The DMSO molecules closest to the C1--OH or C2--OH on glucose are directly involved in the reactions and act as proton acceptors during the process. However, the energy barriers are strongly solvent dependent. Moreover, polarization from the long-range electrostatic interaction affects the mechanisms and energetics of glucose reactions. Experimental measurements conducted in various DMSO/Water mixtures also show that energy barriers are solvent dependent in agreement with our theoretical results. PMID- 24631667 TI - Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries. AB - The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) exposure, are poorly understood. Neutrophils which accumulate at the site of injury, abundantly express myeloperoxidase (MPO), a heme protein that is implicated in oxidant-related antimicrobial and cytotoxic responses. Our previous studies have shown that exposure to SM analog 2-chloroethyl ethyl sulfide (CEES) or NM results in an inflammatory response including increased neutrophilic infiltration and MPO activity. To further define the role of neutrophil-derived MPO in NM-induced skin injury, here we used a genetic approach and examined the effect of NM exposure (12h and 24h) on previously established injury endpoints in C57BL/6J wild type (WT) and B6.129X1-MPOtm1Lus/J mice (MPO KO), homozygous null for MPO gene. NM exposure caused a significant increase in skin bi-fold thickness, epidermal thickness, microvesication, DNA damage and apoptosis in WT mice compared to MPO KO mice. MPO KO mice showed relatively insignificant effect. Similarly, NM induced increases in the expression of inflammatory and proteolytic mediators, including COX-2, iNOS and MMP-9 in WT mice, while having a significantly lower effect in MPO KO mice. Collectively, these results show that MPO, which generates microbicidal oxidants, plays an important role in NM-induced skin injuries. This suggests the development of mechanism-based treatments against NM- and SM-induced skin injuries that inhibit MPO activity and attenuate MPO-derived oxidants. PMID- 24631669 TI - Supramolecular stacking motifs in the solid state of amide and triazole derivatives of cellobiose. AB - 1-Acetamido-1-deoxy-(4-O-beta-d-glucopyranosyl-beta-d-glucopyranose) (5) and 1 deoxy-1-(4-phenyl-1,2,3-triazolyl)-(4-O-beta-d-glucopyranosyl-beta-d glucopyranose) (7) were synthesised from 1-azido-1-deoxy-(4-O-beta-d glucopyranosyl-beta-d-glucopyranose) (2) and crystallised as dihydrates. Crystal structural analysis of 5.2H2O displayed an acetamide C(4) chain and stacked cellobiose residues. The structure of 7.2H2O featured pi-pi stacking and stacking of the cellobiose residues. PMID- 24631670 TI - Two and three dimensional characterization of Zucchini Yellow Mosaic Virus induced structural alterations in Cucurbita pepo L. plants. AB - Infection of plants by Zucchini Yellow Mosaic Virus (ZYMV) induces severe ultrastructural changes. The aim of this study was to investigate ultrastructural changes during ZYMV-infection in Cucurbita pepo L. plants on the two and three dimensional (2D and 3D) level and to correlate these changes with the spread of ZYMV throughout the plant by transmission electron microscopy (TEM) and image analysis. This study revealed that after inoculation of the cotyledons ZYMV moved into roots [3 days post inoculation (dpi)], then moved upwards into the stem and apical meristem (5 dpi), then into the first true leaf (7 dpi) and could finally be found in all plant parts (9 dpi). ZYMV-infected cells contained viral inclusion bodies in the form of cylindrical inclusions (CIs). These CIs occurred in four different forms throughout the cytosol of roots and leaves: scrolls and pinwheels when cut transversely and long tubular structures and bundles of filaments when cut longitudinally. 3D reconstruction of ZYMV-infected cells containing scrolls revealed that they form long tubes throughout the cytosol. The majority has a preferred orientation and an average length and width of 3 MUm and 120 nm, respectively. Image analysis revealed an increased size of cells and vacuoles (107% and 447%, respectively) in younger ZYMV-infected leaves leading to a similar ratio of cytoplasm to vacuole (about 1:1) in older and younger ZYMV infected leaves which indicates advanced cell growth in younger tissues. The collected data advances the current knowledge about ZYMV-induced ultrastructural changes in Cucurbita pepo. PMID- 24631671 TI - Fournier's gangrene caused by Actinomyces funkei, Fusobacterium gonidiaformans and Clostridium hathewayi. AB - We report the first case of Fournier's gangrene caused by three unusual anaerobic organisms: Actinomyces funkei, Fusobacterium gonidiaformans and Clostridium hathewayi. The infection occurred in a 73-year-old man without typical risk factors for the development of Fournier's gangrene. Clinical outcome was good after prolonged antibiotic treatment and extensive debridement of the perineum. The case suggests that A. funkei, F. gonidiaformans and C. hathewayi should be considered as potential pathogens of Fournier's gangrene. Human infections caused by these organisms are very rare but can be underestimated because correct identification is very difficult, especially in polymicrobial infections such as Fournier's gangrene. PMID- 24631672 TI - Ceftriaxone alleviates early brain injury after subarachnoid hemorrhage by increasing excitatory amino acid transporter 2 expression via the PI3K/Akt/NF kappaB signaling pathway. AB - Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a reduction in excitatory amino acid transporter 2 (EAAT2) expression and severe amino acid excitotoxicity. The aim of this study was to explore the neuroprotective effect of ceftriaxone (CEF), a potent compound that up-regulates EAAT2, against EBI and the potential mechanisms using in vitro experiments and a rat model of SAH. Intracisternal treatment with CEF significantly improved neurological outcomes and alleviated extracellular glutamate accumulation after SAH. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining and Western blot analysis of cleaved caspase 3 showed that CEF decreased hippocampal neuronal apoptosis following SAH. Immunofluorescent staining and Western blotting revealed that CEF significantly reversed the down regulation of EAAT2 expression following SAH. In Morris water maze (MWM) tests, CEF remarkably ameliorated the SAH-induced cognitive dysfunction in spatial learning memory and reference memory. CEF promoted the nuclear translocation of p65 as well as the activation of Akt in hippocampal astrocytes in vitro and in vivo. These findings suggest that CEF may exert significant protective effects against EBI following SAH by modulating the PI3K/Akt/NF-kappaB signaling pathway. PMID- 24631673 TI - Beyond the basal ganglia: cFOS expression in the cerebellum in response to acute and chronic dopaminergic alterations. AB - The suggestion of an anatomical and functional relationship between the basal ganglia and cerebellum is recent. Traditionally, these structures were considered as neuronal circuits working separately to organize and control goal-directed movements and cognitive functions. However, several studies in rodents and primates have described an anatomical interaction between cortico-basal and cortico-cerebellar networks. Most importantly, functional changes have been observed in one of these circuits when altering the other one. In this context, we aimed to accomplish an extensive description of cerebellar activation patterns using cFOS expression (cFOS-IR) after acute and chronic manipulation of dopaminergic activity. In the acute study, substantia nigra pars compacta (SNc) activity was stimulated or suppressed by intra cerebral administration of picrotoxin or lidocaine, respectively. In addition, we analyzed cerebellar activity after the induction of a parkinsonism model, the tremulous jaw movements. In this model, tremulous jaw movements were induced in male rats by IP chronic administration of the dopamine antagonist haloperidol (1.5mg/kg). Acute stimulation of SNc by picrotoxin increased cFOS-IR in the vermis and cerebellar hemispheres. However, lidocaine did not produce an effect. After 14days of haloperidol treatment, the vermis and cerebellar hemispheres showed an opposite regulation of cFOS expression. Chronic dopaminergic antagonism lessened cFOS expression in the vermis but up-regulated such expression in the cerebellar hemisphere. Overall, the present data indicate a very close functional relationship between the basal ganglia and the cerebellum and they may allow a better understanding of disorders in which there are dopamine alterations. PMID- 24631674 TI - Expression of transient receptor potential channels TRPC1 and TRPV4 in venoatrial endocardium of the rat heart. AB - The atrial volume receptor reflex arc serves to regulate plasma volume. Atrial volume receptors located in the endocardium of the atrial wall undergo mechanical deformation as blood is returned to the atria of the heart. The mechanosensitive channel(s) responsible for regulating plasma volume remain to be determined. Here we report that the TRP channel family members TRPC1 and TRPV4 were expressed in sensory nerve endings in the atrial endocardium. Furthermore, TRPC1 and TRPV4 were coincident with the nerve ending vesicle marker synaptophysin. Calcitonin gene-related peptide was exclusively confined to the myo- and epicardium of the atria. The small conductance Ca(2+)-activated K(+) channels (SK2 and SK4) were also present, however there was no relationship between SK and TRP channels. SK2 channels were expressed in nerves in the epicardium, while SK4 channels were in some regions of the endocardium but appeared to be present in epithelial cells rather than sensory endings. In conclusion, we have provided the first evidence for TRPC1 and TRPV4 channels as potential contributors to mechanosensation in the atrial volume receptors. PMID- 24631675 TI - Blockade of arginine vasotocin signaling reduces aggressive behavior and c-Fos expression in the preoptic area and periventricular nucleus of the posterior tuberculum in male Amphiprion ocellaris. AB - Many marine fishes change sex in response to social cues when the dominance hierarchy is perturbed. Arginine-vasotocin (AVT) and the mammalian homolog arginine vasopressin are neuropeptides involved in social and reproductive behaviors across vertebrate taxa. The goal of this study was to determine whether AVT signaling influences aggression and expression of c-Fos, a marker of neuroplasticity, in key brain regions of the social decision circuit in Amphiprion ocellaris clownfish, a species where behavioral dominance precedes gonadal sex change from male to female. In experiment 1, juvenile clownfish (average mass 2.5g) were paired together in a tank (a total of 24 pairs), matched approximately for size with one fish randomly receiving either an intraperitoneal injection of the arginine vasopressin V1a receptor antagonist (Manning compound) or saline vehicle, and evaluated for aggressive and submissive behaviors over a 10-min period. The second experiment was a repeat of the first using five pairs of mature, reproductive males, except the animals interacted for 90-min immediately followed by euthanasia for immunohistochemical detection of c-Fos protein. Numbers of c-Fos-positive cells were quantified in the preoptic area of the hypothalamus (POA), the anterior tuberal nucleus (aTn), and periventricular nucleus of the posterior tuberculum (TPp). Manning compound significantly reduced aggression and the probability of winning the contest relative to saline (vehicle) controls. In experiment 2, saline-treated fish displayed approximately twice as many c-Fos-positive cells in the POA and 25% more in the TPp than the Manning-treated fish, no differences were observed in the aTn. Taken together, results suggest AVT signaling is necessary for aggressive behavior and expression of neuroplasticity in the POA and TPp that likely contributes to behavioral dominance and hence, sex change in A. ocellaris. PMID- 24631677 TI - Dopamine down-regulation of protein L-isoaspartyl methyltransferase is dependent on reactive oxygen species in SH-SY5Y cells. AB - Parkinson's disease (PD) is a chronic and progressive neurological disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra. Dopamine, via the oxidative stress that it generates in the cytosol, could contribute to the selective loss of neurons observed in PD. Protein L-isoaspartyl methyltransferase (PIMT) is an enzyme that repairs L-isoaspartyl-containing proteins and possesses anti-apoptotic properties. PIMT expression has been shown to decrease with age. Together, these observations prompted us to investigate whether dopamine can regulate PIMT expression in SH-SY5Y neuroblastoma cells. Here, we report that dopamine down-regulated PIMT at both gene and protein levels. The same inhibition of PIMT protein level was caused by the electron transport chain inhibitor, rotenone, which was accompanied, in both cases, by an increase in cell death and reactive oxygen species (ROS) production. In fact, pre treatment with the antioxidant N-acetyl cysteine blocked PIMT dopamine-associated down-regulation. PCMT1 promoter mapping experiments allowed the identification of two regions that showed different sensitivity to DA action. A first region localized between 61 and 94bp upstream of transcription start site was very sensitive to dopamine inhibition while a second region between 41 and 61bp appeared more resistant to dopamine inhibitory effect. The inhibition of PCMT1 promoter activity was mediated by dopamine-induced ROS since it was prevented by the hydroxyl radical scavenger N,N'-dimethylthiourea. Conversely, H2O2 inhibited in a dose-dependent manner the transcriptional activity of PCMT1 promoter. Therefore, our findings identified new molecular mechanisms, cytosolic dopamine and its resulting ROS, as inhibitors of PIMT expression. This suggests that ROS generated from cytosolic dopamine could reduce both the PCMT1 gene promoter activity and the PIMT protein level thus decreasing its capacity to repair proteins involved in apoptosis and could contribute to neuronal cell death observed in PD. PMID- 24631676 TI - Localization and expression of CaBP1/caldendrin in the mouse brain. AB - Ca(2+) binding protein 1 (CaBP1) and caldendrin are alternatively spliced variants of a subfamily of CaBPs with high homology to calmodulin. Although CaBP1 and caldendrin regulate effectors including plasma membrane and intracellular Ca(2+) channels in heterologous expression systems, little is known about their functions in vivo. Therefore, we generated mice deficient in CaBP1/caldendrin expression (C-KO) and analyzed the expression and cellular localization of CaBP1 and caldendrin in the mouse brain. Immunoperoxidase labeling with antibodies recognizing both CaBP1 and caldendrin was absent in the brain of C-KO mice, but was intense in multiple brain regions of wild-type mice. By Western blot, the antibodies detected two proteins that were absent in the C-KO mouse and consistent in size with caldendrin variants originating from alternative translation initiation sites. By quantitative PCR, caldendrin transcript levels were far greater than those for CaBP1, particularly in the cerebral cortex and hippocampus. In the frontal cortex but not in the hippocampus, caldendrin expression increased steadily from birth. By double-label immunofluorescence, CaBP1/caldendrin was localized in principal neurons and parvalbumin-positive interneurons. In the cerebellum, CaBP1/caldendrin antibodies labeled interneurons in the molecular layer and in basket cell terminals surrounding the soma and axon initial segment of Purkinje neurons, but immunolabeling was absent in Purkinje neurons. We conclude that CaBP1/caldendrin is localized both pre- and postsynaptically where it may regulate Ca(2+) signaling and excitability in select groups of excitatory and inhibitory neurons. PMID- 24631678 TI - Curculigoside A induces angiogenesis through VCAM-1/Egr-3/CREB/VEGF signaling pathway. AB - Curculigoside A may be a powerful way of protecting the brain against a wide variety of injury. In the present study, we sought to elucidate whether Curculigoside A contributes to induce angiogenesis and its mechanisms. To this end, we examined the role of Curculigoside A on proliferation, invasion, and tube formation in the human brain microvascular endothelial cell line (HBMEC) in vitro. For studying mechanism, the cAMP response element-binding protein (CREB) inhibitor 2-naphthol-AS-E-phosphate (KG-501), early growth response 3 (Egr-3) siRNA, vascular endothelial growth factor (VEGF) antagonist sFlt-1 and VEGF receptor 2 (VEGFR2) blocker SU-1498 were used. Human brain microvascular endothelial cell line (HMBEC) proliferation was tested by 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT). Scratch adhesion test was used to assess the ability of invasion. A matrigel tube formation assay was performed to test capillary tube formation ability. Vascular cell adhesion molecule 1 (VCAM 1)/Egr-3/CREB/VEGF pathway activation in HMBEC was tested by Western blot analysis. Our data suggested that Curculigoside A induced angiogenesis in vitro by enhancing the proliferation, invasion and tube formation. VEGF expression was increased by Curculigoside A and counteracted by the soluble VEGF receptor 1 (sFlt-1, VEGF antagonist) and KG-501 in HMBEC. Tube formation was enhanced by Curculigoside A and counteracted by VEGF receptor blocker-SU1498, KG-501 and Egr 3 siRNA. It may be suggested that Curculigoside A induces angiogenesis in vitro via a programed VCAM-1/Egr-3/CREB/VEGF signaling axis. PMID- 24631679 TI - Auditory-cued sensorimotor task reveals disengagement deficits in rats exposed to the autism-associated teratogen valproic acid. AB - Autism Spectrum Disorder (ASD) is often found to co-exist with non-core behavioral manifestations that include difficulties in disengagement of attention to sensory cues. Here we examined whether this behavioral abnormality can be induced in rats prenatally exposed to valproic acid (VPA), a well-established teratogen associated with ASD animal models. We tested rats using an auditory cued sensorimotor task (ACST) based on the premise that ACST will be more sensitive to developmental changes in temporal association cortex (TeA) of the posterior attention system. We show that VPA rats learned the ACST markedly faster than control animals, but they exhibited a profound preoccupation with cues associated with the expectancy at the reward location such that disengagement was disrupted. Control rats on the other hand were able to disengage and utilize auditory cues for re-engagement. However, both control and VPA-treated rats performed similarly when tested on novel object recognition (NOR) and novel context mismatch (NOCM) behavioral tasks that are known to be sensitive to normal perirhinal and prefrontal network functioning respectively. Consistent with disrupted posterior rather than frontal networks, we also report that VPA can selectively act on deep-layer TeA cortical neurons by showing that VPA increased dendritic density in isolated deep-layer TeA but not frontal neurons. These results describe a useful approach to examine the role of cue dependent control of attention systems in rodent models of autism and suggest that disengagement impairments may arise from an inability to modify behavior through the appropriate use of sensory cue associations. PMID- 24631680 TI - Ligand-mediated active targeting for enhanced oral absorption. AB - Although the oral route is the most popular and acceptable way of drug administration owing to good patient compliance and safety, oral drug delivery is faced with continuous challenges regarding poorly soluble, poorly permeable or gastrointestinally unstable drugs such as proteins and polypeptides. The overall bioavailability and therapeutic effect still needs to be further improved by innovative delivery technologies. Recently, various novel strategies, for instance using ligand-decorated carriers, have been investigated for delivery of poorly absorptive therapeutics orally. In this review, we will discuss the state of the art of ligand-mediated targeting to intestinal epithelia for oral delivery of drugs with low bioavailability. PMID- 24631681 TI - Dynamic epigenetic responses to muscle contraction. AB - Skeletal muscle is a malleable organ that responds to a single acute exercise bout by inducing the expression of genes involved in structural, metabolic and functional adaptations. Several epigenetic mechanisms including histone H4 deacetylation and loss of promoter methylation have been implicated in modifying exercise-responsive gene expression. These transient changes suggest that epigenetic mechanisms are not restricted to early stages of human development but are broad dynamic controllers of genomic plasticity in response to environmental factors. PMID- 24631683 TI - Modulation of PGC-1alpha activity as a treatment for metabolic and muscle-related diseases. PMID- 24631684 TI - Time-of-day specific changes in metabolic detoxification and insecticide resistance in the malaria mosquito Anopheles gambiae. AB - Mosquitoes exhibit ~24 h rhythms in physiology and behavior, regulated by the cooperative action of an endogenous circadian clock and the environmental light:dark cycle. Here, we characterize diel (observed under light:dark conditions) time-of-day changes in metabolic detoxification and resistance to insecticide challenge in Anopheles gambiae mosquitoes. A better understanding of mosquito chronobiology will yield insights into developing novel control strategies for this important disease vector. We have previously identified >2000 rhythmically expressed An. gambiae genes. These include metabolic detoxification enzymes peaking at various times throughout the day. Especially interesting was the identification of rhythmic genes encoding enzymes capable of pyrethroid and/or DDT metabolism (CYP6M2, CYP6P3, CYP6Z1, and GSTE2). We hypothesized that these temporal changes in gene expression would confer time-of-day specific changes in metabolic detoxification and responses to insecticide challenge. An. gambiae mosquitoes (adult female Pimperena and Mali-NIH strains) were tested by gene expression analysis for diel rhythms in key genes associated with insecticidal resistance. Biochemical assays for total GST, esterase, and oxidase enzymatic activities were undertaken on time-specific mosquito head and body protein lysates. To determine for rhythmic susceptibility to insecticides by survivorship, mosquitoes were exposed to DDT or deltamethrin across the diel cycle. We report the occurrence of temporal changes in GST activity in samples extracted from the body and head with a single peak at late-night to dawn, but no rhythms were detected in oxidase or esterase activity. The Pimperena strain was found to be resistant to insecticidal challenge, and subsequent genomic analysis revealed the presence of the resistance-conferring kdr mutation. We observed diel rhythmicity in key insecticide detoxification genes in the Mali-NIH strain, with peak phases as previously reported in the Pimperena strain. The insecticide sensitive Mali-NIH strain mosquitoes exhibited a diel rhythm in survivorship to DDT exposure and a bimodal variation to deltamethrin challenge. Our results demonstrate rhythms in detoxification and pesticide susceptibility in An. gambiae mosquitoes; this knowledge could be incorporated into mosquito control and experimental design strategies, and contributes to our basic understanding of mosquito biology. PMID- 24631682 TI - Cell-based therapies for Huntington's disease. AB - Cell-based therapies are a viable option for the long-term treatment of Huntington's disease (HD), which is characterized by progressive neurodegeneration predominately in the striatum and cortex. Current research focuses on genetic suppression of the mutant huntingtin (mHTT) gene and cell replacement therapy of the lost cells in HD. As we discuss here, the recent development of induced pluripotent stem (iPS) cells technology demonstrated the potential of cell-based therapy in rodent models. It was shown that iPSCs were capable of differentiating into lost neurons in HD and stem cell grafts can improve motor deficiency in HD rodent models. Altogether, these findings have shown great promise for developing the foundation of the cell-based therapy. PMID- 24631685 TI - Revising angiotensinogen from phylogenetic and genetic variants perspectives. AB - Angiotensinogen (AGT) belongs to the serpin superfamily. It acts as the unique substrate of all angiotensin peptides, which generates a spectrum of angiotensin peptides in the renin-angiotensin system and regulates hypertension. This serpin belongs to the multiple member group V2 of the intron encoded vertebrate serpin classification. Despite huge advancements in the understanding of angiotensinogen based on biochemical properties and its roles in the RAS, phylogenetic history of AGT remains forgotten. To date, there is no comprehensive study illustrating the phylogenetic history of AGT. Herein, we investigated phylogenetic traits of AGT gene across vertebrates. Gene structures of AGT gene from selected ray-finned fishes varied in exon I and II with insertions of two novel introns in the core domain for ray-finned fishes at the position 77c and 233c. We that found AGT loci is conserved from lampreys to human and estimated to be older than 500 MY. By comparing AGT protein in 57 vertebrate genomes, we illustrated that the reactive center loop (RCL) of AGT protein became from inhibitory (in lampreys, GTEAKAETVVGIMPI?SMPPT) to non-inhibitory (in human, EREPTESTQQLNKPE?VLEVT) during period of 500 MY. We identified 690 AGT variants by analysis of 1092 human genomes with top three variation classes belongs to SNPs (89.7%), somatic SNVs (5.2%) and deletion (2.9%). There are 32 key residues out of 121 missense variants, which are deleterious for AGT protein, computed by combination of SIFT and PolyPhen V2 methods. These results may have clinical implications for understanding hypertension. PMID- 24631686 TI - Long non-coding RNA Loc554202 regulates proliferation and migration in breast cancer cells. AB - Data derived from massive cloning and traditional sequencing methods have revealed that long non-coding RNAs (lncRNA) play important roles in the development and progression of cancer. Although many studies suggest that the lncRNAs have different cellular functions, many of them are not yet to be identified and characterized for the mechanism of their functions. To address this question, we assay the expression level of lncRNAs-Loc554202 in breast cancer tissues and find that Loc554202 is significantly increased compared with normal control, and associated with advanced pathologic stage and tumor size. Moreover, knockdown of Loc554202 decreased breast cancer cell proliferation, induced apoptosis and inhibits migration/invasion in vitro and impeded tumorigenesis in vivo. These data suggest an important role of Loc554202 in breast tumorigenesis. PMID- 24631687 TI - OCILRP2 signaling synergizes with LPS to induce the maturation and differentiation of murine dendritic cells. AB - Osteoclast Inhibitory Lectin-related Protein 2 (OCILRP2) is a typical type II transmembrane protein and belongs to C-type lectin-related protein family. It is preferentially expressed in dendritic cells (DC), B lymphocytes, and activated T lymphocytes. Upon binding to its ligand, OCILRP2 can promote CD28-mediated co stimulation and enhance T cell activation. However, the role of OCILRP2 in DC development and activation is unclear. In this report, we present evidence that recombinant protein OCILRP2-Fc inhibits the generation and LPS-induced maturation of murine bone marrow-derived dendritic cells (BMDCs) by downregulating the expression of CD11c, MHC-II, and co-stimulators CD80 and CD86. OCILRP2-Fc also reduces the capacity of BMDCs to take up antigens, activates T cells, and secret inflammatory cytokines such as IL-6, IL-12, and TNF-alpha. Additionally, we show that OCILRP2-Fc may cause the aforementioned effects through inhibiting NF-kappaB activation. Therefore, OCILRP2 is a new regulator of DC maturation and differentiation following TLR4 activation. PMID- 24631688 TI - Hepatitis C virus represses E-cadherin expression via DNA methylation to induce epithelial to mesenchymal transition in human hepatocytes. AB - Hepatitis C virus (HCV) core protein is known to induce promoter hypermethylation of tumor suppressor genes including E-cadherin to repress their expression when overexpressed in human hepatocytes; however, its actual role during HCV infection is still unknown. Here, we report that infection with HCV derived from pJFH-1 replicon system that mimics natural infection elevates protein levels of DNA methyltransferase 1 and 3b to enhance DNMT activity in human hepatocytes. As a consequence, HCV induced promoter hypermethylation of E-cadherin, resulting in repression of its expression. In addition down-regulation of E-cadherin by HCV led to epithelial-mesenchymal transition that is known to be a critical event during the late stage of tumorigenesis. PMID- 24631689 TI - The relationships of phytosterols and oxyphytosterols in plasma and aortic valve cusps in patients with severe aortic stenosis. AB - Phytosterols such as campesterol and sitosterol are susceptible to oxidation by reactive oxygen species. We hypothesize that the plant sterols (PS) campesterol and sitosterol and their 7-oxygenated metabolites (POPs) correlate within and between human plasma and aortic valve cusps tissues. Plasma and tissue concentrations of PS and POPs were analyzed by gas chromatography-mass spectrometry-selected ion monitoring. Prior to analysis valve cusps tissue was mechanically separated from the calcified parts. PS and POP levels per dry cusps tissue weight were significantly higher compared with the concentrations in the calcified part. Against our hypothesis we found that despite the fact that there is a high correlation between plant sterols in and between plasma and valves cusps tissue, as well as a high correlation between plant sterols and oxyphytosterols and oxyphytosterols themselves within the valve cusps tissue, there was hardly any correlation in the amount of oxyphytosterols in plasma and between plasma and valves. Because plasma samples are easily accessible for large scale population based studies, we have to understand in more detail what the analysis of POPs implies in terms of CVD risk for the future. PMID- 24631690 TI - High-resolution crystal structure of HA33 of botulinum neurotoxin type B progenitor toxin complex. AB - Botulinum neurotoxins (BoNTs) are produced as progenitor toxin complexes (PTCs) by Clostridium botulinum. The PTCs are composed of BoNT and non-toxic neurotoxin associated proteins (NAPs), which serve to protect and deliver BoNT through the gastrointestinal tract in food borne botulism. HA33 is a key NAP component that specifically recognizes host carbohydrates and helps enrich PTC on the intestinal lumen preceding its transport across the epithelial barriers. Here, we report the crystal structure of HA33 of type B PTC (HA33/B) in complex with lactose at 1.46A resolution. The structural comparisons among HA33 of serotypes A-D reveal two different HA33-glycan interaction modes. The glycan-binding pockets on HA33/A and B are more suitable to recognize galactose-containing glycans in comparison to the equivalent sites on HA33/C and D. On the contrary, HA33/C and D could potentially recognize Neu5Ac as an independent receptor, whereas HA33/A and B do not. These findings indicate that the different oral toxicity and host susceptibility observed among different BoNT serotypes could be partly determined by the serotype-specific interaction between HA33 and host carbohydrate receptors. Furthermore, we have identified a key structural water molecule that mediates the HA33/B-lactose interactions. It provides the structural basis for development of new receptor-mimicking compounds, which have enhanced binding affinity with HA33 through their water-displacing moiety. PMID- 24631691 TI - The effect of gender on eye colour variation in European populations and an evaluation of the IrisPlex prediction model. AB - In two recent studies of Spanish individuals, gender was suggested as a factor that contributes to human eye colour variation. However, gender did not improve the predictive accuracy on blue, intermediate and brown eye colours when gender was included in the IrisPlex model. In this study, we investigate the role of gender as a factor that contributes to eye colour variation and suggest that the gender effect on eye colour is population specific. A total of 230 Italian individuals were typed for the six IrisPlex SNPs (rs12913832, rs1800407, rs12896399, rs1393350, rs16891982 and rs12203592). A quantitative eye colour score (Pixel Index of the Eye: PIE-score) was calculated based on digital eye images using the custom made DIAT software. The results were compared with those of Danish and Swedish population samples. As expected, we found HERC2 rs12913832 as the main predictor of human eye colour independently of ancestry. Furthermore, we found gender to be significantly associated with quantitative eye colour measurements in the Italian population sample. We found that the association was statistically significant only among Italian individuals typed as heterozygote GA for HERC2 rs12913832. Interestingly, we did not observe the same association in the Danish and Swedish population. This indicated that the gender effect on eye colour is population specific. We estimated the effect of gender on quantitative eye colour in the Italian population sample to be 4.9%. Among gender and the IrisPlex SNPs, gender ranked as the second most important predictor of human eye colour variation in Italians after HERC2 rs12913832. We, furthermore, tested the five lower ranked IrisPlex predictors, and evaluated all possible 3(6) (729) genotype combinations of the IrisPlex assay and their corresponding predictive values using the IrisPlex prediction model [4]. The results suggested that maximum three (rs12913832, rs1800407, rs16891982) of the six IrisPlex SNPs are useful in practical forensic genetic casework. PMID- 24631692 TI - Mitochondrial DNA sequence heteroplasmy levels in domestic dog hair. AB - To assess the level of mtDNA sequence heteroplasmy in dog hair, we sequenced a 612 base pair fragment of the hypervariable region 1 (HVI) in 576 hairs from six dogs representing a range of age, sex, breed, and hair color. Blood and buccal samples were collected from each dog for reference. Three instances of sequence heteroplasmy were observed at nucleotide positions 15627 (G/A), 15628 (T/C) and 15639 (G/A) in two hairs from different dogs. An HVI sequence heteroplasmy frequency of 0.0034 was obtained. The Probability of Identity (PI) value, or probability that two random, unrelated dog hairs share an HVI sequence, and the Power of Discrimination (PD), or probability that two random unrelated dog hairs have different HVI sequences, were determined from the 88 HVI haplotypes represented in the Veterinary Genetics Laboratory database (n=1006) and found to be 0.086 and 0.914, respectively. PMID- 24631693 TI - Building a forensic ancestry panel from the ground up: The EUROFORGEN Global AIM SNP set. AB - Emerging next-generation sequencing technologies will enable DNA analyses to add pigmentation predictive and ancestry informative (AIM) SNPs to the range of markers detectable from a single PCR test. This prompted us to re-appraise current forensic and genomics AIM-SNPs and from the best sets, to identify the most divergent markers for a five population group differentiation of Africans, Europeans, East Asians, Native Americans and Oceanians by using our own online genome variation browsers. We prioritized careful balancing of population differentiation across the five group comparisons in order to minimize bias when estimating co-ancestry proportions in individuals with admixed ancestries. The differentiation of European from Middle East or South Asian ancestries was not chosen as a characteristic in order to concentrate on introducing Oceanian differentiation for the first time in a forensic AIM set. We describe a complete set of 128 AIM-SNPs that have near identical population-specific divergence across five continentally defined population groups. The full set can be systematically reduced in size, while preserving the most informative markers and the balance of population-specific divergence in at least four groups. We describe subsets of 88, 55, 28, 20 and 12 AIMs, enabling both new and existing SNP genotyping technologies to exploit the best markers identified for forensic ancestry analysis. PMID- 24631694 TI - Developmental validation of a forensic rapid DNA-STR kit: Expressmarker 16. AB - DNA-STR analysis is widely used in the forensic science field and has important requirements on the analysis time to obtain faster inspections. The developed forensic STR kit, referred to as Expressmarker 16 (EX16), could shorten the amplification time to a minimum of 35min. It enables 16 STR loci to be co detected, including 13 CODIS loci, D2S1338, D6S1043 and Amelogenin loci. The kit is validated by a series of tests formed by DNA mixtures, stutter ratios, optimized PCR protocols based on annealing temperature research, species specificities, inhibitors, sensitivity, and parallel tests according to FBI QAS (2009/2011) (QAS, 2009; SWGDAM, 2010). The results demonstrated that EX16 was a useful tool for rapid criminal investigation. PMID- 24631695 TI - Developmental validation of mitochondrial DNA genotyping assays for adept matrilineal inference of biogeographic ancestry at a continental level. AB - Mitochondrial DNA (mtDNA) can be used for matrilineal biogeographic ancestry prediction and can thus provide investigative leads towards identifying unknown suspects, when conventional autosomal short tandem repeat (STR) profiling fails to provide a match. Recently, six multiplex genotyping assays targeting 62 ancestry-informative mitochondrial single nucleotide polymorphisms (mt-SNPs) were developed. This hierarchical system of assays allows detection of the major haplogroups present in Africa, America, Western Eurasia, Eastern Eurasia, Australia and Oceania, thus revealing the broad geographic region of matrilineal origin of a DNA donor. Here, we provide a forensic developmental validation study of five multiplex assays targeting all the 62 ancestry-informative mt-SNPs following the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines. We demonstrate that the assays are highly sensitive; being able to produce full profiles at input DNA amounts of as little as 1pg. The assays were shown to be highly robust and efficient in providing information from degraded samples and from simulated casework samples of different substrates such as blood, semen, hair, saliva and trace DNA samples. Reproducible results were successfully achieved from concordance testing across three independent laboratories depicting the ease and reliability of these assays. Overall, our results demonstrate the suitability of these five mt-SNP assays for application to forensic casework and other purposes aiming to establish an individual's matrilineal genetic ancestry. With this validated tool, it is now possible to determine the matrilineal biogeographic origin of unknown individuals on the level of continental resolution from forensic DNA samples to provide investigative leads in criminal and missing person cases where autosomal STR profiling is uninformative. PMID- 24631696 TI - Twins with hereditary sensory and autonomic neuropathy type IV with preserved periodontal sensation. AB - Turkish twin brothers affected with hereditary sensory and autonomic neuropathy type IV (HSAN IV) are reported. Their clinical findings were generally typical for HSAN IV. Interestingly they both had preserved periodontal sensation. Mutation analysis of the NTRK1 gene showed a homozygous c.2001C>T substitution in exon 15 in both twins. This base substitution is predicted to change a polar, positively charged amino acid arginine to the highly active amino acid cystein at position 654 (p.Arg654Cys). The parents were heterozygous for the mutation. This mutation has been reported previously in one Japanese and one Arab patients. The preserved periodontal sensation has not previously been reported in patients affected with HSAN IV. This preserved sensation in our patients might have been through Ruffini endings, the periodontal mechanoreceptors which have been reported to be present in TrkA knockout mice. Here we report the first twins affected with HSAN IV and the observation that periodontal sensation is not affected by mutation in NTRK1. PMID- 24631697 TI - A maternal de novo non-reciprocal translocation results in a 6q13-q16 deletion in one offspring and a 6q13-q16 duplication in another. AB - Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions. PMID- 24631698 TI - Is there a link between ovarian cancer and tooth agenesis? AB - An epidemiologic study from the year 2008 found a highly significant increase of congenital tooth agenesis in women with ovarian cancer suggesting that a common genetic etiology may predispose women to both conditions. The finding was reminiscent of a previously described family harboring an AXIN2 mutation which could be shown to segregate with both the tooth agenesis and the predisposition to colon cancer transmitted in this family. Since tooth agenesis as a marker for susceptibility to ovarian cancer would be of great relevance to both oncologists and women with inborn missing teeth, the relationship between the two disorders requires a thorough assessment. We examined DNA samples from the ovarian cancer patients who participated in the original study, to look for a possible genetic connection between their ovarian malignancies and tooth agenesis. MSX1, PAX9, AXIN2, EDA, WNT10A, BARX and BRCA1 genes were selected for sequence analysis as they may cause tooth agenesis, are expressed in the female reproductive system, and/or are involved in tumorigenesis in general or specifically in the ovary. Our study revealed evidence that one half of the dually affected patients had an independent causation of the two conditions, thus reducing the previously estimated ovarian cancer risk for women with congenital tooth agenesis quite significantly. PMID- 24631699 TI - The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer. AB - OBJECTIVE: We aimed to estimate the incidence rate of endometrial cancer (EC) and to evaluate the results of EC-surveillance in hereditary nonpolyposis colorectal cancer (HNPCC) families. METHODS: All at-risk women recommended for EC surveillance by the HNPCC-register-2959 women (19,334women years)-were included. Data on EC-surveillance were available for 871 women (6894women years), who had performed 1945 surveillance visits. The average surveillance period was 7.9 (range 0.1-21.7) years and 46% of the women had had less than 3years between their visits. RESULTS: During 19,334women years, 60 women with gynecological malignancies or premalignancies were diagnosed. Thirty-nine women had EC. Of these, 31 were from families with identified MMR gene mutations with the median age at diagnosis of 54 (39-83) years (Incidence Rate, IR=0.63 per 100women years) and four women from each Amsterdam (AMS)-positive and AMS-like families (median age 64 (55-73) years, IR=0.06 and 0.05 per 100women years, respectively, p<.0001). Among the 871 surveilled women, 13 EC were found: 7/13 cases were diagnosed by surveillance examination-two as prevalent cancers, diagnosed at the first visit-and 6/13 based on symptoms. In addition, five complex atypical hyperplasias and four ovarian cancers (OCs) were diagnosed. All these women were MMR mutation carriers. CONCLUSION: Based on 19,334women years of EC-surveillance, our analysis provides a thorough estimation of the EC risk in women with an MMR mutation, or suspected of having Lynch syndrome. We conclude that EC surveillance should only be targeted at MMR-mutation carriers. PMID- 24631700 TI - Identification of patients with persistent trophoblastic disease after complete hydatidiform mole by using a normal 24-hour urine hCG regression curve. AB - OBJECTIVE: The aim of this study was to establish a reference 24-hour urine human chorionic gonadotropin (hCG) regression curve in patients with complete hydatidiform mole (CHM) as diagnostic tool in the prediction of persistent trophoblastic disease (PTD). METHODS: From 2004 to 2011, 312 cases suitable for this study were registered at the Hydatidiform Mole Registry of the Royal Women's Hospital Melbourne, Australia. hCG levels of 61 patients diagnosed as having PTD according to FIGO 2000 criteria were compared with the 95th-percentile (p95) of the normal regression curve derived from hCG levels of 251 cases of uneventful CHM. RESULTS: In the test group of 61 patients PTD was diagnosed by FIGO 2000 criteria after a mean (+/-SD, min.-max.) of 7.6 (+/-3.4, 3.0-16.7) weeks after evacuation of the mole while in the same group hCG values for the first time exceeded the upper limit of the 95th percentile significantly earlier after 4.5 (+/-1.9, 2.0-9.9) weeks (P<0.001). However, hCG levels of 14% of the cases of uneventful CHM at least once exceeded the upper limit of p95, showing that one single value above p95 is not accurate enough for the diagnosis of PTD. CONCLUSIONS: The normal 24-hour urine hCG regression curve may be used as a tool in the follow-up of an individual case of CHM after evacuation. At least one hCG level exceeding the upper limit of p95 within 11weeks after evacuation could be added to the current FIGO criteria, in order to diagnose PTD early, but the lack of it may also prevent unnecessary treatment. PMID- 24631701 TI - Population-based biomarker screening and the development of severe preeclampsia in California. AB - OBJECTIVE: The purpose of this study was to examine the relationship between second-trimester maternal serum biomarkers and the development of early- and late onset severe preeclampsia in euploid pregnancies. STUDY DESIGN: Included were 136,139 pregnancies that obtained second-trimester prenatal screening through the California Prenatal Screening Program with live births in 2006-2008. We identified severe preeclampsia diagnoses from hospital discharge records. We used log binomial regression to examine the association between abnormal second trimester maternal serum biomarkers and the development of severe preeclampsia. RESULTS: Approximately 0.9% of all women (n = 1208) in our sample experienced severe preeclampsia; 329 women at <34 weeks' gestation and 879 women >=34 weeks' gestation. High levels of alpha fetoprotein (AFP), human chorionic gonadotropin, inhibin (multiple of the median, >=95th percentile), and low unconjugated estriol (multiple of the median, <=5th percentile), were associated with severe preeclampsia (relative risk, 2.5-11.7). Biomarkers were more predictive of early onset severe preeclampsia (relative risk, 3.8-11.7). One in 9.5 pregnancies with combined high AFP, inhibin, and low unconjugated estriol levels experienced severe early-onset preeclampsia compared with 1 in 680.5 pregnancies without any abnormal biomarkers. CONCLUSION: The risk of the development of severe preeclampsia increases for women with high second-trimester AFP, human chorionic gonadotropin, inhibin, and/or low unconjugated estriol; this is especially true for early-onset severe preeclampsia. When abnormal biomarkers co-occur, risk dramatically increases. Although the screening value of second-trimester biomarkers is low, abnormal biomarkers, especially when occurring in combination, appear to indicate placental dysfunction that is associated with the development of severe preeclampsia. PMID- 24631703 TI - Prevalence of illicit drug use in pregnant women in a Wisconsin private practice setting. AB - OBJECTIVE: We sought to measure the prevalence of illicit drug use in our obstetric population, to identify the drugs being used, and to determine whether a modified version of the 4Ps Plus screening tool could serve as an initial screen. STUDY DESIGN: In this prospective study, urine samples of 200 unselected patients presenting for initiation of prenatal care in a Wisconsin private practice were analyzed for evidence of the use of illicit drugs. RESULTS: Of 200 patients, 26 (13%) had evidence of drugs of abuse in their urine samples. Marijuana (7%) and opioids (6.5%) were the most commonly identified drugs. Adding 5 questions about drug or alcohol use to the obstetric intake questionnaire proved sensitive in identifying patients with high risks of having a positive drug screen. CONCLUSION: The rate of drug use in our low-risk population was higher than expected and may reflect increasing rates of drug use across the United States. Enhanced screening should be performed to identify patients using illicit drugs in pregnancy to improve their care. Medical centers and communities may benefit from periodic testing of their community prevalence rates to aid in appropriate care planning. PMID- 24631702 TI - Maternal obesity and high-fat diet program offspring metabolic syndrome. AB - OBJECTIVE: We determined the potential programming effects of maternal obesity and high-fat (HF) diet during pregnancy and/or lactation on offspring metabolic syndrome. STUDY DESIGN: A rat model of maternal obesity was created using an HF diet prior to and throughout pregnancy and lactation. At birth, pups were cross fostered, thereby generating 4 paradigms of maternal diets during pregnancy/lactation: (1) control (Con) diet during pregnancy and lactation (Con/Con), (2) HF during pregnancy and lactation (HF/HF), (3) HF during pregnancy alone (HF/Con), and (4) HF during lactation alone (Con/HF). RESULTS: Maternal phenotype during pregnancy and the end of lactation evidenced markedly elevated body fat and plasma corticosterone levels in HF dams. In the offspring, the maternal HF diet during pregnancy alone programmed increased offspring adiposity, although with normal body weight, whereas the maternal HF diet during lactation increased both body weight and adiposity. Metabolic disturbances, particularly that of hyperglycemia, were apparent in all groups exposed to the maternal HF diet (during pregnancy and/or lactation), although differences were apparent in the manifestation of insulin resistant vs insulin-deficient phenotypes. Elevated systolic blood pressure was manifest in all groups, implying that exposure to an obese/HF environment is disadvantageous for offspring health, regardless of pregnancy or lactation periods. Nonetheless, the underlying mechanism may differ because offspring that experienced in utero HF exposure had increased corticosterone levels. CONCLUSION: Maternal obesity/HF diet has a marked impact on offspring body composition and the risk of metabolic syndrome was dependent on the period of exposure during pregnancy and/or lactation. PMID- 24631704 TI - Septate uterus: benign right and malignant left. PMID- 24631705 TI - Maternal mortality in the United States: predictability and the impact of protocols on fatal postcesarean pulmonary embolism and hypertension-related intracranial hemorrhage. AB - OBJECTIVE: The purpose of this study was to examine the efficacy of specific protocols that have been developed in response to a previous analysis of maternal deaths in a large hospital system. We also analyzed the theoretic impact of an ideal system of maternal triage and transport on maternal deaths and the relative performance of cause of death determination from chart review compared with a review of discharge coding data. STUDY DESIGN: We conducted a retrospective evaluation of maternal deaths from 2007-2012 after the introduction of disease specific protocols that were based on 2000-2006 data. RESULTS: Our maternal mortality rate was 6.4 of 100,000 births in just >1.2 million deliveries. A policy of universal use of pneumatic compression devices for all women who underwent cesarean delivery resulted in a decrease in postoperative pulmonary embolism deaths from 7 of 458,097 cesarean births to 1 of 465,880 births (P = .038). A policy that involved automatic and rapid antihypertensive therapy for defined blood pressure thresholds eliminated deaths from in-hospital intracranial hemorrhage and reduced overall deaths from preeclampsia from 15-3 (P = .02.) From 1-3 deaths were related causally to cesarean delivery. Only 7% of deaths were potentially preventable with an ideal system of admission triage and transport. Cause of death analysis with the use of discharge coding data was correct in 52% of cases. CONCLUSION: Disease-specific protocols are beneficial in the reduction of maternal death because of hypertensive disease and postoperative pulmonary embolism. From 2-6 women die annually in the United States because of cesarean delivery itself. A reduction in deaths from postpartum hemorrhage should be the priority for maternal death prevention efforts in coming years in the United States. PMID- 24631706 TI - Effect of physical activity during pregnancy on mode of delivery. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of structured physical exercise programs during pregnancy on the course of labor and delivery. STUDY DESIGN: We conducted a systematic review and metaanalysis using the following data sources: Medline and The Cochrane Library. In our study, we used randomized controlled trials (RCT) that evaluated the effects of exercise programs during pregnancy on labor and delivery. The results are summarized as relative risks. RESULTS: In the 16 RCTs that were included there were 3359 women. Women in exercise groups had a significantly lower risk of cesarean delivery (relative risk, 0.85; 95% confidence interval [CI], 0.73-0.99). Birthweight was not significantly reduced in exercise groups. The risk of instrumental delivery was similar among groups (relative risk, 1.00; 95% CI, 0.82-1.22). Data on Apgar score, episiotomy, epidural anesthesia, perineal tear, length of labor, and induction of labor were insufficient to draw conclusions. With the use of data from 11 studies (1668 women), our analysis showed that women in the exercise groups gained significantly less weight than women in control groups (mean difference, -1.13 kg; 95% CI, -1.49 to -0.78). CONCLUSION: Structured physical exercise during pregnancy reduces the risk of cesarean delivery. This is an important finding to convince women to be active during their pregnancy and should lead the physician to recommend physical exercise to pregnant women, when this is not contraindicated. PMID- 24631707 TI - Association between maternal characteristics, abnormal serum aneuploidy analytes, and placental abruption. AB - OBJECTIVE: The objective of the study was to examine the association between placental abruption, maternal characteristics, and routine first- and second trimester aneuploidy screening analytes. STUDY DESIGN: The study consisted of an analysis of 1017 women with and 136,898 women without placental abruption who had first- and second-trimester prenatal screening results, linked birth certificate, and hospital discharge records for a live-born singleton. Maternal characteristics and first- and second-trimester aneuploidy screening analytes were analyzed using logistic binomial regression. RESULTS: Placental abruption was more frequent among women of Asian race, age older than 34 years, women with chronic and pregnancy-associated hypertension, preeclampsia, preexisting diabetes, previous preterm birth, and interpregnancy interval less than 6 months. First-trimester pregnancy-associated plasma protein-A of the fifth percentile or less, second-trimester alpha fetoprotein of the 95th percentile or greater, unconjugated estriol of the fifth percentile or less, and dimeric inhibin-A of the 95th percentile or greater were associated with placental abruption as well. When logistic models were stratified by the presence or absence of hypertensive disease, only maternal age older than 34 years (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0-2.0), pregnancy-associated plasma protein-A of the 95th percentile or less (OR, 1.9; 95% CI, 1.2-3.1), and alpha fetoprotein of the 95th percentile or greater (OR, 2.3; 95% CI, 1.4-3.8) remained statistically significantly associated for abruption. CONCLUSION: In this large, population based cohort study, abnormal maternal aneuploidy serum analyte levels were associated with placental abruption, regardless of the presence of hypertensive disease. PMID- 24631708 TI - Association between maternal body mass index and congenital heart defects in offspring: a systematic review. AB - The aim of this study was to investigate the relationship between maternal body mass index and all congenital heart defects (CHDs) combined and 11 individual defects. PubMed, ELSEVIER ScienceDirect, and Springer Link (up to February 2013) were searched, and the reference list of retrieved articles was reviewed. Three authors independently extracted the data. The systematic review included 24 studies, 14 of which were included in a metaanalysis. Statistical software was used to perform all statistical analyses. Fixed-effects or random-effects model was used to pool the results of individual study (expressed as odds ratios [ORs] with 95% confidence intervals [CIs]). A dose-response effect was observed between overweight, moderate obesity, and severe obesity and a pregnancy with any CHD (the pooled ORs: OR, 1.08 [95% CI, 1.02-1.15]; OR, 1.15 [95% CI, 1.11-1.20]; and OR, 1.39 [95% CI, 1.31-1.47], respectively) as well as some individual defects such as hypoplastic left heart syndrome, pulmonary valve stenosis, and outflow tract defects. When we excluded mothers with diabetes mellitus, the pooled ORs for all CHDs combined were 1.12 (95% CI, 1.04-1.20) and 1.38 (95% CI, 1.20-1.59) for moderately obese and severely obese, respectively. The highest increased risk was severely obese mothers for tetralogy of Fallot (OR, 1.94; 95% CI, 1.49-2.51). Being underweight did not increase the risk of any of the aforementioned CHDs but did increase the risk of aortic valve stenosis (OR, 1.47; 95% CI, 1.01-2.15]). The results of our study showed that increasing maternal body mass index was associated with an increasing risk of CHDs; severe obesity was an even greater risk factor for the development of CHDs. PMID- 24631709 TI - Accuracy of ultrasound for the prediction of placenta accreta. AB - OBJECTIVE: Ultrasound has been reported to be greater than 90% sensitive for the diagnosis of accreta. Prior studies may be subject to bias because of single expert observers, suspicion for accreta, and knowledge of risk factors. We aimed to assess the accuracy of ultrasound for the prediction of accreta. STUDY DESIGN: Patients with accreta at a single academic center were matched to patients with placenta previa, but no accreta, by year of delivery. Ultrasound studies with views of the placenta were collected, deidentified, blinded to clinical history, and placed in random sequence. Six investigators prospectively interpreted each study for the presence of accreta and findings reported to be associated with its diagnosis. Sensitivity, specificity, positive predictive, negative predictive value, and accuracy were calculated. Characteristics of accurate findings were compared using univariate and multivariate analyses. RESULTS: Six investigators examined 229 ultrasound studies from 55 patients with accreta and 56 controls for 1374 independent observations. 1205/1374 (87.7% overall, 90% controls, 84.9% cases) studies were given a diagnosis. There were 371 (27.0%) true positives; 81 (5.9%) false positives; 533 (38.8%) true negatives, 220 (16.0%) false negatives, and 169 (12.3%) with uncertain diagnosis. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 53.5%, 88.0%, 82.1%, 64.8%, and 64.8%, respectively. In multivariate analysis, true positives were more likely to have placental lacunae (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.4-1.6), loss of retroplacental clear space (OR, 2.4; 95% CI, 1.1 4.9), or abnormalities on color Doppler (OR, 2.1; 95% CI, 1.8-2.4). CONCLUSION: Ultrasound for the prediction of placenta accreta may not be as sensitive as previously described. PMID- 24631710 TI - A rapid and sensitive UHPLC-MS/MS method for quantification of 2-(2 hydroxypropanamido) benzoic acid in rat plasma: application to a pharmacokinetic study. AB - A rapid, sensitive and high throughput UHPLC-MS/MS method was established and validated to assay the concentration of 2-(2-hydroxypropanamido) benzoic acid (HPABA), a promising anti-inflammatory drug, in rat plasma. Plasma samples were processed by liquid-liquid extraction with ethyl acetate and separated on a Shim pack XR-ODS C18 column (75 mm*3.0 mm, 2.2 MUm) at an isocratic flow rate of 0.4 mL/min using acetonitrile-0.1% formic acid in water (50:50, v/v) as mobile phase, and total run time was 2 min. MS/MS detection was accomplished in multiple reaction monitoring (MRM) mode with positive electrospray ionization. The calibration curve was linear over the concentration range of 0.01-50 MUg/mL with lower limit of quantification of 0.01 MUg/mL. The intra- and inter-day precisions were below 8.5% in terms of relative standard deviation (RSD), and the accuracy was within +/-4.0% in terms of relative error (RE). Extraction recovery, matrix effect and stability were satisfactory in rat plasma. The developed method was successfully applied to a pharmacokinetic study of HPABA following intragastric administration of 25, 50, 100mg/kg and an intravenous injection at a dose of 12.5 mg/kg to Sprague-Dawley rats. Results indicated that HPABA had linear pharmacokinetic properties within the tested intragastric dosage range and the absolute bioavailability was above 59.1%. PMID- 24631711 TI - Binding mode and thermodynamic studies on the interaction of the anticancer drug dacarbazine and dacarbazine-Cu(II) complex with single and double stranded DNA. AB - The binding mode and thermodynamic characteristics of the anticancer drug dacarbazine (Dac) with double and single stranded DNA were investigated in the absence and presence of Cu(II) using cyclic voltammetry, square wave voltammetry and fluorescence spectroscopy. The interaction of Dac and Dac-Cu(II) complex with dsDNA indicated their intercalation into the base stacking domain of dsDNA double helix and the strength of interaction is independent on the ionic strength. The interaction of Dac with dsDNA in the presence of Cu(II) leads to a much stronger intercalation. The interaction mode of Dac molecules with ssDNA is electrostatic attraction via negative phosphate on the exterior of the ssDNA with Dac. The binding constants, stoichiometric coefficients and thermodynamic parameters of Dac and Dac-Cu(II) complex with dsDNA and ssDNA were evaluated. Comparison of the mode interaction of Dac with dsDNA and ssDNA was discussed. The decrease of peak current of Dac was proportional to DNA concentration, which was applied for determination of dsDNA and ssDNA concentration. PMID- 24631712 TI - Characterization of rational biomarkers accompanying fever in yeast-induced pyrexia rats using urine metabolic footprint analysis. AB - Fever is a prominent feature of diseases and is an ongoing process that is always accompanied by metabolic changes in the body system. Despite the success of temperature regulation theory, the underlying biological process remains unclear. To truly understand the nature of the febrile response, it is crucial to confirm the biomarkers during the entire biological process. In the current study, a 73-h metabolic footprint analysis of the urine from yeast-induced pyrexia rats was performed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Potential biomarkers were selected using orthogonal partial least squares-discriminate analysis (OPLS-DA), the rational biomarkers were verified by Pearson correlation analysis, and the predictive power was evaluated using receiver operator characteristic (ROC) curves. A metabolic network constructed using traditional Chinese medicine (TCM) grammar systems was used to validate the rationality of the verified biomarkers. Finally, five biomarkers, including indoleacrylic acid, 3-methyluridine, tryptophan, nicotinuric acid and PI (37:3), were confirmed as rational biomarkers because their correlation coefficients were all greater than 0.87 and because all of the correlation coefficients between any pair of these biomarkers were higher than 0.75. The areas under the ROC curves were all greater than 0.84, and their combined predictive power was considered reliable because the greatest area under the ROC curve was 0.968. A metabolic network also demonstrated the rationality of these five biomarkers. Therefore, these five metabolites can be adopted as rational biomarkers to reflect the process of the febrile response in inflammation-induced pyrexia. PMID- 24631713 TI - Potassium channels in the central nervous system of the snail, Helix pomatia: localization and functional characterization. AB - The distribution and functional presence of three voltage-dependent potassium channels, Kv2.1, Kv3.4, Kv4.3, respectively, were studied in the central nervous system of the snail Helix pomatia by immunohistochemical and electrophysiological methods. Cell clusters displaying immunoreactivity for the different channels were observed in all parts of the CNS, although their localization and number partly varied. Differences were also found in their intracellular, perikaryonal and axonal localization, as well as in their presence in non-neuronal tissues nearby the CNS, such as the perineurium and the aorta wall. At ultrastructural level Kv4.3 channel immunolabeling was observed in axon profiles containing large 80-100nm granular vesicles. Blotting analyses revealed specific signals for the Kv2.1, Kv3.4 and Kv4.3 channels, confirming the presence of the channels in the Helix CNS. Voltage-clamp recordings proved that outward currents obtained from neurons displaying Kv3.4 or Kv4.3 immunoreactivity contained transient components while Kv2.1 immunoreactive cells were characterized by delayed currents. The distribution of the K(+)-channels containing neurons suggests specific roles in intercellular signaling processes in the Helix CNS, most probably related to well defined, partly local events. The cellular localization of the K(+)-channels studied supports their involvement in both pre- and postsynaptic events at perikaryonal and axonal levels. PMID- 24631714 TI - Renal perfusion in acute kidney injury with DCE-MRI: deconvolution analysis versus two-compartment filtration model. AB - PURPOSE: To investigate the results of different pharmacokinetic models of a quantitative analysis of renal blood flow (RBF) in acute kidney injury using deconvolution analysis and a two-compartment renal filtration model. MATERIALS AND METHODS: MRI data of ten male Lewis rats were analyzed retrospectively. Six animals were subjected to unilateral acute kidney injury and underwent perfusion imaging by dynamic contrast-enhanced MRI (DCE-MRI). Renal blood flow was estimated from regions-of-interest depicting the cortex in the DCE-MRI perfusion maps. The perfusion models were compared by a paired t-test and Bland-Altman plots. RESULTS: No significant difference was found between the two compartment model and the deconvolution analysis (P=0.2807). Differences between healthy and diseased kidney in the AKI model were significant for both methods (P<0.05). A Bland-Altman plot showed no systematic errors, and values were equally distributed around the mean difference between the methods lying within the range of 1.96 standard deviations. CONCLUSION: Both quantification strategies could detect the kidneys that were impaired by AKI. When just aiming at RBF as a marker, a deconvolution analysis can provide similar values as the 2CFM. If functional parameters beyond RBF like glomerular filtration rate are needed, the 2CFM should be employed. PMID- 24631716 TI - Robust estimation of the cerebral blood flow in arterial spin labelling. AB - The introduction of arterial spin labelling (ASL) techniques in magnetic resonance imaging (MRI) has made feasible a non-invasive measurement of the cerebral blood flow (CBF). However, to date, the low signal-to-noise ratio of ASL gives us no option but to repeat the acquisition to accumulate enough data in order to get a reliable signal. The perfusion signal is then usually extracted by averaging across the repetitions. But the sample mean is very sensitive to outliers. A single incorrect observation can therefore be the source of strong detrimental effects on the perfusion-weighted image estimated with the sample mean. We propose to estimate robust ASL CBF maps with M-estimators to overcome the deleterious effects of outliers. The behavior of this method is compared to z score thresholding as recommended in Tan et al. (Journal of Magnetic Resonance Imaging 2009;29(5):1134-9.). Validation on simulated and real data is provided. Quantitative validation is undertaken by measuring the correlation with the most widespread technique to measure perfusion with MRI: dynamic susceptibility weighted contrast imaging. PMID- 24631715 TI - XeNA: an automated 'open-source' (129)Xe hyperpolarizer for clinical use. AB - Here we provide a full report on the construction, components, and capabilities of our consortium's "open-source" large-scale (~1L/h) (129)Xe hyperpolarizer for clinical, pre-clinical, and materials NMR/MRI (Nikolaou et al., Proc. Natl. Acad. Sci. USA, 110, 14150 (2013)). The 'hyperpolarizer' is automated and built mostly of off-the-shelf components; moreover, it is designed to be cost-effective and installed in both research laboratories and clinical settings with materials costing less than $125,000. The device runs in the xenon-rich regime (up to 1800Torr Xe in 0.5L) in either stopped-flow or single-batch mode-making cryo collection of the hyperpolarized gas unnecessary for many applications. In-cell (129)Xe nuclear spin polarization values of ~30%-90% have been measured for Xe loadings of ~300-1600Torr. Typical (129)Xe polarization build-up and T1 relaxation time constants were ~8.5min and ~1.9h respectively under our spin exchange optical pumping conditions; such ratios, combined with near-unity Rb electron spin polarizations enabled by the high resonant laser power (up to ~200W), permit such high PXe values to be achieved despite the high in-cell Xe densities. Importantly, most of the polarization is maintained during efficient HP gas transfer to other containers, and ultra-long (129)Xe relaxation times (up to nearly 6h) were observed in Tedlar bags following transport to a clinical 3T scanner for MR spectroscopy and imaging as a prelude to in vivo experiments. The device has received FDA IND approval for a clinical study of chronic obstructive pulmonary disease subjects. The primary focus of this paper is on the technical/engineering development of the polarizer, with the explicit goals of facilitating the adaptation of design features and operative modes into other laboratories, and of spurring the further advancement of HP-gas MR applications in biomedicine. PMID- 24631717 TI - Common consensus LNA probe for quantitative PCR assays in cancer: vehicles for minimal residual disease detection in t(11;14) and t(14;18) positive malignant lymphomas. AB - The use of locked nucleic acid (LNA) probes and primers potentially improves sensitivity and specificity of quantitative PCR (qPCR) assays. One area of application is that of minimal residual cancer where PCR techniques have proved to be highly relevant tools in patient follow-up. We present here sensitive and specific consensus qPCR assays for quantification of the malignant lymphoma translocations, t(11;14) and t(14;18), by taking advantage of the thermodynamic properties of LNA. The assays were applied to genomic DNA from patients diagnosed with mantle cell lymphoma (MCL) and follicular lymphoma (FL), respectively. Two consensus forward primers targeting the BCL1 and BCL2 genes were designed together with a common consensus reverse primer and hydrolysis probe, the latter consisting exclusively of LNA, both targeting the J segments of the immunoglobulin heavy chain (IgH) gene. The quantitative range of both assays was 1*10(0) to 5*10(-5), and the sensitivity was 10(-5), without the need for patient specific primers. Peripheral blood (PB) and bone marrow (BM) samples from 36 patients diagnosed with MCL and nine patients diagnosed with FL were analysed using this novel qPCR approach. The level of minimal residual disease (MRD) using t(11;14) and t(14;18) as genetic targets reflected the clinical status of the patients: low levels of MRD at clinical remission, and increasing levels at disease progression. The present assays could prove as useful tools in lymphoma therapy. PMID- 24631718 TI - IgE to penicillins with different specificities can be identified by a multiepitope macromolecule: Bihaptenic penicillin structures and IgE specificities. AB - Quantitation of specific IgE by immunoassay is a recommended in vitro test for the diagnosis of immediate hypersensitivity reactions to betalactams (BLs), particularly when skin test results are negative. IgE antibodies that recognize the common nuclear structure of all BLs or the specific side chain structure can be mainly distinguished by immunoassays. The aim of this study was to develop an immunoassay system to detect IgE antibodies with different specificities. Cellulose discs conjugated with benzylpenicillin (BP), amoxicillin (AX) or both drugs, with poly-l-lysine (PLL) as carrier molecule, were used as solid phases in the radioallergosorbent test (RAST). Direct and inhibition radioimmunoassay studies were made to verify the structures recognized by serum IgE antibodies from penicillin-allergic patients. Our results indicated that the addition of both haptens did not decrease the capacity to capture IgE when serum specific to either BP or AX was used, at least in terms of sensitivity. In addition, the inclusion of two haptens improved significantly the levels of IgE detection in patients who recognized both BP and AX. Therefore, the use of a solid phase with a carrier molecule conjugated with two determinants (AX and BP) is helpful to recognize IgE antibodies against either of these determinants and is useful for screening sera with different specificities. PMID- 24631719 TI - Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice. AB - OBJECTIVES: Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1(-/-) mouse by combining three therapies that each targets unique aspects of the pathogenic cascade. METHODS: We have treated Npc1(-/-) mice with miglustat that targets sphingolipid synthesis and storage, curcumin that compensates for the lysosomal calcium defect by elevating cytosolic calcium, and the non-steroidal anti-inflammatory drug ibuprofen to reduce central nervous system inflammation. RESULTS/INTERPRETATION: We have found that triple combination therapy has a greater neuroprotective benefit compared with single and dual therapies, increasing the time period that Npc1(-/-) mice maintained body weight and motor function and maximally delaying the onset of Purkinje cell loss. In addition, ibuprofen selectively reduced microglial activation, while curcumin had no anti-inflammatory effects, indicating differential mechanisms of action for these two therapies. When taken together, these results demonstrate that targeting multiple unique steps in the pathogenic cascade maximises the clinical benefit in a mouse model of NPC1 disease. PMID- 24631721 TI - An amino acid depleted cell-free protein synthesis system for the incorporation of non-canonical amino acid analogs into proteins. AB - Residue-specific incorporation of non-canonical amino acids into proteins is usually performed in vivo using amino acid auxotrophic strains and replacing the natural amino acid with an unnatural amino acid analog. Herein, we present an efficient amino acid depleted cell-free protein synthesis system that can be used to study residue-specific replacement of a natural amino acid by an unnatural amino acid analog. This system combines a simple methodology and high protein expression titers with a high-efficiency analog substitution into a target protein. To demonstrate the productivity and efficacy of a cell-free synthesis system for residue-specific incorporation of unnatural amino acids in vitro, we use this system to show that 5-fluorotryptophan and 6-fluorotryptophan substituted streptavidin retain the ability to bind biotin despite protein-wide replacement of a natural amino acid for the amino acid analog. We envisage this amino acid depleted cell-free synthesis system being an economical and convenient format for the high-throughput screening of a myriad of amino acid analogs with a variety of protein targets for the study and functional characterization of proteins substituted with unnatural amino acids when compared to the currently employed in vivo methodologies. PMID- 24631720 TI - TOC1: a valuable tool in assessing disease progression in the rTg4510 mouse model of tauopathy. AB - All tauopathies result in various forms of cognitive decline and neuronal loss. Although in some diseases, tau mutations appear to cause neurodegeneration, the toxic "form" of tau remains elusive. Tau is the major protein found within neurofibrillary tangles (NFTs) and therefore it seemed rational to assume that aggregation of tau monomers into NFTs was causal to the disease process. However, the appearance of oligomers rather than NFTs coincides much better with the voluminous neuronal loss in many of these diseases. In this study, we utilized the bigenic mouse line (rTg4510) which conditionally expresses P301L human tau. A novel tau antibody, termed Tau Oligomer Complex 1 (TOC1) was employed to probe mouse brains and assess disease progression. TOC1 selectively recognizes dimers/oligomers and appears to constitute an early stage marker of tau pathology. Its peak reactivity is coincident with other well-known early stage pathological markers such as MC1 and the early-stage phospho-marker CP13. TOC1's reactivity depends on the conformation of the tau species since it does not react with monomer under native conditions, although it does react with monomers under SDS-denaturation. This indicates a conformational change must occur within the tau aggregate to expose its epitope. Tau oligomers preferentially form under oxidizing conditions and within this mouse model, we observe tau oligomers forming at an increased rate and persisting much longer, most likely due to the aggressive P301L mutation. With the help of other novel antibodies, the use of this antibody will aid in providing a better understanding of tau toxicity within Alzheimer's disease and other tauopathies. PMID- 24631722 TI - Versatile peroxidase degradation of humic substances: use of isothermal titration calorimetry to assess kinetics, and applications to industrial wastes. AB - The kinetic constants of a hybrid versatile-peroxidase (VP) which oxidizes complex polymeric humic substances (HS) derived from lignin (humic and fulvic acids) and industrial wastes were determined for the first time using isothermal titration calorimetry (iTC). The reaction conditions were manipulated to enable manganese-peroxidase (MnP) and/or lignin-peroxidase (LiP) activities to be evaluated. The peroxidase reactions exhibited varying degrees of product inhibition or activation; properties which have not previously been reported for VP enzymes. In contrast to previous work (Ertan et al., 2012) on small non polymeric substrates (MnSO4, veratryl alcohol and dyes), all kinetic plots for polymeric HS were sigmoidal, lacked Michaelis-Menten characteristics, and were indicative of positive cooperativity. Under conditions when both LiP and MnP were active, the kinetic data fitted to a novel biphasic Hill Equation, and the rate of enzymatic reaction was significantly greater than the sum of individual LiP plus MnP activities implying synergistic activation. By employing size-exclusion chromatography and electrospray ionization mass spectrometry, the characteristics of the oxidative degradation products of the HS were also monitored. Our study showed that the allosteric behaviour of the VP enzyme promotes a high level of regulation of activity during the breakdown of model and industrial ligninolytic substrates. The work was extended to examine the kinetics of breakdown of industrial wastes (effluent from a pulp and paper plant, and fouled membrane solids extracted from a ground water treatment membrane) revealing unique, VP mediated, kinetic responses. This work demonstrates that iTC can be successfully employed to study the kinetic properties of VP enzymes in order to devise reaction conditions optimized for oxidative degradation of HS present in materials used in a wide range of industries. PMID- 24631723 TI - Influence of light presence and biomass concentration on nutrient kinetic removal from urban wastewater by Scenedesmus obliquus. AB - This work was aimed at studying the effect of light-darkness and high-low biomass concentrations in the feasibility of removing nitrogen and phosphorus from urban treated wastewater by the microalga Scenedesmus obliquus. Laboratory experiments were conducted in batch, where microalgae were cultured under different initial biomass concentrations (150 and 1500mgSSl(-1)) and light conditions (dark or illuminated). Nutrient uptake was more dependent on internal nutrient content of the biomass than on light presence or biomass concentration. When a maximum nitrogen or phosphorus content in the biomass was reached (around 8% and 2%, respectively), the removal of that nutrient was almost stopped. Biomass concentration affected more than light presence on the nutrient removal rate, increasing significantly with its increase. Light was only required to remove nutrients when the maximum nutrient storage capacity of the cells was reached and further growth was therefore needed. Residence times to maintain a stable biomass concentration, avoiding the washout of the reactor, were much higher than those needed to remove the nutrients from the wastewater. This ability to remove nutrients in the absence of light could lead to new configurations of reactors aimed to wastewater treatment. PMID- 24631724 TI - Maternal face processing in Mosuo preschool children. AB - Instinctively responding to maternal face is an evolutionary function of enhancing survival and development. However, because of the confounding nature of familiarity, little is known concerning the neural mechanism involved in maternal face recognition. We had a rare opportunity to examine Mosuo preschool children who were raised in a matrilineal society in which mothers and aunts represent equally familiar faces to the children. The participants were exposed to photographs of their mother's face, aunt's face, and an unfamiliar female's faces during electroencephalography (EEG) recording. The EEG results showed that the mother's face elicited a more negative N1 component, a larger left N170 component, and a larger P300 component; both the mother's and aunt's faces elicited a larger right N170 component. These results suggest that the emotional attachment between mother and child has neural ramifications across three successive face processing stages that are distinguished from the neural effects of facial familiarity. PMID- 24631726 TI - Differential scanning calorimetry approach to investigate the transfer of the multitarget opioid analgesic LP1 to biomembrane model. AB - An emerging approach in pain management is the use of multitarget opioid ligands, owing an improved analgesic effect coupled to a reduced incidence of side effects. With a mu opioid receptor agonist/delta opioid receptor antagonist profile, the benzomorphan-based compound LP1 belongs to multitarget ligands class. Previous in vivo investigations showed that LP1 - subcutaneously administered as oxalate salt - was an antinociceptive agent as potent as morphine with a low tolerance-inducing capability. Because the renal toxicity of oxalate is known, an alternative approach allowing the administration of LP1 freebase could be more biocompatible. In this study the interaction of LP1 freebase and LP1 oxalate salt with multilamellar vesicles, as membrane model, was evaluated using differential scanning calorimetry technique. Despite the good membrane interaction showed by LP1 freebase, it was not capable to diffuse in the aqueous medium and to be uptaken by multilamellar vesicles. On the other hand, LP1 freebase possessed a good transfer profile by a liposomal carrier to a biomembrane model. Considering our findings and the need of safe formulations, studies for the development of a suitable carrier for a systemic administration of LP1 freebase are in progress. PMID- 24631725 TI - Mobile food vendors in urban neighborhoods-implications for diet and diet-related health by weather and season. AB - This study describes mobile food vendors (street vendors) in Bronx, NY, considering neighborhood-level correlations with demographic, diet, and diet related health measures from City data. Vendors offering exclusively "less healthy" foods (e.g., chips, processed meats, sweets) outnumbered vendors offering exclusively "healthier" foods (e.g., produce, whole grains, nuts). Wet days and winter months reduced all vending on streets, but exclusively "less healthy" vending most. In summer, exclusively "less-healthy" vending per capita inversely correlated with neighborhood-mean fruit-and-vegetable consumption and directly correlated with neighborhood-mean BMI and prevalences of hypertension and hypercholesterolemia (Spearman correlations 0.90-1.00, p values 0.037 to <0.001). In winter, "less-healthy" vending per capita directly correlated with proportions of Hispanic residents and those living in poverty (Spearman correlations 0.90, p values 0.037). Mobile food vending may contribute negatively to urban food-environment healthfulness overall, but exacerbation of demographic, diet, and diet-related health disparities may vary by weather, season, and neighborhood characteristics. PMID- 24631728 TI - Synthesis and anticancer structure activity relationship investigation of cationic anthraquinone analogs. AB - We have synthesized a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3 d][1,2,3]triazol-3-ium salts, which can be viewed as analogs of cationic anthraquinones. Unlike the similar analogs that we have reported previously, these compounds show relatively weak antibacterial activities but exert strong anticancer activities (low MUM to nM GI50), in particular, against melanoma, colon cancer, non-small cell lung cancer and central nervous system (CNS) cancer. These compounds are structurally different from their predecessors by having the aromatic group, instead of alkyl chains, directly attached to the cationic anthraquinone scaffold. Further investigation in the structure-activity relationship (SAR) reveals the significant role of electron donating substituents on the aromatic ring in enhancing the anticancer activities via resonance effect. Steric hindrance of these groups is disadvantageous but is less influential than the resonance effect. The difference in the attached groups at N-1 position of the cationic anthraquinone analog is the main structural factor for the switching of biological activity from antibacterial to anticancer. The discovery of these compounds may lead to the development of novel cancer chemotherapeutics. PMID- 24631727 TI - Novel insights on the structural determinants of clozapine and olanzapine multi target binding profiles. AB - The clinical efficacy of antipsychotic drugs has been associated with a certain binding profile for a set of G protein-coupled receptors (GPCR)s. In this work, we use the structurally-related clozapine-olanzapine pair to progress in the understanding of the structural properties that determine their divergent binding profiles and, thereby, their differing therapeutic efficacy. First, we present novel site-directed mutagenesis results that confirm our previous hypothesis on the importance of ligand interaction with positions 5.42 and 5.46 in transmembrane helix 5. Then, we use refined models of ligand-receptor complexes, built from recently published GPCR crystal structures, to gain further insight into the molecular mechanisms responsible for the observed experimental outcomes. In particular, we observe that preventing or potentiating hydrogen bonding with position 5.46, could allow obtaining ligands with, respectively, clozapine or olanzapine-like affinities. Results presented in this study could guide the design of antipsychotic candidates with tailored binding profiles. PMID- 24631729 TI - Pyrroloquinolinone-based dual topoisomerase I/II inhibitor. AB - A new series of pyrroloquinolinones bearing different alkylamino side chains were synthesized and evaluated as cytotoxic compounds against three different human tumor cell lines (HeLa, HL-60 and A431). Some compounds showed interesting antiproliferative activity, in particular against A431 cells. The compounds were tested for their ability to counteract topoisomerase II relaxation activity and the most interesting one (3c) was tested also against topoisomerase I, resulting a dual inhibitor. The molecular interactions between 3c and the intracellular targets were finally investigated through molecular modeling simulations. PMID- 24631730 TI - Novel ruthenium complexes ligated with 4-anilinoquinazoline derivatives: synthesis, characterisation and preliminary evaluation of biological activity. AB - The ruthenium DMSO complexes cis-Ru(II)C12(DMSO)4 and [(DMSO)2H][trans Ru(III)Cl4(DMSO)2] reacted with 4-(3'-chloro-4'-fluoroanilino)-6-(2-(2 aminoethyl)aminoethoxy)-7-methoxyquinazoline (L1), 4-(3'-chloro-4'-fluoroanilino) 6-(2-(1H-imidazol-1-yl)ethoxy)-7-methoxy quinazoline (L2), N-(benzo[d]imidazol-4 yl)-6,7-dimethoxyquinazolin-4-amine hydrochloride (L3), 5-(6,7 dimethoxyquinazolin-4-ylamino)quinolin-8-ol hydrochloride (L4), respectively, to afford [Ru(II)Cl2(DMSO)2(L1)] (1), [Ru(III)Cl3(DMSO)(L1)] (2), [Ru(III)Cl4(DMSO)(H-L2)] (3), [Ru(III)Cl4(DMSO)(H-L3)] (4), and [Ru(III)Cl3(DMSO)(H-L4)] (5), which were characterised by mass spectrometry, NMR, elementary analysis and single crystal X-ray diffraction (complex 1). Experimental screening (ELISA) showed that complexes 1, 2 and 3 are remarkably inhibitory towards epidermal growth factor receptor (EGFR) with IC50 values at submicromolar or nanomolar level. Docking studies indicated that complexation with ruthenium has little interference with the formation of the two essential H bonds between the N3 of the quinazoline ring in L1 and L2 and O-H of Thr766 through a water molecule, and the N1 of the quinazoline ring and N-H of Met769 in EGFR. Moreover, complex 2 was shown to be more active against the EGF-stimulated proliferation of human breast cancer cell line MCF-7 than the better EGFR inhibitor 4-(3'-chloro-4'-fluoroanilino)-6,7-dimethoxyquinazoline, being more potential to induce early-stage apoptosis than gefitinib. These imply that apart from inhibiting EGFR, complex 2 may involve in regulating other biological events related to the proliferation of MCF-7, implicating a novel type of multi targeting metal-based anticancer agents. PMID- 24631731 TI - Isoxazoline containing natural products as anticancer agents: a review. AB - Isoxazolines are an important class of nitrogen and oxygen containing heterocycles that belong to the azoles family which have gained much importance in the field of medicinal chemistry as the anticancer agents. Moreover, natural products are always expectedly regarded as an important hoard of a large number of potential chemotherapeutic candidates. Therefore, this review mainly focuses on the existence of isoxazoline derivatives in natural sources, their isolation and uses there of as anticancer agents besides highlighting the synthetic pathways to achieve these compounds. Structural-activity relationship and the influence of stereochemical aspects on anticancer activity of such compounds have also been discussed. It covers the literature upto 2014 and would certainly provide a great insight to scientific community to accelerate further research for the development of some novel anticancer drugs. PMID- 24631732 TI - A new method for filtering of reactive "warheads" of transition-state analog protease inhibitors. AB - In light of the major contribution of the reactive warhead to the binding energy trend in reversible covalent transition-state analog inhibitors of serine and cysteine hydrolases, would it be possible to rationally design and quickly filter such warheads, especially for large-scale screening? The previously defined W1 and W2 covalent descriptors quantitatively account for the energetic effect of the covalent bonds reorganization, accompanying enzyme-inhibitor covalent binding. The quantum mechanically calculated W1 and W2 reflect the warhead binding energy by modeling of the enzyme-inhibitor reaction core. Here, we demonstrate the use of these descriptors for warhead filtering, and examine its scope and limitations. The W1 and W2 descriptors provide a tool for rational design of various warheads as universal building blocks of real inhibitors without the requirement of 3D structural information about the target enzyme or QSAR studies. These warheads could then be used as hit structural templates in the subsequent optimization of inhibitors recognition sites. PMID- 24631733 TI - Quinone-carbohydrate nonglucoside conjugates as a new type of cytotoxic agents: synthesis and determination of in vitro activity. AB - We have found that 2-methoxy-1,4-naphthoquinones easily react with primary alcohols to produce the corresponding 2-alkoxyderivatives. Using this reaction, we synthesized methyl-6-O-(naphthalene-1,4-dione-2-yl)-alpha-D-glucopyranosides, a new type of water soluble quinone-carbohydrate nonglucoside conjugates. The resulting conjugates induced apoptosis in human cancer HeLa and normal mouse JB6 P(+) Cl41 cells with simultaneous inhibition of p53-dependant transcriptional activity, suggesting that the observed cell death was p53-independent. Furthermore, we analyzed structure-activity relationship and bioactivity of 2 hydroxy- and 2-methoxy-1,4-naphthoquinones as well as carbohydrate nonglucoside conjugates. All compounds containing a quinone moiety were able to inhibit p53 dependant transcriptional activity and exerted moderate inhibitory effects on HeLa cell colony formation. Investigations of structure-activity relationships revealed that cytotoxicity depended on the type of substituent at C-2 of the quinone moiety, decreasing in the following order: methoxyderivatives > carbohydrate nonglucoside conjugates > hydroxyderivatives. Furthermore, cytotoxicity depended on the position of the hydroxy substituent in the quinone moiety in all derivatives and decreased in the following order: 8- > 5- > 5,8 derivatives. In conclusion, this is the first report on synthesis and biological structure-activity relationships of the new class of quinone-carbohydrate nonglucoside conjugates. PMID- 24631734 TI - Safety and immunogenicity of an oral DNA vaccine encoding Sip of Streptococcus agalactiae from Nile tilapia Oreochromis niloticus delivered by live attenuated Salmonella typhimurium. AB - Attenuated Salmonella typhimurium SL7207 was used as a carrier for a reconstructed DNA vaccine against Streptococcus agalactiae. A 1.02 kb DNA fragment, encoding for a portion of the surface immunogenic protein (Sip) of S. agalactiae was inserted into pVAX1. The recombinant plasmid pVAX1-sip was transfected in EPC cells to detect the transient expression by an indirect immunofluorescence assay, together with Western blot analysis. The pVAX1-sip was transformed by electroporation into SL7207. The stability of pVAX1-sip into Salmonella was over 90% after 50 generations with antibiotic selection in vitro while remained stable over 80% during 35 generations under antibiotic-free conditions. The LD50 of SL/pVAX1-sip was 1.7 * 10(11) CFU/fish by intragastric administration which indicated a quite low virulence. Tilapias were inoculated orally at 10(8) CFU/fish, the recombinant bacteria were found present in intestinal tract, spleens and livers and eventually eliminated from the tissues 4 weeks after immunization. Fish immunized at 10(7), 10(8) and 10(9) CFU/fish with different immunization times caused various levels of serum antibody and an effective protection against lethal challenge with the wild-type strain S. agalactiae. Integration studies showed that the pVAX1-sip did not integrate with tilapia chromosomes. The DNA vaccine SL/pVAX1-sip was proved to be safe and effective in protecting tilapias against S. agalactiae infection. PMID- 24631735 TI - The effect of emodin on cytotoxicity, apoptosis and antioxidant capacity in the hepatic cells of grass carp (Ctenopharyngodon idellus). AB - We determined the effect of emodin on the lactate dehydrogenase (LDH) release, superoxide dismutase (SOD), glutathione (GSH), total antioxidant capacity (T AOC), reactive oxygen species (ROS), mitochondria membrane potential (DeltaPsim), and apoptosis in the hepatic cells of grass carp (Ctenopharyngodon idellus). Cultured cells were treated with different concentrations of emodin (0.04-25 MUg/ml) for 24 h. We found that the cytotoxic effect of emodin was mediated by apoptosis, and that this apoptosis occurred in a dose-dependent manner. Emodin (1 25 MUg/ml) significantly induced apoptosis accompanying by DeltaPsim disruption and ROS generation and significantly reduced the SOD activities and T-AOC compared to the control. Thus, the oxidative effect of emodin may be attributed to the loss of the cell's ability to maintain the activity of its radical scavenging enzymes. GSH was also significantly higher after 0.2-1 MUg/ml emodin exposure, indicating that cells failed to maintain their redox balance when compensating for the increased oxidative stress. Our results suggest that emodin (1-25 MUg/ml) exerts its cytotoxic effects via apoptosis by directly affecting the mitochondria. PMID- 24631736 TI - A population-based cohort study of late mortality in adult autologous hematopoietic stem cell transplant recipients in Australia. AB - We assessed overall and cause-specific mortality and risk factors for late mortality in a nation-wide population-based cohort of 4547 adult cancer patients who survived 2 or more years after receiving an autologous hematopoietic stem cell transplantation (HSCT) in Australia between 1992 and 2005. Deaths after HSCT were identified from the Australasian Bone Marrow Transplant Recipient Registry and through data linkage with the National Death Index. Overall, the survival probability was 56% at 10 years from HSCT, ranging from 34% for patients with multiple myeloma to 90% for patients with testicular cancer. Mortality rates moved closer to rates observed in the age- and sex-matched Australian general population over time but remained significantly increased 11 or more years from HSCT (standardized mortality ratio, 5.9). Although the proportion of deaths from nonrelapse causes increased over time, relapse remained the most frequent cause of death for all diagnoses, 10 or more years after autologous HSCT. Our findings show that prevention of disease recurrence remains 1 of the greatest challenges for autologous HSCT recipients, while the increasing rates of nonrelapse deaths due to the emergence of second cancers, circulatory diseases, and respiratory diseases highlight the long-term health issues faced by adult survivors of autologous HSCT. PMID- 24631737 TI - Cytotoxic T-lymphocyte antigen-4 single nucleotide polymorphisms are not associated with outcomes after unrelated donor transplantation: a center for international blood and marrow transplant research analysis. AB - Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes. PMID- 24631738 TI - Incidence and outcome of invasive fungal diseases after allogeneic stem cell transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). AB - Epidemiologic investigation of invasive fungal diseases (IFDs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be useful to identify subpopulations who might benefit from targeted treatment strategies. The Gruppo Italiano Trapianto Midollo Osseo (GITMO) prospectively registered data on 1858 consecutive patients undergoing allo-HSCT between 2008 and 2010. Logistic regression analysis was performed to identify risk factors for proven/probable IFD (PP-IFD) during the early (days 0 to 40), late (days 41 to 100), and very late (days 101 to 365) phases after allo-HSCT and to evaluate the impact of PP IFDs on 1-year overall survival. The cumulative incidence of PP-IFDs was 5.1% at 40 days, 6.7% at 100 days, and 8.8% at 12 months post-transplantation. Multivariate analysis identified the following variables as associated with PP IFDs: transplant from an unrelated volunteer donor or cord blood, active acute leukemia at the time of transplantation, and an IFD before transplantation in the early phase; transplant from an unrelated volunteer donor or cord blood and grade II-IV acute graft-versus-host disease (GVHD) in the late phase; and grade II-IV acute GVHD and extensive chronic GVHD in the very late phase. The risk for PP-IFD was significantly higher when acute GVHD was followed by chronic GVHD and when acute GVHD occurred in patients undergoing transplantation with grafts from other than matched related donors. The presence of PP-IFD was an independent factor in long-term survival (hazard ratio, 2.90; 95% confidence interval, 2.32 to 3.62; P < .0001). Our findings indicate that tailored prevention strategies may be useful in subpopulations at differing levels of risk for PP-IFDs. PMID- 24631739 TI - Lymphocyte subset recovery and outcome after autologous hematopoietic stem cell transplantation for plasma cell myeloma. AB - Rapid immune reconstitution--particularly of natural killer cells (NK cells)- after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with protection from relapse. Whether such an association also exists after autologous stem cell transplantation is less clear. We retrospectively assessed lymphocyte subsets after autologous HSCT in 114 patients and correlated lymphocyte recovery with outcome. CD8 T cell and NK cell counts recovered rapidly to pretransplantation levels, whereas B cell and CD4 T cell recovery were delayed. Compared with patients with low NK cells (<100/uL), high NK cell count at 1 month after HSCT was associated with significantly prolonged progression free survival: for NK cells 100 to 200/uL hazard ratio [HR], .33 (95% confidence interval [CI]; .16 to .80; P = .004); for NK cells > 200/MUL HR, .27 (95% CI, .13 to .58; P = .001). No significant protective effects were associated with rapid recovery of any other lymphocyte subset. None influenced overall survival (OS) or time to next treatment. Early NK cell recovery is associated with better progression-free survival after autologous HSCT. The failure to detect an effect on OS might be due to the salvage strategies available to these patients. PMID- 24631740 TI - Monitoring mixed lineage leukemia expression may help identify patients with mixed lineage leukemia--rearranged acute leukemia who are at high risk of relapse after allogeneic hematopoietic stem cell transplantation. AB - To evaluate the prognostic value of the expression of the mixed lineage leukemia (MLL) gene for predicting the relapse of patients with MLL-rearranged acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo HSCT), the levels of MLL transcripts in bone marrow (BM) specimens were monitored serially by real-time quantitative polymerase chain reaction (RQ-PCR) at predetermined time points in 40 patients with MLL-rearranged AL who were treated with allo-HSCT. These patients were followed for a median of 24.5 months (range, 8 to 60 months). A total of 236 BM samples were collected and analyzed. Of these, 230 were monitored concurrently for minimal residual disease (MRD) by flow cytometry (FCM) for leukemia-associated aberrant immune phenotypes and by RQ-PCR for the expression of the Wilms tumor (WT1) gene. The 3-year cumulative incidence of relapse in patients who experienced MLL-positive patients (MLL > .0000%) (n = 9) after HSCT was 93.5% (95% confidence interval [CI], 87% to 100%) compared with 12.5% (95% CI, 5.6% to 19.4%) for MLL-negative patients (n = 31) (P < .001). For these 2 patient groups, the 3-year overall survival (OS) was 12.5% (95% CI, .8% to 24.2%) and 77.8% (95% CI, 68.4% to 87.2%) (P < .001), respectively, and the 3 year leukemia-free survival (LFS) was 0% and 72.2% (95% CI, 61.1% to 83.3%), respectively (P < .001). MLL positivity was associated with a higher rate of relapse (hazard ratio [HR], 18.643; 95% CI, 3.449 to 57.025; P = .001), lower LFS (HR, 7.267; 95% CI, 2.038 to 25.916; P = .002), and lower OS (HR, 8.259; 95% CI, 2.109 to 32.336; P = .002), as determined by Cox multivariate analysis. The expression of the MLL gene had a higher specificity and sensitivity than WT1 or MRD monitored by FCM for predicting the relapse of the patients with MLL + AL. Our results suggest that monitoring the expression of the MLL gene may help to identify patients with MLL + AL who are at high risk of relapse after allo-HSCT and may provide a guide for suitable intervention. PMID- 24631741 TI - Primate iPS cells as tools for evolutionary analyses. AB - Induced pluripotent stem cells (iPSCs) are regarded as a central tool to understand human biology in health and disease. Similarly, iPSCs from non-human primates should be a central tool to understand human evolution, in particular for assessing the conservation of regulatory networks in iPSC models. Here, we have generated human, gorilla, bonobo and cynomolgus monkey iPSCs and assess their usefulness in such a framework. We show that these cells are well comparable in their differentiation potential and are generally similar to human, cynomolgus and rhesus monkey embryonic stem cells (ESCs). RNA sequencing reveals that expression differences among clones, individuals and stem cell type are all of very similar magnitude within a species. In contrast, expression differences between closely related primate species are three times larger and most genes show significant expression differences among the analyzed species. However, pseudogenes differ more than twice as much, suggesting that evolution of expression levels in primate stem cells is rapid, but constrained. These patterns in pluripotent stem cells are comparable to those found in other tissues except testis. Hence, primate iPSCs reveal insights into general primate gene expression evolution and should provide a rich source to identify conserved and species specific gene expression patterns for cellular phenotypes. PMID- 24631742 TI - Utilization of the AAVS1 safe harbor locus for hematopoietic specific transgene expression and gene knockdown in human ES cells. AB - Human pluripotent stem cells offer a powerful system to study human biology and disease. Here, we report a system to both express transgenes specifically in ES cell derived hematopoietic cells and knockdown gene expression stably throughout the differentiation of ES cells. We characterize a CD43 promoter construct that when inserted into the AAVS1 "safe harbor" locus utilizing a zinc finger nuclease specifically drives GFP expression in hematopoietic cells derived from a transgenic ES cell line and faithfully recapitulates endogenous CD43 expression. In addition, using the same gene targeting strategy we demonstrate that constitutive expression of short hairpin RNAs within a microRNA backbone can suppress expression of PU.1, an important regulator of myeloid cell development. We show that PU.1 knockdown cell lines display an inhibition in myeloid cell formation and skewing towards erythroid development. Overall, we have generated a powerful system to track hematopoietic development from pluripotent stem cells and study gene function through hematopoietic specific gene expression and constitutive gene knockdown. PMID- 24631743 TI - Ethanolic carbon-11 chemistry: the introduction of green radiochemistry. AB - The principles of green chemistry have been applied to a radiochemistry setting. Eleven carbon-11 labeled radiopharmaceuticals have been prepared using ethanol as the only organic solvent throughout the entire manufacturing process. The removal of all other organic solvents from the process simplifies production and quality control (QC) testing, moving our PET Center towards the first example of a green radiochemistry laboratory. All radiopharmaceutical doses prepared are suitable for clinical use. PMID- 24631744 TI - Design of radiolabeled gelatinase inhibitor peptide ((99m)Tc-CLP) and evaluation in rats. AB - In malignant tissues, MMP-9 (gelatinase B, 92 kDa type IV collagenase) and MMP-2 (gelatinase A, 72 kDa type IV collagenase) are the most prevalent matrix metalloproteinases related to the tumor aggressiveness and metastatic potential. Since elevated levels of gelatinases are associated with poor prognosis in cancer patients, these enzymes are potential targets for tumor imaging to possibly predict metastases. In the present study, a cyclic decapeptide, CLP (Cys-Leu-Pro Gly-His-Trp-Gly-Phe-Pro-Ser-Cys), was selected as a basic peptide because of its selective inhibitory activity toward gelatinases. The peptide was labelled with (99m)Tc with a radiolabelling efficiency of 94.6+/-4.1%. After determining the appropriate conditions for radiolabelling, a biodistribution study of radiolabelled peptide in Albino Wistar rats was done. According to biodistribution data, (99m)Tc-CLP showed high uptake in the lung, liver, uterus and spleen. The amount of normal tissue MMPs enzymes is known to be lower than a tumor tissue. In this connection, our findings show that matrix metalloproteinases inhibitory peptide which is CLP is labeled with (99m)Tc with high yield and radiolabeled peptide might be might be utilized for the imaging of gelatinase activity due to overexpression of MMP-2 and MMP-9 in tumor tissue. PMID- 24631745 TI - Calcium supplements as source of trace elements: adequacy and safety of supplements with vitamin C, vitamin D and phosphate formulations. AB - Instrumental neutron activation analysis and atomic absorption spectrometry were used to quantify trace elements in different national and multinational Ca supplements categorized on the basis of Ca with vitamin D, vitamin C and phosphate formulations. The supplements were found to contain low levels of Co, Cr and Cu with elevated amounts of Fe, K and Na. Toxic elements (As, Cd and Sb) were detected in very few samples at very low concentrations. The essential elements contribute to >3% of their respective Dietary Reference Intakes. PMID- 24631746 TI - Determination of optimal acquisition time of [(18)F]FCWAY PET for imaging serotonin 1A receptors in the healthy male subjects. AB - The purpose of this research is to find optimal acquisition time point of [(18)F]FCWAY PET for the assessment of serotonin 1A receptor (5-HT1A) density. To achieve this goal, we examined the specific-to-nonspecific ratios in various brain regions. The cerebellum has very few 5-HT1A receptors in the brain, so we set this region as the reference tissue. As a result, specific-to-nonspecific binding ratios in the frontal, temporal cortex and the hippocampus were steadily increased at 90 min after injection and remained stable at 120 min. In addition, the binding ratio of the late time was significantly higher than that of the previous time points. From these results, we recommend that 90 min p.i. is a better single time point for the analysis rather than previous time points for assessing [(18)F]FCWAY binding to 5-HT1A receptors. PMID- 24631747 TI - Automated radiosynthesis of N-succinimidyl 3-(di-tert butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) for peptides and proteins radiolabeling for positron emission tomography. AB - Recently, silicon fluoride building blocks (SiFA) have emerged as valuable and promising tools to overcome challenges in the labeling of peptides and proteins for positron emission tomography (PET). Herein, we report a fully automated synthesis of N-succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) by a commercially available Scintomics Hot Box 3 synthesis module, to be used as a prosthetic group for peptide and protein labeling. The drying of K2.2.2./K (18)F complex was performed according to the Munich method modified by our group (avoiding azeotropic drying) using oxalic acid to neutralize the base from the (18)F(-) containing QMA eluent. This K2.2.2./K (18)F complex was then used for SiFA (18)F-(19)F isotopic exchange followed by a fast purification by a solid-phase-extraction (SPE) to afford [(18)F]SiFB with an average preparative radiochemical yield (RCY) of 24+/-1% (non-decay corrected (NDC)) within a synthesis time of 30 min. The [(18)F]SiFB produced by automated synthesis was then used for the (18)F-labeling of rat serum albumin (RSA) as a proof of applicability. PMID- 24631748 TI - Determination of L X-ray fluorescence parameters for Ho, Lu, W, Hg and Bi. AB - In this work, L X-ray fluorescence cross sections, L sub-shell fluorescence yields and level widths and radiative vacancy transfer probabilities of L sub shells to Mi, Ni and Oi sub-shells were measured for the elements Ho, Lu, W, Hg and Bi. Energy dispersive X-ray fluorescence (EDXRF) technique was used to measure L X-ray photons. To obtain related parameters, we used 59.54 keV gamma photons of (241)Am radioactive point source. Emitted L X-ray photons from targets were collected by means of a Si(Li) detector with resolution of 180 eV at 5.9 keV. The present results are generally in a good agreement with theoretical calculations and the other results obtained in the literature, within their range considering experimental uncertainty. PMID- 24631749 TI - Study of carD gene sequence in clinical isolates of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis growth rate is closely coupled to rRNA transcription which is regulated through carD gene. The aim of this study was to determine the sequence of carD gene in drug susceptible and resistant clinical isolates of M. tuberculosis and designing of a PCR assay based on carD sequence for rapid detection of this bacterium.Specific primers for amplification of carD gene were carefully designed, so that whole sequence of gene could be amplified; therefore primers were positioned at the upstream (promoter of this gene and ispD gene) and downstream (in ispD gene). DNA from 41 clinical isolates of M. tuberculosis with different pattern of drug resistance was used in the study. PCR conditions and annealing temperature were designed by means of online programs. PCR products were sequenced by ABI system.PCR product of carD gene was a 524 bp fragment. This method could detect all resistant and susceptible strains of M. tuberculosis. The size of amplified fragment was similar in all investigated samples. Sequence analysis showed that there was similar sequence in all of our isolates therefore probably this gene is considered to be conservative. Translation of nucleotide mode to amino acids was showed that TRCF domain in N-terminal of protein CarD was found to be fully conservative.This is the first study on the sequence of carD gene in clinical isolates of M. tuberculosis. This conservative gene is recommended for use as a target for designing of suitable inhibitors as anti tuberculosis drug because its importance for life of MTB. In the other hand, a PCR detection method based on detection of carD gene was recommended for rapid detection in routine test. PMID- 24631750 TI - Studies on the possible aetiological role of different Candida species in pathogenesis of dentine caries by monitoring the calcium release from tooth particles. AB - An in vitro model has been developed for study of cariogenic potential of different Candida species. Slices were prepared from the root of extracted healthy teeth. These disks were covered with inert material, only the central hole, i.e. the root canal dentin surface remained uncovered. These preparates with free root dentin surfaces were incubated in Sabouraud medium in the presence of six-six Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida inconspicua and Candida norvegensis strains. The calcium release was detected for 15 days. Two types of release could be distinguished. C. albicans deliberated calcium more aggressively (type "A" curve), while other Candidas were characterized by less expressed calcium releasing capacity (type "B" curve). Curves type "A" and "B" were divided into four steps in order to characterize more precisely the different dynamics of calcium release. Analyses of the different steps also suggested the more aggressive behaviour of C. albicans. Our results indicate that in addition to cariogenic role of different bacteria, fungi may also actively take part in the dentinal caries progress. PMID- 24631751 TI - Detection and genotype analysis of Giardia duodenalis from asymptomatic Hungarian inhabitants and comparative findings in three distinct locations. AB - The transmission route of giardiasis not yet understood and why some infected individuals remain asymptomatic while others become quite ill. The drinking water quality is supposedly responsible for the prevalence of asymptomatic Giardia duodenalis infections in different areas, therefore asymptomatic giardiasis has been investigated in three water supply areas of Hungary: three hundred stool samples from inhabitants of Budapest, Fuzer and Matrafured were examined by immunological and molecular methods for the presence of G. duodenalis infections. Individuals were asked to fill out a validated questionnaire at the time of stool collection and the interview covered demographic data, family life, education and travel history.In Budapest and in Matrafured in one stool sample G. duodenalis Assemblage A, whereas in Fuzer once G. duodenalis Assemblage A, once Assemblage B and twice mixed infection were detected. We found higher prevalence rate of 4% of G. duodenalis infections of asymptomatic people in the village Fuzer, where the removal of the Giardia cysts of the drinking water treatment plant was not effective. This study throws a light the need to look into the possibility of other risks of Giardia infections such as water transmission routes. To our knowledge, this is the first study evaluating the prevalence of G. duodenalis infections in asymptomatic persons in Hungary. PMID- 24631752 TI - Molecular identification key of the family Streptococcaceae. AB - The gene order conservation (GOC) between the species of family Streptococcaceae was analysed. The rate of GOC in the strains belonging to the same species is 70% or more. When we compared different species belonging to the same genus, the rate of GOC was 30-47% while it was below 20% when the species were from different genera. A molecular identification key was established for identifying those genera and species within the family Streptococcaceae which have an already known full genome sequence (24 Streptococcus and 2 Lactococcus species). Identical genome parts of the species belonging to the same genus were used for determination of genera. These are the sections surrounding the replication origin dnaA, the sequence from gene phaB to the gene accA, and the sequence of alr acpS secA. Sections around the genes pepX, leuS and rplM were used for identifying the species. The gene order analysis and data in molecular identification key showed that S. uberis and S. parauberis also belong to the same species, and our suggestion for their new names is S. uberis subsp. uberis and S uberis subsp. parauberis. Based on this data, a new definition of bacterial species is proposed: two isolates belong to the same species if the order of the genes in their genomes is almost identical. PMID- 24631753 TI - Flow cytometric analysis of the basophil cell activating impact of potential drug delivery nanoparticle-candidate. AB - INTRODUCTION: Carbon nanotubes - as artificial nano-size ranged materials -have increasing role in the modern biomedical, diagnostic and therapeutic applications.There is a promising option for their use as more potential drug carriers. Despite the favourable properties, their impact (accumulation, elimination, etc.) on biological systems is largely unknown. The main limiting factor of medical use of nanomaterials in most cases is the potential hypersensitive side effect. It can develop in different route, but the activation of basophil granulocytes may play a central role in this process. OBJECTIVE: Our aim was to test the direct activation ability of different, surface modified nanotubes on basophil granulocytes in vitro. In parallel we tested the effectiveness of BasoTest planned to use for this study. MATERIALS AND METHODS: Using the blood samples of allergic and healthy volunteers we examined the basophil degranulation in the presence of nanotubes and the expression level changes of cell-surface CD63 on FACS Calibur instrument. Our results were compared to positive(fMLP, Mite, Grass) and negative control samples. RESULTS: The test we have chosen proved to be sufficiently sensitive and specific for further study. Significant basophil activation was observed in the presence of carbon nanotubes in healthy persons and allergic patients, as well. The activating effect of nanotubes was more prevailed in allergic population. CONCLUSION: Our experiments have proven the fact that nanotubes may play a role in the development of hypersensitive allergic reactions through their basophil granulocyte activator effect. PMID- 24631754 TI - Serum interleukin-6 levels in murine models of Candida albicans infection. AB - Two Balb/C mouse models of Candida infection were used to detect serum interleukin-6 (IL-6) responses. The first model used systemic infection by Candida albicans ATCC 10231 strain infected through the lateral tail vein of mice without any specific pretreatment. The median Candida burdens of the kidneys were 1.5 * 106 CFU/ml 24 h postinoculation (p.i.) and 1.2 * 107 CFU/ml 72 h p.i., while median serum IL-6 levels were 479.3 pg/ml and 934.5 pg/ml, respectively. The Candida burden showed significant correlation with serum IL-6 24 h p.i. (R2 = 0.6358; P = 0.0082) but not 72 h p.i.The second model was a mouse vaginitis model applying intravaginal inoculation of mice pretreated with subcutaneous estradiol valerate (10 mg/ml) 3 days before infection. Candida cell count in vaginal lavage fluid was 2.8 * 106 CFU/ml 24 h p.i. and 1.4 * 108 CFU/ml 72 h p.i. Serum IL-6 response was detected in 4 of 15 mice 24 h p.i. and 9 of 15 mice 72 h p.i. Even the responders had low IL-6 serum levels (mean values 29.9 pg/ml and 60.1 pg/ml, respectively) not correlating with Candida cell count in vaginal lavage fluid.In conclusion, serum IL-6 had strong relationship with systemic C. albicans infection while the local C. albicans infection of the vagina led to partial, prolonged and limited serum IL-6 response. PMID- 24631755 TI - Isolation of Kurthia gibsonii from non-gonorrheal urethritis: implications for the pathomechanism upon surveying the literature. AB - The incidence and number of species involved in the spectrum of sexually transmitted infections continue to increase. Laboratories have to be prepared for identification of unusual microbes. In our practice, a male patient had recurring urethritis and balanitis after having repeated unprotected insertive sexual intercourse with female piglets. He also had allergy to scents and some metals, otherwise he showed no general symptoms. Specimens were swabbed from the urethra, inflamed glans, rectum, mouth onto several culture media, subsequently isolates were tested for their morphology, biochemical activity. Kurthia gibsonii was isolated from urethra and glans. No concomitant infection with other microbes was detected, haemoculture was negative. Relying upon antibiotic sensitivity test, he was cured with 2 * 500 mg oral cefuroxime for 15 days, and topical gentamycin cream for 2 months. This is the first reported sexually transmitted, zoonotic infection without generalization by Kurthia spp. We report first the antibiogram of K. gibsonii. Slight differences in the antibiotic sensitivity suggest independent infection and sensitivity of urethral and mucous membrane tissues to distinct K. gibsonii strains. Allergy of the patient might predispose to opportunistic infection. Such aspects ought to be tested in details in further cases. PMID- 24631756 TI - Development of the HPA axis: where and when do sex differences manifest? AB - Sex differences in the response to stress contribute to sex differences in somatic, neurological, and psychiatric diseases. Despite a growing literature on the mechanisms that mediate sex differences in the stress response, the ontogeny of these differences has not been comprehensively reviewed. This review focuses on the development of the hypothalamic-pituitary-adrenal (HPA) axis, a key component of the body's response to stress, and examines the critical points of divergence during development between males and females. Insight gained from animal models and clinical studies are presented to fully illustrate the current state of knowledge regarding sex differences in response to stress over development. An appreciation for the developmental timelines of the components of the HPA axis will provide a foundation for future areas of study by highlighting both what is known and calling attention to areas in which sex differences in the development of the HPA axis have been understudied. PMID- 24631757 TI - Editorial introduction for the Synthetic Biology thematic issue. AB - Synthetic biology strives to develop organisms, enzymes, and processes that do not occur naturally to solve specific biotechnological problems. Often this requires genetic engineering to change a natural process, or to combine genes from different sources to create new ones. This volume includes examples not only of these traditional approaches, but also illustrates how some problems can be solved chemically or biochemically without genetic manipulation. Topics covered therefore range from exploitation of genomic or gene regulation data gleaned from systems biology to the production of nanoparticles at one extreme of scale to biodiesel to replace our dependence upon fossil fuels at the opposite extreme. This introduction sets current synthetic biology within the context of the European regulatory framework within which we must operate. Attention is also drawn to the emerging language that describes it. PMID- 24631758 TI - Selective serotonin reuptake inhibitor use and increased risk of cataract surgery: a population-based, case-control study. AB - PURPOSE: To investigate whether selective serotonin reuptake inhibitor use is associated with an increased risk of cataract surgery. DESIGN: Population-based case-control study. METHODS: setting: Olmsted County, Minnesota. patient population: Eligible patients were county residents in the Rochester Epidemiology Project. Cases included 6024 county residents aged 50+ years who underwent first eye cataract surgery between January 1, 2004 and December 31, 2011. Controls included 6024 residents who never had cataract surgery and were matched to cases by age, sex, and date of surgery. Logistic regression models were used to compute odds ratios for differences in selective serotonin reuptake inhibitor use between cases and controls, and to adjust for confounding variables. observation procedure: Rochester Epidemiology Project databases were used to assess cataract surgery and selective serotonin reuptake inhibitor treatment. main outcome measure: Selective serotonin reuptake inhibitor use. RESULTS: In the cataract surgery cohort of 6024 residents, 1024 (17%) were selective serotonin reuptake inhibitor users compared to 788 (13%) in the matched cohort of 6024 residents never having cataract surgery (P < .001). Selective serotonin reuptake inhibitor use of 1 or more years was associated with an increased risk of cataract surgery (odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.23-1.51; P < .001). The associations were similar in women (OR = 1.37; 95% CI, 1.22-1.55; P < .001) and men (OR = 1.34; 95% CI, 1.12-1.61; P = .002). The risk of cataract surgery was highest with citalopram use (OR = 1.53; 95% CI, 1.33-1.77; P < .001). CONCLUSION: Selective serotonin reuptake inhibitor use of 1 or more years in people aged 50+ years is associated with an increased risk of cataract surgery. PMID- 24631759 TI - Comparison of ocular surface disease index and tear osmolarity as markers of ocular surface dysfunction in video terminal display workers. AB - PURPOSE: To compare the Ocular Surface Disease Index (OSDI) questionnaire and tear osmolarity, to screen ocular surface alterations in video display terminal (VDT) users. DESIGN: Cross-sectional study. METHODS: Sixty-four VDT workers were screened for ocular surface alterations using OSDI and tear osmolarity. Furthermore, tear film break-up time (TBUT), fluorescein corneal stain, and assessment for meibomian glands dysfunction (MGD) were carried out. The alteration of 2 or more among these parameters was considered a sign of ocular surface dysfunction. Data for the statistical analysis were obtained from the eyes with the worst tear osmolarity score. Main outcome measures were OSDI and tear osmolarity. For the statistical analysis the receiver operating characteristic (ROC) curves and Spearman correlation coefficient were used. A P < .05 was considered statistically significant. RESULTS: The area under the ROC curve (AUC) for tear osmolarity (ranging from 0.71 to 0.86) showed, for all the classification variables considered, statistically significantly higher values than those obtained with OSDI (ranging from 0.51 to 0.58) (P < .01). Furthermore, tear osmolarity showed a direct correlation with corneal stain and ocular surface dysfunction and an inverse correlation for TBUT. No correlation was found between OSDI and the parameters considered. CONCLUSIONS: Tear osmolarity can be considered a more reliable test than OSDI, when screening VDT users for possible ocular surface alterations. PMID- 24631760 TI - Male vulnerability explains the occurrence of sexual cannibalism in a moderately sexually dimorphic wolf spider. AB - Sexual cannibalism is a widespread phenomenon among a few animal taxa. Its occurrence is interpreted as female and/or male optimal reproductive decisions or as a non-adaptive side effect of selection for efficiently foraging females. In spite of the amount of research addressed at understanding its evolutionary origins, we lack accurate information about the proximate causes of sexual cannibalism. In a moderately sexually dimorphic wolf spider (Hogna radiata, Araneae, Lycosidae) we assessed the factors mediating the occurrence of sexual cannibalism and its fitness benefits to females. Sexual cannibalism was a rather common outcome of laboratory mating interactions, occurring in more than a quarter percent of courtship interactions involving virgin females. Sexual cannibalism mostly followed mating. Occurrence of sexual cannibalism depended on male vulnerability to female attacks: relatively smaller males were at higher risk of being attacked and older males were less likely to avoid female attacks. Sexual cannibalism had direct and positive effects on female fitness, as sexually cannibalistic females exhibited increased fecundity irrespective of their size, condition and foraging rate. Male consumption was almost complete and represented a relevant food intake to females. We interpret sexual cannibalism as a strategic foraging decision for H. radiata females that adjust their aggressive behaviour towards males so as to limit its potential costs. PMID- 24631761 TI - Nitric oxide synthase regulation of cardiac excitation-contraction coupling in health and disease. AB - Significant advances in our understanding of the ability of nitric oxide synthases (NOS) to modulate cardiac function have provided key insights into the role NOS play in the regulation of excitation-contraction (EC) coupling in health and disease. Through both cGMP-dependent and cGMP-independent (e.g. S nitrosylation) mechanisms, NOS have the ability to alter intracellular Ca(2+) handling and the myofilament response to Ca(2+), thereby impacting the systolic and diastolic performance of the myocardium. Findings from experiments using nitric oxide (NO) donors and NOS inhibition or gene deletion clearly implicate dysfunctional NOS as a critical contributor to many cardiovascular disease states. However, studies to date have only partially addressed NOS isoform specific effects and, more importantly, how subcellular localization of NOS influences ion channels involved in myocardial EC coupling and excitability. In this review, we focus on the contribution of each NOS isoform to cardiac dysfunction and on the role of uncoupled NOS activity in common cardiac disease states, including heart failure, diabetic cardiomyopathy, ischemia/reperfusion injury and atrial fibrillation. We also review evidence that clearly indicates the importance of NO in cardioprotection. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System". PMID- 24631762 TI - 6-carboxydihydroresveratrol 3-O-beta-glucopyranoside--a novel natural product from the Cretaceous relict Metasequoia glyptostroboides. AB - Metasequoia glyptostroboides, a tree native to China, is described as a living fossil and has existed for millions of years. The oldest fossils recorded have been dated to the late Cretaceous era. During the time of its existence, the molecular defence system of the tree has apparently resisted millions of generations of pathogens, which encouraged search for novel natural product from this source. Eight compounds have been characterised from needles of M. glyptostroboides, including the novel natural product 6-carboxydihydroresveratrol 3-O-beta-glucopyranoside. The structure determinations were based on extensive use of 2D NMR spectroscopic techniques and high-resolution mass spectrometry. PMID- 24631763 TI - Plant based products: use and development as repellents against mosquitoes: A review. AB - Global warming and deforestation have resulted in the relocation of many living creatures including insects during the recent years. This has affected the population balance of disease vectors including mosquitoes resulting in outbreaks. Traditionally, mankind has been using plants as means of protection from the mosquitoes which are considered to be environment friendly unlike the synthetic chemicals that cause major risk to human health and the ecosystem. Researchers explored mainly, essential oils and traditional plants using different testing methodologies to find out repellent molecules effective against mosquitoes which is the main focus of this review. Among the promising plant species, Eucalyptus spp., Ocimum spp. and Cymbopogon spp. are the most cited. Data of repellency produced from the bioassay systems is difficult to quantify because of different parameters, testing system and standards of material used against mosquitoes. Mainly, the human forearm based bioassays have been used with different sizes of treatment area in the laboratory and the results have not been tested in the field conditions for residual activity. In addition, effectiveness of essential oils and their protection time can be increased by using vanillin as synergist and formulation techniques like microencapsulation and nanoemulsion. There is a need to develop an alternate in vitro bioassay system that can address the problems of uniformity of the results. PMID- 24631764 TI - Cucurbitane-type triterpenoids from the stems and leaves of Momordica charantia. AB - Six new cucurbitane-type triterpenoids, karavilagenin F (1), karavilosides XII and XIII (2, 3), momordicines VI, VII, and VIII (4, 5 and 6), along with four known ones, 5beta,19-epoxy-25-methoxycucurbita-6,23-diene-3beta,19-diol (7), 5beta,19-epoxycucurbita-6, 23-diene-3beta,19,25-triol (8), kuguacin R (9), and (19R,23E)-5beta,19-epoxy-19-methoxycucurbita-6,23,25-trien-3beta-ol (10), were isolated from the stems and leaves of Momordica charantia L. Their chemical structures were elucidated by extensive 1D NMR and 2D NMR (HSQC, HMBC, COSY, and ROESY), MS experiments, and CD spectrum. Compound 6 showed weak cytotoxicity against five human cancer cells lines with IC50 values of 14.3-20.5MUmol/L. PMID- 24631766 TI - Isocoumarins from American cockroach (Periplaneta americana) and their cytotoxic activities. AB - Four new isocoumarins (1-4), along with three known ones (5-7), were isolated from the 70% ethanol extract of the whole body of the traditional Chinese insect medicine, American cockroach (Periplaneta americana). The structures with absolute configurations of new compounds were elucidated by extensive spectroscopic methods in combination with X-ray diffraction experiment and CD analyses. Compounds 3-5 showed significant cytotoxic activities in HepG2 and MCF 7 cells with IC50 values in the ranges 6.41-23.91 MUM and 6.67-39.07 MUM, respectively. PMID- 24631765 TI - Phytochemical investigation of sesquiterpenes from the fruits of Schisandra chinensis and their cytotoxic activity. AB - Phytochemical investigation of ethanolic extract from the fruits of Schisandra chinensis led to the isolation of four new sesquiterpenes (1-4); their structures were determined by a combination of NMR (1D and 2D) and MS spectroscopic techniques. In addition, all these isolates were screened for their cytotoxic activities against MCF-7, Caco-2, Hela, Lncap, Hep G2 and MDA-MB231 cancer cell lines. Results indicated that compounds 2 and 3 displayed potent cytotoxic activity against Caco2 cell lines with IC50 values of 17.10 MUg/mM and 16.46 MUg/mM, respectively. PMID- 24631767 TI - Alkaloids from Lycoris aurea and their cytotoxicities against the head and neck squamous cell carcinoma. AB - Phytochemical investigation of the 80% EtOH extract of the bulbs of Lycoris aurea led to the isolation of six new alkaloids, 2-demethyl-isocorydione (1), 8 demethyl-dehydrocrebanine (2), 1-hydroxy-anhydrolycorin-7-one (3), (+)-1,2 dihydroxy-anhydrolycorine N-oxide (4), 5,6-dihydro-5-methyl-2 hydroxyphenanthridine (5), and (+)-8-hydroxy-homolycorine-alpha-N-oxide (6), and together with two known compounds, isocorydione (7) and anhydrolycorin-7-one (8). Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D ((1)H-(1)H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. All the alkaloids were in vitro evaluated for their cytotoxic activities against seven tumor cell lines of the head and neck squamous cell carcinoma and anti-inflammatory activities. Compounds 1, 2, 6, and 7 exhibited significant cytotoxicities against all the tested cell lines. Moreover, alkaloids 1, 2, and 7 possessed selective inhibition of Cox-2 (>85%). PMID- 24631768 TI - Reactive oxygen species and excitation-contraction coupling in the context of cardiac pathology. AB - Reactive oxygen species (ROS) are highly reactive oxygen-derived chemical compounds that are by-products of aerobic cellular metabolism as well as crucial second messengers in numerous signaling pathways. In excitation-contraction coupling (ECC), which links electrical signaling and coordinated cardiac contraction, ROS have a severe impact on several key ion handling proteins such as ion channels and transporters, but also on regulating proteins such as protein kinases (e.g. CaMKII, PKA or PKC), thereby pivotally influencing the delicate balance of this finely tuned system. While essential as second messengers, ROS may be deleterious when excessively produced due to a disturbed balance in Na(+) and Ca(2+) handling, resulting in Na(+) and Ca(2+) overload, SR Ca(2+) loss and contractile dysfunction. This may, in the end, result in systolic and diastolic dysfunction and arrhythmias. This review aims to provide an overview of the single targets of ROS in ECC and to outline the role of ROS in major cardiac pathologies, such as heart failure and arrhythmogenesis. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System" PMID- 24631769 TI - In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome. AB - Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed "in silico mutagenesis" by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of the M54T MiRP1 latent mutation and simulated a provocative test. In this setting, application of dofetilide dramatically amplified the predicted QT interval duration in the M54T hMiRP1 mutation compared to wild-type. PMID- 24631770 TI - Targeting cardiac fibroblasts to treat fibrosis of the heart: focus on HDACs. AB - Cardiac fibrosis is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure and cardiac arrhythmias. However the specific cells and signaling pathways mediating this process are poorly understood. Lysine acetylation of nucleosomal histone tails is an important mechanism for the regulation of gene expression. Additionally, proteomic studies have revealed that thousands of proteins in all cellular compartments are subject to reversible lysine acetylation, and thus it is becoming clear that this post translational modification will rival phosphorylation in terms of biological import. Acetyl groups are conjugated to lysine by histone acetyltransferases (HATs) and removed from lysine by histone deacetylases (HDACs). Recent studies have shown that pharmacologic agents that alter lysine acetylation by targeting HDACs have the remarkable ability to block pathological fibrosis. Here, we review the current understanding of cardiac fibroblasts and the fibrogenic process with respect to the roles of lysine acetylation in the control of disease-related cardiac fibrosis. Potential for small molecule HDAC inhibitors as anti-fibrotic therapeutics that target cardiac fibroblasts is highlighted. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium." PMID- 24631771 TI - Targeted deletion of ERK2 in cardiomyocytes attenuates hypertrophic response but provokes pathological stress induced cardiac dysfunction. AB - Mitogen-activated protein kinases (MAPKs) are involved in the regulation of cardiac hypertrophy and myocyte survival. Extracellular signal regulated protein kinase 1 and 2 (ERK1/2) are key components in the MAPK signaling pathways. Dysfunction of ERK1/2 in congenital heart diseases (Noonan syndrome and LEOPARD syndrome) leads to cardiac hypertrophy. ERK2 contributes 70% of protein content to total ERK1/2 content in myocardium; however, the specific role of ERK2 in regulating cardiac hypertrophy is yet to be further defined. To investigate the specific role of ERK2 played in the cardiomyocytes, we generated and examined mice with cardiomyocyte-specific deletion of the erk2 gene (ERK2(cko) mice). Following short-term pathological hypertrophic stresses, the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in the cross-sectional area of individual myocytes, downregulation of hypertrophic foetal gene markers (ANP and BNP), and less interstitial fibrosis. However, increased cardiomyocyte apoptosis was observed. Upon prolonged stimulation, ERK2(cko) mice developed deterioration in cardiac function. However, absence of ERK2 did not affect physiological hypertrophy induced by 4weeks of swimming exercise. These results revealed an essential role for ERK2 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death. PMID- 24631772 TI - Differential effects of S100 proteins A2 and A6 on cardiac Ca(2+) cycling and contractile performance. AB - Defective intracellular calcium (Ca(2+)) handling is implicated in the pathogenesis of heart failure. Novel approaches targeting both cardiac Ca(2+) release and reuptake processes, such as S100A1, have the potential to rescue the function of failing cardiac myocytes. Here, we show that two members of the S100 Ca(2+) binding protein family, S100A2 and S100A6 that share high sequence homology, differentially influence cardiac Ca(2+) handling and contractility. Cardiac gene expression of S100A2 significantly enhanced both contractile and relaxation performance of rodent and canine cardiac myocytes, mimicking the functional effects of its cardiac homologue, S100A1. To interrogate mechanism, Ca(2+) spark frequency, a measure of the gating of the ryanodine receptor Ca(2+) release channel, was found to be significantly increased by S100A2. Therapeutic testing showed that S100A2 rescued the contractile defects of failing cardiac myocytes. In contrast, cardiac expression of S100A6 had no significant effects on contractility or Ca(2+) handling. These data reveal novel differential effects of S100 proteins on cardiac myocyte performance that may be useful in application to diseased cardiac muscle. PMID- 24631773 TI - P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: implication for calcific aortic valve disease. AB - Calcific aortic valve disease (CAVD) is a disorder characterized by an abnormal mineralization, which may have intricate links with inflammation. Interleukin-6 (IL-6) and its cognate cytokines are widely expressed and exert pleiotropic effects on different tissues. In this study, we examined the expression of the IL 6 family of cytokines in human CAVD by using a transcriptomic approach and we performed in-depth functional assays with valve interstitial cells (VICs) to unravel the process regulating IL-6 expression and its role during the mineralization of the aortic valve. We documented by both microarray and q-PCR analyses an elevated expression of IL-6 in human CAVD, which was correlated with the remodeling process. IL-6 was highly expressed by VICs. We found that following treatment with a phosphate-containing medium the level of IL-6 expressed by VICs increased by several-fold. Phosphate-induced expression of IL-6 relied on reduced PI3K/Akt signaling downstream of the P2Y2 receptor (P2Y2R). In this regard, we found by using transfection experiments that Akt-1 is a negative regulator of the NF-kappaB pathway. In addition, by using a siRNA targeting IL-6 we found that phosphate-induced mineralization was largely dependent on IL-6 expression. A transfection of Akt-1 rescued the hypermineralizing phenotype of P2Y2R(-/-) mouse VICS (MVICs). Hence, we documented a novel mechanism whereby P2Y2R and Akt modulate the NF-kappaB pathway and its downstream target IL-6, which is a strong promoter of the mineralization of VICs. PMID- 24631774 TI - Nox2 mediates high fat high sucrose diet-induced nitric oxide dysfunction and inflammation in aortic smooth muscle cells. AB - Diet-induced obesity and metabolic syndrome are important contributors to cardiovascular diseases. The decreased nitric oxide (NO) bioactivity in endothelium and the impaired response of smooth muscle cell (SMC) to NO significantly contribute to vascular pathologies, including atherosclerosis and arterial restenosis after angioplasty. Sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) is an important mediator of NO function in both endothelial cells and SMCs, and its irreversible oxidation impairs its stimulation by NO. We used C57BL/6J mice fed a high fat high sucrose diet (HFHSD) to study the role of SMC SERCA in diet-induced obesity and metabolic syndrome. We found that HFHSD upregulated Nox2 based NADPH oxidase, induced inflammation, increased irreversible SERCA oxidation, and suppressed the response of aortic SERCA to NO. Cultured aortic SMCs from mice fed HFHSD showed increased reactive oxygen species production, Nox2 upregulation, irreversible SERCA oxidation, inflammation, and a decreased ability of NO to inhibit SMC migration. Overexpression of wild type SERCA2b or downregulation of Nox2 restored NO-mediated inhibition of migration in SMCs isolated from HFHSD-fed mice. In addition, tumor necrosis factor alpha (TNFalpha) increased Nox2 which induced SERCA oxidation and inflammation. Taken together, Nox2 induced by HFHSD plays significant roles in controlling SMC responses to NO and TNFalpha-mediated inflammation, which may contribute to the development of cardiovascular diseases in diet-induced obesity and metabolic syndrome. PMID- 24631775 TI - Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. AB - Sudden unexplained deaths (SUD) in apparently healthy individuals, for which the causes of deaths remained undetermined after comprehensive forensic investigations and autopsy, present vexing challenges to medical examiners and coroners. Cardiac channelopathies, a group of inheritable diseases that primarily affect heart rhythm by altering the cardiac conduction system, have been known as one of the likely causes of SUD. Adhering to the recommendations of including molecular diagnostics of cardiac channelopathies in SUD investigation, the Molecular Genetics Laboratory of the New York City (NYC) Office of Chief Medical Examiner (OCME) has been routinely testing for six major channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) since 2008. Presented here are the results of cardiac channelopathy testing in 274 well-characterized autopsy negative SUD cases, all with thorough medicolegal death investigation including complete autopsy by NYC OCME between 2008 and 2012. The cohort consisted of 141 infants (92.9% younger than six-month old) and 133 non-infants (78.2% were between 19 and 58 years old). Among the ethnically diverse cohort, African American infants had the highest risks of SUD, and African American non-infants died at significantly younger age (23.7 years old, mean age-at-death) than those of other ethnicities (30.3 years old, mean age-at-death). A total of 22 previously classified cardiac channelopathy-associated variants and 24 novel putative channelopathy-associated variants were detected among the infants (13.5%) and non-infants (19.5%). Most channelopathy-associated variants involved the SCN5A gene (68.4% in infants, 50% in non-infants). We believe this is the first study assessing the role of cardiac channelopathy genes in a large and demographically diverse SUD population drawn from a single urban medical examiner's office in the United States. Our study supports that molecular testing for cardiac channelopathy is a valuable tool in SUD investigations and provides helpful information to medical examiners/coroners seeking cause of death in SUD as well as potentially life-saving information to surviving family members. PMID- 24631776 TI - Efficacy of drug detection by fully-trained police dogs varies by breed, training level, type of drug and search environment. AB - Some recent publications claim that the effectiveness of police canine drug detection is uncertain and likely minimal, and that the deterrent effect of dogs on drug users is low. It is also claimed that more scientific evidence is needed to demonstrate to what extent dogs actually detect drugs. The aim of this research was to assess experimentally, but in actual training and testing environments used by the Polish police, how effective dogs trained by the police were at illicit substance detection depending on factors such as type of drug, dog breed, dog experience with the searching site, and drug odor residuals. 68 Labrador retrievers, 61 German shepherds, 25 Terriers and 10 English Cocker Spaniels, of both sexes in each breed, were used. Altogether 1219 experimental searching tests were conducted. On average, hidden drug samples were indicated by dogs after 64s searching time, with 87.7% indications being correct and 5.3% being false. In 7.0% of trials dogs failed to find the drug sample within 10min. The ranking of drugs from the easiest to the most difficult to detect was: marijuana, hashish, amphetamine, cocaine, heroin. German shepherds were superior to other breeds in giving correct indications while Terriers showed relatively poor detection performance. Dogs were equally efficient at searching in well known vs. unknown rooms with strange (i.e., non-target novelty) odors (83.2% correct indications), but they were less accurate when searching outside or inside cars (63.5% and 57.9% correct indications respectively). During police examination trials the dogs made more false alerts, fewer correct indications and searching time was longer compared to the final stage of the training. The drug odor may persist at a site for at least 48h. Our experiments do not confirm the recent reports, based on drug users' opinions, of low drug detection efficiency. Usefulness of drug detection dogs has been demonstrated here, even if their effectiveness may not be 100%, but different factors have to be taken into consideration to assure maximum effectiveness. PMID- 24631777 TI - Colistin in multi-drug resistant Pseudomonas aeruginosa blood-stream infections: a narrative review for the clinician. AB - Antimicrobial resistance to Pseudomonas aeruginosa is on the rise. In the absence of new anti-pseudomonal drugs, clinicians have had to resort to older antimicrobials such as colistin for the treatment of multi-drug resistant (MDR) strains. This polymyxin compound acts on the outer membrane of the bacteria resulting in its permeability and cell-death. Its bactericidal action is concentration-dependant. This antibiotic is mainly used as salvage therapy in the treatment of often life-threatening infections due to MDR P. aeruginosa blood stream infections (BSI). Its potential nephrotoxicity and neurotoxicity have been overestimated and have limited the use in its intravenous form. A better understanding of its pharmacokinetics and pharmacodynamics, has facilitated more appropriate dosing strategies with a standard 9 million-unit daily-dose that should be adapted to kidney function. Combination treatment that involves the association of colistin with classical anti-pseudomonal treatment has rarely been clinically tested. In vitro synergy has been reported for certain combinations that could be used to prevent or limit the risk of induced resistance in MDR strains. Positioning colistin in antimicrobial strategies especially as a first line treatment remains to be properly assessed. PMID- 24631778 TI - Advantages of sonication fluid culture for the diagnosis of prosthetic joint infection. AB - OBJECTIVES: The sensitivity of periprosthetic tissue culture is inadequate for the diagnosis of prosthetic joint infection (PJI). We investigated and compared the values of sonication fluid culture and periprosthetic tissue culture for diagnosing PJI. METHODS: Included were patients whose joint prosthesis had been removed for any reason. The resulting sonication fluid and periprosthetic tissues were cultured for 14 days. RESULTS: Of 231 explanted prostheses, aseptic failure was diagnosed in 162 cases (70%) and PJI in 69 (30%). In PJI cases, sonication fluid culture detected 62 microorganisms and periprosthetic tissue culture detected 45. Tissue and sonication fluid cultures showed sensitivities of 61% and 81%, respectively (p < 0.01), with specificity of 100% and 99%, respectively. On day 1, tissue and sonication fluid cultures were positive in 13% and 28% (p = 0.013) of PJI cases respectively, and on day 2, in 26% and 48% (p = 0.002) of cases. Four anaerobes grew in sonication fluid culture after 7-13 days incubation, whereas tissue culture missed 3 of these. Prolonged incubation of sonication fluid did not detect any organisms in the cases of aseptic failure. CONCLUSIONS: Sonication fluid culture provides a more rapid diagnosis and detects about 30% more pathogens, although anaerobic organisms require up to 2 weeks of incubation. PMID- 24631779 TI - Combination of adenosine-deaminase and nucleic acid amplification assays for diagnosing tuberculous pleural effusion. PMID- 24631780 TI - Gene variation in IL10 and susceptibility to chronic hepatitis B. AB - OBJECTIVES: To evaluate the correlation between IL-10 gene polymorphisms and hepatitis B infection. METHODS: Tag single nucleotide polymorphisms (SNPs) were used to investigate the relationship between IL-10 gene polymorphisms and susceptibility to chronic hepatitis B virus (HBV) infection by comparing 996 chronic HBV infection cases to 301 acute infection controls. RESULTS: This study found that rs3024490 G/T allele, located in the intron 1 region and highly prevalent in Chinese populations, was significantly different between the chronic HBV infection cases and the acute infection controls in single allele analysis, genetic models analysis, and haplotypes analysis. CONCLUSIONS: This suggested that the rs3024490 within IL-10 was associated with susceptibility to chronic hepatitis B in a Chinese Han population. PMID- 24631781 TI - Modulation of imprinted gene expression following superovulation. AB - Although assisted reproductive technologies increase the risk of low birth weight and genomic imprinting disorders, the precise underlying causes remain unclear. Using a mouse model, we previously showed that superovulation alters the expression of imprinted genes in the placenta at 9.5days (E9.5) of gestation. Here, we investigate whether effects of superovulation on genomic imprinting persisted at later stages of development and assess the surviving fetuses for growth and morphological abnormalities. Superovulation, followed by embryo transfer at E3.5, as compared to spontaneous ovulation (controls), resulted in embryos of normal size and weight at 14.5 and 18.5days of gestation. The normal monoallelic expression of the imprinted genes H19, Snrpn and Kcnq1ot1 was unaffected in either the placentae or the embryos from the superovulated females at E14.5 or E18.5. However, for the paternally expressed imprinted gene Igf2, superovulation generated placentae with reduced production of the mature protein at E9.5 and significantly more variable mRNA levels at E14.5. We propose that superovulation results in the ovulation of abnormal oocytes with altered expression of imprinted genes, but that the coregulated genes of the imprinted gene network result in modulated expression. PMID- 24631782 TI - Cardiovascular effects of statins, beyond lipid-lowering properties. AB - The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, better known as 'statins', are amongst the most widely used medications in the world. They have become a pivotal component in the primary and secondary prevention of coronary artery and vascular disease. However, a growing amount of evidence has suggested that statins also possess strong pleiotropic effects irrespective of their lipid lowering properties, which include enhancement of endothelial function, anti inflammatory and anti-atherothrombotic properties, and immunomodulation. The following provides a comprehensive and updated review of the clinical evidence regarding the pleiotropic effects of statins in cardiovascular disorders and their potential therapeutic benefits. PMID- 24631783 TI - Risk classification of cancer survival using ANN with gene expression data from multiple laboratories. AB - Numerous cancer studies have combined gene expression experiments and clinical survival data to predict the prognosis of patients of specific gene types. However, most results of these studies were data dependent and were not suitable for other data sets. This study performed cross-laboratory validations for the cancer patient data from 4 hospitals. We investigated the feasibility of survival risk predictions using high-throughput gene expression data and clinical data. We analyzed multiple data sets for prognostic applications in lung cancer diagnosis. After building tens of thousands of various ANN architectures using the training data, five survival-time correlated genes were identified from 4 microarray gene expression data sets by examining the correlation between gene signatures and patient survival time. The experimental results showed that gene expression data can be used for valid predictions of cancer patient survival classification with an overall accuracy of 83.0% based on survival time trusted data. The results show the prediction model yielded excellent predictions given that patients in the high-risk group obtained a lower median overall survival compared with low risk patients (log-rank test P-value<0.00001). This study provides a foundation for further clinical studies and research into other types of cancer. We hope these findings will improve the prognostic methods of cancer patients. PMID- 24631784 TI - Tooth model reconstruction based upon data fusion for orthodontic treatment simulation. AB - This paper proposes a full tooth reconstruction method by integrating 3D scanner data and computed tomography (CT) image sets. In traditional dental treatment, plaster models are used to record patient's oral information and assist dentists for diagnoses. However, plaster models only save surface information, and are therefore unable to provide further information for clinical treatment. With the rapid development of medical imaging technology, computed tomography images have become very popular in dental treatment. Computed tomography images with complete internal information can assist the clinical diagnosis for dental implants or orthodontic treatment, and a digital dental model can be used to simulate and predict results before treatment. However, a method of producing a high quality and precise dental model has yet to be developed. To this end, this paper presents a tooth reconstruction method based on the data fusion concept via integrating external scanned data and CT-based medical images. First, a plaster model is digitized with a 3D scanner. Then, each crown can be separated from the base according to the characteristics of tooth. CT images must be processed for feature enhancement and noise reduction, and to define the tooth axis direction which will be used for root slicing. The outline of each slice of dental root can then be determined by the level set algorithm, and converted to point cloud data. Finally, the crown and root data can be registered by the iterative closest point (ICP) algorithm. With this information, a complete digital dental model can be reconstructed by the Delaunay-based region-growing (DBRG) algorithm. The main contribution of this paper is to reconstruct a high quality customized dental model with root information that can offer significant help to the planning of dental implant and orthodontic treatment. PMID- 24631785 TI - Gamma sensitivity of forest plants of Western Ghats. AB - Seeds of Artocarpus hirsutus Lam., Garcinia xanthochymus Hook., Saraca asoca Roxb., Rourea minor Gaertn., Pterocarpus marsupium Roxb., Terminalia chebula Retz., Aporusa lindleyana (Wt.) bail., Holoptelea integrifolia Roxb. and Oroxylum indicum (L.) Vent. were collected from different regions of Western Ghats and exposed to different doses of gamma radiation using Co-60 source. The effect of irradiation was examined on germination, growth and vigor parameters. Decrease in the germination and growth attributes with increased dose was observed in A. hirsutus, G. xanthochymus and S. asoca and thus indicating sensitivity of these plants to radiation. In contrast, enhancement in the germination (percentage), vigor and generation of leaves was observed for P. marsupium, T. chebula, H. integrifolia and O. indicum. These plants were classified as radiation tolerant because of the ability of their seedlings to successfully establish under radiation stress. R. minor and A. lindleyana were able to maintain viability up to 100 Gy dose, however, any further increase in the dose found to have negative effect. PMID- 24631786 TI - Dissolution and oral absorption of pranlukast nanosuspensions stabilized by hydroxypropylmethyl cellulose. AB - The objective of this study was to investigate the effect of particle size on the dissolution and oral absorption of pranlukast microsuspensions and nanosuspensions stabilized by hydroxypropylmethyl cellulose. Four pranlukast suspensions with different mean particle sizes (0.16, 0.89, 3.13, and 18.21MUm) were prepared by various top-down processes such as jet milling, high pressure homogenization, and bead milling. The dissolution rate and oral absorption of pranlukast suspensions were significantly affected by the particle size. The in vivo pharmacokinetic parameters of pranlukast suspensions were increased with decreasing mean particle size of suspensions. Especially, the AUC0->24h and Cmax values of pranlukast nanosuspension with a particle size of 0.16MUm were approximately 3.5- and 6.3-fold greater, respectively, than that of pranlukast microsuspension with a particle size of 18.21MUm. Therefore, the preliminary results from our study suggest that a pranlukast nanosuspension with a mean particle size of about 0.16MUm may have significant potential for clinical application. PMID- 24631787 TI - Rat hepatitis E virus derived from wild rats (Rattus rattus) propagates efficiently in human hepatoma cell lines. AB - Although rat hepatitis E virus (HEV) has been identified in wild rats, no cell culture systems for this virus have been established. A recent report suggesting the presence of antibodies against rat HEV in human sera encouraged us to cultivate rat HEV in human cells. When liver homogenates obtained from wild rats (Rattus rattus) in Indonesia were inoculated onto human hepatocarcinoma cells, the rat HEV replicated efficiently in PLC/PRF/5, HuH-7 and HepG2 cells, irrespective of its genetic group (G1-G3). The rat HEV particles released from cultured cells harbored lipid-associated membranes on their surface that were depleted by treatment with detergent and protease, with the buoyant density in sucrose shifting from 1.15-1.16 g/ml to 1.27-1.28 g/ml. A Northern blotting analysis revealed genomic RNA of 7.0 kb and subgenomic RNA of 2.0 kb in the infected cells. The subgenomic RNA of G1-G3 each possessed the extreme 5'-end sequence of GUAGC (nt 4933-4937), downstream of the highly conserved sequence of GAAUAACA (nt 4916-4923). The establishment of culture systems for rat HEV would allow for extended studies of the mechanisms of viral replication and functional roles of HEV proteins. Further investigation is required to clarify the zoonotic potential of rat HEV. PMID- 24631788 TI - Comprehensive mapping of a novel NS1 epitope conserved in flaviviruses within the Japanese encephalitis virus serocomplex. AB - Nonstructural protein-1 (NS1) of the Japanese encephalitis virus (JEV) is an immunogenic protein that is a potential candidate for the development of vaccines and diagnostic reagents. NS1 is known to be more specific than the E protein in serological testing of flavivirus infections. However, NS1 exhibits cross reactivity among flaviviruses even within the same genus and more so within a serocomplex. However, the cross-reactive epitopes on JEV NS1 are poorly characterized. The present study describes the full mapping of a linear B-cell epitope that is common and specific to the JEV serocomplex of Flaviviridae. We generated an NS1-specific monoclonal antibody that cross-reacts with the West Nile virus (WNV) NS1 protein by immunizing mice with recombinant JEV NS1. For epitope mapping, 51 partially overlapping peptides spanning the entire NS1 protein were expressed with a glutathione S-transferase (GST) tag and screened using monoclonal antibodies. Two linear epitope-containing peptides were identified using enzyme-linked immunosorbent assay (ELISA). By sequentially removing amino acid residues from the carboxy and amino terminal of peptides, we successfully identified the smallest unit of the linear epitope required to react with the monoclonal antibody. The linear epitope was located in amino acids residues 227ETHTLW232. Furthermore, results of the sequence alignment revealed that the epitope was highly conserved among JEV strains. Notably, the epitope is highly conserved among viruses of the JEV serocomplex. Furthermore, the homologous regions on NS1 proteins from dengue viruses showed no cross-reactivity with the monoclonal antibodies. The epitope was recognized by antisera against the WNV but not against the dengue virus. This novel JEV serocomplex-specific linear B-cell epitope of NS1 would be helpful in the development of new vaccines and diagnostic assays. PMID- 24631789 TI - Functional and effective connectivity of stopping. AB - Behavioral inhibition often is studied by comparing the electroencephalographic responses to stop and to go signals. Most studies simply assess amplitude differences of the N200 and P300 event-related potentials, which seem to best correspond to increased activity in the theta and delta frequency bands, respectively. However, neither have reliable indicators for successful behavioral inhibition been identified nor have the causal dependencies of stop-related neurocognitive processes been addressed yet. By studying functional and effective connectivity underlying stopping behavior, this study opens new directions for the investigation of behavioral inhibition. Group independent component analysis was used to infer functionally coherent networks from electroencephalographic data, which were recorded from healthy human participants during processing of a stop signal task. Then, the temporal dynamics of causal dependencies between independent components were identified by means of Bayesian network estimations. The mean clustering coefficient and the characteristic path length measure indicated time windows between 130 and 180 ms and between 420 and 500 ms to express significantly different connectivity profiles between conditions. Three components showed significant correlations between 120 and 260 ms with stop signal reaction times and the number of failed stops. Two of these components acted as sources of causal flow, one capturing P300/delta characteristics while the other was characterized by alpha power depletion putatively representing the evaluation or processing of stimulus features. Although results suggest that the P300 and associated delta activity seem to be statistically dependent on earlier processes associated with behavioral inhibition, the time window critical for inhibition coincides with early changes in causal patterns and largely precedes peak amplitude differences between go and stop trials. Altogether, utilizing the analysis of stopping-related connectivity, previously undetected patterns emerged that warrant further investigation. PMID- 24631790 TI - Frontal alpha oscillations distinguish leaders from followers: multivariate decoding of mutually interacting brains. AB - Successful social interactions rely upon the abilities of two or more people to mutually exchange information in real-time, while simultaneously adapting to one another. The neural basis of social cognition has mostly been investigated in isolated individuals, and more recently using two-person paradigms to quantify the neuronal dynamics underlying social interaction. While several studies have shown the relevance of understanding complementary and mutually adaptive processes, the neural mechanisms underlying such coordinative behavioral patterns during joint action remain largely unknown. Here, we employed a synchronized finger-tapping task while measuring dual-EEG from pairs of human participants who either mutually adjusted to each other in an interactive task or followed a computer metronome. Neurophysiologically, the interactive condition was characterized by a stronger suppression of alpha and low-beta oscillations over motor and frontal areas in contrast to the non-interactive computer condition. A multivariate analysis of two-brain activity to classify interactive versus non interactive trials revealed asymmetric patterns of the frontal alpha-suppression in each pair, during both task anticipation and execution, such that only one member showed the frontal component. Analysis of the behavioral data showed that this distinction coincided with the leader-follower relationship in 8/9 pairs, with the leaders characterized by the stronger frontal alpha-suppression. This suggests that leaders invest more resources in prospective planning and control. Hence our results show that the spontaneous emergence of leader-follower relationships in dyadic interactions can be predicted from EEG recordings of brain activity prior to and during interaction. Furthermore, this emphasizes the importance of investigating complementarity in joint action. PMID- 24631791 TI - Identification and genetic characterization of a new Brazilian genotype of Toxoplasma gondii from sheep intended for human consumption. AB - Recent studies have demonstrated that strains of Toxoplasma gondii in Brazil are frequently different from those detected in other countries, thus making an accurate phylogenetic analysis difficult. The aim of this study was to genetically characterize T. gondii samples from sheep raised in southern Bahia and intended for human consumption, by means of PCR-RFLP and sequencing techniques. Experimental samples were obtained from 200 sheep brains purchased at butcher's shops in Itabuna, Bahia, Brazil. In total, three samples (#54, #124 and #127) were T. gondii-positive. The application of multilocus PCR-RFLP using ten molecular markers (SAG1, SAG2, SAG3, BTUB, c22-8, PK1, GRA6, L358, c-29-2 and Apico) revealed a single genotype common to all samples of this study, which differed from any other published T. gondii genotypes. An atypical allele was detected in the L358 genetic marker; this has not previously been shown in any other South American T. gondii isolates. Phylogenetic analysis on the sequences from multilocus PCR sequencing revealed that these three samples were classified into the same lineage. Extensive indel regions were detected in the Apico genetic marker. Together, our findings revealed a new Brazilian T. gondii genotype. Further research should be conducted to enrich the database of Brazilian T. gondii genotypes from different regions. This will make it possible to understand the phylogenetic relationship between isolates. PMID- 24631792 TI - Cardiovascular results of an individually controlled complex prevention. AB - Lifestyle modifications (increased level of physical activity, favourable nutrition, and stress management) are important factors in the prevention of and the therapy for cardiovascular (CV) diseases. OBJECTIVES: The effects of an individualized, half-year long exercise program on CV risk factors were investigated in 50 patients with moderately high CV risk factors. PATIENTS AND METHODS: 75 subjects participated in the study. After the eleventh week of regular training, members of Group A performed 55-65 minutes of exercise at 4-5 times a week, while patients in Group B took part in 45-55 minute training sessions at 2-3 times a week. Activities were monitored using POLAR devices and controlled by a cardiologist and an exercise training expert. Members of the control group (C)were also affected by risk factors, they, however, were not involved in any physical activity. RESULTS: A marked improvement was seen in performance level (62% in Group A, 38% in Group B). There was a decrease in the LDL cholesterol level (30% and 21%), total cholesterol (16% and 14%), triglyceride (23% in both groups), and an increase in the HDL-cholesterol level (53% and 26%). Body mass (BM) decreased in both groups (8.7% and 5%).In addition, a decrease was also seen in the resting heart rate (HR) (9.6% and 4.5%) and blood pressure (BP: systolic 8.5% and 5.5 %, diastolic 7% and 4.7%). CONCLUSIONS: In persons affected by CV risk factors, lifestyle modification with personal, HR controlled complex (cardio and resistance) aerobic training effectively decreased CV risk factors and strongly improved state of health and quality of life. PMID- 24631793 TI - Assessment of cerebral tissue oxygen saturation in septic patients during acetazolamide provocation - a near infrared spectroscopy study. AB - Sepsis-associated encephalopathy is a multifactorially determined process of the brain parenchyma. Among other factors, vasogenic causes have been shown to play a role in its development. The aim of the present work was to assess whether cerebral tissue oxygen saturation is influenced by administration of acetazolamide in septic patients compared to controls. PATIENTS AND METHODS: 15 patients with severe sepsis and 10 healthy controls were studied. Cerebral oxygen saturation was assessed by INVOS 51 OOC Cerebral Oxymeter (NIRS) before and after administration of 15 mg/kg BW acetazolamide in both groups. RESULTS: The maximal rise that has been found in the partial pressure of CO(2) in the arterial blood of septic patients after administration of acetazolamide was from 35 +/- 5 mmHg to 41.1 +/- 6.3 mmHg. For the partial pressure of O(2) the observed increase was from 123.7 +/- 47.1 mmHg to 139.9 +/- 49 mmHg. Vasodilatory stimulus resulted in a similar maximal increase in cerebral oxygen saturation in septic patients and in controls (8.9 +/- 6.5% for septic patients and 9.2 +/- 4.6% for healthy persons, respectively). CONCLUSIONS: Cerebral vasoreactivity to acetazolamide is preserved in patients with severe sepsis. PMID- 24631794 TI - HPLC determination of brain biogenic amines following treatment with bispyridinium aldoxime K203. AB - Effect of a new acetylcholine-esterase reactivator, K203 as a new potential antidote in organophosphate intoxications was studied on dopamine (DA), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels in seven brain regions (cerebellum, spinal cord, hippocampus, hypothalamus, striatum, medulla oblongata and frontal cortex) of rats by an optimized and validated HPLC method. No significant change in brain level of these neurotransmitters was found either 15 or 60 min following treatment. However, when 5-HIAA/5-HT ratios were calculated as measure of turnover, significant decreases were found in the cerebellum, hippocampus, hypothalamus and the frontal cortex 15 min following K203 administration, but after 60 min only in the frontal cortex. PMID- 24631795 TI - Investigation of delta-aminolevulinic acid dehydratase polymorphism affecting hematopoietic, hepatic and renal toxicity from lead in Han subjects of southwestern China. AB - This study is to explore the effect of ALAD polymorphism on hematopoietic, hepatic and renal toxicity from lead in occupational exposure workers. METHODS: We conducted a cross-sectional study on 156 workers with occupational exposure to lead between 2002 and 2007. The results of laboratory examinations were analyzed. RESULTS: The authors found that workers with the ALAD 1-1 genotype were associated with higher blood lead level than those with the ALADl-2 genotype. Blood and urine lead levels were much higher in storage battery workers than in cable workers. The urine ALA and blood ZPP levels in workers with the ALAD 1-1 genotype were higher than those with the ALADl-2 genotype. The serum Cr level in workers with the ALADl-1 genotype was much higher than those with the ALADl-2 genotype especially in higher lead exposure level. CONCLUSIONS: The ALAD-2 protein might modify the kinetics of lead in blood at a relatively higher blood lead level and protect against hematopoietic, hepatic and renal toxicity from lead. Urine ALA, blood ZPP and serum Cr levels might be considered as effective biological monitoring partners of lead induced hematopoietic and renal toxicology. PMID- 24631797 TI - Cooperative mechanisms involved in chronic antidiuretic response to bendroflumethiazide in rats with lithium-induced nephrogenic diabetes insipidus. AB - Previous studies of central diabetes insipidus suggested that thiazides acutely exerted a paradoxical antidiuresis by either indirectly activating volume homeostatic reflexes to decrease distal fluid-delivery, or directly stimulating distal water-reabsorption. This study investigated whether the direct and indirect actions of bendroflumethiazide (BFTZ) simultaneously cooperated and also whether the renal nerves were involved in inducing long-term antidiuresis in nephrogenic diabetes insipidus (NDI). BFTZ or vehicle was gavaged into bilateral renal denervated and innervated rats with lithium-induced NDI for 10 days, constituting four groups. At one day before (D0) and one, five and ten days after starting administration of BFTZ or vehicle, rats were placed in metabolic cages to collect urine for 6 hours. BFTZ-treatment in both renal innervated and denervated rats caused equivalent reductions in urine-flow, creatinine clearance, lithium clearance and free-water clearance, but rises in urine-osmolality, fractional proximal reabsorption and fractional distal reabsorption at all days compared to D0, as well as to those of their relevant vehicle-received group. Therefore, the chronic antidiuretic response to BFTZ in conscious NDI rats was exerted through a concomitant cooperation of its direct distal effect of stimulating water-reabsorption and its indirect effect of reducing distal fluid delivery by activating volume-homeostatic mechanisms, which appeared independent of the renal nerves. PMID- 24631796 TI - The impact of dehydroepiandrosterone on indomethacin-induced gastric lesions in rats. AB - Gastric ulcer is a common gastrointestinal disease. One suggested mechanism is increased oxidative stress. Puplished data showed that dehydroepiandrosterone (DHEA) may limit oxidative stress and lipid peroxidation. OBJECTIVE: To investigate the protective effect of DHEA on indomethacin-induced gastric ulcers in rats. METHODS: Forty male rats were randomly divided into four groups: l) CONTROL GROUP: receive the vehicle, 2) DHEA-treated group, 3) Indomethacin induced ulcer group and 4) DHEA pretreated (prior to indomethacin) group. At the end of the experiment, rats were killed and the gastric contents were collected to determine the pH and acid concentration. Gastric mucosa was examined macroscopically and then parts of the tissues were collected for histopathological examination. Other parts of the gastric mucosa were homogenized to measure the levels of lipid peroxidation and oxidative stress parameters. RESULTS: Indomethacin-treated rats showed increased gastric acidity, acid concentration and ulcer index as compared to control rats. This is confirmed by histopathological studies. DHEA pre-treatment proir to indomethacin administration ameliorated all changes seen in the ulcered group. CONCLUSION: DHEA has a protective effect against indomethacin-induced gastric ulcers through decreasing acid secretion, prevention of lipid peroxidation and improving endogenous gastric antioxidant system. PMID- 24631798 TI - The role of sex hormones in induced-systemic inflammation in female albino rats. AB - Estrogen (E(2)) and progesterone (P) hormones have a pro-inflammatory and an anti inflammatory role under different conditions. The current study explored this phenomenon in the context of septic inflammation. MATERIALS AND METHODS: This study involved 48 female albino rats. E(2) (4 mg/100 g body weight (b.w.) and P (5 mg/kg b.w.) were administered to ovariectomized (OVX) rats after systemic inflammation (SI) induced by puncturing the caecum I cm from its end with a single hole by using a 21-gauge needle. Key indices of inflammation and apoptosis were evaluated. RESULTS: OVX animals subjected to SI showed significantly increased levels of serum tumor necrosis factor-alpha (TNF-u), C reactive protein (CRP) and alanine aminotransferase (ALT). They also showed higher levels of expression of the enzyme inducible nitric oxide synthase (iN OS); 312 +/- 43 mg/ml; in the liver, and the activity of both cyclooxygenase 2 (COX-2); 59.4 +/- 3.2 U/ml; and caspase 3 enzymes; 6.3 +/- 0.54 ng/ml; when compared to non-OVX animals subjected to (SI), (180 +/- 3 mg/ml, 16.4 +/- 1.69 U/ml, 0.98 +/- 0.23 ng/ml respectively). Administration of E(2) resulted in a significant reduction of all serum and liver tissue parameters of inflammation (e.g.decreased iNOS; 193 +/- 28 mg/ml and COX-2; 27.6 +/- 3.91 U/ml) and decreased apoptosis (Caspase 3; 1.18 +/- 0.21 ng/ml). In contrast, OVX animals injected with P before induction of SI showed a significant rise of all measured parameters. CONCLUSIONS: E(2) and Pin physiological levels have contrasting though complementary roles in regulation of the immune system possibly allowing a limited inflammatory response while preventing excessive damage to the tissues. PMID- 24631799 TI - Age-related changes in error processing in young children: a school-based investigation. AB - Growth in executive functioning (EF) skills play a role children's academic success, and the transition to elementary school is an important time for the development of these abilities. Despite this, evidence concerning the development of the ERP components linked to EF, including the error-related negativity (ERN) and the error positivity (Pe), over this period is inconclusive. Data were recorded in a school setting from 3- to 7-year-old children (N=96, mean age=5 years 11 months) as they performed a Go/No-Go task. Results revealed the presence of the ERN and Pe on error relative to correct trials at all age levels. Older children showed increased response inhibition as evidenced by faster, more accurate responses. Although developmental changes in the ERN were not identified, the Pe increased with age. In addition, girls made fewer mistakes and showed elevated Pe amplitudes relative to boys. Based on a representative school based sample, findings indicate that the ERN is present in children as young as 3, and that development can be seen in the Pe between ages 3 and 7. Results varied as a function of gender, providing insight into the range of factors associated with developmental changes in the complex relations between behavioral and electrophysiological measures of error processing. PMID- 24631800 TI - Visuospatial working memory in very preterm and term born children--impact of age and performance. AB - Working memory is crucial for meeting the challenges of daily life and performing academic tasks, such as reading or arithmetic. Very preterm born children are at risk of low working memory capacity. The aim of this study was to examine the visuospatial working memory network of school-aged preterm children and to determine the effect of age and performance on the neural working memory network. Working memory was assessed in 41 very preterm born children and 36 term born controls (aged 7-12 years) using functional magnetic resonance imaging (fMRI) and neuropsychological assessment. While preterm children and controls showed equal working memory performance, preterm children showed less involvement of the right middle frontal gyrus, but higher fMRI activation in superior frontal regions than controls. The younger and low-performing preterm children presented an atypical working memory network whereas the older high-performing preterm children recruited a working memory network similar to the controls. Results suggest that younger and low-performing preterm children show signs of less neural efficiency in frontal brain areas. With increasing age and performance, compensational mechanisms seem to occur, so that in preterm children, the typical visuospatial working memory network is established by the age of 12 years. PMID- 24631801 TI - Influence of inspiratory muscle weakness on inspiratory muscle training responses in chronic heart failure patients: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether the impact of inspiratory muscle weakness on inspiratory muscle training (IMT) affects inspiratory function and exercise capacity in chronic heart failure (CHF) patients. DATA SOURCES: Electronic searches were performed using the Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Cochrane Systematic Review, Embase, MEDLINE, and Physiotherapy Evidence Database (PEDro) databases up to August 2013. STUDY SELECTION: Articles were included if participants had CHF and were >18 years old; the design was a randomized controlled trial; intervention was IMT; measurements were of inspiratory muscle function or exercise capacity; and the articles were published in English, Portuguese, or Spanish. Of the 1455 articles identified in the database searches, 9 studies met the inclusion criteria. DATA EXTRACTION: Two independent reviewers selected and extracted information from articles and assessed the quality of the studies using the PEDro scale. The 2 reviewers discussed disagreements until consensus was achieved. DATA SYNTHESIS: Meta-analyses compared IMT with controls/sham for maximal inspiratory pressure, sustained maximal inspiratory pressure, 6-minute walk distance, peak oxygen consumption, and minute ventilation after IMT. Subgroup analyses compared those with and without muscle weakness. CHF with inspiratory muscle weakness showed greater gains in the 6-minute walk distance and peak oxygen consumption compared with those with normative maximal inspiratory pressure. The mean quality analysis score was 7.1, and scores ranged from 6 to 10. CONCLUSIONS: The results emphasize the importance of evaluating the inspiratory muscles to identify patients with CHF and inspiratory muscle weakness; subgroup that showed better results after IMT. PMID- 24631802 TI - Upper limb assessment in multiple sclerosis: a systematic review of outcome measures and their psychometric properties. AB - OBJECTIVE: To provide an overview of applied upper limb outcome measures in multiple sclerosis (MS) according to the International Classification of Functioning, Disability and Health (ICF) levels and to review their psychometric properties in MS. DATA SOURCES: PubMed and Web of Knowledge. STUDY SELECTION: Articles published until June 2013 were selected when written in English, published in the last 25 years, peer reviewed, including >5 persons with MS, and including standardized clinical upper limb outcome measures. Included articles were screened based on title/abstract and full text by 2 independent reviewers. In case of doubt, feedback from a third independent reviewer was obtained. Additionally, references lists were checked for relevant articles. Of the articles, 109 met the selection criteria and were included for data extraction. DATA EXTRACTION: All reported clinical upper limb outcome measures were extracted from the included studies and classified according to the ICF levels by 2 independent reviewers. In addition, available psychometric properties (reliability, validity, responsiveness) in MS were summarized and discussed. DATA SYNTHESIS: A diversity of outcome measures assessing impairments on the body functions and structures level (n=33), upper limb capacity (n=11), and performance (n=8) on the activity level were extracted from 109 articles. Hand grip strength and the nine-hole peg test (NHPT) were the most frequently used outcome measures. However, multiple outcome measures are necessary to encapsulate the multidimensional character of the upper limb function. The psychometric properties were insufficiently documented for most of the outcome measures, except for the NHPT. CONCLUSIONS: The results of this review may help with the selection of appropriate outcome measures and may guide future research regarding the psychometric properties in MS. PMID- 24631803 TI - Relaxation selective pulses in fast relaxing systems. AB - In this work, the selectivity or sharpness of the saturation profiles for relaxation selective pulses (R^rsps) that suppress magnetization possessing relaxation times of T2=T2(rsp) and T1=alphaT2 for alpha?12,infinity was optimized. Along with sharpening the selectivity of the R^rsps, the selective saturation of these pulses was also optimized to be robust to both B0 and B1 inhomogeneities. Frequency-swept hyperbolic secant and adiabatic time-optimal saturation pulse inputs were found to work best in the optimizations, and the pulse lengths required to selectivity saturate the magnetization were always found to be less than the inversion recovery delay, T1ln(2). The selectivity of the optimized relaxation selective pulses was experimentally demonstrated in aqueous solutions with varying concentrations of the paramagnetic species, [Mn(+2)], and for use in solvent suppression. Finally, the "rotational" properties of spin relaxation were explored along with an analytical derivation of adiabatic time-optimal saturation pulses. PMID- 24631804 TI - High-speed countercurrent chromatographic recovery and off-line electrospray ionization mass spectrometry profiling of bisdesmodic saponins from Saponaria officinalis possessing synergistic toxicity enhancing properties on targeted antitumor toxins. AB - Saponaria officinalis L. (Caryophyllaceae), also known as fuller's herb or soapwort is a medicinal plant, which grows from Europe to Central Asia. Medicinal properties attributed to this plant include its antitussive and galactogogue properties. Recently, bisdesmodic saponins with very specific structural features from S. officinalis have been shown to strongly enhance the efficacy of specific targeted toxins (anti-tumor antibodies connected to protein toxins) in-vitro and in-vivo in a synergistic manner. In the presently reported novel approach we used preparative all-liquid high-speed countercurrent chromatography (HSCCC) to recover a total of 22 fractions using biphasic solvent system tert butylmethylether/n-butanol/acetonitrile/water 1:3:1:5 (v/v/v/v) from a complex precipitated crude saponin mixture. Out of these 22 fractions, 3 fractions had the enhancer effect on anti-tumor toxins out of which one fraction (F7) was further tested elaborately in different cell lines. The molecular weight distribution and compound profiles of separated saponins were monitored by off line injections of the sequentially collected fractions to an electrospray ion trap mass-spectrometry system (ESI-IT-MS). The functional saponin fractions were mainly bisdesmosidc and contained saponin m/z 1861 amongst other. Using the bio assay guided monitoring, the highly active fractions containing 2 to 3 bisdesmodic saponins (5MUg/mL) were screened for their effectiveness in enhancing the anti-tumor activity of targeted toxin Sap3-EGF, which was determined using the impedance based real-time cell cytotoxicity evaluation. This novel combination of HSCCC fractionation, MS-target-guided profiling procedure and bio assay guided fractionation yielded 100mg of functional saponins from a 60g crude drug powder in a rapid and convenient manner. PMID- 24631805 TI - Simultaneous determination of 12 illicit drugs in whole blood and urine by solid phase extraction and UPLC-MS/MS. AB - A rapid and sensitive method based on solid phase extraction and ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) for the simultaneous determination of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylene dioxymethamphetamine, N-methyl-1-(3,4-methyl-enedioxyphenyl)-2-butanamine, 3,4 methylenedioxyethylamphetamine, p-methoxymethamphetamine, ephedrine, N methylephedrine, cathinone, methcathinone, and ketamine in whole blood and urine was developed and validated. Following solid phase extraction, the analytes were separated on ACQUITY UPLC BEH Phenyl column (100mm*2.1mm, 1.7MUm) under gradient elution using a mobile phase containing of acetonitrile and 0.3% formic acid in water at a flow rate of 0.4mLmin(-1) and analyzed by a triplequadrupole mass spectrometer in the multiple reaction monitoring (MRM) mode. The proposed method was linear for each analyte with correlation coefficients over 0.99. Recovery validation studies showed accuracy bias below 4.4%. Acceptable precision was also obtained with a relative standard deviation below 8.9%. The sensitivity of the assay was found to be adequate for the quantitation of the illicit drugs in whole blood and urine sample and was higher than reported methods. The present method was proved to be reliable and robust for drug screening in forensic toxicological analysis. PMID- 24631806 TI - New metabolite profiles of Danshensu in rats by ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - In our research, ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry (U-HPLC/Q-TOF-MS) was established for analyzing the metabolite profiles of Danshensu (DSS) in rat feces, bile, urine, plasma and the possible metabolic pathways were subsequently proposed after the oral dose of 80mg/kg; rat biological samples were collected and pretreated by protein precipitation. Then, the samples were injected into an Acquity ultraperformance liquid chromatography BEHC column with mobile phase consisted of acetonitrile (solvent A)-0.1% formic acid-water (solvent B) with a linear gradient elution program. Totally, 17 metabolites of DSS were identified, including 4, 5, 4 and 4 metabolites in the feces, urine, blood, and bile samples respectively. Most of them were to our knowledge reported for the first time. The results indicated that DSS was metabolized via dehydrogenation, deoxygenation, methylation, glucuronidation, and sulfation pathways in vivo. Among these, methylation was considered as the main physiologic processes of it. This study revealed that U-HPLC/Q-TOF-MS was more accurate and sensitive to detect and identify the possible metabolites and to better understand the metabolism of DSS in vivo. PMID- 24631807 TI - Ion-pair reversed-phase high performance liquid chromatography method for the quantification of isoaspartic acid in a monoclonal antibody. AB - Isomerization of aspartic acid residues is one of the major causes of chemical degradation during the shelf life of biological pharmaceuticals. Monoclonal antibody biopharmaceuticals are typically stored at mildly acidic pH conditions, which can lead to the isomerization reaction. The mechanism of this non-enzymatic chemical reaction has been studied in great detail. However, the identification and quantification of the isomerization sites in a given protein still remains a challenge. We developed an ion-pair reversed-phase HPLC method for the separation of an intact monoclonal antibody variant containing a single isoaspartic acid residue from its native counterpart. We identified and characterized the isomerization site using ion-pair reversed-phase HPLC mass spectrometry methods of the reduced and alkylated antibody and the enzymatically cleaved antibody. Lys C followed by Asp-N digestion of the antibody was used for the identification of the isomerization site. Electron transfer dissociation (ETD) mass spectrometry was used to confirm the isomerization site at a DY motif at an aspartic acid residue in the CDR-H3 region of the antibody. Tyrosine at the C-terminus of an aspartic acid residue is typically not regarded as a hot spot for isomerization. Our findings suggest that it is not possible to predict isomerization sites in proteins with confidence and all aspartic acid residues located in the CDR regions of antibodies must be considered as potential isomerization site due to the solvent exposure or the flexibility of these regions of the molecule. Additionally, the effect of the pH on the isomerization rate was evaluated using the ion-pair reversed-phase HPLC method, showing that at a lower pH the isomerization rate is faster. Storage at 25 degrees C for 6 months resulted in an increase of the amount of isoaspartic acid to 6.6% at pH 5.4, 6.0% at pH 5.8, and 5.6% at pH 6.2. PMID- 24631808 TI - Matrix influence on derivatization and ionization processes during selenoamino acid liquid chromatography electrospray ionization mass spectrometric analysis. AB - Considering the importance of derivatization in LC/ESI/MS analysis, the objective of this work was to develop a method for evaluation of matrix effect that would discriminate between matrix effect due to the derivatization reaction yield and from the ESI. Four derivatization reagents (TAHS, DEEMM, DNS, FMOC-Cl) were studied with respect to matrix effects using two selenoamino acids and onion matrix as model system. A novel method for assessing matrix effects of LC/ESI/MS analyses involving derivatization is proposed, named herein post-derivatization spiking, that allows evaluating effect of matrix on ESI ionization without derivatization reaction yield contribution. The proposed post-derivatization spiking method allowed to demonstrate that the reason of reduced analytical signal can be signal suppression in ESI (as in case of DNS derivatives with matrix effects 38-99%), alteration of derivatization reaction yield (TAHS, matrix effects 92-113%, but reaction yields 20-50%) or both (FMOC-Cl, matrix effects 28 88% and reaction yields 50-70%). In case of DEEMM derivatives, matrix reduces reaction yield but enhances ESI/MS signal. A method for matrix effect evaluation was developed. It was also confirmed that matrix effects can be reduced by dilution. PMID- 24631809 TI - Affinity selection of histidine-containing peptides using metal chelate methacrylate monolithic disk for targeted LC-MS/MS approach in high-throughput proteomics. AB - In recent years, bottom-up approach has become the popular method of choice for large scale analysis of complex proteome samples. Peptide fractionation determines the efficiency of the bottom-up method and often the resolving power of reverse phase liquid chromatography (RPLC) is insufficient for efficient protein identification in case of complex biological samples. To overcome the inherent limitation of proteomics associated with sample complexity, we evaluated fast flow metal chelate methacrylate monolithic system - CIM (Convective Interaction Media) disk chelated with Cu(II) for targeted affinity selection of histidine-containing peptides. Initially the Cu(II)-IMAC using CIM disk was evaluated using tryptic digest of protein mixtures of 8 model proteins and was found to be highly efficient in capturing His-containing peptides with high degree of specificity and selectivity. Further the efficiency of His-peptide enrichment using CIM-IMAC was also demonstrated using complex biological samples like total Escherichia coli cell lysate. The analysis of the Cu(II)-IMAC retained peptides from tryptic digests of model protein mixture and E. coli not only demonstrated a significant reduction in sample complexity but also subsequently enabled the identification of additional peptides. His-peptide enrichment also enabled the identification of low abundant proteins that were not detected in the analysis of total E. coli digest. PMID- 24631810 TI - A new approach to develop a standardized method for assessment of acetylcholinesterase inhibitory activity of different extracts using HPTLC and image analysis. AB - A new, validated, sensitive and cheap method for preliminary quantitative evaluation of acetylcholine esterase inhibitory activity is presented. The proposed method combines HPTLC with data analysis by means of image processing software. An in-situ TLC autobiographic method was employed in which regions of the TLC plate which contain acetylcholinesterase inhibitors show up as white spots against the yellow background. Bleaching of the yellow color, caused by substances with acetylcholinesterase inhibitory activity was observed and recorded using a digital camera. ImageJ, JustTLC and Sorbfil, three image processing programs were evaluated for quantitative measurements. For evaluation of the assay efficiency, acetylcholinesterase inhibitory activity of different Amaryllidaceae plant extracts was expressed as Standard Activity Coefficients (SACs), which are relative measures of the activity to the well known acetylcholinesterase inhibitor eserine. We attempted to validate the method according to the ICH guideline. Different statistical data revealed that all image analysis software are able to detect the acetylcholine esterase inhibitory activity at very low concentration levels with the ImageJ program being the best of all three tested software regarding sensitivity, linearity and precision. PMID- 24631811 TI - High-performance liquid chromatography assay with programmed flow elution for cisatracurium in human plasma: application to pharmacokinetics in infants and children. AB - A high-performance liquid chromatography (HPLC) assay with fluorescence detection (FLD) for quantification of cisatracurium in human plasma was developed and fully validated. Liquid-liquid extraction was employed for sample preparation. The separation was carried out on a C18 column with ternary mobile phase composed of 30mmolL(-1) phosphate buffer (pH 3.0), acetonitrile and methanol (60:35:5, v/v/v). Verapamil was used as the internal standard. The isocratic elution with programmed flow rate was employed by setting at 0.8mLmin(-1) from 0 to 3.5min, 0.5mLmin(-1) from 3.5 to 6min, and 1.0mLmin(-1) from 6 to 10min. The fluorescence detection was performed at 236nm for excitation and 324nm for emission. The assay was linear from 50 to 2800ngmL(-1), with a detection limit of 12ngmL(-1). The correlation coefficient (r) for linear regression was 0.9997. The intra-day coefficients of variation (CVs) were less than 2.0%, and the inter-day CVs were less than 4.0%. The mean recoveries were in the range of 92.1-100.4%. The total HPLC run time was less than 10min. The developed HPLC method was fast, simple, sensitive, accurate and suitable for studying the pharmacokinetics of cisatracurium in infants and children after intravenous administration. PMID- 24631812 TI - Identification of metabolites of propyrisulfuron in rats. AB - The metabolites found in the urine, feces and bile of male and female rats administered with (14)C-labeled herbicide, propyrisulfuron [1-(2-chloro-6 propylimidazo[1,2-b]pyridazin-3-ylsulfonyl)-3- (4,6-dimethoxypyrimidin-2-yl)urea] were identified by high-performance liquid chromatography (HPLC) with the ultraviolet (UV) and radioisotope (RI) detectors, tandem mass spectrometry and nuclear magnetic resonance (NMR). Administered (14)C was excreted into the urine (5.7-29.8%) and feces (64.6-97.4%). Urine and bile samples were concentrated and purified using a solid-phase extraction cartridge, and fecal homogenates were extracted using acetonitrile. Conjugates were hydrolyzed with enzyme or hydrochloric acid solution for identification. The proposed major metabolic reactions of propyrisulfuron are as follows: (1) hydroxylation of the pyrimidine ring, propyl group, and imidazopyridazine ring, (2) O-demethylation, (3) cleavage of the pyrimidine ring, and (4) glucuronic acid and sulfate conjugation. The metabolic patterns found are not different among sulfonylurea herbicides. PMID- 24631813 TI - Enantiomeric separation of functionalized ethano-bridged Troger bases using macrocyclic cyclofructan and cyclodextrin chiral selectors in high-performance liquid chromatography and capillary electrophoresis with application of principal component analysis. AB - The enantiomeric separation of a series of racemic functionalized ethano-bridged Troger base compounds was examined by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Using HPLC and CE the entire set of 14 derivatives was separated by chiral stationary phases (CSPs) and chiral additives composed of cyclodextrin (native and derivatized) and cyclofructan (derivatized). Baseline separations (Rs>=1.5) in HPLC were achieved for 13 of the 14 compounds with resolution values as high as 5.0. CE produced 2 baseline separations. The separations on the cyclodextrin CSPs showed optimum results in the reversed phase mode, and the LARIHCTM cyclofructan CSPs separations showed optimum results in the normal phase mode. HPLC separation data of the compounds was analyzed using principal component analysis (PCA). The PCA biplot analysis showed that retention is governed by the size of the R1 substituent in the case of derivatized cyclofructan and cyclodextrin CSPs, and enantiomeric resolution closely correlated with the size of the R2 group in the case of non-derivatized gamma cyclodextrin CSP. It is clearly shown that chromatographic retention is necessary but not sufficient for the enantiomeric separations of these compounds. PMID- 24631814 TI - Monitoring of in vivo manipulation of nitric oxide synthases at the rat retina using the push-pull perfusion sampling and capillary electrophoresis. AB - Proteins play a variety of functional roles in tissues that underlie tissue health. The measurement of protein function is important to both understand normal and dysfunctional tissue states. Low-flow push-pull perfusion sampling (LFPS) has been used to collect submicroliter volumes of extracellular fluid which are well suited to capillary electrophoresis for compositional quantitative analysis. In this study, LFPS is used to deliver pharmacological agents to the in vivo retinal tissues at the probe sampling tip during sampling to measure protein function. Two native nitric oxide synthase enzymes were pharmacologically inhibited and the enzyme product NO metabolite, nitrate, was determined with capillary electrophoresis from the perfusates. LFPS delivered inhibitors including the non-selective N(G)-nitro-Larginine methyl ester (L-NAME), the nNOS selective 7-nitroindazole (7-NI), and eNOS N5-(1-imioethyl)-L-ornithine, dihydrochloride (L-NIO) were perfused to the sampling region either directly over a rat retina optic nerve head or 1-mm peripheral to the ONH. At the PONH, 65, 55 and 60% of baseline nitrate levels, respectively, were observed with inhibitor infusion. These are statistically significant (P<0.05) compared to saline drug infusion. However, infusion of the inhibitors to the ONH did lead to significant nitrate concentration decreases. This data suggests that the endogenous enzymes, nNOS and eNOS, are both spatially and functionally localized to the PONH at the in vivo rat retina. PMID- 24631815 TI - Determination of Celecoxib in human plasma using liquid chromatography with high resolution time of flight-mass spectrometry. AB - A sensitive method for the determination of Celecoxib (CXB) in human plasma samples was developed using liquid chromatography coupled to electrospray ionization and time of flight mass spectrometry (LC-ESI-TOF-MS). A full factorial design of experiments (FF-DOE) methodology was applied to optimize the ESI conditions for CXB determination and also to predict the effects of interactions of multiple parameters affecting ionization (i.e., capillary voltage, fragmentor voltage, electrolyte and electrolyte concentration). The optimum ionization voltages were 4500V and 220V for capillary and fragmentor, respectively. Even though the highest ESI efficiency was obtained without electrolytes, the addition of 1.0mM ammonium acetate was shown to be essential to buffer the matrix effect and ensure a consistent response. In contrast to previous studies, deuterated CXB was used as a recovery (surrogate) standard, which enabled the correction of CXB loss during sample preparation. The extraction recovery using solid phase extraction was 87-98%. The instrumental limit of detection of CXB (LOD), 0.33ng/mL, and matrix affected LOD, 0.55ng/mL, were similar and comparable to the previously reported LC-MS/MS LODs. This method was employed to determine CXB concentrations in human plasma samples. Upon administration of 400mg CXB to the healthy women, the concentrations found in the plasma were 440-3300ng/mL. The inter-day repeatability was less than 4% RSD. PMID- 24631816 TI - Validation and clinical evaluation of a UHPLC method with fluorescence detector for plasma quantification of doxorubicin and doxorubicinol in haematological patients. AB - A rapid and simple UHPLC-fluorescence detection method for the quantification of doxorubicin and its main metabolite, doxorubicinol, in human plasma has been developed. The method was also validated for its application in therapeutic drug monitoring, a clinical approach used in the optimization of oncologic treatments. Following a single protein precipitation step, chromatographic separation was achieved using a C18 column (50mm*2.10mm, particle size 1.7MUm) at 50 degrees C with a mobile phase consisting of water (containing 0.4% triethylamine and 0.4% orthophosphoric acid)/acetonitrile (77:23, v/v). Flow rate was 0.50mL/min and fluorescence detection with an excitation wavelength of 470nm and an emission wavelength of 548nm was used. The method met the specifications of linearity, selectivity, sensitivity, accuracy, precision and stability of the FDA and EMA guidelines for the validation of bioanalytical methods. Linearity for the drug (8 3000ng/mL) and the metabolite (3-150ng/mL) was observed (R(2)>0.992) and the maximum intra-day and inter-day precision coefficients of variation were less than 14% for both. The lower limits of quantification were 8 and 3ng/mL for doxorubicin and doxorubicinol, respectively. The method was successfully applied to the quantify plasma concentrations of doxorubicin and doxorubicinol in 33 patients diagnosed with haematological malignancies in which broad ranges for drug (8.3-2766.0ng/mL) and metabolite (4.8-104.9ng/mL) levels were measured adequately. PMID- 24631817 TI - Comparison of solid phase- and liquid/liquid-extraction for the purification of hair extract prior to multi-class pesticides analysis. AB - The present study focuses on the influence of a purification step - after extraction of pesticides from hair and before analysis of the extract - on the sensitivity of analytical methods including compounds from different chemical classes (both parent and metabolites). Sixty-seven pesticides and metabolites from different chemical classes were tested here: organochlorines, organophosphates, carbamates, pyrethroids, ureas, azoles, phenylpyrazoles and neonicotinoids. Two gas chromatography-negative chemical ionization-tandem mass spectrometry methods and one based on ultra-performance liquid chromatography electrospray tandem mass spectrometry were used. Seven solid-phase extraction cartridges: C18, S-DVB, PS-DVB, GCB, GCB/PSA, SAX/PSA and Florisil/PSA were tested and compared to more classical liquid-liquid extraction procedures using ethyl acetate, hexane and dichloromethane. Although LLE allowed obtaining good results for some compounds, on the whole, SPE clearly provided better recovery for the majority of the pesticide residues tested in the present study. GCB/PSA was clearly the best suited to non-polar compounds such as organochlorines, pyrethroids and organophosphates, with recovery ranging from 45.9% (diflufenican) to 117.1% (parathion methyl). For hydrophilic metabolites (e.g. dialkyl phosphates and other organophosphate metabolites, pyrethroid metabolites, phenols and carbamate metabolites), the best results were obtained with PS-DVB, with recovery ranged from 10.3% (malathion monocarboxylic acid) to 93.1% (para nitrophenol). For hydrophilic parent pesticides (e.g. neonicotinoids, carbamates, azoles) and metabolites without nucleophilic functions, the best recovery was obtained with SAX/PSA, with recovery ranging from 52.1% (3-hydroxycarbofuran) to 100.9% (3,4-dichloroaniline). Solid phase extraction was found to be more suitable than the liquid-liquid extraction for pesticides and their metabolites determination in terms of number of extracted compounds and their recovery. Moreover, the use of solid phase extraction cartridges has enabled the reduction of the analytical background noise, resulting in better chromatographic separations. PMID- 24631818 TI - Drug detection by tandem mass spectrometry on the basis of adduct formation. PMID- 24631819 TI - fRMSDchiral: a novel algorithm to represent differences between positions of stereoisomers in complex with dissymmetric binding site. AB - The ability of molecules to distinguish between optical isomers is crucial for living systems. The change of position of one enantiomer in respect to the position of the second enantiomer within an asymmetric binding site may be analyzed on different levels. Root Mean Square Deviation (RMSD) may be used for such analyses with low precision. Additional fragment level variants of RMSD allow for more precise definition of differences in location of the main molecular features responsible for recognition of stereoisomers by a selector. Three fRMSDchiral parameters appear to be very useful to precisely quantify the change in orientations of stereoisomers. Proposed calculation emerges as interesting assistance in interpretation of consequences of formation differential interaction(s) responsible for a chiral recognition process. PMID- 24631820 TI - Analysis of triazine herbicides using an up-and-down-shaker-assisted dispersive liquid-liquid microextraction coupled with gas chromatography-mass spectrometry. AB - In dispersive liquid-liquid microextraction, a few hundred microliters to a few milliliters of water-miscible dispersive solvent are commonly used to assist emulsification in aqueous samples. In the present study, a consistent and automatic up-and-down-shaker-assisted dispersive liquid-liquid microextraction (UDSA-DLLME) that does not require a dispersive solvent was developed. The enrichment factors (EFs) of the targets obtained using the automatic shaker were 361-1391 for UDSA-DLLME, 51-77 for ultrasonication, and 298-922 for vortexing. The linearity of the method was in the range 0.2-200MUgL(-1), and its limit of detections was within 0.02-0.04MUgL(-1). The intraday and interday relative standard deviations ranged from 5.7 to 10.0% and 5.5 to 10.3%, respectively. The relative recoveries of river and lake samples spiked with 2.0MUgL(-1) of triazines were 94.2-102.2% and 98.5-104.1%, respectively. The technique provided high repeatability and recovery. No matrix interference from river and lake water was observed. The method also achieved high EFs compared with those obtained through other emulsification methods such as vortexing and ultrasonication. UDSA DLLME is an alternative sample preparation technique with good performance. PMID- 24631821 TI - Optimization of liquid chromatographic method for the separation of nine hydrophilic and hydrophobic components in Salviae miltiorrhizae Radix et Rhizoma (Danshen) using microemulsion as eluent. AB - In this study, we have proposed and developed a novel, environmental-friendly and simple method for separation of nine hydrophilic and hydrophobic components in Danshen using microemulsion liquid chromatography. The proposed method was optimized via the preliminary screening experiment and the experimental design. The following factors were investigated in preliminary screening experiment: pH of mobile phase, column type, the nature of surfactant, the nature of oil phase and additives. In order to simultaneously optimize resolution and analysis time, the chromatographic optimization function (COF) was adopted to evaluate chromatograms. The central composite design (CCD) was used to create the matrix of experiments for mapping the chromatographic response surface. Finally, the COF values were fitted into a second order polynomial model and the response surface methodology (RSM) was employed to find the optimal eluent constituents. The reliability of the established model was confirmed by the good agreement obtained between experimental data and predictive values. Based on the results from the preliminary screening experiment and the CCD optimization, the optimal mobile phase was identified as a solution consisting of 6.68% (w/w) polyoxyethylene lauryl ether (Brij35), 0.84% (w/w) cyclohexane, 6.92% (w/w) n-butanol, 85.56% (w/w) phosphate buffer (pH 6.60) and 8mM cetyltrimethyl ammonium bromide (CTAB). PMID- 24631822 TI - A quantitative proteomic screen to identify potential drug resistance mechanism in alpha-difluoromethylornithine (DFMO) resistant Leishmania donovani. AB - Visceral leishmaniasis (VL) caused by Leishmania donovani is a systemic protozoan disease that is fatal if left untreated. The promastigote form of L. donovani is sensitive to growth inhibition by dl-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), the first enzyme of the polyamine biosynthetic pathway. Exposure of a wild type (DI700) cell population to gradually increasing concentrations of DFMO resulted in the selection of a strain of Leishmania (DFMO-16), which was capable of proliferating in 16mM DFMO. To elucidate the molecular basis for this resistance, we undertook a comparative proteomic analysis of DFMO-resistant/sensitive parasites using isobaric tagging for relative and absolute quantification (iTRAQ/LC-MS/MS). Out of the 101 proteins identified in at least 2 of the 3 independent experiments, 82 proteins are 1.5- to 44.0-fold more abundant in DFMO-resistant strain (DFMO-16) while 19 are 2- to 5.0-fold less abundant as compared to the wild-type (DI700) parasites. Proteins with 2-fold or greater abundance in the DFMO-resistant strain include free radical detoxification, polyamine and trypanothione metabolic proteins, proteins involved in metabolism, intracellular survival and proteolysis, elongation factors, signaling molecules and mitochondrial transporters, and many with no annotated function. Differentially modulated proteins contribute to our understanding of molecular mechanism of DFMO-resistance and have the potential to act as biomarkers. BIOLOGICAL SIGNIFICANCE: This study will facilitate a deeper understanding of the phenomenon of acquired drug resistance and possible biomarkers in Leishmania against antiparasitic drug DFMO. Also it will provide information about the metabolic pathways modulated in resistant parasites as an adaptation mechanism to counter drugs. Studies like this are important to safeguard the efficacy of a limited repertoire of anti-parasitic drugs, and to lead the development of new drugs and drug combinations. PMID- 24631823 TI - Comparative proteomics of an extended spectrum beta-lactamase producing Escherichia coli strain from the Iberian wolf. AB - The Iberian wolf (Canis lupus signatus) is an endangered species native to the Iberian Peninsula. Due to their predatory and wild nature, these wolves serve as important indicators of environmental contamination by antimicrobial-resistant bacteria. beta-Lactam antibiotics like cefotaxime are the most commonly used antibacterial agents. Bacterial resistance to these antibiotics occurs predominantly through enzymatic inactivation by extended-spectrum beta lactamases. Escherichia coli strain WA57, isolated from Iberian wolf feces, is a cefotaxime-resistant strain that produces extended-spectrum beta-lactamases. In this study, using 2D-GE combined with MS and bioinformatics, we report significant differences in the abundance of 40 protein spots (p<0.01) from the extracellular, periplasmic, cytoplasmic, and membrane sub-proteomes and the whole cell proteome of WA57 exposed and non-exposed to cefotaxime. A total of 315 protein spots were collected for protein identification. The comparative proteomics presented gives an overview of the complex changes in expression and metabolism that occur when WA57 is stressed with cefotaxime. Abundance of chaperone, porin and export proteins is particularly affected showing that the stress response and transport functions might directly influence the antibiotic resistance of this strain. BIOLOGICAL SIGNIFICANCE: This study highlights the importance of proteomics in detecting protein expression changes in bacterial strains exposed to stress such as that caused by cefotaxime. This approach might help us understand which pathways form barriers for antibiotics. This article is part of a Special Issue entitled: Environmental and structural proteomics. PMID- 24631824 TI - Comparative analysis of secretomes in basidiomycete fungi. AB - Lignocellulose, the major reservoir of organic carbon on Earth, is recalcitrant to turnover and resistant to microbial and enzymatic attack because of the protective action of lignin and the crystalline structure of cellulose. Basidiomycetes are the only organisms known to degrade lignocellulose using two alternative degradation strategies: white rot basidiomycetes break down the lignin moiety extensively before attacking the cellulose, whereas brown rot basidiomycetes cause limited lignin alteration while primarily degrading cellulose. These strategies depend on complex portfolios of extracellular enzymes whose production and export are environment and substrate dependent. More than 265 fungal genomes (more than 90 corresponding to basidiomycetes) have been sequenced. These sequences can be bioinformatically screened to identify presumptive secreted proteins that, however, differ from the experimental data, stressing the importance of using complementary approaches for analyzing these complex systems. The study of fungal secretomes from the scope of their different lignin degradation strategies and lifestyles would facilitate their use in the treatment of lignocellulose as carbon feedstock for biofuel production and further biorefinery processes. In this article, we carry out a comparative review of the analytical tools and strategies used for studying basidiomycetes' secretomes and compare the available results from these two points of view. BIOLOGICAL SIGNIFICANCE: In this article, we review the tools and strategies used in the analysis of basidiomycetes' secretomes and we compare the secretome data available for this type of fungi with a special emphasis on the enzymes involved in lignocellulose degradation. This comparative study provides a basis for distinguishing different lifestyles (saprotrophs, symbionts and parasites) on the basis of their respective secretomes. PMID- 24631825 TI - Omics technologies and their applications to evaluate metal toxicity in mice M. spretus as a bioindicator. AB - Metals are important components of living organisms since many biological functions critically depend on their interaction with some metal in the cell. However, human activities have increased toxic metal levels in the terrestrial and aquatic ecosystems affecting living organisms. The impact of metals on cellular metabolism and global homeostasis has been traditionally assessed in free-living organisms by using conventional biomarkers; however, to obtain a global vision of metal toxicity mechanisms and the responses that metals elicit in the organisms, new analytical methodologies are needed. We review the use of omics approaches to assess the response of living organisms under metal stress illustrating the possibilities of different methodologies on the basis of our previous results. Most of this research has been based on free-living mice Mus spretus, a conventional bioindicator used to monitor metal pollution in Donana National Park (DNP) (SW Spain), which is an important European biological reserve for migrating birds affected by agricultural, mining and industrial activities. The benefits of using omic techniques such as heterologous microarrays, proteomics methodologies (2-DE, iTRAQ(r)), metallomics, ionomics or metabolomics has been remarked; however, the complexity of these areas requires the integration of omics to achieve a comprehensive assessment of their environmental status. This article is part of a Special Issue entitled: Environmental and structural proteomics. BIOLOGICAL SIGNIFICANCE: This work presents new contributions in the study of environmental metal pollution in terrestrial ecosystems using Mus spretus mice as bioindicator in Donana National Park (SW Spain) and surroundings. In addition, it has been demonstrated that the integration of omics multi-analytical approaches provides a very suitable approach for the study of the biological response and metal interactions in exposed and free-living mice (Mus musculus and Mus spretus, respectively) under metal pollution. PMID- 24631826 TI - From target discovery to clinical trials with armed antibody products. AB - Conventional chemotherapy of serious conditions (e.g., cancer and chronic inflammatory diseases) relies on the use of potent bioactive agents, which do not preferentially localize at the site of disease and which may harm healthy tissues. Intense pharmaceutical research efforts are being devoted to the development of targeted therapeutic agents, capable of selectively homing to diseased tissues, while sparing normal body structures. Biological mass spectrometry and chemical proteomics have revolutionized the way targets for ligand-based pharmacodelivery applications are discovered. In this article, we present a personal account on research activities in the field for the last decade, outlining our experience in the discovery of accessible biomarkers and in the development of potent targeted therapeutic agents. BIOLOGICAL SIGNIFICANCE: The present review discusses evolution of proteomic methodologies applied to the discovery of new targets for therapeutic intervention in cancer and inflammatory diseases. Chemical proteomics-driven target discovery allowed the development of new classes of antibody-based targeting biologics, which are having an impact in the oncological and chronic inflammation clinical research. This article is part of a Special Issue entitled: 20years of Proteomics in memory of Viatliano Pallini. Guest Editors: Luca Bini, Juan J. Calvete, Natacha Turck, Denis Hochstrasser and Jean-Charles Sanchez. PMID- 24631827 TI - Expanding resolution of metalloprotein separations from soybean seeds using 2D HPLC-ICP-MS and SDS-PAGE as a third dimension. AB - This work reports on the use of a three dimensional separation system to enhance metalloprotein information when considering soybean seeds. Separations using size exclusion chromatography (SEC) allowed identification of three metal fractions. Following an anion exchange (AEX) chromatographic separation in the second dimension, the resultant sub-fractions were lyophilized and subjected to a third dimension of separation using a polyacrylamide gel electrophoresis (SDS-PAGE). After the separation, the bands were digested, and, in addition to others, the following proteins, previously associated with metals, were identified: 3 lipoxygenase A chain (soybean) complex with 13(S)-hydroperoxy-9(Z),11(E) octadecadienoic acid, beta-amylase [Glycine max], seed lipoxygenase-1, lipoxygenase [G. max], seed lipoxygenase-2 (Pisum sativum) and beta-conglycinin. BIOLOGICAL SIGNIFICANCE: Techniques presenting high resolution are desired due to their capability in resolving great amount of signals (responses) generated from hundreds of proteins generally found in different samples. To the best of our knowledge, this is the first time that bidimensional chromatographic system which allied to another separation dimension is applied for improving protein identification, so that higher number and different proteins were found when comparing 2D dimension with 3D dimension. In fact, this strategy is welcoming in proteomics studies, in order to improve the comprehension of those systems that present large number of proteins. This article is part of a Special Issue entitled: Environmental and structural proteomics. PMID- 24631828 TI - A comparison among the tissue-specific effects of aging and calorie restriction on TFAM amount and TFAM-binding activity to mtDNA in rat. AB - BACKGROUND: Mitochondrial Transcription Factor A (TFAM) is regarded as a histone like protein of mitochondrial DNA (mtDNA), performing multiple functions for this genome. Aging affects mitochondria in a tissue-specific manner and only calorie restriction (CR) is able to delay or prevent the onset of several age-related changes also in mitochondria. METHODS: Samples of the frontal cortex and soleus skeletal muscle from 6- and 26-month-old ad libitum-fed and 26-month-old calorie restricted rats and of the livers from 18- and 28-month-old ad libitum-fed and 28 month-old calorie-restricted rats were used to detect TFAM amount, TFAM-binding to mtDNA and mtDNA content. RESULTS: We found an age-related increase in TFAM amount in the frontal cortex, not affected by CR, versus an age-related decrease in the soleus and liver, fully prevented by CR. The semi-quantitative analysis of in vivo binding of TFAM to specific mtDNA regions, by mtDNA immunoprecipitation assay and following PCR, showed a marked age-dependent decrease in TFAM-binding activity in the frontal cortex, partially prevented by CR. An age-related increase in TFAM-binding to mtDNA, fully prevented by CR, was found in the soleus and liver. MtDNA content presented a common age-related decrease, completely prevented by CR in the soleus and liver, but not in the frontal cortex. CONCLUSIONS: The modulation of TFAM expression, TFAM-binding to mtDNA and mtDNA content with aging and CR showed a trend shared by the skeletal muscle and liver, but not by the frontal cortex counterpart. GENERAL SIGNIFICANCE: Aging and CR appear to induce similar mitochondrial molecular mechanisms in the skeletal muscle and liver, different from those elicited in the frontal cortex. PMID- 24631829 TI - Blood and lymphatic vascular tube formation in mouse. AB - The blood and lymphatic vasculatures are essential for nutrient delivery, gas exchange and fluid homeostasis in all tissues of higher vertebrates. They are composed of a hierarchical network of vessels, which are lined by vascular or lymphatic endothelial cells. For blood vascular lumen formation to occur, endothelial cell cords polarize creating apposing apical cell surfaces, which repulse each other and give rise to a small intercellular lumen. Following cell shape changes, the vascular lumen expands. Various junctional proteins, polarity complexes, extracellular matrix binding and actin remodelling molecules are required for blood vascular lumen formation. In contrast, little is known regarding the molecular mechanisms leading to lymphatic vascular tube formation. Current models agree that lymphatic vessels share a blood vessel origin, but they differ in identifying the mechanism by which a lymphatic lumen is formed. A ballooning mechanism was proposed, in which lymph sacs are connected via their lumen to the cardinal veins. Alternatively, a mechanism involving budding of streams of lymphatic endothelial cells from either the cardinal veins or both the cardinal veins and the intersomitic vessels, and subsequent assembly and lumenisation was recently described. Here, we discuss what is currently known about the molecular and cellular machinery that guides blood and lymphatic vascular tube formation in mouse. PMID- 24631830 TI - Specific RNA-binding antibodies with a four-amino-acid code. AB - Numerous large non-coding RNAs are rapidly being discovered, and many of them have been shown to play vital roles in gene expression, gene regulation, and human diseases. Given their often structured nature, specific recognition with an antibody fragment becomes feasible and may help define the structure and function of these non-coding RNAs. As demonstrated for protein antigens, specific antibodies may aid in RNA crystal structure elucidation or the development of diagnostic tools and therapeutic drugs targeting disease-causing RNAs. Recent success and limitation of RNA antibody development has made it imperative to generate an effective antibody library specifically targeting RNA molecules. Adopting the reduced chemical diversity design and further restricting the interface diversity to tyrosines, serines, glycines, and arginines only, we have constructed a RNA-targeting Fab library. Phage display selection and downstream characterization showed that this library yielded high-affinity Fabs for all three RNA targets tested. Using a quantitative specificity assay, we found that these Fabs are highly specific, possibly due to the alternate codon design we used to avoid consecutive arginines in the Fab interface. In addition, the effectiveness of the minimal Fab library may challenge our view of the protein RNA binding interface and provide a unique solution for future design of RNA binding proteins. PMID- 24631831 TI - Straightforward single-calibrant quantification of seized designer drugs by liquid chromatography-chemiluminescence nitrogen detection. AB - Sixty-one different psychoactive substances were quantified by liquid chromatography-chemiluminescence nitrogen detection (LC-CLND) in 177 samples, using a single secondary standard (caffeine), in a trial concerning the quantitative purity assessment of drug-related material seized by the police in 2011-2012 and customs in 2011-2013 in Finland. The substances found were predominantly substituted phenethylamines, cathinones, tryptamines and synthetic cannabinoids, which were identified by appropriate methods prior to submitting the samples for quantification by LC-CLND. The equimolarity and expanded uncertainty of measurement by LC-CLND were on average 95% and 13%, respectively, based on 16 different substances. The median (mean) purity of stimulant/hallucinogenic drug samples seized at the border was 92.9% (87.6%) and in the street 82.0% (64.5%). The corresponding figures for powdery synthetic cannabinoid samples seized at the border and in the street were 99.0% (96.8%) and 90.0% (92.2%), respectively. There was generally only one active drug to be quantified in each sample. Seized herbal samples contained 0.15-9.2% of between one and three components. LC-CLND was found to be suitable for quantification of the nitrogen-containing drugs encountered in the study, showing sufficient N equimolarity for both stimulant/hallucinogenic drugs and synthetic cannabinoids. The technique possesses great potential as a standard technique in forensic laboratories. PMID- 24631832 TI - Inhalation but not transdermal resorption of hand sanitizer ethanol causes positive ethyl glucuronide findings in urine. AB - BACKGROUND: Ethyl glucuronide (EtG) in urine is considered a specific marker of recent ethanol consumption. There is an ongoing debate about whether inhalation or transdermal resorption of sanitizer ethanol is the underlying cause for positive EtG findings after hand disinfection. METHODS: Desderman((r)) pure (Schulke & Mayr GmbH, Norderstedt) with 78.2g 96% (v/v) ethanol/100g and approx. 10% 2-propanol was used for multiple hand disinfection without and under an exhauster. Simulating a common working day in a clinic, 5 co-workers of our lab used the sanitizer 32 fold within 8h and 2 persons were merely exposed to the sanitizer vapor but without any dermal sanitizer contact. Any additional ethanol intake or exposition was reliably excluded. Spot urine was collected at baseline, after 1, 2, 4, 6 ... 14, and finally 24h after the first sanitizer use. A validated LC-MS/MS was used for MRM and MS(3) of EtG and qualitative analyses of ethyl sulfate and 2-propyl glucuronide. RESULTS: Multiple hand disinfection caused positive EtG findings of up to 2.1mg/L or 1.7mg/g creatinine in 4 out of 5 test persons and even of 0.6mg/L or 0.8mg/g for 2 controls which were merely exposed to the sanitizer vapor but without any sanitizer contact. EtG results between the clinical (0.5mg/g) and the forensic (0.1mg/g) cut-off were obtained even 6h after the last sanitizer exposition. An exhauster prevented the sanitizer vapor inhalation and reduced the EtG excretion to mostly below the detection limit of 0.02mg/g. The maximum value was 0.09mg/g. Ethyl sulfate and 2-propyl glucuronide (2-PpG) were detectable only in the EtG positive samples. 2-PpG is a metabolite of 2-propanol, which is quite frequently used in disinfectants. Thus, the detection of this substance can be used in cases of odd EtG results as an indicator of (unintended) sanitizer exposition. CONCLUSION: Ethanol from hand sanitizers is predominantly incorporated by the respiratory tract but not via the skin. It can cause a distinct ethyl glucuronide excretion and thus analytically true-positive but forensically false-positive EtG findings in the urine of ethanol abstaining persons. Since accidental ethanol inhalation can occur quite frequently in the working place or even private household, such a situation should always be considered when EtG is used as a marker of recent ethanol consumption. PMID- 24631833 TI - Social rank and reproductive performance of pampas deer females (Ozotoceros bezoarticus, Linnaeus, 1758). AB - Our objectives were to determine if success index of pampas deer females is related with females' age and if social rank makes any influence on reproductive performance. Female social rank was determined in 18 groups of animals composed of 1 male: 5-9 females (total=98 females). Date of parturition for each female and sex and birth weight of fawns were recorded for each birth. The females were categorized in three hierarchical ranks: low (<0.33) (group LR), medium (0.33 0.66) (group MR), and high (>0.66) (group HR). The success index increased with age in pampas deer females (P<0.001). Social rank had no effect on calving success, relative calving dates, sex ratio or body weight at birth. In this study, the success index was related with females' age, and the reproductive performance did not differ between females of different social ranks. PMID- 24631834 TI - Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents. AB - Nuclear-cytoplasmic trafficking of proteins is a significant factor in the development of cancer and drug resistance. Subcellular localization of exported proteins linked to cancer development include those involved in cell growth and proliferation, apoptosis, cell cycle regulation, transformation, angiogenesis, cell adhesion, invasion, and metastasis. Here, we examined the basic mechanisms involved in the export of proteins from the nucleus to the cytoplasm. All proteins over 40kDa use the nuclear pore complex to gain entry or exit from the nucleus, with the primary nuclear export molecule involved in these processes being chromosome region maintenance 1 (CRM1, exportin 1 or XPO1). Proteins exported from the nucleus must possess a hydrophobic nuclear export signal (NES) peptide that binds to a hydrophobic groove containing an active-site Cys528 in the CRM1 protein. CRM1 inhibitors function largely by covalent modification of the active site Cys528 and prevent binding to the cargo protein NES. In the absence of a CRM1 inhibitor, CRM1 binds cooperatively to the NES of the cargo protein and RanGTP, forming a trimer that is actively transported out of the nucleus by facilitated diffusion. Nuclear export can be blocked by CRM1 inhibitors, NES peptide inhibitors or by preventing post-translational modification of cargo proteins. Clinical trials using the classic CRM1 inhibitor leptomycin B proved too toxic for patients; however, a new generation of less toxic small molecule inhibitors is being used in clinical trials in patients with both hematological malignancies and solid tumors. Additional trials are being initiated using small-molecule CRM1 inhibitors in combination with chemotherapeutics such as pegylated liposomal doxorubicin. In this review, we present evidence that combining the new CRM1 inhibitors with other classes of therapeutics may prove effective in the treatment of cancer. Potential combinatorial therapies discussed include the use of CRM1 inhibitors and the addition of alkylating agents (melphalan), anthracyclines (doxorubicin and daunomycin), BRAF inhibitors, platinum drugs (cisplatin and oxaliplatin), proteosome inhibitors (bortezomib and carfilzomib), or tyrosine-kinase inhibitors (imatinib). Also, the sequence of treatment may be important for combination therapy. We found that the most effective treatment regimen involved first priming the cancer cells with the CRM1 inhibitor followed by doxorubicin, bortezomib, carfilzomib, or melphalan. This order sensitized both de novo and acquired drug-resistant cancer cell lines. PMID- 24631836 TI - Outsmart tumor exosomes to steal the cancer initiating cell its niche. AB - Exosomes are small vesicles that derive from endosomes and are delivered by many cells, including tumor cells that are a particular rich source of exosomes. Exosomes are suggested to be the most potent intercellular communicators. Being recovered in all body fluids, they can communicate with neighboring as well as distant cells. The latter was first described for dendritic cell exosomes that can initiate T cell activation. However, tumor exosomes (TEX) may impede this crosstalk. Besides with hematopoietic cells, TEX communicate with the tumor cell itself, but also with host stroma cells and endothelial cells. This crosstalk received much attention as there is strong evidence that TEX account for angiogenesis and premetastatic niche formation, which may proceed directly via binding and uptake of TEX by cells in the premetastatic organ or indirectly via TEX being taken up by hematopoietic progenitors in the bone marrow (BM), which mature toward lineages with immunosuppressive features or are forced toward premature release from the BM and homing into premetastatic organs. Knowing these deleterious activities of TEX, it becomes demanding to search for modes of therapeutic interference. I here introduce our hypothesis that metastasis formation may be hampered by tailored exosomes that outsmart TEX. The essential prerequisites are an in depth knowledge on TEX binding, uptake, binding-initiated signal transduction and uptake-promoted target cell reprogramming. PMID- 24631835 TI - Atomic basis of CRM1-cargo recognition, release and inhibition. AB - CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers where some of its cargos are misregulated and mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes structure-function studies that explain CRM1-cargo recognition, release and inhibition. PMID- 24631837 TI - Fetal cannabinoid receptors and the "dis-joint-ed" brain. AB - Microtubule turnover in the growing axons is required for directional axonal growth and synapse formation in the developing brain. In this issue of The EMBO Journal, Tortoriello et al (2014) show that the microtubule-binding protein SCG10/stathmin-2 is a specific molecular target for a CB1 receptor-mediated effect of Delta(9)-tetrahydrocannabinol (THC), the psychoactive ingredient of smoked marijuana, in the fetal brain. Considering the role of CB1 in modulating the specification and long-distance migration of neurons in the perinatal brain, this study reveals an interesting mechanism potentially accounting for connectivity deficits during cortical development following exposure to CB1 agonists or THC during pregnancy. PMID- 24631839 TI - A comprehensive study for the validation of a LC-MS/MS method for the determination of free and total forms of urinary cortisol and its metabolites. AB - Several pathological conditions can be related to the alteration of the urinary levels of cortisol (F) and its metabolites. The determination of each of them in the free and free plus conjugated form can provide a deeper insight into the impaired activity of the cortisol metabolism enzymes, thus improving the diagnosis protocol currently based only on the determination of total amount of urinary cortisol metabolites. In that view, an LC-MS/MS method for the determination of the free and total amount of urinary F, cortisone (E), tetrahydrocortisol (THF), allo-tetrahydrocortisol (A-THF) and tetrahydrocortisone (THE) was thus developed and validated. Deconjugation of glucocorticoids was carried out by enzymatic hydrolysis. Analytes were extracted by solid phase extraction, separated by liquid chromatography and analyzed via electro-spray ionization (negative ion mode) triple-quadrupole mass spectrometry in the selected reaction monitoring mode using a stable isotope-labeled internal standard. Baseline separation for all compounds, in particular the two stereoisomers A-THF and THF, was obtained. Matrix effects, not reported so far, were observed and minimized for the determination of urinary free E and THE. Validated range was 0.5-1000ng/mL for A-THF and THF, 5-800ng/mL for E and THE and 1-1000ng/mL for F, with R(2) values greater than 0.9981. The LOD and LOQ of the described method ranged from 0.1 to 3.0ng/mL, while the extraction recoveries resulted close to 100% for all the glucocorticoids determined. Precision and accuracy were well within +/-10%. As suggested by the results obtained in the preliminary study on polycystic ovary syndrome (PCOS) urine samples, the method can be used to support clinical diagnosis of pathologies related to cortisol metabolism. In fact, levels of free and total glucocorticoids in control subjects were in agreement with previously reported data, as well as free and total A THF/THF ratio in PCOS patients. Conversely, in the latter free F/E and A THF+THF/THE ratios were lower than in control subjects (P<0.01), suggesting a possible alteration of 11beta-HSD1 and 11beta-HSD2 activity, to be further investigated. PMID- 24631838 TI - A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. AB - Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency. PMID- 24631840 TI - Separation and structural elucidation of a new tadalafil analogue diethylaminopretadalafil included as an adulterant in a dietary supplement. AB - A new tadalafil analogue was detected and isolated from a dietary supplement, the structure was elucidated by means of nuclear magnetic resonance (NMR) and mass spectroscopy. The compound was determined to be diethylaminopretadalafil, which might be derived from a precursor in the synthesis of tadalafil. PMID- 24631841 TI - Rapid and sensitive detection of the inhibitive activities of acetyl- and butyryl cholinesterases inhibitors by UPLC-ESI-MS/MS. AB - Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are legitimate therapeutic targets for Alzheimer's disease. The classical approach for screening potential AChE/BChE inhibitors was developed by Ellman. However, the background color of compounds or plant extracts remained uncertain and frequently interfered with the detection of the secondary reaction, thereby easily yielding false positive or false negative results. Rapid, selective, and sensitive ultra performance liquid chromatography combined with electrospray ionization tandem mass spectrometry method was developed and used for the detection of AChE and BChE inhibition by directly determining the common product, choline (Ch). Proper separation was achieved for choline and chlormequat (internal standard) within 1.2min via isocratic elution (0.1% fromic acid:methanol=98:2) on an HSS T3 column following a simple precipitation of proteins for sample treatment. The relative standard deviations of the intra- and inter-day precisions were below 7.34 and 9.09%, respectively, whereas the mean accuracy for the quality control samples was 100.31+/-10.93%. The method exhibited the advantages of small total reaction volume (100MUL), short analysis time (1.2min), high sensitivity (LOQ of 0.036MUM for Ch), and low cost (little consumption enzymes of 0.0035 and 0.008unitmL(-1) for AChE and BChE, and substrates of 5.505 and 7.152MUM for ACh and BCh in individual inhibition, respectively), and without matrix effect (90.00-105.03%). The developed method was successfully applied for detecting the AChE and BChE inhibitive activities for model drugs, including galanthamine, tacrine, neostigmine methylsulfate, eserine, as well as beta-carboline and quinazoline alkaloids from Peganum harmala. PMID- 24631842 TI - Ultrasound promoted one pot synthesis of novel fluorescent triazolyl spirocyclic oxindoles using DBU based task specific ionic liquids and their antimicrobial activity. AB - Spirocyclic oxindoles and triazolyl derivatives posses remarkable biological activities. In present work, we have described an efficient one pot four component domino reaction of 1-(prop-2-ynyl)indoline-2,3-dione, cyclic 1,3 diketones, malononitrile and various aryl azides in DBU based ionic liquids [DBU H]OAc and [DBU-Bu]OH under ultrasonic irradiation for the construction of heterocycles, comprising spiro-oxindole, 2-amino-4H-pyran, and 1,2,3-triazoles substructures. The antimicrobial activity of all compounds has been investigated against six microbial strains. All compounds showed good antimicrobial activity. All newly synthesized compounds exhibit fluorescence in methanol with large stoke shift. PMID- 24631843 TI - Maximising the sensitivity of a gamma spectrometer for low-energy, low-activity radionuclides using Monte Carlo simulations. AB - Monte-Carlo simulations have been utilised to determine the optimum material and thickness for a gamma spectrometer to be used for the assay of radionuclides that emit radiation in the 50-300 keV energy range. Both HPGe and LaBr3(Ce) materials were initially considered for use, however the additional background radiation and lack of resolution in the latter drove the selection of HPGe for further optimisation. Multiple thicknesses were considered for the HPGe detector, with the aim of improving the sensitivity of the system by maximising the efficiency for low energy emissions, and reducing the probability of interaction with (and therefore the continuum from) higher energy photons. The minimum amount of material needed to achieve this was found to be 15 mm for a source that is dominated by high energy (>2.614 MeV) photons, and 20-30 mm for a typical reference source (with photons of energy 59.54 keV-2.614 MeV). PMID- 24631844 TI - The contribution of genetic and genomic approaches to plant domestication studies. AB - The application of genomic approaches to the phenomenon of plant domestication promises a better understanding of the origins of agriculture, but also of the way plant genomes in general are organized and expressed. Building on earlier genetic research, more detailed information has become available on the organization of genetic diversity at the genome level and the effects of gene flow on diversity in different regions of the genome. In addition, putative domestication genes have been identified through population genomics approaches (selective sweeps or divergence scanning). Further information has been obtained on the origin of domestication syndrome mutations and the dispersal and adaptation of crops after domestication. For the future, increasingly multidisciplinary approaches using combinations of genomics and other approaches will prevail. PMID- 24631845 TI - Interplay between chromatin and RNA processing. AB - The processing of pre-mRNAs, including the selection of polyadenylation sites, is influenced by the surrounding chromatin context. We review here recent studies in Arabidopsis thaliana highlighting the intricate and reciprocal interplay between chromatin state and RNA processing. The studies have revealed that transcription can be influenced by the presence, in gene introns, of combination of epigenetic marks typical of heterochromatin. New factors binding to these marks have been identified and shown to play key roles in controlling the use of polyadenylation sites and processing of functional mRNAs. Concomitantly, several proteins of both the splicing and the polyadenylation machineries are also emerging as regulators of DNA methylation patterns and chromatin silencing. PMID- 24631846 TI - Ecological genomics and process modeling of local adaptation to climate. AB - Locally adapted genotypes have higher fitness in their native site in comparison to foreign genotypes. Recent studies have demonstrated both local adaptation to and genomic associations with a range of climate variables. For climate adaptation, the most common genomic pattern is conditional neutrality, as proven by weak across-environment correlations, frequent SNP*environment interactions, and the topology of some developmental and physiological pathways potentially involved in local adaptation. Genomic association approaches readily translate to non-model systems, and genetically explicit climate envelope models will predict future species' distributions under changing climates. Here, we review recent evidence for local adaptation to climate, focusing primarily on the model system, Arabidopsis thaliana, and on studies incorporating genomic tools into field studies or climate analyses. PMID- 24631847 TI - Measuring forgetting: a critical review of accelerated long-term forgetting studies. AB - Accelerated long-term forgetting (ALF) refers to abnormal forgetting over hours to weeks despite normal acquisition or initial consolidation. Since standardised assessments of memory typically only test at delays of up to 40-minutes, ALF may go undetected in clinical practice. The memory difficulties associated with ALF can however cause considerable distress to patients. It is important therefore that clinicians are aware that ALF may represent a distinct phenomenon that will require additional and careful assessment to aid patients' understanding of the condition and assist in developing strategies to address its effects. At the same time, ALF may also provide insight into long-term memory processes. Studies of ALF in patients with epilepsy have so far demonstrated mixed results, which may reflect differences in methodology. This review explores the methodological issues that can affect forgetting, such as the effects of age, general cognitive function, test sensitivity and initial learning. It then evaluates the extent to which existing studies have considered these key issues. We outline the points to consider when designing ALF studies that can be used to help improve their validity. These issues can also help to explain some of the mixed findings in studies of ALF and inform the design of standardised tests for assessing ALF in clinical practice. PMID- 24631849 TI - Issues of rigor and feasibility when observing the quality of program implementation: a case study. AB - Program evaluators have paid little attention in the literature to the manner in which measuring the quality of implementation with observations requires tradeoffs between rigor (reliability and validity) and program evaluation feasibility. We present a case example of how we addressed rigor in light of feasibility concerns when developing and conducting observations for measuring the quality of implementation of a small education professional development program. We discuss the results of meta-evaluative analyses of the reliability of the quality observations, and we present conclusions about conducting observations in a rigorous and feasible manner. The results show that the feasibility constraints that we faced did not notably reduce the rigor of our methods. PMID- 24631850 TI - Utility of a congregational health assessment to identify and direct health promotion opportunities in churches. AB - PURPOSE: The church is a focal point for health education efforts in minority communities due to its status as one of the most prominent and stable institutions. This paper highlights an approach for identifying health programming targets in minority churches. METHODS: Twenty-four churches participated in a one-year Health Ministry Institute (HMI), designed to help churches develop sustainable ministries for health promotion. HMI attendees were instructed on conducting a Congregational Health Assessment (CHA) to identify prevalent health conditions and related behaviors in their churches. Churches collected CHAs over a one-month period. Data were analyzed and results were discussed during a HMI session and used to prioritize health-related issues that could be addressed at individual churches. RESULTS: Seventeen churches (71%) returned surveys (n=887; 70% female; 73% African American). Prevalent health conditions, participation in health-promoting behaviors, interest in learning to live healthy, and interest in health ministry activities were identified using the CHA. CONCLUSIONS: The CHA shows promise for health assessment, and can be used to identify health issues that are of interest and relevance to church congregants and leaders. The CHA may assist churches with implementing effective and sustainable programs to address the identified health issues. PMID- 24631848 TI - Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin. AB - In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1(H-/-)), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1(H-/-) mice with rapamycin. Six to eight week old Acsl1(H-/-) mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including alpha-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1(H-/-) hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1(H-/-) hearts exhibited an 8-fold higher uptake of 2-deoxy[1-(14)C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-(14)C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1(H-/-) mice. PMID- 24631851 TI - Cognitive functioning in idiopathic generalised epilepsies: a systematic review and meta-analysis. AB - Cognitive function in idiopathic generalised epilepsies (IGE) is of increasing research attention. Current research seeks to understand phenotypic traits associated with this most common group of inherited epilepsies and evaluate educational and occupational trajectories. A specific deficit in executive function in a subgroup of IGE, juvenile myoclonic epilepsy (JME) has been a particular focus of recent research. This systematic review provides a quantitative synthesis of cognitive function outcomes in 26 peer-reviewed, case control studies published since 1989. Univariate random-effects meta-analyses were conducted on seven cognitive factor-domains and separately on executive function. Patients with IGE demonstrated significantly lower scores on tests across all cognitive factor-domains except visual-spatial abilities. Effect sizes ranged from 0.42 to 0.88 pooled standard deviation units. The average reduction of scores on tests of executive function in IGE compared to controls was 0.72 standard deviation units. Contrary to current thinking, there was no specific deficit in executive function in JME samples, nor in other IGE syndromes. Of more concern, people with IGE are at risk of pervasive cognitive impairment. PMID- 24631852 TI - Correction and suppression of reaching movements in the cerebral cortex: physiological and neuropsychological aspects. AB - Modification or suppression of reaches occurs in everyday life. We argue that a common modular architecture, based on similar neural structures and principles of kinematic and kinetic control, is used for both direct reaches and for their on line corrections. When a reach is corrected, both the pattern of neural activity in parietal, premotor and motor cortex and the muscle synergies associated with the first movement can be smoothly blended or sharply substituted into those associated with the second one. Premotor cortex provides the early signaling for trajectory updating, while parietal and motor cortex provide the fine-grained encoding of hand kinematics necessary to reshape the motor plan. The cortical contribution to the inhibitory control of reaching is supported by the activity of a network of frontal areas. Premotor cortex has been proposed as a key structure for reaching suppression. Consistent with this, lesions in different nodes of this network result in different forms of motor deficits, such as Optic Ataxia in parietal patients, and commission errors in frontal ones. PMID- 24631853 TI - Experiments on learning in zebrafish (Danio rerio): a promising model of neurocognitive function. AB - The past decade has seen rapid proliferation of behavioral research with zebrafish, and an emergence of interest in their potential as a model of neurocognitive function. Already, zebrafish have been proposed as a model of autism, Alzheimer's, drug abuse, schizophrenia, and other disorders involving cognitive dysfunction. Zebrafish have the sophisticated sensory and motor systems necessary for complex learning experiments, and their power as a genetic and developmental model has already been established. Currently, however, learning procedures remain unrefined, and behavioral variability presents a major problem for researchers. Before zebrafish can be effectively used to study the neurological bases of learning, a set of robust and replicable techniques must be characterized and standardized. The purpose of this review is to provide an overview and critique of learning procedures that have been used with zebrafish and their results. We hope that such an analysis will prove useful in this early stage of research to guide future learning experiments and thereby improve the efficiency and validity of research with this promising new animal model. PMID- 24631854 TI - Diversification of almonds, peaches, plums and cherries - molecular systematics and biogeographic history of Prunus (Rosaceae). AB - Most previous molecular phylogenetic studies of Prunus have been conducted primarily with crop species and their close relatives. As the center of crop diversity of the genus is in Eurasia, the geographic origin of Prunus has inevitably been inferred to be Eurasia as well. The lesser-known tropical Prunus species have not been well represented in previous phylogenetic reconstructions; therefore, their effects on inferences about the phylogenetic structure and geographic origin of Prunus are uncertain. In this study, we examined the phylogeny of Prunus, including an expanded sampling of species from tropical regions in Southeast Asia and the Americas, using sequences from four plastid markers and the nuclear ribosomal ITS region. A penalized likelihood method was used to estimate the absolute age of Prunus and the timing of infrageneric cladogenic events. The geographic origin of Prunus and ancestral sites of cladogenesis were inferred using the Bayes-DIVA approach. Our results indicate that the modern genus appeared ~61Myr in eastern Asia and that diversification of all major lineages may have been triggered by the global warming period of the early Eocene. In addition, our molecular dating estimates suggest that the crown clade that includes the temperate deciduous crop species is older than the one that includes the tropical evergreen species, while incongruence between plastid and nuclear phylogenies suggests that the latter lineage originated via an ancient hybridization event. The most recent common ancestor (MRCA) of the temperate crop species was a component of the continuous boreotropical forests of the Northern Hemisphere, while the MRCA of the tropical species represented the last remains of the boreotropical elements and subsequently radiated throughout the Old and New World tropics from refugial areas at lower latitudes. Complex biogeographic histories leading to the present global distribution of the genus were driven by several geologic events, climatic oscillations, and independent dispersals across continents via the Bering and the North Atlantic Land Bridges during different geologic time periods. PMID- 24631855 TI - Impact of deep coalescence and recombination on the estimation of phylogenetic relationships among species using AFLP markers. AB - Deep coalescence and the nongenealogical pattern of descent caused by recombination have emerged as a common problem for phylogenetic inference at the species level. Here we use computer simulations to assess whether AFLP-based phylogenies are robust to the uncertainties introduced by these factors. Our results indicate that phylogenetic signal can prevail even in the face of extensive deep coalescence allowing recovering the correct species tree topology. The impact of recombination on tree accuracy was related to total tree depth and species effective population size. The correct tree topology could be recovered upon many simulation settings due to a trade-off between the conflicting signals resulting from intra-locus recombination and the benefits of the joint consideration of unlinked loci that better matched overall the true species tree. Errors in tree topology were not only determined by deep coalescence, but also by the timing of divergence and the tree-building errors arising from an insufficient number of characters. DNA sequences generally outperformed AFLPs upon any simulated scenario, but this difference in performance was nearly negligible when a sufficient number of AFLP characters were sampled. Our simulations suggest that the impact of deep coalescence and intra-locus recombination on the reliability of AFLP trees could be minimal for effective population sizes equal to or lower than 10,000 (typical of many vertebrates and tree plants) given tree depths above 0.02 substitutions per site. PMID- 24631856 TI - Molecular phylogenetics of Amorpha (Fabaceae): an evaluation of monophyly, species relationships, and polyploid origins. AB - Amorpha L. (false indigos and lead plants) is a North American legume genus of 16 species of shrubs, which is most diverse in the southeastern United States and distinctive due to the reduction of the corolla to a single petal. Most species have limited distributions, but the tetraploid A. fruticosa species complex is widely distributed and its range overlaps those of all of the other species. Morphological variation in the genus is characterized by gradation of characters among species and it has been the subject of repeated taxonomic study due to the difficulty in delimiting species, especially among A. fruticosa and allies. This study presents the first phylogenetic and network analyses for evaluation of relationships amongst Amorpha species based on three non-coding plastome regions (trnD-trnT, trnH-psbA, petN-psbM) and two low-copy nuclear genes (CNGC5, minD). Plastid DNA analyses supported a monophyletic Amorpha with Parryella filifolia and Errazurizia rotundata as successive sister lineages; however, nuclear gene analyses supported the nesting of these two species and thus a paraphyletic Amorpha. Relationships among species of Amorpha were best resolved in the plastid DNA phylogeny and in most cases were concordant with expectations based on morphology. Relationships based on the nuclear gene phylogenies were less clear due to lack of informative variation (CNGC5) or conflict in the data set (minD). The origins of A. fruticosa were unclear, but the plastid phylogeny revealed that this species shares the same or similar plastid haplotype as other species in a geographic region. Putative recombination of diploid species' alleles was evident in the minD-like network. Phenotypic plasticity in combination with gene flow into this species from different diploids, or even tetraploids, across its range may account for the incredible morphological diversity of the A. fruticosa species complex. Putative progenitors for two other suspected allotetraploid species, A. confusa and A. crenulata, were identified as A. fruticosa and A. herbacea. PMID- 24631857 TI - High mountain origin, phylogenetics, evolution, and niche conservatism of arctic lineages in the hemiparasitic genus Pedicularis (Orobanchaceae). AB - The origin of the arctic flora covering the northernmost treeless areas is still poorly understood. Arctic plants may have evolved in situ or immigrated from the adjacent ecosystems. Frequently arctic species have disjunctive distributions between the Arctic and high mountain systems of the temperate zone. This pattern may result from long distance dispersal or from glacial plant migrations and extinctions of intermediate populations. The hemiparasitic genus Pedicularis is represented in the Arctic by c. 28 taxa and ranks among the six most species-rich vascular plant genera of this region. In this study, we test the hypothesis that these lineages evolved from predecessors occurring in northern temperate mountain ranges, many of which are current centers of diversity for the genus. We generated a nuclear ribosomal and chloroplast DNA phylogeny including almost all of the arctic taxa and nearly half of the genus as a whole. The arctic taxa of Pedicularis evolved 12-14 times independently and are mostly nested in lineages that otherwise occur in the high mountains of Eurasia and North America. It appears that only three arctic lineages arose from the present-day center of diversity of the genus, in the Hengduan Mountains and Himalayas. Two lineages are probably of lowland origin. Arctic taxa of Pedicularis show considerable niche conservatism with respect to soil moisture and grow predominantly in moist to wet soils. The studied characteristics of ecology, morphology, and chromosome numbers of arctic Pedicularis show a heterogeneous pattern of evolution. The directions of morphological changes among the arctic lineages show opposing trends. Arctic taxa are chiefly diploid, the few tetraploid chromosome numbers of the genus were recorded only for arctic taxa. Five arctic Pedicularis are annuals or biennials, life forms otherwise rare in the Arctic. Other genera of the Orobanchaceae consist also of an elevated number of short-lived species, thus hemiparasitism may favor this life form in the Arctic. PMID- 24631858 TI - Dynamic evolution of mitochondrial ribosomal proteins in Holozoa. AB - We studied the highly dynamic evolution of mitochondrial ribosomal proteins (MRPs) in Holozoa. Most major clades within Holozoa are characterized by gains and/or losses of MRPs. The usefulness of gains of MRPs as rare genomic changes in phylogenetics is undermined by the high frequency of secondary losses. However, phylogenetic analyses of the MRP sequences provide evidence for the Acrosomata hypothesis, a sister group relationship between Ctenophora and Bilateria. An extensive restructuring of the mitochondrial genome and, as a consequence, of the mitochondrial ribosomes occurred in the ancestor of metazoans. The last MRP genes encoded in the mitochondrial genome were either moved to the nuclear genome or were lost. The strong decrease in size of the mitochondrial genome was probably caused by selection for rapid replication of mitochondrial DNA during oogenesis in the metazoan ancestor. A phylogenetic analysis of MRPL56 sequences provided evidence for a horizontal gene transfer of the corresponding MRP gene between metazoans and Dictyostelidae (Amoebozoa). The hypothesis that the requisition of additional MRPs compensated for a loss of rRNA segments in the mitochondrial ribosomes is corroborated by a significant negative correlation between the number of MRPs and length of the rRNA. Newly acquired MRPs evolved faster than bacterial MRPs and positions in eukaryote-specific MRPs were more strongly affected by coevolution than positions in prokaryotic MRPs in accordance with the necessity to fit these proteins into the pre-existing structure of the mitoribosome. PMID- 24631859 TI - Improving the outcomes of biopharmaceutical delivery via the subcutaneous route by understanding the chemical, physical and physiological properties of the subcutaneous injection site. AB - Subcutaneous (SC) injection is currently the most common route of self administering biopharmaceuticals such as proteins and peptides. While pharmaceutical scientists have acquired great skill in identifying formulations for these proteins and peptides with multi-year shelf life stability, the SC injection of these formulations can result in inconsistent or particularly low bioavailability outcomes. We hypothesise that upon injection, the chemical, physical and physiological properties of the subcutaneous tissue may play a crucial role in determining the therapeutic outcomes of SC injected biopharmaceuticals. We contend that physical and chemical stresses placed upon the injected protein or peptide as it transitions from the non-physiological environment of its formulation to the homeostatic conditions of the SC tissue can affect its fate following injection, and that by taking this environment into account when formulating, more precisely controlled release of SC injected biopharmaceuticals could be achieved. In this mini-review we describe how events that occur to an injected protein or peptide during this post-injection transition period could affect the diffusion of bioactive material to blood capillaries and lymphatic vessels. With this in mind, we have reviewed the chemical, physical and physiological attributes of the SC tissue and collated studies on how these properties are known to affect protein stability and diffusional properties. Finally, examples where the understanding of the properties of the SC tissue when formulating for SC injected biopharmaceuticals has improved the predictability of drug delivery via the SC route are discussed, with the need for novel tools for rational and informed formulation development highlighted. PMID- 24631861 TI - cRGD grafted liposomes containing inorganic nano-precipitate complexed siRNA for intracellular delivery in cancer cells. AB - Development of effective vector for intracellular delivery of siRNA has always been a challenge due to its hydrophilicity, net negative surface charge and sensitivity against nucleases in biological milieu. The present investigation was aimed to develop a novel non-viral liposomal carrier for siRNA delivery. Nano precipitate of calcium phosphate was entrapped in liposomes composed of a neutral lipid (DPPC), a fusogenic lipid (DOPE), a PEGylated lipid (DSPE-mPEG2000) and cholesterol. siRNA was made permeable through liposomal bilayer and complexed to calcium phosphate precipitates inside the liposomes. siRNA entrapped liposomes were further grafted with cRGD to achieve targeting potential against cancer cells. More than 80% of siRNA was entrapped inside the liposomes having average particle size below 150nm. Cryo-transmission electron microscopy revealed the intra-liposomal calcium phosphate precipitation and unilamellar morphology of prepared liposomes. The viability of A549 lung cancer cells was significantly higher after treatment with siRNA entrapped liposomes as compared to Lipofectamine2000 complexed siRNA. Fluorescent intensity in lung carcinoma cells was significantly higher after exposure to fluorescent siRNA entrapped liposomes than with Lipofectamine2000, which were confirmed by both confocal microscopy and flow cytometry. Live imaging by confocal microscopy ascertained the targeting efficacy of cRGD grafted liposomes compared to naked siRNA and non-grafted liposomes. Developed liposomal formulation showed effective protection of siRNA against serum nucleases along with less haemolytic potential and excellent stability against electrolyte induced flocculation. At 5nM concentration gene expression of target protein was reduced up to 24.1+/-3.4% while Lipofectamine2000 reduced expression level up to 26.35+/-1.55%. In vivo toxicity in mice suggested admirable safety profile for developed lipid based delivery vector. These results advocate that prepared liposomal system would be of high value for intracellular delivery of siRNA. PMID- 24631860 TI - Quantitative measurement of delivery and gene silencing activities of siRNA polyplexes containing pyridylthiourea-grafted polyethylenimines. AB - The activity of synthetic interfering nucleic acids (siRNAs) relies on the capacity of delivery systems to efficiently transport nucleic acids into the cytosol of target cells. The pyridylthiourea-grafted 25KDa polyethylenimine (piPEI) is an excellent carrier for siRNA delivery into cells and it was extensively investigated in this report. Quantification of the siRNA-mediated gene silencing efficiency indicated that the piPEI specific delivery activity at the cell level may be measured and appears relatively constant in various cell lines. Delivery experiments assaying inhibitors of various entry pathways or concanamycin A, an inhibitor of the H(+)/ATPase vacuolar pump showed that the piPEI/siRNA polyplexes did not require any specific entry mode but strongly relied on vacuolar acidification for functional siRNA delivery. Next, piPEI polyplexes containing a siRNA targeting the transcription factor HIF-1alpha, known to be involved in tumor progression, were locally injected into mice xenografted with a human glioblastoma. A 55% reduction of the level of the target mRNA was observed at doses comparable to those used in vitro when the piPEI delivery activity was calculated per cell. Altogether, our study underscores the usefulness of "simple"/rough cationic polymers for siRNA delivery despite their intrinsic limitations. The study underscores as well as that bottom-up strategies make sense. The in vitro experiments can precede in vivo administration and be of high value for selection of the carrier with enhanced specific delivery activity and parallel other research aiming at improving synthetic delivery systems for resilience in the blood and for enhanced tissue-targeting capacity. PMID- 24631863 TI - The role of glucose transporters in the distribution of p-aminophenyl-alpha-d mannopyranoside modified liposomes within mice brain. AB - The effective treatment of central nervous system diseases is a major challenge due to the presence of the blood-brain barrier (BBB). P-aminophenyl-alpha-d mannopyranoside (MAN), a kind of mannose analog, was conjugated onto the surface of liposomes (MAN-LIP) to enhance the brain delivery. In this study, we investigated the brain distribution of MAN-LIP based on our previous studies and tried to explore the relationship between the distribution of MAN-LIP and glucose transporters (GLUTs) on the cells. In vivo optical imaging was used to assess the distribution of liposomes in mice brain. The mice administered with MAN-LIP had significantly higher brain fluorescence intensity and MAN-LIP relatively concentrated in the cerebellum and cerebral cortex. Fluorescent microscope and Western blot were used to evaluate the results of lentiviral vector-mediated hSLC2A1 and hSLC2A3 gene transfection into C6, PC12 and vessels of endothelial cell line, bEND.3. The results from live cell station and flow cytometry showed that the cellular uptake of MAN-LIP was significantly improved by GLUT1 and GLUT3 overexpression cells. The transport experiments also demonstrated that the transendothelial ability of MAN-LIP was much stronger when crossing LV GLUT1/bEND.3 cell monolayers or LV-GLUT3/ bEND.3 cell monolayers, of which GLUT1 and GLUT3 were overexpressed. The combined data indicated that the transcytosis by GLUT1 and GLUT3 was a pathway of MAN-LIP into brain, and the special brain distribution of MAN-LIP was closely related to the non-homogeneous distribution of GLUT1 and GLUT3 in the brain. PMID- 24631862 TI - Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging. AB - The Enhanced Permeability and Retention (EPR) effect is extensively used in drug delivery research. Taking into account that EPR is a highly variable phenomenon, we have here set out to evaluate if contrast-enhanced functional ultrasound (ceUS) imaging can be employed to characterize EPR-mediated passive drug targeting to tumors. Using standard fluorescence molecular tomography (FMT) and two different protocols for hybrid computed tomography-fluorescence molecular tomography (CT-FMT), the tumor accumulation of a ~10 nm-sized near-infrared fluorophore-labeled polymeric drug carrier (pHPMA-Dy750) was evaluated in CT26 tumor-bearing mice. In the same set of animals, two different ceUS techniques (2D MIOT and 3D B-mode imaging) were employed to assess tumor vascularization. Subsequently, the degree of tumor vascularization was correlated with the degree of EPR-mediated drug targeting. Depending on the optical imaging protocol used, the tumor accumulation of the polymeric drug carrier ranged from 5 to 12% of the injected dose. The degree of tumor vascularization, determined using ceUS, varied from 4 to 11%. For both hybrid CT-FMT protocols, a good correlation between the degree of tumor vascularization and the degree of tumor accumulation was observed, within the case of reconstructed CT-FMT, correlation coefficients of ~0.8 and p-values of <0.02. These findings indicate that ceUS can be used to characterize and predict EPR, and potentially also to pre-select patients likely to respond to passively tumor-targeted nanomedicine treatments. PMID- 24631864 TI - Delivering wasp venom for cancer therapy. AB - Cytolytic peptides with potential therapeutic properties have appeared during the last three decades. However, the use of these natural weapons is relatively narrow due to their non-specific cytolytic activity as well as their rapid degradation and excretion when injected in blood. In order to rescue the use of these lytic peptides, we have designed pro-cytotoxic systems based on cytotoxic peptides conjugated to poly(l-glutamic acid) PGA polymer through specific cleavage sequences that are sensitive over-expressed tumor proteases, such as the metalloproteinase-2 (MMP-2) or cathepsin B. The potent cytotoxic peptide tested here, Mitoparan, is inactive when conjugated to the polymer and then become active again once released through the tumor proteases. Furthermore, this pro cytotoxic system was decorated by a particular targeting peptide which binds to HER2 receptors over-expressed in some types of breast tumor cells, thereby increasing the selective release of cytolytic peptides inside tumor cell with exquisite spatiotemporal control. In this way, the system would improve the maximum tolerated dose and the pharmacokinetic parameters of cytotoxic peptides in vivo. PMID- 24631865 TI - Vitamin E-based nanomedicines for anti-cancer drug delivery. AB - This review aims to highlight the development of novel vitamin E conjugates for the vectorization of active pharmaceutical ingredients through nanotechnologies. The physico-chemical and biological properties of vitamin E derivatives offer multiple advantages in drug delivery like biocompatibility, improvement of drug solubility and anticancer activity. Nanomedicines have shown high potential in drug delivery since (i) they may offer better drug biopharmaceutical properties such as longer half-life or better bioavailability and (ii) they have shown benefits in cancer therapy by improving anticancer drug therapeutic index. Vitamin E-based nanomedicines were developed to combine the pharmaceutical properties of both vitamin E and nanomedicines for two purposes: (i) to improve water solubility of hydrophobic drugs and (ii) to enhance the therapeutic efficiency of anticancer agents. This review is divided into three parts: the first one describes the biology and the metabolic functions of vitamin E, the second one focuses on the anticancer activity of two vitamin E derivatives: vitamin E succinate (TOS) and vitamin E polyethylene glycol-succinate (TPGS). Finally, in the third part, we discuss vitamin E derivatives based-nanomedicines. PMID- 24631866 TI - Role of dorsal vagal complex A2 noradrenergic neurons in hindbrain glucoprivic inhibition of the luteinizing hormone surge in the steroid-primed ovariectomized female rat: effects of 5-thioglucose on A2 functional biomarker and AMPK activity. AB - Neuro-glucostasis is required for normal expression of the steroid positive feedback-induced preovulatory pituitary luteinizing hormone (LH) surge, a critical element of female reproduction. Glucoprivic signals from the caudal hindbrain restrain this surge, but the cellular source of this stimulus is unclear. Norepinephrine (NE) exerts well-defined stimulatory effects on the reproductive neuroendocrine axis. Our studies show that medullary A2 noradrenergic neurons are both estrogen- and glucoprivic-sensitive. Here, we investigated the premise that the LH surge is inhibited by A2 cell reactivity to hindbrain glucopenia and diminished preoptic NE neurotransmission. Estradiol- and progesterone-primed ovariectomized (OVX) female rats were injected into the caudal fourth ventricle (CV4) with the glucose anti-metabolite, 5-thioglucose (5TG) or saline (SAL) prior to onset of the LH surge. Pretreatment by intra-CV4 delivery of the selective catecholamine neurotoxin, 6-OHDA, attenuated LH output, but prevented inhibition by 5TG. 5TG modified patterns of steroid feedback associated Fos staining of A2, but not other medullary catecholamine cell groups. Intra-preoptic administration of the alpha1-adrenergic receptor agonist, methoxamine, elicited site-specific reversal of hindbrain glucoprivic suppression of gonadotropin-releasing hormone (GnRH) neuron Fos labeling and LH release. Western blotting of laser-microdissected A2 neurons revealed glucoprivic stimulation of Fos, but inhibition of the catecholamine synthetic enzyme, dopamine-beta-hydroxylase; 5TG also diminished A2 estrogen receptor (ER)-alpha and progesterone receptor profiles, but augmented ER-beta protein. Intriguingly, A2 AMPK activity was decreased in 5TG-treated rats, despite down-regulation of GLUT3 and no change in MCT2 protein expression. Rostral preoptic GnRH neurons also exhibited decreased AMPK activation simultaneous with apparent reduction of neuropeptide signaling to the pituitary. The present studies demonstrate that hindbrain glucoprivation inhibits the LH surge, in part, by reducing preoptic noradrenergic input, and furthermore implicate A2 neurons as a source of this altered signal. Results also suggest that AMPK sensor deactivation does not supersede the impact of pharmacological inhibition of glucose catabolism on A2 cell function nor afferent signaling of hindbrain glucopenia on GnRH neurons. Further studies are needed to determine if decreased AMPK activation in these cell populations reflect compensatory gain in positive energy balance and/or direct effects of estrogen on AMPK. PMID- 24631869 TI - Hitting the 'mark': interpreting lysine methylation in the context of active transcription. AB - Histones and their posttranslational modifications (PTMs) play an important role in regulating DNA-templated processes. While some PTMs directly modulate chromatin architecture via charge effects, others rely on the action of reader or effector proteins that can recognize and bind the modification to fulfill distinct cellular outcomes. One PTM that has been well studied with regard to reader proteins is histone lysine methylation - a PTM linked to many DNA templated processes including transcription, DNA replication and DNA repair. In this review, we summarize the current understanding of how histone lysine methylation is read during the process of active transcription. We also describe how the interpretation of lysine methylation fits into a larger, more complex 'code' of histone PTMs to modulate chromatin structure and function. These insights take into account emerging concepts in the field in an effort to help facilitate future studies. PMID- 24631867 TI - Cytochrome c biogenesis System I: an intricate process catalyzed by a maturase supercomplex? AB - Cytochromes c are ubiquitous heme proteins that are found in most living organisms and are essential for various energy production pathways as well as other cellular processes. Their biosynthesis relies on a complex post translational process, called cytochrome c biogenesis, responsible for the formation of stereo-specific thioether bonds between the vinyl groups of heme b (protoporphyrin IX-Fe) and the thiol groups of apocytochromes c heme-binding site (C1XXC2H) cysteine residues. In some organisms this process involves up to nine (CcmABCDEFGHI) membrane proteins working together to achieve heme ligation, designated the Cytochrome c maturation (Ccm)-System I. Here, we review recent findings related to the Ccm-System I found in bacteria, archaea and plant mitochondria, with an emphasis on protein interactions between the Ccm components and their substrates (apocytochrome c and heme). We discuss the possibility that the Ccm proteins may form a multi subunit supercomplex (dubbed "Ccm machine"), and based on the currently available data, we present an updated version of a mechanistic model for Ccm. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. PMID- 24631870 TI - The advantage of mucus for adhesive locomotion in gastropods. AB - For many gastropods, locomotion is driven by a succession of periodic muscular waves (contractions and relaxations) moving along the foot. The force generated by these waves is coupled to the substratum by a thin layer of pedal mucus. Gastropod pedal mucus has unusual physical properties: the mucus is a viscoelastic solid at small deformation and shows a sharp yield point; then, at greater strains, the mucus is a viscous liquid, although it will recover its solidity if allowed to heal for a certain period. In this paper, to clarify the role of the mucus and the flexible muscular waves in adhesive locomotion, we use a simple mathematical model to verify that directional migration can be realized through the interaction between the periodic muscular waves and the specific physical features of mucus. Our results indicate that the hysteresis property of mucus is essential in controlling kinetic friction for the realization of crawling locomotion. Furthermore, our numerical calculations show that both the hysteresis property of mucus and the contraction ratio of muscle give rise to two styles of locomotion, direct waves and retrograde waves, which until now have been explained by different mechanisms. The biomechanical effectiveness of mucus in adhesive locomotion is also discussed. PMID- 24631871 TI - Status of prophylactic and therapeutic genital herpes vaccines. AB - A half billion people have genital herpes infections worldwide. Approximately one fifth of American women between ages 14 and 49 are HSV-2 seropositive. The development of an effective genital herpes vaccine is a global health necessity based on the mental anguish genital herpes causes for some individuals, the fact that pregnant women with genital herpes risk transmitting infection to their newborn children, and the observation that HSV-2 infection is associated with a 3 fold to 4-fold increased probability of HIV acquisition. We review the strengths and limitations of preclinical animal models used to assess genital herpes vaccine candidates and the goals of prophylactic and therapeutic vaccines. We also discuss the current pipeline of vaccine candidates and lessons learned from past clinical trials that serve as a stimulus for new strategies, study designs and endpoint determinations. PMID- 24631872 TI - First measurements of (236)U concentrations and (236)U/(239)Pu isotopic ratios in a Southern Hemisphere soil far from nuclear test or reactor sites. AB - The variation of the (236)U and (239)Pu concentrations as a function of depth has been studied in a soil profile at a site in the Southern Hemisphere well removed from nuclear weapon test sites. Total inventories of (236)U and (239)Pu as well as the (236)U/(239)Pu isotopic ratio were derived. For this investigation a soil core from an undisturbed forest area in the Herbert River catchment (17 degrees 30' - 19 degrees S) which is located in north-eastern Queensland (Australia) was chosen. The chemical separation of U and Pu was carried out with a double column which has the advantage of the extraction of both elements from a relatively large soil sample (~20 g) within a day. The samples were measured by Accelerator Mass Spectrometry using the 14UD pelletron accelerator at the Australian National University. The highest atom concentrations of both (236)U and (239)Pu were found at a depth of 2-3 cm. The (236)U/(239)Pu isotopic ratio in fallout at this site, as deduced from the ratio of the (236)U and (239)Pu inventories, is 0.085 +/- 0.003 which is clearly lower than the Northern Hemisphere value of ~0.2. The (236)U inventory of (8.4 +/- 0.3) * 10(11) at/m(2) was more than an order of magnitude lower than values reported for the Northern Hemisphere. The (239)Pu activity concentrations are in excellent agreement with a previous study and the (239+240)Pu inventory was (13.85 +/- 0.29) Bq/m(2). The weighted mean (240)Pu/(239)Pu isotopic ratio of 0.142 +/- 0.005 is slightly lower than the value for global fallout, but our results are consistent with the average ratio of 0.173 +/- 0.027 for the southern equatorial region (0-30 degrees S). PMID- 24631873 TI - Toward activated homology models of the human M1 muscarinic acetylcholine receptor. AB - Structure-based virtual screening offers a good opportunity for the discovery of selective M1 muscarinic acetylcholine receptor (mAChR) agonists for the treatment of Alzheimer's disease. However, no 3-D structure of an M1 mAChR is yet available and the homology models that have been previously reported are only able to identify antagonists in virtual screening experiments. In this study, we generated a homology model of the human M1 mAChR, based on the crystal structure of an M3 mAChR as the template. This initial model was modified, using the agonist-bound crystal structure of a beta2-adrenergic receptor as a guide, to give two possible activated structures. The T192 side chain was adjusted in both structures and one of the structures also had the whole of transmembrane (TM) 5 rotated and tilted toward the inner channel of the transmembrane region. The binding sites of all three structures were then refined by induced-fit docking (IFD) with acetylcholine. Virtual screening experiments showed that all three refined models could efficiently differentiate agonists from decoy molecules, with the TM5-modified models also giving good agonist/antagonist selectivity. The whole range of agonists and antagonists was observed to bind within the orthosteric site of the structure obtained by IFD refinement alone, implying that it has inactive state character. In contrast, the two TM5-modified structures were unable to accommodate the antagonists, supporting the proposition that they possess activated state character. PMID- 24631875 TI - Application of microfluidics in waterborne pathogen monitoring: a review. AB - A review of the recent advances in microfluidics based systems for the monitoring of waterborne pathogens is provided in this article. Emphasis has been made on existing, commercial and state-of-the-art systems and research activities in laboratories worldwide. The review separates sample processing systems and monitoring systems, highlighting the slow progress made in automated sample processing for monitoring of pathogens in waterworks and in the field. Future potential directions of research are also highlighted in the conclusions. PMID- 24631868 TI - Interpreting the language of histone and DNA modifications. AB - A major mechanism regulating the accessibility and function of eukaryotic genomes are the covalent modifications to DNA and histone proteins that dependably package our genetic information inside the nucleus of every cell. Formally postulated over a decade ago, it is becoming increasingly clear that post translational modifications (PTMs) on histones act singly and in combination to form a language or 'code' that is read by specialized proteins to facilitate downstream functions in chromatin. Underappreciated at the time was the level of complexity harbored both within histone PTMs and their combinations, as well as within the proteins that read and interpret the language. In addition to histone PTMs, newly-identified DNA modifications that can recruit specific effector proteins have raised further awareness that histone PTMs operate within a broader language of epigenetic modifications to orchestrate the dynamic functions associated with chromatin. Here, we highlight key recent advances in our understanding of the epigenetic language encompassing histone and DNA modifications and foreshadow challenges that lie ahead as we continue our quest to decipher the fundamental mechanisms of chromatin regulation. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. PMID- 24631874 TI - Comparison of human saliva and synthetic histo-blood group antigens usage as ligands in norovirus-like particle binding and blocking assays. AB - Blocking of norovirus-like particle binding to their cellular ligands, histo blood group antigens with immune sera, is considered a surrogate norovirus neutralization assay. We compared human secretor positive saliva and synthetic biotinylated carbohydrates as a source of histo-blood group antigens in binding and blocking assays. Six norovirus capsid-derived virus-like particles belonging to genogroup I (GI-1-2001 and GI-3-2002) and genogroup II (GII-4-1999, GII-4-2010 New Orleans, GII-4-2012 Sydney and GII-12-1998) noroviruses were produced by a recombinant baculovirus expression system and binding profile to saliva type A, B and O and to synthetic antigens (A trimer, B trimer, H type 1, H type 3, Lewis(a) and Lewis(b)) was identified. Good correlation between virus-like particle binding to saliva type A and synthetic A trimer (r = 0.66, p < 0.05) and saliva type B and synthetic B trimer (r = 0.75, p < 0.05) was observed. Binding of each norovirus virus-like particle to the selected histo-blood group antigens was blocked by convalescent sera from NoV-infected subjects or type-specific mouse antisera. Our results support the use of either saliva or synthetic antigens in blocking assay to measure the ability of norovirus antisera to block virus-like particle binding to the carbohydrate ligands. PMID- 24631876 TI - Degradability of creatinine under sewer conditions affects its potential to be used as biomarker in sewage epidemiology. AB - Creatinine was proposed to be used as a population normalising factor in sewage epidemiology but its stability in the sewer system has not been assessed. This study thus aimed to evaluate the fate of creatinine under different sewer conditions using laboratory sewer reactors. The results showed that while creatinine was stable in wastewater only, it degraded quickly in reactors with the presence of sewer biofilms. The degradation followed first order kinetics with significantly higher rate in rising main condition than in gravity sewer condition. Additionally, daily loads of creatinine were determined in wastewater samples collected on Census day from 10 wastewater treatment plants around Australia. The measured loads of creatinine from those samples were much lower than expected and did not correlate with the populations across the sampled treatment plants. The results suggested that creatinine may not be a suitable biomarker for population normalisation purpose in sewage epidemiology, especially in sewer catchment with high percentage of rising mains. PMID- 24631877 TI - Uptake of Ag and TiO2 nanoparticles by zebrafish embryos in the presence of other contaminants in the aquatic environment. AB - The present study aimed at evaluating the uptake of two widely used nanoparticles (NPs), namely, silver (Ag) and titanium dioxide (TiO2) NPs by zebrafish embryos under different simulated environmental conditions. AgNPs and TiO2NPs are widely used in a number of consumer products, and are thus likely to be introduced into the aquatic environments from both domestic and industrial sources. These NPs could interact with other contaminants in aquatic systems, which could affect their uptake by fish and biodistribution kinetics. To provide insights into these interactions, uptake studies were conducted in the presence of 12 elements and 3 major inorganic nutrients using (1) single (AgNPs and TiO2NPs separately), (2) binary (containing either both AgNPs and TiO2NPs or one of the NPs and elements/nutrients) and (3) multi-components (conducted in real water samples collected from a tropical reservoir). In addition to the uptake of NPs, mortality, hatchability and heart rates of zebrafish embryos were also measured as part of these experiments. Results showed that AgNPs were taken up by the embryos to a larger extent as compared to TiO2NPs. Moreover, AgNPs were more toxic to zebrafish embryos as compared to TiO2NPs. In the presence of elements (5 MUg mL(-1)) and nutrients (5 and 10 MUg mL(-1)) together with one of the two NPs (10 MUg mL(-1)), both an increase and a decrease in the uptake of NPs were observed in embryos. Results from this exploratory study show that in the presence of environmental contaminants, the uptake of these NPs can be affected significantly. Furthermore, the toxic effects of NPs depend not only on their relative environmental concentrations, but also on those of other environmental pollutants. PMID- 24631878 TI - Full-scale partial nitritation/anammox experiences--an application survey. AB - Partial nitritation/anammox (PN/A) has been one of the most innovative developments in biological wastewater treatment in recent years. With its discovery in the 1990s a completely new way of ammonium removal from wastewater became available. Over the past decade many technologies have been developed and studied for their applicability to the PN/A concept and several have made it into full-scale. With the perspective of reaching 100 full-scale installations in operation worldwide by 2014 this work presents a summary of PN/A technologies that have been successfully developed, implemented and optimized for high strength ammonium wastewaters with low C:N ratios and elevated temperatures. The data revealed that more than 50% of all PN/A installations are sequencing batch reactors, 88% of all plants being operated as single-stage systems, and 75% for sidestream treatment of municipal wastewater. Additionally an in-depth survey of 14 full-scale installations was conducted to evaluate practical experiences and report on operational control and troubleshooting. Incoming solids, aeration control and nitrate built up were revealed as the main operational difficulties. The information provided gives a unique/new perspective throughout all the major technologies and discusses the remaining obstacles. PMID- 24631879 TI - Microbial communities from different types of natural wastewater treatment systems: vertical and horizontal flow constructed wetlands and biofilters. AB - The prokaryotic microbial communities (Bacteria and Archaea) of three different systems operating in Denmark for the treatment of domestic wastewater (horizontal flow constructed wetlands (HFCW), vertical flow constructed wetlands (VFCW) and biofilters (BF)) was analysed using endpoint PCR followed by Denaturing Gradient Gel Electrophoresis (DGGE). Further sequencing of the most representative bacterial bands revealed that diverse and distinct bacterial communities were found in each system unit, being gamma-Proteobacteria and Bacteroidetes present mainly in all of them, while Firmicutes was observed in HFCW and BF. Members of the Actinobacteria group, although found in HFCW and VFCW, seemed to be more abundant in BF units. Finally, some representatives of alpha, beta and delta Proteobacteria, Acidobacteria and Chloroflexi were also retrieved from some samples. On the other hand, a lower archaeal diversity was found in comparison with the bacterial population. Cluster analysis of the DGGE bacterial band patterns showed that community structure was related to the design of the treatment system and the organic matter load, while no clear relation was established between the microbial assemblage and the wastewater influent. PMID- 24631880 TI - Identifying polyvinylidene fluoride ultrafiltration membrane fouling behavior of different effluent organic matter fractions using colloidal probes. AB - The interaction forces between effluent organic matter (EfOM) fractions and membrane were measured by atomic force microscopy in conjunction with self-made membrane material colloidal probes. The inter-EfOM-fraction and intra-EfOM fraction interactions were investigated using corresponding EfOM-fraction-coated colloidal probe. We combined this analysis with corresponding fouling experiments to identify the EfOM fractions responsible for polyvinylidene fluoride (PVDF) ultrafiltration membrane fouling. Results show that hydrophilic and hydrophobic fractions were the dominant fractions responsible for membrane fouling and flux decline in the initial and later filtration stages, respectively, which was mainly attributed to the stronger PVDF-hydrophilic fraction and intra-hydrophobic fraction interaction forces. This phenomenon, in conjunction with the fact that each interaction force of PVDF-EfOM fraction was stronger than corresponding intra-EfOM-fraction force, suggests that the elimination of the PVDF-hydrophilic fraction interaction force is the best strategy for controlling EfOM fouling. Moreover, the inter-EfOM-fraction interaction force was mainly controlled by the corresponding intra-EfOM-fraction interaction forces. And, while the membrane EfOM fraction and intra-EfOM-fraction interactions for each type of EfOM fraction are equivalent, the EfOM fractions with the molecular weight smaller than the molecular weight cutoff of the membranes used were mainly responsible for membrane fouling rather than the relatively high-molecular-weight fractions. PMID- 24631881 TI - Homicides in Western Norway, 1985-2009, time trends, age and gender differences. AB - This retrospective study from Western Norway is based on the cases of 196 homicide victims from 1985 to 2009. The median age of the victims was 35 years, in both genders. Within the cases, 113 of the victims were male and 83 female, 28 victims were under the age of 18, and 19 victims were not native Norwegians. Ethanol was detected in the blood of a higher proportion of male compared to female victims, whereas a higher proportion of female compared to male victims had both illegal/legal drugs detected in their blood. Most perpetrators were male. Men were most often killed by an acquaintance, women by their present or former intimate partner. In 14 cases of intimate partner homicide the perpetrator committed suicide after killing their female partner. The dominant scene of crime was private homes. Most victims were killed by blunt force, sharp force or gunshot. The head was the body region most often injured in the homicide victims. Female victims were more often killed by manual strangulation than male victims. PMID- 24631882 TI - Quantitative diagnosis of lymphocytic myocarditis in forensic medicine. AB - The aim of this study was to establish quantitative diagnostic criteria for lymphocytic myocarditis on autopsy samples by using a stereological cell profile counting method. We quantified and compared the presence of lymphocytes and macrophages in myocardial autopsy specimens from 112 deceased individuals who had been diagnosed with myocarditis according to the Dallas criteria and 86 control subjects with morphologically normal hearts. We found the mean number to be 52.7 lymphocyte profiles/mm(2) (range 3.7-946; standard deviation 131) in the myocarditis group and 9.7 (range 2.1-25.9; standard deviation 4.6) in the control group. The cut-off value for the diagnosis of myocarditis was determined by calculating sensitivity plus specificity, which reached the highest combination at 13 lymphocyte profiles/mm(2) (sensitivity 68%; specificity 83%). A considerable proportion of subjects in both the myocarditis and control groups had lymphocyte profile counts below 30/mm(2), representing a diagnostic challenge due to the increased risk of creating false negative or false positive results. We found it practically impossible to obtain a reliable macrophage count. The present data add new important information on lymphocyte counts in inflamed and non-inflamed myocardium. We suggest a cut-off value in the range of 11-16 lymphocyte profiles/mm(2) for a reliable diagnosis of lymphocytic myocarditis from autopsy samples. To evaluate small inflammatory changes at low lymphocyte counts, a multidisciplinary approach should be implemented, in which diagnostic tools are used ancillary to histological examination. We advise against semi quantification of macrophages based on cell profile counting. PMID- 24631883 TI - Transient expressions of synthetic biology in plants. AB - Recent developments in transient expression methods have enabled the efficient delivery and expression of multiple genes within the same plant cell over a timescale of days. In some cases, the vectors deployed can be fine-tuned to allow differential expression of the various genes. This has opened the way to the deployment of transient expression for such applications as the production of macromolecular complexes and the analysis and manipulation of metabolic pathways. The ability to observe the effect of gene expression in a matter of days means that transient expression is becoming the method of choice for many plant-based synthetic biology applications. PMID- 24631884 TI - Heterologous production of plant-derived isoprenoid products in microbes and the application of metabolic engineering and synthetic biology. AB - The value associated with plant-derived products has spurred efforts to engineer new production routes. One such option is heterologous biosynthesis which requires reconstitution of a biosynthetic pathway in a host that provides both innate and developed cellular advantages relative to the native producer. This review will summarize success to date in heterologously producing plant-derived isoprenoid products when using hosts such as E. coli and yeast. The article will also address the significant challenges that face such efforts, the approaches that have been used to overcome obstacles, and the tools of metabolic engineering and synthetic biology being applied both in the course of establishing heterologous biosynthesis and optimizing final production metrics. PMID- 24631885 TI - An improved robust stability result for uncertain neural networks with multiple time delays. AB - This paper proposes a new alternative sufficient condition for the existence, uniqueness and global asymptotic stability of the equilibrium point for the class of delayed neural networks under the parameter uncertainties of the neural system. The existence and uniqueness of the equilibrium point is proved by using the Homomorphic mapping theorem. The asymptotic stability of the equilibrium point is established by employing the Lyapunov stability theorems. The obtained robust stability condition establishes a new relationship between the network parameters of the system. We compare our stability result with the previous corresponding robust stability results derived in the past literature. Some comparative numerical examples together with some simulation results are also given to show the applicability and advantages of our result. PMID- 24631886 TI - [Diagnosis, treatment, and follow-up of hepatitis C-virus related liver disease. Hungarian national consensus guideline]. AB - Approximately 70 000 people are infected with hepatitis C virus in Hungary, more than half of whom are not aware of their infection. Early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases (liver cirrhosis and liver cancer) and its complications. In addition, it may increase work productivity and life expectancy of infected individual, and can prevent further viral transmission. Early recognition can substantially reduce the long term financial burden of related morbidity from socioeconomic point of view. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can kill the virus in 40-45% of previously not treated (naive), and in 5-21% of previous treatment-failure patients. Addition of two direct acting first generation protease inhibitor drugs (boceprevir and telaprevir) to the dual therapy increased the chance of sustained clearance of virus to 63-75% and 59-66%, respectively. These two protease inhibitor drugs are available and financed for a segment of Hungarian patients since May 2013. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. For initiation of treatment as well as for on-treatment decisions accurate and timely molecular biology tests are mandatory. Staging of liver damage (fibrosis) non-invasive methods (transient elastography and biochemical methods) are acceptable to avoid concerns of patients related to liver biopsy. Professional decision for treatment is balanced against budget limitations in Hungary, and priority is given to those with urgent need using a national Priority Index system reflecting stage of liver disease as well as additional factors (activity and progression of liver disease, predictive factors and other special circumstances). All naive patients are given a first chance with dual therapy. Those with genotype 1 infection and with on-treatment or historic failure to dual therapy are eligible to receive protease inhibitor based triple therapy provided, they reach financial cutoff eligibility based on Priority Index. Duration of therapy is usually 48 weeks in genotype 1 with a response-guided potential to reduce duration for non-cirrhotic patients. Patients with non-1 genotypes are treated with dual therapy (without protease inhibitors) for a genotype and response driven duration of 16, 24, 48, or 72 week. Careful monitoring for early recognition and management of side-effects as well as viral response and potential breakthrough during protease-inhibitor therapy are recommended. PMID- 24631888 TI - Methods to study Drosophila immunity. AB - Innate immune mechanisms are well conserved throughout evolution, and many theoretical concepts, molecular pathways and gene networks are applicable to invertebrate model organisms as much as vertebrate ones. Drosophila immunity research benefits from an easily manipulated genome, a fantastic international resource of transgenic tools and over a quarter century of accumulated techniques and approaches to study innate immunity. Here we present a short collection of ways to challenge the fruit fly immune system with various pathogens and parasites, as well as read-outs to assess its functions, including cellular and humoral immune responses. Our review covers techniques for assessing the kinetics and efficiency of immune responses quantitatively and qualitatively, such as survival analysis, bacterial persistence, antimicrobial peptide gene expression, phagocytosis and melanisation assays. Finally, we offer a toolkit of Drosophila strains available to the research community for current and future research. PMID- 24631887 TI - [Diagnosis and treatment of chronic hepatitis B and D. Hungarian national consensus guideline]. AB - Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. PMID- 24631889 TI - DNA from natural sources in design of functional devices. AB - The role of DNA as structuring or templating agent has become more significant with the development of nanobiotechnology. Although short single and double stranded DNA have extensively been used as immobilization tool, as a template for nanoparticle preparation and in design of various devices such as nanomotors and biosensors, DNA from natural sources has an advantage of being abundant, cheap and readily available. Therefore, it is not surprising that there is a huge interest in making the use of natural DNA properties for both nano- and micro applications. In this review we attempt to give an overview of the up to date applications of natural DNA, either from viral, marine or mammalian sources, in design of functional devices. This article is meant to be a starting point and a guide to the platforms in which natural DNA is employed such as DNA origami, optoelectronic devices and organic catalysis. PMID- 24631890 TI - Antigen retrieval, blocking, detection and visualisation systems in immunohistochemistry: a review and practical evaluation of tyramide and rolling circle amplification systems. AB - To achieve specificity and sensitivity using immunohistochemistry it is necessary to combine the application of validated primary antibodies with optimised pre treatment, detection and visualisation steps. The influence of these surrounding procedures is reviewed. A practical evaluation of tyramide signal amplification and rolling circle amplification detection methods is provided in which formalin fixed paraffin embedded sections of adenocarcinomas of breast, colon and lung together with squamous metaplasia of lung were immunostained with CD20 and CK19 primary antibodies. The results indicate that the detection systems are of comparable sensitivity and specificity. PMID- 24631891 TI - Methods for studying metabolism in Drosophila. AB - Recent research using Drosophila melanogaster has seen a resurgence in studies of metabolism and physiology. This review focuses on major methods used to conduct this work. These include protocols for dietary interventions, measurements of triglycerides, cholesterol, glucose, trehalose, and glycogen, stains for lipid detection, and the use of gas chromatography-mass spectrometry (GC-MS) to detect major polar metabolites. It is our hope that this will provide a useful framework for both new and current researchers in the field. PMID- 24631892 TI - Age-dependent changes in ultrastructure of the defensive glands of Neocapritermes taracua workers (Isoptera, Termitidae). AB - Protection against predators and competitors is one of the main concerns of termite colonies, which developed a specialised defensive caste, the soldiers. However, soldiers are rare or even missing in several lineages of termites, while workers often develop new defence strategies especially in soil-feeding species. Here, we describe the morphology and ultrastructure of the autothysis-associated glands of Neocapritermes taracua workers and report their age-related changes in structure. The defensive glands of N. taracua workers consist of a pair of labial and a pair of crystal glands, whose secretions mix together through autothysis. Autothysis always occurs at the line of weakness connecting the anterior parts of the crystal-bearing pouches. The crystal glands consist of groups of bicellular secretory units (secretory and corresponding canal cells) which secrete the blue crystal material into external pouches. Their secretory activity is maximal in the middle of worker life, and is considerably lower in very young and old workers. The labial glands are composed of two types of secretory cells: the central and the parietal cells. While the central cells are developed similarly to other termites and secrete proteinaceous secretion into labial gland ducts, the parietal cells develop proteinaceous granules which may eventually bud off the cells. The secretory function of parietal cells is so far unique to N. taracua and differs from other termite species in which they are only responsible of water uptake by acini. The defensive device of N. taracua is truly exceptional as it involves a new gland and a previously undescribed function for parietal cells, being a remarkable example of evolution of morphological innovation. PMID- 24631893 TI - Chemical cocktails in aquatic systems: pesticide effects on the response and recovery of >20 animal taxa. AB - Natural systems are often exposed to individual insecticides or combinations of multiple insecticides. Using an additive and substitutive design, we examined how populations and communities containing >20 animal taxa are affected by four insecticides applied individually and as a mixture for 18 wks in aquatic mesocosms. The four insecticides had distinct lethal effects on the response and recovery of cladocerans, copepods, amphipods, isopods, and amphibians but not snails. The lethal effect on cladocerans and copepods induced trophic cascades that facilitated algal blooms and abiotic changes (higher pH and dissolved oxygen, but lower light transmission). Exposure to endosulfan resulted in a lag effect reducing cladocerans and spring-breeding amphibian abundance. The reduction in spring-breeding amphibian abundance led to cascading indirect effects on summer-breeding amphibians. Finally, the mixture treatment had lethal effects throughout the community that led to long-term effects on amphibian mass and unique indirect consequences on phytoplankton and abiotic variables. PMID- 24631894 TI - Bioaccumulation of perfluoroalkyl compounds in midge (Chironomus riparius) larvae exposed to sediment. AB - Midge larvae (Chironomus riparius) were exposed to sediments from a deposition sampled at a site along the Rhone River (France) downstream of an industrial site releasing various perfluorinated chemicals. This sediment is characterized by high concentrations of perfluoroundecanoic acid (PFUnA) and perfluorotridecanoic acid (PFTrDA) and a low perfluorooctane sulfonate (PFOS) concentration. Concentrations of 23 perfluoroalkyl compounds, including C4-C14 carboxylate acids, C4-C10 sulfonates, and seven precursors, were analyzed in overlying and pore water, sediment, and larvae. Midge larvae accumulated carboxylate acids (C11 C14), PFOS, and two precursors (perfluorooctane sulfonamide: FOSA and 6:2 fluorotelomer sulfonic acid, 6:2 FTSA). These substances accumulated mainly during the fourth instar larvae exponential growth phase. Accumulation of 6:2 FTSA, PFUnA, and PFOS occured via trophic and tegumentary routes. Other compounds mainly accumulated from food. Kinetics followed a partition model, from which uptake and elimination constants were derived. PMID- 24631895 TI - 1-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamides: synthesis, molecular modeling, evaluation of their anti-inflammatory activity and ulcerogenicity. AB - A series of novel 1-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4 triazole-3-carboxamides were synthesized and confirmed with different spectroscopic techniques. The prepared compounds exhibited remarkable anti inflammatory activity that represents 38%-100% of indomethacin activity and 44% 115% of celecoxib activity after 3 h. The anilides 5a-l and hydrazide 6 exhibit low incidence of gastric ulceration compared to indomethacin which was confirmed with histopathological investigation. In vitro COX-1/COX-2 inhibition studies showed compounds 4b (COX-1 IC50 = 45.9 MUM; COX-2 IC50 = 68.2 MUM) and 6 (COX-1 IC50 = 39.8 MUM; COX-2 IC50 = 46.3 MUM) are the most potent COX inhibitors in the tested compounds. The binding mode for some of the tested compounds to the enzymes was predicted using docking studies. PMID- 24631896 TI - Design, synthesis & evaluation of condensed 2H-4-arylaminopyrimidines as novel antifungal agents. AB - A small, focussed library of condensed 2H-4-arylaminopyrimidines, with 3 diversity points, based on an initial design by molecular docking study of this scaffold at the active site of the fungal enzyme of cytochrome P450 family, lanosterol 14alpha-demethylase (CYP51) was synthesized through a one-pot green chemical synthetic protocol. The screening of the synthesised compounds for antifungal activity against Candida albicans, Aspergillus fumigatus &Aspergillus niger revealed activity in many of the compounds as comparable to that of fluconazole. Based on the antifungal activity and physicochemical property data of these derivatives, a meaningful SAR has been proposed. PMID- 24631897 TI - QSAR on antiproliferative naphthoquinones based on a conformation-independent approach. AB - The antiproliferative activities of a series of 36 naphthoquinone derivatives were subjected to a Quantitative Structure-Activity Relationships (QSAR) study. For this purpose a panel of four human cancer cell lines was used, namely HBL-100 (breast), HeLa (cervix), SW-1573 (non-small cell lung) and WiDr (colon). A conformation-independent representation of the chemical structure was established in order to avoid leading with the scarce experimental information on X-ray crystal structure of the drug interaction. The 1179 theoretical descriptors derived with E-Dragon and Recon software were simultaneously analyzed through linear regression models based on the Replacement Method variable subset selection technique. The established models were validated and tested through the use of external test sets of compounds, the Leave-One-Out Cross Validation method, Y-Randomization and Applicability Domain analysis. PMID- 24631898 TI - Rational design, synthesis and evaluation of chromone-indole and chromone pyrazole based conjugates: identification of a lead for anti-inflammatory drug. AB - Conjugates of chromone-indole and chromone-pyrazole were screened for cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitory activities. Compounds 8 and 9 were identified as preferred inhibitors of COX-2 over the other two enzymes. Their IC50 for COX-2 was 29 nM and 20 nM, respectively and selectivity indices (SI) for COX-2 over COX-1 was 46 and 337. NMR, mass spectral studies and molecular modelling also indicated preferential interactions of compounds 8 and 9 with COX-2. Tested on albino mice against capsaicin induced algesia, compound 8 exhibited analgesic potential comparable to diclofenac. In addition to the biological profile, the desirable physico-chemical properties of these compounds make them promising leads for anti-inflammatory drugs. PMID- 24631899 TI - Anti-mycobacterial activity of 1,3-diaryltriazenes. AB - The rapid generation and spread of the drug resistant tuberculosis has led to an ongoing demand for novel compounds for therapeutic use. Identification and study of compounds with the ability to inhibit Mycobacterium tuberculosis is of paramount importance. For this reason, a library of substituted 1,3 diaryltriazenes based on the acting component of the anti-trypanosomal drug, diminazene aceturate was created and evaluated for its potential as anti tubercular agent. Several compounds were identified with sub-micro molar inhibitory concentrations against M. tuberculosis and other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Although the library of the compounds showed a considerable acute cytotoxicity, a genotoxicity could not be observed. Finally, the triazene 14 was selected with the best biological properties (IC50 = 3.26 MUM, NI50 = 24.22 MUM, SI = 7.44). The compound 14 showed the ability to inhibit the growth of intracellular replicating and multi-drug resistant M. tuberculosis. The results suggest the molecule to be an interesting scaffold for further study and optimization. PMID- 24631901 TI - Intrinsically disordered proteins implicated in paramyxoviral replication machinery. AB - The development of mechanistic insight into the molecular basis of how intrinsically disordered proteins function is a key challenge for contemporary molecular biology. Intrinsic protein disorder is abundant in the replication machinery of paramyxoviruses. In order to study this kind of protein, new methods are required that specifically take account of the highly dynamic nature of the chain, and describe this disorder in quantitative terms. Here we review recent studies of conformational disorder in paramyxoviral phosphoproteins and nucleoproteins using solution-based approaches such as nuclear magnetic resonance. PMID- 24631900 TI - The E genotype of hepatitis B: clinical and virological characteristics, and response to interferon. AB - OBJECTIVES: 10 hepatitis B virus (HBV) genotypes are known with different geographic distribution and response to interferon (IFN) therapy. The E genotype is the more prevalent genotype in West and Central Africa, but few data about response to IFN are available. We describe the epidemiological and clinical characteristics in a cohort of patients immigrants from Africa in our country with HBV E genotype chronic hepatitis infection (CHB). METHODS: 63 patients with CHB and E genotype were included; 41 with CHB and low viral load were treated with PEG-IFN monotherapy; 10 with CHB and high viral load with sequential approach (entecavir and PEG-IFN). 12 patients with inactive CHB were followed with blood sample and abdomen ultrasonography every six months. RESULTS: The virological response in the monotherapy group was 17.9%. Hepatitis B surface antigen (HBsAg) loss was observed in 1 patient (2.5%); 56 patients (88%) showed at the time of diagnosis of CHB another infectious diseases that required specific treatment before PEG-IFN; this treatment was also affected by an higher incidence of side-effects (>50%). All patients with high viremia showed a primary non-response to PEG-IFN. CONCLUSIONS: The HBV E genotype evidences the worse response to PEG-IFN and maybe requires novel treatment options. PMID- 24631902 TI - Prospective evaluation of FibroTest(r), FibroMeter(r), and HepaScore(r) for staging liver fibrosis in chronic hepatitis B: comparison with hepatitis C. AB - BACKGROUND & AIMS: Fibrosis blood tests have been validated in chronic hepatitis C. Their diagnostic accuracy is less documented in hepatitis B. The aim of this study was to describe the diagnostic performance of FibroTest(r), FibroMeter(r), and HepaScore(r) for liver fibrosis in hepatitis B compared to hepatitis C. METHODS: 510 patients mono-infected with hepatitis B or C and matched on fibrosis stage were included. Blood tests were performed the day of the liver biopsy. Histological lesions were staged according to METAVIR. RESULTS: Fibrosis stages were distributed as followed: F0 n=76, F1 n=192, F2 n=132, F3 n=54, F4 n=56. Overall diagnostic performance of blood tests were similar between hepatitis B and C with AUROC ranging from 0.75 to 0.84 for significant fibrosis, 0.82 to 0.85 for extensive fibrosis and 0.84 to 0.87 for cirrhosis. Optimal cut-offs were consistently lower in hepatitis B compared to hepatitis C, especially for the diagnosis of extensive fibrosis and cirrhosis, with decreased sensitivity and negative predictive values. More hepatitis B than C patients with F ?3 were underestimated: FibroTest(r): 47% vs. 26%, FibroMeter(r): 24% vs. 6%, HepaScore(r): 41% vs. 24%, p<0.01. Multivariate analysis showed that hepatitis B (0R 3.4, 95% CI 1.2-19.2, p<0.02) and low gammaGT (OR 7.3, 95% CI 2.0-27.0, p<0.003) were associated with fibrosis underestimation. CONCLUSION: Overall the diagnostic performance of blood tests is similar in hepatitis B and C. The risk of underestimating significant fibrosis and cirrhosis is however greater in hepatitis B and cannot be entirely corrected by the use of more stringent cut offs. PMID- 24631903 TI - The effects of chronic photoperiod shifting on the physiology of female Long Evans rats. AB - As the prevalence of shift work is increasing, it is important to elucidate the impact that shift work has on health. Because of the alternating work schedules present in rotating shift work and working at night, shift workers are in a chronic state of circadian disruption. Animal models of circadian disruption are useful because they offer more experimental control than the largely correlational human shift work studies. The effects of chronic circadian disruption on food preference, glucose tolerance, corticosterone secretion, and performance in a stress-inducing task were investigated in female Long-Evans rats. A 64-day photoperiod shifting paradigm was used to induce circadian disruption. Surprisingly, neither the photoperiod shifted animals, nor the control animals demonstrated a preference for either an unhealthy or healthy diet. Nor was there a difference between the groups in weight gained during photoperiod shifting. However, the photoperiod shifted rats gained significantly more weight than control animals, without eating more food during discriminative fear conditioning to context (DFCTC). Surprisingly, chronic photoperiod shifting appeared to facilitate retention in the DFCTC task. The photoperiod shifted animals also had increased serum glucose values during fasting and after a glucose challenge test. The photoperiod shifted animals only had elevated corticosterone during the final two phases of photoperiod shifting. This study demonstrates that chronic photoperiod shifting elicits weight gain when exposed to a stressful event and impairs glucose tolerance in the same individual. PMID- 24631904 TI - Cartilage intermediate layer protein promotes lumbar disc degeneration. AB - Lumbar disc disease (LDD) is one of the most common musculoskeletal disorders, and accompanies intervertebral disc degeneration. CILP encodes cartilage intermediate layer protein, which is highly associated with LDD. Moreover, CILP inhibits transcriptional activation of cartilage matrix genes in nucleus pulposus (NP) cells in vitro by binding to TGF-beta1 and inhibiting the phosphorylation of Smads. However, the aetiology and mechanism of pathogenesis of LDD in vivo are unknown. To demonstrate the role of CILP in LDD in vivo, we generated transgenic mice that express CILP specifically in the intervertebral disc tissues and assessed whether CILP exacerbates disc degeneration. Degeneration of the intervertebral discs was assessed using magnetic resonance imaging (MRI) and histology. The level of phosphorylation of Smad2/3 in intervertebral discs was measured to determine whether overexpressed CILP suppressed TGF-beta signalling. Although the macroscopic skeletal phenotype of transgenic mice appeared normal, histological findings revealed significant degeneration of lumbar discs. MRI analysis of the lumbar intervertebral discs indicated a significantly lower signal intensity of the nucleus pulposus where CILP was overexpressed. Intervertebral disc degeneration was also observed. The number of phosphorylation of Smad2/3 immuno-positive cells in the NP significantly was decreased in CILP transgenic mice compared with normal mice. In summary, overexpression of CILP in the NP promotes disc degeneration, indicating that CILP plays a direct role in the pathogenesis of LDD. PMID- 24631905 TI - Elastic rotation of Escherichia coli F(O)F(1) having epsilon subunit fused with cytochrome b(562) or flavodoxin reductase. AB - Intra-molecular rotation of FOF1 ATP synthase enables cooperative synthesis and hydrolysis of ATP. In this study, using a small gold bead probe, we observed fast rotation close to the real rate that would be exhibited without probes. Using this experimental system, we tested the rotation of FOF1 with the epsilon subunit connected to a globular protein [cytochrome b562 (epsilon-Cyt) or flavodoxin reductase (epsilon-FlavR)], which is apparently larger than the space between the central and the peripheral stalks. The enzymes containing epsilon-Cyt and epsilon FlavR showed continual rotations with average rates of 185 and 148 rps, respectively, similar to the wild type (172 rps). However, the enzymes with epsilon-Cyt or epsilon-FlavR showed a reduced proton transport. These results indicate that the intra-molecular rotation is elastic but proton transport requires more strict subunit/subunit interaction. PMID- 24631906 TI - Mining secreted proteins that function in pepper fruit development and ripening using a yeast secretion trap (YST). AB - Plant cells secrete diverse sets of constitutively- and conditionally-expressed proteins under various environmental and developmental states. Secreted protein populations, or secretomes have multiple functions, including defense responses, signaling, metabolic processes, and developmental regulation. To identify genes encoding secreted proteins that function in fruit development and ripening, a yeast secretion trap (YST) screen was employed using pepper (Capsicum annuum) fruit cDNAs. The YST screen revealed 80 pepper fruit-related genes (CaPFRs) encoding secreted proteins including cell wall proteins, several of which have not been previously described. Transient GFP-fusion assay and an in planta secretion trap were used to validate the secretion of proteins encoded by selected YST clones. In addition, RNA gel blot analyses provided further insights into their expression and regulation during fruit development and ripening. Integrating our data, we conclude that the YST provides a valuable functional genomics tool for the identification of substantial numbers of novel secreted plant proteins that are associated with biological processes, including fruit development and ripening. PMID- 24631907 TI - Basal and inducible anti-inflammatory epoxygenase activity in endothelial cells. AB - The roles of CYP lipid-metabolizing pathways in endothelial cells are poorly understood. Human endothelial cells expressed CYP2J2 and soluble epoxide hydrolase (sEH) mRNA and protein. The TLR-4 agonist LPS (1 MUg/ml; 24 h) induced CYP2J2 but not sEH mRNA and protein. LC-MS/MS analysis of the stable commonly used human endothelial cell line EA.Hy926 showed active epoxygenase and epoxide hydrolase activity: with arachidonic acid (stable epoxide products 5,6-DHET, and 14,15-DHET), linoleic acid (9,10-EPOME and 12,13-EPOME and their stable epoxide hydrolase products 9,10-DHOME and 12,13-DHOME), docosahexaenoic acid (stable epoxide hydrolase product 19,20-DiHDPA) and eicosapentaenoic acid (stable epoxide hydrolase product 17,18-DHET) being formed. Inhibition of epoxygenases using either SKF525A or MS-PPOH induced TNFalpha release, but did not affect LPS, IL 1beta, or phorbol-12-myristate-13-acetate (PMA)-induced TNFalpha release. In contrast, inhibition of soluble epoxide hydrolase by AUDA or TPPU inhibited basal, LPS, IL-1beta and PMA induced TNFalpha release, and LPS-induced NFkappaB p65 nuclear translocation. In conclusion, human endothelial cells contain a TLR-4 regulated epoxygenase CYP2J2 and metabolize linoleic acid>eicosapentaenoic acid > arachidonic acid>docosahexaenoic acid to products with anti-inflammatory activity. PMID- 24631909 TI - Neurorobotics: driving the paradigm shift. PMID- 24631908 TI - Curcumin inhibits 19-kDa lipoprotein of Mycobacterium tuberculosis induced macrophage apoptosis via regulation of the JNK pathway. AB - Recently, synthetic curcumin analogs are reported as potential active compounds against Mycobacterium tuberculosis (MTB). During the process of MTB infection, macrophages show increased apoptosis. The candidate virulence factors such as 19 kDa lipoprotein secreted by the MTB (P19) strongly influences macrophages by activation of Toll-like receptor 2 (TLR2) and mitogen-activated protein kinases (MAPKs). It has been reported that curcumin could affect the apoptosis of tumor cells via regulation of MAPKs. However, its effect on the P19-induced apoptosis of macrophages is unclear. This study investigates the effect of curcumin on the MAPKs signaling and apoptosis in human macrophages. The results showed that curcumin and P19 induced macrophage apoptosis in a time- and dose-dependent manner Low doses of curcumin (10 and 20 MUM) protected macrophages from P19 induced apoptosis, accompanied by decreased production of cytokines and reduced activation of the c-Jun amino-terminal kinase (JNK) and p38 MAPK. The protective effect of curcumin on P19 induced apoptosis of macrophages were enhanced by treatment with the JNK-specific inhibitors, whereas SB203580, the inhibitor of p38 MAPK had no effect. Curcumin had no effect on the activity of extracellular signal-regulated protein kinase (ERK). Taken together, our data show that the JNK pathway, but not the p38 or ERK pathway, plays an important role in the protective effect of curcumin against P19 induced macrophage apoptosis, and regulation of the JNK pathway may partially elucidate the anti-tuberculosis activity of curcumin. PMID- 24631910 TI - Recapitulating flesh with silicon and steel: advancements in upper extremity robotic prosthetics. AB - With the loss of function of an upper extremity because of stroke or spinal cord injury or a physical loss from amputation, an individual's life is forever changed, and activities that were once routine become a magnitude more difficult. Much research and effort have been put into developing advanced robotic prostheses to restore upper extremity function. For patients with upper extremity amputations, previously crude prostheses have evolved to become exceptionally functional. Because the upper extremities can perform a wide variety of activities, several types of upper extremity prostheses are available ranging from passive cosmetic limbs to externally powered robotic limbs. In addition, new developments in brain-machine interface are poised to revolutionize how patients can control these advanced prostheses using their thoughts alone. For patients with spinal cord injury or stroke, functional electrical stimulation promises to provide the most sophisticated prosthetic limbs possible by reanimating paralyzed arms of these patients. Advances in technology and robotics continue to help patients recover vital function. This article examines the latest neurorestorative technologies for patients who have either undergone amputation or lost the use of their upper extremities secondary to stroke or spinal cord injury. PMID- 24631911 TI - Metabolic imaging in the detection of growth hormone-secreting pituitary adenomas. PMID- 24631912 TI - The pathophysiology of cerebral radiation necrosis and the role of laser interstitial thermal therapy. PMID- 24631913 TI - Supplementing the neurosurgical virtuoso: evolution of automation from mythology to operating room adjunct. AB - A central concept of scientific advancement in the medical and surgical fields is the incorporation of successful emerging ideas and technologies throughout the scope of human endeavors. The field of automation and robotics is a pivotal representation of this concept. Arising in the mythology of Homer, the concept of automation and robotics grew exponentially over the millennia to provide the substrate for a paradigm shift in the current and future practice of neurosurgery. We trace the growth of this field from the seminal concepts of Homer and Aristotle to early incorporation into neurosurgical practice. Resulting changes provide drastic and welcome advances in areas of visualization, haptics, acoustics, dexterity, tremor reduction, motion scaling, and surgical precision. PMID- 24631914 TI - The cohesin acetyltransferase Eco1 coordinates rDNA replication and transcription. AB - Eco1 is the acetyltransferase that establishes sister-chromatid cohesion during DNA replication. A budding yeast strain with an eco1 mutation that genocopies Roberts syndrome has reduced ribosomal DNA (rDNA) transcription and a transcriptional signature of starvation. We show that deleting FOB1--a gene that encodes a replication fork-blocking protein specific for the rDNA region--rescues rRNA production and partially rescues transcription genome-wide. Further studies show that deletion of FOB1 corrects the genome-wide replication defects, nucleolar structure, and rDNA segregation that occur in the eco1 mutant. Our study highlights that the presence of cohesin at the rDNA locus has a central role in controlling global DNA replication and gene expression. PMID- 24631915 TI - Osteoclastic giant cell tumor of the pancreas. AB - INTRODUCTION: Pancreatic giant cell tumors are rare, with an incidence of less than 1% of all pancreatic tumors. Osteoclastic giant cell tumor (OGCT) of the pancreas is one of the three types of PGCT, which are now classified as undifferentiated carcinoma with osteoclast-like giant cells. PRESENTATION OF CASE: The patient is a 57 year old woman who presented with a 3 week history of epigastric pain and a palpable abdominal mass. Imaging studies revealed an 18cm*15cm soft tissue mass with cystic components which involved the pancreas, stomach and spleen. Exploratory laparotomy with distal pancreatectomy, partial gastrectomy and splenectomy was performed. Histology revealed undifferentiated pancreatic carcinoma with osteoclast-like giant cells with production of osteoid and glandular elements. DISCUSSION: OGCT of the pancreas resembles benign appearing giant cell tumors of bone, and contain osteoclastic-like multinucleated cells and mononuclear cells. OGCTs display a less aggressive course with slow metastasis and lymph node spread compared to pancreatic adenocarcinoma. Due to the rarity of the cancer, there is a lack of prospective studies on treatment options. Surgical en-bloc resection is currently considered first line treatment. The role of adjuvant therapy with radiotherapy or chemotherapy has not been established. CONCLUSION: Pancreatic giant cell tumors are rare pancreatic neoplasms with unique clinical and pathological characteristics. Osteoclastic giant cell tumors are the most favorable sub-type. Surgical en bloc resection is the first line treatment. Long-term follow-up of patients with these tumors is essential to compile a body of literature to help guide treatment. PMID- 24631916 TI - Biosorption behavior and mechanism of cesium-137 on Rhodosporidium fluviale strain UA2 isolated from cesium solution. AB - In order to identify a more efficient biosorbent for (137)Cs, we have investigated the biosorption behavior and mechanism of (137)Cs on Rhodosporidium fluviale (R. fluviale) strain UA2, one of the dominant species of a fungal group isolated from a stable cesium solution. We observed that the biosorption of (137)Cs on R. fluviale strain UA2 was a fast and pH-dependent process in the solution composed of R. fluviale strain UA2 (5 g/L) and cesium (1 mg/L). While a Langmuir isotherm equation indicated that the biosorption of (137)Cs was a monolayer adsorption, the biosorption behavior implied that R. fluviale strain UA2 adsorbed cesium ions by electrostatic attraction. The TEM analysis revealed that cesium ions were absorbed into the cytoplasm of R. fluviale strain UA2 across the cell membrane, not merely fixed on the cell surface, which implied that a mechanism of metal uptake contributed largely to the cesium biosorption process. Moreover, PIXE and EPBS analyses showed that ion-exchange was another biosorption mechanism for the cell biosorption of (137)Cs, in which the decreased potassium ions were replaced by cesium ions. All the above results implied that the biosorption of (137)Cs on R. fluviale strain UA2 involved a two-step process. The first step is passive biosorption that cesium ions are adsorbed to cells surface by electrostatic attraction; after that, the second step is active biosorption that cesium ions penetrate the cell membrane and accumulate in the cytoplasm. PMID- 24631917 TI - Fractionation of (137)Cs and Pu in natural peatland. AB - High Cs-137 concentrations in plants growing on peatland inspired us to investigate the quantity of its bioavailable fraction in natural peat. Our investigation aims to: a) estimate the quantity of bioavailable Cs-137 and Pu present in peat, b) verify the similarity of Cs-137 and K-40 behaviours, and c) perform a quantification of Cs-137 and Pu transfer from peat to plants. We analysed the vertical distribution of Cs-137 and Pu isotopes in the peat and their concentrations in plants growing on these places. Bioavailability of radionuclides was investigated by sequential extraction. Sequential analyses revealed that it was the upper layer which contained the majority of Cs-137 in an available form while deeper layers retained Cs-137 in immobile fractions. We can conclude that 18% of all Cs-137 in the peat is still bioavailable. Despite of the low quantity of bioavailable fraction of Cs-137 its transfer factor reached extremely high values. In the case of Pu, 64% of its total amount was associated with fulvic/humic acids which resulted in the high transfer factor from peat to plants. 27 years after the Chernobyl nuclear accident, the significant part of radionuclides deposited in peatland is still bioavailable. PMID- 24631918 TI - (40)K in the Black Sea: a proxy to estimate biogenic sedimentation. AB - An approach to estimate the rate of biogenic sedimentation in the Black Sea using the naturally occurring radionuclide (40)K has been considered. It allows assessment of the contribution of suspended matter of biological origin to the overall sediment accumulation in the Black Sea coastal, shelf and deep-water areas. Based upon this method, a relationship between the biogenic fraction of the seabed sediments and the water depth has been established with a view to differentiating the contributions of allochthonous and autochthonous suspended matter to the sedimentation rate. Overall, (40)K can be considered as an easily applicable proxy to assess sedimentation rate of biogenic fraction of particulate matter in marine environments. PMID- 24631919 TI - A model of band-pass phenotypic resistance in a modified Beverton-Holt framework. AB - A new mathematical model of phenotypic bacterial resistance to a periodically applied antibiotic is presented. Using a modified Beverton-Holt framework, and without appealing to any explicit internal timescale or heritable mutations, we map the parameter-space regions corresponding to bacterial colony survival or extinction. It is demonstrated that band-pass behavior, in which colony survival occurs at intermediate - but not short or long - antibiotic application periods, is a possible regime for some initial population values if the bactericidal activity is sufficient. However, below this threshold value of antibiotic efficacy, a "fixed-point catastrophe" occurs, and colony extinction does not occur when the bacteria are challenged with long application periods. These results suggest that the dosing schedule of antibiotics within a clinical setting merits additional scrutiny, since even seemingly unimportant modifications to the frequency of administration may lead to widely diverging patient outcomes. PMID- 24631920 TI - Human biological monitoring for exposure assessment in response to an incident involving hazardous materials. AB - Biological monitoring in humans (HBM) is widely used in the field of occupational and environmental health. In the situation of an unexpected release of hazardous materials HBM may contribute to the medical support and treatment of exposed individuals from the general population or of emergency responders. Such exposure information may also be used to respond to individual concerns such as questions about a possible relationship between the chemicals released during the incident and health effects. In The Netherlands a guideline was prepared to support early decision-making about the possible use of HBM for exposure assessment during or as soon as possible following a chemical incident. The application of HBM in such an emergency setting is not much different from situations where HBM is normally used but there are some issues that need extra attention such as the choice of the biomarker, the biological media to be sampled, the time point at which biological samples should be collected, the ethics approval and technical implementation of the study protocol and the interpretation and communication of the study results. These issues addressed in the new guideline will support the use of HBM in the management of chemical disasters. PMID- 24631921 TI - Dibutyltin promotes oxidative stress and increases inflammatory mediators in BV-2 microglia cells. AB - The organotin dibutyltin (DBT) is used as biocide and as stabilizer in the manufacture of silicones, polyvinyl chloride plastics, polyurethanes and polyester systems. Although the immuno- and neurotoxicity of DBT has been recognized, the underlying mechanisms remained unclear and the impact of DBT on microglia cells has not yet been established. We now used cultured mouse BV-2 cells as a model of activated microglia to investigate the impact of DBT on oxidative stress and pro-inflammatory cytokines. DBT, at subcytotoxic concentrations, increased intracellular reactive oxygen species (ROS), mitochondrial mass, mitochondrial ROS, and the mRNA expression of inducible nitric oxide synthase (iNOS) and NADPH-dependent oxidase-2 (NOX-2). ATP levels were decreased by DBT, followed by activation of AMP-activated protein kinase (AMPK). Moreover, DBT potentiated the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Inhibition of NOX-2 diminished both ROS production and induction of IL-6 expression. The DBT-mediated increase in NF kappaB activity and subsequent up regulation of IL-6 was abolished by co treatment with a NF-kappaB inhibitor. Treatment of cells with pharmacological inhibitors indicated a role for mitogen-activated protein kinases (MAPKs), PI3K/Akt, protein kinase C (PKC) and phospholipase C (PLC) in the DBT-induced toxicity. Finally, the calcium chelator BAPTA-AM diminished oxidative stress and induction of IL-6 expression, indicating the involvement of increased intracellular calcium in the enhanced microglia activity upon exposure to DBT. Together, the results suggest that a potentiation of oxidative stress and pro inflammatory cytokine expression in microglia cells contribute to the toxicity of DBT in the CNS. PMID- 24631922 TI - Impact of physician specialty on classification of physician-perceived patient severity for patients with osteoarthritis. AB - BACKGROUND: Physicians often classify patients' osteoarthritis (OA) severity subjectively. As treatment decisions are influenced by severity classifications, it is important to understand the factors that influence physicians' OA severity ratings. This research sought to empirically identify physician and patient characteristics that lead to a patient being perceived as having more severe OA. METHODS: Data were analyzed from the OA IX Disease Specific Program, a large cross-sectional survey of OA physicians and patients in Germany, the UK, and USA between September 2011 and January 2012. Eligible, consenting physicians completed a Patient Record Form (PRF) for 10 consecutive OA patients. The PRF asked physicians to report the patient's demographics [age, gender, body mass index (BMI), ethnicity], their assessment of the patients' symptom severity, treatment, probability for surgery, to rate their overall OA severity (mild, moderate or severe) and the factors that had influenced the rating. Chi-squared tests and analysis of variance were used to identify patient characteristics that significantly impacted physicians' OA severity ratings. Controlling for the significant patient characteristics, we then examined the impact of physician specialty on physician's OA severity ratings. Finally, we investigated the differences in physician-reported factors that influenced the physicians' rating of patients' severity between physician specialties. RESULTS: Three hundred and sixty-three physicians [220 primary care physicians (PCPs), 48 rheumatologists, 95 orthopedic surgeons] recruited 3561 patients. Patients with greater age and BMI, worse symptoms and greater health care use were given higher OA severity ratings. Controlling for these factors, orthopedic surgeons rated their OA patients as more severe than PCPs and rheumatologists [adjusted odds ratio (OR) 1.8, 95% confidence interval (CI) 1.4-2.4]. Specialists (rheumatologists and orthopedic surgeons) were more likely than PCPs to use joint spaced narrowing based on X-ray and severity of joint deterioration radiographic severity to assess patients' OA severity (joint space narrowing: 79% and 78% vs 55%, P < 0.0001). CONCLUSIONS: Patient age, BMI, presence and severity of symptoms and health care use significantly impacted physicians' OA severity ratings, but radiographic changes appeared to be given greater weight among orthopedic surgeons and rheumatologists than PCPs when assessing patient severity. Whether these differences translate into different treatment recommendations for similar patients is unknown, and warrants study. PMID- 24631923 TI - Association between fixation technique and revision risk in total hip arthroplasty patients younger than 55 years of age. Results from the Nordic Arthroplasty Register Association. AB - OBJECTIVES: To evaluate implant survival following primary total hip replacement (THR) in younger patients. To describe the diversity in use of cup-stem implant combinations. DESIGN: 29,558 primary THRs osteoarthritis (OA) patients younger than 55 years of age performed from 1995 through 2011 were identified using the Nordic Arthroplasty Registry Association database. We estimated adjusted relative risk (aRR) of revision with 95% confidence interval (CI) using Cox regression. RESULTS: In general, no difference was observed between uncemented and cemented implants in terms of risk of any revision. Hybrid implants were associated with higher risk of any revision (aRR = 1.3, CI: 1.1-1.5). Uncemented implants led to a reduced risk of revision due to aseptic loosening (aRR = 0.5, CI: 0.5-0.6), whereas the risk was similar for hybrid and cemented implants. Compared with cemented implants, both uncemented and hybrid implants led to elevated risk of revision due to other causes, as well as elevated risk of revision due to any reason within 2 years. 183 different uncemented cup-stem implant combinations were registered in Denmark, of these, 172 were used in less than 100 operations which is similar to Norway, Sweden and Finland. CONCLUSIONS: Uncemented implants perform better in relation to long-term risk of aseptic loosening, whereas both uncemented and hybrid rather than cemented implants in patients younger than 55 years had more short-term revisions because problems due to dislocation, periprosthetic fracture and infection has not yet been completely solved. The vast majority of cup-stem combinations were used in very few operations. PMID- 24631924 TI - Sub regional estimates of morbidities in the English elderly population. AB - This study focuses on identifying the future trends and spatial concentrations of morbidities in the English elderly population. The morbidities to be estimated are: coronary heart disease; strokes; diabetes; cancer; respiratory illnesses and arthritis in the 60 year and older household residential population. The technique used is a spatial microsimulation of the elderly population of local authorities in England using data from the 2001 Census and the English Longitudinal Study of Ageing. The longitudinal nature of the microsimulated population is then used to estimate the morbidity prevalences for local authorities in 2010/2011. With this knowledge, planners will be able to focus the available health and care resources in those areas with greatest need. For most of these morbidities, there is evidence of a strong correlation between the type of authority and the estimated prevalence rates. PMID- 24631925 TI - Expression, purification and characterization of human vacuolar-type H(+)-ATPase subunit d1 and d2 in Escherichia coli. AB - Vacuolar-type H(+)-ATPase (V-ATPase) is a multi-subunit proton pump. The proton pump is essential for the regulation of pH in various eukaryotic cellular processes. Among the 14 subunits that constitute V-ATPase, d subunit mediates coupling between cytosolic and membrane domains. Whereas d1 is expressed ubiquitously in various types of cells, its isoform d2 is only expressed in specific cells or tissues. To characterize these isoforms, we expressed and purified the isoforms of human V-ATPase d subunits using Escherichia coli over expression system. Subunit d1 and d2 were purified as homogeneous monomers as demonstrated by dynamic light scattering (DLS) analysis. Secondary structures of d subunits were estimated to be composed of 73% alpha-helix and 2% beta-sheet, as analyzed using circular dichroism (CD) analysis. Although sequence identity and secondary structures of d subunits were highly similar, the relative stability against thermal stress was higher for d1 than d2. Efficient expression and purification of d subunits, together with biophysical and biochemical characterization, presented in this study is expected to facilitate further structural analysis to clarify specific inter-molecular interactions involved in multi-subunit assembly and regulation of H(+) transporters. PMID- 24631926 TI - An efficient depyrogenation method for recombinant bacterial outer membrane lipoproteins. AB - Bacterial outer membrane lipoproteins are anchored in the outer membrane lipid layer in close association with lipopolysaccharides (LPS) and with other hydrophobic membrane proteins, making their purification technically challenging. We have previously shown that a thorough delipidation of outer membrane preparations from the Escherichia coli expression host is an important step to eliminate contaminant proteins when purifying recombinant antigens expressed in fusion with the Pseudomonas aeruginosa OprI lipoprotein. Here we report the cloning and expression of three antigens in fusion with OprI (ovalbumin, eGFP and BbPDI) and our efforts to deal with the variable LPS contamination levels observed in different batches of purified lipoproteins. The use of polymyxin B columns or endotoxin removal polycationic magnetic beads for depyrogenation of purified lipoproteins resulted in high protein losses and the use of Triton X-114 or sodium deoxycholate during the course of affinity chromatography showed to be ineffective to reduce LPS contamination. Instead, performing a hot phenol/water LPS extraction from outer membrane preparations prior to metal affinity chromatography allowed the purification of the recombinant fusion lipoproteins with LPS contents below 0.02EU/MUg of protein. The purified recombinant lipoproteins retain their capacity to stimulate bone marrow-derived dendritic cells allowing for the study of their immunomodulatory properties through TLR2/1. This is a simple and easy to scale up method that can also be considered for the purification of other outer membrane lipoproteins. PMID- 24631927 TI - Leaching of polycyclic aromatic hydrocarbons from oil shale processing waste deposit: a long-term field study. AB - The leaching behavior of selected polycyclic aromatic hydrocarbons (PAHs) from an oil shale processing waste deposit was monitored during 2005-2009. Samples were collected from the deposit using a special device for leachate sampling at field conditions without disturbance of the upper layers. Contents of 16 priority PAHs in leachate samples collected from aged and fresh parts of the deposit were determined by GC-MS. The sum of the detected PAHs in leachates varied significantly throughout the study period: 19-315 MUg/l from aged spent shale, and 36-151 MUg/l from fresh spent shale. Among the studied PAHs the low-molecular weight compounds phenanthrene, naphthalene, acenaphthylene, and anthracene predominated. Among the high-molecular weight PAHs benzo[a]anthracene and pyrene leached in the highest concentrations. A spent shale deposit is a source of PAHs that could infiltrate into the surrounding environment for a long period of time. PMID- 24631928 TI - Three-dimensional and chemical changes on the surface of a 3-year clinically retrieved oxidized titanium dental implant. AB - OBJECTIVE: To report the main topographical features in the micro- and nano scales and to assess implant chemical changes of the surface of a 3-year clinically retrieved oxidized titanium dental implant, and compare them with a similar, unused implant. MATERIALS AND METHODS: The surface of the oxidized titanium dental implants was assessed by surface electron microscopy (SEM) analysis at increasing magnifications. X-ray photoelectron spectroscopy (XPS) measurement was performed to analyze the implants surface chemistry. XPS spectra were acquired before and after sputtering with an Ar(+) ion etching of 3keV. RESULTS: With a length of 10-40MUm, and a width of 0.05-0.1MUm, numerous cracks were ubiquitous along the implant surfaces. Chimney-like structures formed micropores between 1 and 5MUm, with up to 40% of them partially or totally broken in the retrieved implant. In relation to chemical composition, Ti and O were predominant in both the unused and in the retrieved implant. N was present in high concentrations (11.49at%) at the retrieved implant surface, in contrast with those observed for the unused implant (1.14at%). Also, C was present in higher concentrations in the retrieved implant surface, while drastically decreased following the sputter-cleaning process. CONCLUSION: While cracks were ubiquitous present from the manufacturing, broken chimney-like structures forming micropores in the clinically retrieved implant may be attributable to excessive mechanical friction forces during the insertion of the implant. Chemical composition of the implant surface may be subjected to changes because of the in vivo environment, with increase of N and C, and decrease of Ca and P. PMID- 24631929 TI - To divide or not to divide: control of the bacterial cell cycle by environmental cues. AB - Whether to divide or not is an important decision that nearly all cells have to make, especially bacteria that are exposed to drastic environmental changes. Under adverse conditions proliferation and growth could compromise cellular integrity and hence must be downregulated. To this end, bacteria have evolved sophisticated mechanisms to transduce environmental information into the cell cycle engine. Recent studies in Escherichia coli, Bacillus subtilis and Caulobacter crescentus indicate that these mechanisms often involve small molecule-based signaling, regulated proteolysis, as well as protein-protein interactions. Most of them delay replication initiation or septum formation by targeting the key regulators DnaA or FtsZ, respectively. Remarkably, while the targets are conserved, the precise mechanisms show a considerable degree of diversity among different species. PMID- 24631930 TI - The mystery of aging and rejuvenation - a budding topic. AB - In the process of yeast budding, an aged and deteriorated mother cell gives rise to a youthful and pristine daughter cell. This remarkable event offers a tractable model system for identifying factors affecting life expectancy and it has been established that multiple aging factors operate in parallel. Herein, we will highlight the identity of such aging factors, how they are asymmetrically segregated, and whether the knowledge of their deteriorating effects might be utilized to approach cellular and tissue rejuvenation in metazoans, including humans. PMID- 24631931 TI - Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2. AB - Hookworm activation-associated secreted proteins can be structurally classified into at least three different groups. The hallmark feature of Group 1 activation associated secreted proteins is a prominent equatorial groove, which is inferred to form a ligand binding site. Furthermore, a conserved tandem histidine motif is located in the centre of the groove and believed to provide or support a yet to be determined catalytic activity. Here, we report three-dimensional crystal structures of Na-ASP-2, an L3-secreted activation-associated secreted protein from the human hookworm Necator americanus, which demonstrate transition metal binding ability of the conserved tandem histidine motif. We further identified moderate phosphohydrolase activity of recombinant Na-ASP-2, which relates to the tandem histidine motif. By panning a random 12-mer peptide phage library, we identified a peptide with high similarity to the human calcium-activated potassium channel SK3, and confirm binding of the synthetic peptide to recombinant Na-ASP-2 by differential scanning fluorimetry. Potential binding modes of the peptide to Na-ASP-2 were studied by molecular dynamics simulations which clearly identify a preferred topology of the Na-ASP-2:SK3 peptide complex. PMID- 24631932 TI - [Mitochondria, oxidative stress and aging]. AB - The free radical theory of aging was defined in the 1950s. On the base of this theory, the reactive oxygen species formed in the metabolic pathways can play pivotal role in ageing. The theory was modified by defining the mitochondrial respiration as the major cellular source of reactive oxygen species and got the new name mitochondrial theory of aging. Later on the existence of a "vicious cycle" was proposed, in which the reactive oxygen species formed in the mitochondrial respiration impair the mitochondrial DNA and its functions. The formation of reactive oxygen species are elevated due to mitochondrial dysfunction. The formation of mitochondrial DNA mutations can be accelerated by this "vicious cycle", which can lead to accelerated aging. The exonuclease activity of DNA polymerase gamma, the polymerase responsible for the replication of mitochondrial DNA was impaired in mtDNA mutator mouse recently. The rate of somatic mutations in mitochondrial DNA was elevated and an aging phenotype could have been observed in these mice. Surprisingly, no oxidative impairment neither elevated reactive oxygen species formation could have been observed in the mtDNA mutator mice, which may question the existence of the "vicious cycle". PMID- 24631933 TI - [Connective tissue and inflammation]. AB - The author summarizes the structure of the connective tissues, the increasing motion of the constituents, which determine the role in establishing the structure and function of that. The structure and function of the connective tissue are related to each other in the resting as well as inflammatory states. It is emphasized that cellular events in the connective tissue are part of the defence of the organism, the localisation of the damage and, if possible, the maintenance of restitutio ad integrum. The organism responds to damage with inflammation, the non specific immune response, as well as specific, adaptive immunity. These processes are located in the connective tissue. Sterile and pathogenic inflammation are relatively similar processes, but inevitable differences are present, too. Sialic acids and glycoproteins containing sialic acids have important roles, and the role of Siglecs is also highlighted. Also, similarities and differences in damages caused by pathogens and sterile agents are briefly summarized. In addition, the roles of adhesion molecules linked to each other, and the whole event of inflammatory processes are presented. When considering practical consequences it is stressed that the structure (building up) of the organism and the defending function of inflammation both have fundamental importance. Inflammation has a crucial role in maintaining the integrity and the unimpaired somato-psychological state of the organism. Thus, inflammation serves as a tool of organism identical with the natural immune response, inseparably connected with the specific, adaptive immune response. The main events of the inflammatory processes take place in the connective tissue. PMID- 24631934 TI - [Penetrating atheromatous ulcer of the thoracic aorta. Treatment options]. AB - INTRODUCTIONS: Atherosclerosis is a generalized degenerative disease of arteries. A rare manifestation of that is the penetrating atheromatous aortic ulceration of the aortic wall which may be complicated by subintimal hematoma, dissection, false aneurysm and rupture (acute aortic syndrome). AIM: The aim of the authors was to analyse their experience with this rare disease. METHOD: In the department of the authors 10,212 patients underwent surgery for cardiovascular diseases. Among these, 18 patients were diagnosed with penetrating atheromatous aortic ulceration located in the thoracic aorta (ascending aorta 2, aortic arch 8, descending aorta 6 and thoracoabdominal aorta 2 patients). Severe comorbidities were present in the majority of patients. RESULTS: Depending on the localisation the authors used various treatment options such as open surgery (4 patients), hybrid techniques (7 patients) and pure endografting (7 patients). One patient died on postoperative day 3. Two patients had late complications due to endoleaks treated successfully by open surgery. CONCLUSIONS: The authors conclude that when this dangerous condition detected in time, a wide variety of open, hybrid and endovascular methods can be applied with good results. PMID- 24631935 TI - [Wernicke's encephalopathy induced by the use of diet pills and unbalanced diet]. AB - Wernicke's encephalopathy is an acute, potentially life-threatening, neurological syndrome resulting from thiamine deficiency. The disorder is still greatly underdiagnosed and, without prompt treatment, the condition can lead to the chronic form of the disease, Korsakoff's syndrome or even death. In developed countries Wernicke's encephalopathy has been associated with alcoholism, but in recent years there has been an increasing number of non-alcoholic cases. Authors report the case of a 23-year-old woman who developed oculomotor dysfunction, encephalopathy and ataxia as a result of an extreme diet and use of diet pills. The diagnosis of Wernicke's encephalopathy was supported by the resolution of neurological signs after parenteral thiamine replacement. This case is presented because of the rare etiology and diagnostic difficulty, and the latest diagnostic and therapic guidelines are also highlighted. PMID- 24631936 TI - [Finding the corpse of Lajos II, King of Hungary (1506-1526). Analysis and re interpretation of the forensic report written in 1926]. PMID- 24631937 TI - [The Bible -- a medical approach. XIII. Rib resection in the Bible -- interpretation with humor. Diagnosis of an infectious disease in the Bible]. PMID- 24631939 TI - Interleukin-1beta induces an inflammatory response and the breakdown of the endothelial cell layer in an improved human THBMEC-based in vitro blood-brain barrier model. AB - BACKGROUND: The blood-brain barrier is necessary to provide an optimal environment for cerebral function. It consists of endothelial cells that interact through interendothelial tight junctions and form a barrier with low permeability. Therefore, the infiltration of lymphocytes into the central nervous system is limited. Pathological conditions, such as chronic-inflammatory diseases and viral infections, induce a breakdown in the blood-brain barrier, which facilitates the accumulation of immune cells in the brain. NEW METHOD: Using the endothelial cell line "transfected human brain microvascular endothelial cells", we established an improved in vitro blood-brain barrier model. Using interleukin 1beta, we refined this model into an inflammatory blood-brain barrier model. RESULTS: The model is characterised by a transendothelial electrical resistance of 250 Ohm cm(2) and a permeability coefficient of 1*10(-6) cm/s for sodium fluorescein. IL-1beta induces a strong inflammatory response, resulting in the increased expression of the adhesion molecule ICAM-1 and the pro-inflammatory cytokines IL-6, IL-8, and TNFalpha. Furthermore, the transendothelial electrical resistance decreased and the paracellular permeability increased in the presence of IL-1beta. Additionally, the expression of the tight junction protein ZO-1 was reduced. As a consequence, an increased number of leukocytes were able to cross the cell layer. COMPARISON WITH EXISTING METHODS: The model presented here exhibits improved characteristics with regards to TEER and permeability. The influence of IL-1beta has not been described before in this model system. CONCLUSION: The inflammatory in vitro blood-brain barrier model provides a useful tool for studying inflammatory processes at the blood-brain barrier, especially processes provoked by IL-1beta. PMID- 24631940 TI - Ammonia recovery from agricultural wastes by membrane distillation: fouling characterization and mechanism. AB - One of the main obstacles impeding implementation of membrane distillation for the recovery and concentration of ammonia from swine manure is wetting caused by fouling. Due to the different types of fouling which can occur in a membrane system, foulants characterization is a complex problem. To elucidate the fouling mechanism, deposit morphology and composition of foulants have been determined using Scanning Electron Microscopy, X-ray Energy Dispersive Spectrometry, Attenuated Total Reflectance Infrared Spectrometry, Ion chromatography and Inductively coupled plasma-optical emission spectroscopy. Based on the analysis of fouled membranes, it is concluded that membrane fouling is dominated by organic fouling in combination with deposits of inorganic elements and microorganisms. After a week of running the membrane process without cleaning, the average fouling layer thickness was estimated to 10-15 MUm. The fouling layer further results in a loss of membrane hydrophobicity. This indicates that fouling could be a severe problem for membrane distillation performance. PMID- 24631941 TI - Microbial electrolysis cells turning to be versatile technology: recent advances and future challenges. AB - Microbial electrolysis cells (MECs) are an electricity-mediated microbial bioelectrochemical technology, which is originally developed for high-efficiency biological hydrogen production from waste streams. Compared to traditional biological technologies, MECs can overcome thermodynamic limitations and achieve high-yield hydrogen production from wide range of organic matters at relatively mild conditions. This approach greatly reduces the electric energy cost for hydrogen production in contrast to direct water electrolysis. In addition to hydrogen production, MECs may also support several energetically unfavorable biological/chemical reactions. This unique advantage of MECs has led to several alternative applications such as chemicals synthesis, recalcitrant pollutants removal, resources recovery, bioelectrochemical research platform and biosensors, which have greatly broaden the application scopes of MECs. MECs are becoming a versatile platform technology and offer a new solution for emerging environmental issues related to waste streams treatment and energy and resource recovery. Different from previous reviews that mainly focus on hydrogen production, this paper provides an up-to-date review of all the new applications of MECs and their resulting performance, current challenges and prospects of future. PMID- 24631942 TI - Comparison of two PAC/UF processes for the removal of micropollutants from wastewater treatment plant effluent: process performance and removal efficiency. AB - Two hybrid membrane processes combining powdered activated carbon (PAC) adsorption with ultrafiltration (UF) were investigated regarding operational performance and efficiency to remove organic micropollutants from municipal wastewater treatment plant effluent. A pressurized PAC/UF (pPAC/UF) and a submerged PAC/UF (sPAK/UF) system were operated continuously over a period of six months. Both UF membrane systems showed good compatibility with the application of PAC showing no abrasion or other negative impacts. The pPAC/UF system reached permeability values up to 290 L/(m2 h bar) at high fluxes of 80 L/(m2 h) compared to the sPAC/UF with a permeability of up to 200 L/(m2 h bar) at fluxes of up to 23 L/(m2 h). Surface analysis of both membranes with scanning electron microscopy revealed no membrane deterioration after the six-month period of operation. On the surface of the pressurized membrane the formation of a PAC layer was observed, which may have contributed to the high permeability by forming a protective coating. Five micropollutants, i.e. sulfamethoxazole, carbamazepine, mecoprop, diclofenac and benzotriazole in ambient effluent concentrations were investigated. Both PAC/UF systems removed 60-95% of the selected micropollutants at a dosage of 20 mg PAC/L and 4 mg Fe(3+)/L. However, extreme peak loads of sulfamethoxazole with concentrations of up to 30 MUg/L caused a considerable performance decrease for more than a week. PMID- 24631944 TI - S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. AB - BACKGROUND: In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC. PATIENTS AND METHODS: Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings. RESULTS: Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623 13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy. CONCLUSIONS: The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC. PMID- 24631945 TI - Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO). AB - BACKGROUND: Current evidence on myelopoietic growth factors is difficult to overview for the practicing haematologist/oncologist. International guidelines are sometimes conflicting, exclude certain patient groups, or cannot directly be applied to the German health system. This guideline by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Medical Oncology (DGHO) gives evidence-based recommendations for the use of G-CSF, pegylated G CSF, and biosimilars to prevent infectious complications in cancer patients undergoing chemotherapy, including those with haematological malignancies. METHODS: We systematically searched and evaluated current evidence. An expert panel discussed the results and recommendations. We then compared our recommendations to current international guidelines. RESULTS: We summarised the data from eligible studies in evidence tables, developed recommendations for different entities and risk groups. CONCLUSION: Comprehensive literature search and expert panel consensus confirmed many key recommendations given by international guidelines. Evidence for growth factors during acute myeloid leukaemia induction chemotherapy and pegfilgrastim use in haematological malignancies was rated lower compared with other guidelines. PMID- 24631946 TI - Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. AB - Despite several studies support a positive association between heavy alcohol consumption and liver cancer risk, a consistent dose-risk relationship has not yet been established. We carried out a systematic review and a meta-analysis of the association between alcohol intake and liver cancer occurrence, following the Meta-analysis Of Observational Studies in Epidemiology guidelines. We searched for cohort and nested case-control studies on the general population published before April 2013, using PubMed and EMBASE. Summary meta-analytic relative risks (RRs) were estimated using random-effect models. We included 16 articles (19 cohorts) for a total of 4445 incident cases and 5550 deaths from liver cancer. Compared with non-drinking, the pooled RRs were 0.91 (95% confidence interval, CI, 0.81-1.02) for moderate drinking (< 3 drinks per day) and 1.16 (95% CI, 1.01 1.34) for heavy drinking (>= 3 drinks per day), with significant heterogeneity among studies. The dose-risk curve suggested a linear relationship with increasing alcohol intake in drinkers, with estimated excess risk of 46% for 50 g of ethanol per day and 66% for 100 g per day. This systematic review suggests a moderate detrimental role of consumption of 3 or more alcoholic drinks per day on liver cancer, and a lack of association with moderate drinking. Our results have to be taken with due caution on account of the possible limitations of the original studies included in the meta-analysis. PMID- 24631943 TI - Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies. AB - Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82-1.18 comparing >=500 with 1-69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and ice cream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77 1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71-1.12) intake and pancreatic cancer risk overall when comparing intakes >=1300 with <500 mg/day. In addition, null associations were observed for dietary and total vitamin D intake and pancreatic cancer risk. Findings were consistent within sex, smoking status, and BMI strata or when the case definition was limited to pancreatic adenocarcinoma. Overall, these findings do not support the hypothesis that consumption of dairy foods, calcium, or vitamin D during adulthood is associated with pancreatic cancer risk. PMID- 24631947 TI - Smarter drugs emerging in pancreatic cancer therapy. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death in the Western world. Owing to a lack of specific symptoms and no accessible precursor lesions, primary diagnosis is commonly delayed, resulting in only 15%-20% of patients with potentially curable disease. The standard of care in advanced pancreatic cancer has improved. Apart from gemcitabine (plus erlotinib), FOLFIRINOX and the combination of gemcitabine plus nab-paclitaxel are novel and promising therapeutic options for patients with metastatic PDAC. A better molecular understanding of pancreatic cancer has led to the identification of a variety of potential molecular therapeutic targets. Many targeted therapies are currently under clinical evaluation in combination with standard therapies for PDAC. This review highlights the current status of targeted therapies and their potential benefit for the treatment of advanced PDAC. PMID- 24631948 TI - Optimal treatment of early-stage ovarian cancer. AB - BACKGROUND: There is no clear consensus regarding systemic treatment of early stage ovarian cancer (OC). Clinical trials are challenging because of the relatively low incidence and good prognosis. Initial results of the International Collaborative Ovarian Neoplasm (ICON)1 trial demonstrated benefit in both overall survival (OS) and recurrence-free survival (RFS) with adjuvant chemotherapy. We report results of 10-year follow-up to establish whether benefits are maintained longer term and discuss how this and other available evidence from randomised trials can be used to guide treatment options regarding the need for, and choice of, adjuvant chemotherapy regimen. PATIENTS AND METHODS: ICON1 recruited women with OC following primary surgery in whom there was uncertainty as to whether adjuvant chemotherapy was indicated. Patients were randomly assigned to adjuvant or no adjuvant chemotherapy. Platinum-based chemotherapy was recommended and 87% received single-agent carboplatin. Analyses of long-term treatment benefits and interaction with risk groups were carried out. A high-risk group of women was defined with stage 1B/1C grade 2/3, any stage 1 grade 3 or clear-cell histology. RESULTS: With a median follow-up of 10 years, the estimated hazard ratio (HR) for RFS was 0.69 [95% confidence interval (CI) 0.51-0.94, P = 0.02] and OS 0.71 (95% CI 0.52-0.98, P = 0.04) in favour of chemotherapy. In absolute terms, there was a 10% (60%-70%) improvement in RFS and a 9% (64%-73%) improvement in OS; the benefit of chemotherapy might be greater in high-risk disease (18% improvement in OS). Uncertainty remains about the optimal chemotherapy regimen. The only randomised trial data available are from a subset of 120 stage 1 patients in ICON3 where the treatment difference, comparing carboplatin with carboplatin/paclitaxel was estimated with relatively wide CIs [progression-free survival HR = 0.71 (95% CI 0.39-1.32) and OS HR = 0.98 (95% CI 0.49-1.93)]. CONCLUSIONS: Extended follow-up from ICON1 confirms that adjuvant chemotherapy should be offered to women with early-stage OC, particularly those with high-risk disease. CLINICAL TRIAL NUMBERS: ISRCTN11916376 for ICON1 and ISRCTN57157825 for ICON3. PMID- 24631949 TI - A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy induced nausea and vomiting over repeated cycles of chemotherapy. AB - BACKGROUND: Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC. PATIENTS AND METHODS: This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naive patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1-4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue). RESULTS: Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing >=4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0-120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles. CONCLUSIONS: NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC. PMID- 24631950 TI - Determinants of physical activity in America: a first characterization of physical activity profile using the National Health and Nutrition Examination Survey (NHANES). AB - OBJECTIVES: To develop and implement methodologies for characterizing accelerometry-derived patterns of physical activity (PA) in the United States in relation to demographics, anthropometrics, behaviors, and comorbidities using the National Health and Nutrition Examination Survey (NHANES) dataset. DESIGN: Retrospective analysis of nationally representative database. SETTING: Computer generated modeling in silico. PARTICIPANTS: A total of 6329 adults in the United States from the NHANES 2003-2004 database. METHODS: To discover subtle multivariate signal in the dynamic and noisy accelerometry data, we developed a novel approach, termed discretized multiple adaptive regression and implemented the algorithm in SAS 9.2 (SAS Institute, Cary, NC). MAIN OUTCOME MEASUREMENTS: Demographic, anthropometric, comorbidity, and behavioral variables. RESULTS: The intensity of PA decreased with both increased age and increased body mass index. Both greater education and greater income correlate with increased activity over short durations and reduced activity intensity over long durations. Numerous predictors demonstrated effects within activity ranges that may be masked by use of the standard activity intensity intervals. These include age, one of the most robust variables, where we discovered decreasing activities inside the moderate activity range. It also includes gender, where women compared with men have increased proportions of active times up to the center of light activity range, and income greater than $45,000, where a complex effect is seen with little correspondence to existing cut-points. CONCLUSIONS: The results presented in this study suggest that the method of multiple regression and heat map visualization can generate insights otherwise hidden in large datasets such as NHANES. A review of the provided heat maps reveals the trends discussed previously involving demographic, anthropometric, comorbidity, and behavioral variables. It also demonstrates the power of accelerometry to expose alterations in PA. Ultimately, this study provides a US population-based norm to use in future studies of PA. PMID- 24631951 TI - RNA metabolism in the pathogenesis of Parkinson's disease. AB - Neurodegenerative diseases such as Parkinson's disease are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. While most disease cases are sporadic with no known cause, a small percentage of disease cases are caused by inherited genetic mutations. The identification of genes associated with the familial forms of the diseases and subsequent studies of proteins encoded by the disease genes in cellular or animal models have offered much-needed insights into the molecular and cellular mechanisms underlying disease pathogenesis. Recent studies of the familial Parkinson's disease genes have emphasized the importance of RNA metabolism, particularly mRNA translation, in the disease process. It is anticipated that continued studies on the role of RNA metabolism in Parkinson's disease will offer unifying mechanisms for understanding the cause of neuronal dysfunction and degeneration and facilitate the development of novel and rational strategies for treating this debilitating disease. PMID- 24631952 TI - Preventive effect of rikkunshito on gastric motor function inhibited by L-dopa in rats. AB - We previously reported that ghrelin prevented l-dopa (LD)-induced inhibition of gastric emptying (GE) of a non-nutrient solution in rats. Parkinson's disease treatment involves the combined administration of l-dopa with the enzyme l-amino acid decarboxylase inhibitor, carbidopa (CD) to reduce peripheral formation of dopamine. We investigated the effect LD/CD given orogastrically (og) on GE of a non-nutrient or nutrient meal and whether og pretreatment with rikkunshito, a kampo medicine clinically used to treat gastroparesis, influenced LD/CD effect on GE and postprandial antral and duodenal motility in conscious rats. LD/CD (20/2 mgkg(-1)) decreased significantly GE to 26.3 +/- 6.0% compared to 61.2 +/- 3.2% in og vehicle monitored 20-min after a non-nutrient meal and to 41.9 +/- 5.8% compared to 72.9 +/- 5.2% in og vehicle monitored 60 min after a nutrient meal. Rikkunshito (0.5 or 1.0 g kg(-1)) reduced the LD/CD (20/2 mg kg(-1)) inhibition of GE of non-nutrient meal (36.9 +/- 7.4% and 46.6 +/- 4.8% respectively vs. 12.1 +/- 7.4% in og vehicle plus LD/CD) while having no effect alone (56.6 +/- 8.5%). The ghrelin antagonist, [d-Lys(3)]-GHRP-6 (1 mg kg(-1)) injected intraperitoneally partially reversed rikkunshito preventive effect on LD/CD inhibited GE. Rikkunshito (1.0 g kg(-1)) blocked LD/CD (20/2 mg kg(-1))-induced delayed GE of a nutrient meal and the reduction of postprandial antral motility. In 6-hydroxydopamine-induced Parkinson's disease rat model, rikkunshito (1.0 g kg(-1), og) also prevented LD/CD-inhibited gastric emptying of a nutrient meal and enhanced fasting plasma levels of acylated ghrelin. These data indicate that oral rikkunshito alleviates the delayed GE induced by LD/CD in naive and PD rat model in part through ghrelin-related mechanisms. PMID- 24631953 TI - Usefulness of catestatin to predict malignant arrhythmia in patients with acute myocardial infarction. AB - Catestatin (CST) displays potent vasodilatory effect and acts on lowering blood pressure in vivo. The clinical utility of CST in patients with acute myocardial infarction (AMI) has not been clearly delineated. The aim of this study was to investigate the predictive value of CST for the development of in-hospital malignant arrhythmia and other adverse cardiac events in patients with AMI. A total of 125 consecutive patients diagnosed with AMI were included. The clinical characteristics and previous history of the patients were collected. Malignant arrhythmia and other major adverse cardiac events (MACE) such as postinfarction angina pectoris or reinfarction and death were recorded during hospitalization. The levels of plasma CST, norepinephrine (NE) and amino-terminal pro-brain sodium peptides (NT-proBNP) were determined by sandwich ELISA. A multiple logistic regression model was used to predict the influence factors of malignant arrhythmia and other MACE during hospitalization of AMI patients. The results showed that the levels of plasma cystatin-C (CysC), high sensitivity C-reactive protein (hs-CRP), NE and NT-proBNP increased in a CST concentration dependent manner. The incidence of malignant arrhythmia significantly increased as the elevation of CST level (P<0.05). Age, CST and NT-proBNP were independent predictors for the MACE occurred during hospitalization. Increased blood glucose (>=6.1mmol/L) and CST were independent predictors for the complicated malignant arrhythmia of AMI patients. These data demonstrated that CST can be used as a new biological marker for prediction of malignant arrhythmia in patients with AMI. PMID- 24631955 TI - Differentiating Puerariae Lobatae Radix and Puerariae Thomsonii Radix using HPTLC coupled with multivariate classification analyses. AB - Puerariae Lobatae Radix (PLR), the root of Pueraria lobata, is a traditional Chinese medicine for treating diabetes and cardiovascular diseases. Puerariae Thomsonii Radix (PTR), the root of Pueraria thomsonii, is a closely related species to PLR and has been used as a PLR substitute in clinical practice. The aim of this study was to compare the classification accuracy of high performance thin-layer chromatography (HPTLC) with that of ultra-performance liquid chromatography (UPLC) in differentiating PLR from PTR. The Matlab functions were used to facilitate the digitalisation and pre-processing of the HPTLC plates. Seven multivariate classification methods were evaluated for the two chromatographic methods. The results demonstrated that the HPTLC classification models were comparable to the UPLC classification models. In particular, k nearest neighbours, partial least square-discriminant analysis, principal component analysis-discriminant analysis and support vector machine-discriminant analysis showed the highest rate of correct species classification, whilst the lowest classification rate was obtained from soft independent modelling of class analogy. In conclusion, HPTLC combined with multivariate analysis is a promising technique for the quality control and differentiation of PLR and PTR. PMID- 24631954 TI - Mammalian short palate lung and nasal epithelial clone 1 (SPLUNC1) in pH dependent airway hydration. AB - The epithelia that line the conducting airways are the lung's first point of contact with inhaled pathogens and toxicants. As such, they are known to play an important role in the lung's innate defense system, which includes (i) the production of airway surface liquid (ASL) that helps cleanse the airways through the physical removal of pathogens and toxicants on the mucociliary escalator and (ii) the secretion of anti-microbial proteins into the ASL to kill inhaled pathogens. Interestingly, the recently crystallized short palate lung and nasal epithelial clone 1 (SPLUNC1) protein appears to be a multi-functional protein. That is, it not only acts as an anti-microbial agent, but also modulates ASL homeostasis by acting as an endogenous inhibitor of the epithelial Na(+) channel (ENaC). This review will focus on the latter function of SPLUNC1, and will discuss new structural and physiological data regarding SPLUNC1's failure to function as a regulator of ASL hydration in CF airways. PMID- 24631956 TI - Evaluation of cathepsin B activity for degrading collagen IV using a surface plasmon resonance method and circular dichroism spectroscopy. AB - Evaluation of cathepsin B activities for degrading collagen IV and heat-denatured collagen IV (gelatin) were performed by surface plasmon resonance (SPR) and circular dichroism (CD) measurements. The optimal pH of cathepsin B activity for degrading each substrate was around 4.0. The DeltaRU(15 min), which is a decrease in the SPR signal at 15 min after injection of cathepsin B, was smaller for collagen IV than for heat-denatured collagen IV owing to the presence of triple helical conformation. An unstable nature of the triple-helical conformation of collagen IV at pH 4.0 was shown by the CD study. Degrading collagen IV by cathepsin B was facilitated owing to a local unwinding of the triple-helical conformation caused by proteolytic cleavage of the non-helical region. The concentration dependence of the initial velocity for degrading collagen IV by cathepsin B at pH 4.0 was biphasic, showing that cathepsin B at low concentration exhibits exopeptidase activity, while the enzyme at high concentration exhibits endopeptidase activity. The kinetic parameters for the exopeptidase activity of cathepsin B toward collagen IV and heat-treated collagen IV were evaluated and discussed in terms of the protease mechanism. PMID- 24631957 TI - Ultra high performance liquid chromatography method for the determination of pentamidine and analog in rat biological fluids. AB - Pentamidine isethionate (PTMD) is an antiprotozoal agent used in different parasitic diseases as Human African Trypanosomiasis or Pneumocystis pneumonia. Given its side effects, numerous analogs are still under development worldwide. PTMD has been recently described having a potential activity in myotonic dystrophy (type 1). Here we present an UPLC method coupled to fluo or PDA detection for PTMD and one analog determination in rat plasma or urine. The chromatographic separation was achieved on a Acquity UPLC(r) HSS T3 analytical column using a mobile phase combining formic acid 0.1% (v/v) and acetonitrile (ACN) at a constant flow rate of 0.4 mL/min. Preliminary, an innovative MUSPE (solid phase extraction) procedure using Oasis(r) WCX sorbent was processed and gave satisfying and reproducible results in terms of extraction yields. Additionally, the methods were successfully validated using the accuracy profiles approach (beta=95% and acceptance limits=15%) over the ranges 2.88-287.52 ng/mL and from 143.76 ng/mL to 1.72 MUg/mL in rat plasma and urine for PTMD and for EBAB, from 4.23 to 423.39 ng/mL and from 211.69 ng/mL to 2.54 MUg/mL for plasma and urine, respectively. The validated protocols were applied to a pharmacokinetic (PK) study on rats and permitted to point out some relevant PK parameters on PTMD and its studied analog. PMID- 24631958 TI - Multi-matrix assay of the first melatonergic antidepressant agomelatine by combined liquid chromatography-fluorimetric detection and microextraction by packed sorbent. AB - A rapid and reliable analytical method has been developed to quantify the melatonergic antidepressant agomelatine in three matrices, and namely saliva, plasma and dried blood spots. The method is based on the use of liquid chromatography with fluorimetric detection exploiting the native fluorescence of agomelatine. For saliva and plasma samples an original microextraction by packed sorbent procedure was implemented obtaining satisfactory extraction yield of the analyte (always higher than 89%) and a good clean-up of the matrices. On the contrary, agomelatine was extracted from dried blood spots by suitable solvent microwave-assisted extraction and injected into chromatographic system. Satisfactory results in terms of sensitivity, linearity, precision, selectivity and accuracy were obtained. Thus, the developed method seems to be suitable for therapeutic drug monitoring of depressed patients under agomelatine therapy. PMID- 24631959 TI - Implementing human factors in clinical practice. AB - OBJECTIVES: To understand whether aviation-derived human factors training is acceptable and useful to healthcare professionals. To understand whether and how healthcare professionals have been able to implement human factors approaches to patient safety in their own area of clinical practice. METHODS: Qualitative, longitudinal study using semi-structured interviews and focus groups, of a multiprofessional group of UK NHS staff (from the emergency department and operating theatres) who have received aviation-derived human factors training. RESULTS: The human factors training was evaluated positively, and thought to be both acceptable and relevant to practice. However, the staff found it harder to implement what they had learned in their own clinical areas, and this was principally attributed to features of the informal organisational cultures. CONCLUSIONS: In order to successfully apply human factors approaches in hospital, careful consideration needs to be given to the local context and informal culture of clinical practice. PMID- 24631960 TI - Systems biochemical responses of rats to Kansui and vinegar-processed Kansui exposure by integrated metabonomics. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried root of Kansui (Euphorbia kansui L.) is an effective and commonly used traditional Chinese medicine. Even so, Kansui cannot be satisfactorily applied clinically because of toxic side effects. In China, the most common Kansui-processing method uses vinegar to reduce its toxicity. The present study was designed to investigate the toxic effects caused by Kansui and evaluate detoxification of Kansui by vinegar processing of Kansui. MATERIALS AND METHOD: Thirty male Sprague Dawley (SD) rats were randomly assigned to five groups of six rats. Two experimental groups were oral gavaged with 7.875 and 15.75 g Kansui/kg body weight, two treated with 7.875 and 15.75 g VP Kansui/kg body weight for 14 d, and the control group concurrently subjected to oral gavage with only distilled water. On day 14, plasma, liver and kidney tissues were collected from all rats for biochemistry assessments, histopathological examination, and NMR analyses. RESULTS: The metabonome of rats treated with Kansui and vinegar-processed (VP-) Kansui was found to differ from that of controls. In liver extracts, the variational metabolites included elevated concentrations of isoleucine, leucine, valine, glutamate, and phenylalanine, with decreased taurine, glucose, and glycogen. However, changes in lysine, methionine, choline, phosphorylcholine, and tyrosine were only observed in Kansui-treated rats. In kidney extracts, prominent changes included elevations in isoleucine, leucine, valine, methionine, creatine/creatinine, and phenylalanine as well as decreased glutamine. Only Kansui treatment induced variations in alanine, lysine, acetate, choline, and phosphorylcholine. CONCLUSION: Perturbations in endogenous metabolites induced by Kansui correlated with disturbances in glycolysis and amino acid and lipid metabolism, while biochemical pathway disorders caused by VP-Kansui only involved glycolysis and amino acid metabolism. All results were confirmed by histopathological examination of liver and kidney tissues and clinical biochemistry analyses. PMID- 24631961 TI - The anti-tumor activity of Antrodia salmonea in human promyelocytic leukemia (HL 60) cells is mediated via the induction of G1 cell-cycle arrest and apoptosis in vitro or in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal mushroom Antrodia salmonea has been used as a traditional Chinese medicine and has demonstrated antioxidant and anti inflammatory effects. MATERIALS AND METHODS: In the present study, we examined the anti-tumor activity of the fermented culture broth of Antrodia salmonea (AS) in vitro and in vivo and revealed its underlying molecular mechanism of action. RESULTS: Treatment of human promyelocytic leukemia (HL-60) cells with AS (50-150 MUg/mL) significantly reduced cell viability and caused G1 arrest via the inhibition of cell-cycle regulatory proteins, including cyclin D1, CDK4, cyclin E, cyclin A, and phosphorylated retinoblastoma protein (p-Rb). Furthermore, AS treatment induced apoptosis, which was associated with DNA fragmentation, followed by a sequence of events, including intracellular ROS generation; mitochondrial dysfunction; Fas ligand activation; cytochrome c release; caspase 3, -8, -9, and PARP activation; and Bcl-2/Bax dysregulation. The results of the in vitro study suggested that AS-induced apoptosis in HL-60 cells was mediated by both the mitochondrial and death receptor pathways. Furthermore, we found that AS treatment was effective in delaying tumor incidence in HL-60 xenografted nude mice and reducing tumor burden. CONCLUSIONS: To the best of our knowledge, this is the first report confirming the anti-tumor activity of this potentially beneficial mushroom against human promyelocytic leukemia. PMID- 24631962 TI - Mycelia glycoproteins from Cordyceps sobolifera ameliorate cyclosporine-induced renal tubule dysfunction in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps sorbolifera has been used in Traditional Chinese Medicine for improving the renal function. Cyclosporine A (CsA) is an important immunosuppressive agent in the prevention of renal allograft rejection, but long-term usage of CsA could lead to chronic nephrotoxicity and renal graft failure. The study was aimed to investigate whether the mycelia glycoproteins of Cordyceps sobolifera (CSP) exert prevention effects on CsA-induced nephrotoxicity. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were randomly assigned into four groups (n=6 per group): normal saline (control group), CSP group, CsA group, and CSP-CsA group (CsA combined treatment with CSP). Glomerular and tubular functions were assessed and histological studies were performed. RESULTS: CSP, prepared by hot water extraction, ethanol precipitation and membrane dialysis, was found to be composed of three glycoproteins with average molecular weights of 543, 31, and 6.3 kDa, respectively. CsA impaired urea clearance and creatinine clearance were significantly improved by concomitant administration of CSP. TUNEL histochemical stain revealed that CSP significantly decreased CsA-induced apoptosis in renal tubular cells. The reducing effect of caspase-3 activation by CSP was suggested through the over-expression of the anti-apoptosis protein Bcl-2 in renal tubule cells. In assessment of CSP protection of renal tubule function, we found that CSP restored CsA induced magnesium wasting by increasing the magnesium reabsorption channels TRMP6 and TRMP7. CONCLUSION: The results suggested that CSP had a significant suppressive activity on CsA-induced apoptosis and protective activity against nephron loss possibly via its restoring activity by increasing the magnesium reabsorption channels TRMP6 and TRMP7 on CsA induced magnesium wasting. PMID- 24631963 TI - Tinnitus-related dissociation between cortical and subcortical neural activity in humans with mild to moderate sensorineural hearing loss. AB - Tinnitus is a phantom sound percept that is strongly associated with peripheral hearing loss. However, only a fraction of hearing-impaired subjects develops tinnitus. This may be based on differences in the function of the brain between those subjects that develop tinnitus and those that do not. In this study, cortical and sub-cortical sound-evoked brain responses in 34 hearing-impaired chronic tinnitus patients and 19 hearing level-matched controls were studied using 3-T functional magnetic resonance imaging (fMRI). Auditory stimuli were presented to either the left or the right ear at levels of 30-90 dB SPL. We extracted neural activation as a function of sound intensity in eight auditory regions (left and right auditory cortices, medial geniculate bodies, inferior colliculi and cochlear nuclei), the cerebellum and a cinguloparietal task positive region. The activation correlated positively with the stimulus intensity, and negatively with the hearing threshold. We found no differences between both groups in terms of the magnitude and lateralization of the sound evoked responses, except for the left medial geniculate body and right cochlear nucleus where activation levels were elevated in the tinnitus subjects. We observed significantly reduced functional connectivity between the inferior colliculi and the auditory cortices in tinnitus patients compared to controls. Our results indicate a failure of thalamic gating in the development of tinnitus. PMID- 24631964 TI - Charge-mediated topical delivery of plasmid DNA with cationic lipid nanoparticles to the skin. AB - Cationic lipid nanoparticles (cLNs) were modified to develop a gene delivery system for topical use via a dermal route. The cLNs were formulated using high pressure homogenization method and were composed of 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP), dioleoylphosphatidylethanolamine (DOPE), Tween 20, and tricaprin as a solid core (1:1:1:1.67, w/w). The prepared cLNs were nanoscale-sized (<100 nm) and were highly positive (51 mV). The cLN/DNA complexes demonstrated enhanced transfection potential in the cells at the optimal ratio without cytotoxic effects. To evaluate its efficacy in topical application, in vitro skin transfer of the cLN/DNA complexes was monitored using the measurement of the surface zeta potential of hairless mouse skin and validated using confocal microscopy of the sectioned skin. The in vivo delivery of plasmid DNA with the cLN formulation was examined using the relative expression levels of mRNA after non-invasive application with the cLN/DNA complexes on hair-removed dorsal skin of mice. The cLNs successfully transferred plasmid DNA to the skin, which was facilitated by the charge-mediated interaction between the cLN/DNA complexes and the skin. These results suggest the promising potential of cLNs as a topical gene delivery system for gene vaccine delivery and cutaneous gene therapy in preclinical and clinical applications. PMID- 24631966 TI - Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization. AB - Anti-neutrophil cytoplasmic antibody associated vasculitides (AAV) are conditions defined by an autoimmune small vessel inflammation. Dying neutrophils are found around the inflamed vessels and the balance between infiltrating neutrophils and macrophages is important to prevent autoimmunity. Here we investigate how sera from AAV patients may regulate macrophage polarization and function. Macrophages from healthy individuals were differentiated into M0, M1, M2a, M2b or M2c macrophages using a standardized protocol, and phenotyped according to their expression surface markers and cytokine production. These phenotypes were compared with those of macrophages stimulated with serum from AAV patients or healthy controls. While the healthy control sera induced a M0 macrophage, AAV serum promoted polarization towards the M2c subtype. No sera induced M1, M2a or M2b macrophages. The M2c subtype showed increased phagocytosis capacity compared with the other subtypes. The M2c polarization found in AAV is consistent with previous reports of increased levels of M2c-associated cytokines. PMID- 24631965 TI - The cyclin dependent kinase inhibitor (R)-roscovitine mediates selective suppression of alloreactive human T cells but preserves pathogen-specific and leukemia-specific effectors. AB - Graft versus host disease (GvHD), mediated by donor T cells, remains the primary cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation and novel therapeutic approaches are required. Cdk2 is a critical node of signal integration and programming of T cell responses towards immunity versus anergy but is dispensable for hematopoiesis and thymocyte development. We examined the effects of pharmacologic Cdk2 inhibition on alloreactive human T cells. Inhibition of Cdk2 blocked expansion of alloreactive T cells upon culture with HLA-mismatched dendritic cells and prevented generation of IFN-gamma producing alloantigen-specific effectors. In contrast, Cdk2 inhibition preserved effectors specific for Wilms' tumor 1 (WT1) leukemia antigen and for CMV as determined by WT1-specific and CMV-specific pentamers. Cdk2 inhibition preserved Treg cells, which have the ability to prevent GvHD while maintaining GvL. Thus, Cdk inhibitors may improve allogeneic HSCT by reducing alloreactivity and GvHD without loss of pathogen-specific and leukemia-specific immunity. PMID- 24631967 TI - Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer's disease. AB - We evaluated the integrity and function of the blood-brain barrier in 3xTg-AD mice aged 3-18 months and in APP/PS1 mice aged 8-months to determine the impacts of changes in amyloid and tau proteins on the brain vascular changes. The vascular volume (Vvasc) was sub-normal in 3xTg-AD mice aged from 6 to 18 months, but not in the APP/PS1 mice. The uptakes of [(3)H]-diazepam by the brains of 3xTg AD, APP/PS1 and their age-matched control mice were similar at all the times studied, suggesting that the simple diffusion of small solutes is unchanged in transgenic animals. The uptake of d-glucose by the brains of 18-month old 3xTg-AD mice, but not by those of 8-month old APP/PS1 mice, was reduced compared to their age-matched controls. Accordingly, the amount of Glut-1 protein was 1.4 times lower in the brain capillaries of 18 month-old 3xTg-AD mice than in those of age matched control mice. We conclude that the brain vascular volume is reduced early in 3xTg-AD mice, 6 months before the appearance of pathological lesions, and that this reduction persists until they are at least 18 months old. The absence of alterations in the BBB of APP/PS1 mice suggests that hyperphosphorylated tau proteins contribute to the vascular changes that occur in AD. PMID- 24631968 TI - Activation of the mTOR signaling pathway in the antidepressant-like activity of the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082 in the FST in rats. AB - Clinical studies have demonstrated rapid and long-lasting antidepressant effects of ketamine in depressive patients. It has been proposed that these effects are related to changes in synaptogenesis in the mechanism involving mammalian target of rapamycin (mTOR) activation. Similar mechanisms have been proposed for a group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. We aimed to investigate whether other mGlu receptor ligands that produce antidepressant-like effects, namely, the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082, induce the activation of mTOR signaling in the prefrontal cortex (PFC) in rats. AMN082 administered 60 min before the test increased the levels of pmTOR and pp70S6K, and the mTORC1 antagonist rapamycin reversed AMN082-induced changes in the forced swim test (FST) in rats. Furthermore, AMN082 administered 23 h before the decapitation of the rats increased the levels of synapsin I and GluR1, although it did not produce any effect in the FST at the same time point. However, MTEP induced a rapid but unsustained antidepressant-like effect, which was not related to the activation of the mTOR cascade. Finally, the antidepressant-like effects of MTEP or AMN082 were not antagonized by NBQX. In summary, the antidepressant like activity of MTEP did not depend on the activation of mTOR signaling. However, we observed a unique feature of the mechanism of AMN082. The drug stimulated the mTOR signaling pathway and synaptic protein levels (like ketamine), while it did not induce a sustained antidepressant effect and its action was not directly dependent on AMPA receptor activation (as in classic antidepressants (ADs)). PMID- 24631969 TI - Rotationally invariant image representation for viewing direction classification in cryo-EM. AB - We introduce a new rotationally invariant viewing angle classification method for identifying, among a large number of cryo-EM projection images, similar views without prior knowledge of the molecule. Our rotationally invariant features are based on the bispectrum. Each image is denoised and compressed using steerable principal component analysis (PCA) such that rotating an image is equivalent to phase shifting the expansion coefficients. Thus we are able to extend the theory of bispectrum of 1D periodic signals to 2D images. The randomized PCA algorithm is then used to efficiently reduce the dimensionality of the bispectrum coefficients, enabling fast computation of the similarity between any pair of images. The nearest neighbors provide an initial classification of similar viewing angles. In this way, rotational alignment is only performed for images with their nearest neighbors. The initial nearest neighbor classification and alignment are further improved by a new classification method called vector diffusion maps. Our pipeline for viewing angle classification and alignment is experimentally shown to be faster and more accurate than reference-free alignment with rotationally invariant K-means clustering, MSA/MRA 2D classification, and their modern approximations. PMID- 24631971 TI - Reactivity and fate of secondary alkane sulfonates (SAS) in marine sediments. AB - This research is focused on secondary alkane sulfonates (SAS), anionic surfactants widely used in household applications that access aquatic environments mainly via sewage discharges. We studied their sorption capacity and anaerobic degradation in marine sediments, providing the first data available on this topic. SAS partition coefficients increased towards those homologues having longer alkyl chains (from up to 141 L kg(-1) for C14 to up to 1753 L kg(-1) for C17), which were those less susceptible to undergo biodegradation. Overall, SAS removal percentages reached up to 98% after 166 days of incubation using anoxic sediments. The degradation pathway consisted on the formation of sulfocarboxylic acids after an initial fumarate attack of the alkyl chain and successive beta oxidations. This is the first study showing that SAS can be degraded in absence of oxygen, so this new information should be taken into account for future environmental risk assessments on these chemicals. PMID- 24631970 TI - Improving coiled coil stability while maintaining specificity by a bacterial hitchhiker selection system. AB - The design and selection of peptides targeting cellular proteins is challenging and often yields candidates with undesired properties. Therefore we deployed a new selection system based on the twin-arginine translocase (TAT) pathway of Escherichia coli, named hitchhiker translocation (HiT) selection. A pool of alpha helix encoding sequences was designed and selected for interference with the coiled coil domain (CC) of a melanoma-associated basic-helix-loop-helix-leucine zipper (bHLHLZ) protein, the microphthalmia associated transcription factor (MITF). One predominant sequence (iM10) was enriched during selection and showed remarkable protease resistance, high solubility and thermal stability while maintaining its specificity. Furthermore, it exhibited nanomolar range affinity towards the target peptide. A mutation screen indicated that target-binding helices of increased homodimer stability and improved expression rates were preferred in the selection process. The crystal structure of the iM10/MITF-CC heterodimer (2.1A) provided important structural insights and validated our design predictions. Importantly, iM10 did not only bind to the MITF coiled coil, but also to the markedly more stable HLHLZ domain of MITF. Characterizing the selected variants of the semi-rational library demonstrated the potential of the innovative bacterial selection approach. PMID- 24631972 TI - Comparative use of lichens, mosses and tree bark to evaluate nitrogen deposition in Germany. AB - To compare three biomonitoring techniques for assessing nitrogen (N) pollution in Germany, 326 lichen, 153 moss and 187 bark samples were collected from 16 sites of the national N deposition monitoring network. The analysed ranges of N content of all investigated biomonitors (0.32%-4.69%) and the detected delta(15)N values (-15.20/00-1.50/00), made it possible to reveal species specific spatial patterns of N concentrations in biota to indicate atmospheric N deposition in Germany. The comparison with measured and modelled N deposition data shows that particularly lichens are able to reflect the local N deposition originating from agriculture. PMID- 24631973 TI - Metal and nutrient dynamics in decomposing tree litter on a metal contaminated site. AB - In a forest on sandy, metal polluted soil, we examined effects of six tree species on litter decomposition rates and accompanied changes in metal (Cd, Zn) and nutrient (base cations, N, C) amounts. Decomposition dynamics were studied by means of a litterbag experiment lasting for 30 months. The decomposition peak occurred within the first year for all tree species, except for aspen. During litter decomposition, high metal litter types released part of their accumulated metals, whereas low metal litter types were characterized by a metal enrichment. Base cations, N and C were released from all litter types. Metal release from contaminated litter might involve risks for metal dispersion towards the soil. On the other hand, metal enrichment of uncontaminated litter may be ecologically relevant as it can be easily transported or serve as food source. PMID- 24631974 TI - On the link between biomagnetic monitoring and leaf-deposited dust load of urban trees: relationships and spatial variability of different particle size fractions. AB - Biomagnetic monitoring of urban tree leaves has proven to be a good estimator of ambient particulate matter. We evaluated its relevancy by determining leaf area normalised weight (mg m(-2)) and SIRM (A) of leaf-deposited particles within three different size fractions (>10 MUm, 3-10 MUm and 0.2-3 MUm) and the SIRM of the leaf-encapsulated particles. Results showed that throughout the in-leaf season, the trees accumulated on average 747 mg m(-2) of dust on their leaves, of which 74 mg m(-2) was within the 0.2-10 MUm (~PM10) size range and 40 mg m(-2) within the 0.2-3 MUm (~PM3) size range. A significant correlation between the SIRM and weight of the surface-deposited particles confirms the potential of biomagnetic monitoring as a proxy for the amount of leaf-deposited particles. Spatial variation of both SIRM and weight throughout the street canyon suggests traffic and wind as key factors for respectively the source and distribution of urban particulates. PMID- 24631975 TI - Limited effect of urban tree vegetation on NO2 and O3 concentrations near a traffic route. AB - Concentrations of NO2 and O3 were measured inside and outside a dense broad leaved forest canopy adjacent to a busy traffic route in the City of Gothenburg, Sweden, with duplicate passive diffusion samplers during six one-week periods starting well before leaf senescence and ending when leaves were largely senescent. Concentrations of NO2 were lower inside the forest canopy during all periods (representing a significant effect, p = 0.016), on average by 7% or 2.7 MUg m(-3). O3 showed a more variable response with an average non-significant effect of 2% lower in the forest stand. There was no systematic trend of the difference in concentrations inside and outside the forest stand of the pollutants with the progression of autumn leaf senescence. Our study indicates that the effect of urban vegetation on air pollution concentrations is small, although it seems to exist for NO2 in a traffic polluted environment. PMID- 24631976 TI - Cumulative risk assessment for plasticizer-contaminated food using the hazard index approach. AB - Phthalates strongly and adversely affect reproduction, development and liver function. We did a cumulative risk assessment for simultaneous exposure to nine phthalates using the hazard index (HI) and the levels of nine phthalates in 1200 foodstuff samples. DEHP (di-2-ethylhexyl phthalate) present the highest level (mean: 0.443 mg/kg) in 1200 samples, and the highest average daily dose (ADD) was found in DEHP, SigmaDBP(i + n) (the sum of dibutyl phthalate [DBP] isomers [DnBP + DiBP]) posed the highest risk potential of all the phthalates. In seven phthalates, the 95th percentiles of the ADDs for SigmaDBP(i + n) in 0-6-yr-old children accounted for 91% (79-107%) of the tolerable daily intake, and the 95th percentiles of the HIs for the anti-androgenic effects of five phthalates in 0-3 yr-old children and 4-6-yr-old girls were >1. We conclude that the health of younger Taiwanese may be adversely affected by overexposure of phthalate contaminated foods. PMID- 24631977 TI - Naturalistic conversation improves daytime motorway driving performance under a benzodiazepine: a randomised, crossover, double-blind, placebo-controlled study. AB - The adverse effects of benzodiazepines on driving are widely recognised. The aims of this study were both to determine the impact of naturalistic conversation on the driving ability of drivers under a benzodiazepine, and to measure the accuracy of drivers' assessments of the joint effects of the benzodiazepine and conversation. Sixteen healthy male participants (29.69 +/- 3.30 years) underwent a randomised, crossover, double-blind, placebo-controlled study with the benzodiazepine lorazepam (2mg). They drove 200 km (125 miles) on a motorway in the morning. We measured two driving ability-related variables (i.e., lane keeping performance), and collected a set of self-assessed variables (i.e., self assessment of driving performance) during two 10-min sequences of interest (no conversation vs. conversation). An analysis of variance revealed an interaction whereby lane-keeping performance under lorazepam was worse in the no-conversation condition than in the conversation condition. No such difference was detected under placebo. Pearson's correlation coefficients revealed that self-assessments were (i) not at all predictive of lane-keeping when performed before the drive, but (ii) moderately predictive of lane-keeping performance when performed during or after the drive. We conclude that conversation with a passenger may contribute to safer lane-keeping when driving under a benzodiazepine. Moreover, a degree of awareness may be attained after some experience of driving under the influence of this type of medication. PMID- 24631978 TI - Profile of women detected drink driving via Roadside Breath Testing (RBT) in Queensland, Australia, between 2000 and 2011. AB - BACKGROUND: Drink driving among women is a growing problem in many motorised countries. While research has shown that male and female drink drivers differ on a number of characteristics, few studies have addressed the circumstances surrounding women's drink driving offences specifically. AIM: To add to previous research by comparing apprehension characteristics among men and women and to extend the understanding of the female drink driving problem by investigating the drink driving characteristics that are unique to women. RESULTS: The sample consisted of the 248,173 (21.5% women) drink drivers apprehended between 2000 and 2011 in Queensland, Australia. Gender comparisons showed that women were older, had lower levels of reoffending, and were more likely to be apprehended in Major Cities compared to men. Comparisons of age group and reoffending and non reoffending among female drink drivers only revealed that higher BAC readings were more common among younger women. Moreover, a substantial minority (13.7%) of women aged 24 years or younger were apprehended with a BAC below 0.05%, reflecting a breach of the zero tolerance BAC for provisional licence holders in Australia. Older women were more likely to be charged with a 'failure to provide a test' offence as a result of refusing to provide a breath or blood sample, indicating that drink driving is associated high levels of stigma for this group. Reoffending occurred among 16.2% of the female drink drivers and these drivers were more likely than non-reoffending drivers to record a mid to high range BAC, to be aged 30-39 or below 21 years, and to be apprehended in Inner Regional or Remote locations. CONCLUSION: Findings highlight the unique circumstances and divergent needs of female drink drivers compared to male drivers and for different groups of female drivers. PMID- 24631979 TI - Influence of built environment on pedestrian's crossing decision. AB - The objective of this experimental study is to identify the differentiation made by pedestrians, in their crossing decision, between various urban environments, notably in terms of perception of walking pleasantness and safety. This experiment further aims to identify the environmental features that pedestrians take into account and the inferences they develop and use to explain their road crossing decision. Sets of photographs presenting five different environments (city center, inner suburbs, public housing in the outskirts, commercial zone in the outskirts and countryside) were presented to 77 participants divided up into three age groups (pre-adolescents, young and middle adults). Their decision to cross or not, their perception of pleasantness and safety, and the elements they take into account to make a decision were collected for each environment presented. The quantitative results show the pedestrians' perceptions of the pleasantness and safety of public spaces, in terms of walking, largely vary with urban environments. Moreover, the crossing decision significantly varies according to the environment. Pedestrians were significantly more inclined to take the decision to cross in city center than in the other sites presented. The qualitative analysis of the interviews shows that the presence and function of the buildings, the quality of the sidewalks and the marked parking spaces are key factors to explain their crossing decision, by enabling them to infer the density of pedestrians and traffic and the vehicle speed. PMID- 24631980 TI - Relating crash frequency and severity: evaluating the effectiveness of shoulder rumble strips on reducing fatal and major injury crashes. AB - To approach the goal of "Toward Zero Deaths," there is a need to develop an analysis paradigm to better understand the effects of a countermeasure on reducing the number of severe crashes. One of the goals in traffic safety research is to search for an effective treatment to reduce fatal and major injury crashes, referred to as severe crashes. To achieve this goal, the selection of promising countermeasures is of utmost importance, and relies on the effectiveness of candidate countermeasures in reducing severe crashes. Although it is important to precisely evaluate the effectiveness of candidate countermeasures in reducing the number of severe crashes at a site, the current state-of-the-practice often leads to biased estimates. While there have been a few advanced statistical models developed to mitigate the problem in practice, these models are computationally difficult to estimate because severe crashes are dispersed spatially and temporally, and cannot be integrated into the Highway Safety Manual framework, which develops a series of safety performance functions and crash modification factors to predict the number of crashes. Crash severity outcomes are generally integrated into the Highway Safety Manual using deterministic distributions rather than statistical models. Accounting for the variability in crash severity as a function geometric design, traffic flow, and other roadway and roadside features is afforded by estimating statistical models. Therefore, there is a need to develop a new analysis paradigm to resolve the limitations in the current Highway Safety Manual methods. We propose an approach which decomposes the severe crash frequency into a function of the change in the total number of crashes and the probability of a crash becoming a severe crash before and after a countermeasure is implemented. We tested this approach by evaluating the effectiveness of shoulder rumble strips on reducing the number of severe crashes. A total of 310 segments that have had shoulder rumble strips installed during 2002-2009 are included in the analysis. It was found that shoulder rumble strips reduce the total number of crashes, but have no statistically significant effect on reducing the probability of a severe crash outcome. PMID- 24631981 TI - The effects of age and workload on 3D spatial attention in dual-task driving. AB - In the present study we assessed whether the limits in visual-spatial attention associated with aging affect the spatial extent of attention in depth during driving performance. Drivers in the present study performed a car-following and light-detection task. To assess the extent of visual-spatial attention, we compared reaction times and accuracy to light change targets that varied in horizontal position and depth location. In addition, because workload has been identified as a factor that can change the horizontal and vertical extent of attention, we tested whether variability of the lead car speed influenced the extent of spatial attention for younger or older drivers. For younger drivers, reaction time (RT) to light-change targets varied as a function of distance and horizontal position. For older drivers RT varied only as a function of distance. There was a distance by horizontal position interaction for younger drivers but not for older drivers. Specifically, there was no effect of horizontal position at any given level of depth for older drivers. However, for younger drivers there was an effect of horizontal position for targets further in depth but not for targets nearer in depth. With regards to workload, we found no statistically reliable evidence that variability of the lead car speed had an effect on the spatial extent of attention for younger or older drivers. In a control experiment, we examined the effects of depth on light detection when the projected size and position of the targets was constant. Consistent with our previous results, we found that drivers' reaction time to light-change targets varied as a function of distance even when 2D position and size were controlled. Given that depth is an important dimension in driving performance, an important issue for assessing driving safety is to consider the limits of attention in the depth dimension. Therefore, we suggest that future research should consider the importance of depth as a dimension of spatial attention in relation to the assessment of driving performance. PMID- 24631983 TI - Pressure-controlled mechanical ventilation is more advantageous in the follow-up of patients with chronic obstructive pulmonary disease after open heart surgery. AB - OBJECTIVE: Cardiopulmonary bypass deteriorates pulmonary functions to a certain extent. Patients with chronic obstructive pulmonary disease (COPD) are associated with increased mortality and morbidity risks in the postoperative period of open heart surgery. In this study we compared 2 different mechanical ventilation modes, pressure-controlled ventilation (PCV) and volume-controlled ventilation (VCV), in this particular patient population. PATIENTS AND METHODS: Forty patients with severe COPD were assigned to 1 of 2 groups and enrolled to receive PCV or VCV in the postoperative period. Arterial blood gases, respiratory parameters, and intensive care unit and hospital stays were compared between the 2 groups. RESULTS: Maximum airway pressure was higher in the VCV group. Pulmonary compliance was lower in the VCV group and minute ventilation was significantly lower in the group ventilated with PCV mode. The respiratory index was increased in the PCV group compared with the VCV group and with preoperative findings. Duration of mechanical ventilation was significantly shorter with PCV; however, intensive care unit and hospital stays did not differ. CONCLUSION: There is not a single widely accepted and established mode of ventilation for patients with COPD undergoing open-heart surgery. Our modest experience indicated promising results with PCV mode; however, further studies are warranted. PMID- 24631982 TI - Regulation of T lymphocyte activation by microRNA-21. AB - MicroRNAs are small noncoding RNAs that act as posttranscriptional regulators of gene expression. To identify microRNAs involved in T cell activation, we performed a microRNA array profiling with Jurkat cells. We found that microRNA-21 (miR-21), which is upregulated in many tumors by targeting a series of tumor suppressor genes to promote tumor growth, was significantly increased in activated Jurkat cells and primary CD4(+) T lymphocytes compared with that in quiescent counterparts. By using a signaling network building tool, miR-21 was predicted regulates ERK and JNK signaling in activated Jurkat cells. Indeed, miR 21 promotes ERK and JNK signaling in activated T cells. Sprouty1, a direct target of miR-21 that has been shown an inhibitor of ERK and JNK, was also inhibited by forced miR-21 expression in activated T cells. Reciprocally, miR-21 levels were induced by MEK or JNK signaling response to T cell receptor (TCR) engagement. Furthermore, transfection with miR-21 mimic promotes activator protein 1 (AP-1) activity and interleukin-2 (IL-2) expression. These results provide a missing function of miR-21 in TCR-mediated signaling transduction in T lymphocytes, suggesting that miR-21 may augment T cell immune response by a positive feedback mechanism. PMID- 24631984 TI - Valve-sparing repair of aortic root aneurysms: an update on the Florida sleeve. AB - Aortic valve-sparing reimplantation remains an effective technique for repair of aortic root aneurysms. Studies indicate that the Florida Sleeve procedure is dimensionally stable and durable in the early postoperative period; however, our technique has evolved. We describe a 10-year institutional experience and the technical update of the Florida Sleeve repair for root aneurysms. PMID- 24631986 TI - Does mild renal failure affect coronary flow reserve after coronary artery bypass graft surgery? AB - INTRODUCTION: There are only a limited number of studies on the link between mild renal failure and coronary artery disease. The purpose of this study is to investigate the effects of mild renal failure on the distal vascular bed by measuring the coronary flow reserve (CFR) in transthoracic echocardiography after coronary artery bypass grafting (CABG). METHODS: The study included 52 consecutive patients (12 women and 40 men) who had undergone uncomplicated CABG. The patients were divided into 2 groups. Group 1 included patients with a preoperative glomerular filtration rate (GFR) of 60-90 (mild renal failure), and group 2 included those with a GFR >90. The CFR measurements were carried out through a second harmonic transthoracic Doppler echocardiography. RESULTS: The mean age was 60.08 +/- 1.56 years in group 1 and 60.33 +/- 1.19 in group 2. The mean preoperative CFR was 1.79 +/- 0.06 in group 1 and 2.05 +/- 0.09 in group 2. The mean postoperative CFR was 2.09 +/- 0.08 in group 1 and 2.37 +/- 0.06 in group 2. There was a statistically significant difference between the 2 groups as to preoperative creatinine clearance, preoperative estimated GFR, postoperative day 7 creatinine clearance, postoperative month 6 creatinine clearance, postoperative day 7 estimated GFR, postoperative month 6 estimated GFR, preoperative CFR, and postoperative CFR (P < .05). CFR was found to be unaffected by the choice of on-pump or off-pump technique (P = .907). After bypass surgery, there was a significant increase in the mean postoperative CFR, when compared with the mean preoperative CFR (P = .001). CONCLUSION: In our study, we detected a decrease in CFR in patients with mild renal failure. We believe that in patients undergoing CABG for coronary artery disease, mild renal failure can produce adverse effects due to deterioration of the microvascular bed. PMID- 24631985 TI - Evaluation of systemic inflammatory response in cardiovascular surgery via interleukin-6, interleukin-8, and neopterin. AB - AIM: The aim of this study was to evaluate the serum levels of interleukin-6 (IL 6), IL-8, and neopterin as a sign of systemic inflammatory response syndrome after open-heart surgery. In this study, we evaluated the influences on the levels of IL-6, IL-8, and neopterin of coronary artery bypass grafting (CABG) and valve replacement surgeries with and without the use of extracorporeal circulation (ECC). MATERIALS AND METHODS: This prospective study was performed in 30 patients. In this study, we evaluated patients who underwent valve replacement surgery (group 1, n = 10), CABG with ECC (group 2, n = 10), or CABG using the beating-heart technique (group 3, n = 10). With the Human Investigation Ethics Committee consent, blood samples were obtained from the patients before the surgery (T0) and after 1 hour (T1), 4 hours (T2), 24 hours (T3), and 48 hours (T4) of protamine injection. IL-6, IL-8, and neopterin levels were measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: The demographic data and preoperative and operative characteristics of the patients were similar. Neopterin IL-6 and IL-8 levels significantly increased first at the fourth hour after the surgery. When compared to the levels before the surgery, this increase was statistically significant. Unlike the other 2 groups of patients, those who experienced CABG with the beating-heart technique (group 3) had decreased neopterin levels at the first hour after the surgery, but this decrease was not statistically significant. Neopterin levels increased later in the OPCAB group, but these increased levels were not as high as the neopterin levels of groups 1 and 2. Neopterin reached maximum levels at the 24th hour and, unlike groups 1 and 2, in group started to decrease at the 48th. CONCLUSIONS: Complement activation, cytokine production, and related cellular responses are important factors during open-heart surgery. It is certain that ECC activates the complement systems, and activated complement proteins cause the production of several cytokines. In our study, neopterin levels in patients who underwent beating-heart method surgery were lower than those in the other groups, and these levels started to decrease at the 48th hour. These data suggest that the systemic inflammatory response was less activated in that patient group. The beating-heart method might be an important alternative in CABG surgery to minimize the complications and mortality related to surgery. PMID- 24631987 TI - A novel approach: trans-ascending aorta balloon aortic valvuloplasty via sternotomy for treating severe valvular aortic stenosis in a low-weight infant. AB - BACKGROUND: Severe congenital aortic stenosis in infants is a life-threatening congenital heart anomaly that is typically treated using percutaneous balloon aortic valvuloplasty. METHODS: The usual route is the femoral artery under radiographic guidance. However, this procedure may be limited by the small size of the femoral artery in low-weight infants. An infant weighing only 7 kg with severe aortic stenosis (peak gradient was 103 mmHg) was successfully treated with a novel approach, that is trans-ascending aorta balloon aortic valvuloplasty guided by transesophageal echocardiography. RESULTS: The patient tolerated the procedure well, and no major complications developed. After the intervention, transesophageal echocardiography indicated a significant reduction of the aortic valvular peak gradient from 103 mmHg to 22 mmHg, no aortic regurgitation was found. Eighteen months after the intervention, echocardiography revealed that the aortic valvular peak gradient had increased to 38 mmHg and that still no aortic regurgitation had occurred. CONCLUSIONS: In our limited experience, trans ascending aorta balloon aortic valvuloplasty for severe aortic stenosis under transesophageal echocardiography guidance effectively reduces the aortic peak gradient. As this is a new procedure, long-term follow up and management will need to be established. It may be an alternative technique to treat congenital aortic stenosis in low-weight patients. PMID- 24631988 TI - Surgical treatment of double valve endocarditis. AB - BACKGROUND: We have retrospectively analyzed the results of the operations made for aortic infective endocarditis with mitral involvement in a single center in 19 years. METHODS: From May 1992 to January 2011, we have operated on 72 patients with infective endocarditis of the aortic valve with mitral valve involvement. Fifty-two patients (72.2%) were male and the mean age was 40.5 +/- 15.5 (9-73) years. The blood cultures were positive in 33 patients (45.8%) and the most commonly identified microorganism was Streptococcus. Nine patients (12.5%) had prosthetic valve endocarditis. The mean duration of follow-up was 6.8 +/- 4.7 (0.1-16.9) years, adding up to a total of 156.1 patient/years. RESULTS: A total of 155 procedures were performed on these 72 patients. The most commonly performed procedure was aortic valve replacement, in 63 patients (87.5%). Aortic annular involvement was present in 9 cases (12.5%). In-hospital mortality was seen in 13 patients (18.1%). Postoperatively, 13 (18.1%) patients had low cardiac output, 9 (12.5%) had heart block, and only 1 of them required permanent pacemaker implantation. The actuarial survival rates for 1, 5, and 10 years were 96.4% +/- 2.5%, 84.4% +/- 5.1%, and 77.4 +/- 6.7%, respectively. CONCLUSIONS: Double-valve endocarditis is a serious condition and the surgeon must be aware of the high rates of mortality and morbidity in these patients. Although no association was found, heart blocks and septic embolization must be handled with caution. The patients generally do well after surgery, and recurrences and reoperations decrease by the second year after operation. PMID- 24631989 TI - Risk factors predicting the postoperative outcome in 134 patients with active endocarditis. AB - BACKGROUND: Surgery remains the cornerstone in management of endocarditis. METHODS: In this retrospective cohort we evaluated the operative outcome of patients with infective endocarditis. The SPSS program was used to analyze the data. RESULTS: A total of 134 predominantly male patients (60%) with a mean age of 55 +/- 12.4 years were examined. The procedures included single valve (n = 88; 66%), double/multiple valves (n = 29; 22%), and valve-coronary artery bypass graft (CABG) (n = 16; 12%). Perioperative mortality was 11.9% (n = 16). In the multivariate analysis, dialysis (odds ratio [OR] = 7.88; 95% confidence interval [CI] [1.78-34.77]; P = .006), sepsis (OR = 19.5; 95% CI [2.76-137.9]; P = .002), and perfusion time (95% CI [1.00-1.02]; P = .003) were independent predictors of perioperative mortality. The overall long-term survival at 28 months was 69.2% +/ 4%. Dialysis (P = .0001) was a predictor of mortality, whereas elevated creatinine in nondialysis patients (P = .0002) was not. In the multivariate analysis, dialysis (hazard ratio [HR] 4.06%; 95% CI [0.936-8.526]; P = .0002), CABG (HR 2.32; 95% CI [1.086-4.978]; P = .0299), chronic obstructive pulmonary disease (HR 2.20; 95% CI [1.027-4.739]; P = .0426), and double/multiple valve procedure (HR 3.0; 95% CI [1.467-6.206]; P = .0027) were risk factors for long term mortality. CONCLUSION: Renal failure but not renal insufficiency is a risk factor for short and long-term mortality. PMID- 24631990 TI - Refractory ascites as the only presenting symptom of chronic calcified constrictive pericarditis: a diagnostic challenge. AB - Extracardiac manifestations of constrictive pericarditis, such as massive ascites and liver cirrhosis, often cover the true situation and lead to a delayed diagnosis. A young female patient was referred to this hospital due to a 4-year history of refractory ascites as the only presenting symptom. A diagnosis of chronic calcified constrictive pericarditis was eventually established based on echocardiography, ultrasonography, and computed tomography. Cardiac catheterization was not performed. Pericardiectomy led to relief of her ascites. Refractory ascites warrants thorough investigation for constrictive pericarditis. PMID- 24631991 TI - Dual protection therapy with staged coronary artery bypass surgery and stenting in patients with left main coronary artery stenosis: long-term results from a single center. AB - OBJECTIVE: We evaluated the efficacy and safety of dual protection therapy with staged coronary artery bypass grafting (CABG) and bare-metal stenting (BMS) in patients with left main coronary artery (LMCA) disease. BACKGROUND: CABG is currently the preferred therapy for complex LMCA disease; however, the long-term patency rates of these grafts are unsatisfactory, and stenting alone for LMCA may be associated with the potentially fatal consequences of stent thrombosis or restenosis. METHODS: Between January 1997 and October 2005, 42 patients underwent staged bypass surgery and BMS, with the latter procedure performed 2 weeks after the initial CABG. Of these patients, 40 received left internal mammary artery (LIMA) grafts, 34 saphenous vein grafts, 6 radial artery grafts, and 3 right IMA (RIMA) grafts. Minimally invasive bypass surgery was performed in 10 patients. RESULTS: There were no operative complications. Forty-two stents were implanted in 42 lesions without complications. During the follow-up period of 135 +/- 55 months, 1 patient died of cancer, 2 of cardiac causes, and 5 patients (12%) experienced target lesion revascularization. The target vessel failure rate was 24%. Forty patients (95%) underwent a 6-month angiographic follow-up. Restenosis was noted in 7 patients (18%). Reocclusion was also noted in 5 LIMA grafts, 5 saphenous vein grafts, 1 radial artery graft, and 1 RIMA graft. Only 1 patient experienced both restenosis of LM stenting and total occlusion of the 2 bypass grafts. CONCLUSIONS: Dual protection therapy with staged CABG and stenting is not an appropriate therapeutic strategy because of unacceptable graft patency rate. A higher occlusive rate of the bypass grafts may result from decreased blood flow because of competing blood flow between the bypass graft and the native coronary vessel. PMID- 24631992 TI - Prophylactic effects of metoprolol on the prevention of atrial fibrillation after cardiac surgery are dose dependent. PMID- 24631993 TI - Giant vegetation in the right ventricle caused by Staphylococcus aureus and Candida mycoderma. AB - INTRODUCTION: Infective endocarditis (IE) is considered a multifactorial disease. Providing an early diagnosis and invasive treatment together with effective antibiotic treatment remain critical tasks for the cardiologist and the surgeon. Right ventricular endocarditis is a rare type of endocarditis usually caused by Staphylococcus aureus and Candida mycoderma. CASE PRESENTATION: We present a 25 year-old male patient who presented with persistent malaise, fever, cough, and anorexia after 55 days of antibiotic treatment. Lung computed tomographic scanning excluded severe lung infection. Transthoracic and transesophageal echocardiography revealed a giant vegetation in the right ventricle. Blood culture was positive for S. aureus and C. mycoderma, and antibiotic therapy was immediately applied. Considering the large burden of infected tissue, an early surgical intervention was planned. The cultures of the vegetation specimen were negative. Intraoperative and histological findings confirmed the echocardiographic diagnosis of IE. CONCLUSIONS: Giant vegetations in the right ventricle caused by S. aureus and C. mycoderma are rare. In addition to medical treatment, more attention should be paid to early surgical consultation. PMID- 24631994 TI - Gestural communication in a new world parrot. AB - Male birds can use visual signals to provide information about their sexual status, via bright coloration, sophisticated sexual displays and elaborate tail and head crests. The majority of forest bird species use vocal communication as their main strategy to show their physiological status during breeding season. It is also used to keep contact between individuals in the same group, in agonistic contexts, and by chicks begging for food. We registered, for the very first time, gestural communication acting in the context of biparental care for the Orange winged Amazon, Amazona amazonica. This parrot presents at least nine different sounds uttered in contexts of alarm, agonistic, foraging, contact flight and others. This finding suggests that despite being a vocal species, this parrot can perform gestural communication related to parental care. The gestures exhibited by this species represent a strategy for survival, a clever way to protect the nest, reducing the risk of attracting the attention of predators. PMID- 24631995 TI - Adapting to social and political transitions - the influence of history on health policy formation in the Republic of the Union of Myanmar (Burma). AB - The Republic of the Union of Myanmar (Burma) has a long and complex history characterized by internal conflict and tense international relations. Post independence, the health sector has gradually evolved, but with health service development and indicators lagging well behind regional expectations. In recent years, the country has initiated political reforms and a reorientation of development policy towards social sector investment. In this study, from a systems and historical perspective, we used publicly available data sources and grey literature to describe and analyze links between health policy and history from the post-independence period up until 2012. Three major periods are discernable in post war health system development and political history in Myanmar. The first post-independence period was associated with the development of the primary health care system extending up to the 1988 political events. The second period is from 1988 to 2005, when the country launched a free market economic model and was arguably experiencing its highest levels of international isolation as well as very low levels of national health investment. The third period (2005-2012) represents the first attempts at health reform and recovery, linked to emerging trends in national political reform and international politics. Based on the most recent period of macro-political reform, the central state is set to transition from a direct implementer of a command and control management system, towards stewardship of a significantly more complex and decentralized administrative order. Historical analysis demonstrates the extent to which these periodic shifts in the macro-political and economic order acts to reset the parameters for health policy making. This case demonstrates important lessons for other countries in transition by highlighting the extent to which analysis of political history can be instructive for determination of more feasible boundaries for future health policy action. PMID- 24631996 TI - Understanding the experiences and quality of life issues of Bahraini women with breast cancer. AB - We explored the experiences of Bahraini women who have survived breast cancer and their perception of quality of life after diagnosis. We conducted in depth, semi structured face-to-face interviews with twelve women diagnosed with breast cancer. A qualitative method using semi-structured interviews on a purposive sample of 12 Bahraini women with breast cancer was conducted. Similarities and differences in women's experience were identified through thematic analysis of interview transcripts using a constant comparative approach. The themes identified were meaning of cancer and quality of life, spirituality and beliefs about causes of breast cancer, coping mechanisms, impact of illness and change in relationships. Quality of life was framed in terms of the ability to perform daily duties with emphasis on the physical component of quality of life. Themes that differed from previous western studies included a heavy emphasis on spiritual practices for comfort; the use of traditional clothing (hijab and abaya) to hide hair and body changes; the important role played by the family and husband in treatment decisions and concerns regarding satisfying the sexual needs of the husband, which were related to a fear of losing the husband to a second wife. Evil eye, stress and God's punishment were believed to be fundamental causes of the disease. The emotional shock of the initial diagnosis, concerns about whether to reveal the diagnosis and a desire to live a normal life were consistent with previous studies. However, cultural and religious issues such as role of the husband and impact of prayers were also important here. These themes are important to healthcare professionals for ensuring an individualized approach to the treatment of women with breast cancer. PMID- 24631997 TI - The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons. AB - INTRODUCTION: High plasma homocysteine levels have been associated with incident osteoporotic fractures, but the mechanisms underlying this association are still unknown. It has been hypothesized that homocysteine might interfere with collagen cross-linking in bone, thereby weakening bone structure. Therefore, we wanted to investigate whether plasma homocysteine levels are associated with bone quality parameters, rather than with bone mineral density. METHODS: Cross-sectional data of the B-PROOF study (n=1227) and of two cohorts of the Rotterdam Study (RS-I (n=2850) and RS-II (n=2023)) were used. Data on bone mineral density of the femoral neck and lumbar spine were obtained in these participants using dual energy X-ray assessment (DXA). In addition, participants of B-PROOF and RS-I underwent quantitative ultrasound measurement of the calcaneus, as a marker for bone quality. Multiple linear regression analysis was used to investigate the associations between natural-log transformed plasma levels of homocysteine and bone mineral density or ultrasound parameters. RESULTS: Natural-log transformed homocysteine levels were inversely associated with femoral neck bone mineral density in the two cohorts of the Rotterdam Study (B=-0.025, p=0.004 and B= 0.024, p=0.024). In B-PROOF, no association was found. Pooled data analysis showed significant associations between homocysteine and bone mineral density at both femoral neck (B=-0.032, p=0.010) and lumbar spine (B=-0.098, p=0.021). Higher natural-log transformed homocysteine levels associated significantly with lower bone ultrasound attenuation in B-PROOF (B=-3.7, p=0.009) and speed of sound in both B-PROOF (B=-8.9, p=0.001) and RS-I (B=-14.5, p=0.003), indicating lower bone quality. Pooled analysis confirmed the association between homocysteine and SOS (B=-13.1, p=0.016). Results from ANCOVA-analysis indicate that differences in SOS and BUA between participants having a plasma homocysteine level above or below median correspond to 0.14 and 0.09 SD, respectively. DISCUSSION: In this study, plasma levels of homocysteine were significantly inversely associated with both bone ultrasound parameters and with bone mineral density. However, the size of the associations seems to be of limited clinical relevance and may therefore not explain the previously observed association between plasma homocysteine and osteoporotic fracture incidence. PMID- 24631998 TI - Health concerns and perceptions of central and coastal New Jersey residents in the 100 days following Superstorm Sandy. AB - Superstorm Sandy made landfall in New Jersey 29-30 October 2012 (130 km/h winds), and many residents were evacuated, were without power for days to several weeks, and suffered property damages or lost their homes. The objective of this study was to understand health concerns within 100 days of this devastating storm that might improve recovery, future preparedness, and resilience. We conducted a survey of New Jersey residents in central (N=407) and shore communities (n=347) about health concerns before, during, and after Superstorm Sandy. People were interviewed at public places, town hall and FEMA meetings, health and university centers, and other gathering places. 47% of shore and 13% of central Jersey respondents evacuated. Both populations were concerned about agents of destruction, survival needs, and possessions before and during the storm, but they were mainly concerned about survival needs thereafter. During the storm, medical issues were the greatest concern for shore respondents (23%) vs secure and safe food and water (29%) for central respondents. Medical concerns increased after the storm. In the future, 42% of shore respondents would prepare more, while 51% of central residents would buy more supplies; 20% (shore) and 11% (central) would heed future evacuation warnings. Before Sandy many residents did not heed warnings and evacuation orders, but worried about property damage, while during and after their major concerns were personal and community health. Prevention of future health and property impacts could be enhanced by stronger evacuation enforcement, better preparedness information, greater attention to the possibility of prolonged power outages, and more attention to medical needs during and after a storm. PMID- 24631999 TI - Fastest strategy to achieve given number of neuronal firing in theta model. AB - We investigate the constrained optimization of excitatory synaptic input patterns to fastest generate given number of spikes in theta neuron model. Optimal input timings and strengths are identified by using phase plane arguments for discrete input kicks with a given total magnitude. Furthermore, analytical results are conducted to estimate the firing time of given number of spikes resulting from a given input train. We obtain the fastest strategy as the total input size increases. In particular, when the parameter -b is large and total input size G is not so large, there are two candidate strategies to fastest achieve given number of spikes, which depend on the considered parameters. The fastest strategy for some cases of G?-b to fire m spikes should partition m spikes into m-n+1 spikes for the highest band, with largest g, and one spike for each subsequent n 1 band. When G is sufficiently large, big kick is the fastest strategy. In addition, we establish an optimal value for the dependent variable, theta, where each input should be delivered in a non-threshold-based strategy to fastest achieve given output of subsequent spikes. Moreover, we find that reset and kick strategy is the fastest when G is small and G?-b. The obtained results can lead to a better understanding of how the period of nonlinear oscillators are affected by different input timings and strengths. PMID- 24632000 TI - Safe semi-supervised learning based on weighted likelihood. AB - We are interested in developing a safe semi-supervised learning that works in any situation. Semi-supervised learning postulates that n(') unlabeled data are available in addition to n labeled data. However, almost all of the previous semi supervised methods require additional assumptions (not only unlabeled data) to make improvements on supervised learning. If such assumptions are not met, then the methods possibly perform worse than supervised learning. Sokolovska, Cappe, and Yvon (2008) proposed a semi-supervised method based on a weighted likelihood approach. They proved that this method asymptotically never performs worse than supervised learning (i.e., it is safe) without any assumption. Their method is attractive because it is easy to implement and is potentially general. Moreover, it is deeply related to a certain statistical paradox. However, the method of Sokolovska et al. (2008) assumes a very limited situation, i.e., classification, discrete covariates, n(')->infinity and a maximum likelihood estimator. In this paper, we extend their method by modifying the weight. We prove that our proposal is safe in a significantly wide range of situations as long as n<=n('). Further, we give a geometrical interpretation of the proof of safety through the relationship with the above-mentioned statistical paradox. Finally, we show that the above proposal is asymptotically safe even when n(')